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When studies on rheumatoid arthritis (RA) that were made many decades ago and could be considered “historical” in nature are analyzed in the context of recent observations, important insights on RA and on the function of rheumatoid factor (RF) become apparent.,RF in the role of antibody to immune complexes (ICs) appears to be involved in activation of the complement system and in the production of chemotactic and inflammatory mediators, creating a condition that can be sustained and reinitiated.,In the synovial cavity, a state of nonresolving inflammation is produced with the formation of citrullinated protein antigen-antibody complexes or other forms of ICs.,This is followed by a second wave of IC production in the form of RF acting as antibody reactive with the initial ICs.,Both of these processes are associated with complement consumption and production of inflammatory mediators.,We present a model of an initiation phase of RA that might represent an example of repetitive formation of ICs and complement-mediated inflammation.,Targeting therapy at this phase of RA to break the cycles of recurrent inflammation might be a novel approach to aid in further control of the disease.
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Bone homeostasis, which involves formation and resorption, is an important process for maintaining adequate bone mass in humans.,Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and bone loss, leading to joint destruction and deformity, and is a representative disease of disrupted bone homeostasis.,The bone loss and joint destruction are mediated by immunological insults by proinflammatory cytokines and various immune cells.,The connection between bone and immunity has been intensely studied and comprises the emerging field of osteoimmunology.,Osteoimmunology is an interdisciplinary science investigating the interplay between the skeletal and the immune systems.,The main contributors in osteoimmunology are the bone effector cells, such as osteoclasts or osteoblasts, and the immune cells, particularly lymphocytes and monocytes.,Physiologically, osteoclasts originate from immune cells, and immune cells regulate osteoblasts and vice versa.,Pathological conditions such as RA might affect these interactions, thereby altering bone homeostasis, resulting in the unfavorable outcome of bone destruction.,In this review, we describe the osteoclastogenic roles of the proinflammatory cytokines and immune cells that are important in the pathophysiology of RA.
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Placebo-controlled clinical trials have demonstrated the efficacy of tocilizumab (TCZ) for remission maintenance and glucocorticoid sparing in patients with giant cell arteritis (GCA).,However, limited data exist on the effectiveness and safety of TCZ for GCA in real-world clinical practice.,This was a retrospective, single-center analysis of patients with GCA treated with intravenous or subcutaneous TCZ (2010-2018).,Outcomes evaluated before and after TCZ initiation included occurrence of flare, time to flare, annualized flare rate, flare characteristics (i.e., polymyalgia rheumatica [PMR] symptoms, cranial manifestations), prednisone use, and safety.,Flare was defined as the recurrence of unequivocal GCA manifestations requiring treatment intensification.,Subgroup analyses of patients with PMR or visual manifestations at GCA diagnosis were performed.,Sixty patients with GCA were included.,The median (IQR) disease duration before and after the start of TCZ was 0.6 (0.2-1.6) and 0.5 (0.3-1.4) years, respectively.,At least 1 flare was observed in 43 patients (71.7%) before and in 18 (30.0%) after TCZ initiation.,Median (IQR) time to flare was 0.5 (0.3-0.7) years before TCZ treatment and 2.1 (0.6-2.6) years after TCZ initiation (HR 0.22; 95% CI 0.10-0.50; p = 0.0003).,The annualized flare rate significantly decreased following TCZ use (before TCZ 1.4 [95% CI 1.0-2.1]; after TCZ 0.6 [95% CI 0.3-1.0] events/year; p < 0.001).,Similar improvements were observed in patients with visual manifestations or PMR symptoms at GCA diagnosis.,TCZ reduced the incidence of new visual manifestations, and no flares associated with permanent vision loss occurred while patients were receiving TCZ.,Mean (SD) prednisone dose at TCZ onset and at the end of follow-up was 30 (18.3) and 5 (6.9) mg/day, respectively (p < 0.0001).,After TCZ initiation, 46.6% of patients successfully discontinued prednisone.,The incidence of adverse events, primarily attributed to glucocorticoids, was similar before and after TCZ initiation.,In this real-world setting, TCZ improved GCA clinical outcomes significantly and demonstrated effectiveness in the subgroups of patients with PMR symptoms and GCA-related visual manifestations at GCA diagnosis.,No new cases of blindness occurred after TCZ initiation.,Adverse events, many attributable to glucocorticoids, were comparable before and after TCZ treatment.
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While clinical signs and symptoms of giant cell arter it is improve promptly after starting glucocorticoid therapy, reports have suggested that the vascular inflammation may persist.,To assess the duration and quality of his to pathologic changes in treated patients, we prospectively obtained second temporal artery biopsies in patients treated for 3 to 12 months after their first diagnostic biopsy. 40 patients (28 women, 12 men, median age 77 years) agreed to have a second temporal artery biopsy randomly assigned to 3, 6, 9, or 12 months subsequent to the first.,Clinical and laboratory evaluation of the patient cohort revealed a typical rapid response and continued suppression of clinical manifestations as a result of glucocorticoid treatment.,His to pathologic findings, evaluated in a blinded fashion by a cardiovascular pathologist, showed unequivocal findings of vasculitis in 7/10 patients with second temporal artery biopsy at 3 months, 9/12 at 6 months, 4/9 at 9 months, and 4/9 at 12 months.,Lymphocytes were present in all positive initial biopsies and remained the dominant cell population in chronically treated patients.,Granulomatous inflammation decreased in a time-dependent fashion from 78%-100% at initial biopsy to 50% at 9 months and 25% at 12 months.,The increased medial fibrosis noted in the second biopsies (60% vs. 33% in primary temporal artery biopsies) suggested that the finding may represent a chronic finding in arteritis.,In summary, the response to glucocorticoids in giant cell arteritis was frequently discordant.,Clinical manifestations were readily suppressed, but vascular changes were gradual and often incomplete.
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To investigate the utility of a blood-based lab test as an aid in identifying patients with Multiple Sclerosis (MS).,Whole blood from subjects with MS, non-MS neurologic diseases, and healthy controls was centrifuged to isolate erythrocytes.,Following the addition of exogenous C-peptide, the supernatant was assayed for remaining C-peptide using an enzyme linked immunosorbent assay (ELISA).,The cohort included subjects with MS (n = 86), other non-MS neurologic diseases (OND n = 75), and healthy controls (n = 39).,The average C-peptide bound to erythrocytes in MS samples (3.51 ± 0.59 pmol) was significantly higher than non-MS subjects (2.23 ± 0.51 pmol; p < 0.001) and healthy controls (1.99 ± 0.32 pmol; p < 0.001).,Using a cutoff of 3.04 pmol of C-peptide uptake, the test exhibited a sensitivity of 98.3% and specificity of 89.5%.,A receiver-operator characteristic (ROC) curve generated from the ratio of the sensitivity to 1-selectivity resulted in an area under the curve of 0.97.,Exogenous C-peptide binding to erythrocytes has potential value in distinguishing MS subjects from non-MS neurologic diseases and healthy controls.,•A blood-based diagnostic for Multiple Sclerosis is reported.,•Based on exogenous C-peptide binding to harvested red cells•Results are independent of age, disease duration, therapies.,A blood-based diagnostic for Multiple Sclerosis is reported.,Based on exogenous C-peptide binding to harvested red cells,Results are independent of age, disease duration, therapies.,Biomarkers and point of care diagnostics are lacking in Multiple Sclerosis (MS), despite hallmark features often found in many diagnosed patients.,Efforts to determine causes of this breakdown are ongoing by many groups.,Here, we report that the addition of a molecule that is naturally occurring in most humans to a sample of blood obtained in a simple blood draw, may serve as a fast and simple auxiliary test during the diagnosing stage of the disease.
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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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The aim was to estimate the impact of individual risk factors and treatment with various disease-modifying antirheumatic drugs (DMARDs) on the incidence of myocardial infarction (MI) in patients with rheumatoid arthritis (RA).,We analysed data from 11,285 patients with RA, enrolled in the prospective cohort study RABBIT, at the start of biologic (b) or conventional synthetic (cs) DMARDs.,A nested case-control study was conducted, defining patients with MI during follow-up as cases.,Cases were matched 1:1 to control patients based on age, sex, year of enrolment and five cardiovascular (CV) comorbidities.,Generalized linear models were applied (Poisson regression with a random component, conditional logistic regression).,In total, 112 patients developed an MI during follow-up.,At baseline, during the first 6 months of follow-up and prior to the MI, inflammation markers (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) but not 28-joint-count disease activity score (DAS28) were significantly higher in MI cases compared to matched controls and the remaining cohort.,Baseline treatment with DMARDs was similar across all groups.,During follow-up bDMARD treatment was significantly more often discontinued or switched in MI cases.,CV comorbidities were significantly less often treated in MI cases vs. matched controls (36 % vs. 17 %, p < 0.01).,In the adjusted regression model, we found a strong association between higher CRP and MI (OR for log-transformed CRP at follow-up: 1.47, 95 % CI 1.00; 2.16).,Furthermore, treatment with prednisone ≥10 mg/day (OR 1.93, 95 % CI 0.57; 5.85), TNF inhibitors (OR 0.91, 95 % CI 0.40; 2.10) or other bDMARDs (OR 0.85, 95 % CI 0.27; 2.72) was not associated with higher MI risk.,CRP was associated with risk of MI.,Our results underline the importance of tight disease control taking not only global disease activity, but also CRP as an individual marker into account.,It seems irrelevant with which class of (biologic or conventional) DMARD effective control of disease activity is achieved.,However, in some patients the available treatment options were insufficient or insufficiently used - regarding DMARDs to treat RA as well as regarding the treatment of CV comorbidities.,The online version of this article (doi:10.1186/s13075-016-1077-z) contains supplementary material, which is available to authorized users.
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HMG-CoA reductase inhibitors (also known as statins) are widely used as lipid-lowering agents in patients with rheumatoid arthritis (RA) to reduce their cardiovascular risk.,However, whether they have an effect on RA disease activity is controversial.,This study aimed to investigate the effect of statins on disease activity in RA patients.,A systematic literature review was performed using the MEDLINE, EMBASE, Cochrane Library, ISI WEB of Knowledge, Scopus, and Clinical Trials Register databases.,Only prospective randomized controlled trials or controlled clinical trials comparing the efficacy of statins with placebo on adult RA patients were included.,The efficacy was measured according to the ACR criteria, EULAR criteria, DAS28, HAQ score, ESR, or CRP.,The Jadad score was used for quality assessment.,The inverse variance method was used to analyze continuous outcomes.,A fixed-effects model was used when there was no significant heterogeneity; otherwise, a random-effects model was used.,For stability of results, we performed leave-one-study-out sensitivity analysis by omitting individual studies one at a time from the meta-analysis.,Publication bias was assessed using Egger test.,A total 13 studies involving 737 patients were included in the meta-analysis; 11 studies were included in the meta-analysis based on DAS28, while the other 2 studies were only included in the meta-analysis based on ESR or CRP.,The standardized mean difference (SMD) in DAS28 between the statin group and the placebo group was −0.55 (95% CI [−0.83, −0.26], P = 0.0002), with an I2 value of 68%.,Subgroup analysis showed that patients with more active disease tended to benefit more from statin therapy (SMD −0.73, P = 0.01) than patients with moderate or low disease activity (SMD −0.38, P = 0.03).,Statin therapy also significantly reduced tender joint counts, swollen joint counts, ESR, and CRP compared with placebo, but the reduction in HAQ score and VAS was not significant (P > 0.05).,This meta-analysis suggested that statin therapy might be effective in the reduction of RA disease activity measured by DAS28, TJC, SJC, as well as ESR and CRP.
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It is known that inoculation of antigen into the anterior chamber (a.c.) of a mouse eye induces a.c.-associated immune deviation (ACAID), which is mediated in part by antigen-specific local and peripheral tolerance to the inciting antigen.,ACAID can also be induced in vivo by intravenous (i.v.) inoculation of ex-vivo-generated tolerogenic antigen-presenting cells (TolAPC).,The purpose of this study was to test if in-vitro-generated retinal antigen-pulsed TolAPC suppressed established experimental autoimmune uveitis (EAU).,Retinal antigen-pulsed TolAPC were injected i.v. into mice 7 days post-induction of EAU.,We observed that retinal antigen-pulsed TolAPC suppressed the incidence and severity of the clinical expression of EAU and reduced the expression of associated inflammatory cytokines.,Moreover, extract of whole retina efficiently replaced interphotoreceptor retinoid-binding protein (IRBP) in the preparation of TolAPC used to induce tolerance in EAU mice.,Finally, the suppression of EAU could be transferred to a new set of EAU mice with CD8+ but not with CD4+regulatory T cells (Treg).,Retinal antigen-pulsed TolAPC suppressed ongoing EAU by inducing CD8+ Treg cells that, in turn, suppressed the effector activity of the IRBP-specific T cells and altered the clinical symptoms of autoimmune inflammation in the eye.,The ability to use retinal extract for the antigen raises the possibility that retinal extract could be used to produce autologous TolAPC and then used as therapy in human uveitis.
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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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Over the past two decades it has been increasingly recognized that vitamin D, aside from its crucial involvement in calcium and phosphate homeostasis and the dynamics of the musculoskeletal system, exerts its influential impact on the immune system.,The mechanistic roles that vitamin D plays regarding immune activation for combating infection, as well as pathologically and mediating autoimmune conditions, have been progressively unraveled.,In vitro and in vivo models have demonstrated that the action of vitamin D on various immunocytes is not unidirectional.,Rather, how vitamin D affects immunocyte functions depends on the context of the immune response, in the way that its suppressive or stimulatory action offers physiologically appropriate and immunologically advantageous outcomes.,In this review, the relationship between various aspects of vitamin D, starting from its adequacy in circulation to its immunological functions, as well as its autoimmune conditions, in particular systemic lupus erythematosus (SLE), a prototype autoimmune condition characterized by immune-complex mediated inflammation, will be discussed.,Concurring with other groups of investigators, our group found that vitamin D deficiency is highly prevalent in patients with SLE.,Furthermore, the circulating vitamin D levels appear to be correlated with a higher disease activity of SLE as well as extra-musculoskeletal complications of SLE such as fatigue, cardiovascular risk, and cognitive impairment.
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Systemic lupus erythematosus (SLE) is a T and B cell-dependent autoimmune disease characterized by the appearance of autoantibodies, a global regulatory T cells (Tregs) depletion and an increase in Th17 cells.,Recent studies have shown the multifaceted immunomodulatory effects of vitamin D, notably the expansion of Tregs and the decrease of Th1 and Th17 cells.,A significant correlation between higher disease activity and lower serum 25-hydroxyvitamin D levels [25(OH)D] was also shown.,In this prospective study, we evaluated the safety and the immunological effects of vitamin D supplementation (100 000 IU of cholecalciferol per week for 4 weeks, followed by 100 000 IU of cholecalciferol per month for 6 months.) in 20 SLE patients with hypovitaminosis D.,Serum 25(OH)D levels dramatically increased under vitamin D supplementation from 18.7±6.7 at day 0 to 51.4±14.1 (p<0.001) at 2 months and 41.5±10.1 ng/mL (p<0.001) at 6 months.,Vitamin D was well tolerated and induced a preferential increase of naïve CD4+ T cells, an increase of regulatory T cells and a decrease of effector Th1 and Th17 cells.,Vitamin D also induced a decrease of memory B cells and anti-DNA antibodies.,No modification of the prednisone dosage or initiation of new immunosuppressant agents was needed in all patients.,We did not observe SLE flare during the 6 months follow-up period.,This preliminary study suggests the beneficial role of vitamin D in SLE patients and needs to be confirmed in randomized controlled trials.
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Patients with rheumatoid arthritis (RA) are at increased risk of lymphoma compared with the general population.,There are concerns that tumour necrosis factor inhibitors (TNFi) may exacerbate this risk.,However, since the excess risk of lymphoma in RA is related to the cumulative burden of inflammation, TNFi may conversely reduce the risk of lymphoma by decreasing the burden of inflammation.,The aim of this study was to compare the risk of lymphoma in subjects with RA treated with TNFi with those treated with non-biological therapy.,Subjects diagnosed by a rheumatologist with RA enrolled in the British Society for Rheumatology Rheumatoid Arthritis Register (BSRBR-RA), a prospective cohort study, were followed until first lymphoma, death or until 30 November 2013.,Rates of lymphoma in the TNFi and non-biological-treated cohorts were compared using Cox regression.,11 931 TNFi-treated patients were compared with 3367 biological-naive patients. 84 lymphomas (88 (95% CI 70 to 109) per 100 000 person-years) were reported in the TNFi cohort and 30 lymphomas (154 (95% CI 104 to 220)) in the biological-naive cohort.,After adjusting for differences in baseline characteristics, there was no difference in the risk of lymphoma for the TNFi versus the biological-naive group: HR 1.00 (95% CI 0.56 to 1.80).,No risk differences were observed for individual TNFi.,In medium-term follow-up, there is no evidence that tumour necrosis factor inhibition influences the risk of lymphoma over the background risk in subjects with RA.
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Rheumatoid arthritis (RA) is a chronic inflammatory disease caused by both genetic and environmental factors.,Smoking has been implicated as one of the most important extrinsic risk factors for its development and severity.,Recent developments have shed light on the pathophysiology of RA in smokers, including oxidative stress, inflammation, autoantibody formation and epigenetic changes.,The association of smoking and the development of RA have been demonstrated through epidemiologic studies, as well as through in vivo and animal models of RA.,With increased use of biological agents in addition to standard disease-modifying antirheumatic drugs (DMARDs), there has been interest in how smoking affects drug response in RA treatment.,Recent evidence suggests the response and drug survival in people treated with anti-tumour necrosis factor (anti-TNF) therapy is poorer in heavy smokers, and possible immunological mechanisms for this effect are presented in the current paper.
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DNA sequence variation within human leukocyte antigen (HLA) genes mediate susceptibility to a wide range of human diseases.,The complex genetic structure of the major histocompatibility complex (MHC) makes it difficult, however, to collect genotyping data in large cohorts.,Long-range linkage disequilibrium between HLA loci and SNP markers across the major histocompatibility complex (MHC) region offers an alternative approach through imputation to interrogate HLA variation in existing GWAS data sets.,Here we describe a computational strategy, SNP2HLA, to impute classical alleles and amino acid polymorphisms at class I (HLA-A, -B, -C) and class II (-DPA1, -DPB1, -DQA1, -DQB1, and -DRB1) loci.,To characterize performance of SNP2HLA, we constructed two European ancestry reference panels, one based on data collected in HapMap-CEPH pedigrees (90 individuals) and another based on data collected by the Type 1 Diabetes Genetics Consortium (T1DGC, 5,225 individuals).,We imputed HLA alleles in an independent data set from the British 1958 Birth Cohort (N = 918) with gold standard four-digit HLA types and SNPs genotyped using the Affymetrix GeneChip 500 K and Illumina Immunochip microarrays.,We demonstrate that the sample size of the reference panel, rather than SNP density of the genotyping platform, is critical to achieve high imputation accuracy.,Using the larger T1DGC reference panel, the average accuracy at four-digit resolution is 94.7% using the low-density Affymetrix GeneChip 500 K, and 96.7% using the high-density Illumina Immunochip.,For amino acid polymorphisms within HLA genes, we achieve 98.6% and 99.3% accuracy using the Affymetrix GeneChip 500 K and Illumina Immunochip, respectively.,Finally, we demonstrate how imputation and association testing at amino acid resolution can facilitate fine-mapping of primary MHC association signals, giving a specific example from type 1 diabetes.
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The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multi-center collaborative consortium established to develop a translational research infrastructure for Nephrotic Syndrome.,This includes a longitudinal observational cohort study, a pilot and ancillary studies program, a training program, and a patient contact registry.,NEPTUNE will enroll 450 adults and children with minimal change disease, focal segmental glomerulosclerosis and membranous nephropathy for detailed clinical, histopathologic, and molecular phenotyping at the time of clinically-indicated renal biopsy.,Initial visits will include an extensive clinical history, physical examination, collection of urine, blood and renal tissue samples, and assessments of quality of life and patient-reported outcomes.,Follow-up history, physical measures, urine and blood samples, and questionnaires will be obtained every 4 months in the first year and bi-annually, thereafter.,Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histologic data for comprehensive analyses using systems biology approaches.,Analytical strategies were designed to transform descriptive information to mechanistic disease classification for Nephrotic Syndrome and to identify clinical, histological, and genomic disease predictors.,Thus, understanding the complexity of the disease pathogenesis will guide further investigation for targeted therapeutic strategies.
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We assessed CSF levels of the light chain subunit of neurofilaments (NfL) at baseline and after fingolimod therapy or placebo in patients with relapsing-remitting multiple sclerosis (RRMS).,Changes in NfL levels were also correlated with relapse and MRI outcomes.,CSF samples were available, at baseline and 12 months after treatment initiation, from a subset of 36 patients with RRMS (fingolimod 0.5 mg: n = 9; fingolimod 1.25 mg: n = 15; placebo: n = 12) participating in the 2-year, phase 3 Fingolimod (FTY720) Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study.,NfL levels were determined in a blinded fashion using a commercial ELISA kit.,Median NfL levels did not differ between treatment groups at baseline (0.5 mg: 644 pg/mL; 1.25 mg: 659 pg/mL; pooled 0.5/1.25 mg: 652 pg/mL, placebo: 886 pg/mL; p value [fingolimod vs placebo] = 0.619, 0.495, and 0.481, respectively).,Following 12 months of treatment, median changes from baseline in NfL levels were lower than zero in the fingolimod groups (0.5 mg: −346 pg/mL, p = 0.039; 1.25 mg: −313 pg/mL, p = 0.035) and pooled 0.5/1.25 mg fingolimod group (−326 pg/mL, 83.3% with reduction, p = 0.002) but not in the placebo group (−214 pg/mL, 66.7% with reduction, p = 0.388).,Reductions in NfL levels at month 12 correlated with an improvement in relapse and MRI outcomes.,Our results suggest a beneficial effect of fingolimod on this marker of axonal injury and support the utility of NfL as a quantitative biomarker in multiple sclerosis.
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Episodic memory deficits are frequent symptoms in Multiple Sclerosis and have been associated with dysfunctions of the hippocampus, a key region for learning.,However, it is unclear whether genetic factors that influence neural plasticity modulate episodic memory in MS.,We thus studied how the Brain Derived Neurotrophic Factor Val66Met genotype, a common polymorphism influencing the hippocampal function in healthy controls, impacted on brain networks underlying episodic memory in patients with Multiple Sclerosis.,Functional magnetic resonance imaging was used to assess how the Brain Derived Neurotrophic Factor Val66Met polymorphism modulated brain regional activity and functional connectivity in 26 cognitively unimpaired Multiple Sclerosis patients and 25 age- and education-matched healthy controls while performing an episodic memory task that included encoding and retrieving visual scenes.,We found a highly significant group by genotype interaction in the left posterior hippocampus, bilateral parahippocampus, and left posterior cingulate cortex.,In particular, Multiple Sclerosis patients homozygous for the Val66 allele, relative to Met66 carriers, showed greater brain responses during both encoding and retrieval while the opposite was true for healthy controls.,Furthermore, a robust group by genotype by task interaction was detected for the functional connectivity between the left posterior hippocampus and the ipsilateral posterior cingulate cortex.,Here, greater hippocampus-posterior cingulate cortex connectivity was observed in Multiple Sclerosis Met66 carriers relative to Val66 homozygous during retrieval (but not encoding) while, again, the reverse was true for healthy controls.,The Val66Met polymorphism has opposite effects on hippocampal circuitry underlying episodic memory in Multiple Sclerosis patients and healthy controls.,Enhancing the knowledge of how genetic factors influence cognitive functions may improve the clinical management of memory deficits in patients with Multiple Sclerosis.
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Rheumatoid arthritis is a systemic, polygenic, and multifactorial syndrome characterized by erosive polyarthritis, damage to joint architecture, and presence of autoantibodies against several self-structures in the serum and synovial fluid.,These autoantibodies (anticitrullinated protein/peptide antibodies (ACPAs), rheumatoid factors (RF), anticollagen type II antibodies, antiglucose-6 phosphate isomerase antibodies, anticarbamylated protein antibodies, and antiacetylated protein antibodies) have different characteristics, diagnostic/prognostic value, and pathological significance in RA patients.,Some of these antibodies are present in the patients' serum several years before the onset of clinical disease.,Various genetic and environmental factors are associated with autoantibody production against different autoantigenic targets.,Both the activating and inhibitory FcγRs and the activation of different complement cascades contribute to the downstream effector functions in the antibody-mediated disease pathology.,Interplay between several molecules (cytokines, chemokines, proteases, and inflammatory mediators) culminates in causing damage to the articular cartilage and bones.,In addition, autoantibodies are proven to be useful disease markers for RA, and different diagnostic tools are being developed for early diagnosis of the clinical disease.,Recently, a direct link was proposed between the presence of autoantibodies and bone erosion as well as in the induction of pain.,In this review, the diagnostic value of autoantibodies, their synthesis and function as a mediator of joint inflammation, and the significance of IgG-Fc glycosylation are discussed.
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Guillain-Barré syndrome (GBS) is a rare, but potentially fatal, immune-mediated disease of the peripheral nerves and nerve roots that is usually triggered by infections.,The incidence of GBS can therefore increase during outbreaks of infectious diseases, as was seen during the Zika virus epidemics in 2013 in French Polynesia and 2015 in Latin America.,Diagnosis and management of GBS can be complicated as its clinical presentation and disease course are heterogeneous, and no international clinical guidelines are currently available.,To support clinicians, especially in the context of an outbreak, we have developed a globally applicable guideline for the diagnosis and management of GBS.,The guideline is based on current literature and expert consensus, and has a ten-step structure to facilitate its use in clinical practice.,We first provide an introduction to the diagnostic criteria, clinical variants and differential diagnoses of GBS.,The ten steps then cover early recognition and diagnosis of GBS, admission to the intensive care unit, treatment indication and selection, monitoring and treatment of disease progression, prediction of clinical course and outcome, and management of complications and sequelae.,In this Consensus Statement, Leonhard et al. provide a globally applicable guideline for the diagnosis and management of Guillain-Barré syndrome, including information on early recognition of the disease, prediction of clinical course and outcome, and management of complications and sequelae.,Classic Guillain-Barré syndrome (GBS) is an acute-onset ascending sensorimotor neuropathy, but the disease can present atypically or as a clinical variant.Abnormal results in electrophysiological studies and a combination of an increased protein level and normal cell count in cerebrospinal fluid are classic features of GBS, but patients with GBS can have normal results in both tests, especially early in the disease course.Respiratory function should be monitored in all patients as respiratory failure can occur without symptoms of dyspnoea.Intravenous immunoglobulin and plasma exchange are equally effective in treating GBS; no other treatments have been proven to be effective.The efficacy of repeat treatment in patients who have shown insufficient clinical response is uncertain; nevertheless, this practice is common in patients who show deterioration after an initial treatment response.Clinical improvement is usually most extensive in the first year after disease onset and can continue for >5 years.,Classic Guillain-Barré syndrome (GBS) is an acute-onset ascending sensorimotor neuropathy, but the disease can present atypically or as a clinical variant.,Abnormal results in electrophysiological studies and a combination of an increased protein level and normal cell count in cerebrospinal fluid are classic features of GBS, but patients with GBS can have normal results in both tests, especially early in the disease course.,Respiratory function should be monitored in all patients as respiratory failure can occur without symptoms of dyspnoea.,Intravenous immunoglobulin and plasma exchange are equally effective in treating GBS; no other treatments have been proven to be effective.,The efficacy of repeat treatment in patients who have shown insufficient clinical response is uncertain; nevertheless, this practice is common in patients who show deterioration after an initial treatment response.,Clinical improvement is usually most extensive in the first year after disease onset and can continue for >5 years.
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Randomized controlled clinical trials and real-world observational studies provide complementary information but with different validity.,Some clinical questions (disease behavior, prognosis, validation of outcome measures, comparative effectiveness, and long-term safety of therapies) are often better addressed using real-world data reflecting larger, more representative populations.,Integration of disease history, clinician-reported outcomes, performance tests, and patient-reported outcome measures during patient encounters; imaging and biospecimen analyses; and data from wearable devices increase dataset utility.,However, observational studies utilizing these data are susceptible to many potential sources of bias, creating barriers to acceptance by regulatory agencies and the medical community.,Therefore, data standardization and validation within datasets, harmonization across datasets, and application of appropriate analysis methods are important considerations.,We review approaches to improve the scope, quality, and analyses of real-world data to advance understanding of multiple sclerosis and its treatment, as an example of opportunities to better support patient care and research.
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To characterize the accrual of long‐term disability in a cohort of actively treated multiple sclerosis (MS) patients and to assess whether clinical and magnetic resonance imaging (MRI) data used in clinical trials have long‐term prognostic value.,This is a prospective study of 517 actively managed MS patients enrolled at a single center.,More than 91% of patients were retained, with data ascertained up to 10 years after the baseline visit.,At this last assessment, neurologic disability as measured by the Expanded Disability Status Scale (EDSS) was stable or improved compared to baseline in 41% of patients.,Subjects with no evidence of disease activity (NEDA) by clinical and MRI criteria during the first 2 years had long‐term outcomes that were no different from those of the cohort as a whole.,25‐OH vitamin D serum levels were inversely associated with short‐term MS disease activity; however, these levels had no association with long‐term disability.,At a median time of 16.8 years after disease onset, 10.7% (95% confidence interval [CI] = 7.2-14%) of patients reached an EDSS ≥ 6, and 18.1% (95% CI = 13.5-22.5%) evolved from relapsing MS to secondary progressive MS (SPMS).,Rates of worsening and evolution to SPMS were substantially lower when compared to earlier natural history studies.,Notably, the NEDA 2‐year endpoint was not a predictor of long‐term stability.,Finally, the data call into question the utility of annual MRI assessments as a treat‐to‐target approach for MS care.,Ann Neurol 2016;80:499-510
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Systemic lupus erythematosus (SLE) is characterized by high-titer serological autoantibodies, including antibodies that bind to double-stranded DNA (dsDNA).,The origin, specificity, and pathogenicity of anti-dsDNA antibodies have been studied from a wider perspective.,These autoantibodies have been suggested to contribute to multiple end-organ injuries, especially to lupus nephritis, in patients with SLE.,Moreover, serum levels of anti-DNA antibodies fluctuate with disease activity in patients with SLE.,By directly binding to self-antigens or indirectly forming immune complexes, anti-dsDNA antibodies can accumulate in the glomerular and tubular basement membrane.,These autoantibodies can also trigger the complement cascade, penetrate into living cells, modulate gene expression, and even induce profibrotic phenotypes of renal cells.,In addition, the expression of suppressor of cytokine signaling 1 is reduced by anti-DNA antibodies simultaneously with upregulation of profibrotic genes.,Anti-dsDNA antibodies may even participate in the pathogenesis of SLE by catalyzing hydrolysis of certain DNA molecules or peptides in cells.,Recently, anti-dsDNA antibodies have been explored in greater depth as a therapeutic target in the management of SLE.,A substantial amount of data indicates that blockade of pathogenic anti-dsDNA antibodies can prevent or even reverse organ damage in murine models of SLE.,This review focuses on the recent research advances regarding the origin, specificity, classification, and pathogenicity of anti-dsDNA antibodies and highlights the emerging therapies associated with them.
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The present review focuses on pathogenic molecular and transcriptional events in patients with lupus nephritis.,These factors are renal DNaseI, exposed chromatin fragments and the corresponding chromatin-reactive autoantibodies.,Lupus nephritis is the most serious complication in human systemic lupus erythematosus, and is characterised by deposition of chromatin fragment-IgG complexes in the mesangial matrix and glomerular basement membranes.,The latter deposition defines end-stage disease.,This event is stringently linked to a renal-restricted shutdown of expression of the DNaseI gene, as determined by loss of DNaseI mRNA level and DNaseI enzyme activity.,The major aim of the present review is to generate new therapeutic strategies based on new insight into the disease pathogenesis.
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We explored the effects of B-cell directed therapy in subjects at risk of developing autoantibodypositive rheumatoid arthritis (RA), who never experienced inflammatory arthritis before, and explored biomarkers predictive of arthritis development.,Individuals positive for both anti-citrullinated peptide antibodies and rheumatoid factor but without arthritis were included in a randomised, double-blind, placebo-controlled study to receive a single infusion of 1000 mg rituximab or placebo.,Eighty-one individuals received treatment and were followed up for a mean of 29.0 (0-54) months, during which 30/81 (37%) individuals developed arthritis.,The observed risk of developing arthritis in the placebo-treated group was 40%, which was decreased by 55% (HR 0.45, 95% CI 0.154 to 1.322) in the rituximab-treated group at 12 months.,Rituximab treatment caused a delay in arthritis development of 12 months compared with placebo treatment at the point when 25% of the subjects had developed arthritis (p<0.0001).,Erythrocyte sedimentation rate and the presence of anti-citrullinated α-enolase peptide 1 at baseline were significant predictors of arthritis development.,A single infusion of 1000 mg rituximab significantly delays the development of arthritis in subjects at risk of developing RA, providing evidence for the pathogenetic role of B cells in the earliest, prearthritis stage of autoantibody positive RA.
