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ID PMID Title PublicationDate abstract
27638812 Improvement in insulin resistance is greater when infliximab is added to methotrexate duri 2016 Dec OBJECTIVES: To determine the change in established biomarkers of cardiovascular (CV) risk, namely, total cholesterol/high-density lipoprotein cholesterol ratio (TC/HDL-C), N-terminal pro-brain natriuretic peptide (NT-proBNP) and insulin resistance (IR) in patients with early RA treated with two different treat-to-target strategies. METHODS: Fasting glucose, lipids, insulin and NT-proBNP were measured at baseline, weeks 26 and 78 in 79 DMARD-naïve RA patients, free of CV disease, as part of a double-blind randomized controlled trial of MTX with either infliximab (IFX) or methylprednisolone as induction therapy. Homeostasis model assessment-estimated IR (HOMA-IR) (glucose*insulin/405) was used to measure IR. Multiple imputation was employed, and linear regression analyses were adjusted for baseline values. RESULTS: Changes in DAS44-CRP did not differ between the treatment arms at weeks 26 and 78. Mean TC/HDL-C, HOMA-IR and NT-proBNP improved in both groups at weeks 26 and 78, although change in NT-proBNP was not statistically significant at week 78. Changes in TC/HDL-C and NT-proBNP were similar between treatment arms, but HOMA-IR values in the IFX + MTX arm were 42% lower than those treated with MTX + methylprednisolone at week 78 (P = 0.003); the difference remained significant after adjustment for baseline BMI, ACPA positivity, smoking status and intramuscular glucocorticoid use (P = 0.007). CONCLUSION: When implementing a treat-to-target approach, treatment of early RA was associated with improvement in TC/HDL-C, HOMA-IR and NT-proBNP, and a greater long-term improvement in HOMA-IR was seen in those treated with IFX. TRIAL REGISTRATION: EU Clinical Trials Register, http://www.clinicaltrialsregister.eu, Eudract-2005-005013-37; ISRTCNregisrty, http://www.isrctn.com, ISRCTN48638981.
26631102 Predictive factors for achieving low disease activity at 52 weeks after switching from tum 2016 Jan This study aimed to identify predictive factors for achieving low disease activity (LDA) in rheumatoid arthritis (RA) patients switching from tumor necrosis factor inhibitors (TNFis) to abatacept (ABT). Patients who were registered in the multicenter observational Tsurumai Biologics Communication Registry (TBCR) were enrolled in this study. Predictive factors for LDA achievement at each time point were determined by univariate and multivariate logistic regression analyses. The cutoffs of 28-point count Disease Activity Score (DAS28)-C-reactive protein (CRP) and ΔDAS28-CRP from baseline up to 24 weeks for LDA achievement at 52 weeks were explored using receiver operating characteristic (ROC) curves. Of 2771 RA patients registered until 2013, 76 with moderate or high disease activity were selected. Twenty-six percent of the patients achieved LDA. Multivariate analysis confirmed that DAS28-CRP at 12 weeks and ΔDAS28-CRP from baseline to 12 weeks were independent factors for LDA achievement at 52 weeks [odds ratio (OR) 0.26, 95% confident interval (CI) (0.12-0.56), OR 0.25, 95% CI (0.11-0.57), respectively]. The best cutoff values of DAS28-CRP at 12 weeks and ΔDAS28-CRP from baseline to 12 weeks for LDA at 52 weeks were 3.9 (sensitivity 0.85, specificity 0.78) and -0.97 (sensitivity 0.70, specificity 0.70), respectively. Seventy-one percent of patients who achieved both of these cutoff values at 12 weeks achieved LDA at 52 weeks. Our findings suggest that the clinical course up to 12 weeks is important for predicting long-term outcomes when switching from TNFis to ABT.
