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Rachel Knevel - One of the best experts on this subject based on the ideXlab platform.
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a genetic variant in osteoprotegerin is associated with progression of Joint Destruction in rheumatoid arthritis
Arthritis Research & Therapy, 2014Co-Authors: Rachel Knevel, D P C De Rooy, Elisabet Lindqvist, Roula Tsonaka, Tore Saxne, M K Leijsma, Nina A Daha, Bobby P C Koeleman, Jeanine J Houwingduistermaat, Joris SchonkerenAbstract:Progression of Joint Destruction in rheumatoid arthritis (RA) is partly heritably; 45 to 58% of the variance in Joint Destruction is estimated to be explained by genetic factors. The binding of RANKL (Receptor Activator for Nuclear Factor κ B Ligand) to RANK results in the activation of TRAF6 (tumor necrosis factor (TNF) receptor associated factor-6), and osteoclast formation ultimately leading to enhanced bone resorption. This bone resorption is inhibited by osteoprotegerin (OPG) which prevents RANKL-RANK interactions. The OPG/RANK/RANKL/TRAF6 pathway plays an important role in bone remodeling. Therefore, we investigated whether genetic variants in OPG, RANK, RANKL and TRAF6 are associated with the rate of Joint Destruction in RA. 1,418 patients with 4,885 X-rays of hands and feet derived from four independent data-sets were studied. In each data-set the relative increase of the progression rate per year in the presence of a genotype was assessed. First, explorative analyses were performed on 600 RA-patients from Leiden. 109 SNPs, tagging OPG, RANK, RANKL and TRAF6, were tested. Single nucleotide polymorphisms (SNPs) significantly associated in phase-1 were genotyped in data-sets from Groningen (Netherlands), Sheffield (United Kingdom) and Lund (Switzerland). Data were summarized in an inverse weighted variance meta-analysis. Bonferonni correction for multiple testing was applied. We found that 33 SNPs were significantly associated with the rate of Joint Destruction in phase-1. In phase-2, six SNPs in OPG and four SNPs in RANK were associated with progression of Joint Destruction with P-value <0.05. In the meta-analyses of all four data-sets, RA-patients with the minor allele of OPG-rs1485305 expressed higher rates of Joint Destruction compared to patients without these risk variants (P = 2.35x10−4). This variant was also significant after Bonferroni correction. These results indicate that a genetic variant in OPG is associated with a more severe rate of Joint Destruction in RA.
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low avidity anticitrullinated protein antibodies acpa are associated with a higher rate of Joint Destruction in rheumatoid arthritis
Annals of the Rheumatic Diseases, 2014Co-Authors: Parawee Suwannalai, Rachel Knevel, Rene E M Toes, Tom W J Huizinga, Annette H M Van Der Helmvan Mil, K Britsemmer, H Scherer, E Nivine W Levarht, Dirkjan Van Schaardenburg, Leendert A TrouwAbstract:Objectives Anticitrullinated protein antibodies (ACPA) are specific for rheumatoid arthritis (RA) and have been implicated in disease pathogenesis. Previously we have shown that ACPA display a considerably lower avidity as compared with antibodies against recall antigens. Nonetheless, ACPA-avidity did vary between patients. As antibody mediated effects are influenced by antibody-avidity, we now investigated ACPA-avidity in relation to biological activity and clinical outcome. Methods We determined the avidity of ACPA and related this with severity of Joint damage in two Dutch early-RA cohorts containing 199 and 132 patients respectively. Differences in effector functions of low- and high-avidity ACPA were studied. Results Extensive variation in ACPA-avidity between patients was observed. This allowed the analysis of the relationship between avidity and severity. The presence of low-avidity ACPA is associated with a higher rate of Joint Destruction. This finding was replicated in an independent cohort. Analysis of the properties of low-versus high-avidity ACPA revealed that low-avidity ACPA are less hampered in their ability to bind ‘new’ citrullinated antigens. Although no differences could be observed regarding cellular activation via Fc-γ receptors, low-avidity ACPA were more potent in activating the complement system. Conclusions Patients with low-avidity ACPA display a higher rate of Joint Destruction. Low-avidity ACPA display a higher potency to interact with more citrullinated antigens in time and show that low-avidity ACPA are more potent in complement activation. These data indicate that (low) avidity impacts on the biological activity of ACPA and associates with a worse radiological outcome.
