Disease Progression In Rheumatoid Arthritis Research Articles

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.

Sinomenine Decreases MyD88 Expression and Improves Inflammation-Induced Joint Damage Progression and Symptoms in Rat Adjuvant-Induced Arthritis

Sinomenine (SIN) is the active principle of the Chinese medical plant Sinomenium acutum which is widely used for the treatment of rheumatoid arthritis (RA) in China. Recently, several groups indicated that myeloid differentiation primary response protein 88 (MyD88) might be associated with disease progression of RA. Here, we observed the effect of SIN on MyD88 expression and showed its therapeutic role in RA. First, immunohistochemical staining in clinical specimens showed that MyD88 was mainly located in characteristic pathological structures of RA synovial tissues. Second, we found that MyD88 was overexpressed in the synovial tissues of the rats with adjuvant-induced arthritis (AIA). Treatment with SIN markedly decreased the expression of MyD88 in AIA rats. Finally, we provided evidences that SIN suppressed inflammation response and inflammation-induced joint destructive progression and arthritis symptoms in AIA rats. Therefore, SIN is an effective therapeutic agent for RA. Targeting MyD88 signaling may provide new methods for the treatment of RA.

Serum level of adiponectin is a surrogate independent biomarker of radiographic disease progression in early rheumatoid arthritis: results from the ESPOIR cohort

IntroductionAdipokines such as adiponectin, leptin, and visfatin/nicotinamide phosphoribosyltransferase (NAMPT) have recently emerged as pro-inflammatory mediators involved in the pathophysiology of rheumatoid arthritis (RA). We aimed to determine whether serum adipokine levels independently predicted early radiographic disease progression in early RA.MethodsIn total, 791 patients were included from the prospective Etude et Suivi des POlyarthrites Indifférenciées Récentes (ESPOIR) cohort who met the American College of Rheumatology-European League Against Rheumatism criteria for RA (n = 632) or had undifferentiated arthritis (UA) (n = 159). Enzyme-linked immunosorbent assay (ELISA) was used to assess baseline serum levels of adiponectin, leptin, and visfatin/NAMPT. In the RA group, we tested the association of serum adipokine levels and (a) baseline radiographic damage and (b) radiographic disease progression, defined as a change >0 or ≥5 in total Sharp-van der Heijde Score (∆SHS) between inclusion and 1 year (∆SHS ≥1 or rapid radiographic progression: ∆SHS ≥5), adjusting for confounders (age, sex, body-mass index, insulin resistance, C-reactive protein level, Disease Activity Score in 28 joints, Health Assessment Questionnaire score, autoantibody status, steroid use, and radiographic evidence of RA damage at inclusion).ResultsAdiponectin level was independently associated with baseline total SHS (adjusted β = 0.12; P = 0.006). It was also associated with ∆SHS ≥1 (adjusted odds ratio (aOR) = 1.84 (1.25 to 2.72)) involving erosive as well as narrowing disease progression (aOR = 1.73 (1.17 to 2.55) and 1.93 (1.04 to 3.57), respectively). Serum adiponectin level predicted ∆SHS ≥5 (aOR = 2.0 (1.14 to 3.52)). Serum leptin level was independently associated only with ∆SHS >0 (aOR = 1.59 (1.05 to 2.42)). Conversely, serum visfatin/NAMPT level and radiographic disease progression were unrelated. Considering the receiver-operated characteristic curves, the best adiponectin cut-offs were 4.14 μg/ml for ∆SHS ≥1 and 6.04 μg/ml for ∆SHS ≥5, with a good specificity (58% and 75% for ∆SHS ≥1 and ∆SHS ≥5, respectively) and high negative predictive values (75% and 92% for ∆SHS ≥1 or ∆SHS ≥5, respectively).ConclusionSerum adiponectin level is a simple useful biomarker associated with early radiographic disease progression in early RA, independent of RA-confounding factors and metabolic status.

