Active RA Patients Research Articles

Identification of follicular helper T cells as a novel cell population potentially involved in the pathogenesis of Rheumatoid Arthritis (HUM3P.251)

Abstract Background. RA is an autoimmune disease characterized by chronic inflammation of the synovium, causing progressive joint destruction. The treatment for RA is largely based on the clinic manifestations, which are remote from the fundamental pathophysiologic defects. Identification of cellular subsets or biomarkers is a necessary first step toward more accurate prognosis and better therapeutic decisions. Here, we identified a novel T cell subset, follicular helper T cells (Tfh) in RA patients, and examined the hypothesis that Tfh cells may account for RA pathogenesis by providing a fostering environment for self-reactive B cells, resulting in autoantibody production. Methods. Peripheral blood was collected from 26 RA patients and healthy donors. Synovial fluid from actively inflamed joints of RA patients was also collected. Clinical disease activity (DAS-28) and serum laboratory results were obtained. Tfh cells were defined by their signature surface markers via flow cytometry. IL-21 expression and plasmablasts were measured by intracellular staining. Results. A novel T cell subset with Tfh cell signature molecule and cytokine was expanded in the peripheral blood of active RA patients. The percentage of Tfh cells correlated positively with the level of pathogenic auto-antibody (anti-CCP) and disease activity. Conclusions. Circulating Tfh cells may serve as a biomarker of pathogenesis in RA patients. Targeting RA-Tfh cells may provide earlier and precise treatment strategies.

The TH17/Treg Imbalance in Rheumatoid Arthritis and Relation to Disease Activity

Objectives: T regulatory cells (Treg) and proinflammatory TH17 cells are newly identified T lymphocyte subsets, which have significant effects on autoimmunity and inflammation. Tregs play key role in the maintenance of self-tolerance. TH17/Treg disturbed balance has been reported to contribute to several autoimmune diseases.Our aim was to assess the Treg/TH17 pattern and TH17 related cytokines, in peripheral blood of Egyptian rheumatoid arthritis patients, and their relation to disease activity score (DAS). Analyzing IL17A and IL23 as indicators of TH17 function, was to study the effect of TH17 in RA.Methods: 100 Egyptian rheumatoid arthritis patients, divided into Group I (14), Group II (48), Group III (38), with low 5.1, activity DAS score respectively; and 50 healthy age and sex matched controls were enrolled. Peripheral blood TH17 and Treg (CD4+CD25+Foxp3+) frequencies were analyzed by flowcytometry, and the serum levels of interleukins (IL17A), (IL23) were determined by ELISA.Results: Active RA patients (groups II and III) revealed an obvious increase in peripheral TH17 frequencies, and levels of TH17-related cytokines, and a significant decrease in Treg (CD4+CD25+Foxp3+) frequencies in group III, when compared to healthy controls. TH17/Treg ratios were positively correlated with serum concentrations of IL17A and IL23 cytokines. Frequencies and levels showed statistical significant correlation with DAS scoring.Conclusions: Our study indicated that TH17/Treg balance was disturbed in peripheral blood of RA patients, leading to an increase of proinflammatory cytokines, correlating with DAS, and suggesting an important role in the development of RA.

Asymptomatic atherosclerosis in egyptian rheumatoid arthritis patients and its relation to disease activity.

Aim. To detect the frequency of subclinical atherosclerosis in rheumatoid arthritis patients without clinically evident atherosclerosis and to correlate its presence with the disease activity. Patients and Methods. Our study includes 112 RA patients (group 1) and 40 healthy controls (group 11). All patients and controls were subjected to full history taking, clinical examination, and laboratory investigations. Carotid intima media wall thickness (IMT) and carotid plaques were measured in both groups by B-mode ultrasonography; also color duplex Doppler ultrasound of the brachial artery was done to detect endothelial function. Results. There is atherosclerosis in 31.3% of asymptomatic RA patients compared with only 5% in controls (P = 0.003**). A significant difference was detected in patients with and without atherosclerosis regarding duration of the disease (P = 0.0001***) and patient's age (P = 0.01*). There is highly statistical significant correlation between atherosclerosis and disease activity index. Conclusion. The frequency of subclinical atherosclerosis was high in long-term active RA patients.

