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Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system.,Different trigger pathologies have been suggested by the primary cytodegenerative “inside-out” and primary inflammation-driven “outside-in” hypotheses.,Recent data indicate that mitochondrial injury and subsequent energy failure are key factors in the induction of demyelination and neurodegeneration.,The brain weighs only a few percent of the body mass but accounts for approximately 20% of the total basal oxygen consumption of mitochondria.,Oxidative stress induces mitochondrial injury in patients with multiple sclerosis and energy failure in the central nervous system of susceptible individuals.,The interconnected mechanisms responsible for free radical production in patients with multiple sclerosis are as follows: (i) inflammation-induced production of free radicals by activated immune cells, (ii) liberation of iron from the myelin sheets during demyelination, and (iii) mitochondrial injury and thus energy failure-related free radical production.,In the present review, the different sources of oxidative stress and their relationships to patients with multiple sclerosis considering tissue injury mechanisms and clinical aspects have been discussed.
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The relationship between the prevalence of multiple sclerosis (MS) and sunlight’s ultraviolet radiation was proved.,Oxidative stress plays a role in the pathogenic traits of MS.,Melatonin possesses antioxidative properties and regulates circadian rhythms.,Sleep disturbances in MS patients are common and contribute to daytime fatigue.,The aim of study was to evaluate 5 mg daily melatonin supplementation over 90 days on serum total oxidant status (TOS), total antioxidant capacity (TAC) and its influence on sleep quality and depression level of MS patients.,A case-control prospective study was performed on 102 MS patients and 20 controls matched for age and sex.,The Kurtzke’s Expanded Disability Status Scale, magnetic resonance imaging examinations, Athens Insomnia Scale (AIS), Beck Depression Inventory questionnaires were completed.,Serum TOS and TAC levels were measured.,We observed higher serum levels of TOS in all MS groups, while after melatonin treatment the TOS levels significantly decreased.,The TAC level was significantly lower only in mitoxantrone-treated group and it increased after melatonin supplementation.,A strong positive correlation between T1Gd(+) number lesions and TAC level in interferon-beta-1A group was observed.,AIS group mean score above 6 defining insomnia were observed in interferon-beta-1B-group, glatiramer acetate-group and mitoxantrone-group: 6.62 ± 2.88, 8.45 ± 2.07, 11.1 ± 3.25, respectively.,After melatonin treatment the AIS mean scores decrease in glatiramer acetate-group and mitoxantrone-group achieving 5.25 ± 1.14 and 7.08 ± 2.39, respectively (p < 0.05).,Finding from our study suggest that melatonin can act as an antioxidant and improves reduced sleep quality in MS patients.
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The Guillain-Barré syndrome (GBS) is considered a T helper 1 (Th1) cells-mediated acute inflammatory peripheral neuropathy.,However, some changes in GBS could not be explained completely by Th1 cells pathogenic role.,Recently, Th17 cells have been identified and can mediate tissue inflammation and autoimmune response.,Therefore, a study on the role of Th17 and Th22 cells and their cytokines in GBS is necessary for exploring the pathogenesis of GBS.,Here, we detected the frequency of Th1, Th17, and Th22 cells by using 4-color flow cytometry and we detected the plasma levels of IL-17 and IL-22 by ELISA in GBS patients, relapsing-remitting multiple sclerosis patients at the acute phase of relapse, viral encephalitis or meningitis patients and healthy controls.,Our data showed that the frequency of circulating Th1, Th17, and Th22 cells was significantly increased in GBS patients.,The plasma levels of IL-17 and IL-22 in GBS and relapsing-remitting multiple sclerosis at the acute phase of relapse were also markedly elevated.,Enhanced circulating Th22 cells were correlated with GBS severity.,Intravenous immunoglobulin therapy downregulated Th17, and Th22 cells and the plasma levels of IL-17 and IL-22 in GBS patients.,Th17 and Th22 cells may be involved in the pathogenesis of GBS, and intravenous immunoglobulin mediates therapeutic effects by downregulating these cells and their cytokines.
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Autoantibodies are infrequently detected in the sera of patients with the demyelinating form of Guillain-Barré syndrome most commonly encountered in the Western world, despite abundant circumstantial evidence suggesting their existence.,We hypothesised that antibody specificities reliant on the cis interactions of neighbouring membrane glycolipids could explain this discrepancy, and would not have been detected by traditional serological assays using highly purified preparations of single gangliosides.,To assess the frequency of glycolipid complex antibodies in a Western European cohort of patients GBS we used a newly developed combinatorial glycoarray methodology to screen against large range of antigens (11 gangliosides, 8 other single glycolipids and 162 heterodimeric glycolipid complexes).,Serum samples of 181 patients from a geographically defined, Western European cohort of GBS cases were analysed, along with 161 control sera.,Serum IgG binding to single gangliosides was observed in 80.0% of axonal GBS cases, but in only 11.8% of cases with demyelinating electrophysiology.,The inclusion of glycolipid complexes increased the positivity rate in demyelinating disease to 62.4%.,There were 40 antigens with statistically significantly increased binding intensities in GBS as compared to healthy control sera.,Of these, 7 complex antigens and 1 single ganglioside also produced statistically significantly increased binding intensities in GBS versus neurological disease controls.,The detection of antibodies against specific complexes was associated with particular clinical features including disease severity, requirement for mechanical ventilation, and axonal electrophysiology.,This study demonstrates that while antibodies against single gangliosides are often found in cases with axonal-type electrophysiology, antibodies against glycolipid complexes predominate in cases with demyelinating electrophysiology, providing a more robust serum biomarker than has ever been previously available for such cases.,This work confirms the activation of the humoral immune system in the dysimmune disease process in GBS, and correlates patterns of antigen recognition with different clinical features.
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Different studies have demonstrated that neutrophil extracellular traps (NETs) may be involved in the pathophysiology of both antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and systemic lupus erythematosus (SLE).,AAV and SLE are clinically and pathologically divergent autoimmune diseases with different autoantibodies.,However, the respective autoantigens recognized in AAV and SLE have been shown to be an intricate part of NETs.,This study aimed to examine whether the mechanisms of NET formation and the composition of NETs are distinct between AAV and SLE.,To investigate this hypothesis, healthy neutrophils were stimulated with serum from patients with AAV (n = 80) and patients with SLE (n = 59), and the mechanisms of NET formation and NET composition were compared.,Both patients with AAV and patients with SLE had excessive NET formation, which correlated with the extent of disease activity (in AAV r = 0.5, P < 0.0001; in SLE r = 0.35, P < 0.01).,Lytic NET formation over several hours was observed in patients with AAV, as compared to rapid (within minutes), non‐lytic NET formation coinciding with clustering of neutrophils in patients with SLE.,AAV‐induced NET formation was triggered independent of IgG ANCAs, whereas SLE immune complexes (ICx) induced NET formation through Fcγ receptor signaling.,AAV‐induced NET formation was dependent on reactive oxygen species and peptidyl arginine deaminases, and AAV‐induced NETs were enriched for citrullinated histones (mean ± SEM 23 ± 2%).,In contrast, SLE‐induced NETs had immunogenic properties, including binding with high mobility group box chromosomal protein 1 (mean ± SEM 30 ± 3%) and enrichment for oxidized mitochondrial DNA, and were involved in ICx formation.,The morphologic features, kinetics, induction pathways, and composition of excessive NET formation are all intrinsically distinct in AAV compared to SLE.,Recognizing the diversity of NET formation between AAV and SLE provides a better understanding of the pathophysiologic role of NETs in these different autoimmune diseases.
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Genetic variations in TNFAIP3 (A20) de-ubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis.,A20 is a negative regulator of NF-κB but the role of its DUB domain and related genetic variants remain unclear.,We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis.,CRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating C103A knock-in (KI) mutation.,Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and C103A KI cells.,Functional studies were performed in A20 C103A U937 cells and in immune cells from A20 C103A mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926.,Neutrophil extracellular trap (NET) formation was addressed ex vivo in neutrophils from A20 C103A mice and SLE-patients with rs2230926.,Genetic disruption of A20 DUB domain in human and murine myeloid cells did not give rise to enhanced NF-κB signalling.,Instead, cells with C103A mutation or rs2230926 polymorphism presented an upregulated expression of PADI4, an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology.,A20 C103A cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition.,Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes.,We propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of PADI4 with resultant protein citrullination and extracellular trap formation.
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B cells are the only cell type that can give rise to antibody-producing cells, and the only cell type whose selective depletion can, today, lead to an improvement of a wide range of immune-mediated inflammatory diseases, including disorders not primarily driven by autoantibodies.,Here, I discuss this paradoxical observation, and propose that the capacity of B cells to act as cytokine-producing cells explains how they can control monocyte activity and subsequently disease pathogenesis.,Together with current data on the effect of anti-CD20 B cell-depleting reagents in the clinic, this novel knowledge on B cell heterogeneity opens the way for novel safer and more efficient strategies to target B cells.,The forthcoming identification of disease-relevant B cell subsets is awaited to permit their monitoring and specific targeting in a personalized medicine approach.,•B cell depletion can improve disease in patients with no pathogenic autoantibodies.,•B cells can produce multiple relevant cytokines in autoimmune diseases.,•B cells control the activity of monocytes via cytokines in autoimmune diseases.,•B cell depletion can lead to improvement of tissue repair in autoimmune diseases.,•Regulatory plasma cells inhibit chronic inflammation in autoimmune diseases.,B cell depletion can improve disease in patients with no pathogenic autoantibodies.,B cells can produce multiple relevant cytokines in autoimmune diseases.,B cells control the activity of monocytes via cytokines in autoimmune diseases.,B cell depletion can lead to improvement of tissue repair in autoimmune diseases.,Regulatory plasma cells inhibit chronic inflammation in autoimmune diseases.
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IL-6-producing B cells contribute to EAE pathology and possibly human MS, whereas ablation of B cell IL-6 is associated with a reduced Th17 response.,B cells have paradoxical roles in autoimmunity, exerting both pathogenic and protective effects.,Pathogenesis may be antibody independent, as B cell depletion therapy (BCDT) leads to amelioration of disease irrespective of autoantibody ablation.,However, the mechanisms of pathogenesis are poorly understood.,We demonstrate that BCDT alleviates central nervous system autoimmunity through ablation of IL-6-secreting pathogenic B cells.,B cells from mice with experimental autoimmune encephalomyelitis (EAE) secreted elevated levels of IL-6 compared with B cells from naive controls, and mice with a B cell-specific IL-6 deficiency showed less severe disease than mice with wild-type B cells.,Moreover, BCDT ameliorated EAE only in mice with IL-6-sufficient B cells.,This mechanism of pathogenesis may also operate in multiple sclerosis (MS) because B cells from MS patients produced more IL-6 than B cells from healthy controls, and this abnormality was normalized with B cell reconstitution after Rituximab treatment.,This suggests that BCDT improved disease progression, at least partly, by eliminating IL-6-producing B cells in MS patients.,Taking these data together, we conclude that IL-6 secretion is a major mechanism of B cell-driven pathogenesis in T cell-mediated autoimmune disease such as EAE and MS.
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ABP 501 is a Food and Drug Administration-approved biosimilar to adalimumab; structural, functional and pharmacokinetic evaluations have shown that the two are highly similar.,We report results from a phase III study comparing efficacy, safety and immunogenicity between ABP 501 and adalimumab.,In this randomised, double-blind, active comparator-controlled, 26-week equivalence study, patients with moderate to severe active rheumatoid arthritis (RA) despite methotrexate were randomised (1:1) to ABP 501 or adalimumab (40 mg) every 2 weeks.,Primary endpoint was risk ratio (RR) of ACR20 between groups at week 24.,Primary hypothesis that the treatments were equivalent would be confirmed if the 90% CI for RR of ACR20 at week 24 fell between 0.738 and 1.355, demonstrating that ABP 501 is similar to adalimumab.,Secondary endpoints included Disease Activity Score 28-joint count-C reactive protein (DAS28-CRP).,Safety was assessed via adverse events (AEs) and laboratory evaluations.,Antidrug antibodies were assessed to determine immunogenicity.,A total of 526 patients were randomised (n=264, ABP 501; n=262 adalimumab) and 494 completed the study.,ACR20 response at week 24 was 74.6% (ABP 501) and 72.4% (adalimumab).,At week 24, the RR of ACR20 (90% CI) between groups was 1.039 (0.954, 1.133), confirming the primary hypothesis.,Changes from baseline in DAS28-CRP, ACR50 and ACR70 were similar.,There were no clinically meaningful differences in AEs and laboratory abnormalities.,A total of 38.3% (ABP 501) and 38.2% (adalimumab) of patients tested positive for binding antidrug antibodies.,Results from this study demonstrate that ABP 501 is similar to adalimumab in clinical efficacy, safety and immunogenicity in patients with moderate to severe RA.,NCT01970475; Results.
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This study compared the efficacy and safety of subcutaneous (SC) versus intravenous (IV) formulations of tocilizumab in patients with rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs (DMARD).,Patients (n=1262) were randomly assigned to receive tocilizumab-SC 162 mg weekly+placebo-IV every 4 weeks or tocilizumab-IV 8 mg/kg every 4 weeks+placebo-SC weekly in combination with traditional DMARD.,The primary outcome was to demonstrate the non-inferiority of tocilizumab-SC to tocilizumab-IV with regard to the proportion of patients in each group achieving an American College of Rheumatology (ACR) 20 response at week 24 using a 12% non-inferiority margin (NIM).,Secondary outcomes were disease activity score using 28 joints (DAS28), ACR responses, health assessment questionnaire scores and safety assessments.,At week 24, 69.4% (95% CI 65.5 to 73.2) of tocilizumab-SC-treated patients versus 73.4% (95% CI 69.6 to 77.1) of tocilizumab-IV-treated patients achieved an ACR20 response (weighted difference between groups −4.0%, 95% CI −9.2 to 1.2); the 12% NIM was met.,ACR50/70 responses, DAS28 and physical function improvements were comparable between the tocilizumab-SC and tocilizumab-IV groups.,The safety profiles of tocilizumab-SC and tocilizumab-IV were similar, and the most common adverse event was infection.,Injection-site reactions (ISR) occurred more frequently in the tocilizumab-SC group than in the tocilizumab-IV (placebo-SC) group.,No anaphylaxis was reported over the 24 weeks.,Tocilizumab-SC 162 mg weekly demonstrated comparable efficacy to tocilizumab-IV 8 mg/kg.,The safety profile of tocilizumab-SC is consistent with the known and well-established safety profile of tocilizumab-IV, with the exception of a higher incidence of ISR, which were more common with tocilizumab-SC administration.
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Interleukin-33 (IL-33), a member of the IL-1 cytokine family, has been recently associated with the development of autoimmune diseases, including systemic lupus erythematosus (SLE).,IL-33 is an alarmin and a pleiotropic cytokine that affects various types of immune cells via binding to its receptor, ST2.,In this study, we determine the impact of intraperitoneal IL-33 treatments in young lupus, NZB/W F1 mice.,Mice were treated from the age of 6 to 11 weeks.,We then assessed the proteinuria level, renal damage, survival rate, and anti-dsDNA antibodies.,The induction of regulatory B (Breg) cells, changes in the level of autoantibodies, and gene expression were also examined.,In comparison to the control group, young NZB/W F1 mice administered with IL-33 had a better survival rate as well as reduced proteinuria level and lupus nephritis.,IL-33 treatments significantly increased the level of IgM anti-dsDNA antibodies, IL-10 expressing Breg cells, and alternatively-induced M2 macrophage gene signatures.,These results imply that IL-33 exhibits a regulatory role during lupus onset via the expansion of protective IgM anti-dsDNA as well as regulatory cells such as Breg cells and M2 macrophages.
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Background.,The IL-33/ST2 axis is involved in humoral immune responses.,Method.,The concentrations of sera IL-33 and sST2 in 74 patients and 34 healthy controls (HC) were measured by ELISA.,Clinical and laboratory data were examined.,The potential association between sera IL-33 and sST2 and the clinical parameters in IgAN patients were analyzed.,Results.,No difference was discovered in IL-33 concentrations between IgAN patients and HCs; however, the sST2 were significantly higher in each stage of IgAN progression than in the HC.,The concentration of sST2 was positively correlated with IL-33 levels in IgAN patients.,Higher levels of sera IL-2, IL-4, IL-10, IL-17A, and IFN-γ were detected in patients compared to the HC.,The concentration of serum sST2 was positively correlated with the levels of IL-10 in IgAN patients.,Furthermore, serum sST2 was negatively correlated with the values of eGFR and serum calcium.,Serum sST2 was positively correlated with 24-hour urinary protein, serum phosphorus, and serum IgA; however, serum IL-33 was not associated with these.,Following treatment, serum sST2 was significantly decreased, while sera IL-4 and IL-10 were significantly increased.,Conclusions.,Increased sST2 and IL-10 but not IL-33 may be involved in the pathogenic process of IgAN.
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Interleukin-27 (IL-27) and its subunit P28 (also known as IL-30) have been shown to inhibit autoimmunity and have been suggested as potential immunotherapeutic for autoimmune diseases such as multiple sclerosis (MS).,However, the potential of IL-27 and IL-30 as immunotherapeutic, and their mechanisms of action have not been fully understood.,In this study, we evaluated the efficacy of adeno-associated viral vector (AAV)-delivered IL-27 (AAV-IL-27) and IL-30 (AAV-IL-30) in a murine model of MS.,We found that one single administration of AAV-IL-27, but not AAV-IL-30 completely blocked the development of experimental autoimmune encephalomyelitis (EAE).,AAV-IL-27 administration reduced the frequencies of Th17, Treg, and GM-CSF-producing CD4+ T cells and induced T cell expression of IFN-γ, IL-10, and PD-L1.,However, experiments involving IL-10-deficient mice and PD-1 blockade revealed that AAV-IL-27-induced IL-10 and PD-L1 expression were not required for the prevention of EAE development.,Surprisingly, neither AAV-IL-27 nor AAV-IL-30 treatment inhibited EAE development and Th17 responses when given at disease onset.,We found that mice with established EAE had significant expansion of CD11b+Gr-1+ cells, and AAV-IL-27 treatment further expanded these cells and induced their expression of Th17-promoting cytokines such as IL-6.,Adoptive transfer of AAV-IL-27-expanded CD11b+Gr-1+ cells enhanced EAE development.,Thus, expansion of CD11b+Gr-1+ cells provides an explanation for the resistance to IL-27 therapy in mice with established disease.
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Pathology studies of progressive multiple sclerosis (MS) indicate a major role of inflammation including Th17-cells and meningeal inflammation with ectopic lymphoid follicles, B-cells and plasma cells, the latter indicating a possible role of the newly identified subset of follicular T-helper (TFH) cells.,Although previous studies reported increased systemic inflammation in progressive MS it remains unclear whether systemic inflammation contributes to disease progression and intrathecal inflammation.,This study aimed to investigate systemic inflammation in progressive MS and its relationship with disease progression, using flow cytometry and gene expression analysis of CD4+ and CD8+T-cells, B-cells, monocytes and dendritic cells.,Furthermore, gene expression of cerebrospinal fluid cells was studied.,Flow cytometry studies revealed increased frequencies of ICOS+TFH-cells in peripheral blood from relapsing-remitting (RRMS) and secondary progressive (SPMS) MS patients.,All MS subtypes had decreased frequencies of Th1 TFH-cells, while primary progressive (PPMS) MS patients had increased frequency of Th17 TFH-cells.,The Th17-subset, interleukin-23-receptor+CD4+T-cells, was significantly increased in PPMS and SPMS.,In the analysis of B-cells, we found a significant increase of plasmablasts and DC-SIGN+ and CD83+B-cells in SPMS.,ICOS+TFH-cells and DC-SIGN+B-cells correlated with disease progression in SPMS patients.,Gene expression analysis of peripheral blood cell subsets substantiated the flow cytometry findings by demonstrating increased expression of IL21, IL21R and ICOS in CD4+T-cells in progressive MS.,Cerebrospinal fluid cells from RRMS and progressive MS (pooled SPMS and PPMS patients) had increased expression of TFH-cell and plasmablast markers.,In conclusion, this study is the first to demonstrate the potential involvement of activated TFH-cells in MS.,The increased frequencies of Th17-cells, activated TFH- and B-cells parallel findings from pathology studies which, along with the correlation between activated TFH- and B-cells and disease progression, suggest a pathogenic role of systemic inflammation in progressive MS.,These observations may have implications for the treatment of progressive MS.
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In vitro data showed that immunoglobulin G (IgG) from patients with lupus nephritis (LN) could bind to cultured human mesangial cells (HMC).,The clinical relevance of such binding was unknown.,Binding of IgG and subclasses was measured in 189 serial serum samples from 23 patients with Class III/IV±V LN (48 during renal flares, 141 during low level disease activity (LLDA)). 64 patients with non-lupus glomerular diseases (NLGD) and 23 healthy individuals were used as controls.,HMC-binding was measured with cellular ELISA and expressed as OD index.,HMC-binding index of total IgG was 0.12±0.09, 0.36±0.25, 0.59±0.37 and 0.74±0.42 in healthy subjects, NLGD, LN patients during LLDA, and LN flares respectively (P = 0.046, LN flare vs.,LLDA; P<0.001, for healthy controls or NLGD vs.,LN during flare or LLDA).,Binding of serum IgG1 to HMC was 0.05±0.05, 0.15±0.11, 0.41±0.38 and 0.55±0.40 for the corresponding groups respectively (P = 0.007, LN flare vs. remission; P<0.001, for healthy controls or NLGD vs.,LN during flare or remission).,IgG2, IgG3 and IgG4 from patients and controls did not show significant binding to HMC.,Total IgG and IgG1 HMC-binding index correlated with anti-dsDNA level (r = 0.26 and 0.39 respectively, P<0.001 for both), and inversely with C3 (r = −0.17 and −0.45, P<0.05 for both).,Sensitivity/specificity of total IgG or IgG1 binding to HMC in predicting renal flares were 81.3%/39.7% (ROC AUC 0.61, P = 0.03) and 83.8%/41.8% (AUC 0.63, P = 0.009) respectively.,HMC-binding by IgG1, but not total IgG, correlated with mesangial immune deposition in LN renal biopsies under electron microscopy.,Our results showed that binding of serum total IgG and IgG1 in LN patients correlates with disease activity.,The correlation between IgG1 HMC-binding and mesangial immune deposition suggests a potential pathogenic significance.
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The strongest serological correlate for lupus nephritis is antibody to double-stranded DNA although the mechanism by which anti-DNA antibodies initiate lupus nephritis is unresolved.,Most recent reports indicate that anti-DNA must bind chromatin in the glomerular basement membrane or mesangial matrix to form glomerular deposits.,Here we determined whether direct binding of anti-DNA antibody to glomerular basement membrane is critical to initiate glomerular binding of anti-DNA in experimental lupus nephritis.,Mice were co-injected with IgG monoclonal antibodies or hybridomas with similar specificity for DNA and chromatin but different IgG subclass and different relative affinity for basement membrane.,Only anti-DNA antibodies that bound basement membrane bound to glomeruli, activated complement, and induced proteinuria whether injected alone or co-injected with a non-basement membrane-binding anti-DNA antibody.,Basement membrane-binding anti-DNA antibodies co-localized with heparan sulfate proteoglycan in glomerular basement membrane and mesangial matrix but not with chromatin.,Thus, direct binding of anti-DNA antibody to antigens in the glomerular basement membrane or mesangial matrix may be critical to initiate glomerular inflammation.,This may accelerate and exacerbate glomerular immune complex formation in human and murine lupus nephritis.
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We aimed to describe the natural history of residual insulin secretion in Type 1 Diabetes TrialNet participants over 4 years from diagnosis and relate this to previously reported alternative clinical measures reflecting β-cell secretory function.,Data from 407 subjects from 5 TrialNet intervention studies were analyzed.,All subjects had baseline stimulated C-peptide values of ≥0.2 nmol/L from mixed-meal tolerance tests (MMTTs).,During semiannual visits, C-peptide values from MMTTs, HbA1c, and insulin doses were obtained.,The percentage of individuals with stimulated C-peptide of ≥0.2 nmol/L or detectable C-peptide of ≥0.017 nmol/L continued to diminish over 4 years; this was markedly influenced by age.,At 4 years, only 5% maintained their baseline C-peptide secretion.,The expected inverse relationships between C-peptide and HbA1c or insulin doses varied over time and with age.,Combined clinical variables, such as insulin-dose adjusted HbA1c (IDAA1C) and the relationship of IDAA1C to C-peptide, also were influenced by age and time from diagnosis.,Models using these clinical measures did not fully predict C-peptide responses.,IDAA1C ≤9 underestimated the number of individuals with stimulated C-peptide ≥0.2 nmol/L, especially in children.,Current trials of disease-modifying therapy for type 1 diabetes should continue to use C-peptide as a primary end point of β-cell secretory function.,Longer duration of follow-up is likely to provide stronger evidence of the effect of disease-modifying therapy on preservation of β-cell function.
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Protégé was a phase 3, randomized, double-blind, parallel, placebo-controlled 2-year study of three intravenous teplizumab dosing regimens, administered daily for 14 days at baseline and again after 26 weeks, in new-onset type 1 diabetes.,We sought to determine efficacy and safety of teplizumab immunotherapy at 2 years and to identify characteristics associated with therapeutic response.,Of 516 randomized patients, 513 were treated, and 462 completed 2 years of follow-up.,Teplizumab (14-day full-dose) reduced the loss of C-peptide mean area under the curve (AUC), a prespecified secondary end point, at 2 years versus placebo.,In analyses of prespecified and post hoc subsets at entry, U.S. residents, patients with C-peptide mean AUC >0.2 nmol/L, those randomized ≤6 weeks after diagnosis, HbA1c <7.5% (58 mmol/mol), insulin use <0.4 units/kg/day, and 8-17 years of age each had greater teplizumab-associated C-peptide preservation than their counterparts.,Exogenous insulin needs tended to be reduced versus placebo.,Antidrug antibodies developed in some patients, without apparent change in drug efficacy.,No new safety or tolerability issues were observed during year 2.,In summary, anti-CD3 therapy reduced C-peptide loss 2 years after diagnosis using a tolerable dose.
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To evaluate feasibility, safety, and efficacy of overnight closed-loop insulin delivery in free-living youth with type 1 diabetes.,Overnight closed loop was evaluated at home by 16 pump-treated adolescents with type 1 diabetes aged 12-18 years.,Over a 3-week period, overnight insulin delivery was directed by a closed-loop system, and on another 3-week period sensor-augmented therapy was applied.,The order of interventions was random.,The primary end point was time when adjusted sensor glucose was between 3.9 and 8.0 mmol/L from 2300 to 0700 h.,Closed loop was constantly applied over at least 4 h on 269 nights (80%); sensor data were collected over at least 4 h on 282 control nights (84%).,Closed loop increased time spent with glucose in target by a median 15% (interquartile range −9 to 43; P < 0.001).,Mean overnight glucose was reduced by a mean 14 (SD 58) mg/dL (P < 0.001).,Time when glucose was <70 mg/dL was low in both groups, but nights with glucose <63 mg/dL for at least 20 min were less frequent during closed loop (10 vs.,17%; P = 0.01).,Despite lower total daily insulin doses by a median 2.3 (interquartile range −4.7 to 9.3) units (P = 0.009), overall 24-h glucose was reduced by a mean 9 (SD 41) mg/dL (P = 0.006) during closed loop.,Unsupervised home use of overnight closed loop in adolescents with type 1 diabetes is safe and feasible.,Glucose control was improved during the day and night with fewer episodes of nocturnal hypoglycemia.
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To test whether safe and effective glycemic control could be achieved in type 1 diabetes using a bihormonal bionic endocrine pancreas driven by a continuous glucose monitor in experiments lasting more than two days and including six high-carbohydrate meals and exercise as challenges to glycemic control.,Six subjects with type 1 diabetes and no endogenous insulin secretion participated in two 51-h experiments.,Blood glucose was managed with a bionic endocrine pancreas controlling subcutaneous delivery of insulin and glucagon with insulin pumps.,A partial meal-priming bolus of insulin (0.035 units/kg/meal, then 0.05 units/kg/meal in repeat experiments) was administered at the beginning of each meal (on average 78 ± 12 g of carbohydrates per meal were consumed).,Plasma glucose (PG) control was evaluated with a reference quality measurement on venous blood every 15 min.,The overall mean PG was 158 mg/dL, with 68% of PG values in the range of 70-180 mg/dL.,There were no significant differences in mean PG between larger and smaller meal-priming bolus experiments.,Hypoglycemia (PG <70 mg/dL) was rare, with eight incidents during 576 h of closed-loop control (0.7% of total time).,During 192 h of nighttime control, mean PG was 123 mg/dL, with 93% of PG values in the range of 70-180 mg/dL and only one episode of mild hypoglycemia (minimum PG 62 mg/dL).,A bihormonal bionic endocrine pancreas achieved excellent glycemic control with minimal hypoglycemia over the course of two days of continuous use despite high-carbohydrate meals and exercise.,A trial testing a wearable version of the system under free-living conditions is justified.
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Retinal optical coherence tomography (OCT) is an imaging biomarker for neurodegeneration in multiple sclerosis (MS).,In order to become validated as an outcome measure in multicenter studies, reliable quality control (QC) criteria with high inter-rater agreement are required.,A prospective multicentre study on developing consensus QC criteria for retinal OCT in MS: (1) a literature review on OCT QC criteria; (2) application of these QC criteria to a training set of 101 retinal OCT scans from patients with MS; (3) kappa statistics for inter-rater agreement; (4) identification reasons for inter-rater disagreement; (5) development of new consensus QC criteria; (6) testing of the new QC criteria on the training set and (7) prospective validation on a new set of 159 OCT scans from patients with MS.,The inter-rater agreement for acceptable scans among OCT readers (n = 3) was moderate (kappa 0·45) based on the non-validated QC criteria which were entirely based on the ophthalmological literature.,A new set of QC criteria was developed based on recognition of: (O) obvious problems, (S) poor signal strength, (C) centration of scan, (A) algorithm failure, (R) retinal pathology other than MS related, (I) illumination and (B) beam placement.,Adhering to these OSCAR-IB QC criteria increased the inter-rater agreement to kappa from moderate to substantial (0.61 training set and 0.61 prospective validation).,This study presents the first validated consensus QC criteria for retinal OCT reading in MS.,The high inter-rater agreement suggests the OSCAR-IB QC criteria to be considered in the context of multicentre studies and trials in MS.
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New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis.,The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan.,These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use.,Ann Neurol 2011
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The process of bone remodeling is the result of the regulated balance between bone cell populations, namely bone-forming osteoblasts, bone-resorbing osteoclasts, and the osteocyte, the mechanosensory cell type.,Osteoclasts derived from the hematopoietic stem cell lineage are the principal cells involved in bone resorption.,In osteolytic diseases such as rheumatoid arthritis, periodontitis, and osteoporosis, the balance is lost and changes in favor of bone resorption.,Therefore, it is vital to elucidate the mechanisms of osteoclast formation and bone resorption.,It has been reported that osteocytes express Receptor activator of nuclear factor κΒ ligand (RANKL), an essential factor for osteoclast formation.,RANKL secreted by osteocytes is the most important factor for physiologically supported osteoclast formation in the developing skeleton and in pathological bone resorption such as experimental periodontal bone loss.,TNF-α directly enhances RANKL expression in osteocytes and promotes osteoclast formation.,Moreover, TNF-α enhances sclerostin expression in osteocytes, which also increases osteoclast formation.,These findings suggest that osteocyte-related cytokines act directly to enhance osteoclast formation and bone resorption.,In this review, we outline the most recent knowledge concerning bone resorption-related cytokines and discuss the osteocyte as the master regulator of bone resorption and effector in osteoclast formation.
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In addition to anti-citrullinated protein antibodies (ACPAs), antibodies targeting carbamylated (i.e., homocitrullinated) proteins (anti-CarP antibodies) have been described in rheumatoid arthritis (RA).,However, the extent to which anti-CarP antibodies are truly distinct from ACPA remains unclear, and few studies have focused on specific autoantigens.,Here, we examine cross-reactivity between ACPA and anti-CarP antibodies, in the context of the candidate autoantigen α-enolase.,Cross-reactivity was examined by immunoblotting of citrullinated and carbamylated proteins using purified ACPA; and by peptide absorption experiments, using the citrullinated α-enolase peptide CEP-1 and a homocitrulline-containing version (carb-CEP-1) in ELISA.,The population-based case-control cohort EIRA (n = 2836 RA; 373 controls) was screened for reactivity with CEP-1 and carb-CEP-1, using the ISAC multiplex array.,Associations between anti-CarP antibodies, smoking and genetic risk factors were analysed using unconditional logistic regression models.,Differences in antibody levels were investigated using the Mann-Whitney U test.,Affinity-purified ACPA was found to bind carbamylated proteins and homocitrulline-containing peptides, demonstrating definitive cross-reactivity between ACPA and anti-CarP antibodies.,Anti-carb-CEP-1 reactivity in EIRA was almost exclusively confined to the CEP-1-positive subset, and this group of RA patients (21 %) displayed a particularly strong ACPA response with marked epitope spreading.,The small RA subset (3 %) with homocitrulline reactivity in the absence of citrulline reactivity did not associate with smoking or risk genes, and importantly had significantly lower anti-carb-CEP-1 antibody levels.,Our data presented herein cast doubt on the specificity of anti-CarP antibodies in RA, which we posit may be a subset of cross-reactive ACPA.,The online version of this article (doi:10.1186/s13075-016-1001-6) contains supplementary material, which is available to authorized users.
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Most cases of neuromyelitis optica spectrum disorders (NMOSD) harbor pathogenic autoantibodies against the water channel aquaporin 4 (AQP4).,Binding of these antibodies to AQP4 on astrocytes initiates damage to these cells, which culminates in the formation of large tissue destructive lesions in the central nervous system (CNS).,Consequently, untreated patients may become permanently blind or paralyzed.,Studies on the induction and breakage of tolerance to AQP4 could be of great benefit for NMOSD patients.,So far, however, all attempts to create suitable animal models by active sensitization have failed.,We addressed this challenge and identified peptides, which mimic the conformational AQP4 epitopes recognized by pathogenic antibodies of NMOSD patients.,Here we show that these mimotopes can induce the production of AQP4-reactive antibodies in Lewis rats.,Hence, our results provide a conceptual framework for the formation of such antibodies in NMOSD patients, and aid to improve immunization strategies for the creation of animal models suitable for tolerance studies in this devastating disease.
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The expansion of a hexanucleotide (GGGGCC) repeat in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).,Both the function of C9ORF72 and the mechanism by which the repeat expansion drives neuropathology are unknown.,To examine whether C9ORF72 haploinsufficiency induces neurological disease, we created a C9orf72-deficient mouse line.,Null mice developed a robust immune phenotype characterized by myeloid expansion, T cell activation, and increased plasma cells.,Mice also presented with elevated autoantibodies and evidence of immune-mediated glomerulonephropathy.,Collectively, our data suggest that C9orf72 regulates immune homeostasis and an autoimmune response reminiscent of systemic lupus erythematosus (SLE) occurs in its absence.,We further imply that haploinsufficiency is unlikely to be the causative factor in C9ALS/FTD pathology.
