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ID PMID Title PublicationDate abstract
23637323 Interaction of HLA-DRB1*09:01 and *04:05 with smoking suggests distinctive mechanisms of r 2013 Jul OBJECTIVE: Although HLA-DRB1 shared epitope (SE) alleles and HLA-DRB1*09:01 have repeatedly been shown to be associated with susceptibility to rheumatoid arthritis (RA), the effect of each allele on levels of anticyclic citrullinated peptide autoantibodies (anti-CCP) and interaction with cigarette smoking in RA remains to be fully defined. We investigated whether HLA-DRB1 risk alleles influence anti-CCP levels and whether each allele interacts with smoking in anti-CCP-positive or -negative RA. METHODS: All patients with RA (n = 1924) and controls (n = 1119) were Korean. The HLA-DRB1 4-digit genotyping was performed by standard PCR-sequencing based typing method. OR and biologic interactions as departures from additivity or multiplicity were analyzed by logistic regression. RESULTS: SE alleles were significantly associated with increased anti-CCP levels. Conversely, HLA-DRB1*09:01 was associated with reduced levels, in both SE-positive and SE-negative patients. Each of SE alleles interacted significantly with smoking, whereas HLA-DRB1*09:01 did not. Interactions between the 2 most significant risk alleles, HLA-DRB1*04:05 and HLA-DRB1*09:01, (attributable proportion = 0.68, 95% CI 0.46-0.89, multiplicity p = 0.012) significantly increased RA susceptibility regardless of anti-CCP and smoking status. Smoking increased the risk for RA by significant interaction with the heterozygote HLA-DRB1*04:05/*09:01. CONCLUSION: HLA-DRB1*09:01 differs from SE alleles with regard to anti-CCP levels and interaction with smoking, suggesting a distinct mechanism of HLA-DRB1*09:01 in the pathogenesis of RA that may bypass anti-CCP formation. Also, a significant increase of the HLA-DRB1*04:05/ *09:01 heterozygote in RA susceptibility may be attributable to the synergistic contribution of 2 different pathways in which 2 alleles participate independently.
24718553 Induced production of anti-etanercept antibody in collagen-induced arthritis. 2014 Jun Etanercept is a widespread biological drug for the treatment of rheumatoid arthritis, which inhibits tumor necrosis factor-α (TNF-α). Recently, the presence of antibodies targeting TNF-α inhibitors such as infliximab and adalimumab, was reported. However, few reports have studied etanercept in a mouse model of arthritis. We investigated the induction of anti-etanercept antibody production, along with the antibody's potential interfering effects on the biological function of etanercept, in mice with collagen-induced arthritis (CIA). CIA mice received an intraperitoneal injection of etanercept (25, 100 or 400 µg per mouse). The degree of inflammation and cartilage erosion was evaluated, and the number of osteoclasts in the ankle joints was assessed by TRAP staining. The level of pro-inflammatory cytokines in the serum was measured. To analyze the anti-osteoporotic effect of etanercept, microfocal computed tomography analyses of femurs and tibias were performed. Etanercept treatment decreased both the incidence and severity of arthritis in a dose-dependent manner, except for the highest dose of 400 µg. The mice that were treated with 25 and 100 µg etanercept showed an improvement in inflammation, cartilage damage, and even bone loss. However, mice treated with 400 µg etanercept showed no significant improvement in any of the tested parameters. Using a customized enzyme-linked immunosorbent assay (ELISA), the presence of the anti-etanercept antibody was detected in the serum in this treatment-refractory group. The therapeutic effect of etanercept was reduced in the CIA mice that developed the anti-etanercept antibody. In conclusion, the production of an anti-etanercept antibody can be induced in CIA mice, and this antibody can considerably reduce the anti-arthritic and anti-osteoporotic effects of etanercept.
