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Find video protocols related to scientific articles indexed in Pubmed.
MRI assessment of suppression of structural damage in patients with rheumatoid arthritis receiving rituximab: results from the randomised, placebo-controlled, double-blind RA-SCORE study.
Ann. Rheum. Dis.
PUBLISHED: 10-29-2014
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To evaluate changes in structural damage and joint inflammation assessed by MRI following rituximab treatment in a Phase 3 study of patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) who were naive to biological therapy.
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Discovery and confirmation of a protein biomarker panel with potential to predict response to biological therapy in psoriatic arthritis.
Ann. Rheum. Dis.
PUBLISHED: 09-03-2014
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Biological therapies, which include antitumour necrosis factor-? and T-cell inhibitors, are potentially effective treatments for psoriatic arthritis (PsA) but are costly and may induce a number of side effects. Response to treatment in PsA is variable and difficult to predict. Here, we sought to identify a panel of protein biomarkers that could be used to predict which patients diagnosed with PsA will respond to biologic treatment.
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From synovial tissue to peripheral blood: myeloid related protein 8/14 is a sensitive biomarker for effective treatment in early drug development in patients with rheumatoid arthritis.
PLoS ONE
PUBLISHED: 08-28-2014
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The change in number of CD68-positive sublining macrophages in serial synovial biopsies has been successfully used to discriminate on the group level between effective and ineffective treatment during early drug development in rheumatoid arthritis (RA) patients. Measurement of a soluble biomarker would clearly have practical advantages. Therefore, we investigated the sensitivity to change of myeloid related protein (MRP)8/14 in serum.
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Heterogeneous expression pattern of interleukin-17A (IL-17A), IL-17F and their receptors in synovium of rheumatoid arthritis, psoriatic arthritis and osteoarthritis: possible explanation for non-response to anti-IL-17 therapy?
Arthritis Res. Ther.
PUBLISHED: 08-22-2014
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IntroductionAccumulating evidence suggests an important role for interleukin (IL)-17 in the pathogenesis of several inflammatory diseases, including rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Accordingly, clinical trials aimed at blocking IL-17 have been initiated but clinical results are highly variable between patients and across different diseases. The objective was to determine the variability in expression of IL-17A, IL-17F and their receptors IL-17RA and IL-17RC in synovium of patients with arthritis.MethodsSynovial biopsies were obtained from patients with RA (n¿=¿11), PsA (n¿=¿15) and inflammatory osteoarthritis (OA, n¿=¿14). For comparison, synovium from non-inflamed knee joints (n¿=¿7) were included obtained from controls. Frozen sections were stained for IL-17A, IL-17F, IL-17RA and IL-17RC, and evaluated by digital image analysis. To determine which cells in the synovium express IL-17A and IL-17F, double stainings with CD4, CD8, CD15, CD68, CD163, CD31, Von Willebrand Factor (vWF), peripheral lymph node addressin (PNAd), lymphatic vessel endothelial hyaluronan receptor 1 (Lyve-1), mast cell tryptase (MCT) and RAR-Related Orphan Receptor gamma t (ROR¿(t)) were performed and evaluated by confocal microscopy.ResultsIL-17A, IL-17F, IL-17RA and IL-17RC were abundantly expressed in synovial tissues of all patient groups. Whereas IL-17RA was mostly present in the synovial sublining, IL-17RC was abundantly expressed in the intimal lining layer. Digital image analysis showed a significant (P¿<¿0.05) increase of only IL-17A in arthritis patients compared to non-inflamed control tissues. The expression of IL-17A, IL-17F and their receptors was similar in the different patient groups, but highly variable between patients. CD4 and CD8 positive cells co-expressed IL-17A and few cells co-expressed IL-17F. IL-17A and IL-17F were not expressed by CD15 positive neutrophils. Mast cells were only occasionally positive for IL-17A or IL-17F. Interestingly, IL-17A and IL-17F staining was also observed in macrophages as well as in blood vessels and lymphatics; this staining probably reflects receptor bound cytokine staining. Many infiltrated cells were positive for the transcription factor ROR¿(t). Colocalization between ROR¿(t) and IL-17A and IL-17F indicates local IL-17 production.ConclusionsIncreased expression of IL-17A is not restricted to synovial tissues of RA and PsA patients but also observed in inflammatory OA. The heterogeneous expression levels may explain non-response to anti-IL17 therapy in subsets of patients.
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Serum 14-3-3? is a Novel Marker that Complements Current Serological Measurements to Enhance Detection of Patients with Rheumatoid Arthritis.
J. Rheumatol.
PUBLISHED: 08-15-2014
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Serum 14-3-3? is a novel joint-derived proinflammatory mediator implicated in the pathogenesis of rheumatoid arthritis (RA). In our study, we assessed the diagnostic utility of 14-3-3? and its association with standard clinical and serological measures.
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FHL2 regulates the resolution of tissue damage in chronic inflammatory arthritis.
Ann. Rheum. Dis.
PUBLISHED: 08-14-2014
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We analysed the role of the adaptor molecule four-and-a-half Lin11, Isl-1 & Mec-3 (LIM) domain protein 2 (FHL2) in the activation of fibroblast-like synoviocytes in human rheumatoid arthritis (RA) and tumour necrosis factor ? (TNF?)-dependent animal models of the disease.
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Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis.
PLoS ONE
PUBLISHED: 08-11-2014
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The inflammatory reflex is a physiological mechanism through which the nervous system maintains immunologic homeostasis by modulating innate and adaptive immunity. We postulated that the reflex might be harnessed therapeutically to reduce pathological levels of inflammation in rheumatoid arthritis by activating its prototypical efferent arm, termed the cholinergic anti-inflammatory pathway. To explore this, we determined whether electrical neurostimulation of the cholinergic anti-inflammatory pathway reduced disease severity in the collagen-induced arthritis model.
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Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation.
Nat Commun
PUBLISHED: 07-28-2014
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Emerging evidence suggests that RANKL-induced changes in chromatin state are important for osteoclastogenesis, but these epigenetic mechanisms are not well understood and have not been therapeutically targeted. In this study, we find that the small molecule I-BET151 that targets bromo and extra-terminal (BET) proteins that 'read' chromatin states by binding to acetylated histones strongly suppresses osteoclastogenesis. I-BET151 suppresses pathologic bone loss in TNF-induced inflammatory osteolysis, inflammatory arthritis and post-ovariectomy models. Transcriptome analysis identifies a MYC-NFAT axis important for osteoclastogenesis. Mechanistically, I-BET151 inhibits expression of the master osteoclast regulator NFATC1 by suppressing expression and recruitment of its newly identified upstream regulator MYC. MYC is elevated in rheumatoid arthritis macrophages and its induction by RANKL is important for osteoclastogenesis and TNF-induced bone resorption. These findings highlight the importance of an I-BET151-inhibited MYC-NFAT axis in osteoclastogenesis, and suggest targeting epigenetic chromatin regulators holds promise for treatment of inflammatory and oestrogen deficiency-mediated pathologic bone resorption.
