Disease Progression In Rheumatoid Arthritis Research Articles

Challenges in imaging in preclinical rheumatoid arthritis.

There exists a preclinical phase to the disease progression of rheumatoid arthritis, in which there is evidence of autoimmunity but no overt clinical arthritis. Identifying patients in this phase would allow for early treatment, to potentially halt manifestation of the disease. Imaging, because it is noninvasive, provides an appealing alternative to gold-standard synovial biopsies for identification of these preclinical patients. Ultrasonography, magnetic resonance imaging, and positron emission tomography all have their advantages and disadvantages as imaging modalities in this regard. Further research into alternative imaging modalities with larger cohorts is required to determine the most effective technique.

Bone structure and perfusion quantification of bone marrow edema pattern in the wrist of patients with rheumatoid arthritis: a multimodality study.

To quantify bone structure and perfusion parameters in regions of bone marrow edema pattern (BMEP), non-edematous bone marrow (NBM), and pannus tissue areas in the wrists of patients with rheumatoid arthritis (RA) using 3-Tesla (3T) magnetic resonance imaging (MRI), and high resolution peripheral quantitative computed tomography (HR-pQCT). Sixteen subjects fulfilling American College of Rheumatology classification were imaged using a HR-pQCT system and a 3T MRI scanner with an 8-channel wrist coil. Coronal T2-weighted and dynamic contrast-enhanced (DCE-MRI) images were acquired. BMEP and pannus tissue areas were segmented semiautomatically in T2-weighted images. NBM areas were placed at a similar distance from the joint space as BMEP regions. MR and HR-pQCT images were registered, and bone variables were calculated within the BMEP and NBM regions. Perfusion parameters in BMEP, pannus tissue, and NBM regions were calculated based on the signal-time curve obtained from DCE-MRI. Eighteen BMEP areas were segmented, 15 of them presented proximal to pannus-filled erosions. Significant increases in bone density and trabecular thickness and number were observed in all BMEP regions compared to NMB (p < 0.05). Significantly elevated perfusion measures were observed in both BMEP and pannus tissue regions compared to NBM (p < 0.05). BMEP regions showed significantly increased bone density and structures as well as perfusion measures, suggesting bone remodeling and active inflammation. Combining MRI and HR-pQCT provides a powerful multimodality approach for understanding BMEP and erosions, and for potentially identifying novel imaging markers for disease progression in RA.

O20. Hypoxic Regulation of Epigenetic Modifications During Disease Progression in Rheumatoid Arthritis

O20. Hypoxic Regulation of Epigenetic Modifications During Disease Progression in Rheumatoid Arthritis

The −308 G/A polymorphism in the tumor necrosis factor-α gene is not associated with development and progression of rheumatoid arthritis in Argentinean patients

A polymorphism in the tumor necrosis factor-alpha (TNF-α) promoter region has been associated with disease susceptibility and progression in rheumatoid arthritis (RA). The presence of an adenosine (TNF2 allele) instead of a guanine (TNF1 allele) at position -308 may be responsible for a general increase in the transcriptional activity of the TNF-α gene. Our aim was to evaluate the association of the TNF2 allele with the risk of disease development and/or progression of RA in an Argentine population cohort. Two hundred and twenty-three consecutive patients with RA according to the 1987 criteria of the American College of Rheumatology were included in the study. Clinical variables, Disease Activity Score 28, Health Assessment Questionnaire and Rheumatoid Arthritis Quality of Life were recorded. The radiographic erosions were determined by the method of Sharp/van der Heijde. A group of 111 healthy subjects matched by sex and age was used as a control. All samples were genotyped for the -308 G/A TNF-α polymorphism. No significant differences were observed either in the frequency of the TNF2 allele or in the genotypic distributions of the -308 G/A TNF-α polymorphism (P>0.05) between the control group and the RA patients. No association was found between the TNF2 allele and the variables related to the course and outcome of the disease (P>0.05). In this cohort of Argentinean patients with RA, the TNF2 allele was neither associated with susceptibility to the disease nor was it associated with the variables related to the course and outcome of the disease.