27273876 Elevated IgA Plasmablast Levels in Subjects at Risk of Developing Rheumatoid Arthritis. 2016 Oct OBJECTIVE: The disease process in rheumatoid arthritis (RA) starts years before the clinical diagnosis is made, and elevated levels of disease-specific autoantibodies can be detected during this period. Early responses to known or novel autoantigens likely drive the eventual production of pathogenic autoimmunity. Importantly, the presence of disease-specific autoantibodies can identify individuals who are at high risk of developing RA but who do not currently have arthritis. The goal of the current study was to characterize plasmablasts from individuals at risk of developing RA. METHODS: We investigated antibody-secreting plasmablasts derived from a well-characterized cohort of individuals who were at risk of developing RA, based on RA-related serum autoantibody positivity, as compared to patients with early (<1 year) seropositive RA as well as healthy control subjects. The plasmablast antibody repertoires of at-risk subjects were analyzed using DNA barcode-based methods with paired heavy- and light-chain gene sequencing. Cells were single-cell sorted, the cell- and plate-specific DNA barcodes were sequentially added, and next-generation sequencing was performed. RESULTS: Total plasmablast levels were similar in the antibody-positive (1%) and control (0.4-1.6%) groups. However, increased frequencies of IgA+ versus IgG+ plasmablasts were observed in the antibody-positive group (39% IgA+ and 37% IgG+) as compared to other groups (1-9% IgA+ and 71-87% IgG+). Paired antibody sequences from antibody-positive subjects revealed cross-isotype clonal families and similar sequence characteristics in the IgA and IgG plasmablast repertoires. Antibody-positive individuals also demonstrated elevated serum levels of IgA isotype anti-cyclic citrullinated peptide 3 antibodies. CONCLUSION: The IgA plasmablast dominance in these antibody-positive individuals suggests that a subset of RA-related autoantibodies may arise from mucosal immune responses and may be involved in early disease pathogenesis in individuals who are at risk of developing RA.
26565676 Therapeutic Targeting of IL-17 and IL-23 Cytokines in Immune-Mediated Diseases. 2016 The discovery of the biological functions of the interleukin-23/-17 axis led to the identification of IL-23 and IL-17 as important participants in the pathogenesis of several immune-mediated diseases. Therapeutic agents targeting these cytokines and/or their receptors have now been developed as potential treatment strategies for common immune-mediated diseases. Anti-IL-17 and anti-IL-12/-23 regimens appear particularly effective in psoriasis, with promising results in spondyloarthropathies also emerging. Overall, these agents appear well tolerated, with adverse-event rates that are commensurate with those in other biologic treatment programs. The strategic utility of these new agents, however, remains uncertain, and further studies will be required to determine their place in the context of existing conventional and biologic immune-modifying agents.
27494687 Betahistine attenuates murine collagen-induced arthritis by suppressing both inflammatory 2016 Oct The objective of this study was to evaluate the potential therapeutic effects of betahistine dihydrochloride (betahistine) in a collagen-induced arthritis (CIA) mouse model. CIA was induced in DBA/1 male mice by primary immunization with 100μl of emulsion containing 2mg/ml chicken type II collagen (CII) mixed with complete Freund's adjuvant (CFA) in an 1:1 ratio, and booster immunization with 100μl of emulsion containing 2mg/ml CII mixed with incomplete Freund's adjuvant (IFA) in an 1:1 ratio. Immunization was performed subcutaneously at the base of the tail. After being boosted on day 21, betahistine (1 and 5mg/kg) was orally administered daily for 2weeks. The severity of CIA was determined by arthritic scores and assessment of histopathological joint destruction. Expression of cytokines in the paw and anti-CII antibodies in the serum was evaluated by ELISA. The proliferative response against CII in the lymph node cells was measured by (3)H-thymidine incorporation assay. The frequencies of different CII specific CD4(+) T cell subsets in the lymph node were determined by flow-cytometric analysis. Betahistine treatment attenuated the severity of arthritis and reduced the levels of pro-inflammatory cytokines, including TNF-α, IL-6, IL-23 and IL-17A, in the paw tissues of CIA mice. Lymph node cells from betahistine-treated mice showed a decrease in proliferation, as well as a lower frequency of Th17 cells. In vitro, betahistine suppressed CD4(+) T cell differentiation into Th17 cells. These results indicate that betahistine is effective in suppressing both inflammatory and Th17 responses in mouse CIA and that it may have therapeutic value as an adjunct treatment for rheumatoid arthritis.