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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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Is influenza vaccination associated with Guillain-Barré syndrome (GBS) among adults aged 65 years or older?,This cross-sectional study of 374 older adults in Taiwan who were hospitalized for GBS found that the risk of GBS did not increase after influenza vaccination regardless of postvaccination risk interval or baseline characteristics.,These findings suggest that influenza vaccination may not increase the risk of GBS among older adults.,This cross-sectional study investigates the association between seasonal influenza vaccination and incidence of Guillain-Barré syndrome among adults 65 years or older in Taiwan.,Although influenza vaccination has been associated with Guillain-Barré syndrome (GBS), the findings among studies of older adult populations are inconsistent.,To determine the risk of GBS after influenza vaccination among older adults.,This cross-sectional study incorporated a self-controlled case series design.,Days 1 to 7, days 1 to 14, and days 1 to 42 after influenza vaccination were identified as risk intervals; days 8 to 180, days 15 to 180, and days 43 to 180 comprised the corresponding control interval.,Population-based data were obtained from Taiwan’s National Health Insurance research database between January 1, 2003, and December 31, 2017.,Data were analyzed from November 1, 2021, through February 28, 2022.,Adults 65 years or older who developed GBS within 180 days after influenza vaccination were enrolled.,Government-funded seasonal influenza vaccination.,Onset of GBS during risk intervals after influenza vaccination compared with control intervals using Poisson regression to calculate incidence rate ratio (IRR).,Of 13 482 122 adults aged 65 years or older who received an influenza vaccination, 374 were hospitalized for GBS.,The mean (SD) age of the study population was 75.0 (6.1) years; 215 (57.5%) were men and 159 (42.5%) were women.,In terms of comorbidities, 33 adults (8.8%) had cancer and 4 (1.1%) had autoimmune diseases.,The IRRs for GBS during days 1 to 7, days 1 to 14, and days 1 to 42 were 0.95 (95% CI, 0.55-1.61; P = .84), 0.87 (95% CI, 0.58-1.29; P = .48), and 0.92 (95% CI, 0.72-1.17; P = .49), respectively.,No results showed statistical significance.,Similarly, no significant differences in IRRs were noted for the overall risk interval (ie, days 1-42) in subgroup analyses pertaining to different age groups (65-74 years [0.93 (95% CI, 0.66-1.31)], 75-84 years [0.85 (95% CI, 0.58-1.26)], and ≥85 years [1.10 (95% CI, 0.57-2.11)]), sex (men, 0.97 [95% CI, 0.71-1.33; P = .87]; women, 0.85 [95% CI, 0.58-1.23; P = .39]), Charlson Comorbidity Index (1.03 [95% CI, 0.77-1.38; P = .84]), or comorbidities (cancer, 0.68 [95% CI, 0.28-1.64; P = .39]; autoimmune disease, 1.10 [95% CI, 0.11-10.53; P = .94]).,These findings suggest that influenza vaccination did not increase the risk of GBS among adults aged 65 years or older in Taiwan regardless of postvaccination period or underlying characteristics.
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The clinical characteristics of Guillain-Barré syndrome (GBS) after coronavirus disease 2019 (COVID-19) remain unclear due to the small number of cases.,We herein report a case of a Japanese patient with post-COVID-19 GBS who presented with facial and limb muscle weakness, sensory deficits, and autonomic dysfunction.,Nerve conduction studies revealed demyelination.,Head magnetic resonance imaging showed contrast enhancement in the bilateral facial nerves.,Systemic management, including intubation, intravenous immunoglobulin therapy, and rehabilitation, improved the patient's condition.,This was the first Japanese case of acute inflammatory demyelinating polyneuropathy after COVID-19 and was characterized by autonomic dysfunction and facial nerve enhancement.
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See Stankoff and Louapre (doi:10.1093/brain/awy114) for a scientific commentary on this article.,Grey matter atrophy in multiple sclerosis affects certain areas preferentially.,Eshaghi et al. use a data-driven computational model to predict the order in which regions atrophy, and use this sequence to stage patients.,Atrophy begins in deep grey matter nuclei and posterior cortical regions, before spreading to other cortical areas.,See Stankoff and Louapre (doi:10.1093/brain/awy114) for a scientific commentary on this article.,Grey matter atrophy is present from the earliest stages of multiple sclerosis, but its temporal ordering is poorly understood.,We aimed to determine the sequence in which grey matter regions become atrophic in multiple sclerosis and its association with disability accumulation.,In this longitudinal study, we included 1417 subjects: 253 with clinically isolated syndrome, 708 with relapsing-remitting multiple sclerosis, 128 with secondary-progressive multiple sclerosis, 125 with primary-progressive multiple sclerosis, and 203 healthy control subjects from seven European centres.,Subjects underwent repeated MRI (total number of scans 3604); the mean follow-up for patients was 2.41 years (standard deviation = 1.97).,Disability was scored using the Expanded Disability Status Scale.,We calculated the volume of brain grey matter regions and brainstem using an unbiased within-subject template and used an established data-driven event-based model to determine the sequence of occurrence of atrophy and its uncertainty.,We assigned each subject to a specific event-based model stage, based on the number of their atrophic regions.,Linear mixed-effects models were used to explore associations between the rate of increase in event-based model stages, and T2 lesion load, disease-modifying treatments, comorbidity, disease duration and disability accumulation.,The first regions to become atrophic in patients with clinically isolated syndrome and relapse-onset multiple sclerosis were the posterior cingulate cortex and precuneus, followed by the middle cingulate cortex, brainstem and thalamus.,A similar sequence of atrophy was detected in primary-progressive multiple sclerosis with the involvement of the thalamus, cuneus, precuneus, and pallidum, followed by the brainstem and posterior cingulate cortex.,The cerebellum, caudate and putamen showed early atrophy in relapse-onset multiple sclerosis and late atrophy in primary-progressive multiple sclerosis.,Patients with secondary-progressive multiple sclerosis showed the highest event-based model stage (the highest number of atrophic regions, P < 0.001) at the study entry.,All multiple sclerosis phenotypes, but clinically isolated syndrome, showed a faster rate of increase in the event-based model stage than healthy controls.,T2 lesion load and disease duration in all patients were associated with increased event-based model stage, but no effects of disease-modifying treatments and comorbidity on event-based model stage were observed.,The annualized rate of event-based model stage was associated with the disability accumulation in relapsing-remitting multiple sclerosis, independent of disease duration (P < 0.0001).,The data-driven staging of atrophy progression in a large multiple sclerosis sample demonstrates that grey matter atrophy spreads to involve more regions over time.,The sequence in which regions become atrophic is reasonably consistent across multiple sclerosis phenotypes.,The spread of atrophy was associated with disease duration and with disability accumulation over time in relapsing-remitting multiple sclerosis.
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Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing.,Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research.,A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis.,Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation.,Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS.,Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS.
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Environmental factors driving the development of type 1 diabetes (T1D) are still largely unknown.,Both animal and human studies have shown an association between altered fecal microbiota composition, impaired production of short-chain fatty acids (SCFA) and T1D onset.,However, observational evidence on SCFA and fecal and oral microbiota in adults with longstanding T1D vs healthy controls (HC) is lacking.,We included 53 T1D patients without complications or medication and 50 HC matched for age, sex and BMI.,Oral and fecal microbiota, fecal and plasma SCFA levels, markers of intestinal inflammation (fecal IgA and calprotectin) and markers of low-grade systemic inflammation were measured.,Oral microbiota were markedly different in T1D (eg abundance of Streptococci) compared to HC.,Fecal analysis showed decreased butyrate producing species in T1D and less butyryl-CoA transferase genes.,Also, plasma levels of acetate and propionate were lower in T1D, with similar fecal SCFA.,Finally, fecal strains Christensenella and Subdoligranulum correlated with glycemic control, inflammatory parameters and SCFA.,We conclude that T1D patients harbor a different amount of intestinal SCFA (butyrate) producers and different plasma acetate and propionate levels.,Future research should disentangle cause and effect and whether supplementation of SCFA-producing bacteria or SCFA alone can have disease-modifying effects in T1D.
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Gut microbiome dysbiosis is associated with numerous diseases, including type 1 diabetes.,This pilot study determines how geographical location affects the microbiome of infants at high risk for type 1 diabetes in a population of homogenous HLA class II genotypes.,High-throughput 16S rRNA sequencing was performed on stool samples collected from 90 high-risk, nonautoimmune infants participating in The Environmental Determinants of Diabetes in the Young (TEDDY) study in the U.S., Germany, Sweden, and Finland.,Study site-specific patterns of gut colonization share characteristics across continents.,Finland and Colorado have a significantly lower bacterial diversity, while Sweden and Washington state are dominated by Bifidobacterium in early life.,Bacterial community diversity over time is significantly different by geographical location.,The microbiome of high-risk infants is associated with geographical location.,Future studies aiming to identify the microbiome disease phenotype need to carefully consider the geographical origin of subjects.
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The presence of lupus anticoagulant (LA) is an independent risk factor for thrombosis.,This laboratory phenomenon is detected as a phospholipid‐dependent prolongation of the clotting time and is caused by autoantibodies against beta2‐glycoprotein I (β2GPI) or prothrombin.,How these autoantibodies cause LA is unclear.,To elucidate how anti‐β2GPI and anti‐prothrombin antibodies cause the LA phenomenon.,The effects of monoclonal anti‐β2GPI and anti‐prothrombin antibodies on coagulation were analyzed in plasma and with purified coagulation factors.,Detection of LA caused by anti‐β2GPI or anti‐prothrombin antibodies required the presence of the procofactor factor V (FV) in plasma.,LA effect disappeared when FV was replaced by activated FV (FVa), both in a model system and in patient plasma, although differences between anti‐β2GPI and anti‐prothrombin antibodies were observed.,Further exploration of the effects of the antibodies on coagulation showed that the anti‐β2GPI antibody attenuated FV activation by activated faxtor X (FXa), whereas the anti‐prothrombin antibody did not.,Binding studies showed that β2GPI‐‐antibody complexes directly interacted with FV with high affinity.,Anti‐prothrombin complexes caused the LA phenomenon through competition for phospholipid binding sites with coagulation factors as reduced FXa binding to lipospheres was observed with flow cytometry in the presence of these antibodies.,Anti‐β2GPI and anti‐prothrombin antibodies cause LA through different mechanisms of action: While anti‐β2GPI antibodies interfere with FV activation by FXa through a direct interaction with FV, anti‐prothrombin antibodies compete with FXa for phospholipid binding sites.,These data provide leads for understanding the paradoxical association between thrombosis and a prolonged clotting time in the antiphospholipid syndrome.
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Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial and venous thrombotic manifestations and/or pregnancy-related complications in patients with persistently high antiphospholipid antibodies (aPL), the most common being represented by anticardiolipin antibodies (aCL), anti-beta 2 glycoprotein-I (aβ2GPI), and lupus anticoagulant (LAC).,A growing number of studies have showed that, in some cases, patients may present with clinical features of APS but with temporary positive or persistently negative titers of aPL.,For these patients, the definition of seronegative APS (SN-APS) has been proposed.,Nevertheless, the negativity to classic aPL criteria does not imply that other antibodies may be present or involved in the onset of thrombosis.,The diagnosis of SN-APS is usually made by exclusion, but its recognition is important to adopt the most appropriate anti-thrombotic strategy to reduce the rate of recurrences.,This research is in continuous development as the clinical relevance of these antibodies is far from being completely clarified.,The most studied antibodies are those against phosphatidylethanolamine, phosphatidic acid, phosphatidylserine, phosphatidylinositol, vimentin/cardiolipin complex, and annexin A5.,Moreover, the assays to measure the levels of these antibodies have not yet been standardized.,In this review, we will summarize the evidence on the most studied non-criteria aPL, their potential clinical relevance, and the antithrombotic therapeutic strategies available in the setting of APS and SN-APS.
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Early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic β cells.,We show here that exposure to pro-inflammatory cytokines unmasks a marked plasticity of the β-cell regulatory landscape.,We expand the repertoire of human islet regulatory elements by mapping stimulus-responsive enhancers linked to changes in the β-cell transcriptome, proteome and 3D chromatin structure.,Our data indicate that the β cell response to cytokines is mediated by the induction of new regulatory regions as well as the activation of primed regulatory elements prebound by islet-specific transcription factors.,We find that T1D-associated loci are enriched of the newly mapped cis-regulatory regions and identify T1D-associated variants disrupting cytokine-responsive enhancer activity in human β cells.,Our study illustrates how β cells respond to a pro-inflammatory environment and implicate a role for stimulus-response islet enhancers in T1D.
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We studied the change in the first-phase insulin response (FPIR) during the progression to type 1 diabetes (T1D).,Seventy-four oral insulin trial progressors to T1D from the Diabetes Prevention Trial-Type 1 with at least one FPIR measurement after baseline and before diagnosis were studied.,The FPIR was examined longitudinally in 26 progressors who had FPIR measurements during each of the 3 years before diagnosis.,The association between the change from the baseline FPIR to the last FPIR and time to diagnosis was studied in the remainder (n = 48).,The 74 progressors had lower baseline FPIR values than nonprogressors (n = 270), with adjustments made for age and BMI.,In the longitudinal analysis of the 26 progressors, there was a greater decline in the FPIR from 1.5 to 0.5 years before diagnosis than from 2.5 to 1.5 years before diagnosis.,This accelerated decline was also evident in a regression analysis of the 48 remaining progressors in whom the rate of decline became more marked with the approaching diagnosis.,The patterns of decline were similar between the longitudinal and regression analyses.,There is an acceleration of decline in the FPIR during the progression to T1D, which becomes especially marked between 1.5 and 0.5 years before diagnosis.
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Myelin sheaths in the central nervous system (CNS) insulate axons and thereby allow saltatory nerve conduction, which is a prerequisite for complex brain function.,Multiple sclerosis (MS), the most common inflammatory autoimmune disease of the CNS, leads to the destruction of myelin sheaths and the myelin-producing oligodendrocytes, thus leaving behind demyelinated axons prone to injury and degeneration.,Clinically, this process manifests itself in significant neurological symptoms and disability.,Resident oligodendroglial precursor cells (OPCs) and neural stem cells (NSCs) are present in the adult brain, and can differentiate into mature oligodendrocytes which then remyelinate the demyelinated axons.,However, for multiple reasons, in MS the regenerative capacity of these cell populations diminishes significantly over time, ultimately leading to neurodegeneration, which currently remains untreatable.,In addition, microglial cells, the resident innate immune cells of the CNS, can contribute further to inflammatory and degenerative axonal damage.,Here, we review the molecular factors contributing to remyelination failure in MS by inhibiting OPC and NSC differentiation or modulating microglial behavior.
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Oligodendrocytes wrap nerve fibers in the central nervous system with layers of specialized cell membrane to form myelin sheaths1.,Myelin is destroyed by the immune system in multiple sclerosis, but myelin is thought to regenerate and neurological function can be recovered.,In animal models of demyelinating disease, myelin is regenerated by newly generated oligodendrocytes, and remaining mature oligodendrocytes do not appear to contribute to this process2-4.,Considering the major differences in oligodendrocyte generation dynamics and adaptive myelination between rodents and humans5-9, it is uncertain how well experimental animals reflect the situation in multiple sclerosis.,We have assessed the generation dynamics of oligodendrocytes in multiple sclerosis patients by measuring the integration of nuclear bomb test derived 14C in genomic DNA10.,The generation of new oligodendrocytes was increased several-fold in normal appearing white matter in a subset of individuals with very aggressive disease, but not in the majority of subjects with multiple sclerosis, demonstrating an inherent potential to substantially increase oligodendrocyte generation but that this fails in most patients.,Oligodendrocytes in shadow plaques, thinly myelinated lesion that are thought to represent remyelinated areas, were old in multiple sclerosis patients.,The absence of new oligodendrocytes in shadow plaques suggests that remyelination of lesions occur transiently or not at all, or that myelin is regenerated by preexisting, and not new, oligodendrocytes in multiple sclerosis.,We report unexpected oligodendrocyte generation dynamics in multiple sclerosis, which should guide the use of current, and the development of new, therapies.
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Immune homeostasis depends on the proper function of regulatory T (Treg) cells.,Compromised Treg cell suppressive activity leads to autoimmune disease, graft rejection and promotes anti-tumor immunity.,Here we report the previously unrecognized requirement of the serine/threonine phosphatase Protein Phosphatase 2A (PP2A) for the function of Treg cells.,Treg cells exhibited high PP2A activity and Treg cell-specific ablation of the PP2A complex resulted in a severe, multi-organ, lymphoproliferative autoimmune disorder.,Mass spectrometric analysis revealed that PP2A associates with components of the mTOR pathway and suppresses mTORC1 activity.,In the absence of PP2A, Treg cells altered their metabolic and cytokine profile and were unable to suppress effector immune responses.,Therefore, PP2A is requisite for the function of Treg cells and the prevention of autoimmunity.
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HIF1α induction by mTOR represents a metabolic checkpoint for the differentiation of TH17 and Treg cells.,Upon antigen stimulation, the bioenergetic demands of T cells increase dramatically over the resting state.,Although a role for the metabolic switch to glycolysis has been suggested to support increased anabolic activities and facilitate T cell growth and proliferation, whether cellular metabolism controls T cell lineage choices remains poorly understood.,We report that the glycolytic pathway is actively regulated during the differentiation of inflammatory TH17 and Foxp3-expressing regulatory T cells (Treg cells) and controls cell fate determination.,TH17 but not Treg cell-inducing conditions resulted in strong up-regulation of the glycolytic activity and induction of glycolytic enzymes.,Blocking glycolysis inhibited TH17 development while promoting Treg cell generation.,Moreover, the transcription factor hypoxia-inducible factor 1α (HIF1α) was selectively expressed in TH17 cells and its induction required signaling through mTOR, a central regulator of cellular metabolism.,HIF1α-dependent transcriptional program was important for mediating glycolytic activity, thereby contributing to the lineage choices between TH17 and Treg cells.,Lack of HIF1α resulted in diminished TH17 development but enhanced Treg cell differentiation and protected mice from autoimmune neuroinflammation.,Our studies demonstrate that HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells.
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Although the aetiology of systemic lupus erythematosus (SLE) is unclear, dysregulated B cell responses have been implicated.,Here we show that an unusual CD11chiT-bet+ B cell subset, with a unique expression profile including chemokine receptors consistent with migration to target tissues, is expanded in SLE patients, present in nephrotic kidney, enriched for autoreactive specificities and correlates with defined clinical manifestations.,IL-21 can potently induce CD11chiT-bet+ B cells and promote the differentiation of these cells into Ig-secreting autoreactive plasma cells.,While murine studies have identified a role for T-bet-expressing B cells in autoimmunity, this study describes and exemplifies the importance of CD11chiT-bet+ B cells in human SLE.,Systemic lupus erythematosus (SLE) is associated with altered B cell responses but the underlying aetiology is still unclear.,Here the authors show that a CD11chiT-bet+ B cell subset with a unique phenotype and transcriptome is increased in patients with SLE, can be expanded by IL-21, and may contribute to autoimmune responses in SLE.
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The Sjögren syndrome has been diagnosed in patients with HTLV-1 associated myelopathy and dry mouth and dry eyes are documented in HTLV-1 carriers.,However the diagnosis of Sjögren syndrome in these subjects has been contested.,In this cross-sectional study, we evaluated the role of immunological factors and proviral load, in sicca syndrome associated with HTLV-1 in patients without myelopathy.,Subjects were recruited in the HTLV-1 Clinic, from 2009 to 2011.,The proviral load and cytokine levels (IFN-γ, TNF-α, IL-5, and IL-10) were obtained from a database containing the values presented by the subjects at admission in the clinic.,Of the 272 participants, 59 (21.7%) had sicca syndrome and in all of them anti-Sjögren syndrome related antigen A (SSA) and antigen B (SSB) were negatives.,The production of TNF-α and IFN-γ was higher in the group with sicca syndrome (P < 0.05) than in HTLV-1 infected subjects without sicca syndrome.,Our data indicates that patients with sicca syndrome associated with HTLV-1 do not have Sjögren syndrome.,However the increased production of TNF-α and IFN-γ in this group of patients may contribute to the pathogenesis of sicca syndrome associated with HTLV-1.
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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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Cognitive and motor performance measures are commonly employed in multiple sclerosis (MS) research, particularly when the purpose is to determine the efficacy of treatment.,The increasing focus of new therapies on slowing progression or reversing neurological disability makes the utilization of sensitive, reproducible, and valid measures essential.,Processing speed is a basic elemental cognitive function that likely influences downstream processes such as memory.,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 MS.,Among the MSOAC goals is acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful to persons with MS.,A critical step for these neuroperformance metrics is elucidation of clinically relevant benchmarks, well-defined degrees of disability, and gradients of change that are deemed clinically meaningful.,This topical review provides an overview of research on one particular cognitive measure, the Symbol Digit Modalities Test (SDMT), recognized as being particularly sensitive to slowed processing of information that is commonly seen in MS.,The research in MS clearly supports the reliability and validity of this test and recently has supported a responder definition of SDMT change approximating 4 points or 10% in magnitude.
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It is not clear how the profile of immune cells in peripheral blood differs between patients with clinically isolated syndrome (CIS) and healthy controls (HC).,This study aimed to identify a CIS peripheral blood signature that may provide clues for potential immunomodulatory approaches early in disease.,Peripheral blood mononuclear cells (PBMCs) were collected from 18 people with CIS, 19 HC and 13 individuals with other demyelinating conditions (ODC) including multiple sclerosis (MS).,Individuals with CIS separated into two groups, namely those with early (≤14 days post-diagnostic magnetic resonance imaging (MRI); n = 6) and late (≥27 days; n = 12) blood sampling.,Transitional B cells were increased in the blood of CIS patients independently of when blood was taken.,However, there were two time-dependent effects found in the late CIS group relative to HC, including decreased CD56bright NK cells, which correlated significantly with time since MRI, and increased CD141+ myeloid dendritic cell (mDC2) frequencies.,Higher CD1c+ B cells and lower non-classical monocyte frequencies were characteristic of more recent demyelinating disease activity (ODC and early CIS).,Analysing cell populations by time since symptoms (subjective) and diagnostic MRI (objective) may contribute to understanding CIS.
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The pathogenesis of multiple sclerosis (MS), an autoimmune disease affecting the brain and spinal cord, remains poorly understood.,Patients with MS typically present with recurrent episodes of neurological dysfunctions such as blindness, paresis, and sensory disturbances.,Studies on experimental autoimmune encephalomyelitis (EAE) animal models have led to a number of testable hypotheses including a hypothetical role of altered gut microbiota in the development of MS.,To investigate whether gut microbiota in patients with MS is altered, we compared the gut microbiota of 20 Japanese patients with relapsing-remitting (RR) MS (MS20) with that of 40 healthy Japanese subjects (HC40) and an additional 18 healthy subjects (HC18).,All the HC18 subjects repeatedly provided fecal samples over the course of months (158 samples in total).,Analysis of the bacterial 16S ribosomal RNA (rRNA) gene by using a high-throughput culture-independent pyrosequencing method provided evidence of a moderate dysbiosis in the structure of gut microbiota in patients with MS.,Furthermore, we found 21 species that showed significant differences in relative abundance between the MS20 and HC40 samples.,On comparing MS samples to the 158 longitudinal HC18 samples, the differences were found to be reproducibly significant for most of the species.,These taxa comprised primarily of clostridial species belonging to Clostridia clusters XIVa and IV and Bacteroidetes.,The phylogenetic tree analysis revealed that none of the clostridial species that were significantly reduced in the gut microbiota of patients with MS overlapped with other spore-forming clostridial species capable of inducing colonic regulatory T cells (Treg), which prevent autoimmunity and allergies; this suggests that many of the clostridial species associated with MS might be distinct from those broadly associated with autoimmune conditions.,Correcting the dysbiosis and altered gut microbiota might deserve consideration as a potential strategy for the prevention and treatment of MS.
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To determine the safety and efficacy of an automated unified safety system (USS) in providing overnight closed-loop (OCL) control in children and adolescents with type 1 diabetes attending diabetes summer camps.,The Diabetes Assistant (DIAS) USS used the Dexcom G4 Platinum glucose sensor (Dexcom) and t:slim insulin pump (Tandem Diabetes Care).,An initial inpatient study was completed for 12 participants to evaluate safety.,For the main camp study, 20 participants with type 1 diabetes were randomized to either OCL or sensor-augmented therapy (control conditions) per night over the course of a 5- to 6-day diabetes camp.,Subjects completed 54 OCL nights and 52 control nights.,On an intention-to-treat basis, with glucose data analyzed regardless of system status, the median percent time in range, from 70-150 mg/dL, was 62% (29, 87) for OCL nights versus 55% (25, 80) for sensor-augmented pump therapy (P = 0.233).,A per-protocol analysis allowed for assessment of algorithm performance.,The median percent time in range, from 70-150 mg/dL, was 73% (50, 89) for OCL nights (n = 41) versus 52% (24, 83) for control conditions (n = 39) (P = 0.037).,There was less time spent in the hypoglycemic range <50, <60, and <70 mg/dL during OCL compared with the control period (P = 0.019, P = 0.009, and P = 0.023, respectively).,The DIAS USS algorithm is effective in improving time spent in range as well as reducing nocturnal hypoglycemia during the overnight period in children and adolescents with type 1 diabetes in a diabetes camp setting.
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In this two-part Bench to Clinic narrative, recent advances in both the preclinical and clinical aspects of artificial pancreas (AP) development are described.,In the preceding Bench narrative, Kudva and colleagues provide an in-depth understanding of the modified glucoregulatory physiology of type 1 diabetes that will help refine future AP algorithms.,In the Clinic narrative presented here, we compare and evaluate AP technology to gain further momentum toward outpatient trials and eventual approval for widespread use.,We enumerate the design objectives, variables, and challenges involved in AP development, concluding with a discussion of recent clinical advancements.,Thanks to the effective integration of engineering and medicine, the dream of automated glucose regulation is nearing reality.,Consistent and methodical presentation of results will accelerate this success, allowing head-to-head comparisons that will facilitate adoption of the AP as a standard therapy for type 1 diabetes.
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Early evaluation of treatment response and prediction of disease evolution are key issues in the management of people with multiple sclerosis (MS).,In the past 20 years, MRI has become the most useful paraclinical tool in both situations and is used clinically to assess the inflammatory component of the disease, particularly the presence and evolution of focal lesions - the pathological hallmark of MS.,However, diffuse neurodegenerative processes that are at least partly independent of inflammatory mechanisms can develop early in people with MS and are closely related to disability.,The effects of these neurodegenerative processes at a macroscopic level can be quantified by estimation of brain and spinal cord atrophy with MRI.,MRI measurements of atrophy in MS have also been proposed as a complementary approach to lesion assessment to facilitate the prediction of clinical outcomes and to assess treatment responses.,In this Consensus statement, the Magnetic Resonance Imaging in MS (MAGNIMS) study group critically review the application of brain and spinal cord atrophy in clinical practice in the management of MS, considering the role of atrophy measures in prognosis and treatment monitoring and the barriers to clinical use of these measures.,On the basis of this review, the group makes consensus statements and recommendations for future research.,In this Consensus statement, the Magnetic Resonance Imaging in MS (MAGNIMS) study group reviews the application of brain and spinal cord atrophy in clinical practice in the management of MS and makes consensus statements and recommendations for future research.
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The mechanisms leading to disability and the long-term efficacy and safety of disease modifying drugs (DMDs) in multiple sclerosis (MS) are unclear.,We aimed at building a prospective cohort of MS patients with standardized collection of demographic, clinical, MRI data and body fluids that can be used to develop prognostic indicators and biomarkers of disease evolution and therapeutic response.,The Swiss MS Cohort (SMSC) is a prospective observational study performed across seven Swiss MS centers including patients with MS, clinically isolated syndrome (CIS), radiologically isolated syndrome or neuromyelitis optica.,Neurological and radiological assessments and biological samples are collected every 6-12 months.,We recruited 872 patients (clinically isolated syndrome [CIS] 5.5%, relapsing-remitting MS [RRMS] 85.8%, primary progressive MS [PPMS] 3.5%, secondary progressive MS [SPMS] 5.2%) between June 2012 and July 2015.,We performed 2,286 visits (median follow-up 398 days) and collected 2,274 serum, plasma and blood samples, 152 cerebrospinal fluid samples and 1,276 brain MRI scans. 158 relapses occurred and expanded disability status scale (EDSS) scores increased in PPMS, SPMS and RRMS patients experiencing relapses.,Most RRMS patients were treated with fingolimod (33.4%), natalizumab (24.5%) or injectable DMDs (13.6%).,The SMSC will provide relevant information regarding DMDs efficacy and safety and will serve as a comprehensive infrastructure available for nested research projects.
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The family members of patients with rheumatoid arthritis (RA) are at increased risk of developing RA and are potential candidates for predictive testing.,This study explored the perceptions of first-degree relatives of people with RA about being at risk of RA and engaging in predictive testing.,34 first-degree relatives (siblings and offspring) of patients with RA from the UK, Germany and Austria participated in semistructured interviews about their perceptions of RA risk and the prospect of predictive testing.,Interviews were audio-recorded, transcribed verbatim and analysed using thematic analysis.,First-degree relatives were aware of their susceptibility to RA, but were unsure of the extent of their risk.,When considering their future risk, some relatives were concerned about the potential impact that RA would have on their lives.,Relatives were concerned that knowing their actual risk would increase their anxiety and would affect decisions about their future.,Also, relatives were concerned about the levels of uncertainty associated with predictive testing.,Those in favour of knowing their future risk felt that they would need additional support to understand the risk information and cope with the emotional impact of this information.,Identifying individuals at risk of RA may allow targeted interventions to reduce the risk and consequence of future disease; however, relatives have concerns about predictive testing and risk information.,The development of strategies to quantify and communicate risk needs to take these views into account and incorporate approaches to mitigate concerns and minimise the psychological impact of risk information.
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Presence of autoantibodies precedes development of seropositive rheumatoid arthritis (SP RA) and seropositive arthralgia patients (SAP) are at risk of developing RA.,The aims of the study are to identify additional serum immune markers discriminating between SP and seronegative (SN) RA, and markers identifying high-risk SAP.,Sera from SAP (n = 27), SP RA (n = 22), SN RA (n = 11) and healthy controls (n = 20) were analyzed using the Human Cytokine 25-Plex Panel.,Selected markers were validated in independent cohorts of SP RA (n = 35) and SN RA (n = 12) patients.,Eleven of 27 SAP developed RA within 8 months (median follow-up time, range 1-32 months), and their baseline serum markers were compared to 16 non-progressing SAP.,SAP and SP RA patients showed a marked overlap in their systemic immune profiles, while SN RA showed a distinct immune profile.,Three of 4 markers discriminating between SP and SN RA (IL-1β, IL-15 and Eotaxin, but not CCL5) were similarly modulated in independent cohorts.,SAP progressing to RA showed trends for increases in IL-5, MIP-1β, IL-1RA and IL-12 compared to non-progressing SAP.,ROC analysis showed that serum IL-5 most accurately discriminated between the two SAP groups (AUC > 0.8), suggesting that baseline IL-5 levels may aid the identification of high-risk SAP.
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Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that can lead to clinical manifestations of systemic diseases.,Its leading features include chronic synovial inflammation and degeneration of the bones and joints.,In the past decades, multiple susceptibilities for rheumatoid arthritis have been identified along with the development of a remarkable variety of drugs for its treatment; which include analgesics, glucocorticoids, nonsteroidal anti-inflammatory medications (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), and biologic response modifiers (bDMARDs).,Despite the existence of many clinical treatment options, the prognosis of some patients remains poor due to complex mechanism of the disease.,Programmed cell death (PCD) has been extensively studied and ascertained to be one of the essential pathological mechanisms of RA.,Its dysregulation in various associated cell types contributes to the development of RA.,In this review, we summarize the role of apoptosis, cell death-associated neutrophil extracellular trap formation, necroptosis, pyroptosis, and autophagy in the pathophysiology of RA to provide a theoretical reference and insightful direction to the discovery and development of novel therapeutic targets for RA.
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Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by symmetric polyarthritis with swelling and pain at synovial joints.,In RA patients, delayed neutrophil apoptosis amplifies the inflammatory response and massively released neutrophil extracellular traps (NETs) induce tissue damage and provide self-antigens.,Andrographolide (AD) is the major active labdane diterpenoid derived from Andrographis paniculata, which has multiple pharmacological effects, including hepatoprotection, anti-angiogenesis, anti-thrombosis, and anti-inflammation.,In the present study, we investigated the effect of AD on an adjuvant-induced arthritis (AA) murine model of RA and found that AD alleviated murine arthritis by reducing neutrophil infiltration and NETosis in the ankle joints and relieved the systematic inflammation.,In vitro experiments showed that AD accelerated the apoptosis of lipopolysaccharide-activated neutrophils and inhibited autophagy-dependent extracellular traps formation of neutrophils.,These findings suggest that AD has considerable potential for RA therapy.