Expression of TIM‐3 on CD4+ and CD8+ T cells in the peripheral blood and synovial fluid of rheumatoid arthritis

Rheumatoid arthritis (RA) is characterized by a chronic inflammatory process that targets the synovial lining of diarthrodial joints. TIM-3 plays a key role in the negative regulation of the immune response. In this study, we investigated the expression of TIM-3 on CD4+ and CD8+ T cells from systemic (peripheral blood) and local (synovial fluid) perspectives of RA. Level of TIM-3+ cells from peripheral blood and synovial fluid of patients as well as peripheral blood of healthy controls was measured by flow cytometry. Results showed that TIM-3 expression was significantly increased in both CD4+ and CD8+ T cells in the peripheral blood of RA (p<0.001 and p<0.001, respectively). Furthermore, patients revealed even higher expression of TIM-3 in CD4+ and CD8+ T cells in synovial fluid than in peripheral blood. When comparing TIM-3 level with the severity of RA, we identified that the percentage of TIM-3 on both peripheral CD4+ and peripheral CD8+ T cells was negatively correlated with disease activity score 28 (DAS28) of the patients. Similarly, TIM-3 on synovial fluid CD4+ and CD8+ T cells also revealed inverse correlation with DAS28 of the cases. Our data demonstrate a negative correlation between TIM-3 and the disease progression of RA.

SUMO-Conjugating Enzyme UBC9 Promotes Proliferation and Migration of Fibroblast-like Synoviocytes in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease with high morbidity and mortality. Fibroblast-like synoviocytes (FLS) in the synovial tissues play critical roles in joint destruction. Recent studies implicate the sumoylation in the regulation of the inflammation and arthritis. Thus, we explored whether SUMO-conjugating enzyme UBC9 is involved in the progression of RA using a mouse collagen-induced arthritis (CIA) model. The effects of UBC9 siRNA on cell invasion and migration in human RA-FLS were also assessed in vitro. Treatment with siRNA against UBC9 for 3weeks reduced the arthritis score and joint destruction. The expression of SUMO-1 and UBC9 protein in CIA joints was inhibited by UBC9 knockdown. Serum levels of anti-collagen (CII) antibodies, vascular endothelial growth factor A (VEGF-A), matrix metalloproteinases (MMP)-3, and MMP-9 were also decreased in CIA mice. In vitro, UBC9 silencing inhibited the secretion of VEGF-A, MMP-3, and MMP-9 from TNF-α-stimulated human RA-FLS. TNF-α-induced RA-FLS proliferation and migration were significantly attenuated by UBC9 knockdown. These findings indicate that SUMO-conjugating enzyme UBC9 promotes proliferation and migration of fibroblast-like synoviocytes in rheumatoid arthritis. Inhibition of UBC9 activity may be a viable therapeutic target in amelioration of disease progression in RA by attenuating FLS proliferation, migration, and invasion.

The supplementary therapeutic DMARD role of low-dose glucocorticoids in rheumatoid arthritis.

The management of rheumatoid arthritis (RA) is primarily based on the use of disease-modifying antirheumatic drugs (DMARDs), mainly comprising synthetic chemical compounds (that is, methotrexate or leflunomide) and biological agents (tumor necrosis factor inhibitors or abatacept). On the other hand, glucocorticoids (GCs), used for decades in the treatment of RA, are effective in relieving signs and symptoms of the disease, but also interfere with radiographic progression, either as monotherapy or in combination with conventional synthetic DMARDs. GCs exert most of their biological effects through a genomic action, using the cytosolic GC receptor and then interacting with the target genes within target cells that can result in increased expression of regulatory - including anti-inflammatory - proteins (transactivation) or decreased production of proinflammatory proteins (transrepression). An inadequate secretion of GCs from the adrenal gland, in relation to stress and inflammation, seems to play an important role in the pathogenesis and disease progression of RA. At present there is clear evidence that GC therapy, especially long-term low-dose treatment, slows radiographic progression by at least 50% when given to patients with early RA, hence satisfying the conventional definition of a DMARD. In addition, long-term follow-up studies suggest that RA treatment strategies which include GC therapy may favorably alter the disease course even after their discontinuation. Finally, a low-dose, modified night-release formulation of prednisone, although administered in the evening (replacement therapy), has been developed to counteract the circadian (night) rise in proinflammatory cytokine levels that contributes to disease activity, and might represent the way to further optimize the DMARD activity exerted by GCs in RA.

