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ID PMID Title PublicationDate abstract
26188879 Intra-articular etanercept treatment in inflammatory arthritis: A randomized double-blind 2015 Oct OBJECTIVE: There is an increased interest in developing gene therapy approaches for local delivery of therapeutic genes in patients with arthritis. Intra-articular (i.a.) gene delivery, using an adeno-associated virus encoding a TNF soluble receptor, resulted in reduced paw swelling in an arthritis animal model, but i.a. treatment with a similar vector did not induce robust clinical improvement in patients. It is unclear whether this can be explained by for instance insufficient transduction efficiency or the fact that TNF is not a good therapeutic target for i.a treatment. The objective of this study was to explore the effects of i.a TNF blockade. METHODS: Thirty-one patients with rheumatoid or psoriatic arthritis were assigned to a single i.a. injection of 25mg etanercept or placebo in a double-blind randomised controlled clinical trial. The primary end point was target joint improvement, determined by a composite change index. RESULTS: Twenty-two patients received etanercept and 9 received placebo. Treatment was generally well tolerated. Treatment with etanercept resulted in a prompt and statistically significant improvement of the index (P<0.001) in comparison with placebo. As expected in light of the half-life of etanercept, the beneficial effect was transient and only statistically significant at week 1 and 2 after i.a. injection. CONCLUSION: The results support the development of novel approaches for long-term inhibition of TNF at the site of inflammation, such as gene therapy. TRIAL REGISTRATION: The Netherlands National Trial Register (NTR), www.trialregister.nl, NTR-1210.
27987498 [Role of galectin-1 in regulation of umbilical cord mesenchymal stem cells on T cells of r 2016 Dec 18 OBJECTIVE: The therapeutic potential of umbilical cord mesenchymal stem cells (UC-MSCs) in rheumatoid arthritis (RA) has attracted more and more attention, because of it can suppress the various inflammatory effects of T cells. Galectin-1 is highly expressed in UC-MSCs, as the first lectin mediating the immunomodulatory effect of MSCs. Our study will investigate the effects of galectin-1 in regulation of UC-MSCs on rheumatoid arthritis T cells. METHODS: Lentivirus transfected shRNA technique was used to knock down the expression of galectin-1 in UC-MSCs to construct UC-MSCs(Gal-1(-)). The effects of UC-MSCs and UC-MSCs(Gal-1(-)) on CD4(+) T cells in RA patients were investigated by contact system, including negative control group (CD4(+) T cells), positive control group [CD4(+) T-phytohemagg lutinin (PHA)], UC-MSCs-CD4(+) T cells co-culture group, UC-MSCs(control shRNA)-CD4(+) T cells co-culture group, and UC-MSCs(Gal-1(-))-CD4(+) T cells co-culture group. The proliferation of CD4(+) T cells was detected by MTS assay. The level of tumor necrosis factors α (TNF-α) in cells supernatant was detected by enzyme linked immunosorbent assay (ELISA). The effect of UC-MSCs on helper T cell (Th) subset was detected by flow cytometry. RESULTS: In vitro, UC-MSCs were capable of inhibiting PHA induced proliferation of CD4(+) T cells from RA patients, but UC-MSCs(Gal-1(-)) did not show the significant inhibitory effect. Galectin-1 affect the TNF-α level of CD4(+) T cells regulated by UC-MSCs. UC-MSCs and UC-MSCs(control shRNA) significantly inhibited the expression of TNF-α in PHA-induced CD4(+) T cells. However, UC-MSCs(Gal-1(-)) had no significant inhibitory effect. Furthermore, the Th1 cells were also significantly suppressed by UC-MSCs and UC-MSCs(control shRNA) (4.83%±1.37% and 5.13%±0.87%,P=0.012 and P=0.018). These was no significant difference in the proportion of the Th1 cells between the control group and UC-MSCs(Gal-1(-)) group (8.51%±2.04% and 6.41%±0.96%,P=0.101). The Th2 cells were protected after silence galectin-1 in UC-MSCs, whereas there was no significant difference. The proportion of Th17 was decreased by co-culture with UC-MSCs and UC-MSCs (control shRNA), but these was also no significant difference. CONCLUSION: UC-MSCs can inhibit the proliferation and differentiation of CD4(+) T cells from RA patients, but these effect declined after knocking down the expression of galectin-1. Galectin-1 maybe take part in the regulation of UC-MSCs on rheumatoid arthritis CD4(+) T cells.
