Etiology Of Rheumatoid Arthritis Research Articles

Etiologies of Rheumatoid Arthritis: Update on Mucosal, Genetic, and Cellular Pathogenesis.

Purpose of ReviewOver the last few years, the scientific community has made significant progress in understanding the etiology of rheumatoid arthritis (RA). In this review, we summarize those key findings and trends.Recent FindingsNew data strongly implicates respiratory exposures, obesity, diet and microbiome, genetics, and their interactions in the etiology of RA. Furthermore, anti-posttranslationally modified protein antibodies (AMPAs) and abnormal glycosylation may be additional biomarkers for RA. Finally, functional genomics techniques implicate loss of certain macrophage populations and proliferation of synovial fibroblasts in RA.SummaryThese findings support the notion that RA originates at mucosal sites, augmented by genetic predisposition, and mediated by certain cell types including macrophages and fibroblasts. Weight loss, physical activity, and diet are additional modifiable factors beyond smoking cessation that can reduce risk of RA. Future epidemiologic and translational studies leveraging multi-omics approaches will help map the precise sequence of events in RA pathogenesis.

Increased Extracellular ATP in Plasma of Rheumatoid Arthritis Patients Activates CD8+T Cells

Rheumatoid arthritis (RA) is an autoimmune disorder with genetic and environmental causes often linked with the disease etiology. A disrupted metabolism has often been a characteristic of RA and an altered metabolic state of immune cells has been associated with their phenotypic and functional changes. The energy in the form of ATP produced by the metabolically active cells may thus initiate a cascade of immune responses there by influencing the disease pathogenesis or progression. Through this study we have focused on determining the role of ATP in etiology of RA and aberrant cellular functions. Blood samples of 80 healthy controls (HC) and 95 RA patients were screened for extracellular ATP concentration, transcriptome analyses, an inflammatory mediator and the results were statistically analysed. In this study, ATP is shown to be excessive in the plasma of RA patients (453.5±16.09% in RA vs. 233.9±10.07% in HC, p<0.0001) and significantly increases with the disease severity. The abundant extracellular ATP could activate circulating cytotoxic CD8+T cells in RA patients to produce Granzyme B. Plasma ATP is thus identified to have a significant potential in progression and prognosis of RA and may thus be studied further to design better therapeutic approaches for the disease.

Rheumatoid arthritis in low-level toluene-exposed workers based on nationwide medical surveillance data in Korea.

There is growing evidence that exposure to organic solvents can play a role in the etiology of rheumatoid arthritis (RA). This prospective cohort study aimed to investigate the association between RA and toluene exposure. The study cohort consisted of Korea Occupational Safety and Health Agency data from male workers exposed to toluene who had undergone a toluene-associated special medical examination at least once between January 1, 2000 and December 31, 2004 (n = 148,870). The morbidity from RA based on hospital admission records was estimated from 2000 to 2005 using National Health Insurance Claim Data. The standardized admission ratio (SAR) for RA was calculated with reference to the general population. Levels of urinary hippuric acid (HA), a metabolite of toluene, were measured and used for exposure assessment. Toluene-exposed workers were at an elevated risk of seropositive rheumatoid arthritis (ICD-10 code M05) with an SAR of 2.38 (95% confidence interval [CI]: 1.14-4.37) and other rheumatoid arthritis (M06) with an SAR of 1.22 (95% CI: 0.91-1.59). When data were stratified according to the duration of toluene exposure and by tertiles of urinary HA level, no significant difference was apparent. SARs of the toluene-exposed workers are higher than that of the general reference population, indicating that exposure to toluene may contribute to an increased risk of RA. Further studies of toluene-exposed workers with longer follow-up are needed.

Relationship between clinical and laboratory findings of rheumatoid arthritis patients with their oral status and disease activity.

Background:Rheumatoid arthritis (RA) is the most common chronic inflammatory joint disease. Complications of RA can cause low quality of life and disabilities. Nowadays, despite all the medical developments, etiology of RA is unclear. Both soft and hard tissue damages occur in RA and periodontitis due to chronic inflammation and also since tissue damage presentation and pathogenesis of RA and periodontitis are the same, this study was done for evaluating the relationship between clinical and laboratory findings in RA patients with their oral status and disease activity.Methods:This case-control study was performed on 236 patients; 118 RA patients and 118 cases of normal people. Gingivitis, dental caries and plaques, oral hygiene and severity of periodontitis were measured based on gingival index, plaque index, clinical attachment level, Decayed Missing Filled index and oral hygiene index-simplified. Disease activity was assessed according to Diseases Activity Score-28. Blood samples were taken to evaluate the level of anti-CCP, RF, ESR, CRP, and CBC. Data were analyzed by t-test and chi-square.Results:RA patients are more susceptible to periodontitis, plaque formation and dental caries. There is a relationship among RA disease and periodontitis, oral hygiene, gingivitis. There is also a reverse relationship between RF level and periodontitis severity likewise dental caries. There is no significant relationship between other laboratory findings and the oral status of patients.Conclusion:This is more likely for RA patients to experience periodontitis which can destruct alveoli bone and it can also cause early tooth loss. Regular examination and early treatment are highly recommended.