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Association of variants in IL2RA with progression of Joint Destruction in rheumatoid arthritis.
Arthritis and rheumatism, 2013Co-Authors: Rachel Knevel, D P C De Rooy, G Grondal, Alexandra Zhernakova, Rene E M Toes, A. Krabben, Kristjan Steinsson, G. Cavet, Cisca Wijmenga, Twj HuizingaAbstract:Objective Heritability studies have suggested an important role of genetic predisposition in the progression of Joint Destruction in rheumatoid arthritis (RA); the heritability is estimated at 45–58%. Several single-nucleotide polymorphisms (SNPs) have been identified as being associated with RA susceptibility. Our objective was to study the association of several of these loci with progression of Joint Destruction. Methods We studied 1,750 RA patients in 4 independent data sets with 4,732 radiographs scored using the modified Sharp/van der Heijde method. Thirteen susceptibility SNPs that were not previously associated with Joint Destruction were tested in 596 Dutch RA patients. Subsequently, significant SNPs were studied in data sets of RA patients from North America and Iceland. Data were summarized in inverse-weighted variance meta-analyses. Further, the association with circulating protein levels was studied and the associated region was fine-mapped. Results In stage 1, 3 loci (AFF3, IL2RA, and BLK) were significantly associated with the rate of Joint Destruction and were further analyzed in the additional data sets. In the combined meta-analyses, the minor (C) allele of IL2RA (rs2104286) was associated with less progression of Joint Destruction (P = 7.2 × 10−4). Furthermore, the IL2RA (rs2104286) protective genotype was associated with lower (0.85-fold [95% confidence interval 0.77–0.93], P = 1.4 × 10−3) circulating levels of soluble interleukin-2 receptor α (sIL-2Rα). Additionally, lower sIL-2Rα levels were associated with a lower rate of Joint Destruction (P = 3.4 × 10−3). The association of IL2RA with the rate of Joint Destruction was further localized to a 40-kb region encompassing the IL2RA intron 1 and the 5′ region of IL2RA and RBM17. Conclusion The present genetic and serologic data suggest that inherited altered genetic constitution at the IL2RA locus may predispose to a less destructive course of RA.
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comparison of methodologies for analysing the progression of Joint Destruction in rheumatoid arthritis
Scandinavian Journal of Rheumatology, 2013Co-Authors: Rachel Knevel, Roula Tsonaka, Twj Huizinga, Jeanine J Houwingduistermaat, M P M Van Der Linden, Le S Cessie, Dmfm Van Der Heijde, Annette H M Van Der Helmvan MilAbstract:Objectives: Progression of Joint Destruction is an important phenotypic feature in rheumatoid arthritis (RA). When factors have small effect sizes, both the avoidance of phenotypic misclassification and discerning true effects from noise are challenging. Assembling radiological measurements repeatedly in time harbours a smaller risk of misclassification than single measurements. Given serial measurements, different methods of analysis can be applied. This study evaluates different statistical methods of analysing longitudinal data.Methods: Three statistical methods were studied: linear regression (LR), generalized estimating equations (GEE), and multivariate normal regression analysis (MRA). All were applied longitudinally, testing for differences in radiological progression rates. As genetic variants are known to have small effect sizes, two genetic variants were studied as examples: rs675520 (located in the TNFAIP3-OLIG3 region) and the presence of the human leucocyte antigen (HLA) shared epitope (SE) a...