TNF-related apoptosis-inducing ligand levels in rheumatoid arthritis, osteoarthritis, and spondyloarthritis

Abstract Introduction Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a tumor necrosis factor (TNF) family member capable of inducing apoptosis in many cell types. Data suggest that TRAIL/TRAIL receptor expression profiles on Tcells might be important in rheumatoid arthritis (RA) pathogenesis. Objectives To characterize the role of TNF-related apoptosis-inducing ligand (TRAIL) in rheumatoid arthritis (RA) and to explore whether TRAIL investigated in serum and synovial fluid were associated with clinical, laboratory, and radiological variables of RA disease activity and severity. Methods Circulating levels of TRAIL were measured by ELISA in serum samples obtained from 50 patients with RA (during activity and quiescence), 20 patients with osteoarthritis, 15 patients with spondyloarthritis, and 50 normal healthy individuals serving as controls. Results The median serum TRAIL concentrations were increasingly higher across the following groups: healthy controls (185pg/ml), and RA patients with active disease (1625 pg/ml; P=0.0001 vs. controls) and inactive disease (1750 pg/ml; P=0.0001 vs. controls) (inactive vs. active RA; P = 0.07). It is noteworthy that RA patients had significant higher median TRAIL concentrations as compared with osteoarthritis patients whether during activity or during quiescence. However, the median levels of TRAIL were statistically comparable in RA and spondyloarthritis patients. The median and mean ± SD synovial fluid TRAIL concentrations were 2100 and 1765.8 ± 752 pg/ml, respectively. The levels of TRAIL in synovial fluid from the patients were higher than those in sera from both the patients and the healthy individuals. TRAIL concentrations in paired sera and synovial fluid samples could be related to each other. Serum and synovial concentrations of TRAIL were correlated positively with the total number of joints with active arthritis and with the overall articular severity score. Patients with Larsen index and total radiographic score of at least 1 had significantly higher serum TRAIL levels than patients with indices and scores 1 or less. Conclusion Upregulated expression of TRAIL might be somewhat useful for the evaluation of RA disease activity and progression, although its increment is not disease specific.

Bone Density and Microarchitecture: Relationship Between Hand, Peripheral, and Axial Skeletal Sites Assessed by HR-pQCT and DXA in Rheumatoid Arthritis

We assessed the relationship of bone density and microarchitecture between hand, peripheral, and axial skeletal sites using high-resolution peripheral quantitative computed tomography (HR-pQCT) and dual-energy X-ray absorptiometry (DXA) in patients with rheumatoid arthritis (RA) and which factors influence these parameters. This was a cross-sectional study of 100 female patients (53.4 ± 9.3 years) with RA. HR-pQCT scans at distal radius and the second metacarpal head were performed to assess cortical and trabecular volumetric bone mineral density (vBMD) and microarchitecture. DXA scans at the hip, lumbar spine, and ultradistal radius were performed to assess areal BMD. There was significant correlation in vBMD and microarchitectural parameters between the second metacarpal head and distal radius (r = 0.201-0.628). Areal BMD at the axial skeleton was moderately associated with vBMD at the peripheral sites (r = 0.354-0.558). Factors related to disease severity/chronicity significantly correlated with vBMD and microarchitecture at the distal radius and the second metacarpal head. Factors related to disease activity were more likely to correlate with vBMD and microarchitecture at the second metacarpal head but not those at the distal radius. HR-pQCT is a promising technique that is capable of providing detailed quantitative assessment of disease-associated periarticular bone loss at both cortical and trabecular bone compartments in patients with RA. Future longitudinal studies will be needed to investigate whether assessment by HR-pQCT can be used as a marker of disease activity and a predictor of disease progression in RA.