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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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Multiple sclerosis (MS) is a demyelinating disease of the central nervous system.,We and others have shown that there is enrichment or depletion of some gut bacteria in MS patients compared to healthy controls (HC), suggesting an important role of the gut bacteria in disease pathogenesis.,Thus, specific gut bacteria that are lower in abundance in MS patients could be used as a potential treatment option for this disease.,In particular, we and others have shown that MS patients have a lower abundance of Prevotella compared to HC, whereas the abundance of Prevotella is increased in patients that receive disease-modifying therapies such as Copaxone® (Glatiramer acetate-GA).,This inverse correlation between the severity of MS disease and the abundance of Prevotella suggests its potential for use as a therapeutic option to treat MS.,Notably we have previously identified a specific strain, Prevotella histicola (P. histicola), that suppresses disease in the animal model of MS, experimental autoimmune encephalomyelitis (EAE) compared with sham treatment.,In the present study we analyzed whether the disease suppressing effects of P. histicola synergize with those of the disease-modifying drug Copaxone® to more effectively suppress disease compared to either treatment alone.,Treatment with P. histicola was as effective in suppressing disease as treatment with Copaxone®, whereas the combination of P. histicola plus Copaxone® was not more effective than either individual treatment.,P. histicola-treated mice had an increased frequency and number of CD4+FoxP3+ regulatory T cells in periphery as well as gut and a decreased frequency of pro-inflammatory IFN-γ and IL17-producing CD4 T cells in the CNS, suggesting P. histicola suppresses disease by boosting anti-inflammatory immune responses and inhibiting pro-inflammatory immune responses.,In conclusion, our study indicates that the human gut commensal P. histicola can suppress disease as efficiently as Copaxone® and may provide an alternative treatment option for MS patients.
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Novel outbreak with coronavirus 2019 began since 31 December 2019.,Coronaviruses can cause multiple systemic infections that respiratory complications are the most obvious symptoms.,In this report, we describe the symptoms of Guillain Barre syndrome (GBS) in one infected patient with COVID-19, for the first time.,We reported a 65-years- old male patient with complaints of acute progressive symmetric ascending quadriparesis.,Two weeks prior to hospitalization, the patient suffered from cough, fever, and RT-PCR was reported positive for COVID-19 infection.,The electrodiagnostic test showed that the patient is an AMSAN variant of GBS.,COVID-19 stimulates inflammatory cells and produces various inflammatory cytokines and as a result, it creates immune-mediated processes.,GBS is an immune-mediated disorder and molecular mimicry as a mechanism of autoimmune disorder plays an important role in creating it.,It is unclear whether COVID-19 induces the production of antibodies against specific gangliosides.,Further investigations should be conducted about the mechanism of GBS in patients with COVID-19, in the future.
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Guillain-Barré syndrome (GBS) is a rare, but potentially fatal, immune-mediated disease of the peripheral nerves and nerve roots that is usually triggered by infections.,The incidence of GBS can therefore increase during outbreaks of infectious diseases, as was seen during the Zika virus epidemics in 2013 in French Polynesia and 2015 in Latin America.,Diagnosis and management of GBS can be complicated as its clinical presentation and disease course are heterogeneous, and no international clinical guidelines are currently available.,To support clinicians, especially in the context of an outbreak, we have developed a globally applicable guideline for the diagnosis and management of GBS.,The guideline is based on current literature and expert consensus, and has a ten-step structure to facilitate its use in clinical practice.,We first provide an introduction to the diagnostic criteria, clinical variants and differential diagnoses of GBS.,The ten steps then cover early recognition and diagnosis of GBS, admission to the intensive care unit, treatment indication and selection, monitoring and treatment of disease progression, prediction of clinical course and outcome, and management of complications and sequelae.,In this Consensus Statement, Leonhard et al. provide a globally applicable guideline for the diagnosis and management of Guillain-Barré syndrome, including information on early recognition of the disease, prediction of clinical course and outcome, and management of complications and sequelae.,Classic Guillain-Barré syndrome (GBS) is an acute-onset ascending sensorimotor neuropathy, but the disease can present atypically or as a clinical variant.Abnormal results in electrophysiological studies and a combination of an increased protein level and normal cell count in cerebrospinal fluid are classic features of GBS, but patients with GBS can have normal results in both tests, especially early in the disease course.Respiratory function should be monitored in all patients as respiratory failure can occur without symptoms of dyspnoea.Intravenous immunoglobulin and plasma exchange are equally effective in treating GBS; no other treatments have been proven to be effective.The efficacy of repeat treatment in patients who have shown insufficient clinical response is uncertain; nevertheless, this practice is common in patients who show deterioration after an initial treatment response.Clinical improvement is usually most extensive in the first year after disease onset and can continue for >5 years.,Classic Guillain-Barré syndrome (GBS) is an acute-onset ascending sensorimotor neuropathy, but the disease can present atypically or as a clinical variant.,Abnormal results in electrophysiological studies and a combination of an increased protein level and normal cell count in cerebrospinal fluid are classic features of GBS, but patients with GBS can have normal results in both tests, especially early in the disease course.,Respiratory function should be monitored in all patients as respiratory failure can occur without symptoms of dyspnoea.,Intravenous immunoglobulin and plasma exchange are equally effective in treating GBS; no other treatments have been proven to be effective.,The efficacy of repeat treatment in patients who have shown insufficient clinical response is uncertain; nevertheless, this practice is common in patients who show deterioration after an initial treatment response.,Clinical improvement is usually most extensive in the first year after disease onset and can continue for >5 years.
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Type 1 diabetes is an autoimmune disease characterised by the destruction of insulin producing beta cells in the pancreas.,Whilst it remains unclear what the original triggering factors for this destruction are, observations from the natural history of human type 1 diabetes, including incidence rates in twins, suggest that the disease results from a combination of genetic and environmental factors.,Whilst many different immune cells have been implicated, including members of the innate and adaptive immune systems, a view has emerged over the past 10 years that beta cell damage is mediated by the combined actions of CD4+ and CD8+ T cells with specificity for islet autoantigens.,In health, these potentially pathogenic T cells are held in check by multiple regulatory mechanisms, known collectively as ‘immunological tolerance’.,This raises the question as to whether type 1 diabetes develops, at least in part, as a result of a defect in one or more of these control mechanisms.,Immunological tolerance includes both central mechanisms (purging of the T cell repertoire of high-affinity autoreactive T cells in the thymus) and peripheral mechanisms, a major component of which is the action of a specialised subpopulation of T cells, known as regulatory T cells (Tregs).,In this review, we highlight the evidence suggesting that a reduction in the functional capacity of different Treg populations contributes to disease development in type 1 diabetes.,We also address current controversies regarding the putative causes of this defect and discuss strategies to correct it as a means to reduce or prevent islet destruction in a clinical setting.,The online version of this article (doi:10.1007/s00125-017-4377-1) contains a slide of the figure for download, which is available to authorised users.
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Regulatory T (Treg) cells can be induced with DNA vaccinations and protect mice from the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS).,Tacrolimus (FK506) has been shown to have functions on inducing immunosuppression and augmenting apoptosis of pathologic T cells in autoimmune disease.,Here we examined the therapeutic effect of DNA vaccine in conjunction with FK506 on EAE.,After EAE induction, C57BL/6 mice were treated with DNA vaccine in conjunction with FK506.,Functional Treg cells were induced in treated EAE mice and suppressed Th1 and Th17 cell responses.,Infiltrated CD4 T cells were reduced while Treg cells were induced in spinal cords of treated EAE mice.,Remarkably, the activated CD4 T cells augmented apoptosis, but the induced Treg cells resisted apoptosis in treated EAE mice, resulting in alleviation of clinical EAE severity.,DNA vaccine in conjunction with FK506 treatment ameliorates EAE by enhancing apoptosis of CD4 T cells and resisting apoptosis of induced Treg cells.,Our findings implicate the potential of tolerogenic DNA vaccines for treating MS.
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PI-3K-mediated repression of FOXO1 and KLF2 promotes proinflammatory cytokine expression by lineage-committed human CCR6+ Th17/Th22 memory cells.,Human memory T cells (TM cells) that produce IL-17 or IL-22 are currently defined as Th17 or Th22 cells, respectively.,These T cell lineages are almost exclusively CCR6+ and are important mediators of chronic inflammation and autoimmunity.,However, little is known about the mechanisms controlling IL-17/IL-22 expression in memory Th17/Th22 subsets.,We show that common γ chain (γc)-using cytokines, namely IL-2, IL-7, and IL-15, potently induce Th17-signature cytokine expression (Il17a, Il17f, Il22, and Il26) in CCR6+, but not CCR6−, TM cells, even in CCR6+ cells lacking IL-17 expression ex vivo.,Inhibition of phosphoinositide 3-kinase (PI-3K) or Akt signaling selectively prevents Th17 cytokine induction by γc-cytokines, as does ectopic expression of the transcription factors FOXO1 or KLF2, which are repressed by PI-3K signaling.,These results indicate that Th17 cytokines are tuned by PI-3K signaling in CCR6+ TM cells, which may contribute to chronic or autoimmune inflammation.,Furthermore, these findings suggest that ex vivo analysis of IL-17 expression may greatly underestimate the frequency and pathogenic potential of the human Th17 compartment.
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Various abnormalities in CD4+CD25+ regulatory T cells (Tregs) in systemic lupus erythematosus (SLE) include increased Foxp3+ cells that are CD25 negative.,Barring methodological technical factors, these cells could be atypical Tregs or activated non-Treg CD4+ cells that express Foxp3.,Two groups have reached opposite conclusions that could possibly reflect the subjects studied.,One group studied untreated new-onset SLE and suggested that these T cells were mostly CD25-Foxp3+ non-Tregs.,The other group studied patients with long-standing disease and suggested that these cells are mostly dysfunctional Tregs.,A third group reported increased Foxp3+CD4+CD25dim rather than CD25- cells in active SLE and these were also non-Tregs.,Thus, it is likely that not all Foxp3+ T cells in SLE have protective suppressive activity.
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Oral administration of antigen can induce immunological tolerance.,Insulin is a key autoantigen in childhood type 1 diabetes.,Here, oral insulin was given as antigen-specific immunotherapy before the onset of autoimmunity in children from age 6 months to assess its safety and immune response actions on immunity and the gut microbiome.,A phase I/II randomised controlled trial was performed in a single clinical study centre in Germany.,Participants were 44 islet autoantibody-negative children aged 6 months to 2.99 years who had a first-degree relative with type 1 diabetes and a susceptible HLA DR4-DQ8-containing genotype.,Children were randomised 1:1 to daily oral insulin (7.5 mg with dose escalation to 67.5 mg) or placebo for 12 months using a web-based computer system.,The primary outcome was immune efficacy pre-specified as induction of antibody or T cell responses to insulin and measured in a central treatment-blinded laboratory.,Randomisation was performed in 44 children.,One child in the placebo group was withdrawn after the first study visit and data from 22 insulin-treated and 21 placebo-treated children were analysed.,Oral insulin was well tolerated with no changes in metabolic variables.,Immune responses to insulin were observed in children who received both insulin (54.5%) and placebo (66.7%), and the trial did not demonstrate an effect on its primary outcome (p = 0.54).,In exploratory analyses, there was preliminary evidence that the immune response and gut microbiome were modified by the INS genotype Among children with the type 1 diabetes-susceptible INS genotype (n = 22), antibody responses to insulin were more frequent in insulin-treated (72.7%) as compared with placebo-treated children (18.2%; p = 0.03).,T cell responses to insulin were modified by treatment-independent inflammatory episodes.,The study demonstrated that oral insulin immunotherapy in young genetically at-risk children was safe, but was not associated with an immune response as predefined in the trial primary outcome.,Exploratory analyses suggested that antibody responses to oral insulin may occur in children with a susceptible INS genotype, and that inflammatory episodes may promote the activation of insulin-responsive T cells.,Clinicaltrials.gov NCT02547519,The main funding source was the German Center for Diabetes Research (DZD e.V.),The online version contains peer reviewed but unedited supplementary material available at 10.1007/s00125-020-05376-1.
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In type 1 diabetes, insulin remains the mature therapeutic cornerstone; yet, the increasing number of individuals developing type 1 diabetes (predominantly children and adolescents) still face severe complications.,Fortunately, our understanding of type 1 diabetes is continuously being refined, allowing for refocused development of novel prevention and management strategies.,Hitherto, attempts based on immune suppression and modulation have been only partly successful in preventing the key pathophysiological feature in type 1 diabetes: the immune-mediated derangement or destruction of beta cells in the pancreatic islets of Langerhans, leading to low or absent insulin secretion and chronic hyperglycaemia.,Evidence now warrants a focus on the beta cell itself and how to avoid its dysfunction, which is putatively caused by cytokine-driven inflammation and other stress factors, leading to low insulin-secretory capacity, autoantigen presentation and immune-mediated destruction.,Correspondingly, beta cell rescue strategies are being pursued, which include antigen vaccination using, for example, oral insulin or peptides, as well as agents with suggested benefits on beta cell stress, such as verapamil and glucagon-like peptide-1 receptor agonists.,Whilst autoimmune-focused prevention approaches are central in type 1 diabetes and will be a requirement in the advent of stem cell-based replacement therapies, managing the primarily cardiometabolic complications of established type 1 diabetes is equally essential.,In this review, we outline selected recent and suggested future attempts to address the evolving profile of the person with type 1 diabetes.,The online version contains a slide of the figure for download available at 10.1007/s00125-021-05398-3.
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The risk of herpes zoster (HZ) is increased in patients with autoimmune diseases (AID), probably due to immunosuppressive therapy.,This prospective cross-sectional study investigated varicella zoster virus (VZV)-specific immunity in relation to subclinical VZV reactivation in 48 AID patients and 48 healthy controls (HCs).,We assessed humoral immunity (serum VZV immunoglobulin g [IgG], IgA, and IgM) and cell-mediated immunity (interferon-γ [IFNγ]-releasing assay) to VZV as well as salivary VZV DNA status.,Subclinical VZV reactivation was confirmed by detecting VZV DNA in saliva or VZV IgM in serum in the absence of typical HZ symptoms.,Median IgA levels were higher in the AID group than in the HC group, while VZV IgG and IgM levels were comparable between the groups.,AID patients showed fewer IFNγ spot-forming cells (SFCs) upon VZV stimulation than HCs (58.2 vs.,122.0 SFCs/106 peripheral blood mononuclear cells [PBMCs], p < 0.0001).,Subclinical VZV reactivation was more frequent in AID patients than in HCs (12.5% vs. 0%, p = 0.01).,AID patients with VZV reactivation received prednisolone more frequently and at a higher dose than AID patients without reactivation.,VZV-specific IFNγ SFCs were significantly lower in patients with VZV reactivation among AID patients (26.3 vs.,62.6 SFCs/106 PBMCs, p < 0.0001).,Results suggest that poor cellular response against VZV might cause clinical and subclinical reactivation of VZV in AID patients.
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Multiple sclerosis (MS) is an inflammatory, demyelinating, central nervous system disease mediated by myelin-specific T cells.,Environmental triggers that cause a breakdown of myelin-specific T cell tolerance are unknown.,We found that CD8+ myelin basic protein (MBP)-specific T cell tolerance can be broken and autoimmunity induced by infection with a virus that does not express MBP cross-reactive epitopes and does not depend on bystander activation.,Instead, the virus activated dual T cell receptor (TCR)-expressing T cells capable of recognizing both MBP and viral antigens.,These results demonstrate the importance of dual TCR T cells in autoimmunity and suggest a mechanism by which a ubiquitous viral infection could trigger autoimmunity in a subset of infected individuals, as hypothesized in the etiology of MS.
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To characterize the accrual of long‐term disability in a cohort of actively treated multiple sclerosis (MS) patients and to assess whether clinical and magnetic resonance imaging (MRI) data used in clinical trials have long‐term prognostic value.,This is a prospective study of 517 actively managed MS patients enrolled at a single center.,More than 91% of patients were retained, with data ascertained up to 10 years after the baseline visit.,At this last assessment, neurologic disability as measured by the Expanded Disability Status Scale (EDSS) was stable or improved compared to baseline in 41% of patients.,Subjects with no evidence of disease activity (NEDA) by clinical and MRI criteria during the first 2 years had long‐term outcomes that were no different from those of the cohort as a whole.,25‐OH vitamin D serum levels were inversely associated with short‐term MS disease activity; however, these levels had no association with long‐term disability.,At a median time of 16.8 years after disease onset, 10.7% (95% confidence interval [CI] = 7.2-14%) of patients reached an EDSS ≥ 6, and 18.1% (95% CI = 13.5-22.5%) evolved from relapsing MS to secondary progressive MS (SPMS).,Rates of worsening and evolution to SPMS were substantially lower when compared to earlier natural history studies.,Notably, the NEDA 2‐year endpoint was not a predictor of long‐term stability.,Finally, the data call into question the utility of annual MRI assessments as a treat‐to‐target approach for MS care.,Ann Neurol 2016;80:499-510
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The Swedish MS registry (SMSreg) is designed to assure quality health care for patients with multiple sclerosis (MS).,It has been active since 2001 and web-based since 2004.,It runs on government funding only and is used in all Swedish neurology departments.,The SMSreg currently includes data on 14,500 of Sweden's estimated 17,500 prevalent patients with MS.,One important function of SMSreg, to which participation is voluntary, is to serve as a tool for decision support and to provide an easy overview of the patient information needed at clinical visits.,This is its core feature and explains why the majority of Swedish MS specialists contribute data.,Another success factor for SMSreg is that entered data can be readily accessed, either through a query function into Excel format or through a set of predesigned tables and diagrams in which parameters can be selected.,Recent development includes a portal allowing patients to view a summary of their registered data and to report a set of patient-reported outcomes.,SMSreg data have been used in close to 100 published scientific reports.,Current projects include an incidence cohort (EIMS), post-marketing cohorts of patients on novel disease-modifying drugs (IMSE), and a prevalence cohort (GEMS).,As these studies combine physical sampling and questionnaire data with clinical documentation and possible linkage to other public registries, together they provide an excellent platform for integrated MS research.
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Rheumatoid arthritis (RA) is an autoimmune disease affecting ∼1% of the general population.,This disease is characterized by persistent articular inflammation and joint damage driven by the proliferating synovial tissue fibroblasts as well as neutrophil, monocyte and lymphocyte trafficking into the synovium.,The factors leading to RA pathogenesis remain poorly elucidated although genetic and environmental factors have been proposed to be the main contributors to RA.,The majority of the early studies focused on the role of lymphocytes and adaptive immune responses in RA.,However, in the past two decades, emerging studies showed that the innate immune system plays a critical role in the onset and progression of RA pathogenesis.,Various innate immune cells including monocytes, macrophages and dendritic cells are involved in inflammatory responses seen in RA patients as well as in driving the activation of the adaptive immune system, which plays a major role in the later stages of the disease.,Here we focus the discussion on the role of different innate immune cells and components in initiation and progression of RA.,New therapeutic approaches targeting different inflammatory pathways and innate immune cells will be highlighted here.,Recent emergence and the significant roles of innate lymphoid cells and inflammasomes will be also discussed.
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Rheumatoid arthritis (RA) is a chronic and progressive joint disease.,It appears that anti-inflammatory feedback mechanisms that could restrain joint inflammation and restore homeostasis are insufficient to perform this control.,In this study, we investigated the contribution of the MER tyrosine kinase-mediated anti-inflammatory response on arthritis and whether targeting MER could be a valid approach to treat RA.,KRN serum transfer arthritis (KRN STA) was induced in either Mertk-deficient mice or in mice that adenovirally overexpressed Pros1.,Human synovial micromasses were treated with MER-specific antibodies or PROS1.,Collagen-induced arthritis (CIA) mice were treated with MER-specific agonistic antibodies or by viral overexpression of Pros1.,Mertk−/− mice showed exacerbated arthritis pathology, whereas Pros1 overexpression diminished joint pathology in KRN STA.,Human synovial micromasses challenged with MER-specific antibodies enhanced the secretion of inflammatory cytokines, whereas stimulating MER with PROS1 reduced the secretion of these cytokines, confirming the protective role of MER.,Next, we treated CIA mice with MER-specific agonistic antibodies, and this unexpectedly resulted in exacerbated arthritis pathology.,This was associated with increased numbers of apoptotic cells in their knee joints and higher serum levels of interleukin (IL)-16C, a cytokine released by secondary necrotic neutrophils.,Apoptotic cell numbers and IL-16C levels were enhanced during arthritis in Mertk−/− mice and reduced in Pros1-overexpressing mice.,MER plays a protective role during joint inflammation and activating MER by its ligand PROS1 ameliorates disease.,Treatment of mice with MER receptor agonistic antibodies is deleterious due to its counterproductive effect of blocking efferocytosis in the arthritic joint.
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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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Autoimmunity and macrophage recruitment into the central nervous system (CNS) are critical determinants of neuroinflammatory diseases.,However, the mechanisms that drive immunological responses targeted to the CNS remain largely unknown.,Here we show that fibrinogen, a central blood coagulation protein deposited in the CNS after blood-brain barrier disruption, induces encephalitogenic adaptive immune responses and peripheral macrophage recruitment into the CNS leading to demyelination.,Fibrinogen stimulates a unique transcriptional signature in CD11b+ antigen-presenting cells inducing the recruitment and local CNS activation of myelin antigen-specific Th1 cells.,Fibrinogen depletion reduces Th1 cells in the multiple sclerosis model, experimental autoimmune encephalomyelitis.,Major histocompatibility complex (MHC) II-dependent antigen presentation, CXCL10- and CCL2-mediated recruitment of T cells and macrophages, respectively, are required for fibrinogen-induced encephalomyelitis.,Inhibition of the fibrinogen receptor CD11b/CD18 protects from all immune and neuropathologic effects.,Our results show that the final product of the coagulation cascade is a key determinant of CNS autoimmunity.,Autoimmune brain inflammation is associated with activation of macrophages and microglia.,Here the authors show that fibrinogen induces encephalitogenic T-cell activation and macrophage recruitment to the central nervous system, and promotes demyelination in a mouse model of multiple sclerosis.
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To examine the risk of serious infection conveyed by tumour necrosis factor α (TNFα) inhibitors in the treatment of rheumatoid arthritis (RA).,Data from patients with RA enrolled in the German biologics register RABBIT were used for analysis.,Baseline patient characteristics, time-varying risk factors (treatment changes, functional capacity) and selection processes caused by dropout, death or switching to non-anti-TNF treatment were taken into account to estimate the adjusted incidence rate ratios (IRRadj) of serious infection during treatment with TNF inhibitors compared with non-biological disease-modifying antirheumatic drug treatment.,Data were available on 5044 patients, in whom 392 serious infections occurred.,The crude rates of serious infections in patients treated with TNF inhibitors declined over the first 3 years of observation (from 4.8 to 2.2/100 patient-years).,This decline was driven by (1) treatment termination or loss to follow-up in patients at increased risk and (2) a risk reduction through decreasing glucocorticoid doses and improvement in function.,Adjusted for selection processes and time-varying risk factors, the following parameters assessed at baseline (age, chronic diseases) or at follow-up prior to the infection were significantly associated with an increased risk: age >60 years, chronic lung or renal disease, low functional capacity, history of serious infections, treatment with glucocorticoids (7.5-14 mg/day, IRRadj 2.1 (95% CI 1.4 to 3.2); ≥15 mg/day, IRRadj 4.7 (95% CI 2.4 to 9.4)) and treatment with TNFα inhibitors (IRRadj 1.8 (95% CI 1.2 to 2.7)).,Reasons for the decline in infection rates observed at the group level were identified.,The results enable expected infection rates to be calculated in individual patients based on their risk profiles.
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Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available.,In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described.,The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues.,The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process.,Levels of evidence, strength of recommendations and levels of agreement were derived.,Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed.,Cost effectiveness of the treatments was additionally examined.,These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.
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Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease including the cardiovascular system.,Atherosclerosis is the most common cardiovascular complication of SLE and a significant risk factor for morbidity and mortality.,Vascular damage/protection mechanism in SLE patients is out of balance, caused by the cascade reaction among oxidative stress, proinflammatory cytokines, Neutrophil Extracellular Traps, activation of B cells and autoantibodies and abnormal T cells.,As a precursor cell repairing vascular endothelium, endothelial progenitor cells (EPCs) belong to the protective mechanism and show the reduced number and impaired function in SLE.,However, the pathological mechanism of EPCs dysfunction in SLE remains ill-defined.,This paper reviews the latest SLE epidemiology and pathogenesis, discusses the changes in the number and function of EPCs in SLE, expounds the role of EPCs in SLE atherosclerosis, and provides new guidance and theoretical basis for exploring novel targets for SLE treatment.
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Cancer and infections are leading causes of mortality in systemic lupus erythematosus (SLE) after diseases of the circulatory system, and therefore preventing these complications is important.,In this study, we examined two categories of preventive services in SLE: cancer surveillance (cervical, breast, and colon) and immunizations (influenza and pneumococcal).,We compared the receipt of these services in SLE to the general population, and identified subgroups of patients who were less likely to receive these services.,We compared preventive services reported by insured women with SLE enrolled in the University of California, San Francisco Lupus Outcomes Study (n = 685) to two representative samples derived from a statewide health interview survey, a general population sample (n = 18,013) and a sample with non-rheumatic chronic conditions (n = 4,515).,In addition, using data from the cohort in both men and women (n = 742), we applied multivariate regression analyses to determine whether characteristics of individuals (for example, sociodemographic and disease factors), health systems (for example, number of visits, involvement of generalists or rheumatologists in care, type of health insurance) or neighborhoods (neighborhood poverty) influenced the receipt of services.,The receipt of preventive care in SLE was similar to both comparison samples.,For cancer surveillance, 70% of eligible respondents reported receipt of cervical cancer screening and mammography, and 62% reported colon cancer screening.,For immunizations, 59% of eligible respondents reported influenza immunization, and 60% reported pneumococcal immunization.,In multivariate regression analyses, several factors were associated with a lower likelihood of receiving preventive services, including younger age and lower educational attainment.,We did not observe any effects by neighborhood poverty.,A higher number of physician visits and involvement of generalist providers in care was associated with a higher likelihood of receiving most services.,Although receipt of cancer screening procedures and immunizations in our cohort was comparable to the general population, we observed significant variability by sociodemographic factors such as age and educational attainment.,Further research is needed to identify the physician, patient or health system factors contributing to this observed variation in order to develop effective quality improvement interventions.
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Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS)1, it has been difficult to demonstrate which variants are causal and what role they play in disease.,Moreover, the modest contribution these variants make to disease risk has raised questions regarding their medical relevance2.,We have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes TNF receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS)3,4, but not with other autoimmune conditions such as rheumatoid arthritis (RA)5, psoriasis6 and Crohn’s disease7.,By analyzing MS GWAS3,4 data in conjunction with the 1000 Genomes Project data8 we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region.,We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF.,Importantly, TNF blocking drugs can promote onset or exacerbation of MS9-11, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693.,This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF blocking drugs.,Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation.
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Multiple sclerosis (OMIM 126200) is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability.1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals;2,3 and systematic attempts to identify linkage in multiplex families have confirmed that variation within the Major Histocompatibility Complex (MHC) exerts the greatest individual effect on risk.4 Modestly powered Genome-Wide Association Studies (GWAS)5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility.11 Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups.,In a collaborative GWAS involving 9772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci.,Within the MHC we have refined the identity of the DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the Class I region.,Immunologically relevant genes are significantly over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.
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The disability rate associated with rheumatoid arthritis (RA) ranks high among inflammatory joint diseases.,However, the cause and potential molecular events are as yet not clear.,Here, we aimed to identify differentially expressed genes (DEGs), pathways and immune infiltration involved in RA utilizing integrated bioinformatics analysis and investigating potential molecular mechanisms.,The expression profiles of GSE55235, GSE55457, GSE55584 and GSE77298 were downloaded from the Gene Expression Omnibus database, which contained 76 synovial membrane samples, including 49 RA samples and 27 normal controls.,The microarray datasets were consolidated and DEGs were acquired and further analyzed by bioinformatics techniques.,Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of DEGs were performed using R (version 3.6.1) software, respectively.,The protein-protein interaction (PPI) network of DEGs were developed utilizing the STRING database.,Finally, the CIBERSORT was used to evaluate the infiltration of immune cells in RA.,A total of 828 DEGs were recognized, with 758 up-regulated and 70 down-regulated.,GO and KEGG pathway analyses demonstrated that these DEGs focused primarily on cytokine receptor activity and relevant signaling pathways.,The 30 most firmly related genes among DEGs were identified from the PPI network.,The principal component analysis showed that there was a significant difference between the two tissues in infiltration immune.,This study shows that screening for DEGs, pathways and immune infiltration utilizing integrated bioinformatics analyses could aid in the comprehension of the molecular mechanisms involved in RA development.,Besides, our study provides valuable data related to DEGs, pathways and immune infiltration of RA and may provide new insight into the understanding of molecular mechanisms.
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A key phenomenon in rheumatoid arthritis is the formation of lymphoid follicles in the inflamed synovial membrane.,C-X-C motif chemokine 13 (CXCL13) is central in this process as it attracts C-X-C chemokine receptor type 5 (CXCR5)-expressing B cells and T follicular helper cells to the follicle.,We here examine the role of CXCL13 and its association with disease in patients with treatment-naïve early rheumatoid arthritis.,Plasma samples from patients in the OPERA trial were examined for CXCL13 at treatment initiation and after 6 months of treatment with either methotrexate plus placebo (DMARD) (n = 37) or methotrexate plus adalimumab (DMARD + ADA) (n = 39).,Treatment outcome was evaluated after 1 and 2 years.,CXCL13 plasma levels in healthy volunteers (n = 38) were also examined.,Baseline CXCL13 plasma levels were increased in early rheumatoid arthritis patients in comparison with healthy volunteers.,Also, plasma CXCL13 correlated positively with disease activity parameters; swollen joint count 28 (rho = 0.34) and 40 (rho = 0.39), visual analog score (rho = 0.38) and simplified disease activity index (rho = 0.25) (all P <0.05).,CXCL13 levels decreased a significantly twofold more in the DMARD + ADA group than in the DMARD group.,Baseline CXCL13 plasma levels in the DMARD group correlated inversely with disease activity parameters; disease activity score in 28 joints, four variables, C-reactive protein based (DAS28CRP) (rho = 0.58, P <0.05) at 12 months.,High baseline CXCL13 was associated with remission (DAS28CRP less than 2.6) after 2 years.,In treatment-naïve early rheumatoid arthritis patients, plasma CXCL13 levels were associated with joint inflammation.,Furthermore, patients with high baseline plasma CXCL13 levels had an improved chance of remission after 2 years.,We propose that high CXCL13 concentrations indicate recent onset of inflammation that may respond better to early aggressive treatment.,Thus, high levels of CXCL13 could reflect the ‘the window of opportunity’ for optimal treatment effect.,Clinicaltrial.gov NCT00660647.,Registered 10 April 2008
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To search for a transmissible agent involved in lupus pathogenesis, we investigated the faecal microbiota of patients with systemic lupus erythematosus (SLE) for candidate pathobiont(s) and evaluated them for special relationships with host immunity.,In a cross-sectional discovery cohort, matched blood and faecal samples from 61 female patients with SLE were obtained.,Faecal 16 S rRNA analyses were performed, and sera profiled for antibacterial and autoantibody responses, with findings validated in two independent lupus cohorts.,Compared with controls, the microbiome in patients with SLE showed decreased species richness diversity, with reductions in taxonomic complexity most pronounced in those with high SLE disease activity index (SLEDAI).,Notably, patients with SLE had an overall 5-fold greater representation of Ruminococcus gnavus (RG) of the Lachnospiraceae family, and individual communities also displayed reciprocal contractions of a species with putative protective properties.,Gut RG abundance correlated with serum antibodies to only 1/8 RG strains tested.,Anti-RG antibodies correlated directly with SLEDAI score and antinative DNA levels, but inversely with C3 and C4.,These antibodies were primarily against antigen(s) in an RG strain-restricted pool of cell wall lipoglycans.,Novel structural features of these purified lipoglycans were characterised by mass spectrometry and NMR.,Highest levels of serum anti-RG strain-restricted antibodies were detected in those with active nephritis (including Class III and IV) in the discovery cohort, with findings validated in two independent cohorts.,These findings suggest a novel paradigm in which specific strains of a gut commensal may contribute to the immune pathogenesis of lupus nephritis.
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Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease in humans and is characterized by the presence of hyperactive immune cells and aberrant antibody responses to nuclear and cytoplasmic antigens, including characteristic anti-double-stranded DNA antibodies.,We performed a cross-sectional study in order to determine if an SLE-associated gut dysbiosis exists in patients without active disease.,A group of 20 SLE patients in remission, for which there was strict inclusion and exclusion criteria, was recruited, and we used an optimized Ion Torrent 16S rRNA gene-based analysis protocol to decipher the fecal microbial profiles of these patients and compare them with those of 20 age- and sex-matched healthy control subjects.,We found diversity to be comparable based on Shannon’s index.,However, we saw a significantly lower Firmicutes/Bacteroidetes ratio in SLE individuals (median ratio, 1.97) than in healthy subjects (median ratio, 4.86; P < 0.002).,A lower Firmicutes/Bacteroidetes ratio in SLE individuals was corroborated by quantitative PCR analysis.,Notably, a decrease of some Firmicutes families was also detected.,This dysbiosis is reflected, based on in silico functional inference, in an overrepresentation of oxidative phosphorylation and glycan utilization pathways in SLE patient microbiota.,Growing evidence suggests that the gut microbiota might impact symptoms and progression of some autoimmune diseases.,However, how and why this microbial community influences SLE remains to be elucidated.,This is the first report describing an SLE-associated intestinal dysbiosis, and it contributes to the understanding of the interplay between the intestinal microbiota and the host in autoimmune disorders.