25101796 Pathway-based association analysis of two genome-wide screening data identifies rheumatoid 2014 Oct The pathways can explain molecular mechanisms of complex diseases from the perspective of biology function. We carried out a genome-wide pathway-based association analysis to identify the risk pathways of rheumatoid arthritis (RA). First, we performed two genome-wide association studies using two RA data sets from GAW16 (Genetic Analysis Workshop 16) and the Wellcome Trust Case Control Consortium, and obtained risk P-value for each single-nucleotide polymorphism (SNP). Next, we mapped all the SNPs to genome-wide autosomal genes and calculated gene-wise risk values by minimum P-value method. We calculated the KEGG (Kyoto Encyclopedia of Gene and Genomes) pathway risk scores according to Fisher combination method and identified the significant pathways by permutation test. At last, we merged the results from the two pathway-based genome-wide association analyses to identify the high-risk pathways, which were found in both the data sets. The results showed that there were nine pathways, focal adhesion pathway, extracellular matrix-receptor interaction pathway, calcium signaling pathway, dopaminergic synapse pathway, long-term potentiation pathway, retrograde endocannabinoid signaling pathway, glutamatergic synapse pathway, cholinergic synapse pathway and morphine addiction pathway, associated with susceptibility to RA. Among these pathways, four pathways were reported as RA-risk pathways in the previous literatures. We also inferred that other five pathways may be related to RA. Further researches of these pathways will help us to understand the molecular mechanisms of RA.
24316895 Physical activity among patients from the Brasília cohort of early rheumatoid arthritis. 2013 Sep INTRODUCTION: The 2012 Consensus of the Brazilian Society of Rheumatology (SBR) for the treatment of Rheumatoid Arthritis (RA) recommends that patients should regularly perform physical exercises. There have been no studies in Brazil on physical activity among patients with early RA. OBJECTIVE: To investigate the physical activity practice among patients with early RA and the possible association between physical activity, disease activity and functional disability. METHODS: Cross-sectional study of patients from the Brasilia cohort of early RA. Demographic data (sex, age and level of schooling), physical activity practice, Disease Activity Score 28 (DAS 28), functional disability (Health Assessment Questionnaire - HAQ), as well as data on smoking status, alcohol consumption, comorbidities and RA treatment were analyzed. RESULTS: A total of 72 patients were evaluated, 90.27% females, mean age 50.2 ± 13.3 years, mean DAS 28: 3.66 and HAQ: 0.69. Of them, 43.05% were regularly active, with walking being the most often practiced exercise (80.64%). The mean duration of exercise was 48.22 ± 27.18 min, with a frequency of 3.7 ± 1.64 times per week. There was no association between physical activity and gender, age, educational level, disease activity, functional disability, alcoholism or smoking, presence of comorbidities and treatment with drugs that alter the course of disease. CONCLUSION: Given the importance of regular physical activity practice, it is necessary to recommend it to patients, especially resistance physical activities, which are not frequent among the patients in our study.
24190231 Newborn infant characteristics and risk of future rheumatoid arthritis: a twin-control stu 2014 Apr Low birth weight has been proposed as a risk factor for rheumatoid arthritis (RA). The twin-control study design provides an opportunity to investigate the significance of potential prenatal determinants for adult morbidity by accounting for maternal characteristics and early environmental and genetic factors. We investigated the association between birth weight and RA in a sample of 42 twin pairs discordant for rheumatoid arthritis in which valid information on birth weight, birth length, and order was available from midwife records. Difference plot and conditional logistic regression were used to investigate the relationship between RA and birth weight or birth order adjusting for birth length and sex. The intra-pairwise birth weight differences, i.e., RA twin minus co-twin, ranged from -750 to 1,100 g, mean 78 g (95 % CI -13 to 70), 146 g (95 % CI (-36 to 329) in monozygotic, 32 g (95 % CI -90 to 154) in dizygotic, same sex and 69 g (95 % CI -122 to 260) in dizygotic, opposite sex twin pairs. The odds ratio for birth weight as risk factor for RA was 1.00 (95 % CI 0.997-1.003) when adjusting for birth length, birth order, and sex, irrespective of ACPA status. The odds ratio for developing RA as first born twin was 2.33 (95 % CI 0.97-5.60) when adjusting for birth length, birth weight, and sex, irrespective of ACPA status. In this twin-control study, birth weight was not associated with the development of RA in adult life. Being born first may predispose to RA.