26818120 Association of HLA-DRB1 alleles with susceptibility to mixed connective tissue disease in 2016 Jan Mixed connective tissue disease (MCTD) is a systemic autoimmune disease, originally defined as a connective tissue inflammatory syndrome with overlapping features of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis/dermatomyositis (PM/DM) and systemic sclerosis (SSc), characterized by the presence of antibodies against components of the U1 small nuclear ribonucleoprotein (U1snRNP). The aim of the study was to assess the frequency of (high-resolution-typed) DRB1 alleles in a cohort of Polish patients with MCTD (n = 103). Identification of the variants potentially associated with risk and protection was carried out by comparison with the DKMS Polish Bone Marrow Donor Registry (41306 alleles). DRB1*15:01 (odds ratio (OR): 6.06; 95% confidence interval (CI) 4.55-8.06), DRB1*04 (OR: 3.69; 95% CI 2.69-5.01) and *09:01 (OR: 8.12; 95% CI 2.15-21.75) were identified as risk alleles for MCTD, while HLA-DRB1*07:01 allele was found to be protective (OR: 0.50; 95% CI 0.28-0.83). The carrier frequency of the DRB1*01 was higher in MCTD patients compared with controls, although the differences were not statistically significant. Our results confirm the modulating influence of HLA-DRB1 genotypes on development of connective tissue diseases such as MCTD.
24863079 Interleukin-6 blockade improves autonomic dysfunction in rheumatoid arthritis. 2015 Jan Autonomic nervous system (ANS) involvement in rheumatoid arthritis (RA) is well recognised and contributes to arrhythmia and sudden death. However, there is no study documented the therapeutic efficacy on autonomic neuropathy (AN) in RA. This is the first reported observation of improvement in AN with interleukin-6 (IL-6) blockade with tocilizumab in RA. We report a case of 61-year old female with seropositive RA with severe disease activity, investigated for autonomic neuropathy. A battery of non invasive tests was used for accurate assessment of AN function based on assessment of peripheral sympathetic autonomic function and cardiovascular reflex tests. Tocilizumab 8 mg/kg intravenous infusion at weeks 0, 4 and 8 was added to her treatment regimen. Cardiovascular autonomic function tests at baseline showed marked abnormalities of parasympathetic cardiovascular reflexes. After the first dose of tocilizumab there was a rapid improvement with normalization of parasympathetic autonomic activity with subsequent doses. IL-6 blockade with tocilizumab seems to have the potential to improve the vagus nerve mediated parasympathetic neuropathy and hence has the potential to restore cholinergic anti-inflammatory pathway.
26637646 Criterion Validity of the activPAL Activity Monitor for Sedentary and Physical Activity Pa 2016 Jul BACKGROUND: Accurate measurement of physical activity and sedentary behavior is an important consideration for health care professionals. The activPAL activity monitor has not been validated against a criterion measure for people with rheumatoid arthritis (RA). OBJECTIVE: The objective of this study was to determine the criterion validity of the activPAL activity monitor for measuring step counts, transition counts, and time spent in sedentary, standing, and walking behaviors in people with RA. DESIGN: A laboratory-based criterion validation study was conducted. METHODS: Participants with a confirmed medical diagnosis of RA were recruited from 2 outpatient rheumatology clinics. The testing procedure consisted of standardized testing components and tasks related to activities of daily living. Participants wore an activPAL activity monitor and were video recorded throughout the testing procedure. Direct observation was used as the criterion measure. Data analysis consisted of validation analysis of the activPAL activity monitor data and the criterion measure data. RESULTS: Twenty-four people participated in the study. Data from 20 participants were included in the final analysis. The activPAL significantly underestimated step counts by 26% and transition counts by 36%. There was no significant difference between the activPAL activity monitor and the criterion measure for time spent in sedentary, standing or light activity, and walking behaviors. LIMITATIONS: Validation of activities of daily living in a laboratory environment is a limitation of this study. CONCLUSIONS: The activPAL activity monitor underestimated step and transition counts and, therefore, is not valid for measuring these outcomes in people with RA. Relative to direct observation, the activPAL activity monitor is valid for measuring time spent in sedentary, standing, and walking behaviors in people with RA.