Exosomes derived from synovial fibroblasts under hypoxia aggravate rheumatoid arthritis by regulating Treg/Th17 balance.

A comparative study of osteoarthritis (OA) and RA mice was implemented to suggest that miR-424 expression was increased in RA, and exosome-miR-424 derived from synovial fibroblasts (SFs-exo) could significantly induce T cells differentiation in which Th17 cells increased and Treg cells decreased via targeting FOXP3. And thus, miR-424 may be a potential therapeutic target for RA.

Synovial Fluid Cell Proteomic Analysis Identifies Upregulation of Alpha-Taxilin Proteins in Rheumatoid Arthritis: A Potential Prognostic Marker

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease affecting the joints and surrounding tissue. Identification of novel proteins associated with the progression of a disease is a prerequisite for understanding the pathogenesis of RA. The present study was undertaken to identify the potential biomarkers from a less explored biological sample such as synovial fluid (SF) cells which is specific for RA and to analyze their functional aspects using proteomic approach. Two-dimensional gel electrophoresis (2-DE) was performed using synovial fluid cells of RA and osteoarthritis (OA) patients, and 7 differentially expressed proteins were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS/MS). Αlpha-Taxilin (α-Taxilin) has been found as one of the novel, significantly up regulated protein in RA. It has been validated in the synovium, synovial fluid (SF), SF cells, and plasma samples by Western blot, enzyme-linked immunosorbent assay (ELISA), fluorescence-activated cell sorting (FACS), immunohistochemistry (IHC), and real-time PCR. The identification of autoantibody against α-Taxilin and in silico studies has further helped us to understand its involvement in disease mechanism. The present study will therefore provide knowledge towards the etiology of RA that pave the way for suitable prognostic marker identification along with other clinical parameters.

Associations of Plasma Extravesicular (EV) MicroRNA Levels in Seropositive and Seronegative Rheumatoid Arthritis (RA)

Rheumatoid arthritis (RA) is an autoimmune disease associated with inflammation. This disease, exacerbated by lower socioeconomic status, disproportionately hinders the quality of life for Hispanic populations. Although the etiology of this disease is still unclear, many speculate the role of epigenetic factors. Among the epigenetic mechanisms proposed to mediate RA are microRNAs (miRNAs). These are a class of small noncoding RNA molecules which predominantly are involved in the post‐transcriptional regulation of gene expression. We hypothesize specific circulating miRNA targets can identify the RA phenotype, and correlate with clinical characteristics of the disease. To test this hypothesis, thirty Hispanic individuals recruited to the Epigenetics of RA (ERA) study samples were investigated. microRNAs were extracted from the serum circulating extracellular vesicles (exosomes) of twenty‐one RA patients and six controls. Levels of 800 miRNA targets were measured blindly using the Nanostring nCounter miRNA Expression Panel and analyzed using nSolver Analysis Software. Five miRNAs (miR‐1261, miR‐4532, miR‐802, miR‐595, miR‐373‐3p) were differentially expressed between seropositive and seronegative RA (p≤0.05). miR‐802 and miR‐1261 positively correlated with ACPA levels (Pearson Coeff.ACPA= 0.608, p=0.001) and ID Pain (Pearson Coeff.ID Pain= 0.472, p=0.041), respectively. No other RA clinical variables were correlated with miRNA levels. Discriminant function analysis identify miR‐1261 (p=0.004) and ACPA (p=0.002) as the strongest biomarkers differentiating seronegative from seropositive RA. We are currently validating these miRNAs associations with RA by qPCR. Understanding which miRNAs play a pivotal role in the etiology of RA in Hispanic patients can provide opportunities to address health disparities in this disease.