Randomised controlled trial of Tumour necrosis factor inhibitors Against Combination Intensive Therapy with conventional disease-modifying antirheumatic drugs in established rheumatoid arthritis: the TACIT trial and associated systematic reviews

Rheumatoid arthritis (RA) is initially treated with methotrexate and other disease-modifying antirheumatic drugs (DMARDs). Active RA patients who fail such treatments can receive tumour necrosis factor inhibitors (TNFis), which are effective but expensive. We assessed whether or not combination DMARDs (cDMARDs) give equivalent clinical benefits at lower costs in RA patients eligible for TNFis. An open-label, 12-month, pragmatic, randomised, multicentre, two-arm trial [Tumour necrosis factor inhibitors Against Combination Intensive Therapy (TACIT)] compared these treatment strategies. We then systematically reviewed all comparable published trials. The TACIT trial involved 24 English rheumatology clinics. Active RA patients eligible for TNFis. The TACIT trial compared cDMARDs with TNFis plus methotrexate or another DMARD; 6-month non-responders received (a) TNFis if in the cDMARD group; and (b) a second TNFi if in the TNFi group. The Heath Assessment Questionnaire (HAQ) was the primary outcome measure. The European Quality of Life-5 Dimensions (EQ-5D), joint damage, Disease Activity Score for 28 Joints (DAS28), withdrawals and adverse effects were secondary outcome measures. Economic evaluation linked costs, HAQ changes and quality-adjusted life-years (QALYs). In total, 432 patients were screened; 104 started on cDMARDs and 101 started on TNFis. The initial demographic and disease assessments were similar between the groups. In total, 16 patients were lost to follow-up (nine in the cDMARD group, seven in the TNFi group) and 42 discontinued their intervention but were followed up (23 in the cDMARD group and 19 in the TNFi group). Intention-to-treat analysis with multiple imputation methods used for missing data showed greater 12-month HAQ score reductions with initial cDMARDs than with initial TNFis [adjusted linear regression coefficient 0.15, 95% confidence interval (CI) -0.003 to 0.31; p = 0.046]. Increases in 12-month EQ-5D scores were greater with initial cDMARDs (adjusted linear regression coefficient -0.11, 95% CI -0.18 to -0.03; p = 0.009) whereas 6-month changes in HAQ and EQ-5D scores and 6- and 12-month changes in joint damage were similar between the initial cDMARD group and the initial TNFi group. Longitudinal analyses (adjusted general estimating equations) showed that the DAS28 was lower in the initial TNFi group in the first 6 months (coefficient -0.63, 95% CI -0.93 to -0.34; p < 0.001) but there were no differences between the groups in months 6-12. In total, 36 patients in the initial cDMARD group and 44 in the initial TNFi group achieved DAS28 remission. The onset of remission did not differ between groups (p = 0.085 on log-rank test). In total, 10 patients in the initial cDMARD group and 18 in the initial TNFi group experienced serious adverse events; stopping therapy because of toxicity occurred in 10 and six patients respectively. Economic evaluation showed that the cDMARD group had similar or better QALY outcomes than TNFi with significantly lower costs at 6 and 12 months. In the systematic reviews we identified 32 trials (including 20-1049 patients) on early RA and 19 trials (including 40-982 patients) on established RA that compared (1) cDMARDs with DMARD monotherapy; (2) TNFis/methotrexate with methotrexate monotherapy; and (3) cDMARDs with TNFis/methotrexate. They showed that cDMARDs and TNFis had similar efficacies and toxicities. Active RA patients who have failed methotrexate and another DMARD achieve equivalent clinical benefits at a lower cost from starting cDMARDs or from starting TNFis (reserving TNFis for non-responders). Only a minority of patients achieve sustained remission with cDMARDs or TNFis; new strategies are needed to maximise the frequency of remission. Current Control Trials ISRCTN37438295. This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 66. See the NIHR Journals Library website for further project information.

AB0006 Genetic Susceptibility Variants for Rheumatoid Arthritis do not Associate with Radiological Progression in Early Active Disease

BackgroundSeveral studies have tested the hypothesis that RA susceptibility variants associate with radiological progression. Their findings are often not replicated; additionally they have examined only a proportion of risk loci...