25339638 Use of a 12-week observational period for predicting low disease activity at 52 weeks in R 2015 May OBJECTIVE: Only a few studies have assessed predictive factors for the long-term efficacy of abatacept. This study aimed to provide clinical evidence of an adequate observational period for predicting low disease activity (LDA) achievement at 52 weeks in RA patients treated with abatacept. METHODS: Participants were all patients registered in a Japanese multicentre registry who were treated with abatacept and had at least 52 weeks of follow-up (n = 254). RESULTS: Areas under the receiver operating characteristic curves for the 28-joint count with CRP (DAS28-CRP) at each time point for LDA achievement at 52 weeks were: 0.686 (cut-off score: 4.6) at baseline, 0.780 (3.8) at 4 weeks, 0.875 (3.3) at 12 weeks, and 0.900 (3.0) at 24 weeks. Although patients with a DAS28-CRP score < 3.0 at 24 weeks had the highest proportion of LDA achievement at 52 weeks (79.3%), the proportion for those with a score < 3.3 at 12 weeks was comparable (77.2%, P = 0.697). Proportions were significantly lower in patients with a score < 3.8 at 4 weeks or < 4.6 at baseline. Multivariate logistic regression demonstrated that a DAS28 score of < 3.3 at 12 weeks was an independent strong predictor for LDA at 52 weeks (adjusted odds ratio: 15.2, P < 0.001). CONCLUSION: Twelve weeks is an adequate observational period to judge the long-term clinical efficacy of abatacept, and is about as early as the period for assessing TNF blockade therapy.
26286017 Outcomes of percutaneous coronary intervention in patients with rheumatoid arthritis and s 2016 Jul OBJECTIVES: Patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have an increased risk of developing coronary atherosclerosis. However, the impact of RA and SLE on the outcomes in patients undergoing percutaneous coronary intervention (PCI) remains largely underdetermined. METHODS: Using the National Health Insurance Research Database of Taiwan, we identified 171 547 adult patients who underwent first-time PCI between 2000 and 2010. Among these patients, 525 had established RA, and 211 had SLE. The ORs of inhospital mortality and HRs of overall mortality and adverse cardiac outcomes after PCI (ie, ischaemic events, repeat revascularisation and major adverse cardiac events (MACE)) in relation to RA and SLE were estimated. RESULTS: After adjustment for potential confounders, including patient characteristics and procedural variables, RA (OR=1.73, 95% CI 1.11 to 2.68) and SLE (OR=3.81, 95% CI 2.02 to 7.16) were independent predictors of inhospital mortality. In addition, RA was independently associated with overall mortality (HR=1.55, 95% CI 1.35 to 1.79), ischaemic events (HR=1.18, 95% CI 1.01 to 1.39) and MACE (HR=1.20, 95% CI 1.07 to 1.34) during long-term follow-up, whereas SLE was independently associated with overall mortality (HR=2.20, 95% CI 1.74 to 2.78), repeat revascularisation (HR=1.27, 95% CI 1.02 to 1.58) and MACE (HR=1.47, 95% CI 1.24 to 1.75). Compared with patients without autoimmune diseases, patients with more recent SLE-related hospitalisations prior to PCI were at higher risk of inhospital mortality (p for trend <0.0001). CONCLUSIONS: This study recognises the inherent risks associated with RA and SLE in patients undergoing PCI and highlights the necessity to improve the caring and secondary prevention strategies for these high-risk patients.