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Describe the unique functions of immunoglobulin G4 (IgG4) in IgG4-neurologic disorders (IgG4-ND) and explain why, in contrast to their IgG1-counterparts, they respond poorly to intravenous immune globulin (IVIg) but effectively to anti-B cell therapies.,The IgG4 structure and isotype switch, B cells and plasmablasts relevant to IgG4 production, and IgG4-induced disruption of the targeted antigens are reviewed and compared with IgG1-mediated autoimmune ND, where IVIg inhibits IgG1-triggered inflammatory effects.,The main IgG4-ND include muscle-specific kinase myasthenia; nodal/paranodal chronic inflammatory demyelinating polyradiculoneuropathy with antibodies to neurofascin-155, contactin-1/caspr-1, or pan-neurofascins; antileucine-rich, glioma-inactivated-1 and contactin-associated protein-like 2 associated-limbic encephalitis, Morvan syndrome, or neuromyotonia; and anti-IgLON5 disorder.,The IgG4, because of its unique structural features in the hinge region, has noninflammatory properties being functionally monovalent and bispecific, unable to engage in cross-linking and internalization of the targeted antigen.,In contrast to IgG1 subclass which is bivalent and monospecific, IgG4 does not activate complement and cannot bind to inhibitory Fcγ receptor (FcγRIIb) to activate cellular and complement-mediated immune responses, the key functions inhibited by IVIg.,Because IVIg contains only 0.7%-2.6% IgG4, its idiotypes are of IgG1 subclass and cannot effectively neutralize IgG4 or sufficiently enhance IgG4 catabolism by saturating FcRn.,In contrast, rituximab, by targeting memory B cells and IgG4-producing CD20-positive short-lived plasma cells, induces long-lasting clinical benefits.,Rituximab is the preferred treatment in IgG4-ND patients with severe disease by effectively targeting the production of pathogenic IgG-4 antibodies.,In contrast, IVIG is ineffective because it inhibits immunoinflammatory functions irrelevant to the mechanistic effects of IgG4 and contains IgG-1 idiotypes that cannot sufficiently neutralize or possibly catabolize IgG4.,Controlled studies with anti-CD19/20 monoclonals that also activate FcγRIIb may be more promising in treating IgG4-ND.
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To investigate the efficacy and safety of belimumab, a fully human immunoglobulin G1λ monoclonal antibody against B-lymphocyte stimulator, in participants with generalized myasthenia gravis (MG) who remained symptomatic despite standard of care (SoC) therapy.,Eligible participants with MG were randomized 1:1 to receive IV belimumab 10 mg/kg or placebo in this phase II, placebo-controlled, multicenter, double-blind study (NCT01480596; BEL115123).,Participants received SoC therapies throughout the 24-week treatment phase and 12-week follow-up period.,The primary efficacy endpoint was mean change from baseline in the Quantitative Myasthenia Gravis (QMG) scale at week 24; safety assessments included the frequency and severity of adverse events (AEs) and serious AEs.,Forty participants were randomized (placebo n = 22; belimumab n = 18).,The mean change in QMG score from baseline at week 24 was not significantly different for belimumab vs placebo (p = 0.256).,There were no statistically significant differences between treatment groups for secondary endpoints, including the MG Composite and MG-Activity of Daily Living scores.,Acetylcholine receptor antibody levels decreased over time in both treatment groups.,No unexpected AEs were identified and occurrence was similar in the belimumab (78%) and placebo (91%) groups.,One participant receiving placebo died (severe sepsis) during the treatment phase.,The primary endpoint was not met for belimumab in participants with generalized MG receiving SoC.,There was no significant difference in mean change in the QMG score at week 24 for belimumab vs placebo.,The safety profile of belimumab was consistent with previous systemic lupus erythematosus studies.,This study provides Class I evidence that for participants with generalized MG, belimumab did not significantly improve QMG score compared with placebo.
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The factors that determine whether remyelination fails or succeeds in multiple sclerosis remain unknown.,By grafting lymphocytes from patients into demyelinated lesions in mice, El Behi, Sanson et al. show that lymphocytes differ in their ability to induce remyelination.,Unravelling the basis of this heterogeneity reveals prerequisites for efficient myelin repair.,One major challenge in multiple sclerosis is to understand the cellular and molecular mechanisms leading to disease severity progression.,The recently demonstrated correlation between disease severity and remyelination emphasizes the importance of identifying factors leading to a favourable outcome.,Why remyelination fails or succeeds in multiple sclerosis patients remains largely unknown, mainly because remyelination has never been studied within a humanized pathological context that would recapitulate major events in plaque formation such as infiltration of inflammatory cells.,Therefore, we developed a new paradigm by grafting healthy donor or multiple sclerosis patient lymphocytes in the demyelinated lesion of nude mice spinal cord.,We show that lymphocytes play a major role in remyelination whose efficacy is significantly decreased in mice grafted with multiple sclerosis lymphocytes compared to those grafted with healthy donors lymphocytes.,Mechanistically, we demonstrated in vitro that lymphocyte-derived mediators influenced differentiation of oligodendrocyte precursor cells through a crosstalk with microglial cells.,Among mice grafted with lymphocytes from different patients, we observed diverse remyelination patterns reproducing for the first time the heterogeneity observed in multiple sclerosis patients.,Comparing lymphocyte secretory profile from patients exhibiting high and low remyelination ability, we identified novel molecules involved in oligodendrocyte precursor cell differentiation and validated CCL19 as a target to improve remyelination.,Specifically, exogenous CCL19 abolished oligodendrocyte precursor cell differentiation observed in patients with high remyelination pattern.,Multiple sclerosis lymphocytes exhibit intrinsic capacities to coordinate myelin repair and further investigation on patients with high remyelination capacities will provide new pro-regenerative strategies.
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To assess whether it is feasible to establish specific cut-off values able to discriminate ‘physiological’ or ‘pathological’ brain volume rates in patients with multiple sclerosis (MS).,The study was based on the analysis of longitudinal MRI data sets of patients with MS (n=206, 87% relapsing-remitting, 7% secondary progressive and 6% primary progressive) and healthy controls (HC; n=35).,Brain atrophy rates were computed over a mean follow-up of 7.5 years (range 1-12) for patients with MS and 6.3 years (range 1-12.5) for HC with the SIENA software and expressed as annualised per cent brain volume change (PBVC/y).,A weighted (on the follow-up length) receiver operating characteristic analysis and the area under the curve (AUC) were used for statistics.,The weighted PBVC/y was −0.51±0.27% in patients with MS and −0.27±0.15% in HC (p<0.0001).,There was a significant age-related difference in PBVC/y between HC older and younger than 35 years of age (p=0.02), but not in patients with MS (p=0.8).,The cut-off of PBVC/y, as measured by SIENA that could maximise the accuracy in discriminating patients with MS from HC, was −0.37%, with 67% sensitivity and 80% specificity.,According to the observed distribution, values of PBVC/y as measured by SIENA that could define a pathological range were above −0.52% with 95% specificity, above −0.46% with 90% specificity and above −0.40% with 80% specificity.,Our evidence-based criteria provide values able to discriminate the presence or absence of ‘pathological’ brain volume loss in MS with high specificity.,Such results could be of great value in a clinical setting, particularly in assessing treatment efficacy in MS.
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Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that is associated with demyelination and neuronal loss.,Over recent years, the immunological and neuronal effects of tryptophan (Trp) metabolites have been largely investigated, leading to the hypothesis that these compounds and the related enzymes are possibly involved in the pathophysiology of MS.,Specifically, the kynurenine pathway of Trp metabolism is responsible for the synthesis of intermediate products with potential immunological and neuronal effects.,More recently, Trp metabolites, originating also from the host microbiome, have been identified in MS, and it has been shown that they are differently regulated in MS patients.,Here, we sought to discuss whether, in MS patients, a specific urinary signature of host/microbiome Trp metabolism can be potentially identified so as to select novel biomarkers and guide toward the identification of specific metabolic pathways as drug targets in MS.
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Astrocytes play important roles in the central nervous system (CNS) during health and disease.,Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-I) in astrocytes during experimental CNS autoimmunity and also in CNS lesions from multiple sclerosis (MS) patients.,IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) and suppressor of cytokine signaling 2 (SOCS2).,The anti-inflammatory effects of nasally administered IFN-β are partly mediated by AhR.,Dietary tryptophan is metabolized by the gut microbiota into AhR agonists that act on astrocytes to limit CNS inflammation.,EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl-3-sulfate (I3S), indole-3-propionic acid (IPA) and indole-3-aldehyde (IAld), or the bacterial enzyme tryptophanase.,In individuals with MS, the circulating levels of AhR agonists were decreased.,These findings suggest that IFN-I produced in the CNS act in combination with metabolites derived from dietary tryptophan by the gut flora to activate AhR signaling in astrocytes and suppress CNS inflammation.
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The nature of the inflammatory response in the MS brain is poorly defined.,Machado-Santos et al. report that chronic inflammation is dominated by tissue resident CD8+ T-cells and CD20+ B-cells, which are activated in lesions with demyelinating or neurodegenerative activity.,Multiple sclerosis is an inflammatory demyelinating disease in which active demyelination and neurodegeneration are associated with lymphocyte infiltrates in the brain.,However, so far little is known regarding the phenotype and function of these infiltrating lymphocyte populations.,In this study, we performed an in-depth phenotypic characterization of T and B cell infiltrates in a large set of multiple sclerosis cases with different disease and lesion stages and compared the findings with those seen in inflammatory, non-inflammatory and normal human controls.,In multiple sclerosis lesions, we found a dominance of CD8+ T cells and a prominent contribution of CD20+ B cells in all disease courses and lesion stages, including acute multiple sclerosis cases with very short disease duration, while CD4+ T cells were sparse.,A dominance of CD8+ T cells was also seen in other inflammatory controls, such as Rasmussen’s encephalitis and viral encephalitis, but the contribution of B cells in these diseases was modest.,Phenotypic analysis of the CD8+ T cells suggested that part of the infiltrating cells in active lesions proliferate, show an activated cytotoxic phenotype and are in part destroyed by apoptosis.,Further characterization of the remaining cells suggest that CD8+ T cells acquire features of tissue-resident memory cells, which may be focally reactivated in active lesions of acute, relapsing and progressive multiple sclerosis, while B cells, at least in part, gradually transform into plasma cells.,The loss of surface molecules involved in the egress of leucocytes from inflamed tissue, such as S1P1 or CCR7, and the upregulation of CD103 expression may be responsible for the compartmentalization of the inflammatory response in established lesions.,Similar phenotypic changes of tissue-infiltrating CD8+ T cells were also seen in Rasmussen’s encephalitis.,Our data underline the potential importance of CD8+ T lymphocytes and B cells in the inflammatory response in established multiple sclerosis lesions.,Tissue-resident T and B cells may represent guardians of previous inflammatory brain disease, which can be reactivated and sustain the inflammatory response, when they are re-exposed to their specific antigen.
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Foamy macrophages, containing myelin degradation products, are abundantly found in active multiple sclerosis (MS) lesions.,Recent studies have described an altered phenotype of macrophages after myelin internalization.,However, mechanisms by which myelin affects the phenotype of macrophages and how this phenotype influences lesion progression remain unclear.,We demonstrate that myelin as well as phosphatidylserine (PS), a phospholipid found in myelin, reduce nitric oxide production by macrophages through activation of peroxisome proliferator-activated receptor β/δ (PPARβ/δ).,Furthermore, uptake of PS by macrophages, after intravenous injection of PS-containing liposomes (PSLs), suppresses the production of inflammatory mediators and ameliorates experimental autoimmune encephalomyelitis (EAE), an animal model of MS.,The protective effect of PSLs in EAE animals is associated with a reduced immune cell infiltration into the central nervous system and decreased splenic cognate antigen specific proliferation.,Interestingly, PPARβ/δ is activated in foamy macrophages in active MS lesions, indicating that myelin also activates PPARβ/δ in macrophages in the human brain.,Our data show that myelin modulates the phenotype of macrophages by PPAR activation, which may subsequently dampen MS lesion progression.,Moreover, our results suggest that myelin-derived PS mediates PPARβ/δ activation in macrophages after myelin uptake.,The immunoregulatory impact of naturally-occurring myelin lipids may hold promise for future MS therapeutics.
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Rheumatoid arthritis (RA) patients with structural progression are in most need of immediate treatment to maintain tissue integrity.,The serum protein fingerprint, type I collagen degradation mediated by matrix metalloproteinases (MMP)-cleavage (C1M), is a biomarker of tissue destruction.,We investigated whether baseline serum C1M levels could identify structural progressors and if the biomarker levels changed during anti-inflammatory treatment with tocilizumab (TCZ).,The LITHE-biomarker study (NCT00106535, n = 585) was a one-year phase III, double-blind, placebo (PBO)-controlled, parallel group study of TCZ 4 or 8 mg/kg every four weeks, in RA patients on stable doses of methotrexate (MTX).,Spearman's ranked correlation was used to assess the correlation between baseline C1M levels and structural progression at baseline and at weeks 24 and 52.,Multivariate regression was performed for delta structural progression.,Change in C1M levels were studied as a function of time and treatment.,At baseline, C1M was significantly correlated to C-reactive protein (P <0.0001), visual analog scale pain (P <0.0001), disease activity score28-erythrocyte sedimentation rate (DAS28-ESR) (P <0.0001), joint space narrowing (JSN) (P = 0.0056) and modified total Sharp score (mTSS) (P = 0.0006).,Baseline C1M was significantly correlated with delta-JSN at Week 24 (R2 = 0.09, P = 0.0001) and at Week 52 (R2 = 0.27, P <0.0001), and with delta-mTSS at 24 weeks (R2 = 0.006, P = 0.0015) and strongly at 52 weeks (R2 = 0.013, P <0.0001) in the PBO group.,C1M levels were dose-dependently reduced in the TCZ + MTX group.,Baseline C1M levels correlated with worsening joint structure over one year.,Serum C1M levels may enable identification of those RA patients that are in most need of aggressive treatment,ClinicalTrials.gov: NCT00106535
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Objective.,To evaluate the efficacy and safety of three dosing and repeat treatment regimens of rituximab (RTX) plus MTX in patients with active RA.,Methods.,Patients with active RA despite stable MTX (10-25 mg/week) were randomly assigned to one of the three treatment regimens comprising two courses of RTX given 24 weeks apart: 2 × 500 and 2 × 500 mg; 2 × 500 and 2 × 1000 mg (dose escalation); and 2 × 1000 and 2 × 1000 mg.,The primary endpoint was proportion of patients achieving ACR20 at Week 48.,Results.,At Week 48, ACR20 responses were not statistically significantly different between the dose regimens.,Compared with RTX 2 × 500 mg (n = 134) or dose escalation (n = 119), ACR and European League Against Rheumatism (EULAR) outcomes in the RTX 2 × 1000 mg group (n = 93) were consistently higher, with significantly more patients achieving EULAR responses (P = 0.0495).,At Week 48, rituximab 2 × 1000 mg was associated with a higher proportion of patients who, following retreatment, maintained or improved their Week 24 responses.,Dose escalation from 2 × 500 to 2 × 1000 mg did not appear to be associated with improved outcomes compared with continual 2 × 500 mg.,All RTX regimens demonstrated comparable safety.,Conclusions.,RTX 2 × 500 and 2 × 1000 mg could not be clearly differentiated, although some efficacy outcomes suggest improved outcomes in the rituximab 2 × 1000 mg group.,Retreatment from Week 24 resulted in a sustained suppression of disease activity through to Week 48.,Trial registration.,ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00422383.
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To determine whether B-cell presence in brainstem and white matter (WM) lesions is associated with poorer pathological and clinical characteristics in advanced MS autopsy cases.,Autopsy tissue of 140 MS and 24 control cases and biopsy tissue of 24 patients with MS were examined for CD20+ B cells and CD138+ plasma cells.,The presence of these cells was compared with pathological and clinical characteristics.,In corresponding CSF and plasma, immunoglobulin (Ig) G ratio and oligoclonal band (OCB) patterns were determined.,In a clinical cohort of 73 patients, the presence of OCBs was determined during follow-up and compared to status at diagnosis.,In 34% of active and 71% of mixed active/inactive lesions, B cells were absent, which correlated with less pronounced meningeal B-cell infiltration (p < 0.0001).,The absence of B cells and plasma cells in brainstem and WM lesions was associated with a longer disease duration (p = 0.001), less frequent secondary progressive MS compared with relapsing and primary progressive MS (p < 0.0001 and p = 0.046, respectively), a lower proportion of mixed active/inactive lesions (p = 0.01), and less often perivascular T-cell clustering (p < 0.0001).,Moreover, a lower CSF IgG ratio (p = 0.006) and more frequent absence of OCBs (p < 0.0001) were noted.,In a clinical cohort, numbers of patients without OCBs in CSF were increased at follow-up (27.4%).,The absence of B cells is associated with a favorable clinical and pathological profile.,This finding may reflect extremes of a continuum of genetic or environmental constitution, but also a regression of WM humoral immunopathology in the natural course of advanced MS.
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The nature of the inflammatory response in the MS brain is poorly defined.,Machado-Santos et al. report that chronic inflammation is dominated by tissue resident CD8+ T-cells and CD20+ B-cells, which are activated in lesions with demyelinating or neurodegenerative activity.,Multiple sclerosis is an inflammatory demyelinating disease in which active demyelination and neurodegeneration are associated with lymphocyte infiltrates in the brain.,However, so far little is known regarding the phenotype and function of these infiltrating lymphocyte populations.,In this study, we performed an in-depth phenotypic characterization of T and B cell infiltrates in a large set of multiple sclerosis cases with different disease and lesion stages and compared the findings with those seen in inflammatory, non-inflammatory and normal human controls.,In multiple sclerosis lesions, we found a dominance of CD8+ T cells and a prominent contribution of CD20+ B cells in all disease courses and lesion stages, including acute multiple sclerosis cases with very short disease duration, while CD4+ T cells were sparse.,A dominance of CD8+ T cells was also seen in other inflammatory controls, such as Rasmussen’s encephalitis and viral encephalitis, but the contribution of B cells in these diseases was modest.,Phenotypic analysis of the CD8+ T cells suggested that part of the infiltrating cells in active lesions proliferate, show an activated cytotoxic phenotype and are in part destroyed by apoptosis.,Further characterization of the remaining cells suggest that CD8+ T cells acquire features of tissue-resident memory cells, which may be focally reactivated in active lesions of acute, relapsing and progressive multiple sclerosis, while B cells, at least in part, gradually transform into plasma cells.,The loss of surface molecules involved in the egress of leucocytes from inflamed tissue, such as S1P1 or CCR7, and the upregulation of CD103 expression may be responsible for the compartmentalization of the inflammatory response in established lesions.,Similar phenotypic changes of tissue-infiltrating CD8+ T cells were also seen in Rasmussen’s encephalitis.,Our data underline the potential importance of CD8+ T lymphocytes and B cells in the inflammatory response in established multiple sclerosis lesions.,Tissue-resident T and B cells may represent guardians of previous inflammatory brain disease, which can be reactivated and sustain the inflammatory response, when they are re-exposed to their specific antigen.
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Interleukin (IL)-17 is an important factor in rheumatoid arthritis (RA) pathogenesis.,MicroRNA (miRNA)s are a family of non coding RNAs and associated with human diseases including RA.,The purpose of this study is to identify the miRNAs in the differentiation of IL-17 producing cells, and analyze their expression pattern in the peripheral blood mononuclear cells (PBMC) and synovium from RA patients.,IL-17 producing cells were expanded from CD4+T cell.,MiRNA microarray was performed to identify the miRNAs in the differentiation of IL-17 producing cells.,Quantitative polymerase chain reaction was performed to examine the expression patterns of the identified miRNAs in the PBMC and synovium from RA and osteoarthritis (OA) patients.,Double staining combining in situ hybridization and immunohistochemistry of IL-17 was performed to analyze the expression pattern of identified miRNA in the synovium.,Six miRNAs, let-7a, miR-26, miR-146a/b, miR-150, and miR-155 were significantly up regulated in the IL-17 producing T cells.,The expression of miR-146a and IL-17 was higher than in PBMC in the patients with low score of Larsen grade and short disease duration.,MiR-146a intensely expressed in RA synovium in comparison to OA.,MiR-146a expressed intensely in the synovium with hyperplasia and high expression of IL-17 from the patients with high disease activity.,Double staining revealed that miR-146a expressed in IL-17 expressing cells.,These results indicated that miR-146a was associated with IL-17 expression in the PBMC and synovium in RA patients.,There is the possibility that miR-146a participates in the IL-17 expression.
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Increasing evidence indicates that microRNAs (miRNAs) play a critical role in the pathogenesis of inflammatory diseases.,The aim of the study was to investigate the expression pattern and function of miRNAs in CD4+ T cells from patients with rheumatoid arthritis (RA).,The expression profile of miRNAs in CD4+ T cells from synovial fluid (SF) and peripheral blood of 33 RA patients was determined by microarray assay and validated by qRT-PCR analysis.,The correlation between altered expression of miRNAs and cytokine levels was determined by linear regression analysis.,The role of miR-146a overexpression in regulating T cell apoptosis was evaluated by flow cytometry.,A genome-wide gene expression analysis was further performed to identify miR-146a-regulated genes in T cells.,miRNA expression profile analysis revealed that miR-146a expression was significantly upregulated while miR-363 and miR-498 were downregulated in CD4+ T cells of RA patients.,The level of miR-146a expression was positively correlated with levels of tumor necrosis factor-alpha (TNF-α), and in vitro studies showed TNF-α upregulated miR-146a expression in T cells.,Moreover, miR-146a overexpression was found to suppress Jurkat T cell apoptosis.,Finally, transcriptome analysis of miR-146a overexpression in T cells identified Fas associated factor 1 (FAF1) as a miR-146a-regulated gene, which was critically involved in modulating T cell apoptosis.,We have detected increased miR-146a in CD4+ T cells of RA patients and its close correlation with TNF-α levels.,Our findings that miR-146a overexpression suppresses T cell apoptosis indicate a role of miR-146a in RA pathogenesis and provide potential novel therapeutic targets.
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The immune system is highly diverse, but characterization of its genetic architecture has lagged behind the vast progress made by genome-wide association studies (GWASs) of emergent diseases.,Our GWAS for 54 functionally relevant phenotypes of the adaptive immune system in 489 healthy individuals identifies eight genome-wide significant associations explaining 6%-20% of variance.,Coding and splicing variants in PTPRC and COMMD10 are involved in memory T cell differentiation.,Genetic variation controlling disease-relevant T helper cell subsets includes RICTOR and STON2 associated with Th2 and Th17, respectively, and the interferon-lambda locus controlling regulatory T cell proliferation.,Early and memory B cell differentiation stages are associated with variation in LARP1B and SP4.,Finally, the latrophilin family member ADGRL2 correlates with baseline pro-inflammatory interleukin-6 levels.,Suggestive associations reveal mechanisms of autoimmune disease associations, in particular related to pro-inflammatory cytokine production.,Pinpointing these key human immune regulators offers attractive therapeutic perspectives.,•GWAS provides understanding of genetic factors shaping adaptive immune system•Common and less common variants explain 10% of variance in cellular variables•Associations pinpoint key regulators of B and T cell differentiation•Associations offer therapeutic targets for controlling pro-inflammatory traits,GWAS provides understanding of genetic factors shaping adaptive immune system,Common and less common variants explain 10% of variance in cellular variables,Associations pinpoint key regulators of B and T cell differentiation,Associations offer therapeutic targets for controlling pro-inflammatory traits,Lagou et al. identify genetic factors explaining interindividual variation in composition of the adaptive immune system.,Factors pinpoint key human immune regulators controlling B and T cell differentiation and levels of disease-relevant T helper and regulatory cells.,These findings shed light on mechanisms of autoimmune disease and offer therapeutic perspectives.
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The peripheral blood (PB) monocyte pool contains osteoclast progenitors (OCPs), which contribute to osteoresorption in inflammatory arthritides and are influenced by the cytokine and chemokine milieu.,We aimed to define the importance of chemokine signals for migration and activation of OCPs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA).,PB and, when applicable, synovial fluid (SF) samples were collected from 129 patients with RA, 53 patients with PsA, and 110 control patients in parallel to clinical parameters of disease activity, autoantibody levels, and applied therapy.,Receptors for osteoclastogenic factors (CD115 and receptor activator of nuclear factor-κB [RANK]) and selected chemokines (CC chemokine receptor 1 [CCR1], CCR2, CCR4, CXC chemokine receptor 3 [CXCR3], CXCR4) were determined in an OCP-rich subpopulation (CD3−CD19−CD56−CD11b+CD14+) by flow cytometry.,In parallel, levels of CC chemokine ligand 2 (CCL2), CCL3, CCL4, CCL5, CXC chemokine ligand 9 (CXCL9), CXCL10, and CXCL12 were measured using cytometric bead array or enzyme-linked immunosorbent assay.,Sorted OCPs were stimulated in culture by macrophage colony-stimulating factor and receptor activator of nuclear factor-κB ligand, and they were differentiated into mature osteoclasts that resorb bone.,Selected chemokines (CCL2, CCL5, CXCL10, and CXCL12) were tested for their osteoclastogenic and chemotactic effects on circulatory OCPs in vitro.,The OCP population was moderately enlarged among PB cells in RA and correlated with levels of tumor necrosis factor-α (TNF-α), rheumatoid factor, CCL2, and CCL5.,Compared with PB, the RANK+ subpopulation was expanded in SF and correlated with the number of tender joints.,Patients with PsA could be distinguished by increased RANK expression rather than total OCP population.,OCPs from patients with arthritis had higher expression of CCR1, CCR2, CCR4, CXCR3, and CXCR4.,In parallel, patients with RA had increased levels of CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10, with significant elevation in SF vs PB for CXCL10.,The subset expressing CXCR4 positively correlated with TNF-α, bone resorption marker, and rheumatoid factor, and it was reduced in patients treated with disease-modifying antirheumatic drugs.,The CCR4+ subset showed a significant negative trend during anti-TNF treatment.,CCL2, CCL5, and CXCL10 had similar osteoclastogenic effects, with CCL5 showing the greatest chemotactic action on OCPs.,In our study, we identified distinct effects of selected chemokines on stimulation of OCP mobilization, tissue homing, and maturation.,Novel insights into migratory behaviors and functional properties of circulatory OCPs in response to chemotactic signals could open ways to new therapeutic targets in RA.,The online version of this article (doi:10.1186/s13075-017-1337-6) contains supplementary material, which is available to authorized users.
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To evaluate the use of CSF neurofilament light chain (NfL) measurements in clinical practice as well as their effect on treatment strategies and outcomes in patients with MS.,This was an observational cohort study of patients with MS who had a CSF NfL measurement between December 2015 and July 2018 as part of their routine clinical care.,Treatment strategies were classified as “No Treatment/No Escalation” (no treatment or no escalation of treatment) or “Treatment/Escalation” (first-line injectable/oral disease-modifying therapies (DMTs), highly active DMTs, or treatment escalation).,Change in Expanded Disability Status Scale (EDSS) scores was evaluated after 1-year follow-up.,Of 203 patients with MS, 117 (58%) had relapsing-remitting MS.,Disease activity was most frequently indicated by elevated CSF NfL (n = 85), followed by clinical (n = 81) and MRI activity (n = 65).,CSF NfL measurements were independently associated with clinical (p = 0.02) and MRI activity (p < 0.001).,Of those with elevated CSF NfL as the only evidence of disease activity (n = 22), 77% had progressive MS (PMS).,In patients with PMS, 17 (20%) had elevated CSF NfL as the sole indicator of disease activity.,Elevated CSF NfL resulted more frequently in Treatment/Escalation than normal CSF NfL (p < 0.001).,Median EDSS change at follow-up was similar between patients receiving No Treatment/No Escalation and Treatment/Escalation decisions (p = 0.81).,CSF NfL measurements informed treatment strategies, alongside clinical and MRI measures.,CSF NfL levels were the only indicator of disease activity in a subset of patients, which was more pronounced in patients with PMS.,Elevated CSF NfL was associated with more Treatment/Escalation strategies, which had an impact on EDSS outcomes at 1 year.
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B lymphocytes are thought to play a relevant role in multiple sclerosis (MS) pathology.,The in vivo analysis of intrathecally produced B cell-related cytokines may help to clarify the mechanisms of B cell recruitment and immunoglobulin production within the central nervous system (CNS) in MS.,Paired cerebrospinal fluid (CSF) and serum specimens from 40 clinically isolated syndrome suggestive of MS or early-onset relapsing-remitting MS patients (CIS/eRRMS) and 17 healthy controls (HC) were analyzed for the intrathecal synthesis of IgG (quantitative formulae and IgG oligoclonal bands, IgGOB), CXCL13, BAFF, and IL-21.,3D-FLAIR, 3D-DIR, and 3D-T1 MRI sequences were applied to evaluate white matter (WM) and gray matter (GM) lesions and global cortical thickness (gCTh).,Compared to HC, CIS/eRRMS having IgGOB (IgGOB+, 26 patients) had higher intrathecal IgG indexes (p < 0.01), lower values of BAFF Index (11.9 ± 6.1 vs 17.5 ± 5.2, p < 0.01), and higher CSF CXCL13 levels (27.7 ± 33.5 vs 0.9 ± 1.5, p < 0.005).,In these patients, BAFF Index but not CSF CXCL13 levels inversely correlated with the intrathecal IgG synthesis (r > 0.5 and p < 0.05 for all correlations).,CSF leukocyte counts were significantly higher in IgGOB+ compared to IgGOB− (p < 0.05) and HC (p < 0.01), and correlated to CSF CXCL13 concentrations (r 0.77, p < 0.001).,The gCTh was significantly lower in patients with higher CSF CXCL13 levels (2.41 ± 0.1 vs 2.49 ± 0.1 mm, p < 0.05), while no difference in MRI parameters of WM and GM pathology was observed between IgGOB+ and IgGOB−.,The intrathecal IgG synthesis inversely correlated with BAFF Index and showed no correlation with CSF CXCL13.,These findings seem to indicate that intrathecally synthesized IgG are produced by long-term PCs that have entered the CNS from the peripheral blood, rather than produced by PCs developed in the meningeal follicle-like structures (FLS).,In this study, CXCL13 identifies a subgroup of MS patients characterized by higher leukocyte counts in the CSF and early evidence of cortical thinning, further suggesting a role for this chemokine as a possible marker of disease severity.
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Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system which is associated with numerous comorbidities.,These include cardiovascular disease, psychiatric and neurologic disturbances, restless leg syndrome, migraine, cancer, autoimmune diseases, and metabolic disorders.,Comorbid disease is an important consideration for clinicians treating patients with MS; early presentation of comorbidities can obscure or delay MS diagnosis, as well as significantly impacting the disease course.,Improved understanding of comorbidities and their emergence in MS populations is important for improving the quality of life and optimizing treatment for patients.,Therefore, we evaluated published studies reporting epidemiologic data on comorbidities and their associated impact on disease progression in patients with MS (PwMS).,The prevalence of neurologic, cardiovascular, metabolic, and autoimmune comorbidities was elevated in PwMS in general, and furthermore, this adversely affected a broad range of outcomes.,Compared with PwMS, cancer rates in people without MS or the general population were lower, which should prompt further studies into the mechanisms of both diseases.,Studies were under-represented in many regions owing to the latitudinal gradient of MS and possible underfunding of studies.,The online version of this article (10.1007/s00415-020-10107-y) contains supplementary material, which is available to authorized users.
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Inflammatory cytokines contribute to proatherogenic changes in lipid metabolism by reduction of HDL-cholesterol (HDL-C) levels, impairment of its antiinflammatory and antioxidant functions.,Therefore, the protective actions of HDL-C can be limited in chronic inflammatory diseases such as multiple sclerosis (MS).,The aim of this study was to assess the association between lipoprotein subfractions and inflammatory status in early stages of multiple sclerosis.,Polyacrylamide gel electrophoresis Lipoprint© System was used for lipoprotein profile analysis in 19 newly diagnosed MS patients, and in matched 19 healthy controls.,Serum levels of interleukin (IL) 1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, interferon-γ and TNF-α were measured by multiplex bead assay.,Concentrations of the measured cytokines and lipoprotein subclasses were comparable between MS patients and controls.,Male, but not female MS patients had significantly higher total HDL-C and small HDL-C subfraction than healthy controls.,Large HDL-C negatively correlated with all measured cytokines except IL-17 in MS but not in controls.,Intermediate HDL-C subfractions correlated positively with all measured cytokines except G-CSF in MS females but not in MS males or controls.,Our results of higher HDL-C and mainly its small HDL-C subfraction suggest that male MS patients are at higher risk of atherosclerosis and the subtle dyslipidemia is present in early stages of the disease.,The correlations between specific HDL-C subfractions and the inflammatory cytokines demonstrate mutual links between systemic inflammation and lipid metabolism in MS.,ClinicalTrials.gov, Identifier: NCT 03052595 Registered on Feb 14, 2017.
