PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (2137)
 

Clipboard (0)
None
Journals
Year of Publication
more »
Document Types
1.  The ACR20 and defining a threshold for response in rheumatic diseases: too much of a good thing 
In the past 20 years great progress has been made in the development of multidimensional outcome measures (such as the Disease Activity Score and ACR20) to evaluate treatments in rheumatoid arthritis, a process disseminated throughout rheumatic diseases. These outcome measures have standardized the assessment of outcomes in trials, making it possible to evaluate and compare the efficacy of treatments. The methodologic advances have included the selection of pre-existing outcome measures that detected change in a sensitive fashion (in rheumatoid arthritis, this was the Core Set Measures). These measures were then combined into a single multidimensional outcome measure and such outcome measures have been widely adopted in trials and endorsed by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) and regulatory agencies. The secular improvement in treatment for patients with rheumatoid arthritis has been facilitated in part by these major methodologic advancements. The one element of this effort that has not optimized measurement of outcomes nor made it easier to detect the effect of treatments is the dichotomization of continuous measures of response, creating responders and non-responder definitions (for example, ACR20 responders; EULAR good responders). Dichotomizing response sacrifices statistical power and eliminates variability in response. Future methodologic work will need to focus on improving multidimensional outcome measurement without arbitrarily characterizing some patients as responders while labeling others as non-responders.
doi:10.1186/ar4428
PMCID: PMC3978644  PMID: 24387346
2.  Messages from the morgue to rheumatology: from Chagas disease to giant cell arteritis 
Autopsy rates have fallen from over 50% to less than 10% in recent decades. The drastic decline creates uncertainty regarding causes of death and has negative effects for research, training, and patient safety, despite advances in imaging and laboratory testing. Rheumatology is as much at a loss as other specialties. Examples are given of important missed diagnoses revealed only at autopsy.
doi:10.1186/ar4418
PMCID: PMC3979100  PMID: 24364914
4.  Low production of reactive oxygen species in granulocytes is associated with organ damage in systemic lupus erythematosus 
Arthritis Research & Therapy  2014;16(3):R120.
Introduction
Polymorphonuclear leukocytes (PMN) are main effector cells in the acute immune response. While the specific role of PMN in systemic lupus erythematosus (SLE) and autoimmunity is still unclear, their importance in chronic inflammation is gaining more attention. Here we investigate aspects of function, bone marrow release and activation of PMN in patients with SLE.
Methods
The following PMN functions and subsets were evaluated using flow cytometry; (a) production of reactive oxygen species (ROS) after ex vivo stimulation with phorbol 12-myristate 13-acetate (PMA) or Escherichia coli (E. coli); (b) capacity to phagocytose antibody-coated necrotic cell material; (c) PMN recently released from bone marrow, defined as percentage of CD10−D16low in peripheral blood, and (d) PMN activation markers; CD11b, CD62L and C5aR.
Results
SLE patients (n = 92) showed lower ROS production compared with healthy controls (n = 38) after activation ex vivo. The ROS production was not associated with corticosteroid dose or other immunotherapies. PMA induced ROS production was significantly reduced in patients with severe disease. In contrast, neither ROS levels after E. coli activation, nor the capacity to phagocytose were associated with disease severity. This suggests that decreased ROS production after PMA activation is a sign of changed PMN behaviour rather than generally impaired functions. The CD10−CD16low phenotype constitute 2% of PMN in peripheral blood of SLE patients compared with 6.4% in controls, indicating a decreased release of PMN from the bone marrow in SLE. A decreased expression of C5aR on PMN was observed in SLE patients, pointing towards in vivo activation.
Conclusions
Our results indicate that PMN from SLE patients have altered function, are partly activated and are released abnormally from bone marrow. The association between low ROS formation in PMN and disease severity is consistent with findings in other autoimmune diseases and might be considered as a risk factor.
doi:10.1186/ar4575
PMCID: PMC4075132  PMID: 24902963
5.  Intrinsic multipotential mesenchymal stromal cell activity in gelatinous Heberden’s nodes in osteoarthritis at clinical presentation 
Arthritis Research & Therapy  2014;16(3):R119.
Introduction
Gelatinous Heberden’s nodes (HNs), also termed synovial cysts, are a common form of generalized osteoarthritis (OA). We sought to determine whether HN cases at clinical presentation contained multipotential stromal cells (MSCs) and to explore whether such cells were more closely related to bone marrow (BM) or synovial fluid (SF) MSCs by transcriptional analysis.
Methods
At clinical presentation, gelatinous material was extracted/extruded from the distal phalangeal joint of OA patients with HNs. From this, plastic adherent cells were culture-expanded for phenotypic and functional characterization and comparison with BM- and SF-MSCs. Mesenchymal related gene expression was studied by using a custom-designed TaqMan Low Density Array to determine transcriptional similarities between different MSC groups and skin fibroblasts.
Results
In all cases, HN material produced MSC-like colonies. Adherent cultures displayed an MSC phenotype (CD29+, CD44+, CD73+, CD81+, and CD90+ and CD14- CD19-, CD31-, CD34-, CD45-, and HLADR-) and exhibited osteogenic, chondrogenic lineage differentiation but weak adipogenesis. Gene cluster analysis showed that HN-MSCs were more closely related to SF- than normal or OA BM-MSCs with significantly higher expression of synovium-related gene markers such as bone morphogenic protein 4 (BMP4), bone morphogenetic protein receptor type 1A (BMPR1A), protein/leucine-rich end leucine-rich repeat protein (PRELP), secreted frizzled-related protein 4 (SFRP4), and tumor necrosis factor alpha-induced protein 6 (TNFAIP6) (P <0.05).