27007811 Comparative Effectiveness of Etanercept and Adalimumab in Patient Reported Outcomes and In 2016 OBJECTIVE: To describe patient preferences in selecting specific biologics and compare clinical response using patient reported outcomes (PROs) among patients with rheumatoid arthritis (RA) started on different anti-tumor necrosis factor (TNF) therapies. METHODS: Participants were enrollees in Kaiser Permanente Northern California. Patients with RA who had at least two provider visits and started a new anti-TNF therapy from 10/2010-8/2011, were eligible for participation in this longitudinal study. Using a telephone survey, patient preferences in biologic selection and RAPID3, MDHAQ, and SF-12 scores were collected at baseline and at 6 months. Patient scores rating injection/infusion-site burning and stinging (ISBS) were collected at 6 months. RESULTS: In all, 267 patients with RA responded to the baseline survey, of whom 57% preferred an injectable biologic, 22% preferred an infused biologic, and 21% had no preference. Motivation for injectable biologics was convenience (92%) and for infusion therapy was dislike or lack of self-efficacy for self-injection (16%). After 6 months of treatment with anti-TNF, 70% of the 177 patients who answered the ISBS question reported ISBS with the last dose; on a scale of 1 (none) to 10 (worst), 41% of these reported a score of 2-5; and 29% reported a score of 6-10. Adalimumab users experienced 3.2 times (95% confidence interval 1.2-8.6) the level of ISBS that etanercept users experienced. There were no significant differences in RAPID3, MDHAQ, or SF-12 scores between etanercept or adalimumab initiators. CONCLUSION: Convenience and fear of self-injection were important considerations to patients selecting a biologic drug. Although more convenient, adalimumab associated with more ISBS than did etanercept, and this rate was higher than reported in clinical trials. At 6 months, PROs did not differ between etanercept and adalimumab users.
24907036 Time trends in total ankle arthroplasty in the USA: a study of the National Inpatient Samp 2016 Jan The objective of this study was to assess the time trends in utilization, clinical characteristics, and outcomes of patients undergoing total ankle arthroplasty (TAA) in the USA. We used the Nationwide Inpatient Sample (NIS) data from 1998 to 2010 to examine time trends in the utilization rates of TAA. We used the Cochran Armitage test for trend to assess time trends across the years and the analysis of variance (ANOVA), Wilcoxon test, or chi-squared test (as appropriate) to compare the first (1998-2000) and the last time periods (2009-2010). TAA utilization rate increased significant from 1998 to 2010: 0.13 to 0.84 per 100,000 overall, 0.14 to 0.88 per 100,000 in females, and from 0.11 to 0.81 per 100,000 in males (p < 0.0001 for each comparison for time trends). Compared to the 1998-2000 period, those undergoing TAA in 2009-2010 were older (41% fewer patients <50 years, p < 0.0001), less likely to have rheumatoid arthritis as the underlying diagnosis (55% fewer patients, p = 0.0001), more likely to have Deyo-Charlson index of 2 or more (197% more, p = 0.0010), and had a shorter length of stay at 2.5 days (17% reduction, p < 0.0001). Mortality was rare ranging from 0 to 0.6% and discharge to inpatient facility ranged 12.6-14.1%; we noted no significant time trends in either (p > 0.05). The utilization rate of TAA increased rapidly in the USA from 1998 to 2010, but post-arthroplasty mortality rate was stable. Underlying diagnosis and medical comorbidity changed over time and both can impact outcomes after TAA. Further studies should examine how the outcomes and complications of TAA have evolved over time.
27567553 Molecular mechanisms of action of anti-TNF-α agents - Comparison among therapeutic TNF-α 2018 Jan Tumor necrosis factor (TNF)-α is a potent pro-inflammatory and pathological cytokines in inflammatory diseases such as rheumatoid arthritis and inflammatory bowel diseases. Anti-TNF-α therapy has been established as an efficacious therapeutic strategy in these diseases. In clinical settings, three monoclonal anti-TNF-α full IgG1 antibodies infliximab, adalimumab, and golimumab, PEGylated Fab' fragment of anti-TNF-α antibody certolizumab pegol, extracellular domain of TNF receptor 2/IgG1-Fc fusion protein etanercept, are almost equally effective for rheumatoid arthritis. Although monoclonal full IgG1 antibodies are able to induce clinical and endoscopic remission in inflammatory bowel diseases, certolizumab pegol without Fc portion has been shown to be less effective for inflammatory bowel diseases compared to full IgG1 antibodies. In addition, there are no evidences that etanercept leads clinical remission in inflammatory bowel diseases. Besides the common effect of anti-TNF-α agents on neutralization of soluble TNF-α, each anti-TNF-α agent has its own distinctive pharmacological properties which cause the difference in clinical efficacies. Here we focus on the distinctions of action of anti-TNF-α agents especially in following points; (1) blocking ability against ligands, transmembrane TNF-α and lymphotoxin, (2) effects toward transmembrane TNF-α-expressing cells, (3) effects toward Fcγ receptor-expressing cells, (4) degradation and distribution in inflamed tissue. Accumulating evidence will give us the idea how to modify anti-TNF-α agents to enhance the clinical efficacy in inflammatory diseases.
