Chronic Synovial Inflammation Research Articles

Have the annual trends of total hip arthroplasty in rheumatoid arthritis patients decreased?

Rheumatoid arthritis (RA) is characterized by chronic systemic and synovial inflammation, resulting in damage to both cartilage and bone. Medical treatment, which has increasingly relied upon disease modifying anti-rheumatic drugs (DMARDs), may fail to slow disease progression and limit joint damage, ultimately warranting surgical intervention. Up to 25% of RA patients will require lower extremity total joint arthroplasty. Though total hip arthroplasty (THA) is known to improve quality of life and functional measures, clarification is still required with respect to the impact of increased DMARD use on annual rates of THA. Thus, the purpose of this study was to evaluate: (I) the annual trends of THAs due to RA in the United States population; (II) the annual trends in the proportion of THAs due to RA in the United States. This study utilized the Nationwide Inpatient Sample (NIS) to identify all patients who underwent THA between 2002 and 2013 (n=3,135,904). Then, THA patients who had a diagnosis of RA, which was defined by the International Classification of Disease 9th revision diagnosis code 714.0, were identified. The incidence of THAs with a diagnosis of RA in the United States was calculated using the United States population as the denominator. Regression models were used to analyze the annual trends of RA in patients who underwent THA. Review of the database identified 90,487 patients who had a diagnosis of RA and underwent THA from 2002 to 2013. The annual prevalence of RA in those who underwent THA slightly decreased over the specified time period, with 28.7 per 1,000 THAs in 2002 and 28.6 per 1,000 THAs in 2013; however, this change was not statistically significant (R2=0.158, P=0.200). The annual rates of THA among RA patients did not show any significant change between 2002 and 2013. DMARD use has decreased both disease progression and joint destruction, and DMARDs are now often utilized as primary treatment. The increase in population of the country during the study period may have overestimated THA trends. Moreover, patients may be more likely to opt for surgical management, given the advances in operative techniques as well as peri- and post-operative course.

Circular RNA expression profiles of peripheral blood mononuclear cells in rheumatoid arthritis patients, based on microarray chip technology.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovial inflammation and finally leads to variable degrees of bone and cartilage erosion. The diagnosis of RA is not an accurate indicator, but a series of scores and the mechanisms underlying it remain only partially understood. The present study explored whether circular RNAs (circRNAs) contribute to the RA pathophysiological mechanism. Total RNA from peripheral blood mononuclear cells of 10 RA patients and 10 healthy controls were extracted and circRNA expression profiling was followed by microarray analysis. In addition, circRNA interactions with microRNAs were performed and microRNA response elements were listed to identify differentially expressed binding site targets in RA. Reverse transcription-quantitative polymerase chain reaction amplification (RT-qPCR) was used to verify the differential expression of circRNAs. A total of 584 circRNAs were differentially expressed in RA patients vs. healthy controls, by circRNA microarray, including 255 circRNAs which were significantly upregulated and 329 downregulated among the RA samples. RT-qPCR validation demonstrated that the expression levels of hsa_circRNA_104194, hsa_circRNA_104593, hsa_circRNA_103334, hsa_circRNA_101407 and hsa_circRNA_102594 were consistent with the results from the microarray analysis. The current study presented differentially expressed circRNAs and their corresponding microRNA binding sites in RA. circRNAs may exhibit a role in the regulation of expression of symbol genes that influence the occurrence and development of RA.

The Contribution of Serum Anti–cyclic Citrullinated Peptide Antibody and Matrix Metalloproteinase-3 in Predicting the Activity of Rheumatoid Arthritis Disease