Conclusions
Gelatinous HNs derived from hand OA at clinical presentation contain a population of MSCs that share transcriptional similarities with SF-derived MSCs. Their aberrant entrapment within the synovial cysts may impact on their normal role in joint homeostasis.
doi:10.1186/ar4574
PMCID: PMC4075346  PMID: 24894724
6.  B cell subsets and dysfunction of regulatory B cells in IgG4-related diseases and primary Sjögren’s syndrome: the similarities and differences 
Arthritis Research & Therapy  2014;16(3):R118.
Introduction
IgG4-related disease (IgG4-RD) is a multisystem-involved autoimmune disease. Abnormally activated and differentiated B cells may play important roles. Regulatory B cells (Breg) are newly defined B cell subgroups with immunosuppressive functions. In this study, we investigated the differences of B cell subsets, the expressions of co-stimulatory molecules on B cells, and the function of Breg cells in patients with IgG4-RD, primary Sjögren’s syndrome (pSS) as well as in healthy controls (HC).
Methods
Newly diagnosed IgG4-RD patients (n = 48) were enrolled, 38 untreated pSS patients and 30 healthy volunteers were recruited as disease and healthy controls. To analyze B cell subsets and B cell activity, PBMCs were surface stained and detected by flow cytometry. The function of Breg cells was tested by coculturing isolated CD19 + CD24hiCD38hi Breg cells with purified CD4 + CD25- T cells. Serum cytokines were measured by ELISA and cytometric bead array. Relationship between clinical data and laboratory findings were analyzed as well.
Results
Compared with pSS patients and HC, IgG4-RD patients had a lower frequency of peripheral Breg cells. Interestingly, CD19 + CD24-CD38hi B cell subsets were significantly higher in peripheral B cells from IgG4-RD patients than in pSS patients and HC, which correlated with serum IgG4 levels. The expression of BAFF-R and CD40 on B cells was significantly lower in IgG4-RD patients compared with those in pSS patients and HC. Unlike HC, Breg cells from pSS patients lacked suppressive functions.
Conclusions
B cells in patients with IgG4-RD and pSS display a variety of abnormalities, including disturbed B cell subpopulations, abnormal expression of key signaling molecules, co-stimulatory molecules, and inflammatory cytokines. In addition, a significantly increased B cell subset, CD19 + CD24-CD38hi B cells, may play an important role in the pathogenesis of IgG4-RD.
doi:10.1186/ar4571
PMCID: PMC4075418  PMID: 24887143
7.  Behçet’s disease in HLA-B*51 negative Germans and Turks shows association with HLA-Bw4-80I 
Arthritis Research & Therapy  2014;16(3):R116.
Introduction
Behçet’s disease (BD) as systemic vasculitis of unknown etiology is associated with HLA-B*51 in European and Asian populations. HLA-A*26 was claimed as an additional BD susceptibility marker in Japanese and Greek patients. This study was performed to test for HLA associations in HLA-B*51 negative German and Turkish BD populations.
Methods
In total, 65 German and 46 Turkish patients lacking HLA-B*51 were analyzed in comparison to healthy HLA-B*51 negative Germans (n = 1500) and Turks (n = 130). HLA-A/B genotypes were determined by SSOP. P-values with correction for multiple testing (pc), χ2-test and odds ratio (OR) were used for statistical evaluation.
Results
HLA-A*26 was significantly more frequent in HLA-B*51− German patients [pc = 0.0076, OR = 3.23, 95% CI 1.63 to 6.39] than in respective controls. HLA-A*26 was also elevated in a smaller group of Turkish patients versus the controls. Significant association of HLA-Bw4 with isoleucine at amino-acid position 80 (HLA-Bw4-80I) was found in the HLA-B*51− German cohort of BD patients [pc = 0.0042, OR = 2.35, 95% CI 1.41 to 3.93) and in the Turkish patients in comparison to the respective controls [p = 0.025, OR = 2.17, 95% CI 1.09 to 4.31]. On the contrary, HLA-Bw4-80 T was reduced in both HLA-B*51− BD patient cohorts.
Conclusions
The study shows a significant association of HLA-Bw4-80I present on HLA-B*51 as well as on other B-locus molecules with BD. This indicates that distinctive Bw4 epitopes on HLA-B locus molecules could play a role in BD pathogenesis. The study also indicates an association with HLA-A*26 in German and Turkish BD patients as a genetic risk factor independent of HLA-B*51.
doi:10.1186/ar4569
PMCID: PMC4075409  PMID: 24887019
8.  Type 1 regulatory T cells specific for collagen type II as an efficient cell-based therapy in arthritis 
Arthritis Research & Therapy  2014;16(3):R115.
Introduction
Regulatory T (Treg) cells play a crucial role in preventing autoimmune diseases and are an ideal target for the development of therapies designed to suppress inflammation in an antigen-specific manner. Type 1 regulatory T (Tr1) cells are defined by their capacity to produce high levels of interleukin 10 (IL-10), which contributes to their ability to suppress pathological immune responses in several settings. The aim of this study was to evaluate the therapeutic potential of collagen type II–specific Tr1 (Col-Treg) cells in two models of rheumatoid arthritis (RA) in mice.
Methods
Col-Treg clones were isolated and expanded from collagen-specific TCR transgenic mice. Their cytokine secretion profile and phenotype characterization were studied. The therapeutic potential of Col-Treg cells was evaluated after adoptive transfer in collagen-antibody– and collagen-induced arthritis models. The in vivo suppressive mechanism of Col-Treg clones on effector T-cell proliferation was also investigated.
Results
Col-Treg clones are characterized by their specific cytokine profile (IL-10highIL-4negIFN-γint) and mediate contact-independent immune suppression. They also share with natural Tregs high expression of GITR, CD39 and granzyme B. A single infusion of Col-Treg cells reduced the incidence and clinical symptoms of arthritis in both preventive and curative settings, with a significant impact on collagen type II antibodies. Importantly, injection of antigen-specific Tr1 cells decreased the proliferation of antigen-specific effector T cells in vivo significantly.