27072520 Increased sensitivity of rheumatoid synoviocytes to Schnurri-3 expression in TNF-α and IL 2016 Jun OBJECTIVE: To compare the effects of TNF-α and IL-17A on osteogenic differentiation of isolated fibroblast-like synoviocytes (FLS) from healthy donors, osteoarthritis (OA) and rheumatoid arthritis (RA) patients. METHODS: FLS were cultured in osteogenic medium, with and without TNF-α and/or IL-17A. Extracellular matrix mineralization was evaluated by alizarin red staining and alkaline phosphatase activity (ALP) measurement. mRNA expression was analyzed by qRT-PCR for Wnt5a, BMP2 and Runx2, genes associated with osteogenesis, for DKK1 and RANKL, genes associated with osteogenesis inhibition and Schnurri-3, a new critical gene in the cross talk with osteoclasts. IL-6 and IL-8 production was measured by ELISA. RESULTS: In osteogenic medium, matrix mineralization and increased ALP activity indicated that FLS can undergo osteogenic differentiation, which was increased with TNF-α and IL-17A. The expression of osteogenesis activators (BMP2 and Wnt5a) was increased with cytokines and that of the osteogenesis inhibitor DKK1 was decreased. There was no difference between all three cell types. In contrast, RA FLS were particularly sensitive to the synergistic increase of Shn3 with TNF-α and IL-17A. Levels of IL-6 and IL-8 were also higher for RA-FLS, compared to healthy and OA FLS. CONCLUSION: IL-17A and/or TNF-α treatment favor an osteogenesis induction in isolated FLS, independent of their origin. RA-FLS were more sensitive to the synergistic increase of Schnurri-3 expression. Combined with the higher levels of inflammation, this may in turn activate osteoclastogenesis, leading to increased bone destruction seen in destructive arthritis.
25917955 Association between lipid levels and major adverse cardiovascular events in rheumatoid art 2015 May OBJECTIVE: Lower levels of low-density lipoprotein (LDL) cholesterol may be associated with increased cardiovascular (CV) risk in rheumatoid arthritis (RA). This study was undertaken to determine whether the complex relationship between levels of LDL and high-density lipoprotein (HDL) cholesterol and CV risk is different in RA patients as compared to non-RA controls. METHODS: Using data from a US health insurance plan (2003-2012), we conducted a cohort study that included patients with RA and non-RA control subjects matched with regard to age, sex, and index date. The nonlinearity of associations between lipid levels and incidence of major adverse CV events (MACE) was tested. We used multivariable Cox proportional hazards regression models to examine for an interaction between lipid levels and RA status in relation to the risk of MACE, after adjustment for CV risk factors. RESULTS: In total, 16,085 RA patients and 48,499 non-RA controls were studied. The mean age was 52.6 years and 78.6% were women. The relationship between LDL cholesterol levels and incidence of MACE was nonlinear and similar between RA patients and non-RA controls (P for interaction = 0.72). No significant increase in CV risk was observed between the lowest quintile of LDL cholesterol levels (≤91.0 mg/dl) and the second, third, or fourth quintiles, whereas the highest quintile (>190.0 mg/dl) conveyed a 40% increase in risk of MACE (hazard ratio [HR] 1.40, 95% confidence interval [95% CI] 1.17-1.68). The relationship between HDL cholesterol levels and incidence of MACE was also nonlinear and similar between RA patients and non-RA controls (P for interaction = 0.39). Compared to the lowest quintile of HDL cholesterol levels, each successive quintile was associated with a reduced risk of MACE (HR 0.45, 95% CI 0.48-0.72 for lowest quintile [≤43.0 mg/dl] versus highest quintile [>71.0 mg/dl]). CONCLUSION: The complex relationship between LDL cholesterol levels, HDL cholesterol levels, and risk of MACE was nonlinear in RA patients and also not statistically significantly different from that in an age- and sex-matched non-RA cohort.