Background: Rheumatoid arthritis is an autoimmune disease characterized by chronic synovial inflammation. The insufficient immune clearance of the apoptotic cell results into the formation of anti-cyclic citrullinated peptide antibodies which may play a critical role in the initiations of inflammatory responses. These antibodies together with Matrix Metalloproteinase-3 play an important role in joint destruction in rheumatoid arthritis disease.Objectives: to study the value of anti-cyclic citrullinated peptide antibodies, and Matrix Metalloproteinase-3 in differentiation between active and inactive rheumatoid arthritis.Patients and Methods: A cross- sectional study was conducted on 60 Iraqi patients with rheumatoid arthritis (16 males and 44 females) aging from 29 to 74 years who presented to the Rheumatology Consultation Clinic of Baghdad Teaching Hospital / Medical City during the period of July 2013 to the end of October 2013. The patients were divided, according to rheumatoid arthritis activity depending on Disease Activity Score 28 and erythrocyte sedimentation rate, into two groups: 30 patients with active rheumatoid arthritis and the other 30 patients with inactive rheumatoid arthritis. Quantitative sandwich enzyme immunoassay technique was used to measure serum level of anti-cyclic citrullinated peptide antibodies, and Matrix Metalloproteinase-3.Results: The means concentration of anti-cyclic citrullinated peptide antibodies, and Matrix Metalloproteinase-3 were significantly higher in rheumatoid arthritis cases with active disease compared to those with inactive disease. The disease activity index DAS28 showed a statistically significant strong positive (direct) linear correlation with serum MMP3 (r=0.762) and serum ACCP (r=0.806). In addition, serum MMP3 showed a statistically significant moderately strong positive (direct) linear correlation with serum ACCP (r=0.64). Both serum MMP3 and ACCP had a higher validity than blood ESR (which is used itself in calculating DAS28) is predicting an active disease status.Conclusion: Anti-cyclic citrullinated peptide antibodies and Matrix Metalloproteinase-3 could be useful biological markers for assessment of rheumatoid arthritis disease activity.

No Increased Risk for Primary Osteoarthritis in Liver Cirrhosis - A Danish Nationwide Cohort Study.

ObjectiveChronic synovial inflammation causes primary osteoarthritis, but it is unknown whether chronic systemic inflammation does, too. Patients with cirrhosis have chronic systemic inflammation and therefore we examined the association between cirrhosis and primary osteoarthritis of the hip and knee.MethodsIn Danish healthcare databases we identified all residents over 60 years diagnosed with cirrhosis in 1994–2011, and for each of them we sampled five age- and gender-matched reference persons from the general population. We excluded everyone with risk factors for secondary osteoarthritis and computed incidence rates of primary osteoarthritis of the hip or knee. We used stratified Cox regression to estimate the hazard ratios of primary osteoarthritis for cirrhosis patients vs. reference persons in strata defined by gender, age, cirrhosis etiology, and ascites vs. no ascites. We also computed separate HRs for primary osteoarthritis of the hips or knees.ResultsWe identified 10,049 cirrhosis patients. Their median age was 67 years, and 65% were men. Among the cirrhosis patients the crude incidence rate of primary osteoarthritis was 8.40 (95% CI: 7.30–9.63) per 1000 person-years. The rate was similar in the reference persons: 8.76 (95% CI: 8.43–9.12) per 1000 person-years. Accordingly, the hazard ratio for primary osteoarthritis for cirrhosis patients vs. reference persons was 0.99 (95% CI: 0.85–1.16), and we found the same null association in all patient strata and in both joints.ConclusionCirrhosis, and thus chronic systemic inflammation, is not a risk factor for primary osteoarthritis.

Cigarette Smoke Induces Immune Responses to Vimentin in both, Arthritis-Susceptible and -Resistant Humanized Mice.

Rheumatoid arthritis (RA) is an autoimmune disease marked by chronic synovial inflammation and both, genetic and environmental factors are involved in its pathogenesis. Human leukocyte antigen (HLA) DRB1*0401 is associated with susceptibility to develop RA, while cigarette smoke (CS) exposure promotes seropositive disease with increased severity in DRB1*0401+ individuals. Smokers have higher levels of antibodies against citrullinated peptides. In this study, we determined whether the response to a known autoantigen, Vimentin (Vim) is shared epitope specific and how CS influences this response using transgenic-mice carrying RA-susceptible,*0401, and -resistant, *0402, genes. Following relatively brief exposure to CS, peptidyl arginine deiminase (PAD) enzyme expression was increased in murine lungs. Cigarette smoking led to production of Interferon (IFN)-γ with reduced levels of Interleukin (IL)-10 by splenocytes of *0401 mice. In contrast, CS augmented Th2 cytokines along with T-regulatory cells in *0402 mice. An increase in levels of antibodies to native and citrullinated Vim was observed in naïve mice of both strains following CS exposure. Our data showed that both arthritis-susceptible and -resistant mice can generate cellular and humoral immunity to Vim; however CS-induced modulation of host immunity is dependent on the interaction with the host HLA genes.