P147 Prevalence of anti-cyclic citrullinated peptide (ACCP) antibodies and their association with rheumatoid factors and other autoimmune parameters

Abstract Background The presence of antibodies against cyclic citrullinated proteins (anti-CCP) precede the development of rheumatoid arthritis (RA) and both anti-CCP antibody and RF positivity indicate more severe disease. This characteristic makes Anti-CCP best biomarker candidate for the prevention of debilitating joint disease. Almost 70% of RA patients are positive for anti-CCP IgG, while only 2% of control subjects are positive for anti-CCP. Understanding the origins of anti-CCP is critical in unraveling the etiology of RA, so we further evaluated the association of the other autoimmune tests/biomarkers with Anti-CCP to describe other comorbid autoimmune diseases/syndrome. Methods We conducted a retrospective analysis of patient data from April 18, 2016, to May 29, 2019, in Texas. The study protocol was approved by the ethics review committee and patients consented for sharing their demographics, clinical information and lab values for diagnostic and research purposes. The study population was described by descriptive statistics. Demographic characteristics and laboratory parameters were compared using chi-square tests. We analyzed blood tests/parameters conducted at the clinics and explored their association with the presence of ACCP. logistic regression models were utilized to calculate the odds ratio to delineate the strength of association of different blood parameters with ACCP. IgG anti-CCP was determined according to the manufacturer’s instruction. Results Eleven thousand, four hundred fifty-nine tests were performed on 7,200 patients with a mean age of 52 years (range 0-98). Almost half (54%) of study individuals were females, two-third (63%) were White, (29%) Hispanic and (7%) African American. Four hundred and six patients (3.5%) were positive for AntiCCP3.1. Among those who were positive for AntiCCP3.1, (22%) were Rh factor IgA (RhIgA) positive, (11%) RhIgG positive, and (9%) RhIgM. Univariate logistic regression showed that the female gender was positively associated (OR = 3.19) with ACCP presence while patients older than 50 had a positive gradient of ACCP positivity with each age category. Compared to White, African Americans were more likely (OR = 3.19) and Hispanics were less likely (OR = 0.44) to be associated with AntiCCP positivity. After controlling for age, gender and ethnicity the presence of RhIgM and RhIgA antibodies were positively associated with positive ACCP. (OR = 13.3, OR = 5.2). antiphosphatidylserine IgM and anticardiolipin IgM antibodies were positively associated with ACCP (OR = 2.1, OR = 3.4). Similarly, the presence of antimitochondrial M2 antibodies and anti-topoisomerase antibodies (SCL-70) were very significantly associated with ACCP (OR = 16.1, OR = 37.8). Conclusion The Anti-CCP antibodies are highly specific for the early diagnosis of RA and with early initiation of treatment, progression to irreversible and destructive diseases can be prevented. Association of Anti-CCP antibodies with other autoimmune antibodies highlights the importance of screening RA patients for primary biliary sclerosis and scleroderma. Similarly, a biomarker's strength of interaction with another biomarker helps in the prognostic utility of these test for preventing co-existing diseases. Disclosures M. Ayass: Other; Physician at Ayass Bioscience. K. Zhu: Other; Employee at Ayass Bioscience. S. Naveed: None. L. Mosleh: Other; Employee at Ayass Bioscience. K. Viswanathan: Other; Employee at Ayass Bioscience. G. Nowshad: Other; Employee at Ayass Bioscience.

Diagnostic Role of Survivin in Rheumatoid Arthritis: A Systematic Review.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, which is characterized by the hyperplasia of synovial tissue. Survivin is a member of the inhibitor of apoptosis protein family, which facilitates the formation of functional T-cell receptor and differentiation of memory T cells. Survivin plays an important role in the expression of major histocompatibility complex molecules and mature dendritic cells, which play the main role in the etiology of RA. This systematic review was conducted to investigate the evidence on the role of survivin as a diagnostic and predictive value in RA patients. All published articles related to the subject of interest and published up to 30 March 2018 were searched in three databases, including Google Scholar, PubMed, and Web of Science. After a detailed evaluation of the full-text version of the papers, 23 articles were entered into the study. The elevation of survivin in the preclinical phase of RA and its association with anti-cyclic citrullinated peptide (CCP) antibodies suggested it as a predictor of RA. Recently, survivin has been introduced as the biomarker of joint damage and poor response to antirheumatic treatment in RA patients. Based on the evidence, survivin level had high specificity and sensitivity in the diagnosis of RA patients. The results of the reviewed studies demonstrated that a positive survivin level was associated with the presence of anti-CCP antibodies.

Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population

ObjectiveThe causality and pathogenic mechanism of microbiome composition remain elusive in many diseases, including autoimmune diseases such as rheumatoid arthritis (RA). This study aimed to elucidate gut microbiome’s role in...

Autoantibodies against citrullinated serum albumin in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, potentially debilitating, inflammatory disease that primarily affects synovial joints. While the etiology of RA remains incompletely understood, it is clear that the disease is autoimmune in nature. A hallmark of RA is that the specific epitopes on self-antigens that are targeted by the immune system are often modified by arginine deimination, also referred to as citrullination. In fact, anti-citrullinated protein autoantibodies (ACPA) at high enough titers are diagnostic of RA and appear to have many different targets. Here, we report that RA patients have IgG autoantibodies that react with human serum albumin (HSA) when it had been citrullinated by protein arginine deiminase (PAD) 4, but not by PAD2. Unmodified albumin was not recognized by autoantibodies. In a cohort of 79 RA patients, 38% had anti-citrullinated HSA (anti-cit-HSA) reactivity above the cut-off of the average plus two standard deviations in a healthy subject cohort (n = 16). The titers of these autoantibodies correlated with ACPA status and seropositivity. There was also a trend toward correlation with the presence of radiographic joint erosions, but this did not reach statistical significance. Finally, patients with anti-cit-HSA were more frequently treated with biologics and combination regimens than patients without these autoantibodies. We conclude that ACPA directed against citrullinated albumin exist in a subset of RA patients. Because of the abundance of albumin, its modification by citrullination, as well as autoantibodies binding to it, may have deleterious consequences for the health of affected RA patients.

Occupational exposure to organic dusts and risk of developing rheumatoid arthritis: findings from a Swedish population-based case–control study

ObjectivesWe estimated the association between occupational exposures to five different organic dusts: wood, animal, paper, textile and flour dust and the risk of developing rheumatoid arthritis (RA).MethodsThis population-based case–control study...

Identification of putative miRNA biomarkers in early rheumatoid arthritis by genome-wide microarray profiling: A pilot study

Despite the existing research, the etiology of rheumatoid arthritis (RA), an autoimmune disease remains poorly understood with early and accurate diagnosis difficult to achieve. MicroRNAs (miRNAs) play an important role in biological processes as modulators of transcription and translation. Previous studies have demonstrated a downregulation of several genes in early RA stages and in addition, miRNAs may serve as early biomarkers of subclinical changes in early RA.When comparing the four groups (ANOVA P < 0.01, fold change > 4), we found 253 differentially expressed miRNAs. Of these, 97 miRNAs were identified as overexpressed in early rheumatoid arthritis. The validation of miRNA microarray expression was performed in a set by RT-qPCR and showed strong agreement with microarray expression data. The putative targets of overexpressed microRNAs in early RA were significantly enriched in apoptosis, tolerance loss and Wnt pathways. Moreover, ROC analysis showed values of AUC 0.76 and P < 0.05 for miR 361-5p, identifying this miRNA as a potential biomarker of disease.We identified specific microRNAs associated with early rheumatoid arthritis and proposed them as early biomarkers of disease. Our results provide novel insight into immune disease physiopathology and describe unreported microRNAs in RA with potential for clinical use.

Galectin-9 Is a Possible Promoter of Immunopathology in Rheumatoid Arthritis by Activation of Peptidyl Arginine Deiminase 4 (PAD-4) in Granulocytes.

The aetiology of rheumatoid arthritis (RA) is unknown, but citrullination of proteins is thought to be an initiating event. In addition, it is increasingly evident that the lung can be a potential site for the generation of autoimmune triggers before the development of joint disease. Here, we identified that serum levels of galectin-9 (Gal-9), a pleiotropic immunomodulatory protein, are elevated in RA patients, and are even further increased in patients with comorbid bronchiectasis, a lung disease caused by chronic inflammation. The serum concentrations of Gal-9 correlate with C-reactive protein levels and DAS-28 score. Gal-9 activated polymorphonuclear leukocytes (granulocytes) in vitro, which was characterized by increased cytokine secretion, migration, and survival. Further, granulocytes treated with Gal-9 upregulated expression of peptidyl arginine deiminase 4 (PAD-4), a key enzyme required for RA-associated citrullination of proteins. Correspondingly, treatment with Gal-9 triggered citrullination of intracellular granulocyte proteins that are known contributors to RA pathogenesis (i.e., myeloperoxidase, alpha-enolase, MMP-9, lactoferrin). In conclusion, this study identifies for the first time an immunomodulatory protein, Gal-9, that triggers activation of granulocytes leading to increased PAD-4 expression and generation of citrullinated autoantigens. This pathway may represent a potentially important mechanism for development of RA.