26053495 Statistical colocalization of genetic risk variants for related autoimmune diseases in the 2015 Jul Determining whether potential causal variants for related diseases are shared can identify overlapping etiologies of multifactorial disorders. Colocalization methods disentangle shared and distinct causal variants. However, existing approaches require independent data sets. Here we extend two colocalization methods to allow for the shared-control design commonly used in comparison of genome-wide association study results across diseases. Our analysis of four autoimmune diseases--type 1 diabetes (T1D), rheumatoid arthritis, celiac disease and multiple sclerosis--identified 90 regions that were associated with at least one disease, 33 (37%) of which were associated with 2 or more disorders. Nevertheless, for 14 of these 33 shared regions, there was evidence that the causal variants differed. We identified new disease associations in 11 regions previously associated with one or more of the other 3 disorders. Four of eight T1D-specific regions contained known type 2 diabetes (T2D) candidate genes (COBL, GLIS3, RNLS and BCAR1), suggesting a shared cellular etiology.
26150601 A phase III randomised, double-blind, parallel-group study comparing SB4 with etanercept r 2017 Jan OBJECTIVES: To compare the efficacy and safety of SB4 (an etanercept biosimilar) with reference product etanercept (ETN) in patients with moderate to severe rheumatoid arthritis (RA) despite methotrexate (MTX) therapy. METHODS: This is a phase III, randomised, double-blind, parallel-group, multicentre study with a 24-week primary endpoint. Patients with moderate to severe RA despite MTX treatment were randomised to receive weekly dose of 50 mg of subcutaneous SB4 or ETN. The primary endpoint was the American College of Rheumatology 20% (ACR20) response at week 24. Other efficacy endpoints as well as safety, immunogenicity and pharmacokinetic parameters were also measured. RESULTS: 596 patients were randomised to either SB4 (N=299) or ETN (N=297). The ACR20 response rate at week 24 in the per-protocol set was 78.1% for SB4 and 80.3% for ETN. The 95% CI of the adjusted treatment difference was -9.41% to 4.98%, which is completely contained within the predefined equivalence margin of -15% to 15%, indicating therapeutic equivalence between SB4 and ETN. Other efficacy endpoints and pharmacokinetic endpoints were comparable. The incidence of treatment-emergent adverse events was comparable (55.2% vs 58.2%), and the incidence of antidrug antibody development up to week 24 was lower in SB4 compared with ETN (0.7% vs 13.1%). CONCLUSIONS: SB4 was shown to be equivalent with ETN in terms of efficacy at week 24. SB4 was well tolerated with a lower immunogenicity profile. The safety profile of SB4 was comparable with that of ETN. TRIAL REGISTRATION NUMBERS: NCT01895309, EudraCT 2012-005026-30.
26076785 MMPI for personality characteristics of patients with different diseases. 2015 In the field of psychosomatic medicine the relationship between personality characteristics and diseases is supposed to be an important issue. The aim of this article is to present group's MMPI profiles obtained for patients with different chronic diseases and to discuss about possible specific features of these different groups. We summarized results obtained by psychological testing of following groups of patients: adult patients treated with chronic maintenance dialysis, patients with diabetic retinopathy, general anxiety group, attack panic syndrome, parents of children with rheumatoid arthritis, as well as adolescents with mental anorexia, cystic fibrosis, diabetes mellitus and leukemia. Two control groups comprised adults and adolescents, both without any health problems, selected randomly. As a psychometric test MMPI-201 was used. Statistic 10 package is used for statistical analysis. In our presentation it can be seen some typical personality characteristics for patients with chronic conditions. These findings could be helpful for clinicians concerning treatment planning and follow-up. In general, the MMPI helps us to obtain a global, factual picture from the self-assessment of the patient, explained in a psycho-technical language. Group's profile could be used in clinical practice for planning treatment and to suppose the prognosis of the illness.
27015606 Cost-Effectiveness of Triple Therapy Versus Etanercept Plus Methotrexate in Early Aggressi 2016 Dec OBJECTIVE: To evaluate the cost-effectiveness of all 4 interventions in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) clinical trial: immediate triple (IT), immediate etanercept (IE), step-up triple (ST), and step-up etanercept (SE). Step-up interventions started with methotrexate and added either etanercept or sulfasalazine plus hydroxychloroquine to patients with persistent disease activity. METHODS: We built a Markov cohort model that uses individual-level data from the TEAR trial, published literature, and supplemental clinical data. Costs were in US dollars, benefits in quality-adjusted life years (QALYs), perspective was societal, and the time horizon was 5 years. RESULTS: The immediate strategies were more efficacious than step-up strategies. SE and IE were more costly than ST and IT, primarily due to treatment cost differences. In addition, IT was the least expensive and most effective strategy when the time horizon was 1 and 2 years. When the time horizon was 5 years, IE was marginally more effective than IT (3.483 versus 3.476 QALYs), but IE was substantially more expensive than IT ($148,800 versus $52,600), producing an incremental cost-effectiveness ratio of $12.5 million per QALY. These results were robust to both one-way deterministic and joint probabilistic sensitivity analyses. CONCLUSION: IT was highly cost-effective in the majority of scenarios. Although IE was more effective in 5 years, a substantial reduction in the cost of biologic agents was required in order for IE to become cost-effective in early aggressive RA under willingness-to-pay thresholds that most health care settings may find acceptable.