Conclusions
Our results demonstrate the therapeutic potential of Col-Treg cells in two models of RA, providing evidence that Col-Treg could be an efficient cell-based therapy for RA patients whose disease is refractory to current treatments.
doi:10.1186/ar4567
PMCID: PMC4075412  PMID: 24886976
9.  Resequencing the susceptibility gene, ITGAM, identifies two functionally deleterious rare variants in systemic lupus erythematosus cases 
Arthritis Research & Therapy  2014;16(3):R114.
Introduction
The majority of the genetic variance of systemic lupus erythematosus (SLE) remains unexplained by the common disease-common variant hypothesis. Rare variants, which are not detectable by genome-wide association studies because of their low frequencies, are predicted to explain part of this ”missing heritability.” However, recent studies identifying rare variants within known disease-susceptibility loci have failed to show genetic associations because of their extremely low frequencies, leading to the questioning of the contribution of rare variants to disease susceptibility. A common (minor allele frequency = 17.4% in cases) nonsynonymous coding variant rs1143679 (R77H) in ITGAM (CD11b), which forms half of the heterodimeric integrin receptor, complement receptor 3 (CR3), is robustly associated with SLE and has been shown to impair CR3-mediated phagocytosis.
Methods
We resequenced ITGAM in 73 SLE cases and identified two previously unidentified, case-specific nonsynonymous variants, F941V and G1145S. Both variants were genotyped in 2,107 and 949 additional SLE cases, respectively, to estimate their frequencies in a disease population. An in vitro model was used to assess the impact of F941V and G1145S, together with two nonsynonymous ITGAM polymorphisms, A858V (rs1143683) and M441T (rs11861251), on CR3-mediated phagocytosis. A paired two-tailed t test was used to compare the phagocytic capabilities of each variant with that of wild-type CR3.
Results
Both rare variants, F941V and G1145S, significantly impair CR3-mediated phagocytosis in an in vitro model (61% reduction, P = 0.006; 26% reduction, P = 0.0232). However, neither of the common variants, M441T and A858V, had an effect on phagocytosis. Neither rare variant was observed again in the genotyping of additional SLE cases, suggesting that there frequencies are extremely low.
Conclusions
Our results add further evidence to the functional importance of ITGAM in SLE pathogenesis through impaired phagocytosis. Additionally, this study provides a new example of the identification of rare variants in common-allele-associated loci, which, because of their extremely low frequencies, are not statistically associated. However, the demonstration of their functional effects adds support to their contribution to disease risk, and questions the current notion of dismissing the contribution of very rare variants on purely statistical analyses.
doi:10.1186/ar4566
PMCID: PMC4060450  PMID: 24886912
10.  Lysine-specific demethylase 1-mediated demethylation of histone H3 lysine 9 contributes to interleukin 1β-induced microsomal prostaglandin E synthase 1 expression in human osteoarthritic chondrocytes 
Arthritis Research & Therapy  2014;16(3):R113.
Introduction
Microsomal prostaglandin E synthase 1 (mPGES-1) catalyzes the terminal step in the biosynthesis of PGE2, a critical mediator in the pathophysiology of osteoarthritis (OA). Histone methylation plays an important role in epigenetic gene regulation. In this study, we investigated the roles of histone H3 lysine 9 (H3K9) methylation in interleukin 1β (IL-1β)-induced mPGES-1 expression in human chondrocytes.
Methods
Chondrocytes were stimulated with IL-1β, and the expression of mPGES-1 mRNA was evaluated using real-time RT-PCR. H3K9 methylation and the recruitment of the histone demethylase lysine-specific demethylase 1 (LSD1) to the mPGES-1 promoter were evaluated using chromatin immunoprecipitation assays. The role of LSD1 was further evaluated using the pharmacological inhibitors tranylcypromine and pargyline and small interfering RNA (siRNA)-mediated gene silencing. The LSD1 level in cartilage was determined by RT-PCR and immunohistochemistry.
Results
The induction of mPGES-1 expression by IL-1β correlated with decreased levels of mono- and dimethylated H3K9 at the mPGES-1 promoter. These changes were concomitant with the recruitment of the histone demethylase LSD1. Treatment with tranylcypromine and pargyline, which are potent inhibitors of LSD1, prevented IL-1β-induced H3K9 demethylation at the mPGES-1 promoter and expression of mPGES-1. Consistently, LSD1 gene silencing with siRNA prevented IL-1β-induced H3K9 demethylation and mPGES-1 expression, suggesting that LSD1 mediates IL-1β-induced mPGES-1 expression via H3K9 demethylation. We show that the level of LSD1 was elevated in OA compared to normal cartilage.
Conclusion
These results indicate that H3K9 demethylation by LSD1 contributes to IL-1β-induced mPGES-1 expression and suggest that this pathway could be a potential target for pharmacological intervention in the treatment of OA and possibly other arthritic conditions.
doi:10.1186/ar4564
PMCID: PMC4060543  PMID: 24886859
11.  Scleroderma-polymyositis overlap syndrome versus idiopathic polymyositis and systemic sclerosis: a descriptive study on clinical features and myopathology 
Arthritis Research & Therapy  2014;16(3):R111.
Introduction
The objective was to characterize the clinical and myopathologic features of patients with scleroderma-polymyositis (SSc-PM) overlap compared with a population of patients with systemic sclerosis (SSc) and polymyositis (PM).