24412895 A treat-to-target strategy with methotrexate and intra-articular triamcinolone with or wit 2015 May OBJECTIVES: To investigate whether a treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid injections suppresses MRI inflammation and halts structural damage progression in patients with early rheumatoid arthritis (ERA), and whether adalimumab provides an additional effect. METHODS: In a double-blind, placebo-controlled trial, 85 disease-modifying antirheumatic drug-naïve patients with ERA were randomised to receive methotrexate, intra-articular glucocorticosteroid injections and placebo/adalimumab (43/42). Contrast-enhanced MRI of the right hand was performed at months 0, 6 and 12. Synovitis, osteitis, tenosynovitis, MRI bone erosion and joint space narrowing (JSN) were scored with validated methods. Dynamic contrast-enhanced MRI (DCE-MRI) was carried out in 14 patients. RESULTS: Synovitis, osteitis and tenosynovitis scores decreased highly significantly (p<0.0001) during the 12-months' follow-up, with mean change scores of -3.7 (median -3.0), -2.2 (-1) and -5.3 (-4.0), respectively. No overall change in MRI bone erosion and JSN scores was seen, with change scores of 0.1 (0) and 0.2 (0). The tenosynovitis score at month 6 was significantly lower in the adalimumab group, 1.3 (0), than in the placebo group, 3.9 (2), Mann-Whitney: p<0.035. Furthermore, the osteitis score decreased significantly during the 12-months' follow-up in the adalimumab group, but not in the placebo group, Wilcoxon: p=0.001-0.002 and p=0.062-0.146. DCE-MRI parameters correlated closely with conventional MRI inflammatory parameters. Clinical measures decreased highly significantly during follow-up. CONCLUSIONS: A treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid in patients with ERA effectively decreased synovitis, osteitis and tenosynovitis and halted structural damage progression as judged by MRI. The findings suggest that addition of adalimumab is associated with further suppression of osteitis and tenosynovitis.
24818335 Early, structured disease modifying anti-rheumatic drug (DMARD) therapy reduces cardiovasc 2013 Aug BACKGROUND: Rheumatoid arthritis, being a chronic disease requires long-term management of patients with drugs. The increasing cost of biologics in this era of disease management led us to devise a treatment regime, optimal for use in a developing country like India, which was economical as well as effective in controlling disease activity. OBJECTIVE: To investigate if combination therapy with DMARDs can reduce cardiovascular risk in early Rheumatoid Arthritis, besides controlling disease activity. METHODS: A small cohort of early Rheumatoid subjects with disease duration less than 1 year were treated with a structured DMARD regime and were followed up over a year. Disease activity score, C-reactive protein (CRP) and cardiac risk markers like lipid panel and carotid intima-medial thickness were monitored at 6 months and 1 year. RESULTS: A significant reduction (p < 0.001) of disease activity as well as cardiac risk parameters were observed. CONCLUSION: Our study showed that treatment of early rheumatoid arthritis with a combination regime of traditional DMARDs is highly effective in controlling disease activity as well as cardiovascular risk.
24513269 Rheumatoid arthritis patients exhibit impaired Candida albicans-specific Th17 responses. 2014 Feb 11 INTRODUCTION: Accumulating data implicate the CD4+ T cell subset (Th17 cells) in rheumatoid arthritis (RA). IL-17 is an inflammatory cytokine that induces tumor necrosis factor (TNF)α, IL-1β and IL-6, all of which are targets of biologic therapies used to treat RA. RA patients are well documented to experience more infections than age-matched controls, and biologic therapies further increase the risk of infection. The Th17/IL-17 axis is vital for immunity to fungi, especially the commensal fungus Candida albicans. Therefore, we were prompted to examine the relationship between RA and susceptibility to C. albicans because of the increasing interest in Th17 cells and IL-17 in driving autoimmunity, and the advent of new biologics that target this pathway. METHODS: We analyzed peripheral blood and saliva from 48 RA and 33 healthy control subjects. To assess C. albicans-specific Th17 responses, PBMCs were co-cultured with heat-killed C. albicans extract, and IL-17A levels in conditioned supernatants were measured by ELISA. The frequency of Th17 and Th1 cells was determined by flow cytometry. As a measure of IL-17A-mediated effector responses, we evaluated C. albicans colonization rates in the oral cavity, salivary fungicidal activity and levels of the antimicrobial peptide β-defensin 2 (BD2) in saliva. RESULTS: Compared to controls, PBMCs from RA subjects exhibited elevated baseline production of IL-17A (P = 0.004), although they had similar capacity to produce IL-17A in response to Th17 cell differentiating cytokines (P = 0.91). However RA PBMCs secreted less IL-17A in response to C. albicans antigens (P = 0.006). Significantly more RA patients were colonized with C. albicans in the oral cavity than healthy subjects (P = 0.02). Concomitantly, RA saliva had reduced concentrations of salivary BD2 (P = 0.02). Nonetheless, salivary fungicidal activity was preserved in RA subjects (P = 0.70). CONCLUSIONS: RA subjects exhibit detectable impairments in oral immune responses to C. albicans, a strongly Th17-dependent opportunistic pathogen, despite an overall elevated baseline production of IL-17A.