Aryl Hydrocarbon Receptor Antagonism Attenuates Growth Factor Expression, Proliferation, and Migration in Fibroblast-Like Synoviocytes from Patients with Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease with high morbidity and mortality. Within the inflammatory milieu, resident fibroblast-like synoviocytes (FLS) in the synovial tissue undergo hyperplasia, which leads to joint destruction. Epidemiologic studies and our previous research suggest that activation of the aryl hydrocarbon receptor (AHR) pathway plays an instrumental role in the inflammatory and destructive RA phenotype. In addition, our recent studies implicate the AHR in the regulation of the expression of several growth factors in established tumor cell lines. Thus, under inflammatory conditions, we hypothesized that the AHR is involved in the constitutive and inducible expression of several growth factors, FLS proliferation and migration, along with protease-dependent invasion in FLS from patients with RA (RA-FLS). Treatment with the AHR antagonist GNF351 inhibits cytokine-induced expression of vascular endothelial growth factor-A (VEGF-A), epiregulin, amphiregulin, and basic fibroblast growth factor mRNA through an AHR-dependent mechanism in both RA-FLS and FLS. Secretion of VEGF-A and epiregulin from RA-FLS was also inhibited upon GNF351 treatment. RA-FLS cell migration, along with cytokine-induced RA-FLS cell proliferation, was significantly attenuated by GNF351 exposure. Treatment of RA-FLS with GNF351 mitigated cytokine-mediated expression of matrix metalloproteinase-2 and -9 mRNA and diminished the RA-FLS invasive phenotype. These findings indicate that inhibition of AHR activity may be a viable therapeutic target in amelioration of disease progression in RA by attenuating growth factor release; FLS proliferation, migration, and invasion; and inflammatory activity.

Interaction between TGF-β1 (869C/T) polymorphism and biochemical risk factor for prediction of disease progression in rheumatoid arthritis

ObjectivesRheumatoid arthritis (RA) is a chronic inflammatory disease. Transforming growth factor-β1 (TGF-β1) may be a promising candidate gene for susceptibility and severity in RA. We aimed to determine whether TGF-β1 polymorphism is associated with susceptibility to RA and progression of joint destruction, as well as to identify the interaction between TGF-β1 polymorphism and biochemical risk factor. MethodsA total of 160 RA patients and 168 healthy unrelated controls were tested for the TGF-β1 (869C/T) polymorphism using polymerase chain reaction. ResultsThe TGF-β1 T allele was associated with susceptibility to RA. Within the RA group, TGF-β1 T allele carriers had a significant increased risk to develop osteoporosis (OR=4.4, 95% CI=-2. 4–8.1, P<0.001), as well as more likely to develop bone erosion (OR=1.7, 95% CI=0. 99–2.7, P=0. 034). Better prediction was achieved when the TGF-β1 TT genotype was used in combination with either elevated, rheumatoid factor (RF) or C-reactive protein (CRP) (OR=6.8, 3.7 respectively). Also, they increased the risk to develop bone erosion in patients with rheumatoid arthritis (OR=3.3, 9.8, P=0.017, 0.001 respectively). ConclusionOur results suggest that TGF-β1 TT genotype may determine the development of osteoporosis and bone erosion in RA. Also, our results points to a synergism between TGF-β1 TT genotype and elevated serum RF or elevated CRP that lead to the development of osteoporosis and bone erosion in patients with rheumatoid arthritis.