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Citrullination of epithelial neutrophil-activating peptide 78/CXCL5 results in conversion from a non-monocyte-recruiting chemokine to a monocyte-recruiting chemokine.
PUBLISHED: 06-12-2014
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To examine whether the citrullinated chemokines epithelial neutrophil-activating peptide 78 (ENA-78)/CXCL5, macrophage inflammatory protein 1?/CCL3, and monocyte chemotactic protein 1/CCL2 are detected in the biologic fluid of patients with rheumatoid arthritis (RA), and if so, to determine the biologic activities of these chemokines.
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JNK-dependent downregulation of FoxO1 is required to promote the survival of fibroblast-like synoviocytes in rheumatoid arthritis.
Ann. Rheum. Dis.
PUBLISHED: 05-10-2014
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Forkhead box O (FoxO) transcription factors integrate environmental signals to modulate cell proliferation and survival, and alterations in FoxO function have been reported in rheumatoid arthritis (RA).
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Btk inhibition suppresses agonist-induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants.
Ann. Rheum. Dis.
PUBLISHED: 04-26-2014
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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).
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CD20+ B cell depletion alters T cell homing.
J. Immunol.
PUBLISHED: 04-02-2014
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Depleting mAbs against the pan B cell marker CD20 are remarkably effective in the treatment of autoimmune-mediated inflammatory disorders, but the underlying mechanisms are poorly defined. The primary objective of this study was to find a mechanistic explanation for the remarkable clinical effect of the anti-CD20 mAbs in a representative nonhuman primate autoimmune-mediated inflammatory disorder model, experimental autoimmune encephalomyelitis (EAE) in common marmosets, allowing detailed analysis of secondary lymphoid organs (SLO). We observed that the depletion of CD20(+) B cells creates a less immunostimulatory environment in the SLO reflected by reduced expression of MHC class II, CD40, CD83, and CD80/CD86. APCs isolated from SLO of B cell-depleted EAE monkeys were also less responsive to mitogenic stimulation. The depleted B cell areas were replenished by T cells, of which the majority expressed CD127 (IL-7R) and CCR7. Such effects were not detected in EAE marmosets treated with mAb against BLyS or APRIL, where B cell depletion via withdrawal of essential survival cytokines was not associated with a marked clinical effect. We propose that at least part of the efficacy of anti-CD20 mAb therapy is attributable to the sustained CCR7 expression on T cells within SLO, limiting their release into the circulation.
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14-3-3? is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage.
Arthritis Res. Ther.
PUBLISHED: 03-25-2014
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The aim of this study was to investigate whether 14-3-3?, a specific isoform of a family of proteins regulating processes such as cellular signalling, activates cell-signalling pathways and induces factors known to contribute to the pathophysiology of rheumatoid arthritis (RA). We also investigated whether 14-3-3? is associated with more severe disease in both early and established RA.
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Intrinsic healing response of the human anterior cruciate ligament: an histological study of reattached ACL remnants.
J. Orthop. Res.
PUBLISHED: 03-07-2014
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A reattachment of the tibial remnant of the torn anterior cruciate ligament (ACL) to the posterior cruciate ligament is sometimes observed during surgery and apparently implies that the human ACL does have a healing response. The aim of this study was to investigate whether this reattachment tissue has similar histological characteristics of a healing response as the medial collateral ligament (MCL), which can heal spontaneously. Standard histology and immunostaining of ?-smooth muscle actin and collagen type 3 was performed. The results shows that the reattached tissue has typical characteristics of a healing response: there attached ACL remnant could not be released by forceful traction; microscopy showed that the collagen fibers of the reattached tissue were disorganized with no preferred direction; increased neovascularization; the presence of lipid vacuoles; the mean number of cells within the biopsy tissue was 631±269 cells per mm2; and 68±20% was expressing ?-SMA; semi-quantitative analysis of collagen type 3 expression showed that collagen type 3 had an high expression with an average score of 3. In conclusion, this study shows that the human proximal 1/3 ACL has an intrinsic healing response with typical histological characteristics similar to the MCL.
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NF-?B-inducing kinase is a key regulator of inflammation-induced and tumour-associated angiogenesis.
J. Pathol.
PUBLISHED: 02-27-2014
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Angiogenesis is essential during development and in pathological conditions such as chronic inflammation and cancer progression. Inhibition of angiogenesis by targeting vascular endothelial growth factor (VEGF) blocks disease progression, but most patients eventually develop resistance which may result from compensatory signalling pathways. In endothelial cells (ECs), expression of the pro-angiogenic chemokine CXCL12 is regulated by non-canonical nuclear factor (NF)-?B signalling. Here, we report that NF-?B-inducing kinase (NIK) and subsequent non-canonical NF-?B signalling regulate both inflammation-induced and tumour-associated angiogenesis. NIK is highly expressed in endothelial cells (ECs) in tumour tissues and inflamed rheumatoid arthritis synovial tissue. Furthermore, non-canonical NF-?B signalling in human microvascular ECs significantly enhanced vascular tube formation, which was completely blocked by siRNA targeting NIK. Interestingly, Nik(-/-) mice exhibited normal angiogenesis during development and unaltered TNF?- or VEGF-induced angiogenic responses, whereas angiogenesis induced by non-canonical NF-?B stimuli was significantly reduced. In addition, angiogenesis in experimental arthritis and a murine tumour model was severely impaired in these mice. These studies provide evidence for a role of non-canonical NF-?B signalling in pathological angiogenesis, and identify NIK as a potential therapeutic target in chronic inflammatory diseases and tumour neoangiogenesis. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Early start and stop of biologics: has the time come?
BMC Med
PUBLISHED: 01-14-2014
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Despite considerable advances in the management of rheumatoid arthritis, results are still not satisfactory for all patients. The treatment goal in rheumatoid arthritis is remission, and there currently are numerous conventional and biological medications available to reach this aim. There are also different treatment strategies but with only limited comparative evidence about their efficacies. More patients now achieve remission while on treatment, but it remains elusive in the majority of patients. Treatment-free remission, the ultimate goal of therapy, is only achieved in very few patients; even when this happens, it is most likely due to the natural course of the disease rather than to any specific therapies. Modern treatment is based on the initiation of aggressive therapy as soon as the diagnosis is established, and on modifying or intensifying therapy guided by frequent assessment of disease activity. In this commentary we will discuss the current treatment paradigm as well as the possibility of an induction-maintenance regimen with biological disease-modifying antirheumatic drugs in early rheumatoid arthritis.