27177082 Anti-TNF-α and anti-arthritic effect of patuletin: A rare flavonoid from Tagetes patula. 2016 Jul Rheumatoid arthritis (RA) poses a serious health problem as a chronic autoimmune joint disease with significant mortality and morbidity. Proinflammatory cytokines TNF-α and IL-1β, reactive oxygen species (ROS), and activated CD4(+) T-cells play key roles in the progression of arthritis. The aim of the study is to evaluate the in vitro and in vivo immunomodulatory and anti-arthritic effect of flavonoid patuletin, isolated from Tagetes patula. ELISA was applied for quantification of TNF-α and IL-1β. Intracellular and extracellular ROS production from phagocytes was measured by the chemiluminescence technique. Proliferation of T-cells was observed using a liquid scintillation counter. Cytotoxicity was assessed by a MTT assay. The serological and histological analysis studies were performed using a rodent model of adjuvant-induced arthritis (AIA). Expression of p38 and NF-κB after treatment of compound was observed by western blotting. Patuletin showed potent inhibitory effects on TNF-α in vitro as well as inhibited the production of both cytokines in vivo. It also showed potent suppression of proliferation of T-cells and significantly inhibited the extracellular and intracellular ROS production. Patuletin revealed significant anti-inflammatory and anti-arthritic activities in the rodent model of adjuvant-induced arthritis (AIA). Histologically, it causes mild bone destruction compared to the arthritic control group, thus representing its anti-arthritic potential. Based on these studies, patuletin could be considered as a potential immunosuppressive and anti-arthritic lead candidate.
27712633 Reduced Risk of Parkinson Disease in Patients With Rheumatoid Arthritis: A Nationwide Popu 2016 Oct OBJECTIVE: To investigate the association between rheumatoid arthritis (RA) and the risk of developing Parkinson disease (PD). PATIENTS AND METHODS: This retrospective cohort study was conducted from January 1, 1998, through December 31, 2010, using data from the Taiwan National Health Insurance Research Database. We identified 33,221 patients with newly diagnosed RA and 132,884 randomly selected age- and sex-matched patients without RA. A multivariable Cox proportional hazards regression model was used to evaluate the risk of developing PD in the RA cohort. RESULTS: The multivariable Cox proportional hazards regression analysis revealed an adjusted hazard ratio of 0.65 (95% CI, 0.58-0.73) for the development of PD in the RA cohort relative to the non-RA cohort. The cumulative incidence of PD was 2.42% lower in the RA cohort than in the non-RA cohort. The risk reduction of PD development in patients affected with RA was independent of treatment with disease-modifying antirheumatic drugs (DMARDs); subgroup analysis of patients treated with biologic DMARDs revealed further risk reduction (adjusted hazard ratio, 0.57; 95% CI, 0.41-0.79). CONCLUSION: Patients with RA have a reduced risk of developing PD. This risk reduction was independent of treatment with DMARDs; however, biologic DMARDs appear to further reduce this risk. Further research is necessary to explore the underlying mechanism.
25891413 Potent anti-inflammatory effects of the narrow spectrum kinase inhibitor RV1088 on rheumat 2015 Aug BACKGROUND AND PURPOSE: To investigate whether a narrow spectrum kinase inhibitor RV1088, which simultaneously targets specific MAPKs, Src and spleen tyrosine kinase (Syk), is more effective at inhibiting inflammatory signalling in rheumatoid arthritis (RA) than single kinase inhibitors (SKIs). EXPERIMENTAL APPROACH: elisas were used to determine the efficacy of RV1088, clinically relevant SKIs and the pharmaceutical Humira on pro-inflammatory cytokine production by activated RA synovial fibroblasts, primary human monocytes and macrophages, as well as spontaneous cytokine synthesis by synovial membrane cells from RA patients. In human macrophages, RNAi knockdown of individual kinases was used to reveal the effect of inhibition of kinase expression on cytokine synthesis. KEY RESULTS: RV1088 reduced TNF-α, IL-6 and IL-8 production in all individual activated cell types with low, nM, IC50 s. SKIs, and combinations of SKIs, were significantly less effective than RV1088. RNAi of specific kinases in macrophages also caused only modest inhibition of pro-inflammatory cytokine production. RV1088 was also significantly more effective at inhibiting IL-6 and IL-8 production by monocytes and RA synovial fibroblasts compared with Humira. Finally, RV1088 was the only inhibitor that was effective in reducing TNF-α, IL-6 and IL-8 synthesis in RA synovial membrane cells with low nM IC50 s. CONCLUSIONS AND IMPLICATIONS: This study demonstrates potent anti-inflammatory effect of RV1088, highlighting that distinct signalling pathways drive TNF-α, IL-6 and IL-8 production in the different cell types found in RA joints. As such, targeting numerous signalling pathways simultaneously using RV1088 could offer a more powerful method of reducing inflammation in RA than targeting individual kinases.