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genetic studies on components of the wnt signalling pathway and the severity of Joint Destruction in rheumatoid arthritis
Annals of the Rheumatic Diseases, 2013Co-Authors: D P C De Rooy, Rachel Knevel, Elisabet Lindqvist, Anthony G Wilson, A. Krabben, Tore Saxne, M K Leijsma, Nina A Daha, Nataliya Yeremenko, S TsonakaAbstract:Background Progression of Joint Destruction in rheumatoid arthritis (RA) is partly heritable; knowledge of genetic factors may increase our understanding of the mechanisms underlying Joint Destruction. The activity of the Wnt/beta-catenin pathway influences osteoblast differentiation. Dickkopf-1 (Dkk-1) and sclerostin (Sost) are negative regulators and lipoprotein receptor-related protein-5 (LRP-5) and Kremen-1 are transmembrane receptors involved in this pathway. Objective To study variants in the genes encoding these proteins in relation to progression of Joint Destruction. Methods 1418 patients with RA of four cohorts with 4885 sets of hands and feet x-rays were studied. Explorative analyses were performed on 600 patients with RA from Leiden on single nucleotide polymorphisms (SNPs) tagging Dkk-1, Sost, Kremen-1 and LRP-5. SNPs significantly associating with Joint damage progression were subsequently genotyped in cohorts from Groningen (NL), Sheffield (UK) and Lund (Sweden). Data were summarised in meta-analyses. Serum levels of functional Dkk-1 and sclerostin were measured and studied in relation to genotypes. Results In the first cohort, six Dkk-1, three Sost, one Kremen-1 and 10 LRP-5 SNPs were significantly associated with radiological progression of Joint Destruction. Three Dkk-1 SNPs were associated significantly with progression of Joint damage in the meta-analysis, also after correction for multiple testing (rs1896368, rs1896367 and rs1528873). Two Sost SNPs tended to significance (rs4792909 and rs6503475, p=0.07 after false discovery rate correction). Gene-gene interactions between SNPs on Dkk-1 and Sost were seen. Serum levels of Dkk-1 were significantly correlated with the genotypes in rs1896368 (p=0.02). Conclusions Patients with RA carrying risk alleles of genetic variants in Dkk-1 have higher serum levels of functional Dkk-1 and more progressive Joint Destruction over time.
Karim Raza - One of the best experts on this subject based on the ideXlab platform.
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11 beta hydroxysteroid dehydrogenase type 1 regulates synovitis Joint Destruction and systemic bone loss in chronic polyarthritis
Journal of Autoimmunity, 2018Co-Authors: Rowan Hardy, Chloe Fenton, Adam P Croft, Amy J Naylor, Rumina Begum, Guillaume Desanti, Christopher D Buckley, Gareth G Lavery, Mark S Cooper, Karim RazaAbstract:Abstract Objective In rheumatoid arthritis, the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is highly expressed at sites of inflammation, where it converts inactive glucocorticoids (GC) to their active counterparts. In conditions of GC excess it has been shown to be a critical regulator of muscle wasting and bone loss. Here we examine the contribution of 11β-HSD1 to the pathology of persistent chronic inflammatory disease. Methods To determine the contribution of 11β-HSD1 to Joint inflammation, Destruction and systemic bone loss associated with persistent inflammatory arthritis, we generated mice with global and mesenchymal specific 11β-HSD1 deletions in the TNF-transgenic (TNF-tg) model of chronic polyarthritis. Disease severity was determined by clinical scoring. Histology was assessed in formalin fixed sections and fluorescence-activated cell sorting (FACS) analysis of synovial tissue was performed. Local and systemic bone loss were measured by micro computed tomography (micro-CT). Measures of inflammation and bone metabolism were assessed in serum and in tibia mRNA. Results Global deletion of 11β-HSD1 drove an enhanced inflammatory phenotype, characterised by florid synovitis, Joint Destruction and systemic bone loss. This was associated with increased pannus invasion into subchondral bone, a marked polarisation towards pro-inflammatory M1 macrophages at sites of inflammation and increased osteoclast numbers. Targeted mesenchymal deletion of 11β-HSD1 failed to recapitulate this phenotype suggesting that 11β-HSD1 within leukocytes mediate its protective actions in vivo. Conclusions We demonstrate a fundamental role for 11β-HSD1 in the suppression of synovitis, Joint Destruction, and systemic bone loss. Whilst a role for 11β-HSD1 inhibitors has been proposed for metabolic complications in inflammatory diseases, our study suggests that this approach would greatly exacerbate disease severity.