Hepatocyte Growth Factor Regulates Immune Reactions Caused by Transplantation and Autoimmune Diseases

Hepatocyte growth factor (HGF) was first identified and cloned as a mitogenic protein for hepatocytes, and subsequent studies revealed that HGF has multiple biological effects on a wide variety of cells, including mitogenic, motogenic, morphogenic, anti-apoptotic, and angiogenic activities. It plays roles in organizing tissues during development and regeneration. HGF may be applied for the treatment of acute onset diseases such as fulminant hepatitis, myocardial infarction, acute renal failure, cerebral infarction, and chronic diseases like liver cirrhosis, chronic renal failure, pulmonary fibrosis, cardiomyopathy, and arteriosclerosis obliterans. HGF also has immunomodulatory activities and we previously demonstrated that its administration inhibited acute graft-versus-host disease (GVHD) after treatment with hematopoietic stem cell transplantation. We also demonstrated that HGF inhibited lupus nephritis induced by chronic GVHD and dermal sclerosis in systemic sclerosis using model mice. More than 7 hundred thousand patients suffer from rheumatoid arthritis (RA) in Japan. Although the prognosis of these patients has improved by the treatment of biological agents such as TNF-α and IL-6 blockers, there remain many for whom these agents have not proved beneficial. Recently, using RA model mice, we demonstrated that the HGF antagonist, NK4, can block disease progression of RA through its anti-angiogenic and immunomodulatory actions. In this review article, we discuss the possible roles of HGF signaling for the treatment of immunological reactions in transplantation and autoimmune diseases.

Associations of alcohol use with radiographic disease progression in African Americans with recent-onset rheumatoid arthritis.

To investigate the associations of alcohol consumption and radiographic disease progression in African Americans with recently diagnosed rheumatoid arthritis (RA). Patients with RA included in the study were participants in the Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis (CLEAR) registry. Patients were categorized based on self-reported alcohol consumption; those consuming < 15 beverages per month versus those with ≥ 15 per month. Association of radiographic disease progression over a 1-year to 3-year period of observation with alcohol consumption was evaluated using multivariate generalized estimating equations. Of 166 patients included in the study, 39% reported that they had never consumed alcohol. Of the 61% who had consumed alcohol, 73% reported that they consumed on average < 15 alcoholic beverages per month and 27% reported consuming ≥ 15 per month. In multivariate analysis, consumption of ≥ 15 alcoholic beverages per month was associated with an increased risk of radiographic disease progression (p = 0.017). There was no evidence of a relationship in those consuming < 15 beverages per month (p = 0.802). There appears to be a dose-dependent relationship between alcohol use and radiographic disease progression in RA. Individuals who consume 15 or more alcoholic beverages per month may have faster rates of radiographic joint damage than those with lower levels of consumption.

THU0120 Do High Molecular Weight Adiponectin Levels Associate with Radiographic Progression in Rheumatoid Arthritis and Hand Osteoarthritis?

BackgroundObesity has been associated with an altered radiographic progression in rheumatoid arthritis (RA) and hand osteoarthritis (OA). While the underlying mechanisms of these associations remain unclear, it has become clear...

SAT0078 Severity of Periodontal Disease Impacts in Joint Damage in Patients with Rheumatoid Arthritis-A Cross Sectional Study in an Urban Peruvian Population.

BackgroundThere is a connection between periodontal disease (PD) and a higher incidence and severity of rheumatoid arthritis (RA) but to our knowledge there is no reported study evaluating the impact...

SAT0556 Predictors of Intensive Anti-Rheumatic Therapy in Early Care for Rheumatoid Arthritis

BackgroundEarly, intensive disease-modifying anti-rheumatic drug (DMARD) therapy is an effective strategy to limit disease progression in rheumatoid arthritis (RA). It was recently reported that DMARD therapy is initiated in advance...

FRI0044 IL-1 dependent SYNDECAN-4 signal transduction is mediated by its heparan sulfate side chains in RA synovial fibroblasts

BackgroundIn rheumatoid arthritis (RA) pathogenesis, activated synovial fibroblasts (SFs) play an important role, because of their tumor-like and agressive behavior. This phenotype is promoted by a steady stimulation with growth-factors...

AB0069 TIE2 signalling induces a pro-inflammatory and pro-angiogenic phenotype in differentiated macrophages, independently of macrophage polarization conditions

BackgroundAngiogenesis, the induction and growth of new blood vessels, has a pivotal role in mammalian embryogenesis and homeostatic processes, as well as in chronic inflammatory diseases like rheumatoid arthritis (RA)....