Methods
A three-way comparison of patients with SSc-PM overlap (n = 25) with patients with SSc (n = 397) and PM (n = 40) on clinical and myopathologic features and causes of death. One neuropathologist blinded for the diagnosis evaluated all recent available muscle biopsies. Biopsies were scored for presence of inflammation, necrotic muscle fibers, rimmed vacuoles, fibrosis, and immunohistochemical staining. Clinical or myopathologic characteristics were compared by using the χ2 test or one-way analysis of variance (ANOVA).
Results
The prevalence of SSc-PM overlap in the Nijmegen Systemic Sclerosis cohort was 5.9%. The mortality was 32% (eight of 25) in SSc-PM, of which half was related to cardiac diseases. The prevalence of pulmonary fibrosis was significantly increased in SSc-PM (83%) (P = 0.04) compared with SSc (49%) and PM (53%). SSc or myositis-specific antibodies were nearly absent in the SSc-PM group. In almost all biopsies (96%) of SSc-PM patients, necrotic muscle fibers were present, which was significantly increased compared with PM patients (P = 0.02).
Conclusions
Patients with SSc-PM have increased prevalence of pulmonary fibrosis and cardiac disease as the cause of death compared with patients with SSc and PM . In addition, we found that necrotizing muscle fibers with inflammation characterize SSc-PM overlap in muscle biopsies. Further research should focus on underlying mechanisms causing necrosis, inflammation, and fibrosis and their relation to pulmonary involvement and mortality in patients with SSc-PM overlap.
doi:10.1186/ar4562
PMCID: PMC4060195  PMID: 24886750
12.  The window of opportunity: a relevant concept for axial spondyloarthritis 
The window of opportunity is a concept critical to rheumatoid arthritis treatment. Early treatment changes the outcome of rheumatoid arthritis treatment, in that response rates are higher with earlier disease-modifying anti-rheumatic drug treatment and damage is substantially reduced. Axial spondyloarthritis is an inflammatory axial disease encompassing both nonradiographic axial spondyloarthritis and established ankylosing spondylitis. In axial spondyloarthritis, studies of magnetic resonance imaging as well as tumor necrosis factor inhibitor treatment and withdrawal studies all suggest that early effective suppression of inflammation has the potential to reduce radiographic damage. This potential would suggest that the concept of a window of opportunity is relevant not only to rheumatoid arthritis but also to axial spondyloarthritis. The challenge now remains to identify high-risk patients early and to commence treatment without delay. Developments in risk stratification include new classification criteria, identification of clinical risk factors, biomarkers, genetic associations, potential antibody associations and an ankylosing spondylitis-specific microbiome signature. Further research needs to focus on the evidence for early intervention and the early identification of high-risk individuals.
doi:10.1186/ar4561
PMCID: PMC4060382
13.  Network analysis identifies protein clusters of functional importance in juvenile idiopathic arthritis 
Arthritis Research & Therapy  2014;16(3):R109.
Introduction
Our objective was to utilise network analysis to identify protein clusters of greatest potential functional relevance in the pathogenesis of oligoarticular and rheumatoid factor negative (RF-ve) polyarticular juvenile idiopathic arthritis (JIA).
Methods
JIA genetic association data were used to build an interactome network model in BioGRID 3.2.99. The top 10% of this protein:protein JIA Interactome was used to generate a minimal essential network (MEN). Reactome FI Cytoscape 2.83 Plugin and the Disease Association Protein-Protein Link Evaluator (Dapple) algorithm were used to assess the functionality of the biological pathways within the MEN and to statistically rank the proteins. JIA gene expression data were integrated with the MEN and clusters of functionally important proteins derived using MCODE.
Results
A JIA interactome of 2,479 proteins was built from 348 JIA associated genes. The MEN, representing the most functionally related components of the network, comprised of seven clusters, with distinct functional characteristics. Four gene expression datasets from peripheral blood mononuclear cells (PBMC), neutrophils and synovial fluid monocytes, were mapped onto the MEN and a list of genes enriched for functional significance identified. This analysis revealed the genes of greatest potential functional importance to be PTPN2 and STAT1 for oligoarticular JIA and KSR1 for RF-ve polyarticular JIA. Clusters of 23 and 14 related proteins were derived for oligoarticular and RF-ve polyarticular JIA respectively.
Conclusions
This first report of the application of network biology to JIA, integrating genetic association findings and gene expression data, has prioritised protein clusters for functional validation and identified new pathways for targeted pharmacological intervention.
doi:10.1186/ar4559
PMCID: PMC4062926  PMID: 24886659
14.  A genetic variant in osteoprotegerin is associated with progression of joint destruction in rheumatoid arthritis 
Arthritis Research & Therapy  2014;16(3):R108.
Introduction
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.
Methods
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.
Results
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.
Conclusions
These results indicate that a genetic variant in OPG is associated with a more severe rate of joint destruction in RA.
doi:10.1186/ar4558
PMCID: PMC4060386  PMID: 24886600
15.  Synovial explant inflammatory mediator production corresponds to rheumatoid arthritis imaging hallmarks: a cross-sectional study 
Arthritis Research & Therapy  2014;16(3):R107.
Introduction
Despite the widespread use of magnetic resonance imaging (MRI) and Doppler ultrasound for the detection of rheumatoid arthritis (RA) disease activity, little is known regarding the association of imaging-detected activity and synovial pathology. The purpose of this study was to compare site-specific release of inflammatory mediators and evaluate the corresponding anatomical sites by examining colour Doppler ultrasound (CDUS) and MRI scans.
Methods
RA patients were evaluated on the basis of CDUS and 3-T MRI scans and subsequently underwent synovectomy using a needle arthroscopic procedure of the hand joints. The synovial tissue specimens were incubated for 72 hours, and spontaneous release of monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), macrophage inflammatory protein 1β (MIP-1β) and IL-8 was measured by performing multiplex immunoassays. Bone marrow oedema (BME), synovitis and erosion scores were estimated on the basis of the rheumatoid arthritis magnetic resonance imaging score (RAMRIS). Mixed models were used for the statistical analyses. Parsimony was achieved by omitting covariates with P > 0.1 from the statistical model.