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Autophagy has emerged as a key mechanism in the survival and function of T and B lymphocytes, and its activation was involved in apoptosis resistance in rheumatoid arthritis (RA).,To investigate whether the relationship between autophagy and apoptosis may impact the response to the therapy, we analyzed ex vivo spontaneous autophagy and apoptosis in patients with RA subjected to treatment with anti-tumor necrosis factor (TNF) drugs and in vitro the effects of TNFα and anti-TNF drugs on cell fate.,Peripheral blood mononuclear cells (PBMCs) from 25 RA patients treated with anti-TNF drugs were analyzed for levels of autophagy marker LC3-II by western blot and for the percentage of annexin V-positive apoptotic cells by flow cytometry.,The same techniques were used to assess autophagy and apoptosis after in vitro treatment with TNFα and etanercept in both PBMCs and fibroblast-like synoviocytes (FLS) from patients with RA.,PBMCs from patients with RA responsive to treatment showed a significant reduction in LC3-II levels, associated with an increased apoptotic activation after 4 months of therapy with anti-TNF drugs.,Additionally, the expression of LC3-II correlated with DAS28.,TNFα was able to induce autophagy in a dose-dependent manner after 24 h of culture in RA PBMCs and FLS.,Moreover, etanercept caused a significant reduction of autophagy and of levels of citrullinated proteins.,Our results show how the crosstalk between autophagy and apoptosis can sustain the survival of immune cells, thus influencing RA progression.,This suggests that inhibition of autophagy represents a possible therapeutic target in RA.,The online version of this article (10.1186/s13075-019-1818-x) contains supplementary material, which is available to authorized users.
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A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological datasets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1.,Here, we performed a genome-wide association study (GWAS) meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single nucleotide polymorphisms (SNPs).,We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 1012-4.,We devised an in-silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci (cis-eQTL)6, and pathway analyses7-9 - as well as novel methods based on genetic overlap with human primary immunodeficiency (PID), hematological cancer somatic mutations and knock-out mouse phenotypes - to identify 98 biological candidate genes at these 101 risk loci.,We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA.,Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
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A clinical picture of dry eye and dry mouth with the histological counterpart of focal lymphocytic sialoadenitis, usually detected in minor salivary glands, is considered the hallmark of Sjögren's syndrome.,The association of sicca complaints and focal sialoadenitis can be also found in a number of other diseases, including some systemic viral infections.,Among these conditions, chronic hepatitis C virus infection, associated with mixed cryoglobulinaemia and extra-hepatic manifestations, and HIV infection, particularly in the phase of diffuse interstitial lymphocytic infiltration, may mimic the clinical and histological aspects of Sjögren's syndrome.,However, each disorder is characterised by specific, disease-related immunopathological aspects.,Besides sicca complaints, the various disorders may also share a number of systemic extra-glandular features and the possible development of mucosa-associated lymphoid tissue lymphomas.,This latter event represents in all of these diseases the final result of an antigen-driven chronic stimulation of B lymphocytes.
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Sjögren's syndrome (SS), a systemic autoimmune disease, is characterized by inflammation of exocrine tissues accompanied by a significant loss of their secretory function.,Clinical symptoms develop late and there are no diagnostic tests enabling early diagnosis of SS.,Thus, particularly to study these covert stages, researchers turn to studying animal models where mice provide great freedom for genetic manipulation and testing the effect of experimental intervention.,The present review summarizes current literature pertaining to both spontaneous and extrinsic-factor induced SS-like diseases in mouse models, discussing advantages and disadvantages related to the use of murine models in SS research.
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Rheumatoid arthritis (RA) refers to an autoimmune rheumatic disease that imposes a huge burden on patients and society.,Early RA diagnosis is critical to preventing disease progression and selecting optimal therapeutic strategies more effectively.,In the present study, the aim was at examining RA’s diagnostic signatures and the effect of immune cell infiltration in this pathology.,Gene Expression Omnibus (GEO) database provided three datasets of gene expressions.,Firstly, this study adopted R software for identifying differentially expressed genes (DEGs) and conducting functional correlation analyses.,Subsequently, we integrated bioinformatic analysis and machine-learning strategies for screening and determining RA’s diagnostic signatures and further verify by qRT-PCR.,The diagnostic values were assessed through receiver operating characteristic (ROC) curves.,Moreover, this study employed cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT) website for assessing the inflammatory state of RA, and an investigation was conducted on the relationship of diagnostic signatures and infiltrating immune cells.,On the whole, 54 robust DEGs received the recognition.,Lymphocyte-specific protein 1 (LSP1), Granulysin (GNLY), and Mesenchymal homobox 2 (MEOX2) (AUC = 0.955) were regarded as RA’s diagnostic markers and showed their statistically significant difference by qRT-PCR.,As indicated from the immune cell infiltration analysis, resting NK cells, neutrophils, activated NK cells, T cells CD8, memory B cells, and M0 macrophages may be involved in the development of RA.,Additionally, all diagnostic signatures might be different degrees of correlation with immune cells.,In conclusion, LSP1, GNLY, and MEOX2 are likely to be available in terms of diagnosing and treating RA, and the infiltration of immune cells mentioned above may critically impact RA development and occurrence.
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Dysregulated functions of B1 cells have been implicated in the disease progression of various autoimmune disorders, but it remains largely unclear whether B1 cells are involved in the pathogenesis of autoimmune arthritis.,In this study, we found that peritoneal B1a cells underwent proliferation and migrated to the inflamed joint tissue with upregulated RANKL expression during collagen-induced arthritis (CIA) development in mice.,Adoptive transfer of B1a cells exacerbated arthritic severity and joint damage while intraperitoneal depletion of B1 cells ameliorated both arthritic symptoms and joint pathology in CIA mice.,In culture, RANKL-expressing B1a cells significantly promoted the expansion of osteoclasts derived from bone marrow cells, which were in accord with the in vivo findings of increased osteoclastogenesis in CIA mice transferred with B1a cells.,Together, these results have demonstrated a pathogenic role of B1a cells in the development of autoimmune arthritis through RANKL-mediated osteoclastogenesis.
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Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the production of autoantibodies to a broad range of self-antigens.,Profiling the autoantibody repertoire using array-based technology has emerged as a powerful tool for the identification of biomarkers in SLE and other autoimmune diseases.,Proteomic microarray has the capacity to hold large number of self-antigens on a solid surface and serve as a high-throughput screening method for the determination of autoantibody specificities.,The autoantigen arrays carrying a wide variety of self-antigens, such as cell nuclear components (nucleic acids and associated proteins), cytoplasmic proteins, phospholipid proteins, cell matrix proteins, mucosal/secreted proteins, glomeruli, and other tissue-specific proteins, have been used for screening of autoantibody specificities associated with different manifestations of SLE.,Arrays containing synthetic peptides and molecular modified proteins are also being utilized for identification of autoantibodies targeting to special antigenic epitopes.,Different isotypes of autoantibodies, including IgG, IgM, IgA, and IgE, as well as other Ig subtypes, can be detected simultaneously with multi-color labeled secondary antibodies.,Serum and plasma are the most common biologic materials for autoantibody detection, but other body fluids such as cerebrospinal fluid, synovial fluid, and saliva can also be a source of autoantibody detection.,Proteomic microarray as a multiplexed high-throughput screening platform is playing an increasingly-important role in autoantibody diagnostics.,In this article, we highlight the use of autoantigen microarrays for autoantibody exploration in SLE.
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Autoimmune diseases are common and debilitating, but their severe manifestations could be reduced if biomarkers were available to allow individual tailoring of the potentially toxic immunosuppressive therapy required for their control.,Gene expression-based biomarkers facilitating individual tailoring of chemotherapy in cancer, but not autoimmunity, have been identified and translated into clinical practice1,2.,We show that transcriptional profiling of purified CD8 T cells, which avoids the confounding influences of unseparated cells3,4, identifies two distinct patient subgroups predicting long-term prognosis in two different autoimmune diseases, anti-neutrophil cytoplasmic antibody (ANCA) - associated vasculitis (AAV), a chronic, severe disease characterized by inflammation of medium and small blood vessels5, and systemic lupus erythematosus (SLE), characterized by autoantibodies, immune complex deposition and diverse clinical manifestations ranging from glomerulonephritis to neurological dysfunction6.,We show that genes defining the poor prognostic group are enriched for genes of the IL7R pathway, TCR signalling and those expressed by memory T cells.,Furthermore, the poor prognostic group is associated with an expanded CD8 T cell memory population.,These subgroups, which are also found in the normal population and can be identified by measuring expression of only three genes, raise the prospect of individualized therapy and suggest novel potential therapeutic targets in autoimmunity.
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IgG antibodies are a key component of adaptive humoral immunity but can cause organ damage if they bind self-antigen, as occurs in the autoimmune disease systemic lupus erythematosus (SLE).,Many of the proinflammatory effects of IgG are mediated by ligating Fcγ receptors (FcγRs) expressed by tissue-resident leukocytes such as macrophages.,One of the most serious complications of SLE is kidney inflammation: lupus nephritis.,Here we show that IgG ligation of FcγRs on macrophages in the kidney leads to a change in their metabolism, resulting in a switch toward glycolysis.,Administration of a glycolysis inhibitor attenuated IgG-associated kidney macrophage activation, proinflammatory cytokine secretion, and kidney inflammation.,Therefore, manipulating macrophage metabolism may be a useful therapeutic strategy in lupus nephritis.,IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE).,We investigated the metabolic profile of macrophages isolated from inflamed tissues in immune complex (IC)-associated diseases, including SLE and rheumatoid arthritis, and following IgG Fcγ receptor cross-linking.,We found that human and mouse macrophages undergo a switch to glycolysis in response to IgG IC stimulation, mirroring macrophage metabolic changes in inflamed tissue in vivo.,This metabolic reprogramming was required to generate a number of proinflammatory mediators, including IL-1β, and was dependent on mTOR and hypoxia-inducible factor (HIF)1α.,Inhibition of glycolysis, or genetic depletion of HIF1α, attenuated IgG IC-induced activation of macrophages in vitro, including primary human kidney macrophages.,In vivo, glycolysis inhibition led to a reduction in kidney macrophage IL-1β and reduced neutrophil recruitment in a murine model of antibody-mediated nephritis.,Together, our data reveal the molecular mechanisms underpinning FcγR-mediated metabolic reprogramming in macrophages and suggest a therapeutic strategy for autoantibody-induced inflammation, including lupus nephritis.
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Urinary excretion of N-benzoyl-glycyl-Nε-(hexanonyl)lysine, a biomarker of oxidative stress, was higher in 26 patients with active systemic lupus erythematosus (SLE) than in 11 non-SLE patients with connective tissue diseases and in 14 healthy volunteers.,We hypothesized that increased oxidative stress in active SLE might be attributable to deranged bioenergetics, defective reduction-oxidation (redox) capacity, or other factors.,We demonstrated that, compared to normal cells, T lymphocytes (T) and polymorphonuclear neutrophils (PMN) of active SLE showed defective expression of facilitative glucose transporters GLUT-3 and GLUT-6, which led to increased intracellular basal lactate and decreased ATP production.,In addition, the redox capacity, including intracellular GSH levels and the enzyme activity of glutathione peroxidase (GSH-Px) and γ-glutamyl-transpeptidase (GGT), was decreased in SLE-T.,Compared to normal cells, SLE-PMN showed decreased intracellular GSH levels, and GGT enzyme activity was found in SLE-PMN and enhanced expression of CD53, a coprecipitating molecule for GGT.,We conclude that deranged cellular bioenergetics and defective redox capacity in T and PMN are responsible for cellular immune dysfunction and are related to increased oxidative stress in active SLE patients.
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It has been reported that patients with IgG4-related disease (IgG4-RD) showed an elevated incidence of eosinophilia.,We aim to explore the clinical patterns of IgG4-RD patients with and without eosinophilia.,Four hundred and twenty-five IgG4-RD patients referred to Peking Union Medical College Hospital were enrolled.,Blood eosinophil count higher than 0.5 × 109/L was defined as eosinophilia.,Clinical features of all the participants were collected and analyzed statistically.,Eighty-seven patients (20%) with eosinophilia were found.,As compared to those with a normal range of blood eosinophil count, male predominance, longer disease duration, increased prevalence of dacryoadenitis, sialadenitis, lymphadenopathy, and skin rash, higher IgG4-RD responder index, more organ involvement and higher levels of serum IgG4 (17.0 g/L vs 6.5 g/L, P < 0.001) was found in patients with eosinophilia.,There was no significant difference in the incidence of allergic disease between the two groups.,Peripheral eosinophil counts were positively correlated with disease duration, the number of involved organs, IgG4-RD responder index, and serum IgG4.,Higher recurrence rate during follow-up period was found in patients with eosinophilia [28.6% (20/70) vs 17.1% (42/245), P = 0.034].,IgG4-RD patients with eosinophilia exhibited different clinical patterns from patients without.,Eosinophilia appeared independent of allergies in IgG4-RD.
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Interleukin- (IL-) 35 is a member of the IL-12 cytokine family and a heterodimeric protein formed by Epstein-Barr-induced gene 3 (EBI3) and IL-12p35.,Emerging evidence shows that IL-35 is a key player in the regulation of cellular communication, differentiation, and inflammation.,Altered IL-35 expression has been found in disease conditions such as cancer, rheumatoid arthritis, and, more recently, asthma.,In cancer, IL-35 is involved in the regulation of tumorigenesis, cancer progression, and metastasis.,In rheumatoid arthritis, IL-35 acts as a negative regulator of inflammation.,Similarly, IL-35 also appears to suppress allergic inflammation in asthma.,In an in vivo murine model of asthma, transfer of adenovirus-mediated IL-35 markedly reduced the degree of airway hyperresponsiveness (AHR) and inflammatory cell infiltration.,Many studies have shown the involvement of IL-35 in a number of aspects of allergic inflammation, such as eosinophil and neutrophil recruitment as well as inhibition of inflammatory mediators of the Th2 subtype.,However, the exact molecular mechanisms underlying the role of IL-35 in human asthma have yet to be fully elucidated.,This review describes the current evidence regarding the role of IL-35 in the pathophysiology of asthma and evaluates the potential of IL-35 as a biomarker for airway inflammation and a therapeutic target for the treatment of asthma.
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The effects of multiple sclerosis (MS) on cognition have gained increasing recognition as one of the major disabling symptoms of the disease.,Despite the prevalence of these symptoms and their impact on quality of life, limited attention has been given to strategies that might help manage the cognitive changes commonly experienced by persons with MS.,The primary purpose of this study was to determine the effectiveness of a novel computer-assisted cognitive rehabilitation intervention MAPSS-MS (Memory, Attention, Problem Solving Skills in MS) in a multi-site trial with persons with MS.,Persons with MS (N = 183) with cognitive concerns were randomly assigned to either the 8-week MAPSS-MS intervention or usual care plus freely available computer games.,Participants completed self-report and performance measures of cognitive functioning, compensatory strategies and depression at baseline, immediately after the MAPSS-MS intervention, and three and six months post-intervention.,Changes in study outcomes were analyzed using intention to treat methodology, ANOVA with repeated measures, and ANCOVA.,Both groups improved significantly on all outcome measures.,The intervention group outperformed the comparison group on all measures, and there were statistically significant differences on selected measures.,Findings suggest that MAPSS-MS is a feasible intervention that could be broadly implemented in community settings.,It has been shown to be modestly successful in improving cognitive functioning.
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Health-related quality of life (QOL) is a key outcome for people with multiple sclerosis (MS).,While modifiable lifestyle factors, like smoking, physical activity and vitamin D, have strong associations with development and progression of MS, few studies have examined such associations with QOL.,Using patient-reported data from 2312 people with MS from 54 countries, regression models explored associations of socio-demographic, therapeutic and lifestyle factors with QOL, using the Multiple Sclerosis Quality of Life-54 (MSQOL-54).,Participants were on average 45.6 years old, 82.4% women, mostly partnered (74.1%), with a university degree (59.5%).,Controlling for socio-demographic factors and disability, factors associated with better physical health composite (PHC) (on a 100 point scale) were: moderate and high physical activity compared to low (5.9 [95% confidence interval: 4.2, 7.6] and 9.9 [CI: 8.1, 11.6] points higher score respectively); non-smoking compared to current smoking (4.6 points [CI: 2.4, 6.7]); better diet (per 10 points on the 100 point Diet Habits Questionnaire scale (DHQ) 1.6 points [CI: 1.0, 2.2] points); normal body mass index (BMI) versus overweight or obese (2.1 points [CI: 0.4, 3.7] and 2.4 points [CI: 0.5, 4.3]); fewer comorbidities (4.4 points [CI: 3.9, 4.9]); and not taking a disease-modifying drug (DMD) (2.1 points [CI: 0.7, 3.4]).,Better mental health composite (MHC) determinants were: moderate and high physical activity compared to low (4.0 points [CI: 2.0, 6.0] and 5.7 points [CI: 3.5, 8.0]); non-smoking compared to current (6.7 points [CI: 4.1, 9.3]); better diet (2.8 points [CI: 1.9, 3.5]); normal BMI versus overweight or obese (3.1 points [CI: 1.1, 5.1] and 3.5 points [CI: 1.3, 5.7]); meditating regularly (2.2 points [CI: 0.2, 4.2]); and no DMD use (2.9 points [CI: 1.3, 4.6]).,While causality cannot be concluded from cross-sectional data, the associations between modifiable lifestyle factors and QOL suggest significant potential for secondary prevention of the known deterioration of QOL for people with MS through lifestyle risk factor modification.,The online version of this article (doi:10.1186/s12883-016-0763-4) contains supplementary material, which is available to authorized users.
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Insulin resistance has been proposed as one of the causes of poor glycemic control in overweight/obese youth with type 1 diabetes (T1D).,However, the role of adjunctive metformin, an insulin sensitizer, on glycemic control in these patients is unclear.,To compare the effect of metformin vs. placebo on hemoglobin A1c (HbA1c), total daily dose (TDD) of insulin, and other parameters in overweight/obese youth with T1D.,Adjunctive metformin therapy will improve glycemic control in overweight/obese youth with T1D.,A 9-mo randomized, double-blind, placebo controlled trial of metformin and placebo in 28 subjects (13m/15f) of ages 10-20years (y), with HbA1c >8% (64 mmol/mol), BMI >85%, and T1D > 12 months was conducted at a university outpatient facility.,The metformin group consisted of 15 subjects (8 m/ 7f), of age 15.0 ± 2.5 y; while the control group was made up of 13 subjects (5m/ 8f), of age 14.5 ± 3.1y.,All participants employed a self-directed treat-to-target insulin regimen based on a titration algorithm of (-2)-0-(+2) units to adjust their long-acting insulin dose every 3rd day from -3 mo through +9 mo to maintain fasting plasma glucose (FPG) between 90-120 mg/dL (5.0-6.7 mmol/L).,Pubertal maturation was determined by Tanner stage.,Over the course of the 9 months of observation, the between-treatment differences in HbA1c of 0.4% (9.85% [8.82 to 10.88] for placebo versus 9.46% [8.47 to 10.46] for metformin) was not significant (p = 0.903).,There were non-significant reduction in fasting plasma glucose (189.4 mg/dL [133.2 to 245.6] for placebo versus 170.5 mg/dL [114.3 to 226.7] for metformin), (p = 0.927); total daily dose (TDD) of short-acting insulin per kg body weight/day(p = 0.936); and the TDD of long-acting insulin per kg body weight per day (1.15 units/kg/day [0.89 to 1.41] for placebo versus 0.90 units/kg/day [0.64 to 1.16] for metformin) (p = 0.221).,There was no difference in the occurrence of hypoglycemia between the groups.,This 9-month RCT of adjunctive metformin therapy in overweight and obese youth with T1D resulted in a 0.4% lower HbA1c value in the metformin group compared to the placebo group.,ClinicalTrial.gov NCT01334125
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Cardiovascular disease is the leading cause of mortality in Type 1 diabetes (T1D).,Vascular dysfunction is an early and critical event in the development of cardiovascular disease.,Children with T1D have vascular dysfunction therefore early interventions to improve vascular health are essential to reduce cardiovascular mortality in T1D.,Metformin is an insulin sensitising agent which is known to improve vascular health outcomes in type 2 diabetes (T2D) and other individuals with insulin resistance.,It has been used safely in children and adolescents with T2D for over 10 years.,This study aims to assess the effect of metformin on vascular health in children with T1D.,This study is a 12 month, double blind, randomised, placebo controlled trial to determine the effect of metformin on vascular health in children (age 8-18) with T1D.,The sample size is 76 with 38 children in the metformin group and 38 children in the placebo group.,Vascular health and biochemical markers will be measured at baseline, 3, 6 and 12 months.,Vascular function will be measured using flow mediated dilatation and glyceryl trinitrate mediated dilatation of the brachial artery and vascular structure will be measured with carotid and aortic intima media thickness, using standardised protocols.,This study will be the first to investigate the effect of metformin on vascular health in children with T1D.,It will provide important information on a potential intervention to improve cardiovascular morbidity and mortality in this population at high risk from cardiovascular disease.,Australia New Zealand Clinical Trials Registry ACTRN12611000148976
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Oxidative injury appears to play a major role in the propagation of demyelination and neurodegeneration in multiple sclerosis (MS).,It has been suggested that endogenous anti-oxidant defense mechanisms within MS lesions are insufficient to prevent spreading of damage.,Thus, current therapeutic approaches (e.g., fumarate treatment) target to up-regulate the expression of a key regulator of anti-oxidative defense, the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2).,In this study, we show that Nrf2 is already strongly up-regulated in active MS lesions.,Nuclear Nrf2 expression was particularly observed in oligodendrocytes and its functional activity is indicated by the expression of one of its downstream targets (heme oxygenase 1) in the same cells.,In contrast, only a minor number of Nrf2-positive neurons were detected, even in highly inflammatory cortical lesions presenting with extensive oxidative injury.,Overall, the most pronounced Nrf2 expression was found in degenerating cells, which showed signs of apoptotic or necrotic cell death.,Via whole-genome microarray analyses of MS lesions, we observed a differential expression of numerous Nrf2-responsive genes, also involved in the defense against oxidative stress, predominantly in areas of initial myelin destruction within actively demyelinating white matter lesions.,Furthermore, the expression patterns of Nrf2-induced genes differed between the white matter and cortical gray matter.,Our study shows that in the MS brain, Nrf2 expression varies in different cell types and is associated with active demyelination in the lesions.,The online version of this article (doi:10.1007/s00401-015-1452-x) contains supplementary material, which is available to authorized users.
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Objective Cerebral atrophy is a correlate of clinical progression in multiple sclerosis (MS).,Mitochondria are now established to play a part in the pathogenesis of MS.,Uniquely, mitochondria harbor their own mitochondrial DNA (mtDNA), essential for maintaining a healthy central nervous system.,We explored mitochondrial respiratory chain activity and mtDNA deletions in single neurons from secondary progressive MS (SPMS) cases.,Methods Ninety-eight snap-frozen brain blocks from 13 SPMS cases together with complex IV/complex II histochemistry, immunohistochemistry, laser dissection microscopy, long-range and real-time PCR and sequencing were used to identify and analyze respiratory-deficient neurons devoid of complex IV and with complex II activity.,Results The density of respiratory-deficient neurons in SPMS was strikingly in excess of aged controls.,The majority of respiratory-deficient neurons were located in layer VI and immediate subcortical white matter (WM) irrespective of lesions.,Multiple deletions of mtDNA were apparent throughout the gray matter (GM) in MS.,The respiratory-deficient neurons harbored high levels of clonally expanded mtDNA deletions at a single-cell level.,Furthermore, there were neurons lacking mtDNA-encoded catalytic subunits of complex IV. mtDNA deletions sufficiently explained the biochemical defect in the majority of respiratory-deficient neurons.,Interpretation These findings provide evidence that neurons in MS are respiratory-deficient due to mtDNA deletions, which are extensive in GM and may be induced by inflammation.,We propose induced multiple deletions of mtDNA as an important contributor to neurodegeneration in MS.
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The inflammasome is a multiprotein complex that acts to enhance inflammatory responses by promoting the production and secretion of key cytokines.,The best-known inflammasome is the NLRP3 (nucleotide-binding oligomerization domain-like receptor [NLR] family pyrin domain-containing 3) inflammasome.,The evidence has shown that the NLRP3 inflammasome, IL-1β, thioredoxin-interacting protein (TXNIP), and pyroptosis play vital roles in the development of diabetes.,This review summarizes the regulation of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) by NLRP3 via modulation of glucose tolerance, insulin resistance, inflammation, and apoptosis mediated by endoplasmic reticulum stress in adipose tissue.,Moreover, NLRP3 participates in intestinal homeostasis and inflammatory conditions, and NLRP3-deficient mice experience intestinal lesions.,The diversity of an individual’s gut microbiome and the resultant microbial metabolites determines the extent of their involvement in the physiological and pathological mechanisms within the gut.,As such, further study of the interaction between the NLRP3 inflammasome and the complex intestinal environment in disease development is warranted to discover novel therapies for the treatment of diabetes.
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Beta-cell (β-cell) injury is the hallmark of autoimmune diabetes.,However, the mechanisms by which autoreactive responses are generated in susceptible individuals are not well understood.,Extracellular vesicles (EV) are produced by mammalian cells under normal and stressed physiological states.,They are an important part of cellular communication, and may serve a role in antigen processing and presentation.,We hypothesized that isolated human islets in culture produce EV that contain diabetes autoantigens (DAA) from these otherwise normal, non-diabetic donors.,Here we report the caspase-independent production of EV by human islets in culture, and the characterization of DAA glutamic acid decarboxylase 65 (GAD65) and zinc transporter 8 (ZnT8), as well as the β-cell resident glucose transporter 2 (Glut2), present within the EV.
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The optimal time to bolus insulin for meals is challenging for children and adolescents with type 1 diabetes (T1D).,Current guidelines to control glucose excursions do not account for individual differences in glycaemic responses to meals.,This study aimed to examine the within- and between-person variability in time to peak (TTP) glycaemic responses after consuming meals under controlled and free-living conditions.,Participants aged 8-15 years with T1D ≥ 1 year and using a continuous glucose monitor (CGM) were recruited.,Participants consumed a standardised breakfast for six controlled days and maintained their usual daily routine for 14 free-living days.,CGM traces were collected after eating.,Linear mixed models were used to identify within- and between-person variability in the TTP after each of the controlled breakfasts, free-living breakfasts (FLB), and free-living dinners (FLD) conditions.,Thirty participants completed the study (16 females; mean age and standard deviation (SD) 10.5 (1.9)).,The TTP variability was greater within a person than the variability between people for all three meal types (between-person vs. within-person SD; controlled breakfast 18.5 vs.,38.9 min; FLB 14.1 vs.,49.6 min; FLD 5.7 vs.,64.5 min).,For the first time, the study showed that within-person variability in TTP glycaemic responses is even greater than between-person variability.
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Physical exercise is an important component in the management of type 1 diabetes across the lifespan.,Yet, acute exercise increases the risk of dysglycaemia, and the direction of glycaemic excursions depends, to some extent, on the intensity and duration of the type of exercise.,Understandably, fear of hypoglycaemia is one of the strongest barriers to incorporating exercise into daily life.,Risk of hypoglycaemia during and after exercise can be lowered when insulin‐dose adjustments are made and/or additional carbohydrates are consumed.,Glycaemic management during exercise has been made easier with continuous glucose monitoring (CGM) and intermittently scanned continuous glucose monitoring (isCGM) systems; however, because of the complexity of CGM and isCGM systems, both individuals with type 1 diabetes and their healthcare professionals may struggle with the interpretation of given information to maximise the technological potential for effective use around exercise (ie, before, during and after).,This position statement highlights the recent advancements in CGM and isCGM technology, with a focus on the evidence base for their efficacy to sense glucose around exercise and adaptations in the use of these emerging tools, and updates the guidance for exercise in adults, children and adolescents with type 1 diabetes.
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Osteoclasts are responsible for the bone erosion associated with rheumatoid arthritis (RA).,The upregulation of the chemokines CCL19 and CCL21 and their receptor CCR7 has been linked to RA pathogenesis.,The purpose of this study was to evaluate the effects of CCL19 and CCL21 on osteoclasts and to reveal their underlying mechanisms.,The expression of CCL19, CCL21 and CCR7 was higher in RA patients than in osteoarthritis patients.,In differentiating osteoclasts, tumor necrosis factor-α, interleukin-1β and lipopolysaccharide stimulated CCR7 expression.,CCL19 and CCL21 promoted osteoclast migration and resorption activity.,These effects were dependent on the presence of CCR7 and abolished by the inhibition of the Rho signaling pathway.,CCL19 and CCL21 promoted bone resorption by osteoclasts in an in vivo mice calvarial model.,These findings demonstrate for the first time that CCL19, CCL21 and CCR7 play important roles in bone destruction by increasing osteoclast migration and resorption activity.,This study also suggests that the interaction of CCL19 and CCL21 with CCR7 is an effective strategic focus in developing therapeutics for alleviating inflammatory bone destruction.
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The efficacy of B cell-depleting therapies for rheumatoid arthritis underscores antibody-independent functions of effector B cells such as cognate T-B interactions and production of pro-inflammatory cytokines.,Receptor activator of nuclear factor κB ligand (RANKL) is a key cytokine involved in bone destruction and is highly expressed in synovial fluid B cells in patients with rheumatoid arthritis.,In this study we sought to clarify the generation mechanism of RANKL+ effector B cells and their impacts on osteoclast differentiation.,Peripheral blood and synovial fluid B cells from healthy controls and patients with rheumatoid arthritis were isolated using cell sorter. mRNA expression of RANKL, osteoprotegerin, tumor necrosis factor (TNF)-α, and Blimp-1 was analyzed by quantitative real-time polymerase chain reaction.,Levels of RANKL, CD80, CD86, and CXCR3 were analyzed using flow cytometry.,Functional analysis of osteoclastogenesis was carried out in the co-culture system using macrophage RAW264 reporter cells.,RANKL expression was accentuated in CD80+CD86+ B cells, a highly activated B-cell subset more abundantly observed in patients with rheumatoid arthritis.,Upon activation via B-cell receptor and CD40, switched-memory B cells predominantly expressed RANKL, which was further augmented by interferon-γ (IFN-γ) but suppressed by interleukin-21.,Strikingly, IFN-γ also enhanced TNF-α expression, while it strongly suppressed osteoprotegerin expression in B cells.,IFN-γ increased the generation of CXCR3+RANKL+ effector B cells, mimicking the synovial B cell phenotype in patients with rheumatoid arthritis.,Finally, RANKL+ effector B cells in concert with TNF-α facilitated osteoclast differentiation in vitro.,Our current findings have shed light on the generation mechanism of pathogenic RANKL+ effector B cells that would be an ideal therapeutic target for rheumatoid arthritis in the future.,The online version of this article (doi:10.1186/s13075-016-0957-6) contains supplementary material, which is available to authorized users.
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Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) regulates a panoply of leukocyte signaling pathways.,A single nucleotide polymorphism (SNP) in PTPN22, rs2476601, is associated with increased risk of Type 1 Diabetes (T1D) and other autoimmune diseases.,Over the past decade PTPN22 has been studied intensely in T cell receptor (TCR) and B cell receptor (BCR) signaling.,However, the effect of the minor allele on PTPN22 function in TCR signaling is controversial with some reports concluding it has enhanced function and blunts TCR signaling and others reporting it has reduced function and increases TCR signaling.,More recently, the core function of PTPN22 as well as functional derangements imparted by the autoimmunity-associated variant allele of PTPN22 have been examined in monocytes, macrophages, dendritic cells, and neutrophils.,In this review we will discuss the known functions of PTPN22 in human cells, and we will elaborate on how autoimmunity-associated variants influence these functions across the panoply of immune cells that express PTPN22.,Further, we consider currently unresolved questions that require clarification on the role of PTPN22 in immune cell function.
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One mechanism by which disease-associated DNA variation can alter disease risk is altering gene expression.,However, linkage disequilibrium (LD) between variants, mostly single-nucleotide polymorphisms (SNPs), means it is not sufficient to show that a particular variant associates with both disease and expression, as there could be two distinct causal variants in LD.,Here, we describe a formal statistical test of colocalization and apply it to type 1 diabetes (T1D)-associated regions identified mostly through genome-wide association studies and expression quantitative trait loci (eQTLs) discovered in a recently determined large monocyte expression data set from the Gutenberg Health Study (1370 individuals), with confirmation sought in an additional data set from the Cardiogenics Transcriptome Study (558 individuals).,We excluded 39 out of 60 overlapping eQTLs in 49 T1D regions from possible colocalization and identified 21 coincident eQTLs, representing 21 genes in 14 distinct T1D regions.,Our results reflect the importance of monocyte (and their derivatives, macrophage and dendritic cell) gene expression in human T1D and support the candidacy of several genes as causal factors in autoimmune pancreatic beta-cell destruction, including AFF3, CD226, CLECL1, DEXI, FKRP, PRKD2, RNLS, SMARCE1 and SUOX, in addition to the recently described GPR183 (EBI2) gene.
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The effectiveness and safety of biological disease-modifying antirheumatic drugs (bDMARDs) by age group (< 65, 65-74, and ≥ 75 years) are uncertain.,We examined retention rates reflecting the effectiveness and safety of bDMARDs in actual clinical practice for clarifying optimal therapeutic strategies for rheumatoid arthritis (RA) by age groups.,Data of patients who were treated with tumor necrosis factor inhibitors (TNFi), abatacept (ABA), and tocilizumab (TCZ) between February 2011 and April 2017 were collected from a prospective observational registry of RA patients.,A total of 1362 patients were enrolled, of which 695 were aged < 65 years, 402 were aged 65-74 years, and 265 were aged ≥ 75 years.,Primary outcome was the drug retention rate in adjusted data using inverse probability of treatment weighting based on generalized propensity scores.,In patients aged < 65 years, 3-year retention rates of TNFi, ABA, and TCZ were 43%, 47%, and 69%, respectively (ABA versus TCZ, p = 0.017; TNFi versus TCZ, p = 0.002).,In patients aged 65-74 years, 3-year retention rates of TNFi, ABA, and TCZ were 44%, 53%, and 60%, respectively (TCZ versus TNFi, p = 0.034).,In patients aged ≥ 75 years, 3-year retention rates for TNFi, ABA, and TCZ were 38%, 63%, and 58%, respectively (ABA versus TNFi, p = 0.017).,We found that the effectiveness and safety of TCZ were maximal in patients aged < 75 years and that patients aged ≥ 75 years might be suitable candidates for TCZ and ABA therapy.,The use of therapeutic strategies appropriate to each age group might improve the outcomes of bDMARD therapy for RA.
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To detail the greatest areas of unmet scientific and clinical needs in rheumatology.,The 21st annual international Advances in Targeted Therapies meeting brought together more than 100 leading basic scientists and clinical researchers in rheumatology, immunology, epidemiology, molecular biology and other specialties.,During the meeting, breakout sessions were convened, consisting of 5 disease-specific groups with 20-30 experts assigned to each group based on expertise.,Specific groups included: rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, systemic lupus erythematosus and other systemic autoimmune rheumatic diseases.,In each group, experts were asked to identify unmet clinical and translational research needs in general and then to prioritise and detail the most important specific needs within each disease area.,Overarching themes across all disease states included the need to innovate clinical trial design with emphasis on studying patients with refractory disease, the development of trials that take into account disease endotypes and patients with overlapping inflammatory diseases, the need to better understand the prevalence and incidence of inflammatory diseases in developing regions of the world and ultimately to develop therapies that can cure inflammatory autoimmune diseases.,Unmet needs for new therapies and trial designs, particularly for those with treatment refractory disease, remain a top priority in rheumatology.