TLR5, a Novel and Unidentified Inflammatory Mediator in Rheumatoid Arthritis that Correlates with Disease Activity Score and Joint TNF-α Levels

The innate immune system plays an important role in rheumatoid arthritis (RA) pathogenesis. Previous studies support the role of TLR2 and 4 in RA and experimental arthritis models; however, the regulation and pathogenic effect of TLR5 is undefined in RA. In this study, we show that TLR5 is elevated in RA and osteoarthritis ST lining and sublining macrophages and endothelial cells compared with normal individuals. Furthermore, expression of TLR5 is elevated in RA synovial fluid macrophages and RA peripheral blood monocytes compared with RA and normal peripheral blood in vitro-differentiated macrophages. We also found that TLR5 on RA monocytes is an important modulator of TNF-α in RA synovial fluid and that TLR5 expression on these cells strongly correlates with RA disease activity and TNF-α levels. Interestingly, TNF-α has a feedback regulation with TLR5 expression in RA monocytes, whereas expression of this receptor is regulated by IL-17 and IL-8 in RA macrophages and fibroblasts. We show that RA monocytes and macrophages are more responsive to TLR5 ligation compared with fibroblasts despite the proinflammatory response being mediated through the same signaling pathways in macrophages and fibroblasts. In conclusion, we document the potential role of TLR5 ligation in modulating transcription of TNF-α from RA synovial fluid and the strong correlation of TLR5 and TNF-α with each other and with disease activity score in RA monocytes. Our results suggest that expression of TLR5 may be a predictor for RA disease progression and that targeting TLR5 may suppress RA.

The role of biologic agents in damage progression in rheumatoid arthritis: indirect comparison of data coming from randomized clinical trials

All biologic agents approved for the treatment of rheumatoid arthritis (RA) have been tested versus methotrexate (MTX) for efficacy on damage progression in several randomized clinical trials (RCTs), but direct head-to-head comparisons have never been conducted. The purpose of this investigation is to analyse data coming from main RA RCTs and to perform an indirect comparison. A systematic review of literature from 1988 to 2011 was conducted. Only randomized, double-blind, controlled, comparative trials, with evaluation of radiographic progression were included. The radiographic score was standardized and mean difference in the percentage of the annual radiographic progression rate was used as the effect measure. Heterogeneity between studies was estimated by I(2) test. For each trial, the effect was plotted according to its standard error in a funnel plot. Of 44 potentially relevant trials, 12 RCTs were included in the study. In order to optimize RCTs comparison, studies were stratified in early and late RA group. Main population characteristics were similar in both early and late RA groups, whereas the standardized baseline radiographic score value significantly differs among trials in both early (range 2.7-21.9) and late (range 23.46-75) RA groups. The standardized annual estimated progression is similar across the late RA group. Strong evidence of heterogeneity (I(2) = 97%, p = 0.00001) but no asymmetry of the funnel plot was observed in the early RA group. Total mean difference was -16.28 (95% confidence interval [CI] -24.42 to -8.14). For the late RA group a random model was used (I(2) = 99%, p = 0.00001) and a total mean difference of -39.25 (95% CI -53.77 to -24.73) was found. All biologic agents provide a favourable effect on disease progression both in early and late RA. The significant heterogeneity among various RCTs did not allow an effective comparison of the performance of biologic agents in each study.

Pleiotropic Targets: The Problem Of Shared Signaling Circuitry In Rheumatoid Arthritis Disease Progression And Protection

The immune response is replete with feedback control at many levels. These protective circuits are even functional within the arthritic joint, tempering disease to varying extents. An optimal therapy would inhibit autoimmune processes while maintaining protective circuitry. However, many of the cells and proteins that serve as important mediators of disease progression also play an active role in these protective circuits. The hypothesis considered in this review is that the inadvertent inhibition of protective circuitry adversely affects efficacy. Conversely, if therapeutics can be designed, which avoid inhibiting known regulatory circuits, efficacy will be improved. Understanding where these processes share signaling molecules will be crucial to the development of the next generation of therapeutics. This review discusses three well-defined signal transduction cascades; IL-2, IFNγ and TNF-α, and demonstrate within two cell types, T cells and macrophages, how these cytokines may contribute both to protection and to disease progression.