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Genetics of rheumatoid arthritis contributes to biology and drug discovery.
Yukinori Okada, Di Wu, Gosia Trynka, Towfique Raj, Chikashi Terao, Katsunori Ikari, Yuta Kochi, Koichiro Ohmura, Akari Suzuki, Shinji Yoshida, Robert R Graham, Arun Manoharan, Ward Ortmann, Tushar Bhangale, Joshua C Denny, Robert J Carroll, Anne E Eyler, Jeffrey D Greenberg, Joel M Kremer, Dimitrios A Pappas, Lei Jiang, Jian Yin, Lingying Ye, Ding-Feng Su, Jian Yang, Gang Xie, Ed Keystone, Harm-Jan Westra, Tonu Esko, Andres Metspalu, Xuezhong Zhou, Namrata Gupta, Daniel Mirel, Eli A Stahl, Dorothée Diogo, Jing Cui, Katherine Liao, Michael H Guo, Keiko Myouzen, Takahisa Kawaguchi, Marieke J H Coenen, Piet L C M van Riel, Mart A F J van de Laar, Henk-Jan Guchelaar, Tom W J Huizinga, Philippe Dieudé, Xavier Mariette, S Louis Bridges, Alexandra Zhernakova, René E M Toes, Paul P Tak, Corinne Miceli-Richard, So-Young Bang, Hye-Soon Lee, Javier Martín, Miguel A González-Gay, Luis Rodriguez-Rodriguez, Solbritt Rantapää-Dahlqvist, Lisbeth Arlestig, Hyon K Choi, Yoichiro Kamatani, Pilar Galán, Mark Lathrop, , Steve Eyre, John Bowes, Anne Barton, Niek de Vries, Larry W Moreland, Lindsey A Criswell, Elizabeth W Karlson, Atsuo Taniguchi, Ryo Yamada, Michiaki Kubo, Jun S Liu, Sang-Cheol Bae, Jane Worthington, Leonid Padyukov, Lars Klareskog, Peter K Gregersen, Soumya Raychaudhuri, Barbara E Stranger, Philip L De Jager, Lude Franke, Peter M Visscher, Matthew A Brown, Hisashi Yamanaka, Tsuneyo Mimori, Atsushi Takahashi, Huji Xu, Timothy W Behrens, Katherine A Siminovitch, Shigeki Momohara, Fumihiko Matsuda, Kazuhiko Yamamoto, Robert M Plenge.
Nature
PUBLISHED: 01-07-2014
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A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ?10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2 - 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses--as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes--to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
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Integration of sequence data from a Consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene.
PLoS ONE
PUBLISHED: 01-01-2014
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Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2 × 10(-6)). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted.
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Safety with ocrelizumab in rheumatoid arthritis: results from the ocrelizumab phase III program.
PLoS ONE
PUBLISHED: 01-01-2014
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The objective was to determine the safety of ocrelizumab (OCR) in patients with rheumatoid arthritis (RA).
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Tie2 signaling cooperates with TNF to promote the pro-inflammatory activation of human macrophages independently of macrophage functional phenotype.
PLoS ONE
PUBLISHED: 01-01-2014
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Angiopoietin (Ang) -1 and -2 and their receptor Tie2 play critical roles in regulating angiogenic processes during development, homeostasis, tumorigenesis, inflammation and tissue repair. Tie2 signaling is best characterized in endothelial cells, but a subset of human and murine circulating monocytes/macrophages essential to solid tumor formation express Tie2 and display immunosuppressive properties consistent with M2 macrophage polarization. However, we have recently shown that Tie2 is strongly activated in pro-inflammatory macrophages present in rheumatoid arthritis patient synovial tissue. Here we examined the relationship between Tie2 expression and function during human macrophage polarization. Tie2 expression was observed under all polarization conditions, but was highest in IFN-? and IL-10 -differentiated macrophages. While TNF enhanced expression of a common restricted set of genes involved in angiogenesis and inflammation in GM-CSF, IFN-? and IL-10 -differentiated macrophages, expression of multiple chemokines and cytokines, including CXCL3, CXCL5, CXCL8, IL6, and IL12B was further augmented in the presence of Ang-1 and Ang-2, via Tie2 activation of JAK/STAT signaling. Conditioned medium from macrophages stimulated with Ang-1 or Ang-2 in combination with TNF, sustained monocyte recruitment. Our findings suggest a general role for Tie2 in cooperatively promoting the inflammatory activation of macrophages, independently of polarization conditions.
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MRP8/14 serum levels as a strong predictor of response to biological treatments in patients with rheumatoid arthritis.
Ann. Rheum. Dis.
PUBLISHED: 12-04-2013
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One-third of rheumatoid arthritis (RA) patients treated with biological therapy show lack of response. The use of predictive biomarkers to identify responders to treatment may provide guidance in optimising treatment strategies and reduce unnecessary side effects and costs.
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Local Synovial Engagement of Angiogenic TIE-2 Is Associated With the Development of Persistent Erosive Rheumatoid Arthritis in Patients With Early Arthritis.
Arthritis Rheum.
PUBLISHED: 08-29-2013
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To examine the role of vascular endothelial growth factor (VEGF) and angiopoietin signaling in the diagnosis and disease outcome of patients with early arthritis.
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FMS-related tyrosine kinase 3 ligand (Flt3L)/CD135 axis in rheumatoid arthritis.
Arthritis Res. Ther.
PUBLISHED: 07-25-2013
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The FMS-related tyrosine kinase 3 ligand (Flt3L)/CD135 axis plays a fundamental role in proliferation and differentiation of dendritic cells (DCs). As DCs play an important role in rheumatoid arthritis (RA) immunopathology we studied in detail the Flt3L/CD135 axis in RA patients.
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Undifferentiated spondyloarthritis vs ankylosing spondylitis and psoriatic arthritis: a real-life prospective cohort study of clinical presentation and response to treatment.
Rheumatology (Oxford)
PUBLISHED: 07-16-2013
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SpA is a phenotypically heterogeneous disease, with AS and PsA as its best studied subtypes. This study aimed to investigate whether, despite a different phenotypic presentation, patients with undifferentiated SpA (uSpA) have similar disease activity and response to treatment to those with AS and PsA.
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Tumor necrosis factor inhibition modulates thrombospondin-1 expression in human inflammatory joint disease through altered NR4A2 activity.
Am. J. Pathol.