25483913 Increased expression of endocan in arthritic synovial tissues: effects of adiponectin on t 2015 Apr This study was performed to evaluate whether endocan expression, which is known to be involved in tumor angiogenesis, was increased in rheumatoid arthritic tissues. In addition, the involvement of adiponectin in the regulation of endocan expression in arthritic joints was examined. Arthritic synovial tissues from patients with rheumatoid arthritis (RA) or osteoarthritis (OA) were immunostained with antibodies to endocan and vascular endothelial growth factor (VEGF). Subsequently, synovial cells and human umbilical vein endothelial cells were cultured and stimulated with interleukin-1 β (IL-1β) or adiponectin. The mRNA and protein levels of endocan were evaluated by polymerase chain reaction and ELISA, respectively. Endocan expression was markedly increased in the inflammatory sites of RA synovial tissues. In OA tissues, endocan expression was higher in tissues displaying moderate and severe inflammation than in those with mild inflammation. In vitro expression levels of endocan and VEGF in endothelial and synovial cells were differentially increased in response to IL-1β stimulation. Adiponectin was a more potent stimulant of endocan than IL-1β at their respective physiological concentrations in synovial cells. Endocan silencing by small interfering RNA transfection of synovial cells decreased in vitro cell migration and invasion. In conclusion, adiponectin is an important factor in the stimulation of endocan expression in synovial cells. Adiponectin-induced endocan expression in synovial cells may stimulate cell migration and invasion as well as angiogenesis in the pannus of arthritic joints.
25027107 Inflammatory factors in the circulation of patients with active rheumatoid arthritis stimu 2014 Oct SUMMARY: The combination of cytokines present in the circulation of patients with active rheumatoid arthritis might contribute to the generalized bone loss that commonly occurs in these patients, by directly inhibiting osteoblast proliferation and differentiation, but especially by enhancing endogenous cytokine (i.e., receptor activator of nuclear factor-kappa B ligand (RANKL) and interleukin-6 (IL)-6) production by osteoblasts, thereby stimulating osteoclastogenesis. INTRODUCTION: Generalized bone loss, as occurs in patients with rheumatoid arthritis (RA), is related to elevated levels of circulating cytokines. Individual cytokines have deleterious effects on proliferation and differentiation of osteoblast cell lines, but little is known about the effect of the interaction between inflammatory factors in the circulation of patients with active RA on human osteoblast function, including their communication towards other bone cells. We investigated whether serum from patients with active RA enhances cytokine production by osteoblasts, thereby effectively altering osteoblast-stimulated osteoclastogenesis. METHODS: Serum was obtained from 20 patients with active RA (active RA sera) and from the same patients in clinical remission (remission RA sera). To determine osteoclastogenesis, RA serum-pretreated primary human osteoblast cultures were established in direct contact with human osteoclast precursors in the presence or absence of osteoprotegerin (OPG) or IL-6 inhibitor. RESULTS: Compared to remission RA sera, active RA sera inhibited osteoblast proliferation and differentiation in vitro as demonstrated by a reduced DNA content and gene expression of KI-67, collagen type 1, osteopontin, and osteocalcin. Active RA sera inhibited OPG expression and enhanced RANKL and IL-6 expression but did not alter IL-8 expression in osteoblasts. IL-1β, IL-17, and tumor necrosis factor-α (TNF-α) expression were undetectable. In coculture, active RA sera treatment of osteoblasts stimulated while addition of OPG or IL-6 inhibitory antibodies significantly reduced the number of osteoclasts. CONCLUSION: Active RA sera contain circulating factors, likely cytokines and chemokines, that might contribute to bone loss by directly inhibiting osteoblast proliferation and differentiation, but especially, these factors modulate endogenous cytokine production by osteoblasts, thereby affecting osteoclastogenesis.