Results
Tissue samples from 58 synovial sites were obtained from 25 patients. MCP-1 was associated with CDUS activity (P = 0.009, approximate Spearman’s ρ = 0.41), RAMRIS BME score (P = 0.01, approximate Spearman’s ρ = 0.42) and RAMRIS erosion score (P = 0.03, approximate Spearman’s ρ = 0.31). IL-6 was associated with RAMRIS synovitis score (P = 0.04, approximate Spearman’s ρ = 0.50), BME score (P = 0.04, approximate Spearman’s ρ = 0.31) and RAMRIS erosion score (P = 0.03, approximate Spearman’s ρ = 0.35). MIP-1β was associated with CDUS activity (P = 0.02, approximate Spearman’s ρ = 0.38) and RAMRIS synovitis scores (P = 0.02, approximate Spearman’s ρ = 0.63). IL-8 associations with imaging outcome measures did not reach statistical significance.
Conclusions
The association between imaging activity and synovial inflammatory mediators underscores the high sensitivity of CDUS and MRI in the evaluation of RA disease activity. The associations found in our present study have different implications for synovial mediator releases and corresponding imaging signs. For example, MCP-1 and IL-6 were associated with both general inflammation and bone destruction, in contrast to MIP-1β, which was involved solely in general synovitis. The lack of association of IL-8 with synovitis was likely underestimated because of a large proportion of samples above assay detection limits among the patients with the highest synovitis scores.
doi:10.1186/ar4557
PMCID: PMC4078218  PMID: 24886513
16.  Ginsenoside Rh1 potentiates dexamethasone’s anti-inflammatory effects for chronic inflammatory disease by reversing dexamethasone-induced resistance 
Arthritis Research & Therapy  2014;16(3):R106.
Introduction
Acquired resistance to glucocorticoids constitutes a major clinical challenge, often overlooked in the search for compounds to improve the effect of classic steroids. We sought to unravel how a plant-original compound, ginsenoside Rh1, potentiates dexmethasone (DEX)’s potential anti-inflammation properties.
Methods
Ginsenoside Rh1 combined with DEX was applied in a short-term and long-term treatment protocol for inflammation. Its potential mechanism on anti-inflammation was explored. In addition, the effect of Rh1 on the side-effect induced by DEX was studied. Furthermore, the in vivo anti-inflammatory effects of Rh1 combined with DEX were evaluated in a collagen-induced arthritis (CIA) mice model.
Results
Ginsenoside Rh1 potentiates DEX’s anti-inflammatory effects even after prolonged DEX treatment. Rh1 could improve the glucocorticoid receptor (GR)’s transrepression on nuclear factor kappa B (NF-κB) and transactivation on dual specificity protein phosphatase 1 (DUSP1), which is responsible for DEX’s anti-inflammatory effects. Parallel Western blot assay and radioligand binding analysis revealed that Rh1 could increase the expression and binding of GR. This is in sharp contrast to DEX alone, showing a direct link among prolonged treatment, decreasing GR and the abolishment of anti-inflammation. Interestingly, Rh1 does not enhance the transactivation of glucocorticoid-responsive elements (GRE) driven genes - gluconeogenic enzyme glucose-6-phosphatase (G6P) and phosphoenolpyruvate carboxykinasee phosphatase (PEPCK) in primary mouse hepatocytes, a mechanism partly held accountable for the metabolic side-effects. Similar results were found in CIA mice.
Conclusion
Rh1 could potentiate DEX’s anti-inflammatory effects and does not cause a hyperglycemic side effect. Ginsenoside Rh1 combined with DEX may be a promising candidate treatment option for chronic inflammatory diseases in need of long-term immunosuppression therapies.
doi:10.1186/ar4556
PMCID: PMC4060561  PMID: 24887434
17.  Synovial phenotypes in rheumatoid arthritis correlate with response to biologic therapeutics 
Introduction
Rheumatoid arthritis (RA) is a complex and clinically heterogeneous autoimmune disease. Currently, the relationship between pathogenic molecular drivers of disease in RA and therapeutic response is poorly understood.
Methods
We analyzed synovial tissue samples from two RA cohorts of 49 and 20 patients using a combination of global gene expression, histologic and cellular analyses, and analysis of gene expression data from two further publicly available RA cohorts. To identify candidate serum biomarkers that correspond to differential synovial biology and clinical response to targeted therapies, we performed pre-treatment biomarker analysis compared with therapeutic outcome at week 24 in serum samples from 198 patients from the ADACTA (ADalimumab ACTemrA) phase 4 trial of tocilizumab (anti-IL-6R) monotherapy versus adalimumab (anti-TNFα) monotherapy.
Results
We documented evidence for four major phenotypes of RA synovium – lymphoid, myeloid, low inflammatory, and fibroid - each with distinct underlying gene expression signatures. We observed that baseline synovial myeloid, but not lymphoid, gene signature expression was higher in patients with good compared with poor European league against rheumatism (EULAR) clinical response to anti-TNFα therapy at week 16 (P =0.011). We observed that high baseline serum soluble intercellular adhesion molecule 1 (sICAM1), associated with the myeloid phenotype, and high serum C-X-C motif chemokine 13 (CXCL13), associated with the lymphoid phenotype, had differential relationships with clinical response to anti-TNFα compared with anti-IL6R treatment. sICAM1-high/CXCL13-low patients showed the highest week 24 American College of Rheumatology (ACR) 50 response rate to anti-TNFα treatment as compared with sICAM1-low/CXCL13-high patients (42% versus 13%, respectively, P =0.05) while anti-IL-6R patients showed the opposite relationship with these biomarker subgroups (ACR50 20% versus 69%, P =0.004).