PUBLISHED: 06-19-2013
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We examined thrombospondin-1 (THBS1, alias TSP-1) expression in human synovial tissue (ST) during the resolution phase of chronic inflammation and elucidated its transcriptional regulation by the orphan receptor 4A2 (NR4A2). In vivo, rheumatoid arthritis (RA) serum and ST revealed altered expression levels and tissue distribution of TSP-1. After anti-tumor necrosis factor therapy, a reciprocal relationship between TSP-1 and NR4A2 expression levels was measured in patients with clinical and ST responses to biological treatment. In vitro, primary RA fibroblast-like synoviocytes (FLSs) expressed minimal TSP-1 mRNA levels with high transcript levels of NR4A2, vascular endothelial growth factor (VEGF), and IL-8 measured. Hypoxic modulation of RA FLSs resulted in inverse expression levels of TSP-1 compared with NR4A2, IL-8, and VEGF. Ectopic NR4A2 expression led to reduced TSP-1 mRNA and protein levels with concomitant increases in proangiogenic mediators. NR4A2 transcriptional activity, independent of DNA binding, repressed the hTSP-1 promoter leading to reduced mRNA and protein release in immortalized K4IM FLSs. Bioinformatic and deletion studies identified a 5 region of the TSP-1 promoter repressed by NR4A2 and proangiogenic transcription factors, including NF-?B and Ets1/2. Stable depletion of NR4A2 levels resulted in a shift in the TSP-1/VEGF expression ratio. Thus, modulation of TSP-1 expression is achieved through anti-tumor necrosis factor therapy effects on specific transcriptional networks, suggesting that enhanced TSP-1 expression may help restore tissue homeostasis during resolution of inflammation.
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How to perform and analyse synovial biopsies.
Best Pract Res Clin Rheumatol
PUBLISHED: 06-05-2013
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Although most of the rheumatologic diseases can be diagnosed based on clinical examination combined with additional laboratory and radiographic tests, histological examination of synovial tissue may lead to the correct diagnosis and adjustment of therapy when neoplastic or granulomatous disease, deposition disease or infection in spite of negative synovial fluid culture is suspected. For research purposes synovial tissue analysis is used to investigate the pathological changes of the synovium in studies aimed at elucidating the aetiology and pathogenetic mechanisms involved in arthritis. In addition, the use of synovial biomarkers has been shown to be instrumental in the developmental process of new therapeutics. In this chapter, several minimally invasive techniques for acquiring synovial tissue samples, handling of the tissue and the analysis thereof are described.
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Immunoglobulin G4+ clones identified by next-generation sequencing dominate the B cell receptor repertoire in immunoglobulin G4 associated cholangitis.
Hepatology
PUBLISHED: 05-08-2013
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Immunoglobulin G4 (IgG4)-associated cholangitis (IAC) is a manifestation of the recently discovered idiopathic IgG4-related disease. The majority of patients have elevated serum IgG4 levels and/or IgG4-positive B-cell and plasma cell infiltrates in the affected tissue. We hypothesized that clonally expanded, class-switched IgG4-positive B cells and plasma cells could be causal to these poorly understood phenomena. In a prospective cohort of six consecutive IAC patients, six healthy controls, and six disease controls, we used a novel next-generation sequencing approach to screen the B-cell receptor (BCR) repertoires, in blood as well as in affected tissue, for IgG4+ clones. A full repertoire analysis of the BCR heavy chain was performed using GS-FLX/454 and customized bioinformatics algorithms (>10,000 sequences/sample; clones with a frequency ?0.5% were considered dominant). We found that the most dominant clones within the IgG+ BCRheavy repertoire of the peripheral blood at baseline were IgG4+ only in IAC patients. In all IAC patients, but none of the controls, IgG4+ BCR clones were among the 10 most dominant BCR clones of any immunoglobulin isotype (IgA, IgD, IgM, and IgG) in blood. The BCR repertoires of the duodenal papilla comprised the same dominant IgG4+ clones as the paired peripheral blood samples. In all IAC patients, after 4 and 8 weeks of corticosteroid therapy the contribution of these IgG4+ clones to the IgG+ repertoire as well as to total BCR repertoire was marginalized, mirroring sharp declines in serum IgG4 titers and regression of clinical symptoms. Conclusion: The novel finding of highly abundant IgG4+ BCR clones in blood and tissue of patients with active IAC, which disappear upon corticosteroid treatment, suggests that specific B cell responses are pivotal to the pathogenesis of IAC. (HEPATOLOGY 2013 ).
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Peripheral joint inflammation in early onset spondyloarthritis is not specifically related to enthesitis.
Ann. Rheum. Dis.
PUBLISHED: 04-25-2013
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OBJECTIVES: A pivotal MRI study of knee arthritis indicated that enthesitis was more frequently observed in established spondyloartritis (SpA) than rheumatoid arthritis (RA). Subsequent MRI and ultrasound studies, however, failed to consistently demonstrate primary synovitis in RA versus primary enthesitis in SpA. Therefore, the current study aimed to reassess enthesitis versus synovitis in peripheral arthritis by a combined imaging and histopathological study in early untreated disease. METHODS: MRI and mini-arthroscopic synovial biopsy sampling were performed in 41 patients with early untreated knee or ankle arthritis, who were diagnosed with SpA (n=13), RA (n=20) or crystal arthropathy (n=8) at follow-up. MRI evaluation of enthesitis and synovitis, and immunohistochemical characterisation of synovitis were performed by two observers blinded to diagnosis. RESULTS: MRI showed similar prevalence of perientheseal fluid/oedema (67% vs 75%), perientheseal bone marrow oedema (0% vs 10%) and entheseal enhancement (46% vs 47%) in SpA versus RA, respectively. The number and distribution of affected entheseal sites were not different between both diseases. The MRI synovitis score was significantly higher in SpA (median 1.4; IQR 1.1-1.5) compared with RA (median 0.5; IQR 0.0-1.3) (p=0.028). Synovial histopathology showed a numerical increase in infiltrating cells in SpA versus RA synovitis which reached significance for CD163 macrophages in the synovial sublining (p=0.030). There were no differences compared with the crystal arthropathy control group. CONCLUSIONS: Enthesitis on MRI is not a specific feature of peripheral arthritis in recent onset SpA versus RA. Synovitis is prominent in both diseases as evaluated by MRI and immunohistochemistry.
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Progression of structural damage is not related to rituximab serum levels in rheumatoid arthritis patients.
Rheumatology (Oxford)
PUBLISHED: 04-24-2013
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The most cost-effective dosing regimen for rituximab treatment in RA is currently unknown. The objective of this study is to determine whether low rituximab serum levels are associated with progression of structural damage in RA patients.
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Pro-atherogenic lipid changes and decreased hepatic LDL receptor expression by tocilizumab in rheumatoid arthritis.