Imaging in paediatric rheumatology: Is it time for imaging?

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of arthritides characterized by chronic synovial inflammation that can lead to structural damage. The main objective of JIA therapies is to induce disease control to avoid disability in childhood. The advances in therapeutic effectiveness have created a need to search for imaging tools that describe more precisely disease activity in children with JIA. Musculoskeletal ultrasound and magnetic resonance imaging have demonstrated to be more sensitive than clinical examination in early detection of synovitis. These modalities can detect both inflammatory and destructive changes. The unique characteristics of the growing skeleton and a scarce validation of imaging in children result in important challenges in evaluating paediatric population. This review describes indications and limitations of these imaging techniques and suggests some advices for a rational use in the management of JIA in clinical practice.

Correlation Between the Expression of MicroRNA-301a-3p and the Proportion of Th17 Cells in Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation and subsequent joint destruction. Previous studies have confirmed that Th17 cells play a critical role in the pathogenesis of RA. MicroRNA (miR)-301a-3p is a regulatory factor for Th17cells differentiation that contributes to the pathogenesis of autoimmune diseases. The purposes of this study were to identify the alteration of Th17 cells and analyze the correlation between the expression of the miR-301a-3p and the proportion of Th17 cells in RA patients. The results showed that the frequency of Th17 cells and the expression of transcription factors (RORγt and STAT3) significantly increased in the peripheral blood mononuclear cells (PBMCs) from RA patients, and the associated proinflammatory cytokines were also upregulated. We also observed that the expression of protein inhibitor of activated STAT3 (PIAS3), the main cellular inhibitor of STAT3, was attenuated in RA patients and negatively correlated with the percentage of Th17 cells in RA. Interestingly, miR-301a-3p, an inhibitor of PIAS3 expression, was overexpressed in the PBMCs from RA patients and positively correlated with the frequency of Th17 cells in patients with RA. Taken together, these data indicated that miR-301a-3p and Th17 cells were augmented in peripheral blood, which may play an important role in the process of RA.

SPECIFIC FEATURES OF THE IMMUNE STATUS IN RHEUMATOID ARTHRITIS IN RELATION TO THE CLIMATIC, GEOGRAPHICAL, AND ENVIRONMENTAL ZONES OF UZBEKISTAN

The feature of rheumatoid arthritis (RA) is the predominant clinical picture of chronic synovial joint inflammation accompanied by progressive cartilage and bone destruction, the pathogenesis of which is greatly due to autoimmune mechanisms. Some investigations demonstrate that a set of poor climatic and geographical factors may influence the development of immune disorders that are a trigger in the development of RA. Objective: to comparative analyze immunological parameters in RA in dwellers from different regions of Uzbekistan. Subjects and methods. The study enrolled RA patients from three Uzbekistan zones: 1) Tashkent (n = 25), 2) Xorazm Region (n = 25); 3) Namangan Region (n = 28). Results and discussion. Comparative analysis of the immune status indicated that the patients living in Zone 2 exhibited a significantly reduced T cell immune response (p < 0.05), a considerably higher count of B lymphocytes (p < 0.001), and significantly lower levels of CD11b+, CD18+, CD25+, and CD95+ cells (p < 0.05) than did those from the two other zones. Examination of the frequency of the monomorphic determinant of histocompatibility Class I (HLA-I) antigens revealed its significant decrease in the patients residing in Zones 1 and 3 (p < 0.05) whereas the RA patients from Zone 2 had a significantly higher frequency of HLA-DR (p < 0.05). Conclusion. The comparative analysis shows that the immunological parameters differ in the patients from the three zones of Uzbekistan, which may suggest that the climatic and geographical factors of the environment may influence the course of the disease.