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Neurofilament light (NFL) has proved to be a good prognostic factor in multiple sclerosis (MS), as its level is proportionally elevated with extended neuraxonal damage.,The involvement of the kynurenine pathway in neuroinflammation has been proved.,The precursor of this pathway is the essential amino acid tryptophan, which is catabolized 95% towards kynurenine metabolites.,Quinolinic acid (QUIN) within the brain is only produced in activated microglia and macrophages, leading to axonal degeneration via the activation of N-Methyl-D-aspartate receptors.,Neopterin is a biomarker for inflammation produced by macrophages.,The association of these biomarkers has not previously been investigated.,Our aim was to assess whether there is an association of the neurodegenerative biomarker NFL with the markers of neuroinflammation, e.g., kynurenine metabolites and neopterin, in the cerebrospinal fluid (CSF).,CSF samples of patients with MS (pwMS; n = 37) and age-matched controls (n = 22) were compared for NFL levels by ELISA, while the kynurenine pathway metabolites tryptophan and neopterin were detected with mass spectrometry.,Spearman’s correlation showed that NFL is an independent predictor of neurological disability in the MS group.,Significant correlations were found between NFL, neopterin, and QUIN, and between kynurenine and neopterin.,Receiver operating characteristic (ROC) curve analysis was used to plot the top three best predictors of MS-related disability that yielded the best specificity and sensitivity.,Normalized NFL (AUC: 0.923), QUIN (AUC: 0.803), and neopterin (AUC: 0.843) were the best independent predictors of neurological disability in pwMS.,The CSF NFL and CSF QUIN, together with neopterin, were elevated in the CSF of pwMS compared to controls.,The combination of the neurodegenerative biomarkers together with biomarkers of neuroinflammation could provide additional information on the underlying pathomechanism of disease activity, which is essential for the identification of patients at risk of developing cumulative disabilities.
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T cells are considered pivotal in the pathology of multiple sclerosis (MS), but their function and antigen specificity are unknown.,To unravel the role of T cells in MS pathology, we performed a comprehensive analysis on T cells recovered from paired blood, cerebrospinal fluid (CSF), normal-appearing white matter (NAWM) and white matter lesions (WML) from 27 MS patients with advanced disease shortly after death.,The differentiation status of T cells in these compartments was determined by ex vivo flow cytometry and immunohistochemistry.,T-cell reactivity in short-term T-cell lines (TCL), generated by non-specific stimulation of T cells recovered from the same compartments, was determined by intracellular cytokine flow cytometry.,Central memory T cells predominated in CSF and effector memory T cells were enriched in NAWM and WML.,WML-derived CD8+ T cells represent chronically activated T cells expressing a cytotoxic effector phenotype (CD95L and granzyme B) indicative for local antigenic stimulation (CD137).,The same lesions also contained higher CD8+ T-cell frequencies expressing co-inhibitory (TIM3 and PD1) and co-stimulatory (ICOS) T-cell receptors, yet no evidence for T-cell senescence (CD57) was observed.,The oligoclonal T-cell receptor (TCR) repertoire, particularly among CD8+ T cells, correlated between TCL generated from anatomically separated WML of the same MS patient, but not between paired NAWM and WML.,Whereas no substantial T-cell reactivity was detected towards seven candidate human MS-associated autoantigens (cMSAg), brisk CD8+ T-cell reactivity was detected in multiple WML-derived TCL towards autologous Epstein-Barr virus (EBV) infected B cells (autoBLCL).,In one MS patient, the T-cell response towards autoBLCL in paired intra-lesional TCL was dominated by TCRVβ2+CD8+ T cells, which were localized in the parenchyma of the respective tissues expressing a polarized TCR and CD8 expression suggesting immunological synapse formation in situ.,Collectively, the data suggest the involvement of effector memory cytotoxic T cells recognizing antigens expressed by autoBLCL, but not the assayed human cMSAg, in WML of MS patients.,The online version of this article (doi:10.1007/s00401-017-1744-4) contains supplementary material, which is available to authorized users.
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Auto-reactive CD8 T-cells play an important role in the destruction of pancreatic β-cells resulting in type 1 diabetes (T1D).,However, the phenotype of these auto-reactive cytolytic CD8 T-cells has not yet been extensively described.,We used high-dimensional mass cytometry to phenotype autoantigen- (pre-proinsulin), neoantigen- (insulin-DRIP) and virus- (cytomegalovirus) reactive CD8 T-cells in peripheral blood mononuclear cells (PBMCs) of T1D patients.,A panel of 33 monoclonal antibodies was designed to further characterise these cells at the single-cell level.,HLA-A2 class I tetramers were used for the detection of antigen-specific CD8 T-cells.,Using a novel Hierarchical Stochastic Neighbor Embedding (HSNE) tool (implemented in Cytosplore), we identified 42 clusters within the CD8 T-cell compartment of three T1D patients and revealed profound heterogeneity between individuals, as each patient displayed a distinct cluster distribution.,Single-cell analysis of pre-proinsulin, insulin-DRIP and cytomegalovirus-specific CD8 T-cells showed that the detected specificities were heterogeneous between and within patients.,These findings emphasize the challenge to define the obscure nature of auto-reactive CD8 T-cells.
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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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Understanding of pancreatic islet biology has greatly increased over the past few decades based in part on an increased understanding of the transcription factors that guide this process.,One such transcription factor that has been increasingly tied to both β-cell development and the development of diabetes in humans is GLIS3.,Genetic deletion of GLIS3 in mice and humans induces neonatal diabetes, while single nucleotide polymorphisms (SNPs) in GLIS3 have been associated with both Type 1 and Type 2 diabetes.,As a significant progress has been made in understanding some of GLIS3’s roles in pancreas development and diabetes, we sought to compare current knowledge on GLIS3 within the pancreas to that of other islet enriched transcription factors.,While GLIS3 appears to regulate similar genes and pathways to other transcription factors, its unique roles in β-cell development and maturation make it a key target for future studies and therapy.
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Type 1 diabetes arises from the autoimmune destruction of insulin-producing beta-cells of the pancreas, resulting in dependence on exogenously administered insulin to maintain glucose homeostasis.,In this study, our aim was to identify genetic risk factors that contribute to progression from islet autoimmunity to clinical type 1 diabetes.,We analyzed 6.8 million variants derived from whole genome sequencing of 160 islet autoantibody positive subjects, including 87 who had progressed to type 1 diabetes.,The Cox proportional-hazard model for survival analysis was used to identify genetic variants associated with progression.,We identified one novel region, 20p12.1 (TASP1; genome-wide P < 5 × 10-8) and three regions, 1q21.3 (MRPS21-PRPF3), 2p25.2 (NRIR), 3q22.1 (COL6A6), with suggestive evidence of association (P < 8.5 × 10-8) with progression from islet autoimmunity to type 1 diabetes.,Once islet autoimmunity is initiated, functional mapping identified two critical pathways, response to viral infections and interferon signaling, as contributing to disease progression.,These results provide evidence that genetic pathways involved in progression from islet autoimmunity differ from those pathways identified once disease has been established.,These results support the need for further investigation of genetic risk factors that modulate initiation and progression of subclinical disease to inform efforts in development of novel strategies for prediction and intervention of type 1 diabetes.
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Emerging evidence links modifiable lifestyle risk factors to disease progression in multiple sclerosis (MS).,We sought further evidence around this hypothesis through detailed analysis of the association with disability of lifestyle behaviours of a large international sample of people with MS.,A total of 2469 people with MS from 57 countries provided self-reported data via cross-sectional online survey on lifestyle (mostly with validated tools) and the primary outcome measure, disability (Patient Determined Disease Steps), categorised from 8 steps into 3 categories, mild, moderate and major disability.,Multinomial logistic regression modelling derived relative risk ratios (RRRs) for disability categories.,RRRs of having moderate vs mild disability were: diet (per 30 points on 100 point scale) 0.72 (95%CI 0.52-0.98), ever smoking 1.32 (1.06-1.65), exercise (moderate/high vs low) 0.35 (0.28-0.44), latitude (per degree from the equator) 1.02 (1.01-1.04), and number of comorbidities (2 vs none) 1.43 (1.04-1.95), (3 vs none) 1.56 (1.13-2.16).,RRRs of having major vs mild disability were: exercise (moderate/high vs low) 0.07 (0.04-0.11), alcohol consumption (moderate vs low) 0.45 (0.30-0.68), plant-based omega 3 supplementation 0.39 (0.18-0.86), and disease-modifying medication use 0.45 (0.29-0.70).,Healthier lifestyle has strong associations with disability in our large international sample of people with MS, supporting further investigation into the role of lifestyle risk factors in MS disease progression.
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Observational studies have demonstrated an association between decreased vitamin D level and risk of multiple sclerosis (MS); however, it remains unclear whether this relationship is causal.,We undertook a Mendelian randomization (MR) study to evaluate whether genetically lowered vitamin D level influences the risk of MS.,We identified single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D (25OHD) level from SUNLIGHT, the largest (n = 33,996) genome-wide association study to date for vitamin D.,Four SNPs were genome-wide significant for 25OHD level (p-values ranging from 6 × 10−10 to 2 × 10−109), and all four SNPs lay in, or near, genes strongly implicated in separate mechanisms influencing 25OHD.,We then ascertained their effect on 25OHD level in 2,347 participants from a population-based cohort, the Canadian Multicentre Osteoporosis Study, and tested the extent to which the 25OHD-decreasing alleles explained variation in 25OHD level.,We found that the count of 25OHD-decreasing alleles across these four SNPs was strongly associated with lower 25OHD level (n = 2,347, F-test statistic = 49.7, p = 2.4 × 10−12).,Next, we conducted an MR study to describe the effect of genetically lowered 25OHD on the odds of MS in the International Multiple Sclerosis Genetics Consortium study, the largest genetic association study to date for MS (including up to 14,498 cases and 24,091 healthy controls).,Alleles were weighted by their relative effect on 25OHD level, and sensitivity analyses were performed to test MR assumptions.,MR analyses found that each genetically determined one-standard-deviation decrease in log-transformed 25OHD level conferred a 2.0-fold increase in the odds of MS (95% CI: 1.7-2.5; p = 7.7 × 10−12; I 2 = 63%, 95% CI: 0%-88%).,This result persisted in sensitivity analyses excluding SNPs possibly influenced by population stratification or pleiotropy (odds ratio [OR] = 1.7, 95% CI: 1.3-2.2; p = 2.3 × 10−5; I 2 = 47%, 95% CI: 0%-85%) and including only SNPs involved in 25OHD synthesis or metabolism (ORsynthesis = 2.1, 95% CI: 1.6-2.6, p = 1 × 10−9; ORmetabolism = 1.9, 95% CI: 1.3-2.7, p = 0.002).,While these sensitivity analyses decreased the possibility that pleiotropy may have biased the results, residual pleiotropy is difficult to exclude entirely.,A genetically lowered 25OHD level is strongly associated with increased susceptibility to MS.,Whether vitamin D sufficiency can delay, or prevent, MS onset merits further investigation in long-term randomized controlled trials.,J.,Brent Richards and colleagues assess whether genetically predicted vitamin D levels associate with risk of multiple sclerosis.,Multiple sclerosis (MS) is a debilitating neurological disorder that affects the nerves in the brain and spinal cord and that usually presents between the ages of 20 and 40 years.,It is an autoimmune disease-a disease in which the body’s immune system attacks healthy tissues.,In the case of MS, the immune system attacks myelin, the fatty tissue that forms an insulating sheath around nerves fibers.,Multiple areas of scarring (sclerosis) in the myelin are produced by immune attack, and the damage slows down or blocks the transmission of electrical signals along the nerves to and from the brain and causes symptoms such as loss of vision, muscle stiffness, and daytime fatigue.,For most affected individuals, MS initially follows a relapsing-remitting course characterized by periods lasting days or weeks during which symptoms flare up, followed by periods during which symptoms becomes milder or disappear.,Half of people with relapsing-remitting MS eventually develop secondary progressive MS, in which their symptoms inexorably worsen.,There is currently no cure for MS, but some treatments can relieve its symptoms or reduce the number of relapses.,Why the immune system attacks myelin to cause MS is unclear but probably involves both genetic and environmental risk factors.,One potential environmental risk factor is reduced levels of vitamin D.,Circulating levels of 25-hydroxyvitamin D (25OHD; the clinical determinant of vitamin D status) are determined in part by exposure to sunlight, and MS is more common at higher latitudes, where exposure to sunlight is decreased.,Other epidemiological studies (investigations that examine disease patterns in populations) also suggest an association between lower vitamin D level and an increased risk of MS but cannot prove that a decreased vitamin D level actually causes MS.,Individuals who develop MS might share another unknown characteristic that increases their risk of MS (confounding), or individuals who have MS might spend less time outdoors and, as a result, have lower circulating vitamin D levels (reverse causation).,It is important to know whether a decreased vitamin D level increases the risk of MS because vitamin D insufficiency is becoming increasingly common.,Here, the researchers undertake a Mendelian randomization study to determine whether circulating vitamin D level has a causal effect on MS susceptibility.,Because gene variants are inherited randomly, they are not prone to confounding.,Reverse causation is also prevented since MS does not change genetic variants.,So, if vitamin D level actually affects MS risk, genetic variants that affect vitamin D level should be associated with altered susceptibility to MS.,The researchers first ascertained the effect on 25OHD level among participants in the Canadian Multicentre Osteoporosis Study of four single nucleotide polymorphisms (SNPs, a type of genetic variant) that were associated with 25OHD level in a genome-wide association study (SUNLIGHT).,Each of the SNPs explained an important proportion of the population-level variance in 25OHD level in the Canadian Multicentre Osteoporosis Study.,The researchers then used the SNPs to examine whether there was an association between genetically reduced 25OHD level and susceptibility to MS among participants in the International Multiple Sclerosis Genetics Consortium study, a genome-wide association study involving up to 14,498 people with MS and 24,091 healthy controls.,They found that a genetic decrease in the natural-log-transformed 25OHD level by one standard deviation was associated with a 2-fold increased risk of MS.,In practical terms, this finding means that increasing an individual’s circulating 25OHD level by approximately 1.5-fold decreases their odds of developing MS by 50%.,These findings show that, among the participants of the International Multiple Sclerosis Genetics Consortium study, all of whom were of European ancestry, genetically lowered 25OHD level was strongly associated with increased susceptibility to MS.,Although the Mendelian randomization approach used here largely avoids the possibility of confounding or reverse causation, the reliability of these findings may be limited by some of the assumptions made by the researchers during their analysis.,Moreover, although these findings support a role for vitamin D in MS susceptibility, they provide no information about whether vitamin D modulates the course of MS after its onset, and they may not apply to people of non-European ancestry.,Nevertheless, these findings provide a strong rationale for undertaking randomized controlled trials to investigate whether vitamin D supplementation can prevent the onset and/or progression of MS.,This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001866.,The UK National Health Service Choices website provides information about multiple sclerosis, including personal stories, and information about vitamin D and how to get vitamin D from sunlight; A “Behind the Headlines” article examines health claims made for vitamin D,The US National Institute of Neurological Disorders and Stroke provides information about multiple sclerosis and links to MS societies,The National Multiple Sclerosis Society, a US not-for-profit organization, provides information about all aspects of MS, including information about vitamin D and MS and personal stories about MS,The Multiple Sclerosis Society, a UK not-for-profit organization, also provides information about MS for patients, carers, and professionals in several languages, including news about the latest research, personal blogs, and forums,The US Office of Dietary Supplements provides information about vitamin D (in English and Spanish),MedlinePlus has links to further information about multiple sclerosis and vitamin D (in English and Spanish),Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
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The Disease Activity Score (DAS) is integral in tailoring the clinical management of rheumatoid arthritis (RA) patients and is an important measure in clinical research.,Different versions have been developed over the years to improve reliability and ease of use.,Combining the original DAS and the newer DAS28 data in both contemporary and historical studies is important for both primary and secondary data analyses.,As such, a methodologically robust means of converting the old DAS to the new DAS28 measure would be invaluable.,Using data from The Early RA Study (ERAS), a sub-sample of patients with both DAS and DAS28 data were used to develop new regression imputation formulas using the total DAS score (univariate), and using the separate components of the DAS score (multivariate).,DAS were transformed to DAS28 using an existing formula quoted in the literature, and the newly developed formulas.,Bland and Altman plots were used to compare the transformed DAS with the recorded DAS28 to ascertain levels of agreement.,The current transformation formula tended to overestimate the true DAS28 score, particularly at the higher end of the scale.,A formula which uses all separate components of the DAS was found to estimate the scores with a higher level of precision.,A new formula is proposed that can be used by other early RA cohorts to convert the original DAS to DAS28.,The online version of this article (10.1007/s00296-018-4184-0) contains supplementary material, which is available to authorized users.
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With the present study we wanted to explore the impact of treatment with a tumor necrosis factor-α -inhibitor (TNFi) on levels of soluble biomarkers in rheumatoid arthritis (RA) patients and to identify predictors of impaired drug levels and development of anti-TNFi antibodies (anti-TNFi Abs).,Blood samples from 26 patients with established RA were taken at baseline and following 6 months of treatment with adalimumab or infliximab.,Samples were analyzed for levels of TNFi, interleukin (IL)-6, and soluble TNF-receptors 1 and -2 (sTNF-R1 and -2) and for presence of anti-TNFi Abs.,Clinical and demographic data were recorded as well.,During the initial 6 months treatment, DAS28(CRP) (Disease activity score in 28 joints using C-reactive protein) and levels of IL-6 and sTNF-R2 decreased significantly in patients without anti-TNFi Abs and in patients retaining detectable drug levels.,The levels of other tested cytokines (TNF-α, TNF-β, IL-1ra, IL-1b, IL-8, IL-10, IL-12(p70), IL-13, IL-17A, IL-17F, and IL-33) were generally below detection limits.,Higher baseline levels of IL-6 associated with undetectable levels of TNFi at follow-up.,Anti-TNFi Abs were associated with decreased drug levels, but no predictors for anti-TNFi Ab development could be found.,The effect of treatment with TNFi on RA disease activity depends on levels of active drug, and by presence of anti-TNFi Abs.,In patients who retain detectable drug levels, and in the absence of anti-TNFi Abs, clinical outcome is improved during treatment, and circulating levels of IL-6 and sTNF-R2 decrease.,Baseline levels of IL-6 may predict depletion of TNFi and may identify patients at risk of treatment failure.
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While no curative treatment exists for multiple sclerosis (MS), several disease-modifying therapies (DMTs) have been developed to reduce relapse rates, slow disability progression, and modify the overall disease course.,However, because of the chronic nature of the disease, long-term therapy adherence can be challenging for some patients with MS.,Low adherence to DMTs has been shown to be associated with higher rates of disease relapses and progression as well as with an increase in medical resource utilization.,As new MS treatments are developed, a comprehensive understanding of current adherence rates and the impact of adherence on clinical and economic outcomes is of particular interest.,Our objective was to conduct a review of the published literature to evaluate rates of adherence to DMTs in MS and the impact of adherence on both clinical and economic outcomes from the patient and payer perspectives.,Systematic literature searches were conducted using MEDLINE, EMBASE, and the Cochrane Central Register for Controlled Trials.,Studies were limited to those completed on human subjects, written in the English language, and published between May 1, 2001, and May 1, 2011.,Additional inclusion criteria required that studies involve a population of patients with MS, utilize the administration of DMTs, and report a measurement of adherence.,Studies reporting persistence measures (e.g., treatment discontinuation rates) or rates of switching between DMTs (with no other measure of adherence reported) were excluded if they did not also assess adherence.,Among the 24 studies meeting inclusion criteria, adherence to DMTs ranged from 41% to 88%.,Weighted mean adherence rates were higher for intramuscular (IM) interferon beta-1a (IFNβ-1a) administered once a week (69.4%), and subcutaneous (SC) IFNβ-1b administered every other day (63.8%) than for SC IFNβ-1a administered 3 times a week (58.4%) and glatiramer acetate administered daily (56.8%).,There was a numerically greater risk of MS relapse or disease progression among patients nonadherent to therapy versus adherent patients, with findings statistically significant in 2 of 4 studies.,Additionally, 2 studies showed statistically significant reductions in inpatient or emergency room utilization and total MS-related medical costs among patients adherent to therapy compared with nonadherent patients.,Higher patient out-of-pocket copayments and coinsurance were significantly associated with lower adherence to DMTs, while the use of interventional or disease therapy management programs were associated with improved adherence.,Lack of medication adherence remains a problem among patients with MS.,Improvements in adherence have the potential to improve patient and payer burden in terms of improved clinical outcomes and lower nonpharmacy medical resource utilization.
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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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IgA nephropathy (IgAN) is the most frequent type of primary glomerulonephritis globally and the leading cause of end-stage renal disease in young adults.,Its pathogenesis is not fully known, but is largely attributed to genetic factors.,This study was aimed to explore the prognostic values of key genes in IgAN.,The gene expression profile GSE93798 of 20 IgAN samples and 22 normal samples using glomeruli from kidney biopsy was adopted.,Totally 447 upregulated and 719 downregulated differentially expressed genes were found in IgAN patients on the R software.,The Gene Ontology enrichment and the Kyoto Encyclopedia of Gene and Genomes pathway were investigated on DAVID, and the protein-protein interaction network and the top 13 hub genes of the differentially expressed genes were built via the plug-in molecular complex detection and cytoHubba of Cytoscape.,From the protein-protein interaction network, of the top 13 hub genes, FOS, EGFR, SIRT1, ALB, TFRC, JUN, IGF1, HIF1A, and SOCS3 were upregulated, while CTTN, ACTR2, CREB1, and CTNNB1 were downregulated.,The upregulated genes took part in the HIF-1 signaling pathway, Choline metabolism in cancer, Pathways in cancer, Amphetamine addiction, Estrogen, TNF, and FoxO signaling pathways, and Osteoclast differentiation, while the downregulated genes were involved in Pathogenic Escherichia coli infection, Bacterial invasion of epithelial cells, prostate cancer, and melanogenesis.,This study based on the Gene Expression Omnibus database updates the knowledge about the mechanism of IgAN and may offer new treatment targets.
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Anti-glomerular basement membrane (GBM) glomerulonephritis does not usually coexist with another glomerulonephritis such as IgA nephropathy.,We present a rare case having a combination of these two diseases, and furthermore, histological evaluation could be performed before and after the development of anti-GBM glomerulonephritis over a period of only10 months.,A 66-year-old woman was admitted with complaints of microscopic hematuria and mild proteinuria for the past 3 years.,Serum creatinine level was normal at that time.,The first renal biopsy was performed.,Light microscopy revealed mesangial proliferative glomerulonephritis with fibro-cellular crescents in one out of 18 glomeruli, excluding one global sclerotic glomerulus.,Immunofluorescence (IF) showed IgA and C3 deposition in the mesangium.,Therefore, the diagnosis was IgA nephropathy.,Eight months later, the patient’s serum creatinine suddenly rose to 4.53 mg/dL and urinalysis showed 100 red blood cells per high power field with nephrotic range proteinuria (12.3 g/gCr).,The serological tests revealed the presence of anti-GBM antibody at the titer of 116 IU/mL.,Treatments were begun after admission, consisting of hemodialysis, plasma exchange, and intravenous methylprednisolone pulse therapy.,At 4 weeks after admission, the second renal biopsy was performed.,Light microscopy revealed crescents in 18 of 25 glomeruli, excluding six global sclerotic glomeruli.,IF showed linear IgG deposition along the GBM in addition to granular IgA and C3 deposition.,Based on these findings, the diagnosis of anti-GBM glomerulonephritis and IgA nephropathy was confirmed.,Renal function was not restored despite treatment, but alveolar hemorrhage was prevented.,We report a patient with a diagnosis of anti-GBM disease during the course of IgA nephropathy.,This case strongly suggests that the presence of autoantibodies should be checked to rule out overlapping autoimmune conditions even in patient who have previously been diagnosed with chronic glomerulonephritis, such as IgA nephropathy, who present an unusually rapid clinical course.
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Vasculitides are characterized by mostly autoimmunologically induced inflammatory processes of vascular structures.,They have various clinical and radiologic appearances.,Early diagnosis and reliable monitoring are indispensable for adequate therapy to prevent potentially serious complications.,Imaging, in addition to laboratory tests and physical examination, constitutes a key component in assessing disease extent and activity.,This review presents current standards and some typical findings in the context of imaging in vasculitis with particular attention to large vessel vasculitides.,Recently, imaging has gained importance in the management of vasculitis, especially regarding large vessel vasculitides (LVV).,Recently, EULAR (European League Against Rheumatism) has launched its recommendations concerning the diagnosis of LVVs.,Imaging is recommended as the preferred complement to clinical examination.,Color-coded duplex sonography is considered the first choice imaging test in suspected giant cell arteritis, and magnetic resonance imaging is considered the first choice in suspected Takayasu’s arteritis.,Due to diversity of clinical and radiologic presentations, diagnosis and therapy monitoring of vasculitides may constitute a challenge.,As a result of ongoing technological progress, a variety of non-invasive imaging modalities now play an elemental role in the interdisciplinary management of vasculitic diseases.
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Diagnosis of large vessel vasculitis (LVV) and evaluation of its inflammatory activity can be challenging.,Our aim was to investigate the value of hybrid positron-emission tomography/magnetic resonance imaging (PET/MRI) in LVV.,All consecutive patients with LVV from the Department of Internal Medicine who underwent PET/MRI were included.,Three PET/MRI patterns were defined: (i) “inflammatory,” with positive PET (>liver uptake) and abnormal MRI (stenosis and/or wall thickening); (ii) “fibrous”, negative PET (≤liver uptake) and abnormal MRI; and (iii) “normal”.,Thirteen patients (10 female; median age: 67-years [range: 23-87]) underwent 18 PET/MRI scans.,PET/MRI was performed at diagnosis (n = 4), at relapse (n = 7), or during remission (n = 7).,Among the 18 scans, eight (44%) showed an inflammatory pattern and three (17%) a fibrous pattern; the other seven were normal.,The distribution of the three patterns did not differ between patients with Takayasu arteritis (TA, n = 10 scans) and those with giant cell arteritis (GCA, n = 8 scans).,PET/MRI findings were normal in 2/10 (20%) TA scans vs.,5/8 (62%) GCA scans (p = 0.3).,Median SUVmax was 4.7 [2.1-8.6] vs.,2 [1.8-2.6] in patients with active disease vs. remission, respectively (p = 0.003).,PET/MRI is a new hybrid imaging modality allowing comprehensive and multimodal analysis of vascular wall inflammation and the vascular lumen.,This technique offers promising perspectives for the diagnosis and monitoring of LVV.
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Indocyanine green (ICG)-enhanced fluorescence optical imaging (FOI) is an established technology for imaging of inflammation in animal models.,In experimental models of arthritis, FOI findings corresponded to histologically proven synovitis.,This is the first comparative study of FOI with other imaging modalities in humans with arthritis.,252 FOI examinations (Xiralite system, mivenion GmbH, Berlin, Germany; ICG bolus of 0.1 mg/kg/body weight, sequence of 360 images, one image per second) were compared with clinical examination (CE), ultrasonography (US) and MRI of patients with arthritis of the hands.,In an FOI sequence, three phases could be distinguished (P1-P3).,With MRI as reference, FOI had a sensitivity of 76% and a specificity of 54%, while the specificity of phase 1 was 94%.,FOI had agreement rates up to 88% versus CE, 64% versus greyscale US, 88% versus power Doppler US and 83% versus MRI, depending on the compared phase and parameter.,FOI showed a higher rate of positive results compared to CE, US and MRI.,In individual patients, FOI correlated significantly (p<0.05) with disease activity (Disease Activity Score 28, r=0.41), US (r=0.40) and RAMRIS (Rheumatoid Arthritis MRI Score) (r=0.56).,FOI was normal in 97.8% of joints of controls.,ICG-enhanced FOI is a new technology offering sensitive imaging detection of inflammatory changes in subjects with arthritis.,FOI was more sensitive than CE and had good agreement with CE, US in power Doppler mode and MRI, while showing more positive results than these.,An adequate interpretation of an FOI sequence requires a separate evaluation of all phases.,For the detection of synovitis and tenosynovitis, FOI appears to be as informative as 1.5 T MRI and US.
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Aiming at therapeutic targets has reduced the risk of organ failure in many diseases such as diabetes or hypertension.,Such targets have not been defined for rheumatoid arthritis (RA).,To develop recommendations for achieving optimal therapeutic outcomes in RA.,A task force of rheumatologists and a patient developed a set of recommendations on the basis of evidence derived from a systematic literature review and expert opinion; these were subsequently discussed, amended and voted upon by >60 experts from various regions of the world in a Delphi-like procedure.,Levels of evidence, strength of recommendations and levels of agreement were derived.,The treat-to-target activity resulted in 10 recommendations.,The treatment aim was defined as remission with low disease activity being an alternative goal in patients with long-standing disease.,Regular follow-up (every 1-3 months during active disease) with appropriate therapeutic adaptation to reach the desired state within 3 to a maximum of 6 months was recommended.,Follow-up examinations ought to employ composite measures of disease activity which include joint counts.,Additional items provide further details for particular aspects of the disease.,Levels of agreement were very high for many of these recommendations (≥9/10).,The 10 recommendations are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA based on evidence and expert opinion.
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A major feature of type 1 diabetes is the appearance of islet autoantibodies before diagnosis.,However, although the genetics of type 1 diabetes is advanced, the genetics of islet autoantibodies needs further investigation.,The primary susceptibility loci in type 1 diabetes, the HLA class I and II genes, are believed to determine the specificity and magnitude of the autoimmune response to islet antigens.,We investigated the association of glutamic acid decarboxylase autoantibodies (GADA) and insulinoma-associated antigen-2 autoantibodies (IA-2A) with the HLA region.,Associations of GADA and IA-2A with HLA-DRB1, HLA-DQB1, HLA-B, HLA-C, HLA-A, MICA, and 3,779 single nucleotide polymorphisms (SNPs) were analyzed in 2,531 childhood-onset case subjects (median time since diagnosis 5 years).,All analyses were adjusted for age-at-diagnosis and duration of diabetes.,GADA and IA-2A were associated with an older age-at-diagnosis (P < 10−19).,For GADA, the primary association was with HLA-DQB1 (P = 9.00 × 10−18), with evidence of a second independent effect in the HLA class I region with SNP, rs9266722 (P = 2.84 × 10−6).,HLA-DRB1 had the strongest association with IA-2A (P = 1.94 × 10−41), with HLA-A*24 adding to the association, albeit negatively (P = 1.21 × 10−10).,There was no evidence of association of either IA-2A or GADA with the highly type 1 diabetes predisposing genotype, HLA-DRB1*03/04.,Despite genetic association of type 1 diabetes and the islet autoantibodies localizing to the same HLA class II genes, HLA-DRB1 and HLA-DQB1, the effects of the class II alleles and genotypes involved are quite different.,Therefore, the presence of autoantibodies is unlikely to be causal, and their role in pathogenesis remains to be established.
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A large, population-based case-control cohort was used to test the hypothesis that glutamic acid decarboxylase-65 (GAD65) and islet antigen-2 autoantibodies (IA-2A) at birth predict type 1 diabetes.,The design was an individually matched case-control study of all Danish type 1 diabetes patients born between 1981 and 2002 and diagnosed before May 1 2004 (median age at diagnosis was 8.8 years).,Dried blood spot samples collected 5 days after birth in the 1981-2002 birth cohorts and stored at −25 °C were identified from 2023 patients and from two matched controls (n=4042).,Birth data and information on parental age and diabetes were obtained from Danish registers.,GAD65A and IA-2A were determined in a radiobinding assay.,HLA-DQB1 alleles were analyzed by PCR using time-resolved fluorescence.,GAD65A and IA-2A were found in 70/2023 (3.5%) patients compared to 21/4042 (0.5%) controls resulting in a hazard ratio (HR) of 7.49 (P<0.0001).,The HR decreased to 4.55 but remained significant (P<0.0003) after controlling for parental diabetes and HLA-DQB1 alleles.,Conditional logistic regression analysis showed a HR of 2.55 (P<0.0001) for every tenfold increase in the levels of GAD65A and IA-2A.,This HR decreased to 1.93 but remained significant (P<0.001) after controlling for parental diabetes and HLA-DQB1 alleles.,These data suggest that GAD65A and IA-2A positivity at birth are associated with an increased risk of developing type 1 diabetes in Danish children diagnosed between 1981 and 2004.
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The intestinal microbiota plays a key role in the maintenance of human health.,Alterations in this microbiota have been described in several autoimmune diseases, including nervous system diseases.,Nevertheless, the information regarding neuromuscular conditions is still limited.,In this study, we aimed at characterizing the intestinal microbiota composition in myasthenia gravis patients (MG).,To this end fecal samples were taken from ten patients, with antibodies against the acetylcholine receptor, and ten age and sex matched controls from the same population (Asturias region, Spain).,Fecal samples were submitted to microbiota analyses by 16S rRNA gene profiling, bifidobacterial ITS-region profiling and qPCR.,The fecal levels of short chain fatty acids were determined by gas chromatography.,MG patients were found to harbor lower relative proportions of Verrucomicrobiaceae and Bifidobacteriaceae, among others, and increased of the phylum Bacteroidetes and the family Desulfovibrionaceae.,The increase of these latter microbial groups was also confirmed at quantitative level by qPCR.,In contrast, no statistically significant differences were found between MG patients and the control group in the bifidobacterial population at the species level or in short chain fatty acids profiles.,Our data indicates an altered fecal microbiota pattern in MG patients and point out at specific microbiota targets for intervention in this population.
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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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Interferon (IFN) signaling pathways play crucial roles in the pathogenesis of rheumatoid arthritis (RA).,Prior studies have mainly studied mixed alterations in the IFN signaling pathway in RA, but these studies have not been sufficient to elucidate how imbalanced IFN signaling subtly influences immune cells.,Single-cell RNA (scRNA) sequencing makes it possible to better understand the alternations in the interferon signaling pathways in RA.,In the present study, we found that IFN signaling pathways were activated in natural killer (NK) cells, monocytes, T cells, B cells, and most immune cell subclasses in RA.,We then explored and analyzed the connections between abnormal IFN signaling pathways and cellular functional changes in RA.,Single-Cell rEgulatory Network Inference and Clustering (SCENIC) analysis and gene regulatory network (GRN) construction were also performed to identify key transcription factors in RA.,Finally, we also investigated altered IFN signaling pathways in multiple RA peripheral blood samples, which indicated that abnormal IFN signaling pathways were universally observed in RA.,Our study contributes to a better understanding of the delicate and precise regulation of IFN signaling in the immune system in RA.,Furthermore, common alternations in IFN signaling pathway-related transcription factors could help to identify novel therapeutic targets for RA treatment.
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Type I interferon signature is one of the most important features of systemic lupus erythematosus (SLE), which indicates an active immune response to antigen invasion.,Characteristics of type I interferon-stimulated genes (ISGs) in SLE patients have not been well described thus far.,We analyzed 35,842 cells of PBMC single-cell RNA sequencing data of five SLE patients and three healthy controls.,Thereafter, 178 type I ISGs among DEGs of all cell clusters were screened based on the Interferome Database and AUCell package was used for ISGs activity calculation.,To determine whether common ISG features exist in PBMCs and kidneys of patients with SLE, we analyzed kidney transcriptomic data from patients with lupus nephritis (LN) from the GEO database.,MRL/lpr mice model were used to verify our findings.,We found that monocytes, B cells, dendritic cells, and granulocytes were significantly increased in SLE patients, while subsets of T cells were significantly decreased.,Neutrophils and low-density granulocytes (LDGs) exhibited the highest ISG activity.,GO and pathway enrichment analyses showed that DEGs focused on leukocyte activation, cell secretion, and pathogen infection.,Thirty-one common ISGs were found expressed in both PBMCs and kidneys; these ISGs were also most active in neutrophils and LDGs.,Transcription factors including PLSCR1, TCF4, IRF9 and STAT1 were found to be associated to ISGs expression.,Consistently, we found granulocyte infiltration in the kidneys of MRL/lpr mice.,Granulocyte inhibitor Avacopan reduced granulocyte infiltration and reversed renal conditions in MRL/lpr mice.,This study shows for the first time, the use of the AUCell method to describe ISG activity of granulocytes in SLE patients.,Moreover, Avacopan may serve as a granulocyte inhibitor for treatment of lupus patients in the future.