26703441 Soluble biglycan: a potential mediator of cartilage degradation in osteoarthritis. 2015 Dec 24 BACKGROUND: Soluble biglycan (sBGN) and soluble decorin (sDCN), are two closely related essential components of extracellular matrix which both have been shown to possess proinflammatory properties. We studied whether sBGN or sDCN were present in synovial fluid (SF) of osteoarthritis (OA) or rheumatoid arthritis (RA) patients and studied sBGN or sDCN potential role in the degradation of OA cartilage. METHODS: SF obtained from meniscus tear, OA, and RA patients were analysed for sBGN and sDCN using enzyme-linked immunosorbent assays. OA chondrocytes and cartilage explants were stimulated for 48 h with 5 μg/ml sBGN or 1 μg/ml lipopolysaccharide. Messenger RNA (mRNA) levels of Toll-like receptors (TLRs), proteinases and cartilage matrix molecules were determined using quantitative real-time polymerase chain reaction. Protein levels of matrix metalloproteinases (MMPs) and cytokines were measured using Luminex xMap technology. Production of nitric oxide (NO), release of proteoglycans and soluble collagen were measured from conditioned culture media using biochemical assays. OA cartilage explant proteoglycans were stained for Safranin O and quantified using image analysis. TLR4 activation by sBGN and sDCN was studied in engineered HEK-293 cells with TLR4 signalling genes inserted together with a reporter gene. RESULTS: sBGN was found in meniscus tear SF (14 ± 2 ng/ml), OA SF (582 ± 307 ng/ml) and RA SF (1191 ± 482 ng/ml). Low levels of sDCN could also be detected in SF of meniscus tear (51 ± 4) ng/ml, OA (52 ± 3 ng/ml), and RA (49 ± 4 ng/ml). Stimulation of chondrocytes with sBGN increased significantly the mRNA and protein expression of catabolic MMPs, including MMP1, MMP9 and MMP13, and of inflammatory cytokines interleukin (IL)-6 and IL-8, whereas the expression of anabolic markers aggrecan and collagen type II was decreased. sBGN induced release of proteoglycans, collagen and NO from chondrocytes and cartilage explants. The catabolic response in explants was dependent of OA cartilage degradation stage. The mechanism of action of sBGN was mainly mediated through the TLR4-nuclear factor-κB pathway. CONCLUSIONS: High levels of sBGN was found in advanced OA and RA SF. sBGN activates chondrocytes mainly via TLR4, which results in net loss of cartilage. Thus, sBGN can be a mediator of OA cartilage degradation and also a potential biomarker for arthritis.
25975695 Evidence for cadherin-11 cleavage in the synovium and partial characterization of its mech 2015 May 15 INTRODUCTION: Engagement of the homotypic cell-to-cell adhesion molecule cadherin-11 on rheumatoid arthritis (RA) synovial fibroblasts with a chimeric molecule containing the cadherin-11 extracellular binding domain stimulated cytokine, chemokine, and matrix metalloproteinases (MMP) release, implicating cadherin-11 signaling in RA pathogenesis. The objective of this study was to determine if cadherin-11 extracellular domain fragments are found inside the joint and if a physiologic synovial fibroblast cleavage pathway releases those fragments. METHODS: Cadherin-11 cleavage fragments were detected by western blot in cell media or lysates. Cleavage was interrupted using chemical inhibitors or short-interfering RNA (siRNA) gene silencing. The amount of cadherin-11 fragments in synovial fluid was measured by western blot and ELISA. RESULTS: Soluble cadherin-11 extracellular fragments were detected in human synovial fluid at significantly higher levels in RA samples compared to osteoarthritis (OA) samples. A cadherin-11 N-terminal extracellular binding domain fragment was shed from synovial fibroblasts after ionomycin stimulation, followed by presenilin 1 (PSN1)-dependent regulated intramembrane proteolysis of the retained membrane-bound C-terminal fragments. In addition to ionomycin-induced calcium flux, tumor necrosis factor (TNF)-α also stimulated cleavage in both two- and three-dimensional fibroblast cultures. Although cadherin-11 extracellular domains were shed by a disintegrin and metalloproteinase (ADAM) 10 in several cell types, a novel ADAM- and metalloproteinase-independent activity mediated shedding in primary human fibroblasts. CONCLUSIONS: Cadherin-11 undergoes ectodomain shedding followed by regulated intramembrane proteolysis in synovial fibroblasts, triggered by a novel sheddase that generates extracelluar cadherin-11 fragments. Cadherin-11 fragments were enriched in RA synovial fluid, suggesting they may be a marker of synovial burden and may function to modify cadherin-11 interactions between synovial fibroblasts.