24769201 Co-culture with human synovium-derived mesenchymal stem cells inhibits inflammatory activi 2014 May 16 Rheumatoid arthritis (RA) and osteoarthritis (OA) are primarily chronic inflammatory diseases. Mesenchymal stem cells (MSCs) have the ability to differentiate into cells of the mesodermal lineage, and to regulate immunomodulatory activity. Specifically, MSCs have been shown to secrete insulin-like growth factor 1 (IGF-1). The purpose of the present study was to examine the inhibitory effects on inflammatory activity from a co-culture of human synovium-derived mesenchymal stem cells (hSDMSCs) and sodium nitroprusside (SNP)-stimulated chondrocytes. First, chondrocytes were treated with SNP to generate an in vitro model of RA or OA. Next, the co-culture of hSDMSCs with SNP-stimulated chondrocytes reduced inflammatory cytokine secretion, inhibited expression of inflammation activity-related genes, generated IGF-1 secretion, and increased the chondrocyte proliferation rate. To evaluate the effect of IGF-1 on inhibition of inflammation, chondrocytes pre-treated with IGF-1 were treated with SNP, and then the production of inflammatory cytokines was analyzed. Treatment with IGF-1 was shown to significantly reduce inflammatory cytokine secretion in SNP-stimulated chondrocytes. Our results suggest that hSDMSCs offer a new strategy to promote cell-based cartilage regeneration in RA or OA.
23880471 Temperature-modulated noncovalent interaction controllable complex for the long-term deliv 2013 Oct 28 The clinical applications of etanercept (Enbrel), an emerging therapeutic protein for rheumatoid arthritis (RA), are limited by its instability and low bioavailability. In this study, a long-term and efficient therapeutic nanocomplex formulation for RA treatment was developed in the form of a temperature-modulated noncovalent interaction controllable (TMN) complex based on a temperature-sensitive amphiphilic polyelectrolyte (succinylated pullulan-g-oligo(L-lactide); SPL). The TMN complexes were prepared by simply mixing the negatively charged SPL copolymer and the positively charged etanercept via electrostatic interaction at 4 °C below the polymer's clouding temperature (CT), and the resulting complex demonstrated significantly improved salt and serum stability with increased hydrophobic interactions at temperatures (physiological condition, 37.5 °C) above the CT. An in vitro study of the bioactivity of etanercept indicated that the TMN complex improves the long-term stability of etanercept in an aqueous environment because of the exposure of the functional active site and the molecular chaperone-like effect of the hydrophobic copolymer. This formulation possessed prolonged in vivo pharmacokinetic parameters. In a collagen-induced arthritis RA rat model, we verified the outstanding therapeutic effect of the TMN complexes. These results imply that this approach would be widely applied to protein and peptide delivery systems.