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High-quality epidemiologic data worldwide are needed to improve our understanding of disease risk, support health policy to meet the diverse needs of people with multiple sclerosis (MS) and support advocacy efforts.,The Atlas of MS is an open-source global compendium of data regarding the epidemiology of MS and the availability of resources for people with MS reported at country, regional and global levels.,Country representatives reported epidemiologic data and their sources via survey between September 2019 and March 2020, covering prevalence and incidence in males, females and children, and age and MS type at diagnosis.,Regional analyses and comparisons with 2013 data were conducted.,A total of 2.8 million people are estimated to live with MS worldwide (35.9 per 100,000 population).,MS prevalence has increased in every world region since 2013 but gaps in prevalence estimates persist.,The pooled incidence rate across 75 reporting countries is 2.1 per 100,000 persons/year, and the mean age of diagnosis is 32 years.,Females are twice as likely to live with MS as males.,The global prevalence of MS has risen since 2013, but good surveillance data is not universal.,Action is needed by multiple stakeholders to close knowledge gaps.
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To determine whether there are nuclear depletion and cellular mislocalization of RNA-binding proteins (RBPs) transactivation response DNA-binding protein of 43 kDa (TDP-43), fused in sarcoma (FUS), and polypyrimidine tract-binding protein (PTB) in MS, as is the case in amyotrophic lateral sclerosis (ALS) and oligodendrocytes infected with Theiler murine encephalomyelitis virus (TMEV), we examined MS lesions and in vitro cultured primary human brain-derived oligodendrocytes.,Nuclear depletion and mislocalization of TDP-43, FUS, and PTB are thought to contribute to the pathogenesis of ALS and TMEV demyelination.,The latter findings prompted us to investigate these RBPs in the demyelinated lesions of MS and in in vitro cultured human brain-derived oligodendrocytes under metabolic stress conditions.,We found (1) mislocalized TDP-43 in oligodendrocytes in active lesions in some patients with MS; (2) decreased PTB1 expression in oligodendrocytes in mixed active/inactive demyelinating lesions; (3) decreased nuclear expression of PTB2 in neurons in cortical demyelinating lesions; and (4) nuclear depletion of TDP-43 in oligodendrocytes under metabolic stress induced by low glucose/low nutrient conditions compared with optimal culture conditions.,TDP-43 has been found to have a key role in oligodendrocyte function and viability, whereas PTB is important in neuronal differentiation, suggesting that altered expression and mislocalization of these RBPs in MS lesions may contribute to the pathogenesis of demyelination and neurodegeneration.,Our findings also identify nucleocytoplasmic transport as a target for treatment.
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To address concerns regarding the effect of MS disease-modifying therapies (DMTs) on the expression of coronavirus 2019 (COVID-19).,Review of the current state of knowledge regarding the viral etiology of COVID-19, mechanisms of injury by SARS-CoV-2 infection, and the effect of individual DMTs on the risk of infection and COVID-19 disease expression.,Although data are limited, MS DMTs do not obviously increase the risk of acquiring symptomatic SARS-CoV-2 infection.,The severe morbidity and mortality of SARS-CoV-2 appear to be largely the consequence of an overly robust immune response rather than the consequence of unchecked viral replication.,The effects of specific MS DMTs on the immune response that may increase the risk of impaired viral clearance and their potential counterbalancing beneficial effects on the development of COVID-19-associated acute respiratory distress syndrome are reviewed.,Although there is currently insufficient real-world experience to definitively answer the question of the effect of a specific MS DMT on COVID-19, registries presently in nascent form should provide these answers.,This review provides an approach to addressing these concerns while the data are being accumulated.,Early insights suggest that the risk of infection and associated morbidity of COVID-19 in this population is little different than that of the population at large.
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Ocrelizumab, a humanized monoclonal anti-CD20 antibody, has shown pronounced effects in reduction of disease activity in multiple sclerosis (MS) patients and has recently been approved for the treatment of patients with relapsing MS (RMS) and primary progressive MS (PPMS).,CD20 is mainly expressed by B cells, but a subset of T cells (CD3+CD20+ T cells) also expresses CD20, and these CD20+ T cells are known to be a highly activated cell population.,The blood of MS patients was analyzed with multicolor flow cytometry before and two weeks after treatment with ocrelizumab regarding the phenotype of peripheral blood mononuclear cells.,CD20-expressing CD3+ T cells were found in blood samples of all MS patients, accounted for 2.4% of CD45+ lymphocytes, and constituted a significant proportion (18.4%) of all CD20+ cells.,CD3+CD20+ T cells and CD19+CD20+ B cells were effectively depleted two weeks after a single administration of 300 mg ocrelizumab.,Our results demonstrate that treatment with ocrelizumab does not exclusively target B cells, but also CD20+ T cells, which account for a substantial amount of CD20-expressing cells.,Thus, we speculate that the efficacy of ocrelizumab might also be mediated by the depletion of CD20-expressing T cells.
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Alemtuzumab is a humanized anti-CD52 monoclonal antibody approved in more than 65 countries for the treatment of relapsing-remitting multiple sclerosis (RRMS).,Compared with subcutaneous interferon-beta-1a, alemtuzumab significantly reduced clinical disease activity and the rate of brain volume loss, and improved disability outcomes in patients with active RRMS who were either treatment naive (CARE-MS I study) or who had an inadequate response (≥ 1 relapse after ≥ 6 months of treatment) to prior therapy (CARE-MS II study).,Adverse events (AEs) associated with alemtuzumab include infusion-associated reactions, infections, and autoimmunity.,The most commonly reported autoimmune AEs observed with alemtuzumab involve the thyroid gland, followed by immune thrombocytopenia and nephropathies.,A monitoring program was designed and implemented to facilitate the early detection of autoimmune events to ensure timely and adequate management.,The aim of this article is to provide physicians (including neurologists, general practitioners, endocrinologists, hematologists, and nephrologists who may be less familiar with the symptoms and treatment of autoimmune events), with practical real-world recommendations for the monitoring and management of autoimmunity associated with alemtuzumab treatment.
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The mechanism of action of oral cladribine, recently licensed for relapsing multiple sclerosis, is unknown.,To determine whether cladribine depletes memory B cells consistent with our recent hypothesis that effective, disease-modifying treatments act by physical/functional depletion of memory B cells.,A cross-sectional study examined 40 people with multiple sclerosis at the end of the first cycle of alemtuzumab or injectable cladribine.,The relative proportions and absolute numbers of peripheral blood B lymphocyte subsets were measured using flow cytometry.,Cell-subtype expression of genes involved in cladribine metabolism was examined from data in public repositories.,Cladribine markedly depleted class-switched and unswitched memory B cells to levels comparable with alemtuzumab, but without the associated initial lymphopenia.,CD3+ T cell depletion was modest.,The mRNA expression of metabolism genes varied between lymphocyte subsets.,A high ratio of deoxycytidine kinase to group I cytosolic 5′ nucleotidase expression was present in B cells and was particularly high in mature, memory and notably germinal centre B cells, but not plasma cells.,Selective B cell cytotoxicity coupled with slow repopulation kinetics results in long-term, memory B cell depletion by cladribine.,These may offer a new target, possibly with potential biomarker activity, for future drug development.,The online version of this article (10.1007/s00415-018-8830-y) contains supplementary material, which is available to authorized users.
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Objectives.,To estimate endothelial dysfunction in patients with rheumatoid arthritis (RA) of short duration in relation to disease activity based on the assessment of 28 joints (DAS28).,Methods.,We studied 29 patients (22 women, mean age 41 (SD, 9) years) with RA of short duration and 29 healthy controls.,The RA subjects were divided into those with low (DAS28: 2.6-5.1, n = 18) or high (DAS28 > 5.1, n = 11) disease activity.,Exclusion criteria included clinically overt atherosclerosis and other coexistent diseases.,Biochemical markers of inflammatory activation and endothelial dysfunction were measured.,Results.,There were no significant intergroup differences in the majority of classical cardiovascular risk factors.,High-sensitivity C-reactive protein, tumor necrosis factor-α, and interleukin-6 were increased in RA subjects.,Compared to the controls, levels of soluble vascular cell adhesion molecule-1, von Willebrand factor, and pentraxin-3 were significantly elevated in RA subjects with low disease activity, exhibiting no further significant rises in those with high disease activity.,Asymmetric dimethyl-L-arginine, soluble E-selectin, monocyte chemotactic protein-1, and osteoprotegerin were increased only in RA patients with high disease activity.,Conclusions.,Our findings might suggest a dissociation of pathways governing generalized and joint-specific inflammatory reactions from those involved in endothelial activation and inflammation within the vascular wall.
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Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease (CVD).,One of the earliest manifestations of CVD is endothelial dysfunction (ED).,ED can occur in both the microcirculation and the macrocirculation, and these manifestations might be relatively independent of each other.,Little is known about the association between endothelial function in the microcirculation and the macrocirculation in RA.,The objectives of the present study were to examine the relationship between microvascular and macrovascular endothelial function in patients with RA.,Ninety-nine RA patients (72 females, mean age (± SD) 56 ± 12 years), underwent assessments of endothelial-dependent (acetylcholine) and endothelial-independent (sodium nitroprusside) microvascular vasodilatory function (laser Doppler imaging with iontophoresis), as well as endothelial-dependent (flow-mediated dilation) and endothelial-independent (glyceryl trinitrate-mediated dilation) macrovascular vasodilatory function.,Vasodilatory function was calculated as the percentage increase after each stimulus was applied relative to baseline values.,Pearson correlations showed that microvascular endothelial-dependent function was not associated with macrovascular endothelial-dependent function (r (90 patients) = 0.10, P = 0.34).,Similarly, microvascular endothelial-independent function was not related to macrovascular endothelial-independent function (r (89 patients) = 0.00, P = 0.99).,Microvascular and macrovascular endothelial function were independent of each other in patients with RA, suggesting differential regulation of endothelial function in these two vascular beds.,Assessments of both vascular beds may provide more meaningful clinical information on vascular risk in RA, but this hypothesis needs to be confirmed in long-term prospective studies.
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Rheumatoid arthritis (RA) is classified as seropositive or seronegative, depending on the presence/absence of rheumatoid factor (RF), primarily IgM RF, and/or anti-citrullinated protein antibodies (ACPA), commonly detected using anti-cyclic citrullinated peptide (CCP) assays.,Known risk factors associate with the more severe seropositive form of RA; less is known about seronegative RA.,Here, we examine risk factors and clinical phenotypes in relation to presence of autoantibodies in the RA subset that is traditionally defined as seronegative.,Anti-CCP2 IgG, 19 ACPA fine-specificities, IgM/IgG/IgA RF, anti-carbamylated-protein (CarP) antibodies, and 17 other autoantibodies, were analysed in 2755 RA patients and 370 controls.,Antibody prevalence, levels, and co-occurrence were examined, and associations with risk factors and disease activity during 5 years were investigated for different antibody-defined RA subsets.,Autoantibodies were detected in a substantial proportion of the traditionally defined seronegative RA subset, with ACPA fine-specificities found in 30%, IgA/IgG RF in 9.4%, and anti-CarP antibodies in 16%, with a 9.6% co-occurrence of at least two types of RA-associated autoantibodies.,HLA-DRB1 shared epitope (SE) associated with the presence of ACPA in anti-CCP2-negative RA; in anti-CCP2-positive RA, the SE association was defined by six ACPA fine-specificities with high co-occurrence.,Smoking associated with RF, but not with ACPA, in anti-CCP2-negative RA.,Presence of ACPA and RF, but not anti-CarP antibodies, in conventionally defined “seronegative” RA, associated with worse clinical outcome.,“Seronegative” RA is not truly a seronegative disease subset.,Additional screening for ACPA fine-specificities and IgA/IgG RF defines a group of patients that resembles seropositive patients with respect to risk factors and clinical picture and may contribute to earlier diagnosis for a subset of anti-CCP2−/IgM RF− patients with a high need for active treatment.
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Anticitrullinated peptide antibody (ACPA) responses for 22 citrullinated peptides in patients with early rheumatoid arthritis (RA) were analysed and related to radiological and clinical outcome during the first 2 years in a prospective inception cohort.,The ACPA reactivities were assessed in 1022 patients with early RA (symptoms <12 months) using the custom-made microarray chip (Thermo Fisher Scientific, Uppsala, Sweden) in a prospective longitudinal study of observational assessments of Disease Activity Score (DAS28 and its components) and radiology during the first 24 months, accounting for the treatment.,Frequency of ACPA reactivities varied between 13.3% and 63.1%.,Of the anticyclic citrullinated peptide-2 (anti-CCP2) antibody-negative patients, ACPA reactivities were positive in 32.6%.,Smoking, human leucocyte antigen-shared epitope (HLA-SE), anti-CCP2/rheumatoid factor, protein tyrosine phosphatase non-receptor type 22 (1858C/T) and DAS28 were significantly associated with number of ACPA reactivities.,The ACPA reactivities modified differently the development of DAS28 over 24 months (identified using trajectories).,Anti-Filaggrin307-324, anti-hnRNP (Peptide)-Z1 and anti-F4-CIT-R antibodies anticipated lower DAS28 values (p<0.01-0.05), while positivity for anti-Fibrinogen(Fib)β62-78(74), and anti-Fibα563-583 predicted higher DAS28 (p<0.01 both).,Interaction between anti-Fibß36-52, anti-Pept-5 and anti-Bla-26 antibodies, respectively, and DAS28 during 24 months decreased significantly the DAS28 values (p<0.01-0.05).,Corticosteroids and biologicals were related to DAS28-area under the curve and Larsen score 24 months.,Anti-vimentin2-17 antibodies remained significantly associated with Larsen score at baseline and 24 months, respectively, and radiological progression, besides biologicals at 24 months adjusted for sex and age.,Several ACPA reactivities modified significantly the DAS28 development during the first 24 months and were significantly associated with Larsen score at baseline, 24 months and radiological progression.
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A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG).,To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes.,Retrospective multicenter study.,The sex ratio was 1:2.8 (m:f).,Median age at onset was 31 years (range 6-70).,The disease followed a multiphasic course in 80 % (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40 % (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36 %) and markedly impaired ambulation due to paresis or ataxia (25 %) as the most common long-term sequelae.,Functional blindess in one or both eyes was noted during at least one ON attack in around 70 %.,Perioptic enhancement was present in several patients.,Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70 %).,Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44 %.,Fourty-one percent had a history of simultaneous ON and myelitis.,Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50 %; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one).,CSF pleocytosis (partly neutrophilic) was present in 70 %, oligoclonal bands in only 13 %, and blood-CSF-barrier dysfunction in 32 %.,Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal.,Full recovery was achieved by plasma exchange in some cases, including after IVMP failure.,Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids.,Methotrexate was effective in 5/6 patients.,Interferon-beta was associated with ongoing or increasing disease activity.,Rituximab and ofatumumab were effective in some patients.,However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion.,Coexisting autoimmunity was rare (9 %).,Wingerchuk’s 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28 %, 32 %, 15 %, 33 %, respectively; MS had been suspected in 36 %.,Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases.,Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD.,The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis.
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Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been suggested to play a role in a subset of patients with neuromyelitis optica and related disorders.,To assess (i) the frequency of MOG-IgG in a large and predominantly Caucasian cohort of patients with optic neuritis (ON) and/or myelitis; (ii) the frequency of MOG-IgG among AQP4-IgG-positive patients and vice versa; (iii) the origin and frequency of MOG-IgG in the cerebrospinal fluid (CSF); (iv) the presence of MOG-IgG at disease onset; and (v) the influence of disease activity and treatment status on MOG-IgG titers.,614 serum samples from patients with ON and/or myelitis and from controls, including 92 follow-up samples from 55 subjects, and 18 CSF samples were tested for MOG-IgG using a live cell-based assay (CBA) employing full-length human MOG-transfected HEK293A cells.,MOG-IgG was detected in 95 sera from 50 patients with ON and/or myelitis, including 22/54 (40.7 %) patients with a history of both ON and myelitis, 22/103 (21.4 %) with a history of ON but no myelitis and 6/45 (13.3 %) with a history of longitudinally extensive transverse myelitis but no ON, and in 1 control patient with encephalitis and a connective tissue disorder, all of whom were negative for AQP4-IgG.,MOG-IgG was absent in 221 further controls, including 83 patients with AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and 85 with multiple sclerosis (MS).,MOG-IgG was found in 12/18 (67 %) CSF samples from MOG-IgG-seropositive patients; the MOG-IgG-specific antibody index was negative in all cases, indicating a predominantly peripheral origin of CSF MOG-IgG.,Serum and CSF MOG-IgG belonged to the complement-activating IgG1 subclass.,MOG-IgG was present already at disease onset.,The antibodies remained detectable in 40/45 (89 %) follow-up samples obtained over a median period of 16.5 months (range 0-123).,Serum titers were higher during attacks than during remission (p < 0.0001), highest during attacks of simultaneous myelitis and ON, lowest during acute isolated ON, and declined following treatment.,To date, this is the largest cohort studied for IgG to human full-length MOG by means of an up-to-date CBA.,MOG-IgG is present in a substantial subset of patients with ON and/or myelitis, but not in classical MS.,Co-existence of MOG-IgG and AQP4-IgG is highly uncommon.,CSF MOG-IgG is of extrathecal origin.,Serum MOG-IgG is present already at disease onset and remains detectable in the long-term course.,Serum titers depend on disease activity and treatment status.
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Residual β-cells found at the time of clinical onset of type 1 diabetes are sufficient to control hyperglycemia if rescued from ongoing autoimmune destruction.,The challenge, however, is to develop an immunotherapy that not only selectively suppresses the diabetogenic response and efficiently reverses diabetes, but also establishes long-term β-cell-specific tolerance to maintain remission.,In the current study, we show that a short course of nondepleting antibodies (Abs) specific for the CD4 and CD8 coreceptors rapidly reversed clinical disease in recent-onset diabetic NOD mice.,Once established, remission was maintained indefinitely and immunity to foreign antigens unimpaired.,Induction of remission involved selective T-cell purging of the pancreas and draining pancreatic lymph nodes and upregulation of transforming growth factor (TGF)-β1 by pancreas-resident antigen-presenting cells.,Neutralization of TGF-β blocked the induction of remission.,In contrast, maintenance of remission was associated with tissue-specific immunoregulatory T cells.,These findings demonstrate that the use of nondepleting Ab specific for CD4 and CD8 is a robust approach to establish long-term β-cell-specific T-cell tolerance at the onset of clinical diabetes.
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Erk1/2-dependent TCR decisions, but not negative selection, are impaired in NOD thymocytes, leading to preferential development of αβ CD4+CD8+ thymocytes over γδ thymocytes and saturation of selection niches in TCR tg mouse models.,Based on analyses of multiple TCR transgenic (tg) models, the emergence of pathogenic T cells in diabetes-prone NOD mice has been ascribed to a failure to censure autoreactive clones in the thymus.,In contrast, using isolated and preselected thymocytes, we show that nonobese diabetic (NOD) genetic variation impairs neither clonal deletion nor downstream transcriptional programs.,However, we find that NOD genetic variation influences αβ/γδ-lineage decisions promoted by early expression of tg αβ-TCRs at the double-negative (DN) stage.,In B6 and other genetic backgrounds, tg αβ-TCRs behave like γδ-TCRs and commit a large fraction of DNs toward the γδ-lineage, thereby decreasing the size of the double-positive (DP) pool, which is efficiently positively and negatively selected.,In NOD DNs, αβ-TCR signalosomes instead behave like pre-TCRs, resulting in high numbers of DPs competing for limited selection niches, and poor positive and negative selection.,Once niche effects are neutralized in mixed bone marrow chimeras, positive and negative selection are equally efficient on B6 and NOD backgrounds.,Biochemical analysis revealed a selective defect in the activation of Erk1/2 downstream of NOD αβ-TCR signalosomes.,Therefore, NOD genetic variation influences αβ/γδ-lineage decisions when the αβ-TCR heterodimer is prematurely expressed, but not the process of negative selection.
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Background: Alemtuzumab is a highly effective drug for the treatment of multiple sclerosis (MS), characterized by specific patterns of depletion and repopulation.,As an induction-like treatment concept, two mandatory infusion courses can inhibit long-term disease activity in the majority of patients, and additional courses can successfully manage subsequent re-emergence of disease activity.,Currently, there are no biomarkers to identify patients with re-emergent disease activity requiring retreatment.,Methods: In this study, we systematically characterized 16 MS patients commencing alemtuzumab.,Clinical parameters, MRI and detailed immunoprofiling were conducted every 3 months for up to 84 months.,Results: Alemtuzumab led to significant decrease in clinical disease activity in all evaluated patients.,Nine out of 16 patients presented with no evidence of disease activity (NEDA)-3 up to 84 months (“complete-responder”), while 7 patients demonstrated clinical or/and subclinical MRI disease activity and received alemutzumab retreatment (“partial-responder”).,In both response categories, all T- and B-cell subsets were markedly depleted after alemtuzumab therapy.,In particular, absolute numbers of Th1 and Th17 cells were markedly decreased and remained stable below baseline levels-this effect was particularly pronounced in complete-responders.,While mean cell numbers did not differ significantly between groups, analysis of event-driven immunoprofiling demonstrated that absolute numbers of Th1 and Th17 cells showed a reproducible increase starting 6 months before relapse activity.,This change appears to predict emergent disease activity when compared with stable disease.,Conclusion: Studies with larger patient populations are needed to confirm that frequent immunoprofiling may assist in evaluating clinical decision-making of alemtuzumab retreatment.
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To assess functional changes in lymphocyte repertoire and subsequent clinical implications during delayed-release dimethyl fumarate (DMF) treatment in patients with multiple sclerosis.,Using peripheral blood from several clinical trials of DMF, immune cell subsets were quantified using flow cytometry.,For some patients, lymphocyte counts were assessed after DMF discontinuation.,Incidence of adverse events, including serious and opportunistic infections, was assessed.,In DMF-treated patients, absolute lymphocyte counts (ALCs) demonstrated a pattern of decline followed by stabilization, which also was reflected in the global reduction in numbers of circulating functional lymphocyte subsets.,The relative frequencies of circulating memory T- and B-cell populations declined and naive cells increased.,No increased incidence of serious infection or malignancy was observed for patients treated with DMF, even when stratified by ALC or T-cell subset frequencies.,For patients who discontinued DMF due to lymphopenia, ALCs increased after DMF discontinuation; recovery time varied by ALC level at discontinuation.,T-cell subsets closely correlated with ALCs in both longitudinal and cross-sectional analyses.,DMF shifted the immunophenotype of circulating lymphocyte subsets.,ALCs were closely correlated with CD4+ and CD8+ T-cell counts, indicating that lymphocyte subset monitoring is not required for safety vigilance.,No increased risk of serious infection was observed in patients with low T-cell subset counts.,Monitoring ALC remains the most effective way of identifying patients at risk of subsequently developing prolonged moderate to severe lymphopenia, a risk factor for progressive multifocal leukoencephalopathy in DMF-treated patients.,EUDRA CT 2015-001973-42, NCT00168701, NCT00420212, NCT00451451, and NCT00835770.
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Regulatory T cells (Tregs) are crucial in maintaining tolerance.,Hence, Treg immunotherapy is an attractive therapeutic option in autoimmune diseases and organ transplantations.,Currently, autoimmune diseases do not have a curative treatment and transplant recipients require life-long immunosuppression to prevent graft rejection.,There has been significant progress in understanding polyclonal and antigen-specific Treg biology over the last decade.,Clinical trials with good manufacturing practice (GMP) Treg cells have demonstrated safety and early efficacy of Treg therapy.,GMP Treg cells can also be tracked following infusion.,In order to improve efficacy of Tregs immunotherapy, it is necessary that Tregs migrate, survive and function at the specific target tissue.,Application of antigen specific Tregs and maintaining cells' suppressive function and survival with low dose interleukin-2 (IL-2) will enhance the efficacy and longevity of infused GMP-grade Tregs.,Notably, stability of Tregs in the local tissue can be manipulated by understanding the microenvironment.,With the recent advances in GMP-grade Tregs isolation and antigen-specific chimeric antigen receptor (CAR)-Tregs development will allow functionally superior cells to migrate to the target organ.,Thus, Tregs immunotherapy may be a promising option for patients with autoimmune diseases and organ transplantations in near future.
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Regulatory T cells (Tregs) have important functions in peripheral immune tolerance.,Dysfunction of Tregs is considered to be a pivotal cause of autoimmune diseases, including rheumatoid arthritis (RA).,However, previous reports describing the proportion of Tregs among CD4+ T cells in RA patients were controversial because a range of markers are used to identify Tregs with little consensus.,To clarify the status of Tregs in RA, we investigated the proportion of Tregs with focusing on the definitions of them.,We identified the studies reporting the proportion of Tregs in RA patients using PubMed and Google Scholar.,We performed a systematic review of them and a meta-analysis to evaluate the proportion of Tregs (FOXP3-positive and/or CD25-positive) among CD4+ T cells in peripheral blood (PB) and synovial fluid (SF) of RA patients and control subjects.,A total 31 studies were selected.,The proportion of Tregs defined by all definitions among CD4+ T cells in PB was not significantly different between RA patients and control subjects (-0.65, [-1.30, 0.01]).,Then we performed sub-analyses based on individual definitions.,The proportion of Tregs defined by either CD25 or FOXP3 alone did not differ between RA patients and control subjects.,The proportion of Tregs defined by both FOXP3 and CD25 was lower in RA patients than that in control subjects (-2.42 [-3.49, -1.34]).,The proportion of Tregs defined by both FOXP3 and CD25 was higher in SF than that in PB among RA patients (3.27 [0.40, 6.14]).,The status of Tregs varied according to the definition system.,The proportion of Tregs defined by stricter and functionally validated methods decreased in PB and increased in SF among RA patients.,If the proportion of Tregs differs in RA, accurate and functionally relevant definitions of Tregs are necessary to elucidate their status in RA.
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Adult‐onset Still’s disease (AOSD) is a severe autoinflammatory disease.,Neutrophil activation with enhanced neutrophil extracellular trap (NET) formation is involved in the pathogenesis of AOSD.,Functional leukocyte immunoglobulin‐like receptor A3 (LIR‐A3; gene name LILRA3) has been reported to be associated with many autoimmune diseases.,We aimed to investigate the association of LILRA3 with disease susceptibility and neutrophil activation in AOSD.,The LILRA3 deletion polymorphism and its tagging single‐nucleotide polymorphism rs103294 were genotyped in 164 patients with AOSD and 305 healthy controls.,The impact of LILRA3 on clinical features and messenger RNA expression was evaluated.,Plasma levels of LIR‐A3 were detected using enzyme‐linked immunosorbent assay (ELISA), and the correlation between LIR‐A3 plasma levels and disease activity and levels of circulating NET‐DNA was investigated.,LIR‐A3-induced NETs were determined using PicoGreen double‐stranded DNA dye and immunofluorescence analysis in human neutrophils and a neutrophil‐like differentiated NB4 cell line transfected with LIR‐B2 small interfering RNA.,The findings from genotyping demonstrated that functional LILRA3 was a risk factor for AOSD (11% in AOSD patients versus 5.6% in healthy controls; odds ratio 2.089 [95% confidence interval 1.030-4.291], P = 0.034), and associated with leukocytosis (P = 0.039) and increased levels of circulating neutrophils (P = 0.027).,Functional LILRA3 messenger RNA expression was higher in the peripheral blood mononuclear cells (P < 0.0001) and neutrophils (P < 0.001) of LILRA3 +/+ patients.,Plasma levels of LIR‐A3 were elevated in patients with AOSD (P < 0.0001) and correlated with disease activity indicators and levels of circulating NET-DNA complexes.,Finally, enhanced NET formation was identified in neutrophils from healthy controls and patients with inactive AOSD after stimulation of the neutrophils with LIR‐A3.,Moreover, NET formation was impaired in NB4 cells after knockdown of LILRB2 gene expression.,Our study provides the first evidence that functional LILRA3 is a novel genetic risk factor for the development of AOSD and that functional LIR‐A3 may play a pathogenic role by inducing formation of NETs.
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GM-CSF is a potential therapeutic target in inflammation and autoimmunity.,This study reviews the literature on the biology of GM-CSF, in particular that describing the research leading to clinical trials targeting GM-CSF and its receptor in numerous inflammatory/autoimmune conditions, such as rheumatoid arthritis.,Granulocyte-macrophage colony-stimulating factor (GM-CSF) has many more functions than its original in vitro identification as an inducer of granulocyte and macrophage development from progenitor cells.,Key features of GM-CSF biology need to be defined better, such as the responding and producing cell types, its links with other mediators, its prosurvival versus activation/differentiation functions, and when it is relevant in pathology.,Significant preclinical data have emerged from GM-CSF deletion/depletion approaches indicating that GM-CSF is a potential target in many inflammatory/autoimmune conditions.,Clinical trials targeting GM-CSF or its receptor have shown encouraging efficacy and safety profiles, particularly in rheumatoid arthritis.,This review provides an update on the above topics and current issues/questions surrounding GM-CSF biology.
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Interferon-alpha (IFN-α) has immunoregulatory functions in autoimmune inflammatory diseases.,The goal of this study was to determine occurrence and clinical consequences of IFN-α in neuromyelitis optica (NMO) patients.,Thirty-six NMO and 41 multiple sclerosis (MS) patients from a population-based retrospective case series were included.,Expanded Disability Status Scale (EDSS) score and MRI findings determined disease activity.,Linear regression was used to assess the effects of the level of IFN-α on disability (EDSS).,IFN-α was determined by sensitive ELISA assays.,IFN-α was detectable in sera from 9/36 NMO patients, significantly more often than in the MS group (2/41) (P = 0.0197).,A higher frequency of IFN-α was observed in NMO patients with acute relapse compared to NMO patients in remission (P < 0.001) and compared to the MS patients with relapse (P = 0.010).,In NMO patients, the levels of IFN-α were significantly associated with EDSS (P = 0.0062).,It may be concluded that IFN-α was detectable in a subgroup of NMO patients.,Association of IFN-α levels with clinical disease activity and severity suggests a role for IFN-α in disease perpetuation and may provide a plausible explanation for a negative effect of IFN-1 treatment in NMO patients.
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Neuromyelitis optica (NMO) is a severe, disabling disease of the central nervous system (CNS) characterized by the formation of astrocyte-destructive, neutrophil-dominated inflammatory lesions in the spinal cord and optic nerves.,These lesions are initiated by the binding of pathogenic aquaporin 4 (AQP4)-specific autoantibodies to astrocytes and subsequent complement-mediated lysis of these cells.,Typically, these lesions form in a setting of CNS inflammation, where the blood-brain barrier is open for the entry of antibodies and complement.,However, it remained unclear to which extent pro-inflammatory cytokines and chemokines contribute to the formation of NMO lesions.,To specifically address this question, we injected the cytokines interleukin-1 beta, tumor necrosis factor alpha, interleukin-6, interferon gamma and the chemokine CXCL2 into the striatum of NMO-IgG seropositive rats and analyzed the tissue 24 hours later by immunohistochemistry.,All injected cytokines and chemokines led to profound leakage of immunoglobulins into the injected hemisphere, but only interleukin-1 beta induced the formation of perivascular, neutrophil-infiltrated lesions with AQP4 loss and complement-mediated astrocyte destruction distant from the needle tract.,Treatment of rat brain endothelial cells with interleukin-1 beta, but not with any other cytokine or chemokine applied at the same concentration and over the same period of time, caused profound upregulation of granulocyte-recruiting and supporting molecules.,Injection of interleukin-1 beta caused higher numbers of blood vessels with perivascular, cellular C1q reactivity than any other cytokine tested.,Finally, the screening of a large sample of CNS lesions from NMO and multiple sclerosis patients revealed large numbers of interleukin-1 beta-reactive macrophages/activated microglial cells in active NMO lesions but not in MS lesions with comparable lesion activity and location.,Our data strongly suggest that interleukin-1 beta released in NMO lesions and interleukin-1 beta-induced production/accumulation of complement factors (like C1q) facilitate neutrophil entry and BBB breakdown in the vicinity of NMO lesions, and might thus be an important secondary factor for lesion formation, possibly by paving the ground for rapid lesion growth and amplified immune cell recruitment to this site.
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Epidemiological studies indicate a high risk of stroke, heart failure and myocardial infarction in patients with multiple sclerosis, especially in its secondary progressive (SPMS) phase.,Some ischaemic events are directly associated with abnormal platelet functions and their prothrombotic activity.,Recent reports, including this study, confirm the increased activation of circulating platelets in SPMS, and also show increased platelet reactivity, among other responses, as well as strong aggregation.,In this current study, we conducted a comparative analysis of the platelet proteome in SPMS patients and in healthy controls, to demonstrate the quantitative and qualitative differences likely to affect functional changes observed in SPMS.,During densitometry evaluation of 2‐D fluorescence difference gel electrophoresis, we observed differences between the electrophoretic patterns of SPMS platelets and the control samples.,To determine a detailed characterisation of the proteome changes in the SPMS patients’ blood platelets, in the next stage, we performed mass spectrometry of selected spots and indicated the increased presence of four proteins (fibrinogen, α‐2 macroglobulin, septin‐14 and tubulin β‐1 chain).,The most important of these is the increased amount of prothrombotic protein, fibrinogen, which seems to confirm the accuracy of the imaging and potentially explains the increased risk of platelet‐origin thrombotic events.,This study provides new knowledge of the potential existence of the molecular mechanisms responsible for the acceleration of the platelet pro‐coagulant function in SPMS.,This can help to identify new targets for therapy, which can then be used not only in the second stage of the disease.
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Inflammatory demyelinating diseases of the CNS comprise a broad spectrum of diseases like neuromyelitis optica (NMO), NMO spectrum disorders (NMO-SD) and multiple sclerosis (MS).,Despite clear classification criteria, differentiation can be difficult.,We hypothesized that the urine proteome may differentiate NMO from MS.,The proteins in urine samples from anti-aquaporin 4 (AQP4) seropositive NMO/NMO-SD patients (n = 32), patients with MS (n = 46) and healthy subjects (HS, n = 31) were examined by quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) after trypsin digestion and iTRAQ labelling.,Immunoglobulins (Ig) in the urine were validated by nephelometry in an independent cohort (n = 9-10 pr. groups).,The analysis identified a total of 1112 different proteins of which 333 were shared by all 109 subjects.,Cluster analysis revealed differences in the urine proteome of NMO/NMO-SD compared to HS and MS.,Principal component analysis also suggested that the NMO/NMO-SD proteome profile was useful for classification.,Multivariate regression analysis revealed a 3-protein profile for the NMO/NMO-SD versus HS discrimination, a 6-protein profile for NMO/NMO-SD versus MS discrimination and an 11-protein profile for MS versus HS discrimination.,All protein panels yielded highly significant ROC curves (AUC in all cases >0.85, p≤0.0002).,Nephelometry confirmed the presence of increased Ig-light chains in the urine of patients with NMO/NMO-SD.,The urine proteome profile of patients with NMO/NMO-SD is different from MS and HS.,This may reflect differences in the pathogenesis of NMO/NMO-SD versus MS and suggests that urine may be a potential source of biomarkers differentiating NMO/NMO-SD from MS.
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To identify lymphocyte and CD4 + T cell subset characteristics, particularly regulatory T cells (Tregs), in active rheumatoid arthritis (RA) patients with coronary artery disease (CAD).,A total of 54 RA patients with CAD (RA-CAD group), 43 RA patients without CAD (pure RA group), and 43 healthy controls (HC group) were enrolled.,The absolute number and frequency of lymphocyte subpopulations and CD4 + T cell subsets were analyzed by flow cytometry.,Serum levels of cytokines were analyzed using a cytometric bead array.,Clinical and laboratory data were collected retrospectively and their correlation with CD4 + T subsets were analyzed.,There was a significant decrease in the absolute number of Treg cells (CD4 + CD25 + Foxp3 + T cells) in the RA-CAD group compared to the pure RA group (p < 0.001).,Similarly, both the absolute number (p = 0.001) and frequency (p = 0.011) of Tregs in the RA-CAD group were decreased compared to the HCs, causing a Th17/Treg imbalance (p = 0.044).,No difference was found in the absolute number and frequency of Treg cells between the pure RA and HC groups.,However, the absolute Th17 cell count was increased in the pure RA group (p = 0.032).,The serum level of cytokine IL-17 was lower in the RA-CAD group than in the pure RA group (p = 0.023).,In the RA-CAD group, the Treg number was negatively correlated with the RA disease activity score and ESR value, and LDL and ApoB100 levels were negatively correlated with the number of Th17 cells.,Active RA patients with CAD sustain more severe immune tolerance damage and Th17/Treg disorder.,Monitoring of lymphocyte and CD4 + T cell subsets, particularly Treg cells, is crucial to understanding immune status in this group.,Focusing on RA activity and CAD risk control, immune-regulatory therapy based on the Treg level may be more beneficial for RA patients with CAD.,The online version contains supplementary material available at 10.1186/s12865-021-00466-0.