AB1177-HPR Occupational Characterization in A Cohort of Rheumatoid Arthritis Patients – Correlation with Disease Activity and Functional Status

BackgroundRheumatoid arthritis (RA) is a disease that in most cases is associated with disability and loss of earning capacity. There is a lack of information about occupation of rheumatoid arthritis...

AB0019 Change in MRNA Expression of Sirtuin-2 and Sirtuin-3 in Rheumatoid Arthritis

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory disease. Sirtuins (SIRTs) are class III histone deacetylase and mammalian SIRT family has seven members, named SIRT1 to SIRT7. SIRTs act epigenetic roles...

SAT0218 Validating Responsiveness and Discrimination of the Rheumatoid Arthritis Magnetic Resonance Imaging SCORE (RAMRIS) – A Meta-Analysis of Randomized Controlled Trials (RCTS) Identified in A Systematic Literature Review

BackgroundRadiographs (hands ± feet) measured with total Sharp scores (TSS) are considered the reference standard for quantifying structural damage in RA clinical trials. Magnetic resonance imaging (MRI) is increasingly utilized...

THU0489 Enho Gene Expression and Serum Adropin Level in Rheumatoid Arthritis and Systemic Lupus Erythematosus

BackgroundRheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are chronic inflammatory diseases. Adipokines, including leptin, adiponectin, resistin, and visfatin have been studied widely in chronic inflammatory diseases due to the...

FRI0370 Over-Expression of Sublining Bcl6 Correlates with Hyperplasia of Synovitis in Rheumatoid Arthritis

BackgroundThe pathological basis in RA is synovitis characterized by hyperplasia of synovial lining and synovial stroma with neovascularisation and inflammatory infiltration. B-cell lymphoma (Bcl) 6 is a nuclear sequence-specific transcriptional...

97. Final 5-Year Safety and Efficacy Results of a Phase 3, Randomized, Placebo-Controlled Trial of Golimumab in Methotrexate-NaïVe Patients with Rheumatoid Arthritis

randomized controlled trial (RCT)—the Combination Anti-Rheumatic Drugs in Early RA (CARDERA) trial—to examine whether responses to intensive combination treatments in early RA differ by ACPA status. Methods: The CARDERA trial randomized 467 patients with early active RA to receive: (i) MTX (ii) MTX/ciclosporin (iii) MTX/prednisolone or (4) MTX/ciclosporin/prednisolone in a factorial-design. Patients were assessed 6 monthly for 2 years. In this analysis we evaluated 431 patients with archived serum available for ACPA status determination (using the anti-CCP2 ELISA assay). To minimize multiple testing we used a mixed-effects repeated measures ANOVA model to test for an interaction between ACPA and treatment on mean changes from baseline for each outcome (Larsen, DAS28, HAQ, EuroQol, PCS and MCS scores). When a significant interaction was present, mean changes in outcomes were compared by treatment group at each time point stratified by ACPA status using t-tests. Odds ratios (ORs) for the onset of new erosions with treatment were calculated stratified by ACPA. Results: Of the 431 RA cases, 310 (72%) were ACPA-positive; 121 (28%) were ACPA-negative. ACPA status influenced the effect of treatment on radiological progression, with a significant ACPA*treatment interactive effect on Larsen score changes seen in the ANOVA model (P< 0.001). ACPA-positive patients had significant reductions in Larsen score progression with all treatments; no effect was seen in ACPAnegative RA. ACPA-positive patients receiving triple therapy had the greatest benefits: mean Larsen score increases over 2 years were 3.66 (95% CI 2.27, 5.05) with triple therapy and 9.58 (95% CI 6.76, 12.39) with monotherapy; OR for new erosions with triple therapy vs monotherapy was 0.32 (95% CI 0.14, 0.72; P1⁄40.003). ACPA-negative patients had minimal radiological progression irrespective of treatment strategy: mean Larsen score increases over 2 years comprised 1.70 (95% CI 0.29, 3.10) with triple therapy and 2.72 (95% CI 1.15, 4.29) with monotherapy; only 7% developed new erosions. The beneficial effects of high-dose corticosteroids on reducing disease activity and improving physical health were confined to ACPA-positive RA. Conclusion: ACPA status influences the need for, and response to, combination DMARDs and high-dose tapering corticosteroids in early RA. Combination DMARDs and corticosteroids only provided radiological, disease activity and physical health benefits in ACPA-positive patients. This suggests that current UK guidelines advocating combination DMARDs and corticosteroids in all early active RA patients require reconsideration. Funding: This research was supported Arthritis Research UK [Grant Number 19739 to ICS], the National Institute for Health Research (NIHR) and the NIHR Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. Disclosure statement: The authors have declared no conflicts of interest.