24764451 Btk inhibition suppresses agonist-induced human macrophage activation and inflammatory gen 2015 Aug OBJECTIVES: Bruton's tyrosine kinase (Btk) is required for B lymphocyte and myeloid cell contributions to pathology in murine models of arthritis. Here, we examined the potential contributions of synovial Btk expression and activation to inflammation in rheumatoid arthritis (RA). MATERIALS AND METHODS: Btk was detected by immunohistochemistry and digital image analysis in synovial tissue from biologically naive RA (n=16) and psoriatic arthritis (PsA) (n=12) patients. Cell populations expressing Btk were identified by immunofluorescent double labelling confocal microscopy, quantitative (q-) PCR and immunoblotting. The effects of a Btk-specific inhibitor, RN486, on gene expression in human macrophages and RA synovial tissue explants (n=8) were assessed by qPCR, ELISA and single-plex assays. RESULTS: Btk was expressed at equivalent levels in RA and PsA synovial tissue, restricted to B lymphocytes, monocytes, macrophages and mast cells. RN486 significantly inhibited macrophage IL-6 production induced by Fc receptor and CD40 ligation. RN486 also reduced mRNA expression of overlapping gene sets induced by IgG, CD40 ligand (CD40L) and RA synovial fluid, and significantly suppressed macrophage production of CD40L-induced IL-8, TNF, MMP-1 and MMP-10, LPS-induced MMP-1, MMP-7 and MMP-10 production, and spontaneous production of IL-6, PDGF, CXCL-9 and MMP-1 by RA synovial explants. CONCLUSIONS: Btk is expressed equivalently in RA and PsA synovial tissue, primarily in macrophages. Btk activity is needed to drive macrophage activation in response to multiple agonists relevant to inflammatory arthritis, and promotes RA synovial tissue cytokine and MMP production. Pharmacological targeting of Btk may be of therapeutic benefit in the treatment of RA and other inflammatory diseases.
25083955 Epstein-Barr virus associated hemophagocytic lymphohistiocytosis in a rheumatic patient re 2014 Aug 1 Hemophagocytic lymphohistiocytosis (HLH) is a life- threatening hyperinflammatory disease that causes extensive organ damage. It is generally triggered by viral, fungal, or parasitic infections in the setting of hematologic disease-induced immune deficiency. Occurrences in rheumatologic disease are less frequent, with the syndrome developing most often in patients with systemic lupus erythematosus and adult-onset Still disease. It is believed that the immunosuppression induced by rheumatologic disease itself and exacerbation by immunomodulatory therapies predispose to infection and subsequently HLH. Abatacept is a relatively new disease-modifying agent for rheumatoid arthritis (RA) that has been associated with varicella zoster virus, cytomegalovirus, and Epstein-Barr virus (EBV) infections, but not previously in the setting of HLH. Here we report a unique case of EBV-associated HLH in a RA patient receiving abatacept therapy.
24757138 Fcγ receptor III and Fcγ receptor IV on macrophages drive autoimmune valvular carditis i 2014 Apr OBJECTIVE: Arthritis and valvular carditis coexist in several human rheumatic diseases, including systemic lupus erythematosus, rheumatic fever, and rheumatoid arthritis. T cell receptor-transgenic K/BxN mice develop spontaneous autoantibody-associated arthritis and valvular carditis. The common Fc receptor γ (FcRγ) signaling chain is required for carditis to develop in K/BxN mice. FcRγ pairs with numerous receptors in a variety of cells. The aim of this study was to identify the FcRγ-associated receptors and Fcγ receptor (FcγR)-expressing cells that mediate valvular carditis in this model. METHODS: We bred K/BxN mice lacking the genes that encode activating Fcγ receptors (FcγRI, FcγRIII, and FcγRIV), and we assessed these mice for valvular carditis. We similarly evaluated complement component C3-deficient K/BxN mice. Immunohistochemistry, bone marrow transplantation, and macrophage depletion were used to define the key FcRγ-expressing cell type. RESULTS: Genetic deficiency of only one of the activating Fcγ receptors did not prevent carditis, whereas deficiency of all 3 activating Fcγ receptors did. Further analysis demonstrated that FcγRIII and FcγRIV were the key drivers of valve inflammation; FcγRI was dispensable. C3 was not required. FcRγ expression by radioresistant cells was critical for valvular carditis to develop, and further analysis indicated that macrophages were the key candidate FcγR-expressing effectors of carditis. CONCLUSION: FcγRIII and FcγRIV act redundantly to promote valvular carditis in K/BxN mice with systemic autoantibody-associated arthritis. Macrophage depletion reduced the severity of valve inflammation. These findings suggest that pathogenic autoantibodies engage Fcγ receptors on macrophages to drive valvular carditis. Our study provides new insight into the pathogenesis of cardiovascular inflammation in the setting of autoantibody-associated chronic inflammatory diseases.