Estrogen inhibits apoptosis and promotes CC motif chemokine ligand 13 expression on synovial fibroblasts in rheumatoid arthritis

Objective: Female patients have a higher prevalence of rheumatoid arthritis (RA) than male patients, suggesting that female sex hormones contribute to the disease pathogenesis. We herein report the findings of our study, which was conducted to clarify the role of estrogen in the pathogenesis of RA.Methods: Cultured human synovial fibroblasts from a patient with RA were treated with 17β-estradiol (E2). The effects of E2 against cellular activation and apoptosis were evaluated. To identify the disease-related genes altered by E2 treatment, the changes in the gene expression of the cells stimulated with and without E2 were evaluated using a microarray analysis.Results: We found that E2-mediated cellular activation signaling through extracellular signal-regulated kinase (ERK)-1/2. E2 possessed a suppressive effect for apoptosis and a promotive effect for tumor necrosis factor (TNF)-α-induced matrix metalloproteinase (MMP)-3 production on the synovial fibroblasts. A microarray analysis revealed that E2 profoundly upregulated CC motif chemokine ligand 13 (CCL13) gene expression.Conclusions: E2 could mediate cellular activation signaling through ERK-1/2 on the synovial fibroblasts. The present data suggest that E2 has adverse effects on the pathogenesis of RA as a result of unregulated cell death, increased TNF-α-induced MMP-3 production, and CCL13 overproduction, subsequently resulting in the disease progression of RA.

Increased Frequency of Circulating Follicular Helper T Cells in Patients with Rheumatoid Arthritis

Follicular helper T (Tfh) cells are recognized as a distinct CD4+ helper T-cell subset, which provides for B-cell activation and production of specific antibody responses, and play a critical role in the development of autoimmune disease. So far, only one study investigated the circulating Tfh cells increased in a subset of SLE patients. Since relatively little is known about the Tfh cells in rheumatoid arthritis (RA) patients, in this study, Tfh-cell frequency, related cytokine IL-21, and transcription factor Bcl-6 were investigated in 53 patients with RA and 31 health controls. Firstly, we found that the frequency of CD4+CXCR5+ICOShigh Tfh cells was increased significantly in the peripheral blood of RA patients, compared with that in healthy controls. It is known that Tfh cells are critical for directing the development of an antibody response by germinal centers B cells; secondly, we observed that the Tfh-cell frequency is accompanied by the level of anti-CCP antibody in RA patients. Furthermore, expression of Bcl-6 mRNA and plasma IL-21 concentrations in RA patients was increased. Taken together, these findings have shown that the increased frequency of circulating Tfh cells is correlated with elevated levels of anti-CCP antibody, indicating the possible involvement of Tfh cells in the disease progression of RA.

Tumour necrosis factor blockade for the treatment of erosive osteoarthritis of the interphalangeal finger joints: a double blind, randomised trial on structure modification

BackgroundAdalimumab blocks the action of tumor necrosis factor-α and reduces disease progression in rheumatoid arthritis and psoriatic arthritis. The effects of adalimumab in controlling progression of structural damage in erosive...

Correlation between radiographic, echographic and MRI changes and rheumatoid arthritis progression

To review the imaging methods used for the evaluation of disease progression in rheumatoid arthritis (RA) and to evaluate the results of their application in pharmacological trials. Literature articles dealing with radiology, echography, and magnetic resonance imaging (MRI) of patients with RA were evaluated in a non-systematic fashion. Conventional radiology is the gold standard for the evaluation of disease progression in RA because of its diffusion, economy, and standardization. Different techniques have been proposed to evaluate radiological damage of the joints, with the Larsen's and Sharp's methods being most widely used. These methods are commonly used for the evaluation of the ability of DMARDs to slow RA progression. Among traditional DMARDs, gold salts, sulphasalazine, methotrexate, cyclosporin, and leflunomide have shown efficacy in slowing the appearance of new erosions. The same effect has been recently demonstrated for infliximab plus methotrexate, anakinra and etanercept. However, conventional radiology has several disadvantages, because it is monoplanar and has a low sensitivity to change. Newer imaging techniques, such as echography and MRI are extensively studied and have been used occasionally in the mediumterm evaluation of DMARDs, with promising results. Although conventional radiology is still the gold standard for the evaluation of disease progression in RA, newer techniques are increasingly studied. In particular, standardization of echographic and MRI imaging of the joints is in progress.