Atherosclerosis
PUBLISHED: 04-05-2013
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Blocking the interleukin-6 pathway by tocilizumab (TCZ) has been associated with changes in the lipoprotein profile, which could adversely impact cardiovascular (CV) risk in patients with rheumatoid arthritis (RA). In the present study, we addressed the effect of TCZ on lipoproteins in both fasting and non-fasting state in RA patients and tested the effect of TCZ on LDL receptor (LDLr) expression in vitro.
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Efficacy and safety of epratuzumab in patients with moderate/severe flaring systemic lupus erythematosus: results from two randomized, double-blind, placebo-controlled, multicentre studies (ALLEVIATE) and follow-up.
Rheumatology (Oxford)
PUBLISHED: 03-28-2013
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To evaluate epratuzumab treatment in patients with moderately-to-severely active SLE in two international, randomized, controlled trials (ALLEVIATE-1 and -2) and an open-label extension study (SL0006).
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Disease-specific and inflammation-independent stromal alterations in spondylarthritis synovitis.
Arthritis Rheum.
PUBLISHED: 03-19-2013
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The molecular processes driving the distinct patterns of synovial inflammation and tissue remodeling in spondylarthritis (SpA) as compared to rheumatoid arthritis (RA) remain largely unknown. Therefore, we aimed to identify novel and unsuspected disease-specific pathways in SpA by a systematic and unbiased synovial gene expression analysis.
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Anti-TNF therapy reduces serum levels of chemerin in rheumatoid arthritis: a new mechanism by which anti-TNF might reduce inflammation.
PLoS ONE
PUBLISHED: 01-29-2013
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Chemerin is a specific chemoattractant for macrophages and dendritic cells (DC). In addition, it can rapidly stimulate macrophage adhesion to extracellular matrix proteins and adhesion molecules and is able to activate fibroblast-like synoviocytes (FLS), suggesting a role in the pathogenesis of rheumatoid arthritis (RA). Chemerin is also an adipocytokine that has been related to the inflammatory state of endothelial cells and as such could be involved in the changes in endothelial cells in RA and perhaps increased cardiovascular morbidity. We investigated whether anti-Tumor Necrosis Factor (TNF) treatment affects chemerin levels.
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Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis.
PLoS Genet.
PUBLISHED: 01-13-2013
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Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (?DAS) in the etanercept subset of patients (P = 8 × 10(-8)), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3 UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1 × 10(-11) in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ?DAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry.
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Presence and role of anti-citrullinated protein antibodies in experimental arthritis models.
Arthritis Rheum.
PUBLISHED: 01-03-2013
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Anti-citrullinated protein antibodies (ACPAs) are the serologic hallmark of rheumatoid arthritis. Functional studies on the role of ACPAs in experimental arthritis have yielded conflicting results, and therefore the present study was undertaken to assess systematically whether citrullinated proteins can really induce ACPAs and modulate arthritis in mice.
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Brief report: a phase IIa, randomized, double-blind, placebo-controlled trial of apilimod mesylate, an interleukin-12/interleukin-23 inhibitor, in patients with rheumatoid arthritis.
Arthritis Rheum.
PUBLISHED: 12-14-2011
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To investigate the safety, tolerability, pharmacokinetics, and efficacy of apilimod mesylate, an oral interleukin-12 (IL-12)/IL-23 inhibitor, in patients with rheumatoid arthritis (RA).
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[Tailored therapy for rheumatic disease within reach].
Ned Tijdschr Geneeskd
PUBLISHED: 11-17-2011
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Personalised medicine has the potential to increase therapeutic effectiveness, reduce side effects and lower cost. This approach has recently taken off in oncology where different malignancies may be treated with specific drugs based on genetic biomarkers or other tumour characteristics. This type of tailored therapy could also be developed for immune-mediated inflammatory disease, for which rheumatoid arthritis (RA) may serve as a prototype. While novel treatments are able to halt or even prevent disease progression, not all RA patients respond, and stratification of patient groups is needed. The identification of biomarkers predictive of the clinical response to specific treatments in subsets of patients may soon become reality in a variety of diseases.
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Rituximab abrogates joint destruction in rheumatoid arthritis by inhibiting osteoclastogenesis.
Ann. Rheum. Dis.
PUBLISHED: 11-08-2011
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To examine how rituximab may result in the inhibition of joint destruction in rheumatoid arthritis (RA) patients.
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Sustained inhibition of progressive joint damage with rituximab plus methotrexate in early active rheumatoid arthritis: 2-year results from the randomised controlled trial IMAGE.
Ann. Rheum. Dis.
PUBLISHED: 10-19-2011
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In the IMAGEstudy, rituximab plus methotrexate (MTX) inhibited joint damage and improved clinical outcomes at 1 year in MTX-naïve patients with early active rheumatoid arthritis.
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Mycophenolate mofetil but not atorvastatin attenuates atherosclerosis in lupus-prone LDLr(-/-) mice.
Ann. Rheum. Dis.
PUBLISHED: 09-27-2011
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Recent clinical and preclinical studies have demonstrated that systemic lupus erythematosus (SLE) is associated with an increased risk for cardiovascular disease (CVD). However, unlike in the general population, little is known regarding the efficacy of atheroprotective interventions in patients with SLE. The current study aims to determine the benefit of lymphocyte inhibition on reducing the atherosclerotic burden in SLE-susceptible LDLr-deficient mice.
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Histone deacetylase inhibitors suppress rheumatoid arthritis fibroblast-like synoviocyte and macrophage IL-6 production by accelerating mRNA decay.
Ann. Rheum. Dis.
PUBLISHED: 09-27-2011
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Histone deacetylase inhibitors (HDACi) display potent therapeutic efficacy in animal models of arthritis and suppress inflammatory cytokine production in rheumatoid arthritis (RA) synovial macrophages and tissue.
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Synovial tissue analysis for the discovery of diagnostic and prognostic biomarkers in patients with early arthritis.
J. Rheumatol.
PUBLISHED: 09-03-2011
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Rheumatoid arthritis (RA) is a chronic disease of unspecified etiology that is manifest by persistent inflammation of the synovium. Considerable efforts have been undertaken globally to study the microenvironment of the inflamed synovium, with many encouraging and enlightening results that bring us closer to unmasking the precise etiologies of RA. Subsequent to these efforts, it has been discovered that CD68-positive macrophages present in abundance in the synovial sublining of the inflamed synovium rescind with treatments that induce clinical improvement in RA. Examination of serial synovial biopsies is now commonly used for screening purposes during early drug development, and the number of centers able to perform synovial tissue biopsy sampling according to standardized methods is increasing. Having implemented the use of serial synovial tissue biopsies to evaluate the effects of new treatments on the group level in early proof of principle studies, it is the ambition of the OMERACT Synovial Tissue Group to identify synovial diagnostic and prognostic biomarkers that could be used in individual patients. Therefore, we started a prospective study termed the Synoviomics Project aimed at the identification of novel diagnostic and prognostic synovial biomarkers. We will use straightforward and powerful technologies to analyze patient material and assess clinical parameters to identify such biomarkers. These markers may be used in the future to identify patients who are at risk of having persistent and destructive disease and to start tailor-made targeted therapies in an early phase to prevent autonomous disease progression and irreversible joint damage.