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Type 1 diabetes (T1D) is an organ-specific autoimmune disease, whereby immune cell-mediated killing leads to loss of the insulin-producing β cells in the pancreas.,Genome-wide association studies (GWAS) have identified over 200 genetic variants associated with risk for T1D.,The majority of the GWAS risk variants reside in the non-coding regions of the genome, suggesting that gene regulatory changes substantially contribute to T1D.,However, identification of causal regulatory variants associated with T1D risk and their affected genes is challenging due to incomplete knowledge of non-coding regulatory elements and the cellular states and processes in which they function.,Here, we performed a comprehensive integrated post-GWAS analysis of T1D to identify functional regulatory variants in enhancers and their cognate target genes.,Starting with 1,817 candidate T1D SNPs defined from the GWAS catalog and LDlink databases, we conducted functional annotation analysis using genomic data from various public databases.,These include 1) Roadmap Epigenomics, ENCODE, and RegulomeDB for epigenome data; 2) GTEx for tissue-specific gene expression and expression quantitative trait loci data; and 3) lncRNASNP2 for long non-coding RNA data.,Our results indicated a prevalent enhancer-based immune dysregulation in T1D pathogenesis.,We identified 26 high-probability causal enhancer SNPs associated with T1D, and 64 predicted target genes.,The majority of the target genes play major roles in antigen presentation and immune response and are regulated through complex transcriptional regulatory circuits, including those in HLA (6p21) and non-HLA (16p11.2) loci.,These candidate causal enhancer SNPs are supported by strong evidence and warrant functional follow-up studies.
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Accumulating neurological disability has a substantial impact on the lives of patients with multiple sclerosis (MS).,As well as the established Expanded Disability Status Scale (EDSS), several other outcome measures are now available for assessing disability progression in MS.,This review extends the findings of a previous analysis of relapsing-remitting MS (RRMS) trials published up to 2012, to determine whether there has been a shift in outcome measures used to assess disability in phase III clinical trials in RRMS and progressive MS.,Forty relevant trials were identified (RRMS, n = 16; progressive MS, n = 18; other/mixed phenotypes, n = 6).,Sustained EDSS worsening, particularly over 3 months, was included as an endpoint in almost all identified trials.,Other disability-related endpoints included the Multiple Sclerosis Functional Composite z-score and scores for the physical component summary of the Multiple Sclerosis Impact Scale and Medical Outcomes Study Short-Form (36-item) Health Survey.,Tests assessing manual dexterity, ambulation, vision and cognition were also employed, and in some trials, composite endpoints were used.,However, there was no obvious trend in choice of disability outcome measures over time.,Sustained EDSS worsening over short time periods continues to be the most widely used measure of disability progression in pivotal MS trials, despite its well-recognised limitations.,A new tool set is needed for use in MS clinical trials that detects the benefit of potential treatments that slow (or reverse) progressive disability.,The online version of this article (10.1007/s40263-018-0530-8) contains supplementary material, which is available to authorized users.
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The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) includes representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with multiple sclerosis (MS).,One of the MSOAC goals is acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful in MS.,This article addresses the history, application, and psychometric properties of one such MSOAC metric of ambulation or walking namely, the timed 25-foot walk (T25FW).,The T25FW has strong reliability over both brief and long periods of time in MS across a large range of disability levels.,The outcome of walking speed from the T25FW has obvious real-world relevance and has correlated strongly with other measures of walking and lower extremity function.,The T25FW is responsive for capturing intervention effects in pharmacological and rehabilitation trials and has an established value for capturing clinically meaningful change in ambulation.,Directions for future research involve validating clinically meaningful improvements on the T25FW as well as determining whether 20% change is clinically meaningful across the disability spectrum.,Researchers might further consider synchronizing accelerometers and motion sensors with the T25FW for capturing walking speed in everyday life and the patient’s real environment.
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To compare 2‐year effectiveness and discontinuation of natalizumab (NTZ) versus fingolimod (FTY) and dimethyl fumarate (DMF) in the treatment of multiple sclerosis (MS).,Patients prescribed NTZ, FTY, or DMF at the Rocky Mountain MS Center at University of Colorado were identified.,Clinician‐reported data were retrospectively collected.,Outcomes include a composite effectiveness measure consisting of new T2 lesion, gadolinium‐enhancing lesion, and/or clinical relapse, individual effectiveness outcomes and discontinuation over 2 years.,Logistic regression was used for data analysis on patients matched by propensity scores and using ATT doubly robust weighting estimator.,A total of 451, 271, and 342 patients were evaluated on NTZ, FTY, and DMF over 2 years, respectively.,Patients had a mean age of 39.8 (NTZ), 42.5(FTY), and 45.8 (DMF) years; were predominantly female (76.7% NTZ; 72.0% FTY; 69.6% DMF); and had a mean MS disease duration of 11-12 years for all groups.,At ≤24 months, 22.2%, 34.7%, and 33.6% experienced a new T2 lesion, gadolinium‐enhancing lesion, and/or clinical relapse on NTZ, FTY, and DMF, respectively.,Using ATT doubly robust weighting estimator, FTY versus NTZ and DMF versus NTZ had an odds ratio of 2.00 (95%CI:[1.41-2.85], P < 0.001) and 2.38 [95% CI: 1.68-3.37], P < 0.001) respectively, for experiencing a new T2 lesion, gadolinium enhancing lesion, and/or clinical relapse.,At ≤24 months, 32.6%, 34.3%, and 47.1% discontinued NTZ, FTY, and DMF, respectively.,The majority of discontinuations were due to becoming JCV positive(12.6%) for NTZ and due to adverse events for both FTY(17%) and DMF(24.0%).,NTZ appears to be more effective and tolerable than FTY and DMF.
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Adherence to disease-modifying therapies (DMTs) results in the reduction of the number and severity of relapses and delays the progression of multiple sclerosis (MS).,Patients with lower adherence rates experience more inpatient visits and higher MS-related medical costs.,Fingolimod, the first oral DMT approved by the US Food and Drug Administration, may improve the access and compliance to MS treatment when compared to injectable DMTs.,This retrospective cohort study used pharmacy claims from Medco Health Solutions, Inc., of patients who initiated DMTs between October 2010 and February 2011.,Initiation was defined as no prescription fills for the same DMT in the prior 12 months.,Patients without a DMT prescription fill 12 months before the index date were considered naïve users.,Compliance was measured via proportion of days covered (PDC) and medication possession ratio (MPR) for 12 months post-index.,Discontinuation was defined as a ≥60-day gap of index DMT supply.,Cox proportional hazard models compared time to discontinuation between cohorts.,Of 1,891 MS patients (mean age: 45.7; female: 76.4%), 13.1% initiated fingolimod, 10.7% interferon beta-1b, 20.0% intramuscular interferon beta-1a, 18.8% subcutaneous interferon beta-1a, and 37.4% glatiramer acetate.,Patients initiating fingolimod had highest average PDC and MPR in both experienced (fingolimod: mean PDC=0.83, 73.7% with PDC≥0.8; mean MPR=0.92, 90.5% with MPR≥0.8) and naïve DMT users (fingolimod: mean PDC=0.80, 66.7% with PDC≥0.8; mean MPR=0.90, 87.4% with MPR≥0.8).,The proportion of patients discontinuing index DMT within 12 months was significantly lower for the fingolimod cohort (naïve: 31.3%; experienced: 25.7%).,Adjusted results found that patients receiving self-injected DMTs discontinued significantly sooner than fingolimod users.,This association was generally stronger in experienced DMT users.,Fingolimod initiators were more compliant, less likely to discontinue treatment, and discontinued later than patients who initiated self-injected DMT.
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Monocytes (Mo) and macrophages (Mϕ) are key components of the innate immune system and are involved in regulation of the initiation, development, and resolution of many inflammatory disorders.,In addition, these cells also play important immunoregulatory and tissue-repairing roles to decrease immune reactions and promote tissue regeneration.,Several lines of evidence have suggested a causal link between the presence or activation of these cells and the development of autoimmune diseases.,In addition, Mo or Mϕ infiltration in diseased tissues is a hallmark of several autoimmune diseases.,However, the detailed contributions of these cells, whether they actually initiate disease or perpetuate disease progression, and whether their phenotype and functional alteration are merely epiphenomena are still unclear in many autoimmune diseases.,Additionally, little is known about their heterogeneous populations in different autoimmune diseases.,Elucidating the relevance of Mo and Mϕ in autoimmune diseases and the associated mechanisms could lead to the identification of more effective therapeutic strategies in the future.
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Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory arthropathy associated with articular damage and attendant comorbidities.,Even although RA treatment has advanced remarkably over the last decade, a significant proportion of patients still do not achieve sustained remission.,The cause of RA is not yet known despite the many potential mechanisms proposed.,It has been confirmed that RA is associated with dysregulated immune system and persistent inflammation.,Therefore, management of inflammation is always the target of therapy.,Sinomenine (SIN) is the prescription drug approved by the Chinese government for RA treatment.,A previous study found that SIN was a robust anti-inflammation drug.,In this study, we screened the different secretory cytokines using inflammation antibody arrays and qRT-PCR in both LPS-induced and SIN-treated RAW264.7 cells followed by evaluation of the ability of SIN to modulate cytokine secretion in a cell model, collagen-induced arthritis (CIA) mouse model, and RA patients.,Several clinical indexes affecting the 28-joint disease activity score (DAS28) were determined before and after SIN treatment.,Clinical indexes, inflammatory cytokine secretion, and DAS28 were compared among RA patients treated with either SIN or methotrexate (MTX).,To explore the mechanism of SIN anti-inflammatory function, RA-associated monocyte/macrophage subsets were determined using flow cytometry in CIA mouse model and RA patients, both treated with SIN.,The results demonstrated that SIN regulated IL-6, GM-CSF, IL-12 p40, IL-1α, TNF-α, IL-1β, KC (CXCL1), Eotaxin-2, IL-10, M-CSF, RANTES, and MCP-1 secretion in vivo and in vitro and reduced RA activity and DAS28 in a clinical setting.,Furthermore, SIN attenuated CD11b+F4/80+CD64+ resident macrophages in the synovial tissue, CD11b+Ly6C+CD43+ macrophages in the spleen and draining lymph nodes of CIA mice.,The percentage of CD14+CD16+ peripheral blood mononuclear cells was reduced by SIN in RA patients.,These data indicated that SIN regulates the secretion of multiple inflammatory cytokines and monocyte/macrophage subsets, thereby suppressing RA progression.,Therefore, along with MTX, SIN could be an alternative cost-effective anti-inflammatory agent for treating RA.
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Macrophages maintain a dynamic balance in physiology.,Various known or unknown microenvironmental signals influence the polarization, activation and death of macrophages, which creates an imbalance that leads to disease.,Rheumatoid arthritis (RA) is characterized by the massive infiltration of a variety of chronic inflammatory cells in synovia.,Abundant activated macrophages found in RA synovia are an early hallmark of RA, and the number of these macrophages can be decreased after effective treatment.,In RA, the proportion of M1 (pro‐inflammatory macrophages) is higher than that of M2 (anti‐inflammatory macrophages).,The increased pro‐inflammatory ability of macrophages is related to their excessive activation and proliferation as well as an enhanced anti‐apoptosis ability.,At present, there are no clinical therapies specific to macrophages in RA.,Understanding the mechanisms and functional consequences of the heterogeneity of macrophages will aid in confirming their potential role in inflammation development.,This review will outline RA‐related macrophage properties (focus on polarization, metabolism and apoptosis) as well as the origin of macrophages.,The molecular mechanisms that drive macrophage properties also be elucidated to identify novel therapeutic targets for RA and other autoimmune disease.
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Background: The risk of rheumatoid arthritis (RA) has been associated with living near traffic; however, there is evidence suggesting that air pollution may not be responsible for this association.,Noise, another traffic-generated exposure, has not been studied as a risk factor for RA.,Objectives: We investigated proximity to traffic, ambient air pollution, and community noise in relation to RA in the Vancouver and Victoria regions of British Columbia, Canada.,Methods: Cases and controls were identified in a cohort of adults that was assembled using health insurance registration records.,Incident RA cases from 1999 through 2002 were identified by diagnostic codes in combination with prescriptions and type of physician (e.g., rheumatologist).,Controls were matched to RA cases by age and sex.,Environmental exposures were assigned to each member of the study population by their residential postal code(s).,We estimated relative risks using conditional logistic regression, with additional adjustment for median income at the postal code.,Results: RA incidence was increased with proximity to traffic, with an odds ratio (OR) of 1.37 (95% CI: 1.11, 1.68) for residence ≤ 50 m from a highway compared with residence > 150 m away.,We found no association with traffic-related exposures such as PM2.5, nitrogen oxides, or noise.,Ground-level ozone, which was highest in suburban areas, was associated with an increased risk of RA (OR = 1.26; 95% CI: 1.18, 1.36 per interquartile range increase).,Conclusions: Our study confirms a previously observed association of RA risk with proximity to traffic and suggests that neither noise levels nor traffic-related air pollutants are responsible for this relationship.,Additional investigation of neighborhood and individual correlates of residence near roadways may provide new insight into risk factors for RA.,Citation: De Roos AJ, Koehoorn M, Tamburic L, Davies HW, Brauer M.,2014.,Proximity to traffic, ambient air pollution, and community noise in relation to incident rheumatoid arthritis.,Environ Health Perspect 122:1075-1080; http://dx.doi.org/10.1289/ehp.1307413
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Methotrexate (MTX) is the first line treatment of rheumatoid arthritis (RA), and methylation changes in bulk T cells have been reported after treatment with MTX.,We have investigated cell-type specific DNA methylation changes across the genome in naïve and memory CD4+ T cells before and after MTX treatment of RA patients.,DNA methylation profiles of newly diagnosed RA patients (N=9) were assessed by reduced representation bisulfite sequencing.,We found that MTX treatment significantly influenced DNA methylation levels at multiple CpG sites in both cell populations.,Interestingly, we identified differentially methylated sites annotated to two genes; TRIM15 and SORC2, previously reported to predict treatment outcome in RA patients when measured in bulk T cells.,Furthermore, several of the genes, including STAT3, annotated to the significant CpG sites are relevant for RA susceptibility or the action of MTX.,We detected CpG sites that were associated with MTX treatment in CD4+ naïve and memory T cells isolated from RA patients.,Several of these sites overlap genetic regions previously associated with RA risk and MTX treatment outcome.
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Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease.,Joint inflammation of RA is closely related to infiltration of immune cells, synovium hyperplasia, and superfluous secretion of proinflammatory cytokines, which lead to cartilage degradation and bone erosion.,The joint synovium of RA patients contains a variety of immune cellular types, among which monocytes/macrophages and T cells are two essential cellular components.,Monocytes/macrophages can recruit and promote the differentiation of T cells into inflammatory phenotypes in RA synovium.,Similarly, different subtypes of T cells can recruit monocytes/macrophages and promote osteoblast differentiation and production of inflammatory cytokines.,In this review, we will discuss how T cell-monocyte/macrophage interactions promote the development of RA, which will provide new perspectives on RA pathogenesis and the development of targeted therapy.
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Variation in methotrexate (MTX) efficacy represents a significant barrier to early and effective disease control in the treatment of autoimmune arthritis.,We hypothesize that the utilization of metabolomic techniques will allow for an improved understanding of the biochemical basis for the pharmacological activity of MTX, and can promote the identification and evaluation of novel molecular biomarkers of MTX response.,In this work, erythroblastoid cells were exposed to MTX at the physiologic concentration of 1,000 nM and analyzed using three metabolomic platforms to give a broad spectrum of cellular metabolites.,MTX pharmacological activity, defined as cellular growth inhibition, was associated with an altered cellular metabolomic profile based on the analysis of 724 identified metabolites.,By discriminant analysis, MTX treatment was associated with increases in ketoisovaleric acid, fructose, galactose, and 2‐deoxycytidine, and corresponding reductions in 2‐deoxyuridine, phosphatidylinositol 32:0, orotic acid, and inosine monophosphate.,Inclusion of data from analysis of folate metabolism in combination with chemometric and metabolic network analysis demonstrated that MTX treatment is associated with dysregulated folate metabolism and nucleotide biosynthesis, which is in line with its known mechanism of action.,However, MTX treatment was also associated with alterations in a diversity of metabolites, including intermediates of amino acid, carbohydrate, and lipid metabolism.,Collectively, these findings support a robust metabolic response following exposure to physiologic concentrations of MTX.,They also identify various metabolic intermediates that are associated with the pharmacological activity of MTX, and are, therefore, potential molecular biomarker candidates in future preclinical and clinical studies of MTX efficacy in autoimmune arthritis.
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The diagnosis of rheumatoid arthritis (RA) is based on a combined approach that includes serological markers such as rheumatoid factor (RF) and anti-citrullinated peptide/protein antibodies (ACPA).,The goal of this study was to evaluate the clinical performance of several RF and ACPA immunoassays for the diagnosis of RA, as well as the diagnostic value of a combinatory approach with these markers.,The study cohort included 1,655 patients from the Swiss Clinical Quality Management registry with sera from 968 patients with RA and 687 disease controls, including patients with axial spondyloarthritis (n = 450) and psoriatic arthritis (n = 237).,ACPA were determined by anti-CCP2 IgG enzyme-linked immunosorbent assay (ELISA), QUANTA Flash® CCP3 IgG [chemiluminescent immunoassay (CIA)], and QUANTA Lite® CCP3 IgG ELISA.,RF was determined by ELISA (QUANTA Lite® RF IgM, RF IgA, and RF IgG) and with two research use only CIAs (QUANTA Flash® RF IgM and RF IgA).,All three ACPA assays showed good discrimination between RA patients and controls and good clinical performance.,Overall, CCP3 performed better than CCP2.,More pronounced differences were observed between the RF assays.,We observed that CIA platforms for both RF IgM and RF IgA showed better performance than the ELISA platforms.,Excellent and good total agreements were found between ELISA and CIA for CCP3 (total agreement 95.3%, kappa = 0.90), and between CCP2 and CCP3 ELISA (total agreement 86.6%, kappa = 0.73), respectively.,RF IgM CIA and ELISA had a good qualitative agreement (86.5%, kappa = 0.73); RF IgA CIA and ELISA showed a moderate total agreement (78.5%, kappa = 0.53).,When combinatory analyses were performed, the likelihood of RA increased with dual positivity and triple positivity and combining different markers resulted in higher odds ratio than the individual markers in all cases.,ACPA and RF showed good clinical performance in this large Swiss cohort of RA patients and controls.,Overall, the performance of CCP3 was superior to CCP2.,The combination of these biomarkers in an interval model represents a potential tool for the diagnosis of RA patients.
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The rheumatology field is moving towards identifying individuals with an increased risk for rheumatoid arthritis (RA) at a stage when arthritis is still absent but persons having clinically suspect arthralgia (CSA).,Incorporating patients’ views in rheumatologic care is pivotal; however, the views of persons with CSA on their condition are unknown.,We aimed to help fill this gap by exploring illness perceptions of persons with CSA and their views on hypothetical prognoses for developing RA.,Persons with CSA were invited to participate in a semi-structured focus group discussion.,Illness perceptions according to the Common Sense Model (CSM) and four a priori formulated themes were explored in detail during the group discussion.,The discussion was audio-taped and transcribed verbatim.,Transcripts were analysed in an interpretative phenomenological approach manner, on the basis of the dimensions of the CSM by three researchers independently.,The views of four participants with CSA were explored during one focus group discussion.,Four dimensions of the CSM were mainly observed: Identity, Consequences, Personal Control and Concern.,None of the patients identified themselves as being a patient.,They did experience pain and impairments in daily functioning and were concerned that their symptoms would progress.,In the absence of physician-initiated treatment, some patients changed lifestyle in order to reduce pain and to promote health.,Patients unanimously said that they could not interpret prognostic information on RA development expressed in hypothetical chances.,Persons with CSA do not consider themselves patients.,Prognostic information related to the development of RA based on risk percentages was considered as not useful by persons with CSA.,Understanding of the illness perceptions of persons with CSA by health care professionals might improve medical management and facilitate shared decision-making.
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Early therapy improves outcomes in rheumatoid arthritis (RA).,It is therefore important to improve predictive algorithms for RA in early disease.,This study evaluated musculoskeletal ultrasound, a sensitive tool for the detection of synovitis and erosions, as a predictor of outcome in very early synovitis.,58 patients with clinically apparent synovitis of at least one joint and symptom duration of ≤3 months underwent clinical, laboratory, radiographic and 38 joint ultrasound assessments and were followed prospectively for 18 months, determining outcome by 1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism criteria.,Sensitivity and specificity for 1987 RA criteria were determined for ultrasound variables and logistic regression models were then fitted to evaluate predictive ability over and above the Leiden rule.,16 patients resolved, 13 developed non-RA persistent disease and 29 developed RA by 1987 criteria.,Ultrasound demonstrated subclinical wrist, elbow, knee, ankle and metatarsophalangeal joint involvement in patients developing RA.,Large joint and proximal interphalangeal joint ultrasound variables had poor predictive ability, whereas ultrasound erosions lacked specificity.,Regression analysis demonstrated that greyscale wrist and metacarpophalangeal joint involvement, and power Doppler involvement of metatarsophalangeal joints provided independently predictive data.,Global ultrasound counts were inferior to minimal power Doppler counts, which significantly improved area under the curve values from 0.905 to 0.962 combined with the Leiden rule.,In a longitudinal study, extended ultrasound joint evaluation significantly increased detection of joint involvement in all regions and outcome groups.,Greyscale and power Doppler scanning of metacarpophalangeal joints, wrists and metatarsophalangeal joints provides the optimum minimal ultrasound data to improve on clinical predictive models for RA.
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Rheumatoid arthritis (RA) is a long-term autoimmune disease of unknown etiology that leads to progressive joint destruction and ultimately to disability.,RA affects as much as 1% of the population worldwide.,To date, RA is not a curable disease, and the mechanisms responsible for RA development have not yet been well understood.,The development of more effective treatments and improvements in the early diagnosis of RA is direly needed to increase patients’ functional capacity and their quality of life.,As opposed to genetic mutation, epigenetic changes, such as DNA methylation, are reversible, making them good therapeutic candidates, modulating the immune response or aggressive synovial fibroblasts (FLS-fibroblast-like synoviocytes) activity when it is necessary.,It has been suggested that DNA methylation might contribute to RA development, however, with insufficient and conflicting results.,Besides, recent studies have shown that circulating cell-free methylated DNA (ccfDNA) in blood offers a very convenient, non-invasive, and repeatable “liquid biopsy”, thus providing a reliable template for assessing molecular markers of various diseases, including RA.,Thus, epigenetic therapies controlling autoimmunity and systemic inflammation may find wider implications for the diagnosis and management of RA.,In this review, we highlight current challenges associated with the treatment of RA and other autoimmune diseases and discuss how targeting DNA methylation may improve diagnostic, prognostic, and therapeutic approaches.
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To assess the incidence of anti-drug antibodies (ADA) in patients with rheumatoid arthritis (RA) treated with the TNF inhibitors etanercept (ETN), adalimumab (ADL), or infliximab (IFX), and determine the potential relationship with trough drug concentration, efficacy, and patient-reported outcomes.,This multi-national, non-interventional, cross-sectional study (NCT01981473) enrolled adult patients with RA treated continuously for 6-24 months with ETN, ADL, or IFX.,ADA and trough drug concentrations were measured by independent assays ≤2 days before the next scheduled dose.,Efficacy measurements included Disease Activity Score 28-joint count (DAS28), low disease activity (LDA), remission, and erythrocyte sedimentation rate (ESR).,Targeted medical histories of injection site/infusion reactions, serum sickness, and thromboembolic events were collected.,Baseline demographics of the 595 patients (ETN: n = 200; ADL: n = 199; IFX: n = 196) were similar across groups.,The mean duration of treatment was 14.6, 13.5, and 13.1 months for ETN, ADL, and IFX, respectively.,All ETN-treated patients tested negative for ADA, whereas 31.2% and 17.4% patients treated with ADL and IFX, respectively, tested positive.,In ADL- or IFX-treated patients, those with ADA had significantly lower trough drug concentrations.,There were negative correlations between trough drug levels and both CRP and ESR in ADL- and IFX-treated patients.,DAS28-ESR LDA and remission rates were higher in patients without ADA.,The rate of targeted medical events reported was low.,ADA were detected in ADL- and IFX-treated but not ETN-treated patients.,Patients without ADA generally showed numerically better clinical outcomes than those with ADA.,This study was registered on www.ClinicalTrials.gov (NCT01981473).
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The confinement forced by COVID-19 can have repercussions on the health of people diagnosed with multiple sclerosis.,The objective of this study is to analyze the relationships between physical activity, a sense of coherence, resilience and coping among people diagnosed with Multiple Sclerosis during the health emergency situation.,To achieve this goal, this transversal descriptive study included 84 patients that belonged to multiple sclerosis associations during the period of confinement.,Participants filled out the Physical Activity (IPAQ-SF), Sense of Coherence (SOC-13), Resilience Scale (ER-14) and coping (COPE-28) questionnaires.,The results showed that the average age was 46.9 and that 67.9% had Relapsing Remittent Multiple Sclerosis diagnosed on average 13.9 years ago.,They had a high degree (33.3%) and moderate degree (34.5%) of physical activity, high levels of resilience, while the level of a sense of coherence was average and the most commonly used strategies for coping were active confrontation and religion.,Physical activity was not related to the rest of the studied variables, but there were correlations between the other variables.,The people with multiple sclerosis who belong to patient associations have remained physically active during the obligatory confinement period and have elevated degrees of resilience and an average sense of coherence, as well as using suitable coping strategies, which is why the social-health resource of belonging to a patient association could be boosting these variables that are beneficial to their health.
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In 2015, the first nationwide, multicenter Multiple Sclerosis (MS) registry was initiated in the Kingdom of Saudi Arabia (KSA) mainly with an objective to describe current epidemiology, disease patterns, and clinical characteristics of MS in Saudi Arabia.,This article aimed to report initial findings of the registry and regional prevalence of MS.,In 2015, a national MS registry was launched in KSA to register all MS patient with confirmed diagnosis according to the 2010 McDonald Criteria.,The registry aimed to identify and recruit all healthcare facilities treating MS patients in the Kingdom, and collect data such as demographics, clinical characteristics (disease onset, diagnosis, presentation of symptoms at onset, disease course, relapse rate, and disability measures), family history, and treatments.,All the included sites have obtained IRB/EC approvals for participating in the registry.,Currently, the registry includes 20 hospitals from different regions across the Kingdom.,The Projected prevalence was calculated based on the assumption that the number of diagnosed MS cases in participating hospitals (in each region) is similar to the number of cases in remaining nonparticipant hospitals in the same region.,As of September 2018, the registry has included 20 hospitals from the different regions across the Kingdom and has collected comprehensive data on 2516 patients from those hospitals, with median age 32 (Range: 11-63) and 66.5% being females.,The reported prevalence of MS for those hospitals was estimated to be 7.70/100,000 population and 11.80/100,000 Saudi nationals.,Based on the assumption made earlier, we projected the prevalence for each region and for the country as a whole.,The overall prevalence of MS at the country level was reported to be 40.40/100,000 total population and 61.95/100,000 Saudi nationals.,Around 3 out of every 4 patients (77.5%) were 40 years of age or younger.,Female to male ratio was 2:1.,The prevalence was higher among females, young and educated individuals across all five regions of Saudi Arabia.,The prevalence of MS has significantly increased in Saudi Arabia but is still much lower than that in the western and other neighboring countries like Kuwait, Qatar, and the UAE.,However, compared to the past rates, Saudi Arabia’s projected prevalence of MS through this national study is 40.40/100,000 population, putting the Kingdom above the low risk zone as per Kurtzke classification.,The projected prevalence was estimated to be much higher among Saudi nationals (61.95/100,000 Saudi-nationals).,The prevalence was higher among female, younger and educated individuals.,Further studies are needed to assess the risk factors associated with increased prevalence in Saudi Arabia.
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Aim of this commentary is to summarize the salient literature views on the relationships between presentation and evolution patterns of thyroid function in children with Hashimoto’s thyroiditis (HT).,According to the most recent reports, children with HT and subclinical hypothyroidism (SH) are more prone to the risk of developing severe thyroid dysfunctions over time, if compared to those presenting with euthyroidism.,In contrast, children presenting with HT and either overt or subclinical hyperthyroidism are incline to exhibit a definitive resolution of the hyperthyroid phase within some months, although there is a wide variability between the different individuals.,The natural history of frank hypothyroidism in the children with HT has never been investigated so far, since in these cases an immediate onset of replacement treatment is mandatory.,1) a deterioration of thyroid status over time may be observed especially in the children presenting with SH, but also in those presenting with euthyroidism; 2) a definitive resolution of the hyperthyroid phase is generally observed in those presenting with either overt or subclinical hyperthyroidism.
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Objective: The aim of this study was to evaluate the clinical course of Hashimoto’s thyroiditis (HT) in children and adolescents and the effects of levothyroxine therapy on the clinical course and laboratory findings.,Methods: The clinical and laboratory data of 101 patients with HT at presentation and during a three-year follow-up period were retrospectively evaluated using patient records.,Results: The mean age of the patients at the time of diagnosis was 12.3±2.90 years and female/male ratio was 5.7/1.,The complaint at the time of hospital presentation was goiter in 57.8% of the patients.,At baseline, 36.7% of the patients were euthyroid, whereas 32.7% had subclinical hypothyroidism, 16.6 % of subjects were evaluated as hypothyroid.,Twelve of the 28 patients who were initially euthyroid and not receiving therapy developed subclinical or overt hypothyroidism during the first 18 months of the follow-up period and were started on thyroid medication.,At presentation, the mean anti-thyroglobulin (anti-Tg) and anti-thyroperoxidase antibody levels were 450±725 IU/mL and 392±428 IU/mL, respectively and at the end of the follow-up period, a significant decrease was observed in the anti-Tg levels of patients receiving levothyroxine from the beginning.,Conclusions: Thyroid functions of the patients with HT should be monitored periodically for hypothyroidism.,Levothyroxine therapy may positively affect the clinical course of the disease and the antibody titers.,Conflict of interest:None declared.
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The purpose of this study was to describe the incidence of type 1 diabetes in children in Philadelphia from 2000-2004, compare the epidemiology to the previous three cohorts in the Philadelphia Pediatric Diabetes Registry, and, for the first time, describe the incidence of type 2 diabetes.,Diabetes cases were obtained through a retrospective population-based registry.,Hospital inpatient and outpatient records were reviewed for cases of type 1 and type 2 diabetes diagnosed from 1 January 2000 to 31 December 2004.,The secondary source of validation was the School District of Philadelphia.,Time series analysis was used to evaluate the changing pattern of incidence over the 20-year period.,The overall age-adjusted incidence rate in 2000-2004 of 17.0 per 100,000 per year was significantly higher than that of previous cohorts, with an average yearly increase of 1.5% and an average 5-year cohort increase of 7.8% (P = 0.025).,The incidence in white children (19.2 per 100,000 per year) was 48% higher than in the previous cohort.,Children aged 0-4 years had a 70% higher incidence (12.2 per 100,000 per year) than the original cohort; this increase was most marked in young black children.,The overall age-adjusted incidence of type 2 diabetes was 5.8 per 100,000 per year and was significantly higher in black children.,The incidence of type 1 diabetes is rising among children in Philadelphia.,The incidence rate has increased by 29% since the 1985-1989 cohort.,The most marked increases were among white children ages 10-14 years and black children ages 0-4 years.,The incidence of type 1 diabetes is 18 times higher than that of type 2 in white children but only 1.6 times higher in black children.
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The NZM2410-derived Sle2 lupus susceptibility locus induces an abnormal B cell differentiation which most prominently leads to the expansion of autoreactive B1a cells.,We have mapped the expansion of B1a cells to three Sle2 sub-loci, Sle2a, Sle2b, and Sle2c.,Sle2 also enhances the breach of B cell tolerance to nuclear antigens in the 56R anti-DNA immunoglobulin transgenic (Tg) model.,This study used the Sle2 sub-congenic strains to map the activation of 56R Tg B cells.,Sle2c strongly sustained the breach of tolerance and the activation of anti-DNA B cells.,The production of Tg-encoded anti-DNA antibodies was more modest in Sle2a expressing mice, but Sle2a was responsible for the recruitment for Tg B cells to the marginal zone, a phenotype that has been found for 56R Tg B cells in mice expressing the whole Sle2 interval.,In addition, Sle2a promoted the production of endogenously encoded anti-DNA antibodies.,Overall, this study showed that at least two Sle2 genes are involved in the activation of anti-DNA B cells, and excluded more than two-thirds of the Sle2 interval from contributing to this phenotype.,This constitutes an important step toward the identification of novel genes that play a critical role in B cell tolerance.
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To compare the effectiveness and safety of three non-tumour necrosis factor (TNF) α inhibitors (rituximab, abatacept, and tocilizumab) in the treatment of rheumatoid arthritis.,Population based prospective study.,53 university and 54 non-university clinical centres in France.,3162 adults (>18 years) with rheumatoid arthritis according to 1987 American College of Rheumatology criteria, enrolled in one of the three French Society of Rheumatology registries; who had no severe cardiovascular disease, active or severe infections, or severe immunodeficiency, with follow-up of at least 24 months.,Initiation of intravenous rituximab, abatacept, or tocilizumab for rheumatoid arthritis.,The primary outcome was drug retention without failure at 24 months.,Failure was defined as all cause death; discontinuation of rituximab, abatacept, or tocilizumab; initiation of a new biologic or a combination of conventional disease modifying antirheumatic drugs; or increase in corticosteroid dose >10 mg/d compared with baseline at two successive visits.,Because of non-proportional hazards, treatment effects are presented as life expectancy difference without failure (LEDwf), which measures the difference between average duration of survival without failure.,Average durations of survival without failure were 19.8 months for rituximab, 15.6 months for abatacept, and 19.1 months for tocilizumab.,Average durations were greater with rituximab (LEDwf 4.1, 95% confidence interval 3.1 to 5.2) and tocilizumab (3.5, 2.1 to 5.0) than with abatacept, and uncertainty about tocilizumab compared with rituximab was substantial (−0.7, −1.9 to 0.5).,No evidence was found of difference between treatments for mean duration of survival without death, presence of cancer or serious infections, or major adverse cardiovascular events.,Among adults with refractory rheumatoid arthritis followed-up in routine practice, rituximab and tocilizumab were associated with greater improvements in outcomes at two years compared with abatacept.