Nonsteroidal Anti-Inflammatory Drugs Increase TNF Production in Rheumatoid Synovial Membrane Cultures and Whole Blood

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase activity and hence PG production. However, the ability of NSAIDs to ameliorate pain and tenderness does not prevent disease progression in rheumatoid arthritis, a disease whose pathogenesis is linked to the presence of proinflammatory cytokines, such as TNF-alpha. To understand this observation, we have examined the effect of NSAIDs on the production of clinically validated proinflammatory cytokines. We show that a variety of NSAIDs superinduce production of TNF from human peripheral blood monocytes and rheumatoid synovial membrane cultures. A randomized, double-blinded, crossover, placebo-controlled trial in healthy human volunteers also revealed that the NSAID drug celecoxib increased LPS-induced TNF production in whole blood. NSAID-mediated increases in TNF are reversed by either the addition of exogenous PGE(2) or by a PGE(2) EP2 receptor agonist, revealing that PGE(2) signaling via its EP2 receptor provides a valuable mechanism for controlling excess TNF production. Thus, by reducing the level of PGE(2), NSAIDs can increase TNF production and may exacerbate the proinflammatory environment both within the rheumatoid arthritis joint and the systemic environment.

Clinical efficacy of TNF-α inhibitors: an update

Over the last decade, TNF-α antagonists became the most powerful tools for controlling patient suffering from a number of rheumatic diseases. Infliximab, etanercept and adalimumab can induce remission and prevent both clinical and radiological disease progression in rheumatoid arthritis with significant improvement in patients’ symptoms, function and quality of life. They improve joint symptoms and significantly retard radiographic progression in psoriatic arthritis. TNF-α antagonists have been demonstrated to reduce disease activity, retard radiologic progression and increase quality of life in ankylosing spondylitis patients. Long-term follow-up studies demonstrated sustained efficacy and acceptable safety profiles that were comparable in rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. Etanercept is the only US FDA-approved TNF antagonist for juvenile rheumatoid arthritis. TNF-α antagonists may improve some clinical manifastations of Behcet’s disases, including uveitis. Tuberculosi...

Integrative modeling of transcriptional regulation in response to antirheumatic therapy

BackgroundThe investigation of gene regulatory networks is an important issue in molecular systems biology and significant progress has been made by combining different types of biological data. The purpose of this study was to characterize the transcriptional program induced by etanercept therapy in patients with rheumatoid arthritis (RA). Etanercept is known to reduce disease symptoms and progression in RA, but the underlying molecular mechanisms have not been fully elucidated.ResultsUsing a DNA microarray dataset providing genome-wide expression profiles of 19 RA patients within the first week of therapy we identified significant transcriptional changes in 83 genes. Most of these genes are known to control the human body's immune response. A novel algorithm called TILAR was then applied to construct a linear network model of the genes' regulatory interactions. The inference method derives a model from the data based on the Least Angle Regression while incorporating DNA-binding site information. As a result we obtained a scale-free network that exhibits a self-regulating and highly parallel architecture, and reflects the pleiotropic immunological role of the therapeutic target TNF-alpha. Moreover, we could show that our integrative modeling strategy performs much better than algorithms using gene expression data alone.ConclusionWe present TILAR, a method to deduce gene regulatory interactions from gene expression data by integrating information on transcription factor binding sites. The inferred network uncovers gene regulatory effects in response to etanercept and thus provides useful hypotheses about the drug's mechanisms of action.