Conclusions
These data demonstrate that underlying molecular and cellular heterogeneity in RA impacts clinical outcome to therapies targeting different biological pathways, with patients with the myeloid phenotype exhibiting the most robust response to anti-TNFα. These data suggest a path to identify and validate serum biomarkers that predict response to targeted therapies in rheumatoid arthritis and possibly other autoimmune diseases.
Trial registration
ClinicalTrials.gov NCT01119859
doi:10.1186/ar4555
PMCID: PMC4060385
18.  A new paradigm of quality of care in rheumatoid arthritis: how our new therapeutics have changed the game 
Demonstrating the effectiveness of expensive new rheumatoid arthritis (RA) therapeutics is imperative to determine whether the quality of care has improved with the introduction of these agents. Our current RA quality measures are primarily process based, but they must become outcomes based to better demonstrate quality. New RA quality measures must be multidimensional, accounting for all of the important outcomes in RA: radiographic, functional status, and disease activity. To fully understand the potential benefits of new therapeutics in RA, outcome measures must be integrated with routine practice.
doi:10.1186/ar4356
PMCID: PMC3979023  PMID: 24164739
19.  Genetic variant in IL33 is associated with susceptibility to rheumatoid arthritis 
Arthritis Research & Therapy  2014;16(2):R105.
Introduction
Interleukin (IL)-33 is a proinflammatory cytokine contributing to the pathogenesis of rheumatoid arthritis (RA). The gene encoding IL-33 may serve as a genetic factor and be associated with the risk of RA. To investigate the potential association between IL33 and RA, we performed a case–control study based on Chinese Han population.
Methods
A three-stage case–control study was performed. Two tag single-nucleotide polymorphisms (SNPs) (rs7044343 and rs10975514), mapping to the IL33 gene, were first genotyped in the discovery population. We further genotyped rs7044343 and rs10975514 in the validation and replication population. The associations between the two tag SNPs and phenotypic subgroups of RA and levels of serum IL-33 were assessed with a logistic regression model.
Results
In the discovery population, the CC genotype of rs7044343 was associated with RA patients (odds ratio (OR) = 0.777, 95% confidence interval (CI), 0.611 to 0.988; P = 0.040). After anti-citrullinated peptide antibody (ACPA) stratification, the CC genotype of rs7044343 was also shown to be a protective genotype in RA without ACPA (OR = 0.610; 95% CI, 0.379 to 0.982; P = 0.042). In the validation population and replication population, the association between rs7044343 and RA, especially ACPA-negative RA, was still significant. A meta-analysis of discovery, validation, and replication panels confirmed the association between CC genotype of rs7044343 and RA (Pcombined = 0.0004; ORcombined = 0.77; 95% CI, 0.67 to 0.89). No evidence was found for heterogeneity between three sample sets (Phet = 0.99; I2 = 0%). Similar results were also obtained in ACPA-negative RA (Pcombined = 0.0002; ORcombined = 0.57; 95% CI, 0.43 to 0.77). No association was detected between rs10975514 polymorphism and RA susceptibility in the discovery and validation population. The serum levels of IL-33 were significantly lower in the patients with the rs7044343 CC genotype.
Conclusion
The CC genotype of rs7044343 in IL33 is associated with RA patients and downregulates IL-33 expression in RA.
doi:10.1186/ar4554
PMCID: PMC4075243  PMID: 24779919
20.  CD4+CD25-Foxp3+ T cells: a marker for lupus nephritis? 
Arthritis Research & Therapy  2014;16(2):R104.
Introduction
Systemic lupus erythematosus (SLE) is a heterogenous autoimmune disease, which can affect different organs. Increased proportions of CD4+CD25-Foxp3+ T cells have been described in SLE patients. The exact role of this cell population in SLE patients still remains unclear. We therefore analyzed this T cell subset in a large cohort of SLE patients with different organ manifestations.
Methods
Phenotypic analyses, proportions and absolute cell numbers of CD4+CD25-Foxp3+ T cells were determined by flow cytometry (FACS) in healthy controls (HC) (n = 36) and SLE patients (n = 61) with different organ manifestations. CD4+CD25-Foxp3+ T cells were correlated with clinical data, the immunosuppressive therapy and different disease activity indices. In patients with active glomerulonephritis, CD4+CD25-Foxp3+ T cells were analyzed in urine sediment samples. Time course analyses of CD4+CD25-Foxp3+ T cells were performed in patients with active disease activity before and after treatment with cyclophosphamide and prednisone.
Results
CD4+CD25-Foxp3+ T cells were significantly increased in active SLE patients and the majority expressed Helios. Detailed analysis of this patient cohort revealed increased proportions of CD4+CD25-Foxp3+ T cells in SLE patients with renal involvement. CD4+CD25-Foxp3+ T cells were also detected in urine sediment samples of patients with active glomerulonephritis and correlated with the extent of proteinuria.
Conclusion
CD4+CD25-Foxp3+ T cells resemble regulatory rather than activated T cells. Comparative analysis of CD4+CD25-Foxp3+ T cells in SLE patients revealed a significant association of this newly described cell population with active nephritis. Therefore CD4+CD25-Foxp3+ T cells might serve as an important tool to recognize and monitor SLE patients with renal involvement.
doi:10.1186/ar4553
PMCID: PMC4060257  PMID: 24774748
21.  Serum C-X-C motif chemokine 13 is elevated in early and established rheumatoid arthritis and correlates with rheumatoid factor levels 
Arthritis Research & Therapy  2014;16(2):R103.
Introduction
We hypothesized that serum levels of C-X-C motif chemokine 13 (CXCL13), a B-cell chemokine, would delineate a subset of rheumatoid arthritis (RA) patients characterized by increased humoral immunity.