26337028 Serum RANKL levels associate with anti- citrullinated protein antibodies in early untreate 2015 Sep 4 INTRODUCTION: Receptor activator of nuclear factor kappa B ligand (RANKL) is a key regulator of bone metabolism. Anti-citrullinated protein antibodies (ACPA) have been suggested to cause bone destruction by osteoclast activation. We investigated the relationship between RANKL and ACPA in patients with early untreated rheumatoid arthritis (RA). METHODS: Patients with newly diagnosed untreated RA (n = 183) were analyzed at baseline and 3 months after initiating methotrexate (MTX) treatment. Serum RANKL (total RANKL), ACPA (anti-CCP2) and ACPA specificities (anti-citrullinated (cit)-vimentin, anti-cit-enolase and anti-cit-fibrinogen) were determined by enzyme-linked immunosorbent assay (ELISA). Synovial RANKL expression was evaluated by immunohistochemistry in a small group of patients (n = 15). The relationship between anti-cit-vim antibodies and bone destruction was further validated in 1116 RA patients included in the EIRA cohort. Pearson's chi-square test, Wilcoxon rank sum test, Wilcoxon signed rank test and linear regression models were used. RESULTS: Serum RANKL concentration was significantly higher (p <0.05) in ACPA-positive (median: 689 pmol/L, IQR 342-1253) compared with ACPA-negative (median: 159 pmol/L, IQR 96-243) patients and this difference was also seen for synovial RANKL expression. Serum RANKL associated with ACPA (p <0.05) and bone erosions in rheumatoid factor (RF)-negative patients (n = 59). Among ACPA specificites, anti-cit-vimentin (amino acids 60-75) was associated with higher RANKL concentration and higher prevalence of bone erosion (p <0.05). Significant reductions in both serum RANKL and ACPA levels were observed after 3 months of MTX treatment (p <0.05). CONCLUSIONS: RANKL was elevated in ACPA-positive and in anti-cit-vimentin-positive patients with early untreated RA and associated with bone erosions. These findings give further support for an early direct pathogenic link between ACPA and bone destruction in RA.
25887374 Hypovitaminosis D in recent onset rheumatoid arthritis is predictive of reduced response t 2015 Mar 15 BACKGROUND: Vitamin D displays immunomodulatory activities and has been proposed as a potential player in the pathogenesis of rheumatoid arthritis (RA). A negative association between serum 25(OH) vitamin D levels and RA activity was demonstrated but longitudinal studies investigating the role of vitamin D levels in predicting RA activity and response to treatment are lacking. Therefore, this study was designed to test the hypothesis of an association between serum 25(OH) vitamin D levels at RA diagnosis and disease activity evaluated by clinimetric, laboratory and ultrasound (US) parameters and to detect the prevalence of remission and response to treatment after 12 months follow-up. METHODS: This is a longitudinal, retrospective study on data obtained from thirty-seven patients with early RA treatment-naïve. Serum inflammatory markers, auto-antibodies and 25(OH) vitamin D levels were obtained at baseline. Hypovitaminosis D was diagnosed for 25(OH) vitamin D levels < 20 ng/ml. Tender joint count (TJCs), swollen joint count (SJCs), Visual Analog Scales (VAS), Disease Activity Score (DAS) 28 score were assessed at baseline and 12 months after diagnosis. Joints synovitis and power-Doppler were evaluated at baseline and 12 months later. RESULTS: At baseline mean 25(OH) vitamin D levels were 24.4 ± 11.9 ng/ml; 35% of study subjects had hypovitaminosis D which strongly associated with higher RA activity and lower prevalence of remission and response to treatment (all p-values < 0.001). The percentage of patients not presenting a reduction of the US synovitis score after 12 months from diagnosis was significantly higher among patients with hypovitaminosis D than in those with normal serum 25(OH) vitamin D at baseline. CONCLUSIONS: In patients with early RA and basal hypovitaminosis D after 12 months follow-up reduction of disease activity and percentage of remission and response to treatment were significantly lower than those observed in patients with normal vitamin D levels. These results provide further support to the immunomodulatory action of vitamin D in RA and suggest a role of basal vitamin D status in the prediction of disease evolution. Vitamin D measurement and possibly vitamin D supplementation should be considered an additional option in the management of early RA patients.