Disease modifying and antiangiogenic activity of 2-Methoxyestradiol in a murine model of rheumatoid arthritis

BackgroundA critical component of disease progression in rheumatoid arthritis (RA) involves neovascularization associated with pannus formation. 2-methoxyestradiol (2ME2) is a naturally occurring molecule with no known physiologic function, although at pharmacologic concentrations it has antiproliferative and antiangiogenic activities. We investigated the impact of orally administered 2ME2 on the initiation and development of proliferative synovitis using the anti-collagen monoclonal antibodies (CAIA) model.MethodsSevere polyarticular arthritis was induced in Balb/c female mice by administration of 2 mg of a monoclonal antibody cocktail intravenously into the tail vein of mice. Twenty-four hours following monoclonal antibody administration, mice were injected with 25 μg of LPS (E. coli strain 0111:B4) via the intraperitoneal route. Treatment with 2ME2 (100, 75, 50, 25, 10, 1 mg/kg, p.o., daily), or vehicle control began 24 hrs following LPS challenge and continued to day 21. Hind limbs were harvested, sectioned and evaluated for DMARD activity and general histopathology by histomorphometric analysis and immunohistochemistry (vWF staining). In a separate study, different dosing regimens of 2ME2 (100 mg/kg; q.d. vs q.w. vs q.w. × 2) were evaluated. The effect of treatment with 2ME2 on gene expression of inflammatory cytokines and angiogenic growth factors in the joint space was evaluated 5 and 14 days after the induction of arthritis.ResultsMice treated with 2ME2 beginning 24 hours post anti-collagen monoclonal antibody injection, showed a dose-dependent inhibition in mean arthritic scores. At study termination (day 21), blinded histomorphometric assessments of sectioned hind limbs demonstrated decreases in synovial inflammation, articular cartilage degradation, pannus formation, osteoclast activity and bone resorption. At the maximal efficacious dosing regimen (100 mg/kg/day), administration of 2ME2 resulted in total inhibition of the study parameters and prevented neovascularization into the joint. Examination of gene expression on dissected hind limbs from mice treated for 5 or 14 days with 2ME2 showed inhibition of inflammatory cytokine message for IL-1β, TNF-α, IL-6 and IL-17, as well as the angiogenic cytokines, VEGF and FGF-2.ConclusionThese data demonstrate that in the CAIA mouse model of RA, 2ME2 has disease modifying activity that is at least partially attributable to the inhibition of neovascular development. Further, the data suggests new mechanistic points of intervention for 2ME2 in RA, specifically inhibition of inflammatory mediators and osteoclast activity.

CM1 Enhances Proinflammatory cytokine Production in Peripheral Blood Mononuclear Cells and Synovial Fluid Mononuclear Cells from Rheumatoid Arthritis Patients (99.53)

Abstract CM1 (centrocyte/-blast marker 1) is expressed on the surface of activated peripheral blood mononuclear cells (PBMCs). Recently, we found that the production of prostaglandin E2 (PGE2) from activated PBMCs was increased by CM1 stimulation via the activation of nuclear factor kappa B (NF-kB). Therefore, this study was attempted to investigate the roles of CM1 in the regulation of rheumatoid arthritis (RA). PBMCs were purified from healthy donors, RA patients and degenerative osteoarthritis (OA) patients, and knee joint synovial fluid mononuclear cells (SFMCs) were purified from RA patients. The expression of CM1 on PBMCs and SFMCs were analyzed by flowcytometry. The production of inflammatory cytokines and PGE2 by CM1 stimulation was measured by ELISA and chromatin immunoprecipitation (ChIP) assay and immunoblotting were performed to examine signaling mediators for inflammatory cytokines by CM1 stimulation. CM1 is highly expressed on PBMCs and SFMCs from RA patients, but not from OA patients. TNF-alpha, IL-1 alpha/beta, IFN-gamma and PGE2 production were markedly increased in PBMCs and SFMCs of RA patients upon CM1 stimulation. The phosphorylation of p38 MAPK was increased in PBMCs and SFMCs from RA patients in a time dependent manner after CM1 stimulation. In addition, the binding of NF-kB to the promoters of TNF-alpha and IL-1 beta after CM1 stimulation was also confirmed by the ChIP assay. Our results strongly suggest that CM1 may play a critical role in the disease progression of RA via the induction of disease-related proinflammatory cytokines and PGE2 production.