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To compare drug survival on adalimumab, etanercept and infliximab in patients with rheumatoid arthritis (RA).,Patients with RA (n=9139; 76% women; mean age 56 years) starting their first tumour necrosis factor (TNF) inhibitor between 2003 and 2011 were identified in the Swedish Biologics Register (ARTIS).,Data were collected through 31 December 2011.,Drug survival over up to 5 years of follow-up was compared overall and by period of treatment start (2003-2005/2006-2009; n=3168/4184) with adjustment for age, sex, education, period, health assessment questionnaire (HAQ), disease duration, concomitant disease modifying antirheumatic drug (DMARD) treatment and general frailty (using hospitalisation history as proxy).,During 20 198 person-years (mean/median 2.2/1.7 years) of follow-up, 3782 patients discontinued their first biological (19/100 person-years; 51% due to inefficacy, 36% due to adverse events).,Compared with etanercept, infliximab (adjusted HR 1.63, 95% CI 1.51 to 1.77) and adalimumab initiators had higher discontinuation rates (1.26, 95% CI 1.16 to 1.37), and infliximab had a higher discontinuation rate than adalimumab (1.28, 95% CI 1.18 to 1.40).,These findings were consistent across periods, but were modified by time for adalimumab versus etanercept (p<0.001; between-drug difference highest the 1st year in both periods).,The discontinuation rate was higher for starters in 2006-2009 than 2003-2005 (adjusted HR 1.12, 95% CI 1.04 to 1.20).,The composition of 1-year discontinuations also changed from 2003-2005 vs 2006-2009: adverse events decreased from 45% to 35%, while inefficacy increased from 43% to 53% (p<0.001).,Discontinuation rates were higher for infliximab compared with adalimumab and etanercept initiators, and for adalimumab versus etanercept during the 1st year.,Discontinuation rates increased with calendar period, as did the percentage discontinuations due to inefficacy.
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Canonically, IgE mediates allergic immune responses by triggering mast cells and basophils to release histamine and Type 2 helper cytokines.,Here, we report that in human systemic lupus erythematosus, IgE antibodies specific for double-stranded DNA activate plasmacytoid dendritic cells (pDCs), an immune cell type linked to viral defense, leading to the secretion of substantial amounts of interferon-α.,The concentrations of dsDNA-specific IgE found in patient serum correlated with disease severity and greatly potentiated pDC functions by triggering phagocytosis via FcεRI followed by Toll-like receptor 9-mediated DNA sensing in phagosomes.,These findings expand the known pathogenic mechanisms of IgE-mediated inflammation beyond those found in allergy and demonstrate that IgE can trigger interferon responses capable of exacerbating self-destructive autoimmune responses.
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Dema et al. show evidence that deficiency of IgE delays lupuslike disease development and severity, as demonstrated by reduced autoantibody production and amelioration of organ pathologies.,Loss of IgE causes a striking decrease in innate immune cell infiltration in secondary lymphoid organs and decreased activation of T cells and basophils.,The (patho)physiological role of IgE in nonallergic inflammatory diseases is not well understood.,Here, we explored the effect of IgE deficiency on the inflammatory response in FcγRIIB-deficient mice as well as in mice carrying both a deletion of FcγRIIB and the chromosomal translocation of Y-linked autoimmune acceleration (Yaa) that hastens and results in a more aggressive lupuslike disease in these mice.,The findings show that deficiency of IgE delays disease development and severity as demonstrated by reduced autoantibody production and amelioration of organ pathologies.,This was associated with decreased numbers of plasma cells and reduced levels of IgG2b and IgG3.,Unexpectedly, the loss of IgE also caused a striking decrease of immune cell infiltration in secondary lymphoid organs with a marked effect on the presence of dendritic cells, monocytes, neutrophils, and eosinophils in these organs and decreased activation of basophils.,The presence of autoreactive IgE in human systemic lupus erythematosus subjects was also associated with increased basophil activation and enhanced disease activity.,These findings argue that IgE facilitates the amplification of autoimmune inflammation.
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To evaluate the efficacy and safety of artificial pancreas treatment in non-pregnant outpatients with type 1 diabetes.,Systematic review and meta-analysis of randomised controlled trials.,Medline, Embase, Cochrane Library, and grey literature up to 2 February 2018.,Randomised controlled trials in non-pregnant outpatients with type 1 diabetes that compared the use of any artificial pancreas system with any type of insulin based treatment.,Primary outcome was proportion (%) of time that sensor glucose level was within the near normoglycaemic range (3.9-10 mmol/L).,Secondary outcomes included proportion (%) of time that sensor glucose level was above 10 mmol/L or below 3.9 mmol/L, low blood glucose index overnight, mean sensor glucose level, total daily insulin needs, and glycated haemoglobin.,The Cochrane Collaboration risk of bias tool was used to assess study quality.,40 studies (1027 participants with data for 44 comparisons) were included in the meta-analysis. 35 comparisons assessed a single hormone artificial pancreas system, whereas nine comparisons assessed a dual hormone system.,Only nine studies were at low risk of bias.,Proportion of time in the near normoglycaemic range (3.9-10.0 mmol/L) was significantly higher with artificial pancreas use, both overnight (weighted mean difference 15.15%, 95% confidence interval 12.21% to 18.09%) and over a 24 hour period (9.62%, 7.54% to 11.7%).,Artificial pancreas systems had a favourable effect on the proportion of time with sensor glucose level above 10 mmol/L (−8.52%, −11.14% to −5.9%) or below 3.9 mmol/L (−1.49%, −1.86% to −1.11%) over 24 hours, compared with control treatment.,Robustness of findings for the primary outcome was verified in sensitivity analyses, by including only trials at low risk of bias (11.64%, 9.1% to 14.18%) or trials under unsupervised, normal living conditions (10.42%, 8.63% to 12.2%).,Results were consistent in a subgroup analysis both for single hormone and dual hormone artificial pancreas systems.,Artificial pancreas systems are an efficacious and safe approach for treating outpatients with type 1 diabetes.,The main limitations of current research evidence on artificial pancreas systems are related to inconsistency in outcome reporting, small sample size, and short follow-up duration of individual trials.
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To assess the proportion of youth with type 1 diabetes under the care of pediatric endocrinologists in the United States meeting targets for HbA1c, blood pressure (BP), BMI, and lipids.,Data were evaluated for 13,316 participants in the T1D Exchange clinic registry younger than 20 years old with type 1 diabetes for ≥1 year.,American Diabetes Association HbA1c targets of <8.5% for those younger than 6 years, <8.0% for those 6 to younger than 13 years old, and <7.5% for those 13 to younger than 20 years old were met by 64, 43, and 21% of participants, respectively.,The majority met targets for BP and lipids, and two-thirds met the BMI goal of <85th percentile.,Most children with type 1 diabetes have HbA1c values above target levels.,Achieving American Diabetes Association goals remains a significant challenge for the majority of youth in the T1D Exchange registry.
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To investigate the long-term safety and efficacy of weekly subcutaneous IgPro20 (Hizentra, CSL Behring) in chronic inflammatory demyelinating polyneuropathy (CIDP).,In a 48-week open-label prospective extension study to the PATH study, patients were initially started on 0.2 g/kg or on 0.4 g/kg weekly and-if clinically stable-switched to 0.2 g/kg weekly after 24 weeks.,Upon CIDP relapse on the 0.2 g/kg dose, 0.4 g/kg was (re)initiated.,CIDP relapse was defined as a deterioration by at least 1 point in the total adjusted Inflammatory Neuropathy Cause and Treatment score.,Eighty-two patients were enrolled.,Sixty-two patients initially received 0.4 g/kg, 20 patients 0.2 g/kg weekly.,Seventy-two received both doses during the study.,Sixty-six patients (81%) completed the 48-week study duration.,Overall relapse rates were 10% in 0.4 g/kg-treated patients and 48% in 0.2 g/kg-treated patients.,After dose reduction from 0.4 to 0.2 g/kg, 51% (27/53) of patients relapsed, of whom 92% (24 of 26) improved after reinitiation of the 0.4 g/kg dose.,Two-thirds of patients (19/28) who completed the PATH study without relapse remained relapse-free on the 0.2 g/kg dose after dose reduction in the extension study.,Sixty-two patients had adverse events (AEs) (76%), of which most were mild or moderate with no related serious AEs.,Subcutaneous treatment with IgPro20 provided long-term benefit at both 0.4 and 0.2 g/kg weekly doses with lower relapse rates on the higher dose.,Long-term dosing should be individualized to find the most appropriate dose in a given patient.,This study provides Class IV evidence that for patients with CIDP, long-term treatment with SCIG beyond 24 weeks is safe and efficacious.
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Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare neurological disorder of the peripheral nervous system.,The economic burden of CIDP is not well understood.,To assess the economic and clinical burden of CIDP and to compare the incremental burden relative to a matched control group without CIDP.,This retrospective case-control analysis was conducted using data from the IQVIA Real-World Data Adjudicated Claims.,Adults newly diagnosed with CIDP between 7/1/2010 and 6/30/2014 were identified and direct matched to controls without CIDP.,Baseline characteristics were assessed and compared over a 6-month pre-index period.,Healthcare resource use, costs and clinical characteristics were assessed and compared over a 2-year follow-up.,Total cost differences over the 2-year follow-up were compared between matched cohorts using a generalized estimating equation model.,The final sample comprised a total of 790 cases matched to 790 controls.,Over the 2-year follow-up, cases more frequently experienced neuropathic pain, back pain and osteoarthritis and more commonly utilized opioids, anti-convulsants and anti-depressants.,Compared to controls, more cases had ≥1 hospitalization (26.2% vs.,9.0%), and cases had a higher mean number of outpatient prescription fills (62.8 vs.,32.0) and physician office visits (34.7 vs.,13.0) (all p<0.0001).,Cases had 7.5x higher mean total costs ($116,330 vs. $15,586, p<0.0001).,Important cost drivers were costs for outpatient ancillary, radiology and HCPCS drugs (mean $76,366 vs. $4,292) and costs for inpatient care (mean $16,357 vs. $2,862) (both p<0.0001).,Among cases, CIDP therapy (inclusive of both outpatient pharmacy and medical claims) accounted for 51.2% of mean total costs.,After further adjusting for baseline clinical characteristics, cases were associated with a 6.1x increase in total costs compared to controls (p<0.0001).,Our findings suggest a substantial clinical and economic burden among patients with CIDP relative to matched controls over a 2-year follow-up.
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Application of antigen-specific immune tolerance in autoimmune disease is a long-sought goal.,We studied diseases with abundant information on the autoimmune target: in multiple sclerosis (MS), various myelin antigens are known targets of T cells and antibodies, whereas in neuromyelitis optica (NMO), the aquaporin-4 channel is attacked by T cells and antibodies.,We tested whether engineered dendritic cells might induce a tolerogenic immune response in these two conditions.,In this in-human clinical study, individual regulatory T cells, secreting IL-10, a key tolerogenic cytokine, were detected after treatment.,These results might lead to more extensive trials with this approach in autoimmune conditions where the antigenic target has been identified, including MS, NMO, myasthenia gravis, and Graves disease.,There are adaptive T-cell and antibody autoimmune responses to myelin-derived peptides in multiple sclerosis (MS) and to aquaporin-4 (AQP4) in neuromyelitis optica spectrum disorders (NMOSDs).,Strategies aimed at antigen-specific tolerance to these autoantigens are thus indicated for these diseases.,One approach involves induction of tolerance with engineered dendritic cells (tolDCs) loaded with specific antigens.,We conducted an in-human phase 1b clinical trial testing increasing concentrations of autologous tolDCs loaded with peptides from various myelin proteins and from AQP4.,We tested this approach in 12 patients, 8 with MS and 4 with NMOSD.,The primary end point was the safety and tolerability, while secondary end points were clinical outcomes (relapses and disability), imaging (MRI and optical coherence tomography), and immunological responses.,Therapy with tolDCs was well tolerated, without serious adverse events and with no therapy-related reactions.,Patients remained stable clinically in terms of relapse, disability, and in various measurements using imaging.,We observed a significant increase in the production of IL-10 levels in PBMCs stimulated with the peptides as well as an increase in the frequency of a regulatory T cell, known as Tr1, by week 12 of follow-up.,In this phase 1b trial, we concluded that the i.v. administration of peptide-loaded dendritic cells is safe and feasible.,Elicitation of specific IL-10 production by peptide-specific T cells in MS and NMOSD patients indicates that a key element in antigen specific tolerance is activated with this approach.,The results warrant further clinical testing in larger trials.
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Autoimmune diabetes mellitus (DM) results from the destruction of pancreatic islet cells by activated T lymphocytes, which have been primed by activated dendritic cells (DC).,Individualized therapy with ex vivo DC manipulation and reinfusion has been proposed as a treatment for DM, but this treatment is limited by cost, and requires specialized facilities.,A means of in situ modulation of the DC phenotype in the host would be more accessible.,Here we report a novel innate immune modulator, 1Z1, generated by conjugating a TLR7 ligand to six units of polyethylene glycol (PEG), which skews DC phenotype in vivo.,1Z1 was less potent in inducing cytokine production by DC than the parent ligand in vitro and in vivo.,In addition, this drug only modestly increased DC surface expression of activation markers such as MHC class II, CD80, and CD86; however, the expression of negative regulatory molecules, such as programmed death ligand 1 (PD-L1), and interleukin-1 receptor-associated kinase M (IRAK-M) were markedly increased.,In vivo transfer of 1Z1 treated DC into prediabetic NOD mice delayed pancreatic insulitis.,Daily administration of 1Z1 effectively prevented the clinical onset of hyperglycemia and reduced histologic islet inflammation.,Daily treatment with 1Z1 increased PD-L1 expression in the CD11c+ population in peri-pancreatic lymph nodes; however, it did not induce an increase in regulatory T cells.,Pharmaceutical modulation of DC maturation and function in situ, thus represents an opportunity to treat autoimmune disease.
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The discovery of microRNAs (miRNAs) and their critical role in genetic control opened new avenues in understanding of various biological processes including immune cell lineage commitment, differentiation, proliferation and apoptosis.,However, a given miRNA may have hundreds of different mRNA targets and a target might be regulated by multiple miRNAs, thus the characterisation of dysregulated miRNA expression profiles could give a better insight into the development of immunological disturbances in autoimmune diseases.,The aim of our study was to examine the changes in miRNA expression profiles in patients with systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS).,Eight SLE patients, 8 pSS patients and 7 healthy subjects were enrolled in the investigation.,MiRNAs were isolated from peripheral blood mononuclear cells, and expression patterns were determined with Illumina next-generation sequencing technology.,Since the immunopathogenesis of pSS and SLE encompasses pronounced B cell hyperactivity along with specific autoantibody production, we paid a special attention on the association between miRNA expression levels and altered peripheral B cell distribution.,In SLE patients 135, while in pSS patients 26 miRNAs showed altered expression.,Interestingly, the 25 miRNAs including miR-146a, miR-16 and miR-21, which were over-expressed in pSS patients, were found to be elevated in SLE group, as well.,On the contrary, we observed the down-regulation of miR-150-5p, which is a novel and unique finding in pSS.,Levels of several miRNAs over-expressed in SLE, were not changed in pSS, such as miR-148a-3p, miR-152, miR-155, miR-223, miR-224, miR-326 and miR-342.,Expression levels of miR-223-5p, miR-150-5p, miR-155-5p and miR-342-3p, which miRNAs are potentially linked to B cell functions, showed associations with the B cell proportions within peripheral blood mononuclear cells.,The observed differences in miRNA expression profiles and the better understanding of immune regulatory mechanisms of miRNAs may help to elucidate the pathogenesis of SLE and pSS.
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T cells play an important role in the pathogenesis of systemic lupus erythematosus (SLE).,Clonal expansion of T cells correlating with disease activity has been observed in peripheral blood (PB) of SLE subjects.,Recently, next-generation sequencing (NGS) of the T cell receptor (TCR) β loci has emerged as a sensitive way to measure the T cell repertoire.,In this study, we utilized NGS to assess whether changes in T cell repertoire diversity in PB of SLE patients correlate with or predict changes in disease activity.,Total RNA was isolated from the PB of 11 SLE patients.,Each subject had three samples, collected at periods of clinical quiescence and at a flare.,Twelve age-matched healthy controls (HC) were used for reference.,NGS was used to profile the complementarity-determining region 3 (CDR3) of the rearranged TCR β loci.,Relative to the HC, SLE patients (at quiescence) demonstrated a 2.2-fold reduction in repertoire diversity in a given PB volume (P <0.0002), a more uneven distribution of the repertoire (Gini coefficient, HC vs SLE, P = 0.015), and a trend toward increased percentage of expanded clones in the repertoire (clone size >1.0 %, HC vs SLE, P = 0.078).,No significant correlation between the overall repertoire diversity and clinical disease activity was observed for most SLE patients with only two of eleven SLE patients showing a decreasing trend in repertoire diversity approaching the flare time point.,We did not observe any overlap of CDR3 amino acid sequences or a preferential Vβ or Jβ gene usage among the top 100 expanded clones from all SLE patients.,In both HC and SLE, the majority of the expanded clones were remarkably stable over time (HC = 5.5 ±0.5 months, SLE = 7.2 ±2.4 months).,A significant decrease in T cell repertoire diversity was observed in PB of SLE patients compared to HC.,However, in most SLE patients, repertoire diversity did not change significantly with increases in disease activity to a flare.,Thus, without a priori knowledge of disease-specific clones, monitoring TCR repertoire in PB from SLE patients is not likely to be useful to predict changes in disease activity.,The online version of this article (doi:10.1186/s13075-015-0655-9) contains supplementary material, which is available to authorized users.
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In patients presenting with a clinically isolated syndrome (CIS), magnetic resonance imaging (MRI) can support and substitute clinical information for multiple sclerosis (MS) diagnosis demonstrating disease dissemination in space (DIS) and time (DIT) and helping to rule out other conditions that can mimic MS.,From their inclusion in the diagnostic work-up for MS in 2001, several modifications of MRI diagnostic criteria have been proposed, in the attempt to simplify lesion-count models for demonstrating DIS, change the timing of MRI scanning for demonstrating DIT, and increase the value of spinal cord imaging.,Since the last update of these criteria, new data regarding the application of MRI for demonstrating DIS and DIT have become available and improvement in MRI technology has occurred.,State-of-the-art MRI findings in these patients were discussed in a MAGNIMS workshop, the goal of which was to provide an evidence-based and expert-opinion consensus on diagnostic MRI criteria modifications.
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In a study based on 96% of the roughly 28,000 patients with multiple sclerosis (MS) in Sweden, Westerlind et al. report relative and absolute MS risks for relatives of patients.,Risks were lower than most of those previously reported, with an MS sibling risk seven times that of randomly selected controls.,Data on familial recurrence rates of complex diseases such as multiple sclerosis give important hints to aetiological factors such as the importance of genes and environment.,By linking national registries, we sought to avoid common limitations of clinic-based studies such as low numbers, poor representation of the population and selection bias.,Through the Swedish Multiple Sclerosis Registry and a nationwide hospital registry, a total of 28 396 patients with multiple sclerosis were identified.,We used the national Multi-Generation Registry to identify first and second degree relatives as well as cousins, and the Swedish Twin Registry to identify twins of patients with multiple sclerosis.,Crude and age corrected familial risks were estimated for cases and found to be in the same range as previously published figures.,Matched population-based controls were used to calculate relative risks, revealing lower estimates of familial multiple sclerosis risks than previously reported, with a sibling recurrence risk (λs = 7.1; 95% confidence interval: 6.42-7.86).,Surprisingly, despite a well-established lower prevalence of multiple sclerosis amongst males, the relative risks were equal among maternal and paternal relations.,A previously reported increased risk in maternal relations could thus not be replicated.,An observed higher transmission rate from fathers to sons compared with mothers to sons suggested a higher transmission to offspring from the less prevalent sex; therefore, presence of the so-called ‘Carter effect’ could not be excluded.,We estimated the heritability of multiple sclerosis using 74 757 twin pairs with known zygosity, of which 315 were affected with multiple sclerosis, and added information from 2.5 million sibling pairs to increase power.,The heritability was estimated to be 0.64 (0.36-0.76), whereas the shared environmental component was estimated to be 0.01 (0.00-0.18).,In summary, whereas multiple sclerosis is to a great extent an inherited trait, the familial relative risks may be lower than usually reported.
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Rheumatoid arthritis (RA) is the most common chronic autoimmune connective tissue disease.,However, early RA is difficult to diagnose due to the lack of effective biomarkers.,This study aimed to identify new biomarkers and mechanisms for RA disease progression at the transcriptome level through a combination of microarray and bioinformatics analyses.,Microarray datasets for synovial tissue in RA or osteoarthritis (OA) were downloaded from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were identified by R software.,Tissue/organ-specific genes were recognized by BioGPS.,Enrichment analyses were performed and protein-protein interaction (PPI) networks were constructed to understand the functions and enriched pathways of DEGs and to identify hub genes.,Cytoscape was used to construct the co-expressed network and competitive endogenous RNA (ceRNA) networks.,Biomarkers with high diagnostic value for the early diagnosis of RA were validated by GEO datasets.,The ggpubr package was used to perform statistical analyses with Student’s t-test.,A total of 275 DEGs were identified between 16 RA samples and 10 OA samples from the datasets GSE77298 and GSE82107.,Among these DEGs, 71 tissue/organ-specific expressed genes were recognized.,Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that DEGs are mostly enriched in immune response, immune-related biological process, immune system, and cytokine signal pathways.,Fifteen hub genes and gene cluster modules were identified by Cytoscape.,Eight haematologic/immune system-specific expressed hub genes were verified by GEO datasets.,GZMA, PRC1, and TTK may be potential biomarkers for diagnosis of early RA.,NEAT1-miR-212-3p/miR-132-3p/miR-129-5p-TTK, XIST-miR-25-3p/miR-129-5p-GZMA, and TTK_hsa_circ_0077158- miR-212-3p/miR-132-3p/miR-129-5p-TTK might be potential RNA regulatory pathways to regulate the disease progression of early RA.,This work identified three haematologic/immune system-specific expressed genes, namely, GZMA, PRC1, and TTK, as potential biomarkers for the early diagnosis and treatment of RA and provided insight into the mechanisms of disease development in RA at the transcriptome level.,In addition, we proposed that NEAT1-miR-212-3p/miR-132-3p/miR-129-5p-TTK, XIST-miR-25-3p/miR-129-5p-GZMA, and TTK_hsa_circ_0077158-miR-212-3p/miR-132-3p/miR-129-5p-TTK are potential RNA regulatory pathways that control disease progression in early RA.
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Rheumatoid arthritis (RA) is an autoimmune disease that causes the chronic inflammation of the joints.,Intercellular communication containing synovial fibroblasts seems to play a major role in RA pathogenesis.,In this study, to better understand intercellular communication related to RA pathogenesis, we identified exosomal microRNAs (miRNAs) derived from synovial fibroblasts.,Exosomes were collected from an RA synovial fibroblast (RASF) cell line, namely, MH7A, with or without stimulation by tumor necrosis factor alpha (TNF-α).,We used small RNA sequencing to analyze the profile of small RNAs, including miRNAs, in MH7A exosomes and cells.,By using differential expression analysis, we identified four miRNAs (miR-155-5p, miR-146a-5p, miR-323a-5p, and miR-1307-3p) that are upregulated in exosomes with TNF-α stimulation.,The identification of miR-155-5p and miR-146a-5p which have been reported in RA patients demonstrated the validity of our experimental model.,Other two miRNAs were newly identified. miR-323a-5p was predicted to target the protein encoding gene CD6, which attenuates T-cell activation signals, and miR-1307-3p was predicted to target the protein encoding gene N-myc downstream-regulated gene 2 (NDRG2), which inhibits osteoclast-related gene expression.,The results suggested that these miRNAs might be involved in RA pathogenesis.,We hope our results will help us understand the role of RASF exosomes in RA pathogenesis.
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We investigated clinical, biological, and electrophysiological risk factors for mechanical ventilation (MV) and patient outcomes in Bangladesh using one of the largest, prospective Guillain‐Barré syndrome (GBS) cohorts in developing world.,A total of 693 GBS patients were included in two GBS studies conducted between 2006 and 2016 in Dhaka, Bangladesh.,Associations between baseline characteristics and MV were tested using Fisher's exact test, χ2 test, or Mann-Whitney U‐test, as appropriate.,Risk factors for MV were assessed using multivariate logistic regression.,Survival analysis was performed using Kaplan-Meier method; comparisons between groups performed using log‐rank test.,Of 693 patients, 155 (23%) required MV (median age, 26 years; interquartile range [IQR] 17-40).,Among the ventilated patients, males were predominant (68%) than females.,The most significant risk factor for MV was bulbar involvement (adjusted odds ratio [AOR]:19.07; 95% CI = 89.00-192.57, P = 0.012).,Other independently associated factors included dysautonomia (AOR:4.88; 95% CI = 1.49-15.98, P = 0.009) and severe muscle weakness at study entry (AOR:6.12; 95% CI = 0.64-58.57, P = 0.048).,At 6 months after disease onset, 20% of ventilated and 52% of non‐ventilated patients (P < 0.001) had recovered completely or with minor symptoms.,Mortality rate was significantly higher among ventilated patients than non‐ventilated patients (41% vs.,7%, P < 0.001).,Bulbar involvement, dysautonomia and severe muscle weakness were identified as the most important risk factors for MV among GBS patients from Bangladesh.,The findings may help to develop predictive models for MV in GBS in developing countries to identify impending respiratory failure and proper clinical management of GBS patients.
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To assess the safety and feasibility of small volume plasma exchange (SVPE) for patients with Guillain-Barré syndrome (GBS).,Non-randomised, single-arm, interventional trial.,National Institute of Neurosciences and Hospital, Dhaka, Bangladesh.,Twenty adult (>18 years) patients with GBS presented within 2 weeks of onset of weakness who were unable to walk unaided for more than 10 m.,SVPE involves blood cell sedimentation in a blood bag and removal of supernatant plasma after blood cells are retransfused.,This procedure was repeated three to six times a day, for eight consecutive days.,Fresh frozen plasma (FFP) and normal saline were used as replacement fluid.,Serious adverse events (SAEs) were defined as severe sepsis and deep venous thrombosis related to the central venous catheter (CVC) used during SVPE.,SVPE was considered safe if less than 5/20 patients experienced an SAE, and feasible if 8 L plasma could be removed within 8 days in at least 15/20 patients.,Median patient age 33 years (IQR 23-46; range 18-55); 13 (65%) were male.,Median Medical Research Council (MRC) sum score was 20 (IQR 0-29; range 0-36); three (15%) patients required mechanical ventilation.,One patient developed SAE (severe sepsis, possibly related to CVC).,The median plasma volume exchanged was 140 mL/kg (range 110-175) and removal of 8 L plasma was possible in 15 (75%) patients.,Patients received a median 1 g/kg IgG via FFP although a substantial proportion of IgG was probably removed again by the SVPE sessions.,GBS disability score improved by at least one grade in 14 (70%) patients 4 weeks after SVPE started.,No patients died.,SVPE seems a safe and feasible alternative treatment to standard plasma exchange (PE) or intravenous immunoglobulin (IVIg) for GBS; further studies of clinical efficacy in low-income and middle-income countries are warranted.,NCT02780570.
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Vaccination is a cornerstone for reducing the risk of COVID-19 infection during a pandemic.,Although the currently used COVID-19 vaccine is considered safe, some concerns persist regarding the likelihood of flares of rheumatic diseases.,Still’s disease is a rare auto-inflammatory disorder of unknown etiology, and the data on the flare of Still’s disease following COVID-19 vaccination are limited.,Therefore, we hereby present the case of a 34-year-old female patient with Still’s disease who experienced a flare after a ChAdOx1 nCoV-19 vaccination.,The patient visited the emergency department complaining of fever, arthralgia, myalgia, pleuritic chest pain and macular salmon-pink rash on her back for the past 2 days.,She had maintained low Still’s disease activity with etanercept and low-dose glucocorticoid for 14 years.,She received the ChAdOx1 nCoV-19 vaccine 7 days before the flare.,Laboratory investigations revealed leucocytosis and elevated serum levels of erythrocyte sedimentation rate, C-reactive protein, and ferritin.,Computed tomography showed no specific findings.,She received methylprednisolone pulse therapy, etanercept, and methotrexate for treating the Still’s disease flare.,However, her symptoms were not fully controlled, and she developed pericarditis, pleuritis, fever and macular rashes expanding to her extremities.,After excluding infectious conditions by blood culture and pleural fluid analysis, we administered tocilizumab with methotrexate and prednisolone.,Her symptoms and laboratory findings improved significantly, and she was discharged without symptoms 7 days later.,Although rare, this case of a patient with Still’s disease undergoing a flare following vaccination suggests that close observation of disease activity is warranted following COVID-19 vaccination.
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Guillain-Barré syndrome (GBS) is a rare immune-mediated disorder of the peripheral nerves.,Although its cause is not fully understood, the syndrome often follows infection with a virus or bacteria, although in rare occasions, vaccination may precede GBS.,We describe a case of a 62-year-old woman who presented with paraesthesia and progressive weakness of both lower limbs over 3 days.,Clinical examination and investigation findings including lumbar puncture and nerve conduction studies were consistent with the diagnosis of GBS.,She had no history of either diarrhoea or respiratory tract infections preceding her presentation.,However, she had her first intramuscular dose of the Oxford/AstraZeneca COVID-19 vaccine 11 days prior to her presentation.,Although no direct link could be ascertained, the purpose of this report is to highlight the incidence and consider this issue while evaluating any case of GBS in the light of the current pandemic and vaccination programme.
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Natural killer cells and NKT-like cells are the first line immune defense against tumor and virus infection.,Deficient NK and NKT-like cell effector function may contribute to increased susceptibility to infection in SLE patients.,We sought to examine the perforin and granzyme B expression, interferon-gamma (IFN-γ), and tumor-necrosis factor-alpha (TNF-α) production and CD107a degranulation of NK and NKT-like cells from SLE patients and their regulation by IL-15.,We established that (1) perforin expression on SLE NK cells was decreased but unrelated to disease activity; (2) the MFI of granzyme B was increased in NK cells from SLE patients with active disease, associated with increased percentages of granzyme B+ CD56bright NK cells; (3) NK cells from active SLE patients, both CD56dim and CD56bright NK subsets, produced higher IFN-γ compared to controls; (4) CD56dim, but not CD56bright NK cells from active SLE patients, produced lower TNF-α, compared to inactive SLE patients and controls; (5) CD107a degranulation of SLE NK cells was comparable to controls; (6) IL-15 enhanced perforin/granzyme B expression, IFN-γ/TNF-α production, and CD107a degranulation of NK cells from SLE patients; and (7) similar observations were found for CD56+CD3+ NKT-like cells.,Taken together, we demonstrated the differential expression of the heightened granzyme B and decreased TNF-α in NK and NKT-like cells in SLE patients.,Higher granzyme B expression of NK and NKT-like cells in active SLE patients, further enhanced by circulating IL-15, may contribute to the maintenance of inflammation in SLE.
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Natural killer (NK) cells may play an important role in the pathogenesis of SLE.,Interleukin(IL)-15, an NK-enhancing cytokine, is over-expressed in SLE patients.,In the present study, we examined the effect of IL-15 on NK cytotoxicity of SLE patients, and the expression of various activating and inhibitory NK receptors on NK cells from SLE patients in relation to disease activity.,We also sought to determine how IL-15 would affect the NK receptor expression on NK cells from SLE patients.,PBMCs were collected from 88 SLE patients with inactive disease activity (SLEDAI score<6) and active disease activity (SLEDAI score≥6), 26 age-matched healthy adults were used as controls.,PBMC were incubated in the presence or absence of IL-15 (10ng/ml) for eighteen hours.,CD3-CD56+ lymphoctes were gated using flow cytometry and further divided into CD56dim and CD56bright subsets according to the MFI of CD56.,We observed that 1.,Serum IL-15 was elevated in SLE patients, and higher in active disease than in inactive disease; 2.,NK cytotoxicity of SLE patients was deficient compared to controls and showed an impaired response to IL-15 compared to controls; 3.,CD69, CD94, NKG2A, NKp30, and CD158b on NK cells from SLE patients were higher than controls, and could be further enhanced by IL-15; 4.,NKp46 expression from SLE patients was higher than controls, but down-regulated by IL-15; 5.,Deficient NKG2D and NKAT-2 expression were found on NK cells from SLE patients, which were enhanced by IL-15; 6.,A unique NKp46- subset and CD158b+ subsets were observed in NK cells from SLE patients but not controls.,7.,Unlike controls, CD158k on NK cells from SLE patients failed to respond to IL-15.,Taken together, we demonstrated the aberrant NCR and iNKR expression on NK cells and their distinct response to IL-15 in SLE patients.,As IL-15 predominantly aggravates the aberrant NKR expression found in SLE, IL-15 antagonist may have therapeutic benefits in SLE patients.
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Sustained clinical remission (CR) without drug treatment has not been achieved in patients with rheumatoid arthritis (RA).,This implies a substantial difference between CR and the healthy state, but it has yet to be quantified.,We report a longitudinal monitoring of the drug response at multi-omics levels in the peripheral blood of patients with RA.,Our data reveal that drug treatments alter the molecular profile closer to that of HCs at the transcriptome, serum proteome, and immunophenotype level.,Patient follow-up suggests that the molecular profile after drug treatments is associated with long-term stable CR.,In addition, we identify molecular signatures that are resistant to drug treatments.,These signatures are associated with RA independently of known disease severity indexes and are largely explained by the imbalance of neutrophils, monocytes, and lymphocytes.,This high-dimensional phenotyping provides a quantitative measure of molecular remission and illustrates a multi-omics approach to understanding drug response.,Little information is available on molecular changes in response to treatment of rheumatoid arthritis (RA).,Here the authors report a multi-omics study collecting patients' transcriptome, proteome, and immunophenotype data to help understand the impact of drug treatments on RA molecular phenotypes.
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The aim of this study was to assess the feasibility of diagnosing early rheumatoid arthritis (RA) by measuring selected metabolic biomarkers.,We compared the metabolic profile of patients with RA with that of healthy controls and patients with psoriatic arthritis (PsoA).,The metabolites were measured using two different chromatography-mass spectrometry platforms, thereby giving a broad overview of serum metabolites.,The metabolic profiles of patient and control groups were compared using multivariate statistical analysis.,The findings were validated in a follow-up study of RA patients and healthy volunteers.,RA patients were diagnosed with a sensitivity of 93% and a specificity of 70% in a validation study using detection of 52 metabolites.,Patients with RA or PsoA could be distinguished with a sensitivity of 90% and a specificity of 94%.,Glyceric acid, D-ribofuranose and hypoxanthine were increased in RA patients, whereas histidine, threonic acid, methionine, cholesterol, asparagine and threonine were all decreased compared with healthy controls.,Metabolite profiling (metabolomics) is a potentially useful technique for diagnosing RA.,The predictive value was without regard to the presence of antibodies against cyclic citrullinated peptides.
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To unravel the hierarchy of cellular/molecular pathways in the disease tissue of early, treatment-naïve rheumatoid arthritis (RA) patients and determine their relationship with clinical phenotypes and treatment response/outcomes longitudinally.,144 consecutive treatment-naïve early RA patients (<12 months symptoms duration) underwent ultrasound-guided synovial biopsy before and 6 months after disease-modifying antirheumatic drug (DMARD) initiation.,Synovial biopsies were analysed for cellular (immunohistology) and molecular (NanoString) characteristics and results compared with clinical and imaging outcomes.,Differential gene expression analysis and logistic regression were applied to define variables correlating with treatment response and predicting radiographic progression.,Cellular and molecular analyses of synovial tissue demonstrated for the first time in early RA the presence of three pathology groups: (1) lympho-myeloid dominated by the presence of B cells in addition to myeloid cells; (2) d iffuse-myeloid with myeloid lineage predominance but poor in B cells nd (3) pauci-immune characterised by scanty immune cells and prevalent stromal cells.,Longitudinal correlation of molecular signatures demonstrated that elevation of myeloid- and lymphoid-associated gene expression strongly correlated with disease activity, acute phase reactants and DMARD response at 6 months.,Furthermore, elevation of synovial lymphoid-associated genes correlated with autoantibody positivity and elevation of osteoclast-targeting genes predicting radiographic joint damage progression at 12 months.,Patients with predominant pauci-immune pathology showed less severe disease activity and radiographic progression.,We demonstrate at disease presentation, prior to pathology modulation by therapy, the presence of specific cellular/molecular synovial signatures that delineate disease severity/progression and therapeutic response and may pave the way to more precise definition of RA taxonomy, therapeutic targeting and improved outcomes.