Wim B Van Den Berg - One of the best experts on this subject based on the ideXlab platform.
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amplifying elements of arthritis and Joint Destruction
Annals of the Rheumatic Diseases, 2007Co-Authors: Wim B Van Den Berg, Leo A B Joosten, Peter L E M Van Lent, Shahla Abdollahiroodsaz, Marije I KoendersAbstract:Rheumatoid arthritis (RA) is a systemic autoimmune disease characterised by chronic Joint inflammation and variable degrees of bone and cartilage erosion. Studies in animal models of arthritis provide insight into elements which can amplify destructive features. The presence of immune complexes in the Joint makes arthritis more erosive. Although considerable bone erosion still occurs in the absence of FcgammaR triggering by immune complexes, through cytokine-induced RANKL and direct osteoclast activation, cartilage erosion is heavily dependent on the FcgammaR pathway. T cell factors such as IFNgamma and IL17 further amplify erosion through upregulation of the damaging FcgammaRI and stimulation of the influx of granulocytes, respectively. Apart from immune elements, environmental pressure and components of tissue damage contribute through innate pathways. Spontaneous T cell-dependent arthritis in IL1Ra-/- mice is absent under germ-free conditions, and markedly suppressed in TLR4-deficient mice. Moreover, TLR4 blocking with a receptor antagonist suppresses erosive arthritis.
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il 1 independent role of il 17 in synovial inflammation and Joint Destruction during collagen induced arthritis
Journal of Immunology, 2001Co-Authors: Erik Lubberts, Leo A B Joosten, B Oppers, Jay K Kolls, Paul Schwarzenberger, Liduine Van Den Bersselaar, Christina Coenende J J Roo, Fons A J Van De Loo, Wim B Van Den BergAbstract:T cell IL-17 displays proinflammatory properties and is expressed in the synovium of patients with rheumatoid arthritis. Its contribution to the arthritic process has not been identified. Here, we show that blocking of endogenous IL-17 in the autoimmune collagen-induced arthritis model results in suppression of arthritis. Also, Joint damage was significantly reduced. In contrast, overexpression of IL-17 enhanced collagen arthritis. Moreover, adenoviral IL-17 injected in the knee Joint of type II collagen-immunized mice accelerated the onset and aggravated the synovial inflammation at the site. Radiographic and histologic analysis showed markedly increased Joint Destruction. Elevated levels of IL-1beta protein were found in synovial tissue. Intriguingly, blocking of IL-1alphabeta with neutralizing Abs had no effect on the IL-17-induced inflammation and Joint damage in the knee Joint, implying an IL-1 independent pathway. This direct potency of IL-17 was underscored in the unabated IL-17-induced exaggeration of bacterial cell wall-induced arthritis in IL-1beta(-/-) mice. In conclusion, this data shows that IL-17 contributes to Joint Destruction and identifies an IL-1-independent role of IL-17. These findings suggest IL-17 to be a novel target for the treatment of destructive arthritis and may have implications for tissue Destruction in other autoimmune diseases.
Erik Lubberts - One of the best experts on this subject based on the ideXlab platform.