26961485 Efficacy and safety of low-dose tacrolimus for active rheumatoid arthritis with an inadequ 2016 Jul BACKGROUND/AIMS: To determine the efficacy and safety of low-dose tacrolimus in Korean rheumatoid arthritis (RA) subjects with an inadequate response to methotrexate (MTX). METHODS: This was a multicenter, open-label study conducted at five Korean sites. Fifty-six patients with active RA, despite treatment for ≥ 1 month with a stable, maximally tolerated dosage of oral MTX (median dosage, 15 mg/wk), were enrolled and received 1.5 mg/day of tacrolimus as a single oral dose once per day for 16 weeks while continuing to receive MTX. All other disease-modifying anti-rheumatic drugs were discontinued, whereas stable dosages of nonsteroidal anti-inflammatory drugs and oral corticosteroids (≤ 10 mg/day of prednisone or an equivalent corticosteroid) were allowed. The primary clinical response criterion was the American College of Rheumatology's definition of 20% improvement (ACR20) at the end of treatment. RESULTS: The ACR20 response rate was 42.9% (24 of 56 patients) in patients who had received tacrolimus at least once. The overall ACR50 and ACR70 responses at the end of treatment for all patients were 30.4% and 10.7%, respectively. Throughout the treatment period, 37 patients experienced 71 adverse events (AEs) in total, and four patients left the study because of AEs. In addition, 15 patients in total experienced treatment-related AEs. Throughout the treatment period, two patients were reported to experience two serious AEs, and one patient left the study because of a serious AE. CONCLUSIONS: In patients whose active RA persists despite treatment with MTX, low-dose tacrolimus in combination with MTX appears to be safe and well tolerated, and provides clinical benefit.
27241313 APL1, an altered peptide ligand derived from human heat-shock protein 60, increases the fr 2016 Jul Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by a chronic relapsing-remitting joint inflammation. Perturbations in the balance between CD4 + T cells producing IL-17 and CD4 + CD25(high)FoxP3 + Tregs correlate with irreversible bone and cartilage destruction in RA. APL1 is an altered peptide ligand derived from a CD4+ T-cell epitope of human HSP60, an autoantigen expressed in the inflamed synovium, which increases the frequency of CD4 + CD25(high)FoxP3+ Tregs in peripheral blood mononuclear cells from RA patients. The aim of this study was to evaluate the suppressive capacity of Tregs induced by APL1 on proliferation of effector CD4+ T cells using co-culture experiments. Enhanced Treg-mediated suppression was observed in APL1-treated cultures compared with cells cultured only with media. Subsequent analyses using autologous cross-over experiments showed that the enhanced Treg suppression in APL1-treated cultures could reflect increased suppressive function of Tregs against APL1-responsive T cells. On the other hand, APL1-treatment had a significant effect reducing IL-17 levels produced by effector CD4+ T cells. Hence, this peptide has the ability to increase the frequency of Tregs and their suppressive properties whereas effector T cells produce less IL-17. Thus, we propose that APL1 therapy could help to ameliorate the pathogenic Th17/Treg balance in RA patients.
26090496 The Role of Posttranslational Protein Modifications in Rheumatological Diseases: Focus on 2015 The definition of posttranslational modification (PTM) encompasses a wide group of chemical reactions that allow modification and modulation of protein functions. The regulation of PTMs is crucial for the activity and survival of the cells. Dysregulation of PTMs has been observed in several pathological conditions, including rheumatoid arthritis (RA). RA is a systemic autoimmune