Neutrophil Transmigration into the Joint of RA-Induced Mouse Is Markedly Blocked By EC-18, Via STAT3 Signaling

▪Neutrophil trafficking during the inflammatory response is effectively regulated by the enhanced IL-6 expression which orchestrates chemokine production and leukocyte apoptosis. Inappropriate regulation of leukocyte trafficking can lead to impaired neutrophil clearance and increased tissue damage from the accumulation of neutrophil-secreted proteases and reactive oxygen species at the site of inflammation. In collagen-induced arthritis (CIA) mouse model, arthritic symptoms were recapitulated with an increase of IL-6 level in the synovium, which was recuperated by the treatment of EC-18 to the level comparable with commercial therapeutics (such as Remicade or Methotrexate). When the tissues were stained with neutrophil-specific antibodies, EC-18 significantly reduced the infiltration of neutrophils into the synovium. EC-18, a monoacetyl-diglyceride (1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol), has been isolated from the antlers of Sika deer (Cervus nippon Temminck), which were known to have immunosuppressive and anti-arthritic activities. In this study, we have discovered that EC-18 regulates the activity of signal transducer and activator of transcription 3 (STAT3), which is a master regulator of IL-6 expression. EC-18 caused the decrease of IL-6 production in a macrophage cell line, RAW264.7, and RA-fibroblast-like synoviocyte (RA-FLS) via the regulation of STAT3 signaling without affecting NF-κB signaling, which is also a well-known regulator of IL-6 expression. The expression of RANKL, a key factor for osteoclast differentiation and activation, was also regulated by STAT3, and decreased by EC-18 treatment. In fact, EC-18 inhibited osteoclastogenesis of hematopoietic stem cells. Therefore, blocking STAT3 activity by EC-18 treatment was able to inhibit the inflammatory cytokine loop triggering RANKL expression, thereby inhibiting joint destruction. Cardinal features of rheumatoid arthritis (RA) are chronic synovial inflammation and joint damage caused by the activity of cytokines and proteins expressed from cells in synovial fluid. Interleukin (IL)-6, a multifunctional pro-inflammatory cytokine, plays a critical role in the pathogenesis of joint and systemic inflammation in RA. Therefore, EC-18 could be utilized as a potential therapeutic agent for the treatment of sustained inflammation and joint destruction. DisclosuresNo relevant conflicts of interest to declare.

Monitoring Therapy Response of Experimental Arthritis with Radiolabeled Tracers Targeting Fibroblasts, Macrophages, or Integrin αvβ3.

Rheumatoid arthritis is an autoimmune disease resulting in chronic synovial inflammation. Molecular imaging could be used to monitor therapy response, thus enabling tailored therapy regimens and enhancing therapeutic outcome. Here, we hypothesized that response to etanercept could be monitored by radionuclide imaging in arthritic mice. We tested 3 different targets, namely fibroblast activation protein (FAP), macrophages, and integrin αvβ3. Male DBA/1J mice with collagen-induced arthritis were treated with etanercept. SPECT/CT scans were acquired at 1, 24, and 48 h after injection of (111)In-RGD2 (integrin αvβ3), (111)In-anti-F4/80-A3-1 (antimurine macrophage antibody), or (111)In-28H1 (anti-FAP antibody), respectively, with nonspecific controls included. Mice were dissected after the last scan, and scans were analyzed quantitatively and were correlated with macroscopic scoring. Experimental arthritis was imaged with (111)In-28H1 (anti-FAP), (111)In-anti-F4/80-A3-1, and (111)In-RGD2. Tracer uptake in joints correlated with arthritis score. Treatment decreased joint uptake of tracers from 23 ± 15, 8 ± 4, and 2 ± 1 percentage injected dose per gram (%ID/g) to 11 ± 11 (P < 0.001), 4 ± 4 (P < 0.001), and 1 ± 0.2 %ID/g (P < 0.01) for (111)In-28H1, (111)In-anti-F4/80-A3-1, and (111)In-RGD2, respectively. Arthritis-to-blood ratios (in mice with arthritis score 2 per joint) were higher for (111)In-28H1 (5.5 ± 1; excluding values > 25), (111)In-anti-F4/80-A3-1 (10.4 ± 4), and (111)In-RGD2 (7.2 ± 1) than for control (111)In-DP47GS (0.7 ± 0.5; P = 0.002), (111)In-rat IgG2b (0.5 ± 0.2; P = 0.002), or coinjection of excess RGD2 (3.5), indicating specific uptake of all tracers in arthritic joints. (111)In-28H1, (111)In-anti-F4/80-A3-1, and (111)In-RGD2 can be used to specifically monitor the response to therapy in experimental arthritis at the molecular level. Further studies, however, still need to be performed.