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During induction of trained immunity, monocytes and macrophages undergo a functional and transcriptional reprogramming toward increased activation.,Important rewiring of cellular metabolism of the myeloid cells takes place during induction of trained immunity, including a shift toward glycolysis induced through the mTOR pathway, as well as glutaminolysis and cholesterol synthesis.,Subsequently, this leads to modulation of the function of epigenetic enzymes, resulting in important changes in chromatin architecture that enables increased gene transcription.,However, in addition to the beneficial effects of trained immunity as a host defense mechanism, we hypothesize that trained immunity also plays a deleterious role in the induction and/or maintenance of autoimmune and autoinflammatory diseases if inappropriately activated.
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Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system.,Foxp3+ regulatory T (Treg) cells are reduced in frequency and dysfunctional in patients with MS, but the underlying mechanisms of this deficiency are unclear.,Here, we show that induction of human IFN-γ−IL-17A−Foxp3+CD4+ T cells is inhibited in the presence of circulating exosomes from patients with MS.,The exosomal miRNA profile of patients with MS differs from that of healthy controls, and let-7i, which is markedly increased in patients with MS, suppresses induction of Treg cells by targeting insulin like growth factor 1 receptor (IGF1R) and transforming growth factor beta receptor 1 (TGFBR1).,Consistently, the expression of IGF1R and TGFBR1 on circulating naive CD4+ T cells is reduced in patients with MS.,Thus, our study shows that exosomal let-7i regulates MS pathogenesis by blocking the IGF1R/TGFBR1 pathway.,MiRNAs are small RNA molecules that can regulate gene expression.,Here the authors show that expression of several exosomal miRNAs are altered in patients with multiple sclerosis, and that let-7i modulates regulatory T cell homeostasis to contribute to pathogenesis.
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Interleukin (IL)-17-producing T helper cells (TH17) are a recently identified CD4+ T cell subset distinct from T helper type 1 (TH1) and T helper type 2 (TH2) cells1.,TH17 cells can drive antigen specific autoimmune diseases and are considered the main population of pathogenic T cells driving experimental autoimmune encephalomyelitis (EAE)2, the mouse model for multiple sclerosis.,The factors that are needed for the generation of TH17 cells have been well-characterized3-6.,However, where and how the immune system controls TH17 cells in vivo remains unclear.,Here, by using a model of tolerance induced by CD3-specific antibody, a model of sepsis and influenza A viral infection (H1N1), we show that pro-inflammatory TH17 cells can be redirected to and controlled in the small intestine.,TH17-specific IL-17A secretion induced expression of the chemokine CCL20 in the small intestine, facilitating the migration of these cells specifically to the small intestine via the CCR6/CCL20 axis.,Moreover, we found that TH17 cells are controlled by two different mechanisms in the small intestine: first, they are eliminated via the intestinal lumen and simultaneously pro-inflammatory TH17 cells acquire a regulatory phenotype with in vitro and in vivo immune-suppressive properties (rTH17).,These results identify mechanisms limiting TH17 cell pathogenicity and implicate the gastrointestinal tract as a site for control of TH17 cells.
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This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID‐19) in people with multiple sclerosis (PwMS).,We retrospectively collected data of PwMS with suspected or confirmed COVID‐19.,All the patients had complete follow‐up to death or recovery.,Severe COVID‐19 was defined by a 3‐level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death.,We evaluated baseline characteristics and MS therapies associated with severe COVID‐19 by multivariate and propensity score (PS)‐weighted ordinal logistic models.,Sensitivity analyses were run to confirm the results.,Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID‐19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy.,Thirty‐eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized.,After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti‐CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID‐19.,Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001).,Results were confirmed by the PS‐weighted analysis and by all the sensitivity analyses.,This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action.,However, some specific elements of risk emerged.,These will need to be considered while the COVID‐19 pandemic persists.,ANN NEUROL 2021;89:780-789
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Although most autoimmune diseases are considered to be CD4 T cell- or antibody-mediated, many respond to CD20-depleting antibodies that have limited influence on CD4 and plasma cells.,This includes rituximab, oblinutuzumab and ofatumumab that are used in cancer, rheumatoid arthritis and off-label in a large number of other autoimmunities and ocrelizumab in multiple sclerosis.,Recently, the COVID-19 pandemic created concerns about immunosuppression in autoimmunity, leading to cessation or a delay in immunotherapy treatments.,However, based on the known and emerging biology of autoimmunity and COVID-19, it was hypothesised that while B cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit protective immunity following infection and vaccination.,As such, drug-induced B cell subset inhibition, that controls at least some autoimmunities, would not influence innate and CD8 T cell responses, which are central to SARS-CoV-2 elimination, nor the hypercoagulation and innate inflammation causing severe morbidity.,This is supported clinically, as the majority of SARS-CoV-2-infected, CD20-depleted people with autoimmunity have recovered.,However, protective neutralizing antibody and vaccination responses are predicted to be blunted until naive B cells repopulate, based on B cell repopulation kinetics and vaccination responses, from published rituximab and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data, shown here.,This suggests that it may be possible to undertake dose interruption to maintain inflammatory disease control, while allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available.,Graphical AbstractBased on the known and emerging biology of autoimmune diseases and COVID-19, it was hypothesised that whilst B-cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit or blunt the protective immunity following infection and vaccination.,This is supported clinically, as the majority of SARS-CoV-2 infected, CD20-depleted people with autoimmunity, have recovered.,However, in CD-20 treated people until naïve B-cells repopulate, based on B-cell repopulation-kinetics and vaccination responses, from published rituximab, and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data shown here suggests that it may be possible to undertake dose-interruption to maintain inflammatory disease control, whilst allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available.,Based on the known and emerging biology of autoimmune diseases and COVID-19, it was hypothesised that whilst B-cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit or blunt the protective immunity following infection and vaccination.,This is supported clinically, as the majority of SARS-CoV-2 infected, CD20-depleted people with autoimmunity, have recovered.,However, in CD-20 treated people until naïve B-cells repopulate, based on B-cell repopulation-kinetics and vaccination responses, from published rituximab, and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data shown here suggests that it may be possible to undertake dose-interruption to maintain inflammatory disease control, whilst allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available.
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Our aim was to assess the ability of tocilizumab monotherapy to reduce progressive structural joint damage in rheumatoid arthritis patients at high risk of progression.,This study was a subanalysis from a prospective 1-year, multicenter, X-ray-reader-blinded, randomized controlled trial of tocilizumab [Study of Active Controlled Monotherapy Used for Rheumatoid Arthritis, an IL-6 Inhibitor (SAMURAI) trial].,All patients were categorized into two or three groups according to four independent predictive markers for progressive joint damage [urinary C-terminal crosslinking telopeptide (uCTX-II), urinary pyridinoline/deoxypyridinoline (uPYD/DPD) ratio, body mass index (BMI), and joint-space narrowing (JSN) score at baseline].,One-year progression of joint destruction was assessed in high-risk versus low-risk groups receiving tocilizumab monotherapy and compared with patients receiving conventional disease-modifying antirheumatic drugs (DMARDs) (n = 157 and 145, respectively).,In patients at high risk of progression of erosion as estimated by high uCTX-II, uPYD/DPD, or low BMI, and at high risk of progression of JSN as estimated by low BMI or high JSN score, the 52-week changes in radiological erosion and JSN, respectively, were significantly less in patients treated with tocilizumab monotherapy compared with those receiving DMARDs for each type of risk factor.,In patients at low risk, those receiving tocilizumab also progressed less than those on DMARDs, although the difference did not reach statistical significance.,Tocilizumab monotherapy is more effective in reducing radiological progression in patients presenting with risk factors for rapid progression than in low-risk patients.,Patients at high risk for progression may benefit more from tocilizumab treatment.
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Aiming at therapeutic targets has reduced the risk of organ failure in many diseases such as diabetes or hypertension.,Such targets have not been defined for rheumatoid arthritis (RA).,To develop recommendations for achieving optimal therapeutic outcomes in RA.,A task force of rheumatologists and a patient developed a set of recommendations on the basis of evidence derived from a systematic literature review and expert opinion; these were subsequently discussed, amended and voted upon by >60 experts from various regions of the world in a Delphi-like procedure.,Levels of evidence, strength of recommendations and levels of agreement were derived.,The treat-to-target activity resulted in 10 recommendations.,The treatment aim was defined as remission with low disease activity being an alternative goal in patients with long-standing disease.,Regular follow-up (every 1-3 months during active disease) with appropriate therapeutic adaptation to reach the desired state within 3 to a maximum of 6 months was recommended.,Follow-up examinations ought to employ composite measures of disease activity which include joint counts.,Additional items provide further details for particular aspects of the disease.,Levels of agreement were very high for many of these recommendations (≥9/10).,The 10 recommendations are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA based on evidence and expert opinion.
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Multiple sclerosis (MS) likely results from an imbalance between regulatory and inflammatory immune processes.,CD39 is an ectoenzyme that cleaves ATP to AMP and has been suggested as a novel regulatory T cells (Treg) marker.,As ATP has numerous proinflammatory effects, its degradation by CD39 has anti-inflammatory influence.,The purpose of this study was to explore regulatory and inflammatory mechanisms activated in fingolimod treated MS patients.,Peripheral blood mononuclear cells (PBMCs) were isolated from relapsing-remitting MS patients before starting fingolimod and three months after therapy start. mRNA expression was assessed in ex vivo PBMCs.,The proportions of CD8, B cells, CD4 and CD39-expressing cells were analysed by flow cytometry.,Treg proportion was quantified by flow cytometry and methylation-specific qPCR.,Fingolimod treatment increased mRNA levels of CD39, AHR and CYP1B1 but decreased mRNA expression of IL-17, IL-22 and FOXP3 mRNA in PBMCs.,B cells, CD4+ cells and Treg proportions were significantly reduced by this treatment, but remaining CD4+ T cells were enriched in FOXP3+ cells and in CD39-expressing Tregs.,In addition to the decrease in circulating CD4+ T cells and CD19+ B cells, our findings highlight additional immunoregulatory mechanisms induced by fingolimod.
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Th1 lymphocytes preferentially infiltrate into the spinal cord during EAE via a VLA-4-mediated mechanism while Th17 lymphocyte infiltration is dependent on LFA-1 expression.,The integrin α4β1 (VLA-4) is used by encephalitogenic T cells to enter the central nervous system (CNS).,However, both Th1 and Th17 cells are capable of inducing experimental autoimmune encephalomyelitis (EAE), and the molecular cues mediating the infiltration of Th1 versus Th17 cells into the CNS have not yet been defined.,We investigated how blocking of α4 integrins affected trafficking of Th1 and Th17 cells into the CNS during EAE.,Although antibody-mediated inhibition of α4 integrins prevented EAE when MOG35-55-specific Th1 cells were adoptively transferred, Th17 cells entered the brain, but not the spinal cord parenchyma, irrespective of α4 blockade.,Accordingly, T cell-conditional α4-deficient mice were not resistant to actively induced EAE but showed an ataxic syndrome with predominantly supraspinal infiltrates of IL-23R+CCR6+CD4+ T cells.,The entry of α4-deficient Th17 cells into the CNS was abolished by blockade of LFA-1 (αLβ2 integrin).,Thus, Th1 cells preferentially infiltrate the spinal cord via an α4 integrin-mediated mechanism, whereas the entry of Th17 cells into the brain parenchyma occurs in the absence of α4 integrins but is dependent on the expression of αLβ2.,These observations have implications for the understanding of lesion localization, immunosurveillance, and drug design in multiple sclerosis.
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Although fingolimod is registered in Europe for treatment of relapsing-remitting multiple sclerosis (RRMS) if earlier disease modifying therapy (DMT) has failed, no data regarding its efficacy in this patient group are available.,This observational cohort study of the NeuroTransData network includes German RRMS outpatients with failure of earlier therapy with injectable DMT (iDMT), therefore switching to either another iDMT (n = 133) or to fingolimod (n = 300).,Statistical comparison of clinical baseline characteristics showed more severely affected patients in the fingolimod group.,A propensity-score matched group comparison was performed (n = 99 in each group) covering more than 2-year observation time.,Fingolimod showed statistically significant superior efficacy in comparison to iDMT regarding annualized relapse rate (0.21 versus 0.33 per year), time-to-relapse and likelihood of relapse (iDMT hazard ratio 1.7), proportion and likelihood of patients with EDSS progression (15.10 versus 31.00 %; iDMT hazard ratio 1.7), persistence on medication and likelihood of discontinuation (iDMT hazard ratio 3.0).,Significantly more patients were free of relapse and EDSS progression with fingolimod than with their second iDMT (64.4 versus 46.5 %, p < 0.03).,This real-life evidence in German RRMS outpatients support data from controlled clinical studies and can quantitatively support clinical decision finding processes if iDMT therapy fails in RRMS.
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Achieving good adherence to self-injected treatments for multiple sclerosis can be difficult.,Injection devices may help to overcome some of the injection-related barriers to adherence that can be experienced by patients.,We sought to assess short-term adherence to, and tolerability of, interferon (IFN) β-1a administered via electronic autoinjection device in patients with relapsing-remitting multiple sclerosis (RRMS).,BRIDGE (RebiSmart to self-inject Rebif serum-free formulation in a multidose cartridge) was a 12-week, multicentre, open-label, single-arm, observational, Phase IV study in which patients self-administered IFN β-1a (titrated to 44 μg), subcutaneously (sc), three times weekly, via electronic autoinjection device.,Patients were assessed at baseline and 4-weekly intervals to Week 12 or early termination (ET) for: physical examinations; diary card completion (baseline, Weeks 4, 8 only); neurological examinations (baseline, Week 12/ET only); MS Treatment Concern Questionnaire (MSTCQ; Weeks 4, 8, 12 only); Convenience Questionnaire (Week 12 only); Hospital Anxiety and Depression Scale (HADS); and Paced Auditory Serial Addition Task (PASAT; baseline only).,Adherence was defined as administration of ≥ 80% of scheduled injections, recorded by the autoinjection device.,Overall, 88.2% (105/119; intent-to-treat population) of patients were adherent; 67.2% (80/119) administered all scheduled injections.,Medical reasons accounted for 35.6% (31/87) of missed injections, forgetfulness for 20.6% (18/87).,Adherence did not correlate with baseline Expanded Disability Status Scale (P = 0.821) or PASAT (P = 0.952) scores, or pre-study therapy (P = 0.303).,No significant changes (baseline-Week 12) in mean HADS depression (P = 0.482) or anxiety (P = 0.156) scores were observed.,'Overall convenience' was the most important reported benefit of the autoinjection device.,Device features associated with handling and ease of use were highly rated.,Mean MSTCQ scores for 'flu-like' symptoms (P = 0.022) and global side effects (P = 0.002) significantly improved from Week 4-12.,Mean MSTCQ scores for pain at injection site and injection pain increased from Week 4-12 (P < 0.001).,Adverse events were mild/moderate.,No new safety signals were identified.,Convenience and ease of use of the autoinjection device may improve adherence and, therefore, outcomes, in patients with RRMS receiving sc IFN β-1a.,EU Clinical Trials Register (EU-CTR; http://www.clinicaltrialsregister.eu): 2009-013333-24
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The safety profile of adalimumab was previously reported in 23,458 patients across multiple indications.,Here we report the long-term safety of adalimumab in adults with plaque psoriasis (Ps), hidradenitis suppurativa (HS), rheumatoid arthritis (RA), ankylosing spondylitis, psoriatic arthritis, non-radiographic axial spondyloarthritis, peripheral spondyloarthritis, Crohn’s disease (CD), ulcerative colitis (UC), and non-infectious uveitis (UV).,Safety data from 77 clinical trials were pooled.,Safety assessments included adverse events (AEs) and serious AEs (SAEs) that occurred after the first study dose and within 70 days (5 half-lives) after the last study dose.,A total of 29,967 patients were included, representing 56,916 patient-years (PY) of exposure.,The most frequently reported SAE of interest was infection (3.7/100 PY) with highest incidences in CD, RA, UV, and UC (3.5/100 PY-6.9/100 PY); serious infections in Ps (1.8/100 PY) and HS (2.8/100 PY) were lower.,The observed number of deaths was below what would be expected in an age- and sex-adjusted population for most adalimumab-treated patients (including Ps).,Lack of real-life data and limited long-term data (> 5 years) for most patients are limitations of this analysis.,The safety profile of adalimumab was consistent with previous findings and no new safety signals were observed.
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Objectives.,To evaluate the risk of serious infections (SIs) in patients with RA treated with anti-TNF therapy with emphasis on the risk across different ages.,Methods.,Using data from the British Society for Rheumatology Biologics Register, a prospective observational study, we compared the risk of SI between 11 798 anti-TNF-treated patients and 3598 non-biologic DMARD (nbDMARD)-treated patients.,Results.,A total of 1808 patients had at least one SI (anti-TNF: 1512; nbDMARD: 296).,Incidence rates were: anti-TNF 42/1000 patient-years of follow-up (95% CI 40, 44) and nbDMARD 32/1000 patient-years of follow-up (95% CI 28, 36).,The adjusted hazard ratio (adjHR) for SI in the anti-TNF cohort was 1.2 (95% CI 1.1, 1.5).,The risk did not differ significantly between the three agents adalimumab, etanercept and infliximab.,The risk was highest during the first 6 months of therapy [adjHR 1.8 (95% CI 1.3, 2.6)].,Although increasing age was an independent risk factor for SI in both cohorts, there was no difference in relative risk of infection in patients on anti-TNF therapy in the older population.,There was no difference in hospital stay for SI between cohorts.,Mortality within 30 days of SI was 50% lower in the anti-TNF cohort [odds ratio 0.5 (95% CI 0.3, 0.8)].,Conclusions.,These data add to currently available evidence suggesting that anti-TNF therapy is associated with a small but significant overall risk of SI.,This must be balanced against the risks associated with poor disease control or alternative treatments.
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Enteroviral infections have been associated with autoimmunity and type 1 diabetes (T1D), but reliable methods to ascertain localization of single infected cells in the pancreas were missing.,Using a single-molecule-based fluorescent in situ hybridization (smFISH) method, we detected increased virus infection in pancreases from organ donors with T1D and with disease-associated autoantibodies (AAb+).,Although virus-positive β cells are found at higher frequency in T1D pancreases, compared to control donors, but are scarce, most virus-positive cells are scattered in the exocrine pancreas.,Augmented CD45+ lymphocytes in T1D pancreases show virus positivity or localization in close proximity to virus-positive cells.,Many more infected cells were also found in spleens from T1D donors.,The overall increased proportion of virus-positive cells in the pancreas of AAb+ and T1D organ donors suggests that enteroviruses are associated with immune cell infiltration, autoimmunity, and β cell destruction in both preclinical and diagnosed T1D.,Enterovirus-infected cells are significantly increased in AAb+ and T1D pancreasesMost of the virus-positive cells are scattered within the exocrine pancreasVirus-positive β cells are rare but more in T1D compared to control donorsAlso elevated in T1D donors, there is more infection in spleens than in pancreases,Enterovirus-infected cells are significantly increased in AAb+ and T1D pancreases,Most of the virus-positive cells are scattered within the exocrine pancreas,Virus-positive β cells are rare but more in T1D compared to control donors,Also elevated in T1D donors, there is more infection in spleens than in pancreases,By highly sensitive, single-molecule-based fluorescent in situ hybridization for viral RNA, Geravandi et al. found significantly increased enterovirus-infected cells in pancreases from organ donors with type 1 diabetes (T1D) and with disease-associated autoantibodies (AAb+), which were identified as exocrine, endocrine, and immune cells and scattered within the pancreas.
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Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic beta cells are killed by infiltrating immune cells and by cytokines released by these cells.,Signaling events occurring in the pancreatic beta cells are decisive for their survival or death in diabetes.,We have used RNA sequencing (RNA-seq) to identify transcripts, including splice variants, expressed in human islets of Langerhans under control conditions or following exposure to the pro-inflammatory cytokines interleukin-1β (IL-1β) and interferon-γ (IFN-γ).,Based on this unique dataset, we examined whether putative candidate genes for T1D, previously identified by GWAS, are expressed in human islets.,A total of 29,776 transcripts were identified as expressed in human islets.,Expression of around 20% of these transcripts was modified by pro-inflammatory cytokines, including apoptosis- and inflammation-related genes.,Chemokines were among the transcripts most modified by cytokines, a finding confirmed at the protein level by ELISA.,Interestingly, 35% of the genes expressed in human islets undergo alternative splicing as annotated in RefSeq, and cytokines caused substantial changes in spliced transcripts.,Nova1, previously considered a brain-specific regulator of mRNA splicing, is expressed in islets and its knockdown modified splicing. 25/41 of the candidate genes for T1D are expressed in islets, and cytokines modified expression of several of these transcripts.,The present study doubles the number of known genes expressed in human islets and shows that cytokines modify alternative splicing in human islet cells.,Importantly, it indicates that more than half of the known T1D candidate genes are expressed in human islets.,This, and the production of a large number of chemokines and cytokines by cytokine-exposed islets, reinforces the concept of a dialog between pancreatic islets and the immune system in T1D.,This dialog is modulated by candidate genes for the disease at both the immune system and beta cell level.
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Multiple sclerosis (MS) is an autoimmune, chronic, progressive disease leading to a combination of inflammation, demyelination, and neurodegeneration throughout the central nervous system (CNS).,The outcome of these processes can be visualized in magnetic resonance imaging (MRI) scans as brain atrophy, or brain volume loss (BVL), as well as lesions, “black holes” and spinal cord atrophy.,MRI outcomes such as BVL have been used as biomarkers of neurodegeneration and other measures of MS disease progression in clinical research settings.,Several FDA-approved medications seek to alleviate disease progression by reducing the impact of such factors as demyelination and neurodegeneration, but there are still many shortcomings that current clinical research aims to mitigate.,This review attempts to provide an overview of the FDA-approved medications available for treating multiple sclerosis and their effect on neurodegeneration, measured by BVL.
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The relationship of relapses to long-term disability in multiple sclerosis is uncertain.,Relapse reduction is a common therapeutic target but clinical trials have shown dissociation between relapse suppression and disability accumulation.,We investigated relationships between relapses and disability progression for outcomes of requiring assistance to walk, being bedridden and dying from multiple sclerosis [Disability Status Scale 6, 8, 10] by analysing 28 000 patient-years of evolution in 806-bout onset patients from the London Ontario natural history cohort.,Having previously shown no effect of relapse frequency among progressive multiple sclerosis subtypes, here we examined these measures in the pre-progressive or relapsing-remitting phase.,Survival was compared among groups stratified by (i) early relapses-number of attacks during the first 2 years of multiple sclerosis; (ii) length of first inter-attack interval; (iii) interval between onset and Disability Status Scale 3 (moderate disability); (iv) number of attacks from the third year of disease up to onset of progression; and (v) during the entire relapsing-remitting phase.,Early clinical features can predict hard disability outcomes.,Frequent relapses in the first 2 years and shorter first inter-attack intervals predicted shorter times to reach hard disability endpoints.,Attack frequencies, in the first 2 years, of 1 versus ≥3, gave differences of 7.6, 12.8 and 20.3 years in times from disease onset to Disability Status Scale 6, 8 and 10, respectively.,Time to Disability Status Scale 3 highly and independently predicted time to Disability Status Scale 6, 8 and 10.,In contrast, neither total number of relapsing-remitting phase attacks nor of relapses experienced during the relapsing-remitting phase after the second year up to onset of progression showed a deleterious effect on times from disease onset, from progression onset and from Disability Status Scale 3 to these hard endpoints.,The failure of a regulatory mechanism tied to neurodegeneration is suggested.,Relapse frequency beyond Year 2 does not appear to predict the key outcome of secondary progression or times to Disability Status Scale 6, 8 or 10, highlighting two distinct disease phases related to late outcome.,These appear to be separated by a watershed within the relapsing-remitting phase, just a few years after clinical onset.,Higher early relapse frequencies and shorter first inter-attack intervals herald more rapid deterioration via interaction with the neurodegeneration characterizing secondary progression.,They increase the probability of its occurrence, its latency and influence-to a lesser degree-its slope.,The prevention or delay of the progressive phase of the disease is implicated as a key therapeutic target in relapsing-remitting patients.
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Adalimumab‐adbm is a monoclonal antibody developed as a biosimilar to adalimumab (Humira, AbbVie Inc.).,The key objectives of this study were using a population pharmacokinetic (PPK) approach to assess pharmacokinetic (PK) similarity between adalimumab‐adbm and Humira in patients with active rheumatoid arthritis (RA), to quantify the effects of potential covariates on adalimumab PK and to assess the impact of switching treatment from Humira to adalimumab‐adbm on PK.,A PPK model was firstly developed using intensive PK data from the phase‐1 study in healthy subjects (NCT02045979).,PPK models were developed separately for phase‐3 base study (NCT02137226) and its extension study (NCT02640612) in patients with active RA.,PPK models were developed for adalimumab from adalimumab‐adbm and Humira treatment in healthy subjects and RA patients.,Weight and anti‐drug antibodies were found to be important predictors of adalimumab clearance.,Adalimumab PK was similar between adalimumab‐adbm and Humira.,The estimated effect of Humira on clearance, relative to the adalimumab‐adbm, was 1.02 (i.e., Humira has 0.02 greater clearance).,Similarly, the effect of treatment arms (switching) on clearance was estimated to be 1.00 and 0.997 for Humira:Humira:BI and Humira:BI:BI arms, respectively, relative to the BI:BI:BI arm (BI refers to adalimumab‐adbm) in the phase‐3 extension study.,PK similarity between adalimumab‐adbm and Humira in patients with active RA was demonstrated using PPK approach.,Adalimumab PK was also similar when switching treatment from Humira to adalimumab‐adbm at either week 24 or 48.
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We present a study protocol for a multi-centre, randomised, double-blind, parallel-group, placebo-controlled trial that seeks to test the feasibility, acceptability and effectiveness of a 52-week period of treatment with the first-in-class co-stimulatory blocker abatacept for preventing or delaying the onset of inflammatory arthritis.,The study aimed to recruit 206 male or female subjects from the secondary care hospital setting across the UK and the Netherlands.,Participants who were at least 18 years old, who reported inflammatory sounding joint pain (clinically suspicious arthralgia) and who were found to be positive for serum autoantibodies associated with rheumatoid arthritis (RA) were eligible for enrolment.,All study subjects were randomly assigned to receive weekly injections of investigational medicinal product, either abatacept or placebo treatment over the course of a 52-week period.,Participants were followed up for a further 52 weeks.,The primary endpoint was defined as the time to development of at least three swollen joints or to the fulfilment of the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for RA using swollen but not tender joints, whichever endpoint was met first.,In either case, swollen joints were confirmed by ultrasonography.,Participants, care givers, and those assessing the outcomes were all blinded to group assignment.,Clinical assessors and ultrasonographers were also blinded to each other’s assessments for the duration of the study.,There is limited experience of the design and implementation of trials for the prevention of inflammatory joint diseases.,We discuss the rationale behind choice and duration of treatment and the challenges associated with defining the “at risk” state and offer pragmatic solutions in the protocol to enrolling subjects at risk of RA.,Current Controlled Trials, ID: ISRCTN46017566.,Registered on 4 July 2014.,The online version of this article (10.1186/s13063-019-3403-7) contains supplementary material, which is available to authorized users.
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Fibroblast-like synoviocytes (FLSs) are key effector cells in the pathogenesis of rheumatoid arthritis (RA) and display a unique aggressive tumor-like phenotype with remarkable hyperplasia, increased cell migration and invasion.,How FLSs undergo these changes in RA remains unknown.,We previously reported a novel function of transcription factor SOX5 in RA-FLSs that promote cell migration and invasion.,In this study, we found that miR-15a/16 directly targets the SOX5 3’UTR and suppresses SOX5 expression.,Moreover, miR-15a/16 is significantly down-regulated in RA-FLSs, which negatively correlates with SOX5 expression.,Transfection with miR-15a/16 mimics in RA-FLSs inhibits cell migration, invasion, IL-1β and TNFα expression.,Overexpression SOX5 in RA-FLSs decreases miR-15a/16 expression and rescues miR-15a/16-mediated inhibitory effect.,Furthermore, RA patients with the lower baseline serum miR-15a/16 level present poor response of 3 months disease-modifying antirheumatic drugs (DMARDs) therapy.,Collectively, this study reveals that miR-15a/16/SOX5 axis functions as a key driver of RA-FLSs invasion, migration and inflammatory response in a mutual negative feedback loop and correlates with DMARDs treatment response in RA.
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The present study explored whether miR-145-5p can aggravate the development and progression of rheumatoid arthritis (RA) by regulating the expression of matrix metalloproteinases (MMPs).,ELISAs, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blotting were used to examine the expression levels of MMP-1, MMP-3, MMP-9, and MMP-13 in fibroblast-like synoviocytes (FLS) from patients with RA.,Levels of MMP-1, MMP-3, MMP-9, and MMP-13 were assessed in the right hind ankles of a murine collagen-induced arthritis (CIA) model by RT-qPCR and immunohistochemical (IHC) analysis.,The effects of activation or inhibition of the nuclear factor-κB (NF-κB) pathway on MMPs were evaluated by RT-qPCR and western blotting.,Subcellular localization of NF-κB p65 was visualized by confocal microscopy.,Overexpression of miR-145-5p increased the expression of MMP-3, MMP-9, and MMP-13 in RA-FLS.,Moreover, injection of a miR-145-5p agomir into mice increased MMP-3, MMP-9, and MMP-13, as demonstrated by RT-qPCR and IHC analysis.,A chemical inhibitor that selectively targets NF-κB (BAY11-7082) significantly attenuated MMP-9 expression, while it did not influence the levels of MMP-3 and MMP-13.,Immunofluorescence analysis revealed that nuclear localization of p65 was significantly enhanced, indicating that miR-145-5p enhances activation of the NF-κB pathway by promoting p65 nuclear translocation. miR-145-5p overexpression also significantly increased phosphorylated p65 levels; however, the levels of IkB-a were reduced in response to this miRNA.,Moreover, our results indicated that miR-145-5p aggravated RA progression by activating the NF-κB pathway, which enhanced secretion of MMP-9.,In conclusion, modulation of miR-145-5p expression is potentially useful for the treatment of RA inflammation, by regulating the expression of MMPs, and MMP-9 in particular, through inhibition of the NF-κB pathway.
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Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS).,The immune response in MS patients leads to the infiltration of immune cells in the CNS and their subsequent activation.,Immune cell activation induces a switch towards glycolysis.,During glycolysis, the dicarbonyl product methylglyoxal (MGO) is produced.,MGO is a glycating agent that can rapidly form advanced glycation endproducts (AGEs).,In turn, AGEs are able to induce inflammatory responses.,The glyoxalase system is the endogenous defense system of the body to reduce the burden of MGO thereby reducing AGE formation.,This system consists of glyoxalase-1 and glyoxalase-2 which are able to detoxify MGO to D-lactate.,We investigated whether AGE levels are induced in experimental autoimmune encephalitis (EAE), an inflammatory animal model of MS.,Twenty seven days post EAE induction, MGO and AGE (Nε-(carboxymethyl)lysine (CML), Nε-(carboxyethyl)lysine (CEL), 5-hydro-5-methylimidazolone (MG-H1)) levels were significantly increased in the spinal cord of mice subjected to EAE.,Yet, pyridoxamine treatment and glyoxalase-1 overexpression were unable to counteract AGE production during EAE and did not influence the clinical course of EAE.,In conclusion, AGEs levels increase during EAE in the spinal cord, but AGE-modifying treatments do not inhibit EAE-induced AGE production and do not affect disease progression.
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Myelin-containing macrophages and microglia are the most abundant immune cells in active multiple sclerosis (MS) lesions.,Our recent transcriptomic analysis demonstrated that collectin placenta 1 (CL-P1) is one of the most potently induced genes in macrophages after uptake of myelin.,CL-P1 is a type II transmembrane protein with both a collagen-like and carbohydrate recognition domain, which plays a key role in host defense.,In this study we sought to determine the dynamics of CL-P1 expression on myelin-containing phagocytes and define the role that it plays in MS lesion development.,We show that myelin uptake increases the cell surface expression of CL-P1 by mouse and human macrophages, but not by primary mouse microglia in vitro.,In active demyelinating MS lesions, CL-P1 immunoreactivity was localized to perivascular and parenchymal myelin-laden phagocytes.,Finally, we demonstrate that CL-P1 is involved in myelin internalization as knockdown of CL-P1 markedly reduced myelin uptake.,Collectively, our data indicate that CL-P1 is a novel receptor involved in myelin uptake by phagocytes and likely plays a role in MS lesion development.
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Investigate whether the efficacy and safety of intravenous tocilizumab (TCZ) demonstrated at week 52 in patients with early rheumatoid arthritis (RA) are maintained to week 104.,Methotrexate (MTX)-naive patients with early progressive RA were randomly assigned to double-blind 4 mg/kg TCZ+MTX, 8 mg/kg TCZ+MTX, 8 mg/kg TCZ+placebo or placebo+MTX for 104 weeks.,Patients not receiving 8 mg/kg TCZ and not achieving Disease Activity Score-28 joints (DAS28-erythrocyte sedimentation rate (ESR)) ≤3.2 at week 52 switched to escape therapy (8 mg/kg TCZ+MTX).,Analyses were exploratory.,Intent-to-treat and safety populations included 1157 and 1153 patients, respectively.,DAS28-ESR remission (<2.6) rates were maintained from weeks 52 to 104 (eg, 8 mg/kg TCZ+MTX, 49.3% to 47.6%).,Placebo+MTX and 4 mg/kg TCZ+MTX escape patients' week 104 response rates were 51.4% and 30.5%, respectively.,Inhibition of radiographic progression was maintained with 8 mg/kg TCZ (eg, 8 mg/kg TCZ+MTX mean (SD) change from baseline in modified total Sharp score: 0.13 (1.28), week 52; 0.19 (2.08), week 104).,The safety profile of TCZ was consistent with that of previous reports.,Patients with early RA treated with TCZ monotherapy or TCZ+MTX maintained clinical benefits during their second year of treatment with no new safety signals.,NCT01007435; Results.
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The type I interferon (IFN) signature in rheumatoid arthritis (RA) has shown clinical relevance in relation to disease onset and therapeutic response.,Identification of the cell type(s) contributing to this IFN signature could provide insight into the signature’s functional consequences.,The aim of this study was to investigate the contribution of peripheral leukocyte subsets to the IFN signature in early arthritis.,Blood was collected from 26 patients with early arthritis and lysed directly or separated into peripheral blood mononuclear cells (PBMCs) and polymorphonuclear granulocytes (PMNs).,PBMCs were sorted into CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD14+ monocytes by flow cytometry.,Messenger RNA expression of three interferon response genes (IRGs RSAD2, IFI44L, and MX1) and type I interferon receptors (IFNAR1 and IFNAR2) was determined in whole blood and blood cell subsets by quantitative polymerase chain reaction.,IRG expression was averaged to calculate an IFN score for each sample.,Patients were designated “IFNhigh” (n = 8) or “IFNlow” (n = 18) on the basis of an IFN score cutoff in whole peripheral blood from healthy control subjects.,The difference in IFN score between IFNhigh and IFNlow patients was remarkably large for the PMN fraction (mean 25-fold) compared with the other subsets (mean 6- to 9-fold), indicating that PMNs are the main inducers of IRGs.,Moreover, the relative contribution of the PMN fraction to the whole-blood IFN score was threefold higher than expected from its abundance in blood (p = 0.008), whereas it was three- to sixfold lower for the other subsets (p ≤ 0.063), implying that the PMNs are most sensitive to IFN signaling.,Concordantly, IFNAR1 and IFNAR2 were upregulated compared with healthy controls selectively in patient PMNs (p ≤ 0.0077) but not in PBMCs.,PMNs are the main contributors to the whole-blood type I IFN signature in patients with early arthritis, which seems due to increased sensitivity of these cells to type I IFN signaling.,Considering the well-established role of neutrophils in the pathology of arthritis, this suggests a role of type I IFN activity in the disease as well.,The online version of this article (doi:10.1186/s13075-016-1065-3) contains supplementary material, which is available to authorized users.