Targeting Cytokines, Chemokines and Adhesion Molecules in Rheumatoid Arthritis

The therapy of rheumatoid arthritis (RA) was revolutionized by basic research studies and biopharmaceutical development of the first generation of anti-rheumatic biologic agents (i.e. biological response modifiers), which targeted the pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and interleukin-6 (IL-6). Further studies resulted in biological response modifiers that have also targeted activated T- and B-lymphocytes both of which play a prominent role in RA pathogenesis and disease progression. Despite the relatively impressive RA diseasemodifying effects of these biologic agents during the post-FDA approval period, there are reports of moderate to severe adverse events associated with their continuous use. Additionally, there is accumulating evidence indicating that antirheumatic biologic agents, while dampening RA disease activity as measured by the American College of Rheumatology (ACR) criteria in clinical trials or other arthritis disease activity instruments employed in studies after approval of these anti-rheumatic medicines by the FDA do not entirely halt the erosive joint cartilage and bone destruction characteristic of RA. There is also still some uncertainty as to how long the available anti-rheumatic biologics can be continuously employed as RA therapies. Since the development of TNF-α/IL-1/IL-6 anti-rheumatic biologics, several additional cytokines with pro-inflammatory activity as well as their receptors, which initiate upstream pathophysiologic effects, have been identified and characterized. In several cases, these cytokines have been cloned and sequenced. Thus, cytokines, such as IL-7, IL12/IL-23, IL-15, IL-16, IL-17/IL-18, IL-19/IL-20/IL-22 and IL-32, have been implicated in arthritis development in animal models of RA and measurements in synovial tissue and synovial fluid obtained from patients with RA also suggested a role for them in RA disease progression, if not in its pathogenesis. There has also been compelling evidence that cytokines with chemokine-activity and adhesion molecules also play a crucial role in RA via their capacity to recruit and retain leukocytes, macrophages, monocytes and endothelial-cell complexes in RA synovial joints. Taken together, non-TNF-α/non-IL-1/non-IL-6 cytokines, chemokines and their receptors as well as adhesion molecules appear to be worthwhile targets for drug development in RA.

Antibody responses to Porphyromonas gingivalis ( P. gingivalis) in subjects with rheumatoid arthritis and periodontitis

Summary Antibody titers to P. gingivalis are increased in patients with rheumatoid arthritis and are associated with disease-specific autoimmunity. Background Periodontitis (PD) has been implicated as a risk factor for rheumatoid arthritis (RA). We sought to characterize antibody titers to P. gingivalis (a pathogen in PD) in subjects with RA, PD, and in healthy controls and to examine their relationship with disease autoantibodies. Methods P. gingivalis antibody was measured in subjects with RA ( n = 78), PD ( n = 39), and in controls ( n = 40). Group frequencies of bacterial titer elevations were compared using the Chi-square test and antibody titers were compared using non-parametric tests. Correlations of P. gingivalis titer with C-reactive protein (CRP), antibody to cyclic citrullinated peptide (anti-CCP), and rheumatoid factor (RF) were examined in those with RA while CRP and autoantibody concentrations were compared based on seropositivity to P. gingivalis. Results Antibody titers to P. gingivalis were highest in PD, lowest in controls, and intermediate in RA ( p = 0.0003). Elevations in P. gingivalis (titer ≥ 800) were more common in RA and PD (67% and 77%, respectively) than in controls (40%) ( p = 0.002). In RA, there were significant correlations with P. gingivalis titer with CRP, anti-CCP-IgM, and -IgG-2. CRP ( p = 0.006), anti-CCP-IgM ( p = 0.01) and -IgG2 ( p = 0.04) concentrations were higher in RA cases with P. gingivalis titers ≥ 800 compared to cases with titers < 800. Conclusion Antibodies to P. gingivalis are more common in RA subjects than controls, although lower than that in PD. Associations of P. gingivalis titers with RA-related autoantibody and CRP concentrations suggests that infection with this organism plays a role in disease risk and progression in RA.