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OMERACT 10 Sharp Symposium: important findings in examination of imaging methods for measurement of joint damage in rheumatoid arthritis.
J. Rheumatol.
PUBLISHED: 09-03-2011
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The Sharp Symposium was held at the Outcome Measures in Rheumatology Clinical Trials 2010 meeting (OMERACT 10) in honor of the late John Sharp, consummate rheumatologist and researcher. The symposium focused on the status of current scoring methods in radiography, magnetic resonance imaging (MRI), and ultrasound (US) in rheumatoid arthritis (RA), as well as on the use of soluble and tissue biomarkers in RA, with the aim of updating recommendations regarding methods for enhanced detection, monitoring, and prediction of joint damage in clinical trials.
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A personalized medicine approach to biologic treatment of rheumatoid arthritis: a preliminary treatment algorithm.
Rheumatology (Oxford)
PUBLISHED: 09-02-2011
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RA is a syndrome consisting of different pathogenetic subsets in which distinct molecular mechanisms may drive common final pathways. Recent work has provided proof of principle that biomarkers may be identified predictive of the response to targeted therapy. Based on new insights, an initial treatment algorithm is presented that may be used to guide treatment decisions in patients who have failed one TNF inhibitor. Key questions in this algorithm relate to the question whether the patient is a primary vs a secondary non-responder to TNF blockade and whether the patient is RF and/or anti-citrullinated peptide antibody positive. This preliminary algorithm may contribute to more cost-effective treatment of RA, and provides the basis for more extensive algorithms when additional data become available.
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Advancements in adeno-associated viral gene therapy approaches: exploring a new horizon.
F1000 Med Rep
PUBLISHED: 09-01-2011
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Gene therapy is a promising new therapeutic strategy that has been explored in a wide variety of diseases, ranging from cancer to hemophilia, and ocular disorders to autoimmune diseases, among others. Proof of concept of gene transfer approaches has been shown in over 100 studies of animal models of disease, although only a few are under development for clinical application. The US Food and Drug Administration and the European Medicines Agency have not approved any viral human gene therapy products for sale so far, but the amount of gene-related research and development occurring in the United States and Europe continues to grow at a fast rate. This review summarizes the current status of developments in the field of viral gene therapy using adeno-associated virus as a vector, with a special focus on arthritis. For rheumatoid arthritis, and to a lesser extent for other immune-related inflammatory disorders, several cell and gene transfer approaches have been investigated at the preclinical level and a few have been implemented in clinical trials. Finally, both the potential and the hurdles that are faced during development of a viral gene therapy through to its clinical application are discussed.
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Function of histone deacetylase inhibitors in inflammation.
Crit. Rev. Immunol.
PUBLISHED: 07-12-2011
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Histone deacetylases (HDACs) display multi-faceted roles in coordinating the interaction of intracellular signaling pathways with chromatin remodeling and transcription factor function to finely specify gene alterations and maintenance of gene expression during cellular activation, proliferation, and differentiation. These processes, epigenetic and non-epigenetic, are critical to the development of both the adaptive and innate arms of the mammalian immune system, and the measured initiation and resolution of immune responses. Pharmacological modulators of HDAC activity have demonstrated uniformly potent anti-inflammatory effects in experimental animal models of these diseases, in relevant immune and stromal cell populations from patients, as well as initial successes in the clinic. Recent studies have identified key roles for specific HDACs in regulating immune function, as well as alterations in HDAC expression and function in a number of immune-mediated inflammatory diseases (IMIDs), which may contribute to pathology in these diseases. Here, we review recent advances in our understanding of HDAC function in the immune system, their contribution to IMIDs, and the therapeutic potential of altering HDAC activity in IMIDs.
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Experiences and needs for work participation in employees with rheumatoid arthritis treated with anti-tumour necrosis factor therapy.
Disabil Rehabil
PUBLISHED: 06-15-2011
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To investigate the experiences and needs with respect to work participation of employees with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor (TNF) therapy.
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Animal models for arthritis: innovative tools for prevention and treatment.
Ann. Rheum. Dis.
PUBLISHED: 05-30-2011
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The development of novel treatments for rheumatoid arthritis (RA) requires the interplay between clinical observations and studies in animal models. Given the complex molecular pathogenesis and highly heterogeneous clinical picture of RA, there is an urgent need to dissect its multifactorial nature and to propose new strategies for preventive, early and curative treatments. Research on animal models has generated new knowledge on RA pathophysiology and aetiology and has provided highly successful paradigms for innovative drug development. Recent focus has shifted towards the discovery of novel biomarkers, with emphasis on presymptomatic and emerging stages of human RA, and towards addressing the pathophysiological mechanisms and subsequent efficacy of interventions that underlie different disease variants. Shifts in the current paradigms underlying RA pathogenesis have also led to increased demand for new (including humanised) animal models. There is therefore an urgent need to integrate the knowledge on human and animal models with the ultimate goal of creating a comprehensive pathogenesis map that will guide alignment of existing and new animal models to the subset of disease they mimic. This requires full and standardised characterisation of all models at the genotypic, phenotypic and biomarker level, exploiting recent technological developments in omics profiling and computational biology as well as state of the art bioimaging. Efficient integration and dissemination of information and resources as well as outreach to the public will be necessary to manage the plethora of data accumulated and to increase community awareness and support for innovative animal model research in rheumatology.
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Advances in rheumatology: new targeted therapeutics.
Arthritis Res. Ther.
PUBLISHED: 05-25-2011
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Treatment of inflammatory arthritides - including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis - has seen much progress in recent years, partially due to increased understanding of the pathogenesis of these diseases at the cellular and molecular levels. These conditions share some common mechanisms. Biologic therapies have provided a clear advance in the treatment of rheumatological conditions. Currently available TNF-targeting biologic agents that are licensed for at east one of the above-named diseases are etanercept, infliximab, adalimumab, golimumab, and certolizumab. Biologic agents with a different mechanism of action have also been approved in rheumatoid arthritis (rituximab, abatacept, and tocilizumab). Although these biologic agents are highly effective, there is a need for improved management strategies. There is also a need for education of family physicians and other healthcare professionals in the identification of early symptoms of inflammatory arthritides and the importance of early referral to rheumatologists for diagnosis and treatment. Also, researchers are developing molecules - for example, the Janus kinase inhibitor CP-690550 (tofacitinib) and the spleen tyrosine kinase inhibitor R788 (fostamatinib) - to target other aspects of the inflammatory cascade. Initial trial results with new agents are promising, and, in time, head-to-head trials will establish the best treatment options for patients. The key challenge is identifying how best to integrate these new, advanced therapies into daily practice.