Methods
Serum from patients with established RA (the Dartmouth RA Cohort) was analyzed for CXCL13, rheumatoid factor (RF) levels, anticitrullinated peptide/protein antibody (ACPA) and total immunoglobulin G (IgG); other parameters were obtained by chart review. A confirmatory analysis was performed using samples from the Sherbrooke Early Undifferentiated PolyArthritis (EUPA) Cohort. The Wilcoxon rank-sum test, a t-test and Spearman’s correlation analysis were utilized to determine relationships between variables.
Results
In both the Dartmouth and Sherbrooke cohorts, CXCL13 levels were selectively increased in seropositive relative to seronegative RA patients (P = 0.0002 and P < 0.0001 for the respective cohorts), with a strong correlation to both immunoglobulin M (IgM) and IgA RF levels (P < 0.0001). There was a weaker relationship to ACPA titers (P = 0.03 and P = 0.006, respectively) and total IgG (P = 0.02 and P = 0.14, respectively). No relationship was seen with regard to age, sex, shared epitope status or inclusion high-sensitivity C-reactive protein (hsCRP) in either cohort or regarding the presence of baseline erosions in the Sherbrooke Cohort, whereas a modest relationship with Disease Activity Score in 28 joints CRP (DAS28-CRP) was seen in the Dartmouth cohort but not the Sherbrooke cohort.
Conclusion
Using both established and early RA cohorts, marked elevations of serum CXCL13 levels resided nearly completely within the seropositive population. CXCL13 levels exhibited a strong relationship with RF, whereas the association with clinical parameters (age, sex, DAS28-CRP and erosions) or other serologic markers (ACPA and IgG) was either much weaker or absent. Elevated serum CXCL13 levels may identify a subset of seropositive RA patients whose disease is shaped by or responsive to RF production.
doi:10.1186/ar4552
PMCID: PMC4060390  PMID: 24766912
22.  Blocking the janus-activated kinase pathway reduces tumor necrosis factor alpha-induced interleukin-18 bioactivity by caspase-1 inhibition 
Arthritis Research & Therapy  2014;16(2):R102.
Introduction
Our objective was to examine the role of the janus-activated kinase (JAK) pathway in the modulation of tumor necrosis factor-α (TNF)-induced-IL-18 bioactivity by reduction of caspase-1 function.
Methods
Caspase-1 expression in rheumatoid arthritis (RA) synovial fibroblasts treated with TNF was assessed by qRT-PCR and Western blot. Interleukin (IL)-18 was assessed by enzyme-linked immunosorbent assay (ELISA) in cell lysates and conditioned media and detected by immunofluorescence (IF) staining in RA synovial fibroblasts. The critical pathways for TNF-induced caspase-1 expression were determined by using chemical inhibitors of signaling followed by TNF stimulation. IL-18 bioactivity was assessed using human myelomonocytic KG-1 cells.
Results
TNF induced RA synovial fibroblast caspase-1 expression at the protein level in a time-dependant manner (P < 0.05). Blocking the JAK pathway reduced TNF-induced-caspase-1 expression at the transcriptional and protein levels by approximately 60% and 40%, respectively (P < 0.05). Blocking the JAK pathway reduced TNF-induced-caspase-1 expression at the transcriptional, protein, and activity levels by approximately 60%, 40%, and 53%, respectively (P < 0.05). We then confirmed by IF that TNF-induced IL-18 and investigated roles of the ERK1/2 and JAK pathways. Blocking the JAK pathway, TNF induced intracytoplasmic granular IL-18 expression suggesting a defect of caspase-1. Finally, blocking the JAK pathway, we observed a reduction of IL-18 bioactivity by 52% in RA synovial fibroblasts (P < 0.05).
Conclusions
These results provide a new way to regulate TNF-induced-IL-18 bioactivity by blocking capase-1. These data present a novel role for JAK inhibition in RA patients and emphasize JAK inhibition use as a new therapeutic option in RA management.
doi:10.1186/ar4551
PMCID: PMC4060193  PMID: 24762050
23.  Classification and characteristics of Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis in a nationwide, prospective, inception cohort study 
Arthritis Research & Therapy  2014;16(2):R101.
Introduction
We investigated the clinical and serological features of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japan using data from a nationwide, prospective, inception cohort study.
Methods
In total, 156 Japanese patients with newly diagnosed AAV were classified according to the European Medicines Agency (EMEA) algorithm with exploratory surrogate markers for AAV-related non-granulomatous pulmonary lesions, predefined as alveolar haemorrhage and interstitial lung disease (ILD), and their clinical and serological features were evaluated.
Results
Using the EMEA algorithm, we identified 14 patients (9.0%) with eosinophilic granulomatosis with polyangiitis (EGPA), 33 (21.2%) with granulomatosis with polyangiitis (GPA), 78 (50.0%) with microscopic polyangiitis and renal-limited vasculitis (MPA/RLV), and 31 (19.9%) with unclassifiable vasculitis. The average ages of patients with EGPA (male/female, 5/9), GPA (12/21), and MPA/RLV (35/43) and unclassifiable (9/22) were 58.0, 63.6, 71.1, and 70.6 years, respectively. Myeloperoxidase (MPO)-ANCA and proteinase-3 ANCA positivity was 50.0% and 0% for EGPA, 54.6% and 45.5% for GPA, 97.4% and 2.6% for MPA/RLV, and 93.5% and 3.2% for unclassifiable, respectively. According to the Birmingham Vasculitis Activity Score (BVAS), cutaneous (71.4%) and nervous system (92.9%) manifestations were prominent in EGPA and ear, nose, and throat manifestations (84.9%) and chest manifestations (66.7%) in GPA. Renal manifestations developed frequently in MPA/RLV (91.0%) and GPA (63.6%). The average serum creatinine levels were 0.71 mg/dL for EGPA, 1.51 mg/dL for GPA, 2.46 mg/dL for MPA/RLV, and 0.69 mg/dL for unclassifiable. The percentages of patients with ILD were 14.3% for EGPA, 9.0% for GPA, 47.4% for MPA/RLV, and 61.3% for unclassifiable. Patients with ILD (n = 61) had significantly lower BVAS (P = 0.019) with fewer ear, nose, and throat and cardiovascular manifestations than patients without ILD (n = 95).