26443046 Chronic Inflammatory Disease Is an Independent Risk Factor for Coronary Flow Velocity Rese 2016 Feb BACKGROUND: Chronic inflammatory disease (CID) is a complex multisystem disease characterized by chronic inflammation, which can lead to coronary microvascular dysfunction (CMD) and can also predispose to coronary artery calcium deposition, even in the absence of obstructive coronary artery disease. METHODS: Twenty-one patients with systemic lupus erythematosus (SLE; mean age, 60 ± 11 years), 21 patients with systemic sclerosis (SSc; mean age, 66 ± 11 years), 32 patients with rheumatoid arthritis (RA; mean age, 65 ± 9 years), and 23 control subjects with comparable traditional risk factors for coronary artery disease (mean age, 65 ± 10 years) were prospectively enrolled in the outpatient clinic. All study participants underwent transthoracic Doppler-derived echocardiography for coronary flow velocity reserve (CFVR) measurement in the left anterior descending coronary artery; CFVR < 2.5 defined CMD. Coronary artery calcium score in the left anterior descending coronary artery was also assessed by computed tomography. RESULTS: None of study participants had obstructive coronary artery disease. The prevalence of CMD was 26% in the control group, 67% in the SLE group, 76% in the SSc group, and 63% in the RA group (P < .05, CID groups vs control group). CFVR was significantly lower in all three CID groups than in the control group (control group, 3.01 ± 0.72; SLE group, 2.23 ± 0.71; SSc group, 2.14 ± 0.54; RA group, 2.33 ± 0.62; P < .05, CID groups vs control group). In contrast, coronary artery calcium scores were similar in the four groups and had no relation to CMD. The odds ratios for CMD in patients with SLE, SSc, and RA were 16.70, 25.78, and 8.44 (P < .05) after adjusting for age, body mass index, the presence or absence of anemia, and hemoglobin level. Multiple linear regression analysis showed that only the presence of CID was independently associated with reduced CFVR among all study participants. CONCLUSIONS: CID strongly contributes to CMD identified by qualitative evaluation of CFVR independently of traditional coronary risk factors of atherosclerosis but does not predispose to coronary artery calcification.
27466816 Immune Recognition of Citrullinated Proteoglycan Aggrecan Epitopes in Mice with Proteoglyc 2016 BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease affecting the joints. Anti-citrullinated protein antibodies (ACPA) are frequently found in RA. Previous studies identified a citrullinated epitope in cartilage proteoglycan (PG) aggrecan that elicited pro-inflammatory cytokine production by RA T cells. We recently reported the presence of ACPA-reactive (citrullinated) PG in RA cartilage. Herein, we sought to identify additional citrullinated epitopes in human PG that are recognized by T cells or antibodies from RA patients. METHODS: We used mice with PG-induced arthritis (PGIA) as a screening tool to select citrulline (Cit)-containing PG peptides that were more immunogenic than the arginine (R)-containing counterparts. The selected peptide pairs were tested for induction of pro-inflammatory T-cell cytokine production in RA and healthy control peripheral blood mononuclear cell (PBMC) cultures using ELISA and flow cytometry. Anti-Cit and anti-R peptide antibodies were detected by ELISA. RESULTS: Splenocytes from mice with PGIA exhibited greater T-cell cytokine secretion in response to the Cit than the R version of PG peptide 49 (P49) and anti-P49 antibodies were found in PGIA serum. PBMC from ACPA+ and ACPA- RA patients, but not from healthy controls, responded to Cit49 with robust cytokine production. High levels of anti-Cit49 antibodies were found in the plasma of a subset of ACPA+ RA patients. Another PG peptide (Cit13) similar to the previously described T-cell epitope induced greater cytokine responses than R13 by control (but not RA) PBMC, however, anti-Cit13 antibodies were rarely detected in human plasma. CONCLUSIONS: We identified a novel citrullinated PG epitope (Cit49) that is highly immunogenic in mice with PGIA and in RA patients. We also describe T-cell and antibody reactivity with Cit49 in ACPA+ RA. As citrullinated PG might be present in RA articular cartilage, Cit PG epitope-induced T-cell activation or antibody deposition may occur in the joints of RA patients.