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Interferons (IFNs) are considered to be key molecules in the pathogenesis of systemic lupus erythematosus (SLE).,We measured levels of type I, II and III IFNs in a large cohort of patients with systemic lupus erythematosus (SLE) and controls and explored associations among high levels of different IFN types and distinct SLE features.,Four hundred ninety-seven well-characterized SLE patients and 322 population controls were included.,Disease activity was assessed by SLE Disease Activity Index (SLEDAI) and Systemic Lupus Activity Measure (SLAM).,Functional type I IFN activity was estimated by a WISH reporter cell assay.,Levels of IFN-γ were estimated by MSD 30-plex assay.,IFN-α and IFN-λ1 were measured by ELISA.,Values above the third quartile of patients’ measurements were defined as high.,Associations among high IFN results and SLE features were investigated by nominal regression analysis.,All IFN measurements were higher in SLE patients than in controls.,High type I IFN activity correlated with levels of IFN-γ and IFN-α and associated with active SLE in most domains: weight loss, fatigue, fever, rash, lymphadenopathy, arthritis, nephritis and haematological manifestations.,Specific SLE subsets were linked to the upregulation of different subtypes of circulating IFNs: high IFN-γ to arthritis, nephritis and anti-Ro60 antibodies and high IFN-α to mucocutaneous engagement and anti-Ro52 and anti-La antibodies.,Isolated high IFN-λ1 was coupled to anti-nucleosome antibodies and less severe SLE.,High functional type I IFN activity captures active SLE in most domains, but more distinct patterns of organ involvement are associated with profiles of circulating IFNs.,High IFN-γ as well as high functional type I IFN activity is a characteristic of severe SLE with nephritis and arthritis, while elevated levels of IFN-α associate with active mucocutaneous inflammation and a more benign cardiovascular profile.,IFN-λ1 in isolation is associated with milder disease.,Our findings suggest that IFNs contribute to the heterogeneity of clinical manifestations in SLE, and measuring circulating IFNs could assist in designing clinical trials with therapies targeting IFN pathways.,The online version of this article (10.1186/s13075-019-1878-y) contains supplementary material, which is available to authorized users.
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Two rheumatic autoimmune diseases, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), have distinct clinical features despite their genetic similarities.,We hypothesized that disease-specific variants exclusively associated with only one disease could contribute to disease-specific phenotypes.,We calculated the strength of disease specificity for each variant in each disease against the other disease using summary association statistics reported in the largest genome-wide association studies of RA and SLE.,Most of highly disease-specific associations were explained by non-coding variants that were significantly enriched within regulatory regions (enhancers or H3K4me3 histone modification marks) in specific cell or organ types. (e.g., In RA, regulatory T primary cells, CD4+ memory T primary cells, thymus and lung; In SLE, CD19+ B primary cells, mobilized CD34+ primary cells, regulatory T primary cells and monocytes).,Consistently, genes in the disease-specific loci were significantly involved in T cell- and B cell-related gene sets in RA and SLE.,In summary, this study identified disease-specific variants between RA and SLE, and provided statistical evidence for disease-specific cell types, organ and gene sets that may drive the disease-specific phenotypes.
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Expressions of G protein-coupled receptors (GPCR) on immune and tissue resident cells are the consequence of the cellular environment, which is highly variable.,As discussed here, antibodies directed to GPCR (GPCR abs), their levels and correlations to other abs, serve as biomarkers for various diseases.,They also could reflect the individual interplay between the environment and the immune system.,Thus, GPCR abs could display pathogenic chronic conditions and could help to identify disease-related pathways.,Moreover, by acting as ligands to their corresponding receptors, GPCR abs modulate autoimmune as well as non-autoimmune diseases.,This article introduces GPCR abs as drivers for diseases by their capability to induce a specific signaling and by determining immune cell homeostasis.,The identification of the individual GPCR ab function is challenging but might be pivotal in the comprehension of the aetiology of diseases.,This, hopefully, will lead to the identification of novel therapeutic strategies.,This article provides an overview about concepts and recent developments in research.,Accordingly, GPCR abs could represent ideal candidates for precision medicine.,Here, we introduce the term antibodiom to cover the network of abs with GPCR abs as prominent players.
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For a long time, viruses have been shown to modify the clinical picture of several autoimmune diseases, including type 1 diabetes (T1D), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome (SS), herpetic stromal keratitis (HSK), celiac disease (CD), and multiple sclerosis (MS).,Best examples of viral infections that have been proposed to modulate the induction and development of autoimmune diseases are the infections with enteric viruses such as Coxsackie B virus (CVB) and rotavirus, as well as influenza A viruses (IAV), and herpesviruses.,Other viruses that have been studied in this context include, measles, mumps, and rubella.,Epidemiological studies in humans and experimental studies in animal have shown that viral infections can induce or protect from autoimmunopathologies depending on several factors including genetic background, host-elicited immune responses, type of virus strain, viral load, and the onset time of infection.,Still, data delineating the clear mechanistic interaction between the virus and the immune system to induce autoreactivity are scarce.,Available data indicate that viral-induced autoimmunity can be activated through multiple mechanisms including molecular mimicry, epitope spreading, bystander activation, and immortalization of infected B cells.,Contrarily, the protective effects can be achieved via regulatory immune responses which lead to the suppression of autoimmune phenomena.,Therefore, a better understanding of the immune-related molecular processes in virus-induced autoimmunity is warranted.,Here we provide an overview of the current understanding of viral-induced autoimmunity and the mechanisms that are associated with this phenomenon.
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Calprotectin (S100A8/S100A9 protein) is known as a damage-associated molecular pattern (DAMP) protein and reflects mainly neutrophil activation.,Serum calprotectin levels might be a good alternative to acute-phase protein as a biomarker in inflammatory rheumatic diseases.,The aim of this study is to investigate the association of serum calprotectin with disease activity and severity in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), and psoriatic arthritis (PsA).,Serum calprotectin was measured in patients with RA, axSpA, and PsA from the prospective Swiss Clinical Quality Management (SCQM) registry.,Asymptomatic first-degree relatives of RA patients were used as healthy controls (HC).,Outcomes included swollen joint count (SJC), Disease Activity Score (DAS), Health Assessment questionnaire (HAQ), joint radiographs, and ultrasound power Doppler (USPD) score for RA; Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score (ASDAS) and coxitis for axSpA; and SJC and Disease Activity Index for PSoriatic Arthritis (DAPSA) for PsA.,Comparison of outcomes by calprotectin quartile levels was performed using Kruskal-Wallis tests for continuous outcomes or trend tests for categorical outcomes.,A total of 1729 subjects [RA = 969, axSpA = 451, PsA = 237, and HC = 72] were included.,Median levels of serum calprotectin were higher in each disease group compared to HC (p < 0.01).,In RA patients, all clinical outcomes were statistically different between quartiles of serum calprotectin, indicating an association between calprotectin levels and higher disease activity (SJC, DAS, and USPD scores) and severity (joint radiographs and HAQ).,In axSpA, an association between calprotectin levels and ASDAS score (p < 0.01) and prevalence of coxitis (p = 0.02) was observed.,For PsA patients, SJC and DAPSA did not differ across calprotectin quartiles.,This large study supports the association of serum calprotectin levels with disease activity in both RA and axSpA, but not in PsA.
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The change in number of CD68-positive sublining macrophages in serial synovial biopsies has been successfully used to discriminate on the group level between effective and ineffective treatment during early drug development in rheumatoid arthritis (RA) patients.,Measurement of a soluble biomarker would clearly have practical advantages.,Therefore, we investigated the sensitivity to change of myeloid related protein (MRP)8/14 in serum.,139 RA patients who received known effective biologics (infliximab, adalimumab and rituximab) and 28 RA patients who received placebo/ineffective therapies were included.,MRP8/14 levels were analyzed in baseline and follow-up serum samples and the standardized response mean (SRM) was calculated to determine the sensitivity to change of MRP8/14 in comparison to C-reactive protein (CRP) levels and the disease activity score evaluated in 28 joints (DAS28).,In patients treated with effective treatment, the SRM for MRP8/14 was moderate (0.56), but in patients treated with placebo/ineffective treatment the SRM was 0.06, suggesting that this biomarker is perhaps not susceptible to placebo effects in proof-of-concept studies of relatively short duration.,In contrast, the SRM for DAS28 was high for effective treatment (1.07), but also moderate for ineffective treatment (0.58), representing the placebo effect.,The SRM for CRP was low in the effective (0.33) and ineffective (0.23) treatment groups.,These data support the notion that quantification of changes in MRP8/14 serum levels could be used to predict potential efficacy of novel antirheumatic drugs in an early stage of drug development.,A positive result would support the rationale for larger, conventional clinical trials to determine whether the effects are clinically relevant.
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The main aim of the study is to evaluate the efficacy and safety profile of ocrelizumab (OCR), rituximab (RTX), and cladribine (CLA), employed as natalizumab (NTZ) exit strategies in relapsing-remitting multiple sclerosis (RRMS) patients at high-risk for progressive multifocal leukoencephalopathy (PML).,This is a multicentre, retrospective, real-world study on consecutive RRMS patients from eleven tertiary Italian MS centres, who switched from NTZ to OCR, RTX, and CLA from January 1st, 2019, to December 31st, 2019.,The primary study outcomes were the annualized relapse rate (ARR) and magnetic resonance imaging (MRI) outcome.,Treatment effects were estimated by the inverse probability treatment weighting (IPTW), based on propensity-score (PS) approach.,Additional endpoint included confirmed disability progression (CDP) as measured by Expanded Disability Status Scale and adverse events (AEs).,Patients satisfying predefined inclusion and exclusion criteria were 120; 64 switched to OCR, 36 to RTX, and 20 to CLA.,Patients from the 3 groups did not show differences for baseline characteristics, also after post hoc analysis.,The IPTW PS-adjusted models revealed that patients on OCR had a lower risk for ARR than patients on CLA (ExpBOCR 0.485, CI 95% 0.264-0.893, p = 0.020).,This result was confirmed also for 12-month MRI activity (ExpBOCR 0.248 CI 95% 0.065-0.948, p = 0.042).,No differences were found in other pairwise comparisons (OCR vs RTX and RTX vs CLA) for the investigated outcomes.,AEs were similar among the 3 groups.,Anti-CD20 drugs were revealed to be effective and safe options as NTZ exit strategies.,All investigated DMTs showed a good safety profile.,The online version contains supplementary material available at 10.1007/s13311-021-01037-2.
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Cladribine is a purine nucleoside analog initially developed in the 1970s as a treatment for various blood cancers.,Due to the molecule’s ability to preferentially reduce T and B lymphocytes, it has been developed into an oral formulation for the treatment of multiple sclerosis (MS).,The unique proposed mechanism of action of cladribine allows for the therapy to be delivered orally over two treatment-week cycles per year, one cycle at the beginning of the first month and one cycle at the beginning of the second month of years 1 and 2, with the potential for no further cladribine treatment required in years 3 and 4.,This review summarizes the clinical development program for cladribine tablets in patients with MS, including the efficacy endpoints and results from the 2-year phase III CLARITY study in patients with relapsing-remitting MS (RRMS), the 2-year CLARITY EXTENSION study, and the phase III ORACLE-MS study in patients with a first clinical demyelinating event at risk for developing MS.,Efficacy results from the phase II ONWARD study, in which cladribine tablets were administered as an add-on to interferon-β therapy in patients with RRMS, are also summarized.,A review of all safety data, including lymphopenia, infections, and malignancies, is provided based on data from all trials in patients with MS, including the initial parenteral formulation studies.,Based on these data, cladribine tablets administered at 3.5 mg/kg over 2 years have been approved across the globe for various forms of relapsing MS.,The development of cladribine tablets for the treatment of multiple sclerosis: a comprehensive review (MP4 279143 kb),The development of cladribine tablets for the treatment of multiple sclerosis: a comprehensive review (MP4 279143 kb),Enhanced Digital Features To view enhanced digital features for this article, go to 10.1007/s40265-020-01422-9
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Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG).,Prior NMO diagnostic criteria required optic nerve and spinal cord involvement but more restricted or more extensive CNS involvement may occur.,The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus.,The new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG).,The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations.,More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable.,The IPND also proposed validation strategies and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSD and opticospinal MS.
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Neuromyelitis optica (NMO) is an autoimmune disease targeting aquaporin 4 (AQP4), localized mainly at the astrocytic foot processes.,Loss of AQP4 and glial fibrillary acidic protein (GFAP) was reported, but the pathological significance of astrocytopathy is still controversial.,Here we show that active lesions in NMO display a wide spectrum of pathology even within a single tissue block of an individual patient.,We have distinguished six different lesion types.,The first reflects complement deposition at the surface of astrocytes, associated with granulocyte infiltration and astrocyte necrosis and followed by demyelination, global tissue destruction and the formation of cystic, necrotic lesions (lesion type 2).,Such destructive lesions lead to Wallerian degeneration in lesion-related tracts (lesion type 3).,Around active NMO lesions AQP4 may selectively be lost in the absence of aquaporin 1 (AQP1) loss or other structural damage (lesion type 4).,Another pattern is characterized by clasmatodendrosis of astrocytes, defined by cytoplasmic swelling and vacuolation, beading and dissolution of their processes and nuclear alterations resembling apoptosis, which was associated with internalization of AQP4 and AQP1 and astrocyte apoptosis in the absence of complement activation.,Such lesions give rise to extensive astrocyte loss, which may occur in part in the absence of any other tissue injury, such as demyelination or axonal degeneration (lesion type 5).,Finally, lesions with a variable degree of astrocyte clasmatodendrosis are found, which show plaque-like primary demyelination that is associated with oligodendrocyte apoptosis, but with preservation of axons (lesion type 6).,In active multiple sclerosis (MS) lesions astrocytes reveal changes of reactive protoplasmatic or fibrillary gliosis.,Only in a subset of lesions, in patients with aggressive disease, loss of AQP4 is observed in the initial stage of their formation, which is associated with retraction of astrocyte processes in the absence of complement deposition, granulocyte infiltration or loss of AQP1 or astrocytes.,Our data underline the primary assault of astrocytes in NMO lesions, but also indicate that different mechanisms of tissue injury operate in parallel in the same patient and even within the same lesion.,The online version of this article (doi:10.1007/s00401-013-1116-7) contains supplementary material, which is available to authorized users.
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Randomized controlled clinical trials and real-world observational studies provide complementary information but with different validity.,Some clinical questions (disease behavior, prognosis, validation of outcome measures, comparative effectiveness, and long-term safety of therapies) are often better addressed using real-world data reflecting larger, more representative populations.,Integration of disease history, clinician-reported outcomes, performance tests, and patient-reported outcome measures during patient encounters; imaging and biospecimen analyses; and data from wearable devices increase dataset utility.,However, observational studies utilizing these data are susceptible to many potential sources of bias, creating barriers to acceptance by regulatory agencies and the medical community.,Therefore, data standardization and validation within datasets, harmonization across datasets, and application of appropriate analysis methods are important considerations.,We review approaches to improve the scope, quality, and analyses of real-world data to advance understanding of multiple sclerosis and its treatment, as an example of opportunities to better support patient care and research.
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Treatment of multiple sclerosis (MS) has become increasingly multifaceted and comprises not only a variety of disease-modifying drugs with different mechanism of action but also a wide range of symptomatic therapies.,Today, it is not possible for the family physician or even many general neurologists to master the current treatment algorithm, and this calls for the establishment of multidisciplinary MS Care Units.,The core of the MS Care Unit would, in addition to MS neurologists and nurses, typically comprise neuropsychologists, clinical psychologists, physiotherapists, occupational therapists and secretaries, and will work together with a group of different specialists on formalized diagnostic workup procedures, protocols for initiation and follow-up of disease-modifying therapies.,It is obvious that the terms of performance of different MS Care Units will vary across regions and need to be balanced with clinical practice according to local conditions.,Although the main objective for establishment of MS Care Units will be to offer the single MS patient seamless and correct management of the disease to increase patient satisfaction and quality of life, it may even be cost-effective for the society by maintaining the working ability and reducing the costs of home help and custodial care by keeping people with MS resourceful.
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Experimental autoimmune encephalomyelitis (EAE) depends on the initial activation of CD4+ T cells responsive to myelin autoantigens.,The key antigen presenting cell (APC) population that drives the activation of naïve T cells most efficiently is the dendritic cell (DC).,As such, we should be able to trigger EAE by transfer of DC that can present the relevant autoantigen(s).,Despite some sporadic reports, however, models of DC-driven EAE have not been widely adopted.,We sought to test the feasibility of this approach and whether activation of the DC by toll-like receptor (TLR)-4 ligation was a sufficient stimulus to drive EAE.,Host mice were seeded with myelin basic protein (MBP)-reactive CD4+ T cells and then were injected with DC that could present the relevant MBP peptide which had been exposed to lipopolysaccharide as a TLR-4 agonist.,We found that this approach induced robust clinical signs of EAE.,DC are sufficient as APC to effectively drive the differentiation of naïve myelin-responsive T cells into autoaggressive effector T cells.,TLR-4-stimulation can activate the DC sufficiently to deliver the signals required to drive the pathogenic function of the T cell.,These models will allow the dissection of the molecular requirements of the initial DC-T cell interaction in the lymphoid organs that ultimately leads to autoimmune pathology in the central nervous system.
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Increasing evidence indicates that microRNAs (miRNAs) play a critical role in the pathogenesis of inflammatory diseases.,The aim of the study was to investigate the expression pattern and function of miRNAs in CD4+ T cells from patients with rheumatoid arthritis (RA).,The expression profile of miRNAs in CD4+ T cells from synovial fluid (SF) and peripheral blood of 33 RA patients was determined by microarray assay and validated by qRT-PCR analysis.,The correlation between altered expression of miRNAs and cytokine levels was determined by linear regression analysis.,The role of miR-146a overexpression in regulating T cell apoptosis was evaluated by flow cytometry.,A genome-wide gene expression analysis was further performed to identify miR-146a-regulated genes in T cells.,miRNA expression profile analysis revealed that miR-146a expression was significantly upregulated while miR-363 and miR-498 were downregulated in CD4+ T cells of RA patients.,The level of miR-146a expression was positively correlated with levels of tumor necrosis factor-alpha (TNF-α), and in vitro studies showed TNF-α upregulated miR-146a expression in T cells.,Moreover, miR-146a overexpression was found to suppress Jurkat T cell apoptosis.,Finally, transcriptome analysis of miR-146a overexpression in T cells identified Fas associated factor 1 (FAF1) as a miR-146a-regulated gene, which was critically involved in modulating T cell apoptosis.,We have detected increased miR-146a in CD4+ T cells of RA patients and its close correlation with TNF-α levels.,Our findings that miR-146a overexpression suppresses T cell apoptosis indicate a role of miR-146a in RA pathogenesis and provide potential novel therapeutic targets.
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Patients with rheumatoid arthritis (RA) are at increased risk of lymphoma compared with the general population.,There are concerns that tumour necrosis factor inhibitors (TNFi) may exacerbate this risk.,However, since the excess risk of lymphoma in RA is related to the cumulative burden of inflammation, TNFi may conversely reduce the risk of lymphoma by decreasing the burden of inflammation.,The aim of this study was to compare the risk of lymphoma in subjects with RA treated with TNFi with those treated with non-biological therapy.,Subjects diagnosed by a rheumatologist with RA enrolled in the British Society for Rheumatology Rheumatoid Arthritis Register (BSRBR-RA), a prospective cohort study, were followed until first lymphoma, death or until 30 November 2013.,Rates of lymphoma in the TNFi and non-biological-treated cohorts were compared using Cox regression.,11 931 TNFi-treated patients were compared with 3367 biological-naive patients. 84 lymphomas (88 (95% CI 70 to 109) per 100 000 person-years) were reported in the TNFi cohort and 30 lymphomas (154 (95% CI 104 to 220)) in the biological-naive cohort.,After adjusting for differences in baseline characteristics, there was no difference in the risk of lymphoma for the TNFi versus the biological-naive group: HR 1.00 (95% CI 0.56 to 1.80).,No risk differences were observed for individual TNFi.,In medium-term follow-up, there is no evidence that tumour necrosis factor inhibition influences the risk of lymphoma over the background risk in subjects with RA.
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To examine the association of serum lipids, inflammation and seropositivity on coronary heart disease (CHD) and stroke in patients with rheumatoid arthritis (RA).,The incidence of hospitalised myocardial infarction (MI) or stroke was calculated in a cohort of patients with RA receiving care within the national Veterans Health Administration from 1998 to 2011.,Cox proportional hazard models were used to examine the association between these outcomes and low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) as time-varying variables, divided into quintiles.,There were 37 568 patients with RA in the cohort with mean age of 63 years (SD 12.1); 90% were men.,There was a no clear association between LDL-C and CHD/stroke.,Compared with lower HDL-C (<34 mg/dL), higher HDL-C (≥54 mg/dL) was inversely associated with MI (hazard ratio (HR)=0.68, 95% CI 0.55 to 0.85) and stroke (HR=0.69, 95% CI 0.50 to 0.96).,Higher CRP >2.17 mg/dL (vs CRP <0.26 mg/dL) was associated with increased risk (HR=2.43, 95% CI 1.77 to 3.33) for MI and 2.02 (95% CI 1.32 to 3.08) for stroke.,ESR >47 mm/h compared with <8 mm/h had an HR 1.87 (95% CI 1.39 to 2.52) for MI and 2.00 (95% CI 1.26 to 3.18) for stroke.,The association between MI was significant for RA seropositivity (HR=1.23, 95% CI 1.03 to 1.48).,In this predominantly older male RA cohort, there was no clear association between LDL-C and CHD, whereas higher HDL-C was inversely associated with MI and stroke.,CRP and ESR were similarly associated with increase MI risk and stroke, reflecting the prominent role of inflammation in CHD risk in RA.
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Drug refractory epilepsy (RE) is a chronic neurological disease with varied etiology that represents a group of patients whose seizures do not respond to antiepileptic drugs.,The immune system may have a role in seizure and epilepsy development, but the specific mechanisms of inflammation that lead to epileptogenesis and contribute to RE are unknown.,Here, we used mass cytometry to comprehensively study the immune system of pediatric patients with RE and compared their immune profile and function with patients with age-matched autoimmune encephalitis (AIE) and healthy controls.,Patients with RE and AIE displayed similar immune profiles overall, with changes in CD4+ and CD8+ T cell subsets and an unbalance toward proinflammatory IL-17 production.,In addition, patients with RE uniquely showed an altered balance in NK cell subsets.,A systems-level intercellular network analysis identified rewiring of the immune system, leading to loss of inhibitory/regulatory intercellular connections and emergence of proinflammatory pathogenic functions in neuroinflammatory immune cell networks in patients with AIE and RE.,These data underscore the contribution of systemic inflammation to the pathogenesis of seizures and epileptogenesis and have direct translational implications in advancing diagnostics and therapeutics design.,The architecture of the immunome in pediatric refractory epilepsy is dominated by a emergence of pro-inflammatory, IL-17 dependent pathways.
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Despite the discovery of CSF and serum diagnostic autoantibodies in autoimmune encephalitis, there are still very limited CSF biomarkers for diagnostic and monitoring purposes in children with inflammatory or autoimmune brain disease.,The cause of encephalitis is unknown in up to a third of encephalitis cohorts, and it is important to differentiate infective from autoimmune encephalitis given the therapeutic implications.,To study CSF cytokines and chemokines as diagnostic biomarkers of active neuroinflammation, and assess their role in differentiating demyelinating, autoimmune, and viral encephalitis.,We measured and compared 32 cytokine/chemokines using multiplex immunoassay and APRIL and BAFF using ELISA in CSF collected prior to commencing treatment from paediatric patients with confirmed acute disseminated encephalomyelitis (ADEM, n = 16), anti-NMDAR encephalitis (anti-NMDAR E, n = 11), and enteroviral encephalitis (EVE, n = 16).,We generated normative data using CSF from 20 non-inflammatory neurological controls.,The sensitivity of CSF cytokine/chemokines to diagnose encephalitis cases was calculated using 95th centile of control values as cut off.,We correlated CSF cytokine/chemokines with disease severity and follow up outcome based on modified Rankin scale.,One-way hierarchical correlational cluster analysis of molecules was performed in different encephalitis and outcome groups.,In descending order, CSF TNF-α, IL-10, IFN-α, IL-6, CXCL13 and CXCL10 had the best sensitivity (>79.1%) when all encephalitis patients were included.,The combination of IL-6 and IFN-α was most predictive of inflammation on multiple logistic regression with area under the ROC curve 0.99 (CI 0.97-1.00).,There were no differences in CSF cytokine concentrations between EVE and anti-NMDAR E, whereas ADEM showed more pronounced elevation of Th17 related (IL-17, IL-21) and Th2 (IL-4, CCL17) related cytokine/chemokines.,Unlike EVE, heat map analysis showed similar clustering of cytokine/chemokine molecules in immune mediated encephalitis (ADEM and anti-NMDAR E).,Th1 and B cell (CXCL13 and CXCL10) molecules clustered together in patients with severe encephalopathy at admission and worse disability at follow up in all encephalitis.,There was no correlation between CSF neopterin and IFN-γ or IFN-α.,A combination panel of cytokine/chemokines consisting of CSF TNF-α, IL-10, IFN-α, IL-6, CXCL13 and CXCL10 measured using multiplex immunoassay may be used to diagnose and monitor intrathecal inflammation in the brain.,Given their association with worse outcome, certain key chemokines (CXCL13, CXCL10) could represent potential therapeutic targets in encephalitis.
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Descriptions of insulitis in human islets throughout the natural history of type 1 diabetes are limited.,We determined insulitis frequency (the percent of islets displaying insulitis to total islets), infiltrating leukocyte subtypes, and β-cell and α-cell mass in pancreata recovered from organ donors with type 1 diabetes (n = 80), as well as from donors without diabetes, both with islet autoantibodies (AAb+, n = 18) and without islet autoantibodies (AAb−, n = 61).,Insulitis was observed in four of four donors (100%) with type 1 diabetes duration of ≤1 year and two AAb+ donors (2 of 18 donors, 11%).,Insulitis frequency showed a significant but limited inverse correlation with diabetes duration (r = −0.58, P = 0.01) but not with age at disease onset.,Residual β-cells were observed in all type 1 diabetes donors with insulitis, while β-cell area and mass were significantly higher in type 1 diabetes donors with insulitis compared with those without insulitis.,Insulitis affected 33% of insulin+ islets compared with 2% of insulin− islets in donors with type 1 diabetes.,A significant correlation was observed between insulitis frequency and CD45+, CD3+, CD4+, CD8+, and CD20+ cell numbers within the insulitis (r = 0.53-0.73, P = 0.004-0.04), but not CD68+ or CD11c+ cells.,The presence of β-cells as well as insulitis several years after diagnosis in children and young adults suggests that the chronicity of islet autoimmunity extends well into the postdiagnosis period.,This information should aid considerations of therapeutic strategies seeking type 1 diabetes prevention and reversal.
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In situ tetramer staining reveals the presence of islet antigen-reactive CD8+ T cells in pancreatic islets from deceased type 1 diabetes patients.,A direct association of islet-autoreactive T cells with β cell destruction in human pancreatic islets from type 1 diabetes (T1D) patients has never been demonstrated, and little is known about disease progression after diagnosis.,Frozen pancreas samples were obtained from 45 cadaveric T1D donors with disease durations ranging from 1 wk to >50 yr, 14 nondiabetic controls, 5 nondiabetics with islet autoantibodies, 2 cases of gestational diabetes, and 6 T2D patients.,Sections were systematically analyzed for the presence of insulin-sufficient β cells, CD8+ insulitic lesions, and HLA class I hyperexpression.,Finally, consecutive sections from HLA-A2-expressing individuals were probed for CD8 T cell reactivity against six defined islet autoantigens associated with T1D by in situ tetramer staining.,Both single and multiple CD8 T cell autoreactivities were detected within individual islets in a subset of patients up to 8 yr after clinical diagnosis.,Pathological features such as HLA class I hyperexpression and insulitis were specific for T1D and persisted in a small portion of the patients with longstanding disease.,Insulitic lesions consistently presented in a multifocal pattern with varying degrees of infiltration and β cell loss across affected organs.,Our observations provide the first direct proof for islet autoreactivity within human islets and underscore the heterogeneous and chronic disease course.
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Microbial cells significantly outnumber human cells in the body, and the microbial flora at mucosal sites are shaped by environmental factors and, less intuitively, act on host immune responses, as demonstrated by experimental data in germ-free and gnotobiotic studies.,Our understanding of this link stems from the established connection between infectious bacteria and immune tolerance breakdown, as observed in rheumatic fever triggered by Streptococci via molecular mimicry, epitope spread and bystander effects.,The availability of high-throughput techniques has significantly advanced our capacity to sequence the microbiome and demonstrated variable degrees of dysbiosis in numerous autoimmune diseases, including rheumatoid arthritis, type 1 diabetes, multiple sclerosis and autoimmune liver disease.,It remains unknown whether the observed differences are related to the disease pathogenesis or follow the therapeutic and inflammatory changes and are thus mere epiphenomena.,In fact, there are only limited data on the molecular mechanisms linking the microbiota to autoimmunity, and microbial therapeutics is being investigated to prevent or halt autoimmune diseases.,As a putative mechanism, it is of particular interest that the apoptosis of intestinal epithelial cells in response to microbial stimuli enables the presentation of self-antigens, giving rise to the differentiation of autoreactive Th17 cells and other T helper cells.,This comprehensive review will illustrate the data demonstrating the crosstalk between intestinal microbiome and host innate and adaptive immunity, with an emphasis on how dysbiosis may influence systemic autoimmunity.,In particular, a gut-liver axis involving the intestinal microbiome and hepatic autoimmunity is elucidated as a paradigm, considering its anatomic and physiological connections.
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Diabetes is a condition of multifactorial origin, involving several molecular mechanisms related to the intestinal microbiota for its development.,In type 2 diabetes, receptor activation and recognition by microorganisms from the intestinal lumen may trigger inflammatory responses, inducing the phosphorylation of serine residues in insulin receptor substrate-1, reducing insulin sensitivity.,In type 1 diabetes, the lowered expression of adhesion proteins within the intestinal epithelium favours a greater immune response that may result in destruction of pancreatic β cells by CD8+ T-lymphocytes, and increased expression of interleukin-17, related to autoimmunity.,Research in animal models and humans has hypothesized whether the administration of probiotics may improve the prognosis of diabetes through modulation of gut microbiota.,We have shown in this review that a large body of evidence suggests probiotics reduce the inflammatory response and oxidative stress, as well as increase the expression of adhesion proteins within the intestinal epithelium, reducing intestinal permeability.,Such effects increase insulin sensitivity and reduce autoimmune response.,However, further investigations are required to clarify whether the administration of probiotics can be efficiently used for the prevention and management of diabetes.
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Although quotient of alpha2 macroglobulin (Qα2MG) was previously reported to be useful for the evaluation of blood-brain barrier (BBB) function, it is not commonly used.,We therefore evaluated BBB function among the various subsets of neuropsychiatric systemic lupus erythematosus (NPSLE) using quotient Q α2MG.,Furthermore, we determined the correlation between Q α2MG and cerebrospinal (CSF) interleukin (IL)-6 level and quotient complement component 3 (Q C3).,To determine intrathecal production of C3, the C3 index (Q C3/Q α2MG) was also calculated.,Fifty-six patients with SLE were included in this study.,Of these, 48 were diagnosed with NPSLE, consisting of 30 diffuse NPSLE patients (acute confusional state (ACS): n = 14, non-ACS: n = 16) and 18 patients with focal NPSLE.,CSF IL-6 concentration, and paired serum and CSF levels of α2MG and C3, were measured by enzyme-linked immuno solvent assay (ELISA).,The Q α2MG, Q C3, and C3 index were then calculated.,Q α2MG, Q C3, and IL-6 concentrations in the CSF were significantly elevated in NPSLE compared with non-NPSLE.,Among the subsets of NPSLE, significant increases in Q α2MG, CSF IL-6, and Q C3 were observed in ACS compared with non-ACS or focal NPSLE.,There was a positive correlation between CSF IL-6 level and Q α2MG, as well as between Q C3 and Q α2MG, in diffuse NPSLE.,There were no significant differences in C3 index between NPSLE and non-NPSLE, as well as among the subgroups of NPSLE.,Our study suggests that BBB disruption is present in ACS, and elevated levels of IL-6 and C3 in CSF in diffuse NPSLE, especially in ACS, might result from their entry to the CSF from the systemic circulation through the damaged BBB, as well as increased intrathecal production.,Furthermore, Q α2MG might be useful for the evaluation of BBB integrity.
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To evaluate the safety and efficacy of a humanized anti-interleukin-6 receptor antibody, tocilizumab (TCZ), in patients with neuromyelitis optica (NMO).,Seven patients with anti-aquaporin-4 antibody (AQP4-Ab)-positive NMO or NMO spectrum disorders were recruited on the basis of their limited responsiveness to their current treatment.,They were given a monthly injection of TCZ (8 mg/kg) with their current therapy for a year.,We evaluated the annualized relapse rate, the Expanded Disability Status Scale score, and numerical rating scales for neurogenic pain and fatigue.,Serum levels of anti-AQP4-Ab were measured with AQP4-transfected cells.,Six females and one male with NMO were enrolled.,After a year of TCZ treatment, the annualized relapse rate decreased from 2.9 ± 1.1 to 0.4 ± 0.8 (p < 0.005).,The Expanded Disability Status Scale score, neuropathic pain, and general fatigue also declined significantly.,The ameliorating effects on intractable pain exceeded expectations.,Interleukin-6 receptor blockade is a promising therapeutic option for NMO.,This study provides Class IV evidence that in patients with NMO, TCZ reduces relapse rate, neuropathic pain, and fatigue.