24687234 Tumour necrosis factor α antagonists in the treatment of rheumatoid arthritis: an immunol 2014 Apr Rheumatoid arthritis (RA) is one of the most prevalent autoimmune conditions, affecting approximately 1% of the adult population. It is associated with decreased quality of life and considerable morbidity and mortality. Various inflammatory cells, including macrophages, neutrophils, mast cells, natural killer cells, B and T cells and stromal cells play key pathophysiological roles in joint inflammation and RA progression. Several cytokines, including interleukin (IL)-1α and/or IL-1β, and tumour necrosis factor (TNF)-α, are involved at each stage of RA pathogenesis; namely, by augmenting autoimmunity, sustaining long-term inflammatory synovitis and promoting joint damage. Different cell types are involved in RA pathogenesis through upregulation of several cytokine and soluble pro-inflammatory mediators. As early as the late 1980s, TNF had been identified as a potential target in RA. Five anti-TNF drugs, infliximab, adalimumab, certolizumab pegol, etanercept and golimumab, are now approved for the treatment of RA in various countries. All are bivalent monoclonal antibodies, with the exception of the monovalent certolizumab and etanercept, which is an engineered dimeric receptor. Although all react with and neutralise soluble TNF in vitro, structural differences in the molecules may contribute to differences in their therapeutic effects and the occurrence of side effects. Pegylated certolizumab permits once-monthly dosing. Other mechanisms of action proposed to be important for the efficacy of anti-TNF agents are as follows: induction of apoptosis of both monocytes and T cells; neutralization of membrane TNF; antibody-dependent cell-mediated and complement-dependent cytotoxicity; and reverse signaling via membrane TNF.
23758132 Does oxidative inactivation of CD45 phosphatase in rheumatoid arthritis underlie immune hy 2013 Dec 20 The protein tyrosine phosphatase (PTP) CD45 is critical in regulating the earliest steps in T-cell-receptor signaling but, similar to all PTPs, it is susceptible to oxidative inactivation. Given the widely reported effects of oxidant damage associated with rheumatoid arthritis (RA), we examined whether CD45 phosphatase activity was altered in CD4(+) T cells from RA patients and related this to CD4(+) T-cell function and redox status. CD45 phosphatase specific activity in T cells from RA peripheral blood (PB) and synovial fluid was 56% and 59% lower than in healthy control (HC) PB, respectively. In contrast, CD45 activity in T cells from disease controls (DSC) was not significantly different from HC. Both reduced glutathione (GSH) (p<0.001) and oxidized glutathione (GSSG) (p<0.05) were significantly lower in RA PB T cells compared with HC PB T cells. Treatment of RA PB T cells with the GSH precursor N-acetyl cysteine increased CD45 phosphatase activity and proliferation, while it decreased Lck kinase phosphorylation, which is regulated by CD45. Our observations lead to the hypothesis that the largely reversible oxidative inactivation of the CD45 phosphatase may underlie the decreased signaling efficiency and functional responsiveness which are characteristic of RA PB CD4(+) T cells.
24354986 Deficient spontaneous in vitro apoptosis and increased tmTNF reverse signaling-induced apo 2013 INTRODUCTION: In vitro apoptosis of peripheral monocytes in rheumatoid arthritis (RA) is disturbed and influenced by cytokine production and transmembrane TNF (tmTNF) reverse signaling. The goal of the study was the analysis of the predictive value of the rate of in vitro apoptosis for the therapeutic response to anti-TNF treatment. METHODS: Spontaneous and tmTNF reverse signaling-induced apoptosis were determined in vitro in monocytes from 20 RA patients prior to initiation of therapeutic TNF inhibition with etanercept, and the subsequent clinical response was monitored. RESULTS: Spontaneous in vitro apoptosis was significantly reduced in RA patients compared to controls. Deficiency in spontaneous apoptosis was associated with an insufficient therapeutic response according to the European League Against Rheumatism (EULAR) response criteria and less reduction of the disease activity determined by disease activity score (DAS) 28. High susceptibility to reverse signaling-induced apoptosis was also associated with less efficient reduction in the DAS28. Of note, a strong negative correlation between the two apoptotic parameters was discernible, possibly indicative of two pathogenetically relevant processes counter-regulating each other. tmTNF reverse signaling induced in vitro production of soluble IL1-RI and IL-1RII only in monocytes not deficient in spontaneous apoptosis, and the levels of soluble IL1-RII were found to be predictive of a good clinical response to Etanercept. CONCLUSION: Although tmTNF reverse signaling is able to induce apoptosis of RA monocytes in vitro, this process appears to occur in vitro preferentially in patients with suboptimal therapeutic response. Resistance to spontaneous in vitro apoptosis, in contrast, is a predictor of insufficient response to treatment.