Primary Hypertrophic Osteoarthropathy: An Update on Patient Features and Treatment

To the Editor: Hypertrophic osteoarthropathy (HO) is a disorder characterized by changes to the skin and bones, and occurs either in a rare familial primary form [primary hypertrophic osteoarthropathy, (PHO)], also called pachydermoperiostosis (PDP), with a 9:1 male:female prevalence ratio, or more commonly secondary to an underlying pathology1. Key features include digital clubbing, periostosis with bone and joint enlargement, and skin changes, such as pachydermia, abnormal furrowing, seborrhea, and hyperhidrosis. Specific developmental abnormalities have been found in some patients with PHO, such as wide cranial sutures, Wormian bones, and patent ductus arteriosus 2. In adults, when all major clinical features are present, PHO is relatively easy to diagnose. However, for the pediatrician, who often has to contend with an incomplete clinical presentation3, diagnosis may be a challenge. The discovery of mutations in 2 prostaglandin pathway genes HPGD and SLCO2A1 has clarified the autosomal recessive inheritance [Mendelian Inheritance in Man (MIM) #259100, MIM #614441] of this genetically heterogeneous condition4,5,6,7. Here we present 4 previously undescribed patients who exemplify the gene-dependent presentations of PHO and provide diagnostic and treatment advice. The subjects’ written consent was obtained in conformance to the Declaration of Helsinki. Key clinical features are listed in Table 1. Secondary causes of HO were excluded8, and DNA sequence analysis (Supplementary Data available online at jrheum.org) confirmed the clinical diagnoses of PHO/PDP. View this table: Table 1. Patients’ clinical features. A 20-year-old male patient had begun limping at the age of 14 months. At 3 years old, chronic arthritis of both knees was investigated by arthroscopy, with nonspecific chronic synovial inflammation at biopsy. Oligoarticular juvenile idiopathic arthritis (JIA) was diagnosed, and the patient was treated with nonsteroidal antiinflammatory drugs (NSAID), with clinical improvement. At age 5, coarse facies was noted. … Address correspondence to Dr. Gabriella Giancane, Department of Pediatric Immunology, University Medical Centre Utrecht, 3508 AB, Utrecht, the Netherlands. E-mail: gabriella.giancane{at}gmail.com, ggiancan{at}umcutrecht.nl

Vaccine development for rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic synovial joint inflammation, destruction of articular cartilage and erosion of subchondral bone. Major advances have been made in the medical management of RA with the introduction of various types of biologic drugs which neutralize the activity of pro-inflammatory cytokines as well as T-cell and B-cell proliferation. Furthermore, a Janus Kinase small molecule inhibitor which suppresses Signal Transducers and Activators of Transcription protein phosphorylation has now been added to the RA drug armamentarium. Despite the development of these novel drugs, there are still no “preventive” measures available for RA. The recent discovery that autoantibodies are produced against cyclic citrullinated proteins/peptides in a significant number of individuals with or without undifferentiated arthritis which can precede the clinical symptoms of RA has provided an impetus for a prophylactic vaccine therapy for RA. Experimental evidence which showed that various vaccine formulations ameliorated arthritis in well-validated animal models has now led to the development of “Rheumavax” which has already been evaluated with promising results in a phase I RA clinical trial.

Treatment of rheumatoid arthritis by molecular-targeted agents: efficacy and limitations

Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation due to unknown causes. Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biological DMARDs (bDMARDs), and tofacitinib, a targeted sDMARD, can be used to treat RA. In clinical trials, molecular-targeted therapies showed a significant reduction in RA symptoms and provided pain relief for patients with active RA. Even if patients did not show clinical improvement with combination therapy with a bDMARD and methotrexate (MTX), some patients showed a significant inhibition in structural damage. The clinical efficacies of tofacitinib were shown to be equivalent to adalimumab, a bDMARD, in patients with RA treated with MTX. MTX is the first-line agent for the treatment of RA. Higher doses of MTX might be needed to maintain the effects of bDMARDs. Patients receiving some bDMARDs have been shown to have a higher risk for serious infections; thus, pre-screening for infections is important before beginning treatment with bDMARDs. The rates of patients maintaining targeted levels of disease activity after stopping bDMARDs are relatively low. It is uncertain whether remission or low disease activity can be maintained after stopping molecular-targeted therapies. The development of bDMARDs and targeted-molecular sDMARDs has provided a wide range of treatment options for RA. Patients with active RA should be treated with a treat-to-target strategy after assessment of risks and benefits.