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Despite important advances in the treatment of multiple sclerosis (MS) over recent years, the introduction of several disease-modifying therapies (DMTs), the burden of progressive disability and premature mortality associated with the condition remains substantial.,This burden, together with the high healthcare and societal costs associated with MS, creates a compelling case for early treatment optimization with highly efficacious therapies.,Often, patients receive several first-line therapies, while more recent and in part more effective treatments are still being introduced only after these have failed.,However, with the availability of highly efficacious therapies, a novel treatment strategy has emerged, where the aim is to achieve no evidence of disease activity (NEDA).,Achieving NEDA necessitates regular monitoring of relapses, disability and functionality.,However, there is only a poor correlation between conventional magnetic resonance imaging measures like T2 hyperintense lesion burden and the level of clinical disability.,Hence, MRI-based measures of brain atrophy have emerged in recent years potentially reflecting the magnitude of MS-related neuroaxonal damage.,Currently available DMTs differ markedly in their effects on brain atrophy: some, such as fingolimod, have been shown to significantly slow brain volume loss, compared to placebo, whereas others have shown either no, inconsistent, or delayed effects.,In addition to regular monitoring, treatment optimization also requires early intervention with efficacious therapies, because accumulating evidence shows that effective intervention during a limited period early in the course of MS is critical for maintaining neurological function and preventing subsequent disability.,Together, the advent of new MS therapies and evolving management strategies offer exciting new opportunities to optimize treatment outcomes.
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To compare natalizumab and fingolimod on both clinical and MRI outcomes in patients with relapsing-remitting multiple sclerosis (RRMS) from 27 multiple sclerosis centers participating in the French follow-up cohort Observatoire of Multiple Sclerosis.,Patients with RRMS included in the study were aged from 18 to 65 years with an Expanded Disability Status Scale score of 0-5.5 and an available brain MRI performed within the year before treatment initiation.,The data were collected for 326 patients treated with natalizumab and 303 with fingolimod.,The statistical analysis was performed using 2 different methods: logistic regression and propensity scores (inverse probability treatment weighting).,The confounder-adjusted proportion of patients with at least one relapse within the first and second year of treatment was lower in natalizumab-treated patients compared to the fingolimod group (21.1% vs 30.4% at first year, p = 0.0092; and 30.9% vs 41.7% at second year, p = 0.0059) and supported the trend observed in nonadjusted analysis (21.2% vs 27.1% at 1 year, p = 0.0775).,Such statistically significant associations were also observed for gadolinium (Gd)-enhancing lesions and new T2 lesions at both 1 year (Gd-enhancing lesions: 9.3% vs 29.8%, p < 0.0001; new T2 lesions: 10.6% vs 29.6%, p < 0.0001) and 2 years (Gd-enhancing lesions: 9.1% vs 22.1%, p = 0.0025; new T2 lesions: 16.9% vs 34.1%, p = 0.0010) post treatment initiation.,Taken together, these results suggest the superiority of natalizumab over fingolimod to prevent relapses and new T2 and Gd-enhancing lesions at 1 and 2 years.,This study provides Class IV evidence that for patients with RRMS, natalizumab decreases the proportion of patients with at least one relapse within the first year of treatment compared to fingolimod.
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A 6-month phase 2 study of fingolimod demonstrated efficacy and safety in Japanese patients with relapsing-remitting multiple sclerosis (MS).,Here we report a 6-month observational extension that evaluated efficacy and safety in patients who received fingolimod continuously for 12 months or who switched from placebo to fingolimod.,Of 147 patients who completed the 6-month core study, 143 entered the extension.,Those originally randomized to placebo were re-randomized to fingolimod 1.25 mg or 0.5 mg.,During the extension, all patients were switched to open-label fingolimod 0.5 mg.,Magnetic resonance imaging (MRI) and relapse outcomes were maintained or improved in patients treated with fingolimod for 12 months versus those treated for 6 months.,No new safety events were reported over 12 months of treatment.,Infections occurred in similar proportions of continuously treated and switched patients, while cardiac and liver adverse events occurred in fewer continuously treated than switched patients.,Four patients were aquaporin-4 (AQP4) antibody-positive, three of whom showed rapid disease exacerbations within 10 days of fingolimod initiation.,Continuous fingolimod treatment for up to 12 months was associated with maintained or improved efficacy and a manageable safety profile, consistent with that previously seen.,Results in a small number of patients suggest lack of benefit in AQP4 antibody-positive patients.,Meaningful statistical interpretation was limited by the small sample size in each treatment group, owing to the number of patients who completed the core study.,ClinicalTrials.gov NCT00670449
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Treatment options for patients suffering from progressive forms of multiple sclerosis (MS) remain inadequate.,Mast cells actively participate in the pathogenesis of MS, in part because they release large amounts of various mediators that sustain the inflammatory network.,Masitinib, a selective oral tyrosine kinase inhibitor, effectively inhibits the survival, migration and activity of mast cells.,This exploratory study assessed the safety and clinical benefit of masitinib in the treatment of primary progressive MS (PPMS) or relapse-free secondary progressive MS (rfSPMS).,Multicenter, randomized, placebo-controlled, proof-of-concept trial.,Masitinib was administered orally at 3 to 6 mg/kg/day for at least 12 months, with dose adjustment permitted in event of insufficient response with no toxicity.,The primary response endpoint was the change relative to baseline in the multiple sclerosis functional composite score (MSFC).,Clinical response was defined as an increase in MSFC score relative to baseline of > 100%.,Thirty-five patients were randomized to receive masitinib (N = 27) or placebo (N = 8).,Masitinib was relatively well tolerated with the most common adverse events being asthenia, rash, nausea, edema, and diarrhea.,The overall frequency of adverse events was similar to the placebo group, however, a higher incidence of severe and serious events was associated with masitinib treatment.,Masitinib appeared to have a positive effect on MS-related impairment for PPMS and rfSPMS patients, as evidenced by an improvement in MSFC scores relative to baseline, compared with a worsening MSFC score in patients receiving placebo; +103% ± 189 versus -60% ± 190 at month-12, respectively.,This positive, albeit non-statistically significant response was observed as early as month-3 and sustained through to month-18, with similar trends seen in the PPMS and rfSPMS subpopulations.,A total of 7/22 (32%) assessable masitinib patients reported clinical response following 12 months of treatment (according to the modified intent-to-treat population, observed cases) compared with none in the placebo group.,The Expanded Disability Status Scale remained stable for both treatment groups.,These data suggest that masitinib is of therapeutic benefit to PPMS and rfSPMS patients and could therefore represent an innovative avenue of treatment for this disease.,This exploratory trial provides evidence that may support a larger placebo-controlled investigation.
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Objectives: Considering the critical role of microRNAs (miRNAs) in regulation of cell activation, we investigated their role in circulating type-2 conventional dendritic cells (cDC2s) of patients with primary Sjögren's syndrome (pSS) compared to healthy controls (HC).,Methods: CD1c-expressing cDC2s were isolated from peripheral blood.,A discovery cohort (15 pSS, 6 HC) was used to screen the expression of 758 miRNAs and a replication cohort (15 pSS, 11 HC) was used to confirm differential expression of 18 identified targets.,Novel targets for two replicated miRNAs were identified by SILAC in HEK-293T cells and validated in primary cDC2s.,Differences in cytokine production between pSS and HC cDC2s were evaluated by intracellular flow-cytometry. cDC2s were cultured in the presence of MSK1-inhibitors to investigate their effect on cytokine production.,Results: Expression of miR-130a and miR-708 was significantly decreased in cDC2s from pSS patients compared to HC in both cohorts, and both miRNAs were downregulated upon stimulation via endosomal TLRs.,Upstream mediator of cytokine production MSK1 was identified as a novel target of miR-130a and overexpression of miR-130a reduced MSK1 expression in cDC2s. pSS cDC2s showed higher MSK1 expression and an increased fraction of IL-12 and TNF-α-producing cells.,MSK1-inhibition reduced cDC2 activation and production of IL-12, TNF-α, and IL-6.,Conclusions: The decreased expression of miR-130a and miR-708 in pSS cDC2s seems to reflect cell activation. miR-130a targets MSK1, which regulates pro-inflammatory cytokine production, and we provide proof-of-concept for MSK1-inhibition as a therapeutic avenue to impede cDC2 activity in pSS.
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Current treatments for rheumatoid arthritis (RA) do not reverse underlying aberrant immune function.,A genetic predisposition to RA, such as HLA-DR4 positivity, indicates that dendritic cells (DC) are of crucial importance to pathogenesis by activating auto-reactive lymphocytes.,Here we show that microRNA-34a provides homoeostatic control of CD1c+ DC activation via regulation of tyrosine kinase receptor AXL, an important inhibitory DC auto-regulator.,This pathway is aberrant in CD1c+ DCs from patients with RA, with upregulation of miR-34a and lower levels of AXL compared to DC from healthy donors.,Production of pro-inflammatory cytokines is reduced by ex vivo gene-silencing of miR-34a. miR-34a-deficient mice are resistant to collagen-induced arthritis and interaction of DCs and T cells from these mice are reduced and do not support the development of Th17 cells in vivo.,Our findings therefore show that miR-34a is an epigenetic regulator of DC function that may contribute to RA.,Axl is a TAM receptor that can inhibit Toll-like receptor (TLR) -induced pro-inflammatory production by dendritic cells (DC).,Here the authors show that miR-34a targets Axl to control CD1c+ DC activity in mice, and that miR-34a-deficient mice are resistant to collagen-induced arthritis, whereas DCs from patients with rheumatoid arthritis have high levels of miR- 34a.
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Systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and Sjögren’s syndrome (SjS) are inflammatory systemic autoimmune diseases (SADs) that share several clinical and pathological features.,The shared biological mechanisms are not yet fully characterized.,The objective of this study was to perform a meta-analysis using publicly available gene expression data about the three diseases to identify shared gene expression signatures and overlapping biological processes.,Previously reported gene expression datasets were selected and downloaded from the Gene Expression Omnibus database.,Normalization and initial preprocessing were performed using the statistical programming language R and random effects model-based meta-analysis was carried out using INMEX software.,Functional analysis of over- and underexpressed genes was done using the GeneCodis tool.,The gene expression meta-analysis revealed a SAD signature composed of 371 differentially expressed genes in patients and healthy controls, 187 of which were underexpressed and 184 overexpressed.,Many of these genes have previously been reported as significant biomarkers for individual diseases, but others provide new clues to the shared pathological state.,Functional analysis showed that overexpressed genes were involved mainly in immune and inflammatory responses, mitotic cell cycles, cytokine-mediated signaling pathways, apoptotic processes, type I interferon-mediated signaling pathways and responses to viruses.,Underexpressed genes were involved primarily in inhibition of protein synthesis.,We define a common gene expression signature for SLE, RA and SjS.,The analysis of this signature revealed relevant biological processes that may play important roles in the shared development of these pathologies.,The online version of this article (doi:10.1186/s13075-014-0489-x) contains supplementary material, which is available to authorized users.
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Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are two severe autoimmune connective tissue diseases.,The fundamental knowledge about their etiology is limited and the conditions display complex pathogenesis, multifaceted presentations, and unpredictable courses.,Despite significant efforts, the lack of fully validated biomarkers enabling diagnosis, classification, and monitoring of disease activity represents significant unmet clinical needs.,In this discovery study, we have for the first time used recombinant antibody microarrays for miniaturized, multiplexed serum protein profiling of SLE and SSc, targeting mainly immunoregulatory proteins.,The data showed that several candidate SLE-associated multiplexed serum biomarker signatures were delineated, reflecting disease (diagnosis), disease severity (phenotypic subsets), and disease activity.,Selected differentially expressed markers were validated using orthogonal assays and a second, independent patient cohort.,Further, biomarker signatures differentiating SLE versus SSc were demonstrated, and the observed differences increased with severity of SLE.,In contrast, the data showed that the serum profiles of SSc versus healthy controls were more similar.,Hence, we have shown that affinity proteomics could be used to de-convolute crude, nonfractionated serum proteomes, extracting molecular portraits of SLE and SSc, further enhancing our fundamental understanding of these complex autoimmune conditions.
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Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a relatively unknown autoimmune entity.,Scant reports of post-infection/vaccination anti-NMDAR encephalitis exist.,We, hereby, reviewed the relevant cases and added to the literature a possible case of anti-NMDAR encephalitis following COVID-19 vaccination with BBIBP-CorV (Sinopharm).,A 50-year-old Persian woman with previously known rituximab-treated MS presented complaining of worsening neurological symptoms all gradually starting and worsening after receiving the second dose of BBVIP-CorV 2 weeks before.,Notable findings in her physical examination included ataxic gait and Babinski sign.,Considering an acute MS relapse, corticosteroid pulse therapy was initiated, and she was referred for MRI, which revealed multiple new plaques.,Her serum sample interestingly tested positive for anti-NMDAR antibodies.,CSF analysis was unfortunately not performed.,She responded well to the corticosteroid pulse therapy and showed substantial resolution of the symptoms.,Considering its relatively low cost of workup and the benefits of correct early diagnosis, clinicians are advised to consider autoimmune encephalitis encountering patients with progressive neurological symptoms after the administration of vaccines, including the ones for COVID-19 which are currently being used extensively.
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As the coronavirus disease 2019 (COVID-19) pandemic is ongoing and new variants of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are emerging, there is an urgent need for COVID-19 vaccines to control disease outbreaks by herd immunity.,Surveillance of rare safety issues related to these vaccines is progressing, since more granular data emerge with regard to adverse events of COVID-19 vaccines during post-marketing surveillance.,Interestingly, four cases of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) presenting with pauci-immune crescentic glomerulonephritis (GN) after COVID-19 mRNA vaccination have already been reported.,We here expand our current knowledge of this rare but important association and report a case of AAV presenting with massive rhabdomyolysis and pauci-immune crescentic GN after Pfizer-BioNTech COVID-19 mRNA vaccination.,As huge vaccination programs are ongoing worldwide, post-marketing surveillance systems must continue to assess vaccine safety important for the detection of any events associated with COVID-19 vaccination.,This is especially relevant in complex diseases where diagnosis is often challenging, as in our patient with AAV presenting with massive rhabdomyolysis and pauci-immune crescentic GN.
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The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development.,Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types.,We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals.,These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements.,Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling.,Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth.,Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.,The incidence of type 1 diabetes is increasing, potentially implicating non-genetic factors.,Here the authors conduct an epigenome-wide association study in disease-discordant twins and find increased DNA methylation variability at genes associated with immune cell metabolism and the cell cycle.
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Monozygotic (MZ) twin pair discordance for childhood-onset Type 1 Diabetes (T1D) is ∼50%, implicating roles for genetic and non-genetic factors in the aetiology of this complex autoimmune disease.,Although significant progress has been made in elucidating the genetics of T1D in recent years, the non-genetic component has remained poorly defined.,We hypothesized that epigenetic variation could underlie some of the non-genetic component of T1D aetiology and, thus, performed an epigenome-wide association study (EWAS) for this disease.,We generated genome-wide DNA methylation profiles of purified CD14+ monocytes (an immune effector cell type relevant to T1D pathogenesis) from 15 T1D-discordant MZ twin pairs.,This identified 132 different CpG sites at which the direction of the intra-MZ pair DNA methylation difference significantly correlated with the diabetic state, i.e.,T1D-associated methylation variable positions (T1D-MVPs).,We confirmed these T1D-MVPs display statistically significant intra-MZ pair DNA methylation differences in the expected direction in an independent set of T1D-discordant MZ pairs (P = 0.035).,Then, to establish the temporal origins of the T1D-MVPs, we generated two further genome-wide datasets and established that, when compared with controls, T1D-MVPs are enriched in singletons both before (P = 0.001) and at (P = 0.015) disease diagnosis, and also in singletons positive for diabetes-associated autoantibodies but disease-free even after 12 years follow-up (P = 0.0023).,Combined, these results suggest that T1D-MVPs arise very early in the etiological process that leads to overt T1D.,Our EWAS of T1D represents an important contribution toward understanding the etiological role of epigenetic variation in type 1 diabetes, and it is also the first systematic analysis of the temporal origins of disease-associated epigenetic variation for any human complex disease.
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Insights from prospective, longitudinal studies of individuals at risk for developing type 1 diabetes have demonstrated that the disease is a continuum that progresses sequentially at variable but predictable rates through distinct identifiable stages prior to the onset of symptoms.,Stage 1 is defined as the presence of β-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic, stage 2 as the presence of β-cell autoimmunity with dysglycemia and is presymptomatic, and stage 3 as onset of symptomatic disease.,Adoption of this staging classification provides a standardized taxonomy for type 1 diabetes and will aid the development of therapies and the design of clinical trials to prevent symptomatic disease, promote precision medicine, and provide a framework for an optimized benefit/risk ratio that will impact regulatory approval, reimbursement, and adoption of interventions in the early stages of type 1 diabetes to prevent symptomatic disease.
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We studied the utility of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) for improving the accuracy of type 1 diabetes (T1D) risk classification in TrialNet Natural History Study (TNNHS) participants.,The cumulative incidence of T1D was compared between normoglycemic individuals with DPTRS values >7.00 and dysglycemic individuals in the TNNHS (n = 991).,It was also compared between individuals with DPTRS values <7.00 or >7.00 among those with dysglycemia and those with multiple autoantibodies in the TNNHS.,DPTRS values >7.00 were compared with dysglycemia for characterizing risk in Diabetes Prevention Trial-Type 1 (DPT-1) (n = 670) and TNNHS participants.,The reliability of DPTRS values >7.00 was compared with dysglycemia in the TNNHS.,The cumulative incidence of T1D for normoglycemic TNNHS participants with DPTRS values >7.00 was comparable to those with dysglycemia.,Among those with dysglycemia, the cumulative incidence was much higher (P < 0.001) for those with DPTRS values >7.00 than for those with values <7.00 (3-year risks: 0.16 for <7.00 and 0.46 for >7.00).,Dysglycemic individuals in DPT-1 were at much higher risk for T1D than those with dysglycemia in the TNNHS (P < 0.001); there was no significant difference in risk between the studies among those with DPTRS values >7.00.,The proportion in the TNNHS reverting from dysglycemia to normoglycemia at the next visit was higher than the proportion reverting from DPTRS values >7.00 to values <7.00 (36 vs.,23%).,DPTRS thresholds can improve T1D risk classification accuracy by identifying high-risk normoglycemic and low-risk dysglycemic individuals.,The 7.00 DPTRS threshold characterizes risk more consistently between populations and has greater reliability than dysglycemia.
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Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease.,It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear.,Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls.,We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients.,The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice.,Thus, rare gene variants are common in SLE and likely contribute to genetic risk.,Function-altering variants of immune-related genes cause rare autoimmune syndromes, whereas their contribution to common autoimmune diseases remains uncharacterized.,Here the authors show that rare variants of lupus-associated genes are present in the majority of lupus patients and healthy controls, but only the variants found in lupus patients alter gene function.
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The aim was to determine the effect of the Bruton tyrosine kinase (Btk)-selective inhibitor PCI-32765, currently in Phase I/II studies in lymphoma trials, in arthritis and immune-complex (IC) based animal models and describe the underlying cellular mechanisms.,PCI-32765 was administered in a series of murine IC disease models including collagen-induced arthritis (CIA), collagen antibody-induced arthritis (CAIA), reversed passive anaphylactic reaction (RPA), and passive cutaneous anaphylaxis (PCA).,Clinical and pathologic features characteristic of each model were examined following treatment.,PCI-32765 was then examined in assays using immune cells relevant to the pathogenesis of arthritis, and where Btk is thought to play a functional role.,These included proliferation and calcium mobilization in B cells, cytokine and chemokine production in monocytes/macrophages, degranulation of mast cells and its subsequent cytokine/chemokine production.,PCI-32765 dose-dependently and potently reversed arthritic inflammation in a therapeutic CIA model with an ED50 of 2.6 mg/kg/day.,PCI-32765 also prevented clinical arthritis in CAIA models.,In both models, infiltration of monocytes and macrophages into the synovium was completely inhibited and importantly, the bone and cartilage integrity of the joints were preserved.,PCI-32765 reduced inflammation in the Arthus and PCA assays.,In vitro, PCI-32765 inhibited BCR-activated primary B cell proliferation (IC50 = 8 nM).,Following FcγR stimulation, PCI-32765 inhibited TNFα, IL-1β and IL-6 production in primary monocytes (IC50 = 2.6, 0.5, 3.9 nM, respectively).,Following FcεRI stimulation of cultured human mast cells, PCI-32765 inhibited release of histamine, PGD2, TNF-α, IL-8 and MCP-1.,PCI-32765 is efficacious in CIA, and in IC models that do not depend upon autoantibody production from B cells.,Thus PCI-32765 targets not only B lymphocytes but also monocytes, macrophages and mast cells, which are important Btk-expressing effector cells in arthritis.
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Treatment cycling with biologic disease-modifying anti-rheumatic drugs, such as tumor necrosis factor inhibitors (TNFi), is common among patients with rheumatoid arthritis (RA) and can result in reduced clinical efficacy and increased economic burden.,Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA.,To evaluate and compare the economic effect of tofacitinib 5 mg twice daily (BID) treatment directly after methotrexate (MTX) in the MTX-inadequate responder population, or after MTX and 1 TNFi (adalimumab [ADA] or etanercept [ETN]) or 2 TNFi (ADA and ETN) in TNF-inadequate responder patients with RA, from a U.S. payer perspective.,A decision-tree economic model was used to evaluate costs over 2 years.,Treatment response was modeled as American College of Rheumatology (ACR) 20/50/70 response.,ACR response rates at 6-month intervals were derived from U.S. prescribing information for monotherapy and combination therapy.,Safety event rates were sourced from a meta-analysis.,It was assumed that 75% of patients switched therapy after an adverse event or lack of response.,Cost inputs included drugs, monitoring and administration (including physician visits), health care utilization, and treatment for adverse events.,The population comprised all organization members (i.e., RA and non-RA members); RA patients receiving TNFi were estimated using epidemiologic data.,Results were based on an organization size of 1 million.,Economic endpoints were total 2-year costs, costs per member per month (PMPM), and costs per ACR20/50 responder.,1,321 patients were included for analysis.,Based on ACR20 switch criteria and either 100% or 50% monotherapy rates for all treatments, total 2-year costs and costs PMPM were lower for patients receiving tofacitinib as second-line therapy after MTX and as third-line therapy after MTX and 1 TNFi; costs were highest for patients who cycled through 2 TNFi.,Similar trends were observed for switch criteria based on ACR50 response and addition of 20% rebates for ADA and ETN and 0% for tofacitinib, although differences were mitigated slightly.,A treatment strategy with tofacitinib as either second- or third-line therapy after MTX may be a lower cost treatment option, compared with fourth-line introduction of tofacitinib after cycling through 2 TNFi following MTX.
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Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA).,Tofacitinib modulates the signaling of cytokines that are integral to lymphocyte activation, proliferation, and function.,Thus, tofacitinib therapy may result in suppression of multiple elements of the immune response.,Serious infections have been reported in tofacitinib RA trials.,However, limited head-to-head comparator data were available within the tofacitinib RA development program to directly compare rates of serious infections with tofacitinib relative to biologic agents, and specifically adalimumab (employed as an active control agent in two randomized controlled trials of tofacitinib).,A systematic literature search of data from interventional randomized controlled trials and long-term extension studies with biologics in RA was carried out.,Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) consensus was followed for reporting results of the review and meta-analysis.,Incidence rates (unique patients with events/100 patient-years) for each therapy were estimated based on data from randomized controlled trials and long-term extension studies using a random-effects model.,Relative and absolute risk comparisons versus placebo used Mantel-Haenszel methods.,The search produced 657 hits.,In total, 66 randomized controlled trials and 22 long-term extension studies met the selection criteria.,Estimated incidence rates (95 % confidence intervals [CIs]) for abatacept, rituximab, tocilizumab, and tumor necrosis factor inhibitors were 3.04 (2.49, 3.72), 3.72 (2.99, 4.62), 5.45 (4.26, 6.96), and 4.90 (4.41, 5.44), respectively.,Incidence rates (95 % CIs) for tofacitinib 5 and 10 mg twice daily (BID) in phase 3 trials were 3.02 (2.25, 4.05) and 3.00 (2.24, 4.02), respectively.,Corresponding incidence rates in long-term extension studies were 2.50 (2.05, 3.04) and 3.19 (2.74, 3.72).,The risk ratios (95 % CIs) versus placebo for tofacitinib 5 and 10 mg BID were 2.21 (0.60, 8.14) and 2.02 (0.56, 7.28), respectively.,Risk differences (95 % CIs) versus placebo for tofacitinib 5 and 10 mg BID were 0.38 % (−0.24 %, 0.99 %) and 0.40 % (−0.22 %, 1.02 %), respectively.,In interventional studies, the risk of serious infections with tofacitinib is comparable to published rates for biologic disease-modifying antirheumatic drugs in patients with moderate to severely active RA.,The online version of this article (doi:10.1186/s13075-015-0880-2) contains supplementary material, which is available to authorized users.
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Previous studies suggest that children who progress to type 1 diabetes (T1D) later in life already have an altered serum lipid molecular profile at birth.,Here, we compared cord blood lipidome across the three study groups: children who progressed to T1D (PT1D; n = 30), children who developed at least one islet autoantibody but did not progress to T1D during the follow-up (P1Ab; n = 33), and their age-matched controls (CTR; n = 38).,We found that phospholipids, specifically sphingomyelins, were lower in T1D progressors when compared to P1Ab and the CTR.,Cholesterol esters remained higher in PT1D when compared to other groups.,A signature comprising five lipids was predictive of the risk of progression to T1D, with an area under the receiver operating characteristic curve (AUROC) of 0.83.,Our findings provide further evidence that the lipidomic profiles of newborn infants who progress to T1D later in life are different from lipidomic profiles in P1Ab and CTR.
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Insights from prospective, longitudinal studies of individuals at risk for developing type 1 diabetes have demonstrated that the disease is a continuum that progresses sequentially at variable but predictable rates through distinct identifiable stages prior to the onset of symptoms.,Stage 1 is defined as the presence of β-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic, stage 2 as the presence of β-cell autoimmunity with dysglycemia and is presymptomatic, and stage 3 as onset of symptomatic disease.,Adoption of this staging classification provides a standardized taxonomy for type 1 diabetes and will aid the development of therapies and the design of clinical trials to prevent symptomatic disease, promote precision medicine, and provide a framework for an optimized benefit/risk ratio that will impact regulatory approval, reimbursement, and adoption of interventions in the early stages of type 1 diabetes to prevent symptomatic disease.
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The upheaval caused by the coronavirus disease 2019 (COVID-19) pandemic has allowed to large population to use new vaccines urgently.,Although vaccine development programs and available epidemiological data reassure us, there are concerns about specific risks associated with vaccinations in patients with autoimmune-autoinflammatory diseases.,These patients have the potential to decrease humoral and cellular immune responses caused by biologic agents and develop an acute flare of underlying disease following vaccination.,We herein present a rare case of a 49-year-old female with a flare of adult-onset Still’s disease (AOSD) after the first dose of BNT162b2 mRNA COVID-19 vaccination.,She had been diagnosed with AOSD 7 years earlier and had achieved remission with tocilizumab.,This patient came to the emergency room with fever and nausea that occurred 4 days after the first vaccination.,Based on laboratory results and clinical manifestations, we suspected AOSD flare and was treated with steroid pulse therapy.,In this report, we also discuss possible mechanisms linking vaccination with a flare of AOSD.,Considering the close time relationship between COVID-19 vaccinations and a flare of AOSD, physicians should be aware of adverse events from this new vaccination and evaluate the benefits and risks of vaccination for each patient.,• COVID-19 vaccination may cause an AOSD flare in patients who are in remission with tocilizumab.
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Autoimmune diseases, including autoimmune endocrine diseases (AIED), are thought to develop following environmental exposure in patients with genetic predisposition.,The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and vaccines against it could represent new environmental triggers for AIED.,We report a patient, with history of vitiligo vulgaris and 8 years of type 2 diabetes, who came to our institution because of fever, weight loss, asthenia and thyrotoxicosis occurred 4 weeks later the administration of BNT162B2 (Pfizer-BioNTech) SARS-CoV-2 vaccine.,Clinical, biochemical and instrumental work-up demonstrated Graves’ disease and autoimmune diabetes mellitus.,The occurrence of these disorders could be explained through different mechanism such as autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome), mRNA “self-adjuvant” effect, molecular mimicry between human and viral proteins and immune disruption from external stimuli.,However further studies are needed to better understand the underlying pathogenesis of AIED following SARS-CoV-2 vaccine.
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To compare the efficacy and safety of ABT‐494, a novel selective JAK‐1 inhibitor, with placebo in patients with moderate‐to‐severe rheumatoid arthritis (RA) and an inadequate response or intolerance to at least 1 anti-tumor necrosis factor (anti‐TNF) agent.,In this 12‐week, double‐blind, placebo‐controlled, dose‐ranging study, 276 RA patients receiving a stable dose of methotrexate (MTX) who had previously received treatment with at least 1 anti‐TNF agent were randomized equally to receive immediate‐release ABT‐494 at 3, 6, 12, or 18 mg twice daily or matching placebo twice daily.,The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12.,At week 12, significantly more patients receiving ABT‐494 (53-71%) than those receiving placebo (34%) achieved an ACR20 response (by nonresponder imputation analysis) (P < 0.05), with a dose‐response relationship among all ABT‐494 doses (P < 0.001).,ACR50 and ACR70 response rates were significantly higher in those receiving ABT‐494 (36-42% and 22-26%, respectively) than in those receiving placebo (16% and 4%, respectively).,Changes from baseline in the Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) were significantly greater for all doses of ABT‐494 than for placebo (P ≤ 0.01).,Onset of action of ABT‐494 was rapid, with significant differences from placebo at week 2 both in ACR20 response rate (for 12 and 18 mg) and in change in the DAS28‐CRP (P < 0.001 for 6-18 mg).,The most frequent adverse events (AEs) were headache, nausea, upper respiratory tract infection, and urinary tract infection.,Infection rates were higher at higher doses of ABT‐494, but no infections were serious.,No deaths were reported among those receiving ABT‐494.,In patients with an inadequate response or intolerance to anti‐TNF agents, ABT‐494 added to MTX showed rapid, dose‐dependent improvements in RA signs and symptoms, with safety and tolerability similar to those of other drugs of this class.,No new AEs were identified.
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Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA).,Systemic inflammation is proposed to play a fundamental role in the altered lipid metabolism associated with RA; however, the underlying mechanisms are unknown.,We undertook this study to compare cholesterol and lipoprotein kinetics in patients with active RA with those in matched healthy volunteers.,This was a phase I open‐label mechanism‐of‐action study.,Cholesterol and lipoprotein kinetics were assessed with 13C‐cholesterol and 13C‐leucine infusions.,RA patients were reevaluated after receiving oral tofacitinib 10 mg twice daily for 6 weeks.,Levels of high‐density lipoprotein (HDL) cholesterol, low‐density lipoprotein (LDL) cholesterol, total cholesterol, and apolipoprotein A‐I (Apo A‐I) as well as HDL cholesterol particle number were lower in RA patients (n = 36) than in healthy volunteers (n = 33).,In contrast, the cholesterol ester fractional catabolic rate was higher in RA patients, but no differences were observed in cholesterol ester transfer protein, cholesterol ester production rate, HDL‐associated Apo A‐I fractional catabolic rate, or LDL‐associated Apo B fractional catabolic rate.,Following tofacitinib treatment in RA patients, the cholesterol ester fractional catabolic rate decreased and cholesterol levels increased.,The decrease in cholesterol ester fractional catabolic rate correlated significantly with the increase in HDL cholesterol.,Additionally, HDL cholesterol particle number increased and markers of HDL cholesterol function improved.,This is the first study to assess cholesterol and lipoprotein kinetics in patients with active RA and matched healthy volunteers.,The data suggest that low cholesterol levels in patients with active RA may be driven by increases in cholesterol ester catabolism.,Tofacitinib treatment reduced cholesterol ester catabolism, thereby increasing cholesterol levels toward those in healthy volunteers, and markers of antiatherogenic HDL function improved.