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The role of B cells in multiple sclerosis (MS) is increasingly recognized.,B cells undergo compartmentalized redistribution in blood and cerebrospinal fluid (CSF) during active MS, whereby memory B cells accumulate in the CSF.,While B-cell trafficking across the blood-brain barrier has been intensely investigated, cellular diapedesis through the blood-CSF barrier (BCSFB) is incompletely understood.,To investigate how B cells interact with the choroid plexus to transmigrate into the CSF we isolated circulating B cells from healthy donors (HC) and MS patients, utilized an inverted cell culture filter system of human choroid plexus papilloma (HIBCPP) cells to determine transmigration rates of B-cell subsets, immunofluorescence, and electron microscopy to analyze migration routes, and qRT-PCR to determine cytokines/chemokines mediating B-cell diapedesis.,We also screened the transcriptome of intrathecal B cells from MS patients.,We found, that spontaneous transmigration of HC- and MS-derived B cells was scant, yet increased significantly in response to B-cell specific chemokines CXCL-12/CXCL-13, was further boosted upon pre-activation and occurred via paracellular and transcellular pathways.,Migrating cells exhibited upregulation of several genes involved in B-cell activation/migration and enhanced expression of chemokine receptors CXCR4/CXCR5, and were predominantly of isotype class switched memory phenotype.,This antigen-experienced migratory subset displayed more pronounced chemotactic activities in MS than in HC and was retrieved in intrathecal B cells from patients with active MS.,Trafficking of class-switched memory B cells was downscaled in a small cohort of natalizumab-exposed MS patients and the proportions of these phenotypes were reduced in peripheral blood yet were enriched intrathecally in patients who experienced recurrence of disease activity after withdrawal of natalizumab.,Our findings highlight the relevance of the BCSFB as important gate for the entry of potentially harmful activated B cells into the CSF.
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The choroid plexus (CP) is strategically located between the peripheral blood and the cerebrospinal fluid, and is involved in the regulation of central nervous system (CNS) homeostasis.,In multiple sclerosis (MS), demyelination and inflammation occur in the CNS.,While experimental animal models of MS pointed to the CP as a key route for immune cell invasion of the CNS, little is known about the distribution of immune cells in the human CP during progressive phases of MS.,Here, we use immunohistochemistry and confocal microscopy to explore the main immune cell populations in the CP of progressive MS patients and non-neuroinflammatory controls, in terms of abundance and location within the distinct CP compartments.,We show for the first time that the CP stromal density of granulocytes and CD8+ T cells is higher in progressive MS patients compared to controls.,In line with previous studies, the CP of both controls and progressive MS patients contains relatively high numbers of macrophages and dendritic cells.,Moreover, we found virtually no B cells or plasma cells in the CP.,MHCII+ antigen-presenting cells were often found in close proximity to T cells, suggesting constitutive CNS immune monitoring functions of the CP.,Together, our data highlights the role of the CP in immune homeostasis and indicates the occurrence of mild inflammatory processes in the CP of progressive MS patients.,However, our findings suggest that the CP is only marginally involved in immune cell migration into the CNS in chronic MS.
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Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system that is classified as an immune-mediated inflammatory disease.,In managed care, patients with MS can be managed through care coordination that engages an interprofessional approach to a comprehensive spectrum of preventive, medical, rehabilitative, cognitive, and long-term health care services.,In addition, the management paradigm for MS is currently in a stage of rapid evolution, with a number of new agents, including more oral drugs, expected to become available in the near future.,Pharmacy and therapeutic committees may soon be faced with evaluating a hierarchy of new scientific data to differentiate the safety and efficacy of these new agents.,Decisions will need to be made regarding the utility of these potential new agents among existing therapies with longer-term safety and efficacy data available in the scientific literature.,For those MS patients managed under Medicaid, formulary and medication management decisions may be further impacted by psychosocial, cultural, educational, attitudinal, and/or economic factors that may be unique to the Medicaid population.,The need to maximize immediate and long-term resource utilization is usually an important consideration when managing a Medicaid population.,There is also an increasing focus on quality measures and quality outcomes by the Centers for Medicare and Medicaid Services.,Many managed care professionals can be involved in establishing quality measures and quality improvement processes to effectively appropriate and manage the resources required for Medicaid patients with MS.,As a result, medication and medical management of this special population can involve a comprehensive approach by managed care professionals.,For purposes of this article, the term “special populations” applies to patients with MS who are managed under Medicaid plans.,To review (a) particular challenges managed care organizations (MCOs) encounter when managing special populations of Medicaid patients with MS, (b) recent efficacy and safety data for oral therapies for relapsing forms of MS, (c) costs of current MS therapies, and (d) potential strategies for managed care to improve care of their MS patient population and optimize clinical and economic outcomes.,Review of recent published literature, abstracts related to MS presented at major medical conferences, and recommendations from key organizations including the U.S.,Department of Health and Human Services and the National Multiple Sclerosis Society.,The health economics of MS are a central issue for MCOs managing Medicaid patient populations.,Additional challenges include the anticipated expansion of the marketplace to include several new oral agents and the lack of consensus guidelines for management of patients with MS.,The benefit-risk profile of new agents will need to be considered in the context of established first-line parenteral drugs.,Management of patients with MS should include an individualized approach for each patient as part of a shared decision-making process.,In the overall management of special patient populations, case management and collaborative practice models in managed care may help to ensure that critical benchmarks are achieved.
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The relationship of relapses to long-term disability in multiple sclerosis is uncertain.,Relapse reduction is a common therapeutic target but clinical trials have shown dissociation between relapse suppression and disability accumulation.,We investigated relationships between relapses and disability progression for outcomes of requiring assistance to walk, being bedridden and dying from multiple sclerosis [Disability Status Scale 6, 8, 10] by analysing 28 000 patient-years of evolution in 806-bout onset patients from the London Ontario natural history cohort.,Having previously shown no effect of relapse frequency among progressive multiple sclerosis subtypes, here we examined these measures in the pre-progressive or relapsing-remitting phase.,Survival was compared among groups stratified by (i) early relapses-number of attacks during the first 2 years of multiple sclerosis; (ii) length of first inter-attack interval; (iii) interval between onset and Disability Status Scale 3 (moderate disability); (iv) number of attacks from the third year of disease up to onset of progression; and (v) during the entire relapsing-remitting phase.,Early clinical features can predict hard disability outcomes.,Frequent relapses in the first 2 years and shorter first inter-attack intervals predicted shorter times to reach hard disability endpoints.,Attack frequencies, in the first 2 years, of 1 versus ≥3, gave differences of 7.6, 12.8 and 20.3 years in times from disease onset to Disability Status Scale 6, 8 and 10, respectively.,Time to Disability Status Scale 3 highly and independently predicted time to Disability Status Scale 6, 8 and 10.,In contrast, neither total number of relapsing-remitting phase attacks nor of relapses experienced during the relapsing-remitting phase after the second year up to onset of progression showed a deleterious effect on times from disease onset, from progression onset and from Disability Status Scale 3 to these hard endpoints.,The failure of a regulatory mechanism tied to neurodegeneration is suggested.,Relapse frequency beyond Year 2 does not appear to predict the key outcome of secondary progression or times to Disability Status Scale 6, 8 or 10, highlighting two distinct disease phases related to late outcome.,These appear to be separated by a watershed within the relapsing-remitting phase, just a few years after clinical onset.,Higher early relapse frequencies and shorter first inter-attack intervals herald more rapid deterioration via interaction with the neurodegeneration characterizing secondary progression.,They increase the probability of its occurrence, its latency and influence-to a lesser degree-its slope.,The prevention or delay of the progressive phase of the disease is implicated as a key therapeutic target in relapsing-remitting patients.
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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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Objective To review the association between current enterovirus infection diagnosed with molecular testing and development of autoimmunity or type 1 diabetes.,Design Systematic review and meta-analysis of observational studies, analysed with random effects models.,Data sources PubMed (until May 2010) and Embase (until May 2010), no language restrictions, studies in humans only; reference lists of identified articles; and contact with authors.,Study eligibility criteria Cohort or case-control studies measuring enterovirus RNA or viral protein in blood, stool, or tissue of patients with pre-diabetes and diabetes, with adequate data to calculate an odds ratio and 95% confidence intervals.,Results The 24 papers and two abstracts (all case-control studies) that met the eligibility criteria included 4448 participants.,Study design varied greatly, with a high level of statistical heterogeneity.,The two separate outcomes were diabetes related autoimmunity or type 1 diabetes.,Meta-analysis showed a significant association between enterovirus infection and type 1 diabetes related autoimmunity (odds ratio 3.7, 95% confidence interval 2.1 to 6.8; heterogeneity χ2/df=1.3) and clinical type 1 diabetes (9.8, 5.5 to 17.4; χ2/df=3.2).,Conclusions There is a clinically significant association between enterovirus infection, detected with molecular methods, and autoimmunity/type 1 diabetes.,Larger prospective studies would be needed to establish a clear temporal relation between enterovirus infection and the development of autoimmunity and type 1 diabetes.
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Supplemental Digital Content is available in the text.,Individuals with type 1 diabetes mellitus (T1DM) have a high risk of cardiovascular complications, but it is unknown to what extent fulfilling all cardiovascular treatment goals is associated with residual risk of mortality and cardiovascular outcomes in those with T1DM compared with the general population.,We included all patients ≥18 years of age with T1DM who were registered in the Swedish National Diabetes Register from January 1, 1998, through December 31, 2014, a total of 33 333 patients, each matched for age and sex with 5 controls without diabetes mellitus randomly selected from the population.,Patients with T1DM were categorized according to number of risk factors not at target: glycohemoglobin, blood pressure, albuminuria, smoking, and low-density lipoprotein cholesterol.,Risk of all-cause mortality, acute myocardial infarction, heart failure hospitalization, and stroke was examined in relation to the number of risk factors at target.,The mean follow-up was 10.4 years in the diabetes group.,Overall, 2074 of 33 333 patients with diabetes mellitus and 4141 of 166 529 controls died.,Risk for all outcomes increased stepwise for each additional risk factor not at target.,Adjusted hazard ratios for patients achieving all risk factor targets compared with controls were 1.31 (95% confidence interval [CI], 0.93-1.85) for all-cause mortality, 1.82 (95% CI, 1.15-2.88) for acute myocardial infarction, 1.97 (95% CI, 1.04-3.73) for heart failure hospitalization, and 1.17 (95% CI, 0.51-2.68) for stroke.,The hazard ratio for patients versus controls with none of the risk factors meeting target was 7.33 (95% CI, 5.08-10.57) for all-cause mortality, 12.34 (95% CI, 7.91-19.48) for acute myocardial infarction, 15.09 (95% CI, 9.87-23.09) for heart failure hospitalization, and 12.02 (95% CI, 7.66-18.85) for stroke.,A steep-graded association exists between decreasing number of cardiovascular risk factors at target and major adverse cardiovascular outcomes among patients with T1DM.,However, risks for all outcomes were numerically higher for patients with T1DM compared with controls, even when all risk factors were at target, with risk for acute myocardial infarction and heart failure hospitalization statistically significantly higher.
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Helen Colhoun and colleagues report findings from a Scottish registry linkage study regarding contemporary risks for cardiovascular events and all-cause mortality among individuals diagnosed with type 1 diabetes.,Randomized controlled trials have shown the importance of tight glucose control in type 1 diabetes (T1DM), but few recent studies have evaluated the risk of cardiovascular disease (CVD) and all-cause mortality among adults with T1DM.,We evaluated these risks in adults with T1DM compared with the non-diabetic population in a nationwide study from Scotland and examined control of CVD risk factors in those with T1DM.,The Scottish Care Information-Diabetes Collaboration database was used to identify all people registered with T1DM and aged ≥20 years in 2005-2007 and to provide risk factor data.,Major CVD events and deaths were obtained from the national hospital admissions database and death register.,The age-adjusted incidence rate ratio (IRR) for CVD and mortality in T1DM (n = 21,789) versus the non-diabetic population (3.96 million) was estimated using Poisson regression.,The age-adjusted IRR for first CVD event associated with T1DM versus the non-diabetic population was higher in women (3.0: 95% CI 2.4-3.8, p<0.001) than men (2.3: 2.0-2.7, p<0.001) while the IRR for all-cause mortality associated with T1DM was comparable at 2.6 (2.2-3.0, p<0.001) in men and 2.7 (2.2-3.4, p<0.001) in women.,Between 2005-2007, among individuals with T1DM, 34 of 123 deaths among 10,173 who were <40 years and 37 of 907 deaths among 12,739 who were ≥40 years had an underlying cause of death of coma or diabetic ketoacidosis.,Among individuals 60-69 years, approximately three extra deaths per 100 per year occurred among men with T1DM (28.51/1,000 person years at risk), and two per 100 per year for women (17.99/1,000 person years at risk). 28% of those with T1DM were current smokers, 13% achieved target HbA1c of <7% and 37% had very poor (≥9%) glycaemic control.,Among those aged ≥40, 37% had blood pressures above even conservative targets (≥140/90 mmHg) and 39% of those ≥40 years were not on a statin.,Although many of these risk factors were comparable to those previously reported in other developed countries, CVD and mortality rates may not be generalizable to other countries.,Limitations included lack of information on the specific insulin therapy used.,Although the relative risks for CVD and total mortality associated with T1DM in this population have declined relative to earlier studies, T1DM continues to be associated with higher CVD and death rates than the non-diabetic population.,Risk factor management should be improved to further reduce risk but better treatment approaches for achieving good glycaemic control are badly needed.,Please see later in the article for the Editors' Summary,Background.,People with diabetes are more likely to have cardiovascular disease such as heart attacks and strokes.,They also have a higher risk of dying prematurely from any cause.,Controlling blood sugar (glucose), blood pressure, and cholesterol can help reduce these risks.,Some people with type 1 diabetes can achieve tight blood glucose control through a strict regimen that includes a carefully calculated diet, frequent physical activity, regular blood glucose testing several times a day, and multiple daily doses of insulin.,Other drugs can reduce blood pressure and cholesterol levels.,Keeping one's weight in the normal range and not smoking are important ways in which all people, including those with type 1 diabetes can reduce their risks of heart disease and premature death.,Why Was This Study Done?,Researchers and doctors have known for almost two decades what patients with type 1 diabetes can do to minimize the complications from the disease and thereby reduce their risks for cardiovascular disease and early death.,So for some time now, patients should have been treated and counseled accordingly.,This study was done to evaluate the current risks for have cardiovascular disease and premature death amongst people living with type 1 diabetes in a high-income country (Scotland).,What Did the Researchers Do and Find?,From a national register of all people with type 1 diabetes in Scotland, the researchers selected those who were older than 20 years and alive at any time from January 2005 to May 2008.,This included about 19,000 people who had been diagnosed with type 1 diabetes before 2005.,Another 2,600 were diagnosed between 2005 and 2008.,They also obtained data on heart attacks and strokes in these patients from hospital records and on deaths from the natural death register.,To obtain a good picture of the current relative risks, they compared the patients with type 1 diabetes with the non-diabetic general Scottish population with regard to the risk of heart attacks/strokes and death from all causes.,They also collected information on how well the people with diabetes controlled their blood glucose, on their weight, and whether they smoked.,They found that the current risks compared with the general Scottish population are quite a bit lower than those of people with type 1 diabetes in earlier decades.,However, people with type 1 diabetes in Scotland still have much higher (more than twice) the risk of heart attacks, strokes, or premature death than the general population.,Moreover, the researchers found a high number of deaths in younger people with diabetes from coma-caused by either too much blood sugar (hyperglycemia) or too little (hypoglycemia).,Severe hyperglycemia and hypoglycemia happen when blood glucose control is poor.,When the scientists looked at test results for HbA1c levels (a test that is done once or twice a year to see how well patients controlled their blood sugar over the previous 3 months) for all patients, they found that the majority of them did not come close to controlling their blood glucose within the recommended range.,When the researchers compared body mass index (a measure of weight that takes height into account) and smoking between the people with type 1 diabetes and the general population, they found similar proportions of smokers and overweight or obese people.,What Do these Findings Mean?,The results represent a snapshot of the recent situation regarding complications from type 1 diabetes in the Scottish population.,The results suggest that within this population, strategies over the past two decades to reduce complications from type 1 diabetes that cause cardiovascular disease and death are working, in principle.,However, there is much need for further improvement.,This includes the urgent need to understand why so few people with type 1 diabetes achieve good control of their blood sugar, and what can be done to improve this situation.,It is also important to put more effort into keeping people with diabetes from taking up smoking or getting them to quit, as well as preventing them from getting overweight or promoting weight reduction, because this could further reduce the risks of cardiovascular disease and premature death.,Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001321,National Diabetes Information Clearinghouse, a service of the US National Institute of Diabetes and Digestive and Kidney Diseases, has information on heart disease and diabetes, on general complications of diabetes, and on the HbA1c test (on this site and some others called A1C test) that measures control of blood sugar over the past 3 months,Diabetes.co.uk provides general information on type 1 diabetes, its complications, and what people with the disease can do to reduce their risks,The Canadian Diabetes Association offers a cardiovascular risk self-assessment tool and other relevant information,The American Diabetes Association has information on the benefits and challenges of tight blood sugar control and how it is tested,The Juvenile Diabetes Research Foundation funds research to prevent, cure, and treat type 1 diabetes,Diabetes UK provides extensive information on diabetes for patients, carers, and clinicians
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Cognitive impairment occurs in about 50% of multiple sclerosis (MS) patients, and the use of self-reported outcomes for evaluating treatment and managing care among subjects with cognitive dysfunction has been questioned.,The aim of this study was to provide new evidence about the suitability of self-reported outcomes for use in this specific population by exploring the internal structure, reliability and external validity of a specific quality of life (QoL) instrument, the Multiple Sclerosis International Quality of Life questionnaire (MusiQoL).,Design: cross-sectional study.,Inclusion criteria: MS patients of any disease subtype.,Data collection: sociodemographic (age, gender, marital status, education level, and occupational activity) and clinical data (MS subtype, Expanded Disability Status Scale, disease duration); QoL (MusiQoL and SF36); and neuropsychological performance (Stroop color-word test).,Statistical analysis: confirmatory factor analysis, item-dimension correlations, Cronbach's alpha coefficients, Rasch statistics, relationships between MusiQoL dimensions and other parameters.,One hundred and twenty-four consecutive patients were enrolled.,QoL scores did not differ between the 69 cognitively non-impaired patients and the 55 cognitively impaired patients, except for the symptoms dimension.,The confirmatory factor analysis performed among the impaired subjects showed that the structure of the questionnaire matched with the initial structure of the MusiQoL.,The unidimensionality of the MusiQoL dimensions was preserved, and the internal validity indices were satisfactory and close to those of the reference population.,Our study suggests that executive dysfunction did not compromise the reliability and the validity of the self-reported QoL questionnaires.
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Nearly half of all patients diagnosed with multiple sclerosis (MS) will develop cognitive dysfunction.,Studies highlighted from no/weak impact to a strong impact of cognitive impairment on quality of life (QoL).,The aim of this study was to assess the impact of cognitive dysfunction on self-reported QoL in MS patients while considering key confounding factors.,Design: cross-sectional study.,Inclusion criteria: MS patients of any disease subtype.,Data collection: sociodemographic (age, gender, marital status, education level, and occupational activity) and clinical data (MS subtype, disease duration); MS disability (Expanded Disability Status Scale, EDSS); depression (Beck Depression Inventory); fatigue (Modified Fatigue Impact Scale); QoL (SF36 and MusiQoL); and neuropsychological performance (Brief Repeatable Battery of Neuropsychological Tests, BRB-N).,Statistical analysis: multiple linear regressions (forward-stepwise selection).,One hundred and twenty-four patients were enrolled.,Performance on BRB-N subtests varied widely (6% to 70% abnormal).,The BRB-N classified 37-78% of the patients as cognitively impaired, depending on the definition of cognitive impairment.,No links were found between the MusiQoL index and cognitive subtests, whereas marital status, EDSS, and depression were found to be independent predictive factors.,The present study demonstrated the weak and scarce association between cognitive impairment and QoL, when the key confounding factors were considered.,These results need to be confirmed with larger samples and more accurate tests of cognitive function.
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These guidelines on the management of primary sclerosing cholangitis (PSC) were commissioned by the British Society of Gastroenterology liver section.,The guideline writing committee included medical representatives from hepatology and gastroenterology groups as well as patient representatives from PSC Support.,The guidelines aim to support general physicians, gastroenterologists and surgeons in managing adults with PSC or those presenting with similar cholangiopathies which may mimic PSC, such as IgG4 sclerosing cholangitis.,It also acts as a reference for patients with PSC to help them understand their own management.,Quality of evidence is presented using the AGREE II format.,Guidance is meant to be used as a reference rather than for rigid protocol-based care as we understand that management of patients often requires individual patient-centred considerations.
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Sclerosing cholangitis (SC) is defined as a condition with progressive stenosis and destruction of the bile ducts due to diffuse inflammation and fibrosis and currently includes three categories: primary sclerosing cholangitis (PSC), secondary cholangitis, and IgG4-related sclerosing cholangitis (IgG4-SC).,SC categories share similar clinical features, such as cholestasis.,Patients with SC present with cholestatic symptoms, including jaundice and pruritus, and blood tests reveal elevation of cholestatic enzymes.,Cholangiography, endoscopic or magnetic, is inevitably required for making a diagnosis.,Although the presentation of IgG4-SC and PSC are similar, the comorbidities, treatment response, and outcomes differ significantly, and therefore, it is strongly advisable to be familiar with these two diseases to make a correct diagnosis.,Differentiation of cholangiocarcinoma from IgG4-SC and PSC is also extremely important.,In this review, the clinical characteristics, comorbidities, treatment and outcomes of IgG4-SC and PSC will be outlined based on experience mainly from Japan.
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Background: Neutralizing anti-drug antibodies (ADA) can greatly reduce the efficacy of biopharmaceuticals used to treat patients with multiple sclerosis (MS).,However, the biological factors pre-disposing an individual to develop ADA are poorly characterized.,Thus, there is an unmet clinical need for biomarkers to predict the development of immunogenicity, and subsequent treatment failure.,Up to 35% of MS patients treated with beta interferons (IFNβ) develop ADA.,Here we use machine learning to predict immunogenicity against IFNβ utilizing serum metabolomics data.,Methods: Serum samples were collected from 89 MS patients as part of the ABIRISK consortium-a multi-center prospective study of ADA development.,Metabolites and ADA were quantified prior to and after IFNβ treatment.,Thirty patients became ADA positive during the first year of treatment (ADA+).,We tested the efficacy of six binary classification models using 10-fold cross validation; k-nearest neighbors, decision tree, random forest, support vector machine and lasso (Least Absolute Shrinkage and Selection Operator) logistic regression with and without interactions.,Results: We were able to predict future immunogenicity from baseline metabolomics data.,Lasso logistic regression with/without interactions and support vector machines were the most successful at identifying ADA+ or ADA- cases, respectively.,Furthermore, patients who become ADA+ had a distinct metabolic response to IFNβ in the first 3 months, with 29 differentially regulated metabolites.,Machine learning algorithms could also predict ADA status based on metabolite concentrations at 3 months.,Lasso logistic regressions had the greatest proportion of correct classifications [F1 score (accuracy measure) = 0.808, specificity = 0.913].,Finally, we hypothesized that serum lipids could contribute to ADA development by altering immune-cell lipid rafts.,This was supported by experimental evidence demonstrating that, prior to IFNβ exposure, lipid raft-associated lipids were differentially expressed between MS patients who became ADA+ or remained ADA-.,Conclusion: Serum metabolites are a promising biomarker for prediction of ADA development in MS patients treated with IFNβ, and could provide novel insight into mechanisms of immunogenicity.
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As an alternative to mitophagy, neutrophils spontaneously extrude mitochondrial (mt) DNA devoid of oxidized residues (Ox).,Activated lupus neutrophils or healthy neutrophils treated with IFN/αRNP release ox-mtDNA bound to TFAM, which induces high levels of IFN-α in pDCs.,Autoantibodies against nucleic acids and excessive type I interferon (IFN) are hallmarks of human systemic lupus erythematosus (SLE).,We previously reported that SLE neutrophils exposed to TLR7 agonist autoantibodies release interferogenic DNA, which we now demonstrate to be of mitochondrial origin.,We further show that healthy human neutrophils do not complete mitophagy upon induction of mitochondrial damage.,Rather, they extrude mitochondrial components, including DNA (mtDNA), devoid of oxidized (Ox) residues.,When mtDNA undergoes oxidation, it is directly routed to lysosomes for degradation.,This rerouting requires dissociation from the transcription factor A mitochondria (TFAM), a dual high-mobility group (HMG) protein involved in maintenance and compaction of the mitochondrial genome into nucleoids.,Exposure of SLE neutrophils, or healthy IFN-primed neutrophils, to antiribonucleotide protein autoantibodies blocks TFAM phosphorylation, a necessary step for nucleoid dissociation.,Consequently, Ox nucleoids accumulate within mitochondria and are eventually extruded as potent interferogenic complexes.,In support of the in vivo relevance of this phenomenon, mitochondrial retention of Ox nucleoids is a feature of SLE blood neutrophils, and autoantibodies against Ox mtDNA are present in a fraction of patients.,This pathway represents a novel therapeutic target in human SLE.
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There is concern that the global burden of coronavirus disease of 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection might yield an increased occurrence of Guillain-Barré syndrome (GBS).,It is currently unknown whether concomitant SARS-CoV-2 infection and GBS are pathophysiologically related, what biomarkers are useful for diagnosis, and what is the optimal treatment given the medical comorbidities, complications, and simultaneous infection.,We report a patient who developed severe GBS following SARS-CoV-2 infection at the peak of the initial COVID-19 surge (April 2020) in New York City and discuss diagnostic and management issues and complications that may warrant special consideration in similar patients.
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•A novel coronavirus (COVID-19) was detected in Wuhan City, Hubei Province of China.,•The most symptoms of disease have reported fever, cough, dyspnea, myalgia, headache, and diarrhea.,•We followed up GBS symptoms in one infected patient with COVID-19.,•The limbs weakness of patient completely improved after treatment with IVIG.,A novel coronavirus (COVID-19) was detected in Wuhan City, Hubei Province of China.,The most symptoms of disease have reported fever, cough, dyspnea, myalgia, headache, and diarrhea.,We followed up GBS symptoms in one infected patient with COVID-19.,The limbs weakness of patient completely improved after treatment with IVIG.
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Myeloid cells contribute to inflammation and demyelination in the early stages of multiple sclerosis (MS), but it is still unclear to what extent these cells are involved in active lesion formation in progressive MS (PMS).,Here, we have harnessed the power of single-cell mass cytometry (CyTOF) to compare myeloid cell phenotypes in active lesions of PMS donors with those in normal-appearing white matter from the same donors and control white matter from non-MS donors.,CyTOF measurements of a total of 74 targeted proteins revealed a decreased abundance of homeostatic and TNFhi microglia, and an increase in highly phagocytic and activated microglia states in active lesions of PMS donors.,Interestingly, in contrast to results obtained from studies of the inflammatory early disease stages of MS, infiltrating monocyte-derived macrophages were scarce in active lesions of PMS, suggesting fundamental differences of myeloid cell composition in advanced stages of PMS.
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MicroRNA (miRNA) expression in the serum of multiple sclerosis (MS) patients has been correlated with white matter (WM) magnetic resonance imaging (MRI) abnormalities.,The expression levels and cellular specificity of the target genes of these miRNAs are unknown in MS brain.,The aim of this study was to analyze and validate the expression of miRNAs, previously reported as dysregulated in sera of MS patients, in white‐matter lesions (WMLs) of progressive MS brains.,We performed global miRNA expression profiling analysis in demyelinated WMLs of progressive MS brains (n = 5) and compared the significantly altered miRNAs to previously identified miRNAs from sera of MS patients.,Top dysregulated miRNAs common between the two datasets were validated in an independent cohort of MS brains by quantitative PCR (qPCR) and in situ hybridization.,Among the miRNAs that were significantly changed in WML tissues, 11 were similar to pathogenic and 12 were common to protective miRNAs previously identified in sera and correlating with WM MRI abnormalities.,Importantly, the expression levels of 58% of the protective miRNAs (7 of 12) were decreased in MS lesions compared to surrounding normal‐appearing tissue.,Target genes of these miRNAs were also altered in MS lesions and queries of cell‐specific databases identified astrocytes and microglia as the key cellular expressers of these genes in MS brains.,We identified miRNAs that correlate with MRI abnormalities in lesioned tissue from MS brains.
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Innate immune cells play a crucial role in the pathophysiology of rheumatoid arthritis (RA) via release of cytokines.,Small-molecule inhibitors of Janus kinases (JAKi) are clinically efficacious in patients with RA.,However, the isoform-specific action of each JAKi is difficult to assess, since JAKs form heterodimeric complexes with cytokine receptors.,We assessed the effects of several JAKi on GM-CSF-primed human innate immune cells.,Treatment with JAKi (tofacitinib, baricitinib, upadacitinib) prevented GM-CSF-induced JAK2/STAT5 phosphorylation at higher concentrations (400 nM) in THP-1 cells.,Whereas compared with baricitinib or upadacitinib, the inhibitory effects of tofacitinib on the GM-CSF-induced JAK2/STAT5 phosphorylation were weak at lower concentrations (≤ 100 nM).,All JAKi inhibited GM-CSF-induced IL-1β production by human neutrophils.,However, the inhibitory effects of baricitinib on IL-1β production were larger compared to those of tofacitinib or upadacitinib at lower concentrations (≤ 100 nM).,Similarly, all JAKi inhibited GM-CSF-induced caspase-1(p20) production by human neutrophils.,We conclude that incubation with JAKi prevents GM-CSF-mediated JAK2/STAT5 activation in human innate immune cells.,Although baricitinib and upadacitinib almost completely blocked GM-CSF-mediated JAK2/STAT5 signaling, the inhibitory effects of tofacitinib were weaker at lower concentrations suggesting that variation exists among these JAKi in the inhibition of JAK2 signaling pathways.
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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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IL-2 is the master-regulator cytokine for T cell dependent responses and is crucial for proliferation and survival of T cells.,However, IL-2-based treatments remained marginal, in part due to short half-life.,Thus, we aimed to extend IL-2 half-life by flanking the IL-2 core with sequences derived from the extensively glycosylated hinge region of the NCR2 receptor.,We termed this modified IL-2: “S2A”.,Importantly, S2A blood half-life was extended 14-fold compared to the clinical grade IL-2, Proleukin.,Low doses inoculation of S2A significantly enhanced induction of Tregs (CD4+ Regulatory T cells) in vivo, as compared to Proleukin, while both S2A and Proleukin induced low levels of CD8+ T cells.,In a B16 metastatic melanoma model, S2A treatment was unable to reduce the metastatic capacity of B16 melanoma, while enhancing induction and recruitment of Tregs, compared to Proleukin.,Conversely, in two autoimmune models, rheumatoid arthritis and DSS-induced colitis, S2A treatment significantly reduced the progression of disease compared to Proleukin.,Our results suggest new avenues for generating long-acting IL-2 for long-standing treatment and a new technique for manipulating short-life proteins for clinical and research uses.
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Interleukin (IL)-12 and IL-23 have been implicated in the pathogenesis of rheumatoid arthritis (RA).,The safety and efficacy of ustekinumab, a human monoclonal anti-IL-12/23 p40 antibody, and guselkumab, a human monoclonal anti-IL-23 antibody, were evaluated in adults with active RA despite methotrexate (MTX) therapy.,Patients were randomly assigned (1:1:1:1:1) to receive placebo at weeks 0, 4 and every 8 weeks (n=55), ustekinumab 90 mg at weeks 0, 4 and every 8 weeks (n=55), ustekinumab 90 mg at weeks 0, 4 and every 12 weeks (n=55), guselkumab 50 mg at weeks 0, 4 and every 8 weeks (n=55), or guselkumab 200 mg at weeks 0, 4 and every 8 weeks (n=54) through week 28; all patients continued a stable dose of MTX (10-25 mg/week).,The primary end point was the proportion of patients with at least a 20% improvement in the American College of Rheumatology criteria (ACR 20) at week 28.,Safety was monitored through week 48.,At week 28, there were no statistically significant differences in the proportions of patients achieving an ACR 20 response between the combined ustekinumab group (53.6%) or the combined guselkumab group (41.3%) compared with placebo (40.0%) (p=0.101 and p=0.877, respectively).,Through week 48, the proportions of patients with at least one adverse event (AE) were comparable among the treatment groups.,Infections were the most common type of AE.,Treatment with ustekinumab or guselkumab did not significantly reduce the signs and symptoms of RA.,No new safety findings were observed with either treatment.,NCT01645280.
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Primary Sjögren’s syndrome (pSS) is an autoimmune disease with autoantibodies overproduction, including rheumatoid factors (RF).,RF-IgA, IgG immunoglobulin classes are suggested as potential biomarkers of pSS.,We studied 76 patients with pSS (ACR/Eular 2017); laboratory tests included ESR, C-reactive protein, concentrations of gamma globulins, RF, Anti-SS-A/Ro, and anti-SS-B/La.,Eye dryness and keratoconjunctivitis sicca were confirmed with Schirmer’s test, the ocular staining score (OSS) using lissamine green, fluorescein staining and biopsy of minor salivary gland with the histopathological evaluation.,Differences between groups were analyzed with U Mann-Whitney test.,Correlations between quantitative variables were assessed with the Spearman correlation coefficient..,The best diagnostic values of immunoglobulin concentration for discriminating pSS patients and healthy individuals are for RF-IgA.,With cut-off of 21.5 EU/mL, the sensitivity is 72% and specificity is 100%.,Very high specificity (100%) is also obtained for RF-IgM concentration of 74.1 EU/mL.,Sensitivity is, however, smaller than that for RF-IgA and amounted to 61%.,The RF-IgG is the poorest indicator of pSS with 51% of sensitivity and 95% of specificity.,To summarize RF-IgA strongly associate with anti-SS-A and anti-SS-B autoantibodies.,Both RF-IgA and RF-IgM may be used as diagnostic tools for pSS.,Conclusions: among the three studied rheumatoid factor subtypes, RF-IgA showed the best diagnostic accuracy for pSS.,RF-IgA correlated with anti-SS-A/Ro and anti-SS-B antibodies even more closely than RF-IgM.,The assessment of the RF-IgA serum concentration may be helpful in the process of establishing pSS diagnosis.
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Classification of patients with rheumatoid arthritis (RA) as quickly as possible improves their prognosis.,This reason motivates specially dedicated early arthritis (EA) clinics.,Here, we have used 1062 EA patients with two years of follow-up to explore the value of anti-carbamylated protein (anti-CarP) antibodies, a new type of RA specific autoantibodies, for classification.,Specifically, we aimed to determine whether the addition of anti-CarP antibodies to IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies, which are helpful in RA classification, improves it or not.,Our analysis showed that incorporation of the anti-CarP antibodies to combinations of the other two antibodies (all joint by the OR Boolean operator) produces a modest increase in sensitivity (2.2% higher), at the cost of decreased specificity (8.1% lower).,The cost-benefit ratio was more favorable in the patients lacking the other autoantibodies.,However, it did not improve by considering different titer levels of the anti-CarP antibodies, or after exhaustively exploring other antibody combinations.,Therefore, the place in RA classification of these antibodies is questionable in the context of current treatments and biomarkers.,This conclusion does not exclude their potential value for stratifying patients in joint damage, disease activity, disability, or mortality categories.
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