Disease activity improvement in rheumatoid arthritis treated with tumor necrosis factor-α inhibitors correlates with increased soluble Fas levels.

Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation and hyperplasia. Tumor necrosis factor-α (TNF-α) plays a pivotal role in RA by interfering with the Fas-Fas ligand (FasL) proapoptotic pathway. We investigated the circulating levels of soluble Fas (sFas) and soluble FasL (sFasL), and their possible correlation with disease activity and improvement after anti-TNF-α treatment in RA. Serum levels of sFas and sFasL were measured by quantitative ELISA in 52 patients with RA before and after 3 months of anti-TNF-α treatment (adalimumab, n = 32; infliximab, n = 20). Disease activity measures [Disease Activity Score at 28 joints-erythrocyte sedimentation rate (DAS28-ESR), C-reactive protein (CRP)] were recorded before and after treatment. Forty age-matched and sex-matched healthy subjects served as controls. No significant differences in serum sFas levels were detected between anti-TNF-α-naive patients with RA and controls. After anti-TNF-α treatment, serum sFas levels significantly increased in patients with RA compared to both anti-TNF-α-naive patients and controls. Increased sFas levels inversely correlated with disease activity variables (DAS28-ESR: r = -0.739, CRP: r = -0.636, both p < 0.001). No significant differences in sFasL levels were detected in patients with RA before and after anti-TNF-α treatment. In RA, an increase in sFas levels closely correlates with improvement in disease activity induced by TNF-α inhibitors, suggesting their ability to modulate Fas-mediated synoviocyte apoptosis.

Ginsenoside metabolite compound k alleviates adjuvant-induced arthritis by suppressing T cell activation.

Ginsenoside metabolite compound K (CK) is the degradation product of ginsenosides in the intestine by bacteria and has many pharmacological activities including anti-inflammatory effects. Rheumatoid arthritis (RA) is an inflammatory and autoimmune disease characterized by chronic synovial inflammation and articular damage in multiple joints. However, the effect of CK on RA remains unclear. In this study, the effect of CK on adjuvant arthritis (AA) and the underlying mechanisms that focused on T cell activation were investigated. Complete Freund's adjuvant was used to induce AA rats. After the onset of arthritis, rats were given CK (10, 40, and 160 mg/kg) or MTX (0.5 mg/kg). To evaluate the severity of arthritis, arthritis index and paw swelling were evaluated every 3 days. Histopathology of joint and spleen were assayed. Subsets of T cells including CD4+CD62L+ (naïve T cells), CD4+CD25+ (activated T cells), and CD4+CD25 + Foxp3+ cells (Treg) and CD25 expression were assayed by flow cytometry. Proliferation of T cell was evaluated by (3)H-TdR. IL-2 level was assayed by ELISA. We found that CK attenuated arthritis index and paw swelling, restored the histopathological change of joint and spleen, downregulated the percentage of activated T cells, and upregulated naïve T cells and Treg cells in spleen. CK significantly suppressed T cell activation (as indicated by T cell proliferation, CD25 expression, and IL-2 production). In conclusion, our results suggest that CK alleviates autoimmune arthritis by suppressing T cell activation.

Iguratimod Synergizes with Methotrexate to Exert Anti-Inflammatory and Bone-Protective Effect and Block the Progression of Collagen-Induced Arthritis in Mices