SAT0062 Blockade of connective tissue growth factor (CTGF) ameliorates murine model of rheumatoid arthritis

BackgroundOur previous study demonstrated changes in the profiles of serum protein biomarkers in infliximab-treated rheumatoid arthritis (RA) patients using a novel approach to proteomic research (1). Several proteins exhibited vast...

THU0085 Effect of CSF-1R Kinase Inhibitor on FDG PET, MMP Optical, and Microct Imaging in a Rat SCW Model of Rheumatoid Arthritis: Use of Functional and Structural Imaging as Translation Tools

BackgroundTissue macrophage recruitment and osteoclastogenesis is dependent on the activation of colony stimulating factor-1 (CSF-1) receptor (R). To target macrophages and block osteoclastogenesis a JNJ compound was identified as a...

Increased Soluble CD4 in Serum of Rheumatoid Arthritis Patients Is Generated by Matrix Metalloproteinase (MMP)-Like Proteinases

Higher soluble CD4 (sCD4) levels in serum have been detected in patients of infectious and chronic inflammatory diseases. However, how and why sCD4 is produced remains poorly understood. We establish sensitive ELISA and WB assays for sCD4 detection in conditioned medium of in vitro cell culture system and serum of chronic inflammatory patients. Serum samples from patients with systemic lupus erythematosus (SLE) (n = 79), rheumatoid arthritis (RA) (n = 59), ankylosing spondylitis (AS) (n = 25), gout (n = 31), and normal controls (n = 99) were analyzed using ELISA for sCD4 detection. Results from each assay were analyzed by the Kruskal-Wallis test. Dunn’s multiple comparison post-test was then applied between groups. We confirm that cells expressing exogenous CD4 produce sCD4 in a constitutive and PMA-induced manner. Importantly, sCD4 production in a heterologous expression system is inhibited by GM6001 and TAPI-0, suggesting receptor shedding by matrix metalloproteinase (MMP)-like proteinases. Moreover, similar findings are recapitulated in human primary CD4+ T cells. Finally, we show that serum sCD4 levels are increased in patients of chronic inflammatory diseases including RA and SLE, but not in those with gout. Intriguingly, sCD4 levels in RA patients are correlated positively with the disease activities and higher sCD4 levels seem to associate with poor prognosis. Taken together, we conclude that CD4 is shed from cell surface by a MMP-like sheddase and sCD4 level is closely related with the inflammatory condition in certain chronic diseases. Hence, sCD4 might be considered an important parameter for RA disease progression with potential diagnostic importance.

Reproducible metacarpal joint space width measurements using 3D analysis of images acquired with high-resolution peripheral quantitative computed tomography

ObjectiveJoint space narrowing is an important feature of progressive joint damage and functional impairment in rheumatoid arthritis (RA). Methods to provide a continuous measurement of joint space width have not been adopted in research or clinical settings. High-resolution peripheral quantitative computed tomography (HR-pQCT) (Scanco Medical AG, Brüttisellen, Switzerland) accurately and reproducibly images bone microstructure at a nominal isotropic voxel dimension of 82μm. Given the ability of HR-pQCT to detect bone margins with high precision, we developed methodology to measure a three-dimensional (3D) metacarpophalangeal (MCP) joint space width and tested the reproducibility of the scan protocol with hand repositioning. Materials and methodsConsecutive HR-pQCT scans of the 2nd and 3rd MCP joints of ten subjects with early RA (70% female, mean age 45 years), with repositioning between scans, were obtained. The periosteal edges of the metacarpal head and proximal phalanx base were detected using the μCT Evaluation Program V6.0 (Scanco Medical AG). Using the method of ‘fitting maximal spheres’, the joint space width and distribution of joint space thickness was estimated. ResultsThe mean minimum joint space width of the 2nd MCP was 1.82mm (SD 0.20) and of the 3rd MCP 1.84mm (SD 0.23). Reproducibility with repositioning was reliable, with overlapping filtered histograms and a root square mean coefficient of variance of 4.8%. ConclusionsWe provide reproducible methodology for evaluating the joint space width of the MCP joints. When combined with the assessment of erosions and periarticular bone density, HR-pQCT may be the ideal technology to assess disease activity and progression in RA.