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Infection and inflammation of the reproductive tract are significant causes of male factor infertility.,Ascending infections caused by sexually transmitted bacteria or urinary tract pathogens represent the most frequent aetiology of epididymo-orchitis, but viral, haematogenous dissemination is also a contributory factor.,Limitations in adequate diagnosis and therapy reflect an obvious need for further understanding of human epididymal and testicular immunopathologies and their contribution to infertility.,A major obstacle for advancing our knowledge is the limited access to suitable tissue samples.,Similarly, the key events in the inflammatory or autoimmune pathologies affecting human male fertility are poorly amenable to close examination.,Moreover, the disease processes generally have occurred long before the patient attends the clinic for fertility assessment.,In this regard, data obtained from experimental animal models and respective comparative analyses have shown promise to overcome these restrictions in humans.,This narrative review will focus on male fertility disturbances caused by infection and inflammation, and the usefulness of the most frequently applied animal models to study these conditions.,An extensive search in Medline database was performed without restrictions until January 2018 using the following search terms: ‘infection’ and/or ‘inflammation’ and ‘testis’ and/or ‘epididymis’, ‘infection’ and/or ‘inflammation’ and ‘male genital tract’, ‘male infertility’, ‘orchitis’, ‘epididymitis’, ‘experimental autoimmune’ and ‘orchitis’ or ‘epididymitis’ or ‘epididymo-orchitis’, antisperm antibodies’, ‘vasectomy’.,In addition to that, reference lists of primary and review articles were reviewed for additional publications independently by each author.,Selected articles were verified by each two separate authors and discrepancies discussed within the team.,There is clear evidence that models mimicking testicular and/or epididymal inflammation and infection have been instructive in a better understanding of the mechanisms of disease initiation and progression.,In this regard, rodent models of acute bacterial epididymitis best reflect the clinical situation in terms of mimicking the infection pathway, pathogens selected and the damage, such as fibrotic transformation, observed.,Similarly, animal models of acute testicular and epididymal inflammation using lipopolysaccharides show impairment of reproduction, endocrine function and histological tissue architecture, also seen in men.,Autoimmune responses can be studied in models of experimental autoimmune orchitis (EAO) and vasectomy.,In particular, the early stages of EAO development showing inflammatory responses in the form of peritubular lymphocytic infiltrates, thickening of the lamina propria of affected tubules, production of autoantibodies against testicular antigens or secretion of pro-inflammatory mediators, replicate observations in testicular sperm extraction samples of patients with ‘mixed atrophy’ of spermatogenesis.,Vasectomy, in the form of sperm antibodies and chronic inflammation, can also be studied in animal models, providing valuable insights into the human response.,This is the first comprehensive review of rodent models of both infectious and autoimmune disease of testis/epididymis, and their clinical implications, i.e. their importance in understanding male infertility related to infectious and non-infectious/autoimmune disease of the reproductive organs.
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There are various autoimmunogenic antigens (AIs) in testicular germ cells (TGCs) recognized as foreign by the body’s immune system.,However, there is little information of TGC-specific AIs being available.,The aim of this study is to identify TGC-specific AIs.,We have previously established that immunization using viable syngeneic TGC can also induce murine experimental autoimmune orchitis (EAO) without using any adjuvant.,This study is to identify TGC-specific AIs by TGC liquid chromatography-tandem mass spectrometry analysis, followed by two-dimensional gel electrophoresis that reacted with serum IgG from EAO mice.,In this study, we identified 11 TGC-specific AIs that reacted with serum from EAO mice.,Real-time RT-PCR analysis showed that the mRNA expressions of seven TGC-specific AIs were significantly higher in only mature testis compared to other organs.,Moreover, the recombinant proteins of identified 10 (except unnamed protein) TGC-specific AIs were created by using human embryonic kidney 293 (HEK293) cells and these antigencities were reconfirmed by Western blot using EAO serum reaction.,These results indicated Atp6v1a, Hsc70t, Fbp1 and Dazap1 were candidates for TGC-specific AIs.,Identification of these AIs will facilitate new approaches for understanding infertility and cancer pathogenesis and may provide a basis for the development of novel therapies.
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Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk of cardiovascular disease (CVD).,We investigated whether single nucleotide polymorphisms (SNPs) at autoimmunity risk loci were associated with CVD in SLE and RA.,Patients with SLE (n=1045) were genotyped using the 200K Immunochip SNP array (Illumina).,The allele frequency was compared between patients with and without different manifestations of CVD.,Results were replicated in a second SLE cohort (n=1043) and in an RA cohort (n=824).,We analysed publicly available genetic data from general population, performed electrophoretic mobility shift assays and measured cytokine levels and occurrence of antiphospholipid antibodies (aPLs).,We identified two new putative risk loci associated with increased risk for CVD in two SLE populations, which remained after adjustment for traditional CVD risk factors.,An IL19 risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5×10−5) and RA (OR 2.8 (1.4 to 5.6), P=3.8×10−3), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5×10−7), but not in population controls.,The IL19 risk allele affected protein binding, and SLE patients with the risk allele had increased levels of plasma-IL10 (P=0.004) and aPL (P=0.01).,An SRP54-AS1 risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5×10−5) but not in RA.,The SRP54-AS1 risk allele is an expression quantitative trait locus for four genes.,The IL19 risk allele was associated with stroke/MI in SLE and RA, but not in the general population, indicating that shared immune pathways may be involved in the CVD pathogenesis in inflammatory rheumatic diseases.
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This article estimates the frequency of cardiovascular (CV) events that occurred after diagnosis in a large Spanish cohort of patients with systemic lupus erythematosus (SLE) and investigates the main risk factors for atherosclerosis.,RELESSER is a nationwide multicenter, hospital-based registry of SLE patients.,This is a cross-sectional study.,Demographic and clinical variables, the presence of traditional risk factors, and CV events were collected.,A CV event was defined as a myocardial infarction, angina, stroke, and/or peripheral artery disease.,Multiple logistic regression analysis was performed to investigate the possible risk factors for atherosclerosis.,From 2011 to 2012, 3658 SLE patients were enrolled.,Of these, 374 (10.9%) patients suffered at least a CV event.,In 269 (7.4%) patients, the CV events occurred after SLE diagnosis (86.2% women, median [interquartile range] age 54.9 years [43.2-66.1], and SLE duration of 212.0 months [120.8-289.0]).,Strokes (5.7%) were the most frequent CV event, followed by ischemic heart disease (3.8%) and peripheral artery disease (2.2%).,Multivariate analysis identified age (odds ratio [95% confidence interval], 1.03 [1.02-1.04]), hypertension (1.71 [1.20-2.44]), smoking (1.48 [1.06-2.07]), diabetes (2.2 [1.32-3.74]), dyslipidemia (2.18 [1.54-3.09]), neurolupus (2.42 [1.56-3.75]), valvulopathy (2.44 [1.34-4.26]), serositis (1.54 [1.09-2.18]), antiphospholipid antibodies (1.57 [1.13-2.17]), low complement (1.81 [1.12-2.93]), and azathioprine (1.47 [1.04-2.07]) as risk factors for CV events.,We have confirmed that SLE patients suffer a high prevalence of premature CV disease.,Both traditional and nontraditional risk factors contribute to this higher prevalence.,Although it needs to be verified with future studies, our study also shows-for the first time-an association between diabetes and CV events in SLE patients.
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Noncoding RNAs (ncRNAs), including microRNAs (miRNAs), represent a family of RNA molecules that do not translate into protein.,Nevertheless, they have the ability to regulate gene expression and play an essential role in immune cell differentiation and function.,MicroRNAs were found to be differentially expressed in various tissues, and changes in their expression have been associated with several pathological processes.,Yet, their roles in systemic lupus erythematosus (SLE) and lupus nephritis (LN) remain to be elucidated.,Both SLE and LN are characterized by a complex dysfunction of the innate and adaptive immunity.,Recently, significant findings have been made in understanding SLE through the use of genetic variant identification and expression pattern analysis and mouse models, as well as epigenetic analyses.,Abnormalities in immune cell responses, cytokine and chemokine production, cell activation, and apoptosis have been linked to a unique expression pattern of a number of miRNAs that have been implicated in the immune pathogenesis of this autoimmune disease.,The recent evidence that significantly increased the understanding of the pathogenesis of SLE drives a renewed interest in efficient therapy targets.,This review aims at providing an overview of the current state of research on the expression and role of miRNAs in the immune pathogenesis of SLE and LN.
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There is increased interest in using microRNAs (miRNAs) as biomarkers in different diseases.,Present in body fluids, it is controversial whether or not they are mainly enclosed in exosomes, thus we studied if urinary miRNAs are concentrated inside exosomes and if the presence of systemic lupus erythematosus with or without lupus nephritis modifies their distribution pattern.,We quantified specific miRNAs in urine of patients with systemic lupus erythematosus (n = 38) and healthy controls (n = 12) by quantitative reverse-transcription PCR in cell-free urine, exosome-depleted supernatant and exosome pellet obtained by ultracentrifugation.,In control group, miR-335* and miR-302d were consistently higher in exosomes than in exosome-depleted supernatant, and miR-200c and miR-146a were higher in cell-free fraction.,In lupus patients, all urinary miRNAs tested were mainly in exosomes with lower levels outside them (p<0.05 and p<0.01, respectively).,This pattern is especially relevant in patients with active lupus nephritis compared to the control group or to the SLE patients in absence of lupus nephritis, with miR-146a being the most augmented (100-fold change, p<0.001).,Among the exosomal miRNAs tested, only the miR-146a discriminates the presence of active lupus nephritis.,In conclusion, urinary miRNAs are contained primarily in exosomes in systemic lupus erythematosus, and the main increment was found in the presence of active lupus nephritis.,These findings underscore the attractiveness of exosomal miRNAs in urine, a non-invasive method, as potential renal disease markers.
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Using the ImmunoChip custom genotyping array, we analysed 14,498 multiple sclerosis subjects and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (p-value < 1.0 × 10-4).,In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 multiple sclerosis subjects and 26,703 healthy controls.,In these 80,094 individuals of European ancestry we identified 48 new susceptibility variants (p-value < 5.0 × 10-8); three found after conditioning on previously identified variants.,Thus, there are now 110 established multiple sclerosis risk variants in 103 discrete loci outside of the Major Histocompatibility Complex.,With high resolution Bayesian fine-mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association.,This study enhances the catalogue of multiple sclerosis risk variants and illustrates the value of fine-mapping in the resolution of GWAS signals.
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Multiple sclerosis (OMIM 126200) is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability.1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals;2,3 and systematic attempts to identify linkage in multiplex families have confirmed that variation within the Major Histocompatibility Complex (MHC) exerts the greatest individual effect on risk.4 Modestly powered Genome-Wide Association Studies (GWAS)5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility.11 Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups.,In a collaborative GWAS involving 9772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci.,Within the MHC we have refined the identity of the DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the Class I region.,Immunologically relevant genes are significantly over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.
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To describe the disruptions in care experienced by persons with Multiple Sclerosis in Italy due to the COVID-19 pandemic and the self-reported impact on their health and wellbeing.,A cross-sectional online survey was completed by 2722 persons with Multiple Sclerosis, after Italy instituted a national lockdown in response to the pandemic.,Persons with Multiple Sclerosis reported that the pandemic caused broad disruptions to usual health and social care services, which impacted on their health and wellbeing.,Disruptions in care were consistently associated with negative self-reported impacts on the expected progression of the disease, on out-of-pocket expenditure and on carer’s stress.,Psychological consequences were associated with interruption to usual psychological support, and concerns about the safety of care delivered in person.,The quality of life of persons with Multiple Sclerosis depends greatly on prompt access to a broad range of health and care services.,Negative psychological impacts reported by persons with Multiple Sclerosis with less severe disabilities show that accessible integrated services are crucial for maintenance of their wellbeing.,Most persons with Multiple Sclerosis with more severe disability experienced negative impacts on perceived health.,Their carers compensating for lack of social input resulted in care overburden.,As continuity of care is crucial for persons with Multiple Sclerosis, as well as for persons with chronic conditions in general, strategies must be in place to ensure it is included in future pandemic response plans.
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Since 2019, a new coronavirus infection (COVID-19) due to an agent called SARS-CoV-2 spread rapidly worldwide.,Patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMO-SD) are often treated with immunosuppressants.,Beyond their effect on the risk of COVID-19 infection, the consequences on the long-term immune response against the coronavirus remain unknown.,Among 13 MS or NMOSD patients with confirmed COVID-19 included, all 5 patients treated with anti-CD20 therapies had a negative SARS-CoV-2 serology.,To date, maximal precautions to prevent coronavirus infection should be maintained in MS/NMOSD patients already exposed to COVID-19 during anti-CD20 therapy.
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COVID-19 pandemic has changed the way to manage MS and NMOSD, not only concerning treatment, but also regarding social distance and the increasing use of telemedicine (TM) to minimize the risk of infection.,Currently, there is no data regarding TM among MS and NMOSD South American experts.,To investigate TM experiences from South American MS and/or NMOSD experts in the follow-up of their patients focusing on TM.,A cross-sectional study was performed.,141 MS and/or NMOSD experts from Argentina, Chile, Colombia and Brazil were invited to answer an web-based survey.,A total of 129 (91.48 %) experts completed the survey.,Only 19.4% had experience in TM previous COVID-19 pandemic, while 79.8% are currently using TM, most using video call (52.3%).,Using TM, 44.1% of the experts were able to perform neurological examination, 85.6% believed to be able to identify a relapse, 48.6% use Patient Determined Disease Steps and 38.7% kept using the conventional Expanded Disability Status Scale.,Our survey demonstrates preparedness and responsiveness among South American MS and/or NMOSD experts.,Despite scarce prior TM experience, most experts felt confident to use TM as a new tool for monitoring their patients.
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•1,019 people with MS (PwMS) were surveyed online during the COVID-19 pandemic in April 2020.,•A majority reported interruptions to MS care and limited access to COVID-19 testing.,•Worry about COVID-19 was higher in female and non-white PwMS.•10% of PwMS reported changing their disease modifying therapy in some way as a result of COVID-19.,1,019 people with MS (PwMS) were surveyed online during the COVID-19 pandemic in April 2020.,A majority reported interruptions to MS care and limited access to COVID-19 testing.,Worry about COVID-19 was higher in female and non-white PwMS.,10% of PwMS reported changing their disease modifying therapy in some way as a result of COVID-19.,People with multiple sclerosis (PwMS) experienced changes in health behaviors and access to MS care due to the COVID-19 pandemic.,The USA has the highest recognized number of Covid19 infections globally.,The extent of the impact of COVID-19 has not been well characterized in large samples of PwMS to date.,The MS patient perspective on COVID-19 would complement the physician-reported cases of MS and COVID-19 in the literature.,A cross-sectional survey of adult PwMS was performed online, using the U.S.-based patient-powered iConquerMS™ platform, in April 2020.,There were 1,145 respondents (response rate: 20%). 1,019 had a diagnosis of MS and responded completely (average age: 54.2 years, range: 20-81; 79% female; 64% relapsing remitting, 22% secondary progressive, 12% primary progressive; 88% in the USA). 748 (73%) used a DMT in the last year, primarily higher-efficacy therapies: ocrelizumab (n=238), dimethyl fumarate (n=85), fingolimod (n=80).,The most frequent comorbidities were depression (41%), hypertension (26%), and asthma (12%).,Women were more worried than men about COVID-19 (p=0.001); non-white-identifying PwMS believed it was a greater danger to their health than white-identifying PwMS (p=0.002).,Through the continuum of symptoms to care, 61% of PwMS (n=617) reported symptoms associated with COVID-19, 39% (n=395) knew someone exposed to COVID-19, 4% (n=38) were aware of a personal COVID-19 exposure, 13% (n=128) wanted testing for COVID-19 but could not access it, and 4% (n=43) were tested.,Specific to their MS care, 64% (n=650) canceled a medical visit, 22% (n=222) canceled a neurologist visit, 11% (n=112) canceled an MRI, 21% (n=212) canceled a laboratory test, and 10% (n=98) changed their DMT in some way due to COVID19 including 65 delaying at least one dose. 37% (n=382) had a telehealth visit due to COVID-19. 37% of PwMS (n=374) experienced employment changes, most commonly working from home (n=194) and having work hours reduced (n=65) while 32 lost their jobs.,Of the 7 cases who tested positive for COVID-19 (<1% of participants) (5 female; age range: 29-64 years), DMTs included dimethyl fumarate (n=2), ocrelizumab (n=1), rituximab (n=1), and a clinical trial drug (n=1).,A majority of people with MS reported interruptions to their MS care along the MS care pathway alongside limited access to COVID-19 testing.,Postponements and delays in care were common with 10% of participants reporting a change in their DMT administration.,Less than 1% of this self-referred convenience online cohort had a positive test for COVID-19 although more than half reported symptoms that are associated with COVID-19.
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Cortical lesions constitute an important part of multiple sclerosis pathology.,Although inflammation appears to play a role in their formation, the mechanisms leading to demyelination and neurodegeneration are poorly understood.,We aimed to identify some of these mechanisms by combining gene expression studies with neuropathological analysis.,In our study, we showed that the combination of inflammation, plaque-like primary demyelination and neurodegeneration in the cortex is specific for multiple sclerosis and is not seen in other chronic inflammatory diseases mediated by CD8-positive T cells (Rasmussen’s encephalitis), B cells (B cell lymphoma) or complex chronic inflammation (tuberculous meningitis, luetic meningitis or chronic purulent meningitis).,In addition, we performed genome-wide microarray analysis comparing micro-dissected active cortical multiple sclerosis lesions with those of tuberculous meningitis (inflammatory control), Alzheimer’s disease (neurodegenerative control) and with cortices of age-matched controls.,More than 80% of the identified multiple sclerosis-specific genes were related to T cell-mediated inflammation, microglia activation, oxidative injury, DNA damage and repair, remyelination and regenerative processes.,Finally, we confirmed by immunohistochemistry that oxidative damage in cortical multiple sclerosis lesions is associated with oligodendrocyte and neuronal injury, the latter also affecting axons and dendrites.,Our study provides new insights into the complex mechanisms of neurodegeneration and regeneration in the cortex of patients with multiple sclerosis.
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CD47 exerts different effects on disease in distinct cell types and locations and during different stages of experimental autoimmune encephalomyelitis.,Comparison of transcriptomic and proteomic data from pathologically similar multiple sclerosis (MS) lesions reveals down-regulation of CD47 at the messenger RNA level and low abundance at the protein level.,Immunohistochemical studies demonstrate that CD47 is expressed in normal myelin and in foamy macrophages and reactive astrocytes within active MS lesions.,We demonstrate that CD47−/− mice are refractory to experimental autoimmune encephalomyelitis (EAE), primarily as the result of failure of immune cell activation after immunization with myelin antigen.,In contrast, blocking with a monoclonal antibody against CD47 in mice at the peak of paralysis worsens EAE severity and enhances immune activation in the peripheral immune system.,In vitro assays demonstrate that blocking CD47 also promotes phagocytosis of myelin and that this effect is dependent on signal regulatory protein α (SIRP-α).,Immune regulation and phagocytosis are mechanisms for CD47 signaling in autoimmune neuroinflammation.,Depending on the cell type, location, and disease stage, CD47 has Janus-like roles, with opposing effects on EAE pathogenesis.
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The introduction of a third‐dose vaccination along with new variants of concern raises questions regarding serology and T‐cell responses in patients with multiple sclerosis (pwMS) treated with B‐cell depletion who develop attenuated humoral response to vaccines.,The aim of this study was to longitudinally evaluate humoral and cellular response to SARS‐CoV‐2 mRNA vaccine in ocrelizumab‐treated pwMS before and following a third vaccine dose.,Following the third vaccine dose, patients who are low or nonresponders following initial vaccination did not increase antibody titers.,In healthy controls and ocrelizumab‐treated pwMS, cellular response decreased 6 months after initial vaccination and increased significantly after the third dose.,ANN NEUROL 2022;91:796-800
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Modern disease-modifying therapies (DMTs) in multiple sclerosis (MS) have variable modes of action and selectively suppress or modulate the immune system.,In this review, we summarize the predicted and intended as well as unwanted adverse effects on leukocytes in peripheral blood as a result of treatment with DMTs for MS.,We link changes in laboratory tests to the possible therapeutic risks that include secondary autoimmunity, infections, and impaired response to vaccinations.,Profound knowledge of the intended effects on leukocyte counts, in particular lymphocytes, explained by the mode of action, and adverse effects which may require additional laboratory and clinical vigilance or even drug discontinuation, is needed when prescribing DMTs to treat patients with MS.
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Serum amyloid A (SAA) is an acute phase protein with a significant importance for patients with inflammatory rheumatic diseases (IRD).,The central role of SAA in pathogenesis of IRD has been confirmed by recent discoveries, including its involvement in the activation of the inflammasome cascade and recruitment of interleukin 17 producing T helper cells.,Clinical utility of SAA in IRD was originally evaluated nearly half a century ago.,From the first findings, it was clear that SAA could be used for evaluating disease severity and monitoring disease activity in patients with rheumatoid arthritis and secondary amyloidosis.,However, cost-effective and more easily applicable markers, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), overwhelmed its use in clinical practice.,In the light of emerging evidences, SAA has been discerned as a more sensitive biomarker in a wide spectrum of IRD, especially in case of subclinical inflammation.,Furthermore, a growing number of studies are confirming the advantages of SAA over many other biomarkers in predicting and monitoring response to biological immunotherapy in IRD patients.,Arising scientific discoveries regarding the role of SAA, as well as delineating SAA and its isoforms as the most sensitive biomarkers in various IRD by recently developing proteomic techniques are encouraging the revival of its clinical use.,Finally, the most recent findings have shown that SAA is a biomarker of severe Coronavirus disease 2019 (COVID-19).,The aim of this review is to discuss the SAA-involving immune system network with emphasis on mechanisms relevant for IRD, as well as usefulness of SAA as a biomarker in various IRD.,Therefore, over a hundred original papers were collected through an extensive PubMed and Scopus databases search.,These recently arising insights will hopefully lead to a better management of IRD patients and might even inspire the development of new therapeutic strategies with SAA as a target.
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Synovial infiltration of monocytes is commonly associated with inflammation in rheumatoid arthritis (RA).,Toll-like receptors (TLRs) are innate sensors that recognize cell debris and microbial components in host, a process contributing to maintain chronic inflammation in RA.,We assessed the expression levels of TLR2 and TLR9 in monocyte subsets of active RA patients and characterized their cytokine profiles in response to synthetic and viral TLR2 and TLR9 agonists, including Epstein-Barr virus (EBV) which is suspected to contribute to RA symptoms.,Prevalence of monocyte subsets CD14++ CD16−, CD14+ CD16+ and CD14low CD16++ was evaluated in blood and synovial fluids of active RA patients and levels of TLR2 and TLR9 in monocyte subsets were measured by flow cytometry.,Enriched monocytes derived from RA patients and healthy donors were stimulated in vitro with synthetic TLR2 and TLR9 agonists and with EBV particles or viral DNA.,Intracellular cytokine profiles were determined in respective monocyte subsets.,Finally, the presence of EBV genome was evaluated by real-time PCR in blood and synovial monocytes of RA patients.,Numbers of CD14+ CD16+ and CD14low CD16++ were found to increase in blood of RA patients compared to healthy controls, while all three subsets were detected in synovial fluids.,TLR2 is abundantly expressed on blood and synovial CD14++ CD16− and CD14+ CD16+ monocytes from RA patients.,Levels of TLR9 were increased on all three subsets of blood monocytes but markedly enhanced in monocytes isolated from synovial fluids.,Compared to healthy controls, CD14++ CD16− monocytes of RA patients displayed an enlarged capacity to produce proinflammatory cytokines after stimulation with synthetic TLR2 and TLR9 agonists while both CD14++ CD16− and CD14+ CD16+ monocytes showed increased response to EBV stimulation.,The presence of EBV genome was also detected in monocytes and neutrophils of a significant proportion of patients.,Patients with active RA show an increased expression of TLR2 and TLR9 on monocyte subsets and display higher production of inflammatory cytokines in response to TLR agonists.,The presence of EBV genome in monocytes and neutrophils reinforces the suspected role of the virus in the exacerbation of RA symptoms.
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Accumulating evidence suggests tRNA-derived fragments (tRFs) play important roles in cellular homeostasis.,Here we aimed to explore aberrant expression of tRFs in CD4+ T cells from patients with systemic lupus erythematosus (SLE) and their potential function in the SLE pathogenesis.,First, small RNA sequencing was performed on CD4+ T cells from four SLE patients and three healthy controls (HCs).,Candidate tRFs were then validated in CD4+ T cells from 97 SLE patients and their relevant disease controls using qRT-PCR.,Then sequencing was used to investigate the profiles of HC-derived CD4+ T cells transfected with tRF-3009.,Lastly, tRF-3009 siRNA or tRF-3009 mimics were transfected into CD4+ T cells with/without IFN-α.,Changes in oxygen consumption rate (OCR), ATP, and ROS production were analyzed.,We identified 482 differentially expressed tRFs from SLE CD4+ T cells and chose tRF-3009 for further analysis due to its upregulation and the positive correlations between its expression and SLEDAI, active lupus nephritis and serum IFN-α levels.,In vitro, tRF-3009 over-expressing CD4+ T cell profiling and putative analysis linked this product to the type I IFN and oxidative phosphorylation (OXPHOS) pathways.,Interestingly, IFN-α is capable of inducing ROS and ATP production in CD4+ T cells, while knockdown of tRF-3009 reversed this process.,Overexpression of tRF-3009 in CD4+ T cells alone was sufficient to upregulate OCR, ROS, and ATP production.,Our study is the first to link aberrant tRF expression and SLE. tRF-3009 may participate in metabolic modulation of IFN-α-induced CD4+ T cell OXPHOS in lupus.,The online version contains supplementary material available at 10.1186/s12967-021-02967-3.
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The long noncoding RNAs (lncRNAs) are RNA transcripts more than 200 nucleotides in length, which do not encode proteins.,The lncRNAs are emerging as an important regulator of biological process, such as chromatin remodeling, gene transcription, protein transport, and trafficking through diverse mechanisms.,The lncRNAs play crucial role in various multigenetics human diseases including cancers and neurological diseases and currently its role in autoimmune diseases is attracting many researchers.,Recent studies have reported that differentiation and activation of immune cells, T cells, B cells, macrophages, and NK cells have correlation with lncRNAs, which have also an essential role in autoimmune diseases such as rheumatoid arthritis and SLE.,Therefore, elucidation of the roles of lncRNAs in autoimmunity could be beneficial to understand the pathogenesis of autoimmune diseases.,In this review article we attempt to highlight the recent progress regarding lncRNAs studies and summarize its role in autoimmune diseases.
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Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG).,Prior NMO diagnostic criteria required optic nerve and spinal cord involvement but more restricted or more extensive CNS involvement may occur.,The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus.,The new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG).,The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations.,More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable.,The IPND also proposed validation strategies and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSD and opticospinal MS.
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Neuromyelitis Optica (NMO) is an autoimmune disease primarily targeting the spinal cord and optic nerve leading to paralysis and blindness.,The discovery of an antibody against the astrocytic water channel, aquaporin-4 (AQP4), in the majority of patients, has led to the presumption that the antibody was necessary for disease pathogenesis.,The potential role of T cells in the central nervous system, however, has not been thoroughly examined.,We generated an anti-AQP4 antibody seronegative model of NMO using pathogenic AQP4-reactive T cells in mice by immunizing AQP4 null mice with peptides corresponding to the second extracellular loop of AQP4, loop C.,When polarized to a Th17 phenotype and transferred to wild-type mice, these cells caused tail and limb weakness.,Histology showed demyelination and T cell infiltration in the spinal cord, optic nerve and brain.,Animals receiving cells re-stimulated in culture with non-specific proteins resulted in no behavioral disease, indicating that specific targeting of AQP4 is essential for this phenotype.,In summary, we show that AQP4-reactive T cells are sufficient to trigger an NMO-like disease in mice, independent of antibodies, indicating that pathogenic AQP4-reactive T cells may play a similar role in humans.
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To evaluate the performance of the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) criteria in terms of earlier patients’ classification in comparison to the 1982/1997 ACR or the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria.,Patients from a Latin America, multiethnic, multicentre cohort, where SLE was defined using the physicians’ diagnosis, were included.,To calculate the sensitivity of the 2019 EULAR/ACR criteria, the 1982/1997 ACR criteria were considered the gold standard.,Additionally, comparison of the 1982/1997 ACR criteria and the 2012 SLICC criteria with the 2019 EULAR/ACR criteria was performed.,The sensitivity of the 2019 EULAR/ACR criteria when compared with the 1982/1997 ACR criteria as the gold standard was 91.3%.,This new set of criteria allowed an earlier SLE patient classification in 7.4% (mean 0.67 years) and 0.6% (mean 1.47 years) than the 1982/1997 ACR and the 2012 SLICC criteria, respectively.,Patients accruing the 2019 EULAR/ACR earlier than the 1982/1997 ACR criteria were more likely to have high anti-dsDNA titres; those accruing them later were less likely to have mucocutaneous and joint manifestations; this was not observed when comparing them with the 2012 SLICC criteria.,The 2019 EULAR/ACR criteria classified earlier only a small proportion of Latin America patients than with the two other criteria sets in real-life clinical practice scenarios.,Further studies in different patient populations are needed before these new criteria are adopted worldwide.
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The purpose is to discuss the advances that genetics and genomics have provided to better understand the molecular mechanisms behind SLE and how to solve its heterogeneity.,I propose new ideas that can help us stratify lupus in order to find the best therapies for each patient, and the idea of substituting clinical diagnosis with molecular diagnosis according to their molecular patterns, an idea that may not only include lupus but also other diseases.,The study of rare mutations may provide insight into groups of lupus patients where type I interferon signature is important and help understand those with an atypical clinical presentation.,Recent papers used longitudinal blood transcriptome data correlating with disease activity scores to stratify lupus into molecular clusters.,The implication of neutrophils in the risk to develop nephritis was established, but also that neutrophils and lymphocytes may correlate with activity differentiating the mechanisms of flares and separating patients into clinically separate groups.,The role of type I interferon signature is important; however, the stratification of SLE patients according to the genes and cellular compartments being modulated during disease activity may be even more important to define those patients who may benefit the most with new anti-type I IFN receptor therapies.
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In the daily management of type 1 diabetes (T1D), determining the correct insulin dose to be injected at meal-time is fundamental to achieve optimal glycemic control.,Wearable sensors, such as continuous glucose monitoring (CGM) devices, are instrumental to achieve this purpose.,In this paper, we show how CGM data, together with commonly recorded inputs (carbohydrate intake and bolus insulin), can be used to develop an algorithm that allows classifying, at meal-time, the post-prandial glycemic status (i.e., blood glucose concentration being too low, too high, or within target range).,Such an outcome can then be used to improve the efficacy of insulin therapy by reducing or increasing the corresponding meal bolus dose.,A state-of-the-art T1D simulation environment, including intraday variability and a behavioral model, was used to generate a rich in silico dataset corresponding to 100 subjects over a two-month scenario.,Then, an extreme gradient-boosted tree (XGB) algorithm was employed to classify the post-prandial glycemic status.,Finally, we demonstrate how the XGB algorithm outcome can be exploited to improve glycemic control in T1D through real-time adjustment of the meal insulin bolus.,The proposed XGB algorithm obtained good accuracy at classifying post-prandial glycemic status (AUROC = 0.84 [0.78, 0.87]).,Consequently, when used to adjust, in real-time, meal insulin boluses obtained with a bolus calculator, the proposed approach improves glycemic control when compared to the baseline bolus calculator.,In particular, percentage time in target [70, 180] mg/dL was improved from 61.98 (±13.89) to 67.00 (±11.54; p < 0.01) without increasing hypoglycemia.
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The clinical benefits of real time continuous glucose monitoring (rtCGM) use have been well demonstrated in both CSII- and MDI-treated individuals in large clinical trials.,However, recommendations for patient use of rtCGM in everyday life situations are lacking.,This article provides guidance to clinicians and patients with type 1 diabetes (T1D) in effective use of rtCGM data, including glucose rate of change (ROC) arrows, for insulin dosing adjustments and other treatment decisions.,The recommendations presented here are based on our own clinical experiences as endocrinologists, our personal experiences living with T1D using rtCGM, and findings from a recent survey of T1D patients who have successfully used rtCGM in their self-management.,It is important that both clinicians and people with diabetes understand the utility and limitations of rtCGM.,Maintaining a collaborative clinician-user relationship remains an important factor in safe, successful rtCGM use.
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Interferon-α (IFNα), a type I interferon, is expressed in the islets of type 1 diabetic individuals, and its expression and signaling are regulated by T1D genetic risk variants and viral infections associated with T1D.,We presently characterize human beta cell responses to IFNα by combining ATAC-seq, RNA-seq and proteomics assays.,The initial response to IFNα is characterized by chromatin remodeling, followed by changes in transcriptional and translational regulation.,IFNα induces changes in alternative splicing (AS) and first exon usage, increasing the diversity of transcripts expressed by the beta cells.,This, combined with changes observed on protein modification/degradation, ER stress and MHC class I, may expand antigens presented by beta cells to the immune system.,Beta cells also up-regulate the checkpoint proteins PDL1 and HLA-E that may exert a protective role against the autoimmune assault.,Data mining of the present multi-omics analysis identifies two compound classes that antagonize IFNα effects on human beta cells.,The cytokine IFNα is expressed in the islets of individuals with type 1 diabetes and contributes to local inflammation and destruction of beta cells.,Here, the authors provide a global multiomics view of IFNα-induced changes in human beta cells at the level of chromatin, mRNA and protein expression.