25274888 Detection of subclinical synovitis with macrophage targeting and positron emission tomogra 2014 Nov OBJECTIVE: To determine whether macrophage targeting by (R)-11C-PK11195 positron emission tomography (PET) can visualize subclinical joint inflammation in patients with rheumatoid arthritis (RA) without clinical arthritis during or after treatment, with flare as clinical outcome measure. METHODS: (R)-11C-PK11195 PET and contrast-enhanced magnetic resonance imaging (MRI) of hands/wrists were performed in 29 patients with RA without clinical arthritis. (R)-11C-PK11195 PET uptake (semiquantitative score 0-3) in metacarpophalangeal, proximal interphalangeal, and wrist joints (i.e., 22 joints per patient) was scored and summed to obtain a cumulative PET score (range 0-66). Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) was performed on similar joints. Synovitis and bone marrow edema scores (>1) were summed to obtain a cumulative MRI score (range 0-288). Occurrence of flare was determined during 3-year followup. RESULTS: Flare was observed in 17/29 patients (59%). (R)-11C-PK11195 PET showed enhanced tracer uptake in 16/29 patients (55%), of which 11 (69%) developed a flare. Highest cumulative PET scores (>6, n=3) corresponded with highest cumulative MRI scores (>39) and were related to development of flare in hands/wrists within 6 months. Cumulative PET scores of patients developing a flare were higher than those of patients without a flare [median (interquartile range) 2 (0-4.5) vs 0 (0-1), p<0.05]. In contrast, no significant differences were found between cumulative MRI scores of patients with and without a flare. CONCLUSION: (R)-11C-PK11195 PET showed enhanced uptake, pointing to presence of subclinical synovitis in over half of patients without clinical arthritis. (R)-11C-PK11195 PET may be of value for prediction of exacerbation of RA, since cumulative PET scores > 1 were associated with development of flare within 3 years.
23654356 Retinal venular calibre is increased in patients with autoimmune rheumatic disease: a case 2013 Jun AIM: To examine retinal vessel calibre in autoimmune rheumatic disease. MATERIALS AND METHODS: Patients with autoimmune rheumatic disease were recruited from a Rheumatology clinic. Retinal vessel calibre was measured from fundus photographs, and summarised as the central retinal artery and vein equivalents (CRAE and CRVE) using a semi-automated computer-assisted method. RESULTS: The 124 patients studied had rheumatoid arthritis (n = 76, 61%), systemic lupus erythematosus (n = 17, 14%), psoriatic arthritis (n = 11, 9%) or another rheumatological disease (n = 20, 16%). Retinal venular calibre was increased in patients with autoimmune rheumatic disease (+11.6 µm, 95% Confidence interval [CI] 3.8 - 19.3, p = 0.01) compared with other hospital patients, after adjusting for baseline differences. This increase was also present in the subgroup with rheumatoid arthritis (p = 0.01). Patients with a rheumatic disease and elevated C-reactive protein (CRP) levels had wider retinal venules than those with a lower CRP (mean CRVE: 247.8 ± 28.0 versus 216.6 ± 25.3, p < 0.01), and than other hospital patients with increased CRP (mean CRVE: 247.8 ± 28.0 versus 216.4 ± 25.9, p < 0.01). CONCLUSIONS: Individuals with an autoimmune rheumatic disease have wider retinal venules than other hospital patients. This increase in calibre may be due to the underlying inflammatory activity.