Oxidative Stress Status In Patients With Rheumatoid Arthritis.

Background: Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis, which is an autoimmune disease characterized by chronic inflammation of synovial joints, ultimately leading to joint destructions and permanent disability. In RA oxidative stress are impaired (which caused by free radicals) might have an essential role in the etiology of RA. Objectives: The objective of this study was to determine oxidative stress by measuring malondialdehyde and enzymatic status by estimating superoxide dismutase, catalase and glutathione peroxidase in patients of RA and then comparing with healthy individuals. Setting and design:&nbsp;&nbsp; A total 42 patients with Rheumatoid Arthritis (20 females, 22 males) in the age of 30-50 years were included, as a control, 50 matched healthy volunteers (20 females and 30 males) were involve, non of the subjects smokes nor receiving any form of drugs. Subjects with any acute infections or with coexisting system disease such as coronary artery disease, hypertension or chronic renal failure were excluded. Methods: Antioxidant enzymes in erythrocyte , superoxide dismutase (SOD), glutathione peroxidase (Gpx)&nbsp; and Cayalase (CAT) was measured. Malondialdehyde (MDA) along with Copper, Zink and Iron are measured by using the serum of the patients and control group. Results: The serum level of MDL was higher in RA patients compared with the control group, the differences among both groups was statistically significant (P &lt; 0.001) Conclusion There is oxidative stress in RA patients evidenced by increased serum MDA and decreased antioxidant enzymes activity.

Risk of cancer after long-term therapy of autoimmune disorders with glucocorticoids or DMARDs—a controversial issue

Most autoimmune diseases like RA (rheumatoid arthritis) are usually associated with lifelong treatment. The etiology of RA remains unclear, but it depends on a high-risk genetic background and an environmental trigger, which leads to autoimmune dysregulation and results in autoinflammation. This process preferentially affects joints but may spread to different organs and systems. Several studies have illustrated that patients with RA have an increased overall incidence of malignancy compared to the general population (risk of 5–10%). However, it remains unclear if biological agents like DMARDs (disease-modifying antirheumatic drugs) are associated with a potential increased risk of generating new neoplasms. Data indicate that it is unlikely that RA patients who have received biological agents have a much higher risk of developing lymphoproliferative disorder, other hematologic malignancies or solid tumors compared to MTX (methotrexate) users. In most cases, it also depends on the activity of the underlying rheumatic disease. Thus, clinical decision making must carefully weigh benefits and risks of both aspects of antirheumatic treatment and the risk of elevating the likelihood of developing cancer. The decision to treat with a DMARD must always be based on clinical features and reflect the risk pattern of the individual patient. Up to now, there is no clear evidence that proves the link between long-term DMARD or glucocorticoid use and the increased incidence of newly developed neoplasms. The pathophysiological context is still not well understood and the underlying link between RA and lymphoma still needs to be addressed.

Evaluation of Toll-like Receptor 2 Gene Expression in Rheumatoid Arthritis and Correlation with the Disease Activity

Background: Rheumatoid Arthritis (RA) is an autoimmune, chronic, and systematic disease. It affects joints and bones. The exact etiology of RA is still unclear. Varied genetic and environmental factors have been associated with the increased risk for RA. Overactivation of Toll-Like Receptors (TLRs) could initiate the development of autoimmune diseases including RA. Objective: The aim of the study was to evaluate TLR2 gene expression in rheumatoid arthritis patients and investigate its correlation with the disease activity. Materials and Methods: This study included 60 patients and 20 healthy individuals. The patients were diagnosed with RA according to the 2010 American College of Rheumatology/ European League Against Rheumatism criteria (ACR/EULAR). All included subjects did not have any joint disorders and /or autoimmune diseases. RA disease activity was determined by the disease activity score of 28 joints. Whole blood was collected from all participants. Total RNA extraction was done. TLR2 mRNA expression was assessed by reverse transcription-PCR (RT-PCR). Results: TLR2 mRNA expression was found to be significantly higher in RA patients compared to healthy controls. Also, a strong positive correlation was found between TLR2 expression level and the disease activity score. A non significant positive correlation was found between TLR2 expression and serum Rheumatoid Factor (RF) level. Conclusion: TLR2 pathway may have an important role in RA pathogenesis and could be a new biomarker for diagnosis and monitoring disease activity.