25888724 Carotid artery plaque in women with rheumatoid arthritis and low estimated cardiovascular 2015 Mar 11 INTRODUCTION: We previously reported that most patients with rheumatoid arthritis (RA) and moderate cardiovascular disease (CVD) risk according to the Systematic COronary Evaluation score (SCORE) experience carotid artery plaque. In this study, we aimed to identify patient characteristics that can potentially predict carotid plaque presence in women with RA and a concurrent low CVD risk according to the SCORE. METHODS: A cohort of 144 women with an evaluated low risk of CVD (SCORE value of zero) was assembled amongst 550 consecutive patients with RA that underwent CVD risk factor recording and carotid artery ultrasound. Participants had no established CVD, moderate or severe chronic kidney disease, or diabetes. We assessed carotid plaque(s) presence and its associated patient characteristics. RESULTS: Carotid artery plaque was present in 35 (24.3%) of women with RA. Age, the number of synthetic disease-modifying agents (DMARDs) and total cholesterol concentrations were independently associated with plaque in multivariable stepwise backward regression analysis (odds ratio (95% confidence interval)=1.15 (1.07 to 1.24), P<0.0001, 1.51 (1.05 to 2.17), P=0.03 and 1.66 (1.00 to 2.73) P=0.04), respectively). The area under the curve (AUC) of the receiver operating curve (ROC) for the association with plaque was 0.807 (P<0.0001), 0.679 (P=0.001) and 0.599 (P=0.08) for age, total cholesterol concentrations and number of synthetic DMARDs used, respectively. The optimal cutoff value in predicting plaque presence for age was 49.5 years with a sensitivity and specificity of 74% and 75%, respectively, and for total cholesterol concentration, it was 5.4 mmol/l with a sensitivity and specificity of 63% and 70%, respectively. The plaque prevalence was 37.5% in patients (n=80; 55.6%) with age>49.5 years or/and total cholesterol concentration of >5.4 mmol/l, respectively, compared to only 7.8% in those (n=64; 44.4%) with age≤49.5 years or/and total cholesterol concentration of ≤5.4 mmol/l, respectively. CONCLUSIONS: Approximately one-third of women with RA who experience a low SCORE value and are aged >49.5 years or/and have a total cholesterol concentration of >5.4 mmol/l, experience high-risk atherosclerosis, which requires intensive CVD risk management.
28005419 Aging of the Immune System. Mechanisms and Therapeutic Targets. 2016 Dec Beginning with the sixth decade of life, the human immune system undergoes dramatic aging-related changes, which continuously progress to a state of immunosenescence. The aging immune system loses the ability to protect against infections and cancer and fails to support appropriate wound healing. Vaccine responses are typically impaired in older individuals. Conversely, inflammatory responses mediated by the innate immune system gain in intensity and duration, rendering older individuals susceptible to tissue-damaging immunity and inflammatory disease. Immune system aging functions as an accelerator for other age-related pathologies. It occurs prematurely in some clinical conditions, most prominently in patients with the autoimmune syndrome rheumatoid arthritis (RA); and such patients serve as an informative model system to study molecular mechanisms of immune aging. T cells from patients with RA are prone to differentiate into proinflammatory effector cells, sustaining chronic-persistent inflammatory lesions in the joints and many other organ systems. RA T cells have several hallmarks of cellular aging; most importantly, they accumulate damaged DNA. Because of deficiency of the DNA repair kinase ataxia telangiectasia mutated, RA T cells carry a higher burden of DNA double-strand breaks, triggering cell-indigenous stress signals that shift the cell's survival potential and differentiation pattern. Immune aging in RA T cells is also associated with metabolic reprogramming; specifically, with reduced glycolytic flux and diminished ATP production. Chronic energy stress affects the longevity and the functional differentiation of older T cells. Altered metabolic patterns provide opportunities to therapeutically target the immune aging process through metabolic interference.