Conclusions
MPO-ANCA-positive MPA/RLV is the most common form of AAV in Japanese patients, and one-half of patients with GPA were positive for MPO-ANCA. ILD is an important clinical manifestation in Japanese patients with AAV. Unclassifiable vasculitis with MPO-ANCA positivity and ILD may represent a novel variant of MPA.
Trial Registration
The University Hospital Medical Information Network Clinical Trials Registry: UMIN000001648. Registered 28 February 2009.
doi:10.1186/ar4550
PMCID: PMC4060546  PMID: 24758294
24.  Tumor necrosis factor inhibitor therapy but not standard therapy is associated with resolution of erosion in the sacroiliac joints of patients with axial spondyloarthritis 
Arthritis Research & Therapy  2014;16(2):R100.
Introduction
Radiography is an unreliable and insensitive tool for the assessment of structural lesions in the sacroiliac joints (SIJ). Magnetic resonance imaging (MRI) detects a wider spectrum of structural lesions but has undergone minimal validation in prospective studies. The Spondyloarthritis Research Consortium of Canada (SPARCC) MRI Sacroiliac Joint (SIJ) Structural Score (SSS) assesses a spectrum of structural lesions (erosion, fat metaplasia, backfill, ankylosis) and its potential to discriminate between therapies requires evaluation.
Methods
The SSS score assesses five consecutive coronal slices through the cartilaginous portion of the joint on T1-weighted sequences starting from the transitional slice between cartilaginous and ligamentous portions of the joint. Lesions are scored dichotomously (present/absent) in SIJ quadrants (fat metaplasia, erosion) or halves (backfill, ankylosis). Two readers independently scored 147 pairs (baseline, 2 years) of scans from a prospective cohort of patients with SpA who received either standard (n = 69) or tumor necrosis factor alpha (TNFα) inhibitor (n = 78) therapy. Smallest detectable change (SDC) was calculated using analysis of variance (ANOVA), discrimination was assessed using Guyatt’s effect size, and treatment group differences were assessed using t-tests and the Mann–Whitney test. We identified baseline demographic and structural damage variables associated with change in SSS score by univariate analysis and analyzed the effect of treatment by multivariate stepwise regression adjusted for severity of baseline structural damage and demographic variables.
Results
A significant increase in mean SSS score for fat metaplasia (P = 0.017) and decrease in mean SSS score for erosion (P = 0.017) was noted in anti-TNFα treated patients compared to those on standard therapy. Effect size for this change in SSS fat metaplasia and erosion score was moderate (0.5 and 0.6, respectively). Treatment and baseline SSS score for erosion were independently associated with change in SSS erosion score (β = 1.75, P = 0.003 and β = 0.40, P < 0.0001, respectively). Change in ASDAS (β = −0.46, P = 0.006), SPARCC MRI SIJ inflammation (β = −0.077, P = 0.019), and baseline SSS score for fat metaplasia (β = 0.085, P = 0.034) were independently associated with new fat metaplasia.
Conclusion
The SPARCC SSS method for assessment of structural lesions has discriminative capacity in demonstrating significantly greater reduction in erosion and new fat metaplasia in patients receiving anti-TNFα therapy.
doi:10.1186/ar4548
PMCID: PMC4060567  PMID: 24755322
25.  14-3-3η is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage 
Introduction
The aim of this study was to investigate whether 14-3-3η, 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 14-3-3η is associated with more severe disease in both early and established RA.
Methods
We investigated the effect of 14-3-3η on the activation of RA-relevant signalling cascades and induction of proinflammatory mediators that contribute to the joint damage process. 14-3-3η titres from 33 patients with early RA (mean RA duration = 1.8 months) and from 40 patients with established RA were measured in serum drawn at the 3-year time point of the Behandel Strategieën study. The relationship between 14-3-3η titres and standard clinical variables was investigated by correlation analysis. The association with radiographic damage and radiographic progression over at least a 2-year period was investigated using univariate and multivariate regression analyses.
Results
14-3-3η activated selected members of the mitogen-activated protein kinase (MAPK) family, mainly extracellular regulated kinase 1/2 and c-Jun kinase, but not p38MAPK. Activation by 14-3-3η, using levels spanning the concentration range found in RA patient serum, resulted in the induction of inflammatory transcripts such as interleukin 1 (IL-1) and IL-6 and factors linked to the joint damage process, such as receptor activator of nuclear factor κB ligand and matrix metalloproteinase 1. Serum 14-3-3η correlated significantly with rheumatoid factor (RF) (r = 0.43) and anticitrullinated protein antibodies (ACPAs) (r = 0.31) in the early RA cohort, but not with C-reactive protein (CRP) or the Disease Activity Score in 28 joints in either cohort. Serum 14-3-3η concentrations were significantly higher in patients with radiographically assessed joint damage and in those who had radiographic progression. By multivariate analysis, we show that 14-3-3η complemented markers such as CRP, RF and ACPA in informing RA radiographic status and/or progression.
Conclusions
Extracellular 14-3-3η activates key signalling cascades and induces factors associated with the pathogenesis of RA at concentrations found in patients with RA, and its expression is higher in patients with radiographic damage and RA progression.
doi:10.1186/ar4547
PMCID: PMC4060379  PMID: 24751211

Results 1-25 (2137)