Investigation of the Asp299Gly and Thr399Ile polymorphisms of TLR4 gene in Rheumatoid Arthritis

Objective: Rheumatoid arthritis (RA) is a chronic and inflammatory disease characterized by synovial inflammation that causes cartilage and bone destruction as well as systemic defects, including cardiovascular, pulmonary, psychological, and skeletal disorders. The etiology of RA is unclear. Evidence suggests that RA is influenced by both genetic and environmental factors and the inflammatory and autoimmune activities take important roles in the development of this disease. In the onset of RA, an interaction between the resident cells of synovium and cells of the innate and adaptive immune system reported. Fibroblast-like synoviocytes (FLS) are one of the resident cells and they play a central role, with a tumor-like behavior, in joint destruction and development of chronic inflammation. Toll-like receptors (TLRs) are transmembrane glycoproteins that are related to inflammation via synthesis of proinflammatory cytokines like TNF-α, IL-6, and IL-1β. Some studies report an association between the activation of FLS and the cytokine environment, cell-to-cell contacts, or the activation of TLR2, TLR4, and TLR3. TLRs and especially TLR4 is involved in the recognition of endogenous molecules released by injured tissues and necrotic cells. TLR4 gene involved in a wide variety of both infectious and non-infectious diseases and two polymorphisms of TLR4, Asp299Gly and Thr399Ile, changed the binding capacity and electrical charge of the protein. There are conflicting or even contradictory results about these polymorphisms and we aimed to determine the distribution of the allele frequencies of these polymorphisms and compare the result of RA patients with healthy subjects. Methods: DNA extraction was realized by salting out method from peripheral blood lymphocytes of RA patients and healthy controls. PCR amplification carried out with appropriate primer pairs against the related DNA sequences. Genotyping performed by the restriction fragment length polymorphism method. Results and Conclusion: According to the results obtained from RA patients and healthy controls, we have not found any statistical difference between both groups. Including the other polymorphisms of the TLR family into this type of studies, will give more information about the role of TLR family in rheumatoid arthritis.

Epigenetic Changes in the Pathogenesis of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease that affects about 1% of the world’s population. The etiology of RA remains unknown. It is considered to occur in the presence of genetic and environmental factors. An increasing body of evidence pinpoints that epigenetic modifications play an important role in the regulation of RA pathogenesis. Epigenetics causes heritable phenotype changes that are not determined by changes in the DNA sequence. The major epigenetic mechanisms include DNA methylation, histone proteins modifications and changes in gene expression caused by microRNAs and other non-coding RNAs. These modifications are reversible and could be modulated by diet, drugs, and other environmental factors. Specific changes in DNA methylation, histone modifications and abnormal expression of non-coding RNAs associated with RA have already been identified. This review focuses on the role of these multiple epigenetic factors in the pathogenesis and progression of the disease, not only in synovial fibroblasts, immune cells, but also in the peripheral blood of patients with RA, which clearly shows their high diagnostic potential and promising targets for therapy in the future.

Anti-Inflammatory Action of Blueberry Polyphenols in HIG-82 Rabbit Synoviocytes.

Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease resulting in joint destruction and disability in the adult population. The etiology of RA is not well understood and presently there is no known cure for this disease. The accumulation and proliferation of fibroblast-like synoviocytes may be involved in cartilage destruction. Both in vitro and in vivo studies support an anti-inflammatory role of dietary polyphenols, the bioactive constituents found in fruits and vegetables. The objective of this study was to investigate the anti-inflammatory role of blueberry polyphenols (BBPs) using rabbit synoviocytes stimulated with tumor necrosis factor alpha (TNFα). Rabbit synoviocytes (HIG-82) were treated with varying doses of BBPs and stimulated with TNFα. Stimulation of rabbit synoviocytes with the proinflammatory cytokine TNFα increased cell proliferation by ∼19% compared with the nonstimulated control. Cell proliferation was significantly decreased in a dose-dependent manner by the treatment with BBPs. Post-TNFα stimulation, cells treated with BBPs resulted in decreases in interleukin 1 beta and nuclear factor kappa B (NFκB) concentration. Reverse transcription-polymerase chain reaction analysis showed that matrix metalloproteinase 3 increased fivefold in the control TNFα-stimulated group, but was decreased by threefold in the blueberry treatment group. These results suggest that downregulation of proinflammatory cytokines and transcription factor NFκB by naturally occurring bioactives such as BBPs may be a potential therapeutic strategy for reducing inflammation associated with RA.