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Persistent activation of dendritic cells after resolution of allergic airway inflammation breaks tolerance to inhaled allergens in mice.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 05-11-2011
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Polysensitization of patients who are allergic is a common feature. The underlying immunologic mechanism is not clear. The maturation status of dendritic cells (DCs) is considered to be important for priming naive T cells in the draining lymph nodes. We hypothesized that chronic airway inflammation can induce an enhanced maturation of airway DCs and facilitate subsequent priming to neoallergens.
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TNF blockade abrogates the induction of T cell-dependent humoral responses in an allotransplantation model.
J. Leukoc. Biol.
PUBLISHED: 05-11-2011
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TNF blockade modulates many aspects of the immune response and is commonly used in a wide array of immune-mediated inflammatory diseases. As anti-TNF induces anti-dsDNA IgM antibodies but not other antinuclear reactivities in human arthritis, we investigated here the effect of TNF blockade on the induction of TD humoral responses using cardiac allograft and xenograft models. A single injection of an anti-rat TNF antibody in LEW.1A recipients grafted with congenic LEW.1W hearts almost completely abrogated the induction of IgM and IgG alloantibodies. This was associated with decreased Ig deposition and leukocyte infiltration in the graft at Day 5. TNF blockade did not affect germinal-center formation in the spleen or expression of Th1/Th2 cytokines, costimulatory and regulatory molecules, and TLRs in spleen and graft of the recipient animals. Clinically, the abrogation of the induction of the alloantibodies was associated with a marked prolongation of graft survival. In contrast, anti-TNF did not alter acute xenograft rejection mediated by TI antibodies in a hamster-to-rat model. Taken together, these data indicate that TNF blockade abrogates the induction of TD humoral responses and accordingly, may have a beneficial effect in antibody-mediated inflammatory pathologies.
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A functional variant in microRNA-146a promoter modulates its expression and confers disease risk for systemic lupus erythematosus.
PLoS Genet.
PUBLISHED: 04-30-2011
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Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic predisposition, characterized by an upregulated type I interferon pathway. MicroRNAs are important regulators of immune homeostasis, and aberrant microRNA expression has been demonstrated in patients with autoimmune diseases. We recently identified miR-146a as a negative regulator of the interferon pathway and linked the abnormal activation of this pathway to the underexpression of miR-146a in SLE patients. To explore why the expression of miR-146a is reduced in SLE patients, we conducted short parallel sequencing of potentially regulatory regions of miR-146a and identified a novel genetic variant (rs57095329) in the promoter region exhibiting evidence for association with SLE that was replicated independently in 7,182 Asians (P(meta)?=?2.74×10(-8), odds ratio?=?1.29 [1.18-1.40]). The risk-associated G allele was linked to reduced expression of miR-146a in the peripheral blood leukocytes of the controls. Combined functional assays showed that the risk-associated G allele reduced the protein-binding affinity and activity of the promoter compared with those of the promoter containing the protective A allele. Transcription factor Ets-1, encoded by the lupus-susceptibility gene ETS1, identified in recent genome-wide association studies, binds near this variant. The manipulation of Ets-1 levels strongly affected miR-146a promoter activity in vitro; and the knockdown of Ets-1, mimicking its reduced expression in SLE, directly impaired the induction of miR-146a. We also observed additive effects of the risk alleles of miR-146a and ETS1. Our data identified and confirmed an association between a functional promoter variant of miR-146a and SLE. This risk allele had decreased binding to transcription factor Ets-1, contributing to reduced levels of miR-146a in SLE patients.
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Synovitis in psoriatic arthritis: immunohistochemistry, comparisons with rheumatoid arthritis, and effects of therapy.
Curr Rheumatol Rep
PUBLISHED: 04-20-2011
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Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy associated with psoriasis that affects the peripheral joints, spine, and entheses. Most patients with PsA present with peripheral synovitis of the oligoarticular or polyarticular subtype. As one of the targets of this disease, studies on the synovium may provide insight into the mechanisms involved in this condition. Key findings from the available studies comparing synovial tissue of PsA and rheumatoid arthritis patients are discussed in this review. Also, changes in the synovial infiltrate, expression of proinflammatory cytokines and adhesion molecules, and vascularity in synovial tissue after treatment with various medications are addressed. Finally, a model for proof-of-principle study design using serial synovial biopsies is described, which could be used to predict clinical (in)efficacy in early clinical trial design in PsA.
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The value of rheumatoid factor and anti-citrullinated protein antibodies as predictors of response to infliximab in rheumatoid arthritis: an exploratory study.
Rheumatology (Oxford)
PUBLISHED: 03-30-2011
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It remains unclear whether autoantibodies are useful biomarkers to tailor the choice of biological treatment in RA. We investigated the relationship between the presence and levels of different RF and ACPA isotypes and the response to TNF blockade in an exploratory study.
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Synovial tissue response to treatment in rheumatoid arthritis.
Open Rheumatol J
PUBLISHED: 03-27-2011
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The recognition of the synovial tissue, as the primary target of inflammation in RA, has driven research in this field, not only to clarify the disease pathogenesis but also to evaluate local changes in response to treatment. Special interest has been given to the identification of sensitive synovial biomarkers that could be of help in demonstrating proof of principle in early stages of drug development. Synovial sublining macrophages have been shown to correlate with scores for disease activity in cross-sectional studies. Moreover, decreased disease activity as measured by the disease activity score evaluated in 28 joints (DAS28) after effective treatment, has consistently been associated with a reduction of the number of CD68+ synovial sublining macrophages across different therapies. This observation highlights a possible final common pathway in the mechanism of action of various therapies and supports the notion that macrophages have a central role in RA pathogenesis.When considering experimental therapies, the study of serial synovial biopsies in relatively small numbers of patients, in the context of proof of principle trials, successfully distinguished between effective and ineffective treatments. This attractive approach can be used during early drug development for screening proposes, supporting which new treatments have higher probability to be beneficial in a large scale clinical trial.In this paper we review the effects of RA treatments on the synovial tissue, including targeted therapies, with particular attention to their effect on synovial biomarkers.
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Inflammatory memories: is epigenetics the missing link to persistent stromal cell activation in rheumatoid arthritis?