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Antibodies targeting PD-1 and its ligand PDL1 are used in cancer immunotherapy but may lead to autoimmune diseases, including type 1 diabetes (T1D).,It remains unclear whether PDL1 is expressed in pancreatic islets of people with T1D and how is it regulated.,The expression of PDL1, IRF1, insulin and glucagon was evaluated in samples of T1D donors by immunofluorescence.,Cytokine-induced PDL1 expression in the human beta cell line, EndoC-βH1, and in primary human pancreatic islets was determined by real-time RT-PCR, flow cytometry and Western blot.,Specific and previously validated small interference RNAs were used to inhibit STAT1, STAT2, IRF1 and JAK1 signaling.,Key results were validated using the JAK inhibitor Ruxolitinib.,PDL1 was present in insulin-positive cells from twelve T1D individuals (6 living and 6 deceased donors) but absent from insulin-deficient islets or from the islets of six non-diabetic controls.,Interferons-α and -γ, but not interleukin-1β, induced PDL1 expression in vitro in human islet cells and EndoC-βH1 cells.,Silencing of STAT1 or STAT2 individually did not prevent interferon-α-induced PDL1, while blocking of JAKs - a proposed therapeutic strategy for T1D - or IRF1 prevented PDL1 induction.,These findings indicate that PDL1 is expressed in beta cells from people with T1D, possibly to attenuate the autoimmune assault, and that it is induced by both type I and II interferons via IRF1.
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Graves’ orbitopathy (GO) is an autoimmune condition, which is associated with poor clinical outcomes including impaired quality of life and socio-economic status.,Current evidence suggests that the incidence of GO in Europe may be declining, however data on the prevalence of this disease are sparse.,Several clinical variants of GO exist, including euthyroid GO, recently listed as a rare disease in Europe (ORPHA466682).,The objective was to estimate the prevalence of GO and its clinical variants in Europe, based on available literature, and to consider whether they may potentially qualify as rare.,Recent published data on the incidence of GO and Graves’ hyperthyroidism in Europe were used to estimate the prevalence of GO.,The position statement was developed by a series of reviews of drafts and electronic discussions by members of the European Group on Graves’ Orbitopathy.,The prevalence of GO in Europe is about 10/10,000 persons.,The prevalence of other clinical variants is also low: hypothyroid GO 0.02-1.10/10,000; GO associated with dermopathy 0.15/10,000; GO associated with acropachy 0.03/10,000; asymmetrical GO 1.00-5.00/10,000; unilateral GO 0.50-1.50/10,000.,GO has a prevalence that is clearly above the threshold for rarity in Europe.,However, each of its clinical variants have a low prevalence and could potentially qualify for being considered as a rare condition, providing that future research establishes that they have a distinct pathophysiology.,EUGOGO considers this area of academic activity a priority.
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The possibility of an association of Graves’ disease (GD) with subsequent cancers raised by certain studies.,Using a database on 18 156 hospitalised GD patients, subsequent cancers were ascertained.,Increased risks of thyroid and parathyroid tumours were limited to the early follow-up period, which is probably a surveillance bias.,Cancer sites with observed excess included the mouth and breast, in contrast to decreased risks of colon cancer, melanoma and non-Hodgkin's lymphoma.,Increased subsequent cancers in GD patients appeared to be balanced by decreased risks at other sites; chance cannot be excluded.
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Salivary gland epithelial cells (SGECs) have been implicated in the pathogenesis of Sjögren’s syndrome due to aberrant antigen-presentation function.,This study examined the hypothesis that oral dysbiosis modulates the antigen-presentation function of SGECs, which regulates CD4 T cell proliferation in primary Sjögren’s syndrome (pSS).,Saliva samples from 8 pSS patients and 16 healthy subjects were analyzed for bacterial 16S ribosomal DNA.,As a result, 39 differentially abundant taxa were identified.,Among them, the phylum Proteobacteria comprised 21 taxa, and this phylum was mostly enriched in the healthy controls.,The proteobacterium Haemophilus parainfluenzae was enriched in the healthy controls, with the greatest effect size at the species level.,Treatment of A253 cells in vitro with H. parainfluenzae upregulated PD-L1 expression, and H. parainfluenzae-pretreated A253 cells suppressed CD4 T cell proliferation.,The suppression was partially reversed by PD-L1 blockade.,Among low-grade xerostomia patients, salivary abundance of H. parainfluenzae decreased in pSS patients compared to that in non-pSS sicca patients.,Our findings suggest that H. parainfluenzae may be an immunomodulatory commensal bacterium in pSS.
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Rheumatoid arthritis (RA) and periodontitis (PD) are chronic inflammatory diseases that appear to occur in tandem.,However, the mutual impact PD exerts on RA and vice versa has not yet been defined.,To address this issue, we set up an animal model and analyzed how two prime inducers of periodontitis-Porphyromonas gingivalis (Pg) and Aggregatibacter actinomycetemcomitans (Aa)-differ in their pathogenic potential.,Our experimental setup included collagen induced arthritis (CIA) in the mouse, oral inoculation with Pg or Aa to induce alveolar bone loss and the combination of both diseases in inverted orders of events.,Neither pathobiont impacted on macroscopic arthritis and arthritis did not exacerbate alveolar bone loss.,However, there were subtle differences between Pg and Aa with the former inducing more alveolar bone loss if PD was induced before CIA.,On a molecular level, Pg and Aa led to differential expression patterns in the synovial membranes that were reminiscent of cellular and humoral immune responses, respectively.,The Pg and Aa specific signatures in the synovial proteomes suggest a role for oral pathogens in shaping disease subtypes and setting the stage for subsequent therapy response.
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Rheumatoid arthritis (RA) is associated with heightened mortality due to atherosclerotic cardiovascular disease (CVD).,Inflammatory pathways in RA negatively affect vascular physiology and promote metabolic disturbances that contribute to CVD.,We hypothesized that the peroxisome proliferator activated receptor‐γ (PPAR‐γ) pioglitazone could promote potent vasculoprotective and anti‐inflammatory effects in RA.,One hundred forty‐three non‐diabetic adult RA patients (76.2% female, age 55.2±12.1 [mean±SD]) on stable RA standard of care treatment were enrolled in a randomized, double‐blind placebo controlled crossover trial of 45 mg daily pioglitazone versus placebo, with a 3‐month duration/arm and a 2‐month washout period.,Pulse wave velocity of the aorta (PWV), brachial artery flow mediated dilatation (FMD), nitroglycerin mediated dilatation (NMD), microvascular endothelial function (reactive hyperemia index [RHI]), and circulating biomarkers of inflammation, insulin resistance, and atherosclerosis risk all were quantified.,RA disease activity was assessed with the 28‐Joint Count Disease Activity Score (DAS‐28) C‐reactive protein (CRP) and the Short Form (36) Health Survey quality of life questionnaire.,When added to standard of care RA treatment, pioglitazone significantly decreased pulse wave velocity (ie, aortic stiffness) (P=0.01), while FMD and RHI remained unchanged when compared to treatment with placebo.,Further, pioglitazone significantly reduced RA disease activity (P=0.02) and CRP levels (P=0.001), while improving lipid profiles.,The drug was well tolerated.,Addition of pioglitazone to RA standard of care significantly improves aortic elasticity and decreases inflammation and disease activity with minimal safety issues.,The clinical implications of these findings remain to be established.,URL: ClinicalTrials.gov Unique Identifier: NCT00554853.
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We and others have previously shown that antibodies against cyclic citrullinated proteins (anti-CCP) precede the development of rheumatoid arthritis (RA) and in a more recent study we reported that individuals who subsequently developed RA had increased concentrations of several cytokines and chemokines years before the onset of symptoms of joint disease.,Here we aimed to evaluate the prevalence and predictive values of anti-CCP antibodies of IgG, IgM and IgA isotype in individuals who subsequently developed RA and also to relate these to cytokines and chemokines, smoking, genetic factors and radiographic score.,A case-control study (1:4 ratio) was nested within the Medical Biobank and the Maternity cohorts of Northern Sweden.,Patients with RA were identified from blood donors predating the onset of disease by years.,Matched controls were selected randomly from the same registers.,IgG, IgA and IgM anti-CCP2 antibodies were determined using EliA anti-CCP assay on ImmunoCAP 250 (Phadia AB, Uppsala, Sweden).,Of 86 patients with RA identified as blood donors prior to the onset of symptoms, samples were available from 71 for analyses.,The median (Q1 to Q3) predating time was 2.5 years (1.1 to 5.9 years).,The sensitivity of anti-CCP antibodies in the pre-patient samples was 35.2% for IgG, 23.9% for IgA, and 11.8% for IgM.,The presence of IgG and IgA anti-CCP antibodies was highly significant compared with controls.,IgG and IgA anti-CCP2 predicted RA significantly in conditional logistic regression models odds ratio (OR) = 94.1, 95% confidence interval (CI) 12.7 to 695.4 and OR = 11.1, 95% CI 4.4 to 28.1, respectively, the IgM anti-CCP showed borderline significance OR = 2.5 95% CI 0.9 to 6.3.,Concentrations of all anti-CCP isotypes increased the closer to the onset of symptoms the samples were collected with an earlier and higher increase for IgG and IgA compared with IgM anti-CCP.,IgA and IgG anti-CCP positive individuals had different patterns of up-regulated chemokines and also, smoking brought forward the appearance of IgA anti-CCP antibodies in pre-RA individuals.,Anti-CCP2 antibodies of both the IgG and IgA isotypes pre-dated the onset of RA by years; also, both IgG and IgA anti-CCP2 antibodies predicted the development of RA, with the highest predictive value for IgG anti-CCP2 antibodies.
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Various inflammatory biomarkers show prognostic potential for multiple sclerosis (MS)-risk after clinically isolated syndromes.,However, biomarkers are often examined singly and their interrelation and precise aspects of their associated pathological processes remain unclear.,Clarification of these relationships could aid the appropriate implementation of prognostic biomarkers in clinical practice.,To investigate the interrelation between biomarkers of inflammation, demyelination and neurodegeneration in acute optic neuritis and to assess their association to measures of MS risk.,A prospective study at a tertiary referral centre from June 2011 to December 2012 of 56 patients with optic neuritis as a first demyelinating symptom and 27 healthy volunteers.,Lumbar puncture was performed within 28 (median 16) days of onset.,CSF levels of CXCL13, matrix metalloproteinase (MMP)-9, CXCL10, CCL-2, osteopontin and chitinase-3-like-1, myelin basic protein (MBP) and neurofilament light-chain (NF-L) were determined.,MS-risk outcome measures were dissemination in space (DIS) of white matter lesions on cerebral MRI, CSF oligoclonal bands and elevated IgG-index.,In the interrelation analysis the biomarkers showed close correlations within two distinct groups: Biomarkers of leukocyte infiltration (CXCL13, MMP-9 and CXCL10) were strongly associated (p<0.0001 for all).,Osteopontin and chitinase-3-like-1 were also tightly associated (p<0.0001) and correlated strongly to tissue damage markers (NF-L and MBP).,The biomarkers of leukocyte infiltration all associated strongly with MS-risk parameters, whereas CHI3L1 and MBP correlated with MRI DIS, but not with CSF MS-risk parameters and osteopontin and NF-L did not correlate with any MS-risk parameters.,Our findings suggest two distinct inflammatory processes: one of leukocyte infiltration, represented by CXCL13, CXCL10 and MMP-9, strongly associated with and potentially predicting MS-risk; the other represented by osteopontin and CHI3L1, suggesting tissue damage-related inflammation, potentially predicting residual disabilities after attack and perhaps cumulative damage over time.,These hypotheses should be further addressed in follow-up studies.
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In multiple sclerosis relapses refractory to intravenous corticosteroid therapy, plasma exchange is recommended.,Immunoadsorption (IA) is regarded as an alternative therapy, but its efficacy and putative mechanism of action still needs to be established.,We prospectively treated 11 patients with multiple sclerosis who had optical neuritis and fulfilled the indications for apheresis therapy (Trial registration DE/CA25/00007080-00).,In total, five IA treatments were performed using tryptophan-IA.,Clinical activity (visual acuity, Expanded Disability Status Scale, Incapacity Status Scale), laboratory values and visual evoked potentials were measured before, during and after IA, with a follow-up of six months.,Moreover, proteomic analyses were performed to analyze column-bound proteins as well as corresponding changes in patients’ sera.,After the third IA, we detected an improvement of vision in eight of eleven patients, whom we termed responders.,Amongst these, the mean visual acuity improved from 0.15 ± 0.12 at baseline to 0.47 ± 0.32 after the third IA (P = 0.0252) up to 0.89 ± 0.15 (P < 0.0001) at day 180 ± 10 after IA.,Soluble interleukin-2 receptor decreased in responders (P = 0.03), whereas in non-responders it did not.,Proteomic analyses of proteins adsorbed to IA columns revealed that several significant immunological proteins as well as central nervous system protein fragments, including myelin basic protein, had been removed by IA.,IA was effective in the treatment of corticosteroid-refractory optic neuritis.,IA influenced the humoral immune response.,Strikingly, however, we found strong evidence that demyelination products and immunological mediators were also cleared from plasma by IA.
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Type 1 diabetes (T1D) is an autoimmune disease that is caused, in part, by T cell-mediated destruction of insulin-producing β-cells.,High risk for disease, in those with genetic susceptibility, is predicted by the presence of two or more autoantibodies against insulin, the 65-kDa form of glutamic acid decarboxylase (GAD65), insulinoma-associated protein 2 (IA-2), and zinc transporter 8 (ZnT8).,Despite this knowledge, we still do not know what leads to the breakdown of tolerance to these autoantigens, and we have an incomplete understanding of T1D etiology and pathophysiology.,Several new autoantibodies have recently been discovered using innovative technologies, but neither their potential utility in monitoring disease development and treatment nor their role in the pathophysiology and etiology of T1D has been explored.,Moreover, neoantigen generation (through posttranslational modification, the formation of hybrid peptides containing two distinct regions of an antigen or antigens, alternative open reading frame usage, and translation of RNA splicing variants) has been reported, and autoreactive T cells that target these neoantigens have been identified.,Collectively, these new studies provide a conceptual framework to understand the breakdown of self-tolerance, if such modifications occur in a tissue- or disease-specific context.,A recent workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases brought together investigators who are using new methods and technologies to identify autoantigens and characterize immune responses toward these proteins.,Researchers with diverse expertise shared ideas and identified resources to accelerate antigen discovery and the detection of autoimmune responses in T1D.,The application of this knowledge will direct strategies for the identification of improved biomarkers for disease progression and treatment response monitoring and, ultimately, will form the foundation for novel antigen-specific therapeutics.,This Perspective highlights the key issues that were addressed at the workshop and identifies areas for future investigation.
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Type 1 diabetes results from T cell-mediated β-cell destruction.,The HLA-A*24 class I gene confers significant risk of disease and early onset.,We tested the hypothesis that HLA-A24 molecules on islet cells present preproinsulin (PPI) peptide epitopes to CD8 cytotoxic T cells (CTLs).,Surrogate β-cell lines secreting proinsulin and expressing HLA-A24 were generated and their peptide ligandome examined by mass spectrometry to discover naturally processed and HLA-A24-presented PPI epitopes.,A novel PPI epitope was identified and used to generate HLA-A24 tetramers and examine the frequency of PPI-specific T cells in new-onset HLA-A*24+ patients and control subjects.,We identified a novel naturally processed and HLA-A24-presented PPI signal peptide epitope (PPI3-11; LWMRLLPLL).,HLA-A24 tetramer analysis reveals a significant expansion of PPI3-11-specific CD8 T cells in the blood of HLA-A*24+ recent-onset patients compared with HLA-matched control subjects.,Moreover, a patient-derived PPI3-11-specific CD8 T-cell clone shows a proinflammatory phenotype and kills surrogate β-cells and human HLA-A*24+ islet cells in vitro.,These results indicate that the type 1 diabetes susceptibility molecule HLA-A24 presents a naturally processed PPI signal peptide epitope.,PPI-specific, HLA-A24-restricted CD8 T cells are expanded in patients with recent-onset disease.,Human islet cells process and present PPI3-11, rendering themselves targets for CTL-mediated killing.
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Although IgG oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF) are a frequent phenomenon in multiple sclerosis (MS) patients, their relationship with grey matter lesions, intrathecal/meningeal inflammation and clinical evolution has not been clarified yet.,The aim of our study was to assess the relationship between the OCBs, the inflammatory/neurodegenerative CSF profile at diagnosis, the cortical lesion load and the clinical evolution after 10 years.,This is a 10-year observational, cross-sectional study based on a combined MRI, cognitive and CSF profiling of the examined patients.,Forty consecutive OCB-negative (OCB−) and 50 OCB-positive (OCB+) MS patients were included in this study.,Both groups had mean disease duration of 10 years and were age and gender matched.,Each patient underwent neurological and neuropsychological evaluation and 3-T MRI.,Analysis of the presence and levels of 28 inflammatory mediators was performed in the CSF obtained from 10 OCB− MS, 11 OCB+ MS and 10 patients with other neurological conditions.,Increased number of CLs was found in OCB+ compared to OCB− patients (p < 0.0001), whereas no difference was found in white matter lesion (WML) load (p = 0.36).,The occurrence of OCB was also associated with increased levels of neurofilament light chains and of several inflammatory mediators linked to B lymphocyte activity and lymphoid-neogenesis (CXCL13, CXCL12, CXCL10, TNFSF13, TNFSF13B, IL6, IL10) and other pro-inflammatory molecules, such as IFN-γ, TNF, MMP2, GM-CSF, osteopontin and sCD163.,Finally, the occurrence of OCB was found associated with poor prognosis, from both physical and cognitive points of view.,OCB at MS onset are associated with more severe GM pathology and with a more severe physical disability and cognitive impairment after 10 years.,Increased levels of cytokines linked to B cell activation, lymphoid-neogenesis, and pro-inflammatory immune response in the CSF of OCB+ patients support the hypothesis of crucial role played by compartmentalized, intrathecal B cell response in the pathogenesis of CLs and OCB production.,The online version of this article (doi:10.1186/s12974-017-0812-y) contains supplementary material, which is available to authorized users.
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Iron may contribute to the pathogenesis and progression of multiple sclerosis (MS) due to its accumulation in the human brain with age.,Our study focused on nonheme iron distribution and the expression of the iron-related proteins ferritin, hephaestin, and ceruloplasmin in relation to oxidative damage in the brain tissue of 33 MS and 30 control cases.,We performed (1) whole-genome microarrays including 4 MS and 3 control cases to analyze the expression of iron-related genes, (2) nonheme iron histochemistry, (3) immunohistochemistry for proteins of iron metabolism, and (4) quantitative analysis by digital densitometry and cell counting in regions representing different stages of lesion maturation.,We found an age-related increase of iron in the white matter of controls as well as in patients with short disease duration.,In chronic MS, however, there was a significant decrease of iron in the normal-appearing white matter (NAWM) corresponding with disease duration, when corrected for age.,This decrease of iron in oligodendrocytes and myelin was associated with an upregulation of iron-exporting ferroxidases.,In active MS lesions, iron was apparently released from dying oligodendrocytes, resulting in extracellular accumulation of iron and uptake into microglia and macrophages.,Iron-containing microglia showed signs of cell degeneration.,At lesion edges and within centers of lesions, iron accumulated in astrocytes and axons.,Iron decreases in the NAWM of MS patients with increasing disease duration.,Cellular degeneration in MS lesions leads to waves of iron liberation, which may propagate neurodegeneration together with inflammatory oxidative burst.
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Autoimmune diseases are usually complex and multifactorial, characterized by aberrant production of autoreactive immune cells and/or autoantibodies against healthy cells and tissues.,However, the pathogenesis of autoimmune diseases has not been clearly elucidated.,The activation, differentiation, and development of CD8+ T cells can be affected by numerous inflammatory cytokines, transcription factors, and chemokines.,In recent years, epigenetic modifications have been shown to play an important role in the fate of CD8+ T cells.,The discovery of these modifications that contribute to the activation or suppression of CD8+ cells has been concurrent with the increasing evidence that CD8+ T cells play a role in autoimmunity.,These relationships have been studied in various autoimmune diseases, including multiple sclerosis (MS), systemic sclerosis (SSc), type 1 diabetes (T1D), Grave's disease (GD), systemic lupus erythematosus (SLE), aplastic anemia (AA), and vitiligo.,In each of these diseases, genes that play a role in the proliferation or activation of CD8+ T cells have been found to be affected by epigenetic modifications.,Various cytokines, transcription factors, and other regulatory molecules have been found to be differentially methylated in CD8+ T cells in autoimmune diseases.,These genes are involved in T cell regulation, including interferons, interleukin (IL),tumor necrosis factor (TNF), as well as linker for activation of T cells (LAT), cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), and adapter proteins.,MiRNAs also play a role in the pathogenesis of these diseases and several known miRNAs that are involved in these diseases have also been shown to play a role in CD8+ regulation.
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Although Act1 (adaptor for IL-17 receptors) is necessary for IL-17-mediated inflammatory responses, Act1- (but not Il17ra-, Il17rc-, or Il17rb-) deficient mice develop spontaneous SLE- and Sjögren’s-like diseases.,Here, we show that Act1 functions as a negative regulator in T and B cells via direct inhibition of STAT3.,Mass spectrometry analysis detected an Act1-STAT3 complex, deficiency of Act1 (but not Il17ra-, Il17rc-, or Il17rb) results in hyper IL-23- and IL-21-induced STAT3 activation in T and B cells, respectively.,IL-23R deletion or blockade of IL-21 ameliorates SLE- and Sjögren’s-like diseases in Act1−/− mice.,Act1 deficiency results in hyperactivated follicular Th17 cells with elevated IL-21 expression, which promotes T-B cell interaction for B cell expansion and antibody production.,Moreover, anti-IL-21 ameliorates the SLE- and Sjögren’s-like diseases in Act1-deficient mice.,Thus, IL-21 blocking antibody might be an effective therapy for treating SLE- and Sjögren’s-like syndrome in patients containing Act1 mutation.,Adaptor for IL-17 receptors (Act1) is known to be crucial for IL-17-mediated immune responses.,Here the authors show that Act1 also functions as a negative regulator of T and B cells by direct inhibition of STAT3.
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Rheumatoid arthritis (RA) is a progressive inflammatory disorder characterized by swollen joints, discomfort, tightness, bone degeneration and frailty.,Genetic, agamogenetic and sex-specific variables, Prevotella, diet, oral health and gut microbiota imbalance are all likely causes of the onset or development of RA, perhaps the specific pathways remain unknown.,Lactobacillus spp. probiotics are often utilized as relief or dietary supplements to treat bowel diseases, build a strong immune system and sustain the immune system.,At present, the action mechanism of Lactobacillus spp. towards RA remains unknown.,Therefore, researchers conclude the latest analysis to effectively comprehend the ultimate pathogenicity of rheumatoid arthritis, as well as the functions of probiotics, specifically Lactobacillus casei or Lactobacillus acidophilus, in the treatment of RA in therapeutic and diagnostic reports.,RA is a chronic inflammation immunological illness wherein the gut microbiota is affected.,Probiotics are organisms that can regulate gut microbiota, which may assist to relieve RA manifestations.,Over the last two decades, there has been a surge in the use of probiotics.,However, just a few research have considered the effect of probiotic administration on the treatment and prevention of arthritis.,Randomized regulated experimental trials have shown that particular probiotics supplement has anti-inflammatory benefits, helps people with RA enhance daily activities and alleviates symptoms.,As a result, utilizing probiotic microorganisms as therapeutics could be a potential possibility for arthritis treatment.,This review highlights the known data on the therapeutic and preventative effects of probiotics in RA, as well as their interactions.
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Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized.,Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation.,Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis.,Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation.,Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis.,Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset.,These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function.,Intestinal dysbiosis is associated with an ever-growing list of autoimmune diseases.,Here the authors show that both mice and humans with autoimmune arthritis can have dysbiosis and barrier leakiness prior to major signs of inflammatory arthritis, and treatment of mice with a zonulin antagonist can limit collagen-induced arthritis.
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Epigenetic mechanisms can integrate gene-environment interactions that mediate disease transition from preclinical to clinically overt rheumatoid arthritis (RA).,To better understand their role, we evaluated microRNA (miRNA, miR) expression profile in indigenous North American patients with RA who were positive for anticitrullinated protein antibodies; their autoantibody-positive, asymptomatic first-degree relatives (FDRs); and disease-free healthy control subjects (HCs).,Total RNA was isolated from whole blood samples obtained from HC (n = 12), patients with RA (n = 18), and FDRs (n = 12).,Expression of 35 selected relevant miRNAs, as well as associated downstream messenger RNA (mRNA) targets of miR-103a-3p, was determined by qRT-PCR.,Whole blood expression profiling identified significantly differential miRNA expression in patients with RA (13 miRNAs) and FDRs (10 miRNAs) compared with HCs.,Among these, expression of miR-103a-3p, miR-155, miR-146a-5p, and miR-26b-3p was significantly upregulated, whereas miR-346 was significantly downregulated, in both study groups.,Expression of miR-103a-3p was consistently elevated in FDRs at two time points 1 year apart.,We also confirmed increased miR-103a-3p expression in peripheral blood mononuclear cells from patients with RA compared with HCs.,Predicted target analyses of differentially expressed miRNAs in patients with RA and FDRs showed overlapping biological networks.,Consistent with these curated networks, mRNA expression of DICER1, AGO1, CREB1, DAPK1, and TP53 was downregulated significantly with miR-103a-3p expression in FDRs.,We highlight systematically altered circulating miRNA expression in at-risk FDRs prior to RA onset, a profile they shared with patients with RA.,Prominently consistent miR-103a-3p expression indicates its utility as a prognostic biomarker for preclinical RA while highlighting biological pathways important for transition to clinically detectable disease.,The online version of this article (doi:10.1186/s13075-017-1459-x) contains supplementary material, which is available to authorized users.
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Identification of parameters for early diagnosis and treatment response would be beneficial for patients with early rheumatoid arthritis (ERA) to prevent ongoing joint damage. miRNAs have features of potential biomarkers, and an altered expression of miRNAs was shown in established rheumatoid arthritis (RA).,To analyse RA associated miRNAs in the sera of patients with ERA to find markers of early disease, clinical activity or predictors of disease outcome.,Total RNA was isolated from whole sera in ERA patients (prior to and after 3 and 12 months of therapy with disease modifying antirheumatic drugs), in patients with established RA and in healthy controls (HC) using phenol-chloroform extraction.,Expression of miR-146a, miR-155, miR-223, miR-16, miR-203, miR-132 and miR-124a was analysed by TaqMan Real Time PCR.,From all analysed miRNAs, levels of miR-146a, miR-155 and miR-16 were decreased in the sera of ERA patients in comparison with established RA.,A change in circulating miR-16 in the first 3 months of therapy was associated with a decrease in DAS28 in long term follow-up in ERA (p=0.002).,Levels of circulating miR-223 in treatment naïve ERA correlated with C reactive protein (p=0.008), DAS28 (p=0.031) and change in DAS28 after 3 months (p=0.003) and 12 months (p=0.011) of follow-up.,However, neither miR-16 nor miR-223 could distinguish ERA from HC.,Differential expression of circulating miR-146a, miR-155 and miR-16 in the sera of ERA patients may characterise an early stage of the disease.,We suggest miR-223 as a marker of disease activity and miR-16 and miR-223 as possible predictors for disease outcome in ERA.
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Data on the impact of biological therapies on the T-cell phenotype in rheumatoid arthritis are limited.,Here, we prospectively measured the percentages of 15 circulating T-cell subtypes using flow cytometry.,We obtained transversal and longitudinal data in 30 anti-TNF responders, 19 secondary anti-TNF nonresponders, and 43 IL-6R antagonist responders, before, 8 weeks and at least 6 months after biological therapy.,Untreated RA patients and healthy controls were also included.,The important findings are the following: (1) the proportion of regulatory T-cells (Tregs) which are decreased in untreated RA patients becomes normal in all long-term-treated groups; (2) in anti-TNF responders as well as in nonresponders, the frequencies of naïve CD4+ and CD8+ cells are lower, whereas those of proinflammatory Th1, Th2, and Th17 cells and HLA-DR+-activated cells are higher than those in untreated RA or healthy controls; (3) in IL-6R responders, Th1 proportion is decreased, while that of Th2 and Th17 is increased as compared to that in anti-TNF-treated patients and controls; (4) pending confirmation, a CD4CD69 ratio < 2.43 at baseline, could be useful to predict a good therapeutic response to anti-TNF therapy.,This study provides comprehensive information regarding the long-term impacts of those biological therapies on the ecotaxis of T-cells in RA.,The ClinicalTrials.gov registration number of our study is NCT03266822.
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Rheumatoid arthritis (RA) is a complex and clinically heterogeneous autoimmune disease.,Currently, the relationship between pathogenic molecular drivers of disease in RA and therapeutic response is poorly understood.,We analyzed synovial tissue samples from two RA cohorts of 49 and 20 patients using a combination of global gene expression, histologic and cellular analyses, and analysis of gene expression data from two further publicly available RA cohorts.,To identify candidate serum biomarkers that correspond to differential synovial biology and clinical response to targeted therapies, we performed pre-treatment biomarker analysis compared with therapeutic outcome at week 24 in serum samples from 198 patients from the ADACTA (ADalimumab ACTemrA) phase 4 trial of tocilizumab (anti-IL-6R) monotherapy versus adalimumab (anti-TNFα) monotherapy.,We documented evidence for four major phenotypes of RA synovium - lymphoid, myeloid, low inflammatory, and fibroid - each with distinct underlying gene expression signatures.,We observed that baseline synovial myeloid, but not lymphoid, gene signature expression was higher in patients with good compared with poor European league against rheumatism (EULAR) clinical response to anti-TNFα therapy at week 16 (P =0.011).,We observed that high baseline serum soluble intercellular adhesion molecule 1 (sICAM1), associated with the myeloid phenotype, and high serum C-X-C motif chemokine 13 (CXCL13), associated with the lymphoid phenotype, had differential relationships with clinical response to anti-TNFα compared with anti-IL6R treatment. sICAM1-high/CXCL13-low patients showed the highest week 24 American College of Rheumatology (ACR) 50 response rate to anti-TNFα treatment as compared with sICAM1-low/CXCL13-high patients (42% versus 13%, respectively, P =0.05) while anti-IL-6R patients showed the opposite relationship with these biomarker subgroups (ACR50 20% versus 69%, P =0.004).,These data demonstrate that underlying molecular and cellular heterogeneity in RA impacts clinical outcome to therapies targeting different biological pathways, with patients with the myeloid phenotype exhibiting the most robust response to anti-TNFα.,These data suggest a path to identify and validate serum biomarkers that predict response to targeted therapies in rheumatoid arthritis and possibly other autoimmune diseases.,ClinicalTrials.gov NCT01119859
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Network abnormalities could help explain physical disability in multiple sclerosis (MS), which remains poorly understood.,This study investigates functional network efficiency changes in the sensorimotor system.,We included 222 MS patients, divided into low disability (LD, Expanded Disability Status Scale (EDSS) ⩽3.5, n = 185) and high disability (HD, EDSS ⩾6, n = 37), and 82 healthy controls (HC).,Functional connectivity was assessed between 23 sensorimotor regions.,Measures of efficiency were computed and compared between groups using general linear models corrected for age and sex.,Binary logistic regression models related disability status to local functional network efficiency (LE), brain volumes and demographics.,Functional connectivity patterns of regions important for disability were explored.,HD patients demonstrated significantly higher LE of the left primary somatosensory cortex (S1) and right pallidum compared to LD and HC, and left premotor cortex compared to HC only.,The logistic regression model for disability (R2 = 0.38) included age, deep grey matter volume and left S1 LE.,S1 functional connectivity was increased with prefrontal and secondary sensory areas in HD patients, compared to LD and HC.,Clinical disability in MS associates with functional sensorimotor increases in efficiency and connectivity, centred around S1, independent of structural damage.
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Analysis of isolated meninges and cerebrospinal fluid (CSF) of post-mortem MS cases has shown increased gene and protein expression for the pro-inflammatory cytokines: tumour necrosis factor (TNF) and interferon-γ (IFNγ).,Here we tested the hypothesis that persistent production of these cytokines in the meningeal compartment and diffusion into underlying GM can drive chronic MS-like GM pathology.,Lentiviral transfer vectors were injected into the sagittal sulcus of DA rats to deliver continuous expression of TNF + IFNγ transgenes in the meninges and the resulting neuropathology analysed after 1 and 2 months.,Injection of TNF + IFNγ viral vectors, with or without prior MOG immunisation, induced extensive immune cell infiltration (CD4+ and CD8+ T-cells, CD79a + B-cells and macrophages) in the meninges by 28 dpi, which remained at 2 months.,Control GFP viral vector did not induce infiltration.,Subpial demyelination was seen underlying these infiltrates, which was partly dependant on prior myelin oligodendrocyte glycoprotein (MOG) immunisation.,A significant decrease in neuronal numbers was seen at 28 and 56 days in cortical layers II-V that was independent of MOG immunisation.,RNA analysis at 28 dpi showed an increase in expression of necroptotic pathway genes, including RIP3, MLKL, cIAP2 and Nox2.,PhosphoRIP3+ and phosphoMLKL+ neurons were present in TNF + IFNγ vector injected animals, indicating activation of necroptosis.,Our results suggest that persistent expression of TNF in the presence of IFNγ is a potent inducer of meningeal inflammation and can activate TNF signalling pathways in cortical cells leading to neuronal death and subpial demyelination and thus may contribute to clinical progression in MS.
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