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il 1 independent role of il 17 in synovial inflammation and Joint Destruction during collagen induced arthritis
Journal of Immunology, 2001Co-Authors: Erik Lubberts, Leo A B Joosten, B Oppers, Liduine Van Den Bersselaar, Jay K Kolls, Paul Schwarzenberger, Wim B Van Den BergAbstract:T cell IL-17 displays proinflammatory properties and is expressed in the synovium of patients with rheumatoid arthritis. Its contribution to the arthritic process has not been identified. Here, we show that blocking of endogenous IL-17 in the autoimmune collagen-induced arthritis model results in suppression of arthritis. Also, Joint damage was significantly reduced. In contrast, overexpression of IL-17 enhanced collagen arthritis. Moreover, adenoviral IL-17 injected in the knee Joint of type II collagen-immunized mice accelerated the onset and aggravated the synovial inflammation at the site. Radiographic and histologic analysis showed markedly increased Joint Destruction. Elevated levels of IL-1β protein were found in synovial tissue. Intriguingly, blocking of IL-1αβ with neutralizing Abs had no effect on the IL-17-induced inflammation and Joint damage in the knee Joint, implying an IL-1 independent pathway. This direct potency of IL-17 was underscored in the unabated IL-17-induced exaggeration of bacterial cell wall-induced arthritis in IL-1β −/− mice. In conclusion, this data shows that IL-17 contributes to Joint Destruction and identifies an IL-1-independent role of IL-17. These findings suggest IL-17 to be a novel target for the treatment of destructive arthritis and may have implications for tissue Destruction in other autoimmune diseases.
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il 1 independent role of il 17 in synovial inflammation and Joint Destruction during collagen induced arthritis
Journal of Immunology, 2001Co-Authors: Erik Lubberts, Leo A B Joosten, B Oppers, Jay K Kolls, Paul Schwarzenberger, Liduine Van Den Bersselaar, Christina Coenende J J Roo, Fons A J Van De Loo, Wim B Van Den BergAbstract:T cell IL-17 displays proinflammatory properties and is expressed in the synovium of patients with rheumatoid arthritis. Its contribution to the arthritic process has not been identified. Here, we show that blocking of endogenous IL-17 in the autoimmune collagen-induced arthritis model results in suppression of arthritis. Also, Joint damage was significantly reduced. In contrast, overexpression of IL-17 enhanced collagen arthritis. Moreover, adenoviral IL-17 injected in the knee Joint of type II collagen-immunized mice accelerated the onset and aggravated the synovial inflammation at the site. Radiographic and histologic analysis showed markedly increased Joint Destruction. Elevated levels of IL-1beta protein were found in synovial tissue. Intriguingly, blocking of IL-1alphabeta with neutralizing Abs had no effect on the IL-17-induced inflammation and Joint damage in the knee Joint, implying an IL-1 independent pathway. This direct potency of IL-17 was underscored in the unabated IL-17-induced exaggeration of bacterial cell wall-induced arthritis in IL-1beta(-/-) mice. In conclusion, this data shows that IL-17 contributes to Joint Destruction and identifies an IL-1-independent role of IL-17. These findings suggest IL-17 to be a novel target for the treatment of destructive arthritis and may have implications for tissue Destruction in other autoimmune diseases.
Leo A B Joosten - One of the best experts on this subject based on the ideXlab platform.
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amplifying elements of arthritis and Joint Destruction
Annals of the Rheumatic Diseases, 2007Co-Authors: Wim B Van Den Berg, Leo A B Joosten, Peter L E M Van Lent, Shahla Abdollahiroodsaz, Marije I KoendersAbstract:Rheumatoid arthritis (RA) is a systemic autoimmune disease characterised by chronic Joint inflammation and variable degrees of bone and cartilage erosion. Studies in animal models of arthritis provide insight into elements which can amplify destructive features. The presence of immune complexes in the Joint makes arthritis more erosive. Although considerable bone erosion still occurs in the absence of FcgammaR triggering by immune complexes, through cytokine-induced RANKL and direct osteoclast activation, cartilage erosion is heavily dependent on the FcgammaR pathway. T cell factors such as IFNgamma and IL17 further amplify erosion through upregulation of the damaging FcgammaRI and stimulation of the influx of granulocytes, respectively. Apart from immune elements, environmental pressure and components of tissue damage contribute through innate pathways. Spontaneous T cell-dependent arthritis in IL1Ra-/- mice is absent under germ-free conditions, and markedly suppressed in TLR4-deficient mice. Moreover, TLR4 blocking with a receptor antagonist suppresses erosive arthritis.