Rheumatoid Arthritis (RA) is an autoimmune disease characterized by chronic synovial inflammation and disability. The most widely used Disease-Modifying Antirheumatic Drug (DMARD) is methotrexate and it continues to be the gold standard. However, the use of high-dose methotrexate is associated with severe adverse effects. Iguratimod, which is currently used in clinics in China and Japan, is a novel oral DMARD for the treatment of RA. In this study, the effect of combination of methotrexate and iguratimod on murine Collagen-Induced Arthritis (CIA) and its mechanism was determined. Oral administration of iguratimod (3 mg/kg, 10 mg/kg) combined with methotrexate (1 mg/kg) potently blocked CIA development and delayed its progression, which was stronger than iguratimod or methotrexate used alone. Furthermore, infiltration of inflammatory cells into the synovium was remarkably inhibited by combination therapy and importantly, no bone erosion and joint destructions were observed in combination therapy group. In addition, combined administration of these two DMARDs suppressed production of cytokines (IL-17, IFN-γ, IL-6 and TNF-α) and antibodies (IgG and IgG2b) in serum, as well as humoral and cellular responses in CIA mice. Consistent with its effects in vivo, iguratimod combined with methotrexate significantly suppressed T and B cells responses in vitro. Taken together, our findings suggest that combination treatment with iguratimod and methotrexate should be an intriguing and preferable therapeutic strategy for treating RA.

Impact of rheumatoid arthritis on sexual function.

Sexuality is a complex aspect of the human being's life and is more than just the sexual act. Normal sexual functioning consists of sexual activity with transition through the phases from arousal to relaxation with no problems, and with a feeling of pleasure, fulfillment and satisfaction. Rheumatic diseases may affect all aspects of life including sexual functioning. The reasons for disturbing sexual functioning are multifactorial and comprise disease-related factors as well as therapy. Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by progressive joint destruction resulting from chronic synovial inflammation. It leads to various degrees of disability, and ultimately has a profound impact on the social, economic, psychological, and sexual aspects of the patient's life. This is a systemic review about the impact of RA on sexual functioning.

The importance of early treatment for the prognosis of rheumatoid arthritis

Chronic synovial inflammation in rheumatoid arthritis (RA) leads to progressive damage to articular cartilage and bone, ultimately resulting in disability. Therefore, control of the articular inflammation is of great importance to prevent joint damage. A variety of disease-modifying antirheumatic drugs (DMARDs) are available for RA patients. Conventional synthetic DMARDs, and in particular biological DMARDs, have been shown to effectively inhibit joint destruction in RA. Longitudinal assessments of radiographic changes in patients with RA in clinical trials and in large patient registries have clearly shown that delays in the initiation of DMARD therapy results in significantly increased progression of joint damage. Patients started early on DMARDs had significantly lower radiographic damage progression than patients initiating DMARD treatment later. These effects were maintained for several years, suggesting that early in the development of RA a therapeutic window of opportunity exists in which DMARD therapy decisively influences the long-term prognosis. Therefore, to improve the clinical outcome of RA, our efforts should be directed towards diagnosing RA earlier and introducing DMARD therapy immediately after the diagnosis has been made.

A Metabolically-Stabilized Phosphonate Analog of Lysophosphatidic Acid Attenuates Collagen-Induced Arthritis

Rheumatoid arthritis (RA) is a destructive arthropathy with systemic manifestations, characterized by chronic synovial inflammation. Under the influence of the pro-inflammatory milieu synovial fibroblasts (SFs), the main effector cells in disease pathogenesis become activated and hyperplastic while releasing a number of signals that include pro-inflammatory factors and tissue remodeling enzymes. Activated RA SFs in mouse or human arthritic joints express significant quantities of autotaxin (ATX), a lysophospholipase D responsible for the majority of lysophosphatidic acid (LPA) production in the serum and inflamed sites. Conditional genetic ablation of ATX from SFs resulted in attenuation of disease symptoms in animal models, an effect attributed to diminished LPA signaling in the synovium, shown to activate SF effector functions. Here we show that administration of 1-bromo-3(S)-hydroxy-4-(palmitoyloxy)butyl-phosphonate (BrP-LPA), a metabolically stabilized analog of LPA and a dual function inhibitor of ATX and pan-antagonist of LPA receptors, attenuates collagen induced arthritis (CIA) development, thus validating the ATX/LPA axis as a novel therapeutic target in RA.

OP0239 Phenotypic and Molecular Profile of Innate Lymphoid Cells in Chronic Synovial Inflammation

BackgroundInnate lymphoid cells (ILCs) represent a novel family of effector and regulatory cells in innate immunity and tissue remodelling [1]. The family comprises several phenotypically and functionally distinct subsets that...