Autoimmun Rev
PUBLISHED: 03-12-2011
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Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction. Synovial fibroblasts are recognized as key cells in the pathogenesis of RA since they attract and activate immune cells and produce matrix degrading enzymes. Most notably synovial fibroblasts from patients with RA are stably activated and produce high levels of disease-promoting molecules without further stimulation by immune cells. Accumulating data suggest that epigenetic changes in stromal cell populations might be crucially involved in the pathology of RA and other chronic inflammatory diseases. In the current review, we discuss the mechanisms by which epigenetic changes might cause the stable activation of synovial fibroblasts in RA and how changes in the epigenome might alter immune function and inflammatory response and thereby promote the development of chronic diseases.
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Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis.
Ann. Rheum. Dis.
PUBLISHED: 03-06-2011
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Since initial approval for the treatment of rheumatoid arthritis (RA), rituximab has been evaluated in clinical trials involving various populations with RA. Information has also been gathered from registries. This report therefore updates the 2007 consensus document on the use of rituximab in the treatment of RA.
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The costimulatory molecule CD27 maintains clonally diverse CD8(+) T cell responses of low antigen affinity to protect against viral variants.
Immunity
PUBLISHED: 02-21-2011
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CD70 and CD27 are costimulatory molecules that provide essential signals for the expansion and differentiation of CD8(+) T cells. Here, we show that CD27-driven costimulation lowered the threshold of T cell receptor activation on CD8(+) T cells and enabled responses against low-affinity antigens. Using influenza infection to study in vivo consequences, we found that CD27-driven costimulation promoted a CD8(+) T cell response of overall low affinity. These qualitative effects of CD27 on T cell responses were maintained into the memory phase. On a clonal level, CD27-driven costimulation established a higher degree of variety in memory CD8(+) T cells. The benefit became apparent when mice were reinfected, given that CD27 improved CD8(+) T cell responses against reinfection with viral variants, but not with identical virus. We propose that CD27-driven costimulation is a strategy to generate memory clones that have potential reactivity to a wide array of mutable pathogens.
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Restoring the balance of the autonomic nervous system as an innovative approach to the treatment of rheumatoid arthritis.
Mol. Med.
PUBLISHED: 02-17-2011
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The immunomodulatory effect of the autonomic nervous system has raised considerable interest over the last decades. Studying the influence on the immune system and the role in inflammation of the sympathetic as well as the parasympathetic nervous system not only will increase our understanding of the mechanism of disease, but also could lead to the identification of potential new therapeutic targets for chronic immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA). An imbalanced autonomic nervous system, with a reduced parasympathetic and increased sympathetic tone, has been a consistent finding in RA patients. Studies in animal models of arthritis have shown that influencing the sympathetic (via ?- and ?-adrenergic receptors) and the parasympathetic (via the nicotinic acetylcholine receptor ?7nAChR or by electrically stimulating the vagus nerve) nervous system can have a beneficial effect on inflammation markers and arthritis. The immunosuppressive effect of the parasympathetic nervous system appears less ambiguous than the immunomodulatory effect of the sympathetic nervous system, where activation can lead to increased or decreased inflammation depending on timing, doses and kind of adrenergic agent used. In this review we will discuss the current knowledge of the role of both the sympathetic (SNS) and parasympathetic nervous system (PNS) in inflammation with a special focus on the role in RA. In addition, potential antirheumatic strategies that could be developed by targeting these autonomic pathways are discussed.
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Patient global assessment in psoriatic arthritis: a multicenter GRAPPA and OMERACT study.
J. Rheumatol.
PUBLISHED: 02-15-2011
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During OMERACT 8, delegates selected patient global assessment (PGA) of disease as a domain to be evaluated in randomized controlled trials in psoriatic arthritis (PsA). This study assessed the reliability of the PGA, measured by means of 0-100 mm visual analog scale (VAS), and the additional utility of separate VAS scales for joints (PJA) and skin (PSA).
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Effect of soluble ICAM-1 on a Sjögrens syndrome-like phenotype in NOD mice is disease stage dependent.
PLoS ONE
PUBLISHED: 02-10-2011
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Intercellular adhesion molecule-1 (ICAM-1) is involved in migration and co-stimulation of T and B cells. Membrane bound ICAM-1 is over expressed in the salivary glands (SG) of Sjögrens syndrome (SS) patients and has therefore been proposed as a potential therapeutic target. To test the utility of ICAM-1 as a therapeutic target, we used local gene therapy in Non Obese Diabetic (NOD) mice to express soluble (s)ICAM-1 to compete with membrane bound ICAM-1 for binding with its receptor. Therapy was given prior to and just after the influx of immune cells into the SG.
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Why CCR2 and CCR5 blockade failed and why CCR1 blockade might still be effective in the treatment of rheumatoid arthritis.
PLoS ONE
PUBLISHED: 02-06-2011
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The aim of this study was to provide more insight into the question as to why blockade of CCR1, CCR2, and CCR5 may have failed in clinical trials in rheumatoid arthritis (RA) patients, using an in vitro monocyte migration system model.
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Altered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation.
Arthritis Rheum.
PUBLISHED: 02-01-2011
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MicroRNA (miRNA) are recognized as important regulators of a variety of fundamental biologic processes. Previously, we described increased expression of miR-155 and miR-146a in rheumatoid arthritis (RA) and showed a repressive effect of miR-155 on matrix metalloproteinase (MMP) expression in RA synovial fibroblasts (RASFs). The present study was undertaken to examine alterations in expression of miR-203 in RASFs and analyze its role in fibroblast activation.
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Body mass index and clinical response to infliximab in rheumatoid arthritis.
Arthritis Rheum.
PUBLISHED: 02-01-2011
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Adipose tissue has immunomodulating effects in rheumatoid arthritis (RA), although the exact role is, at present, unclear. The purpose of this study was to determine whether body mass index (BMI) affects response to infliximab in RA patients investigated prospectively.
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Prostaglandin E2 synthesizing enzymes in rheumatoid arthritis B cells and the effects of B cell depleting therapy on enzyme expression.
PLoS ONE
PUBLISHED: 01-27-2011
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B cells may play an important role in promoting immune activation in the rheumatoid synovium and can produce prostaglandin E(2) (PGE(2)) when activated. In its turn, PGE(2) formed by cyclooxygenase (COX) and microsomal prostaglandin E(2) synthase 1 (MPGES1) contributes to the rheumatoid arthritis (RA) pathological process. Therapeutic depletion of B cells results in important improvement in controlling disease activity in rheumatoid patients. Therefore we investigated the expression of PGE(2) pathway enzymes in RA B cells and evaluated the effects of B cell depleting therapy on their expression in RA tissue.
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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.