TNFα promotes Th17 cell differentiation through IL-6 and IL-1β produced by monocytes in rheumatoid arthritis.

TNFα plays an important role in autoimmune pathogenesis and is the main therapeutic target of rheumatoid arthritis. However, its underlying mechanism is not completely understood. In this study, we described that Th17 cells were accumulated in synovial fluid, which was attributable to TNFα aberrantly produced in rheumatoid synovium. Interestingly, TNFα cannot induce IL-17 production of CD4+ T cells directly, but through the monocytes high levels of IL-1β and IL-6 in a TNFRI and TNFRII dependent manner from the active RA patients are produced. TNFα was shown to enhance the phosphorylation level of STAT3 and the expression level of transcription factor RORC of CD4+ T cells when cultured with CD14+ monocytes. Treatment with an approved TNFα blocking antibody showed marked reduction in the levels of IL-6, IL-1β, and IL-17 and the expression level of STAT3 phosphorylation in relation to Th17 cell differentiation in patients with rheumatoid arthritis. The study provides new evidence supporting the critical role of TNFα in the pathogenic Th17 cell differentiation in rheumatoid arthritis.

FRI0149 Nocturnal hypertension in ra: a possible association with cardiovascular events

BackgroundAlthough cardiovascular mortality is increased in RA patients relative to the general population, the reasons for high prevalence of cardiovascular events in RA patients is not completely understood. On the...

SAT0582-HPR Occupational Characterization and Relation between Working Condition and Disease Activity or Functionality in Patients with Rheumatoid Arthritis

BackgroundRheumatoid arthritis (RA) is a disease that in most cases is associated with disability and loss of earning capacity. There is a lack of information about occupation of rheumatoid arthritis...

FRI0483-HPR Occupational characterization and relation between working condition and disease activity or functionality in patients with rheumatoid arthritis

BackgroundRheumatoid arthritis (RA) is a disease that in most cases is associated with disability and loss of earning capacity. There is a lack of information about occupation of rheumatoid arthritis...

AB0309 Parathormone levels inversely correlate with clinical disease activity indexes in three severity subgroups of rheumatoid arthritis affected patients

BackgroundRheumatoid arthritis (RA) is associated to an increased incidence of osteoporosis: more 15-20% at the standard measured sites. The main mechanisms leading to increased bone resorption in RA are the...

AB0048 CD8+ T cells in rheumatoid arthritis - differences between remission and active disease

BackgroundFor the past years there has been a clear increase in the interest for T cells in autoimmune diseases (1), where it was found that CD8 T cells can have...

AB0545 Tocilizumab improves BMD compared with abatacept in patients with TNF blockers-resiistant active RA

ObjectivesTo compare the effect of tocilizumab(TCZ) plus methotrexate (MTX), with the effect of abatacept(ABT) plus MTX on bone mineral density(BMD) in TNF blockers resistant active rheumatoid arthritis(RA; without osteoporosis) patients,...

SAT0068 The Ts-Index as Sign Of Central Sensitization in Women with Active Rheumatoid Arthritis: A Comparative Cross Sectional Study

BackgroundDespite better disease control, RA patients still rate pain as a major burden. That pain in some cases persists without signs of inflammation of the joints may indicate, that central...

AB0306 The influence of the definition of patient global assessment in assessment of ACR/eular remission and minimal disease activity in rheumatoid arthritis: A 3-month cohort study in patients starting etanercept

BackgroundThe wording and form of the patient global assessment (PGA) question may influence the response and thus whether or not a patient meets the ACR/EULAR criteria for remission.ObjectivesTo assess the...