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il 1 independent role of il 17 in synovial inflammation and Joint Destruction during collagen induced arthritis
Journal of Immunology, 2001Co-Authors: Erik Lubberts, Leo A B Joosten, B Oppers, Liduine Van Den Bersselaar, Jay K Kolls, Paul Schwarzenberger, Wim B Van Den BergAbstract:T cell IL-17 displays proinflammatory properties and is expressed in the synovium of patients with rheumatoid arthritis. Its contribution to the arthritic process has not been identified. Here, we show that blocking of endogenous IL-17 in the autoimmune collagen-induced arthritis model results in suppression of arthritis. Also, Joint damage was significantly reduced. In contrast, overexpression of IL-17 enhanced collagen arthritis. Moreover, adenoviral IL-17 injected in the knee Joint of type II collagen-immunized mice accelerated the onset and aggravated the synovial inflammation at the site. Radiographic and histologic analysis showed markedly increased Joint Destruction. Elevated levels of IL-1β protein were found in synovial tissue. Intriguingly, blocking of IL-1αβ with neutralizing Abs had no effect on the IL-17-induced inflammation and Joint damage in the knee Joint, implying an IL-1 independent pathway. This direct potency of IL-17 was underscored in the unabated IL-17-induced exaggeration of bacterial cell wall-induced arthritis in IL-1β −/− mice. In conclusion, this data shows that IL-17 contributes to Joint Destruction and identifies an IL-1-independent role of IL-17. These findings suggest IL-17 to be a novel target for the treatment of destructive arthritis and may have implications for tissue Destruction in other autoimmune diseases.
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il 1 independent role of il 17 in synovial inflammation and Joint Destruction during collagen induced arthritis
Journal of Immunology, 2001Co-Authors: Erik Lubberts, Leo A B Joosten, B Oppers, Jay K Kolls, Paul Schwarzenberger, Liduine Van Den Bersselaar, Christina Coenende J J Roo, Fons A J Van De Loo, Wim B Van Den BergAbstract:T cell IL-17 displays proinflammatory properties and is expressed in the synovium of patients with rheumatoid arthritis. Its contribution to the arthritic process has not been identified. Here, we show that blocking of endogenous IL-17 in the autoimmune collagen-induced arthritis model results in suppression of arthritis. Also, Joint damage was significantly reduced. In contrast, overexpression of IL-17 enhanced collagen arthritis. Moreover, adenoviral IL-17 injected in the knee Joint of type II collagen-immunized mice accelerated the onset and aggravated the synovial inflammation at the site. Radiographic and histologic analysis showed markedly increased Joint Destruction. Elevated levels of IL-1beta protein were found in synovial tissue. Intriguingly, blocking of IL-1alphabeta with neutralizing Abs had no effect on the IL-17-induced inflammation and Joint damage in the knee Joint, implying an IL-1 independent pathway. This direct potency of IL-17 was underscored in the unabated IL-17-induced exaggeration of bacterial cell wall-induced arthritis in IL-1beta(-/-) mice. In conclusion, this data shows that IL-17 contributes to Joint Destruction and identifies an IL-1-independent role of IL-17. These findings suggest IL-17 to be a novel target for the treatment of destructive arthritis and may have implications for tissue Destruction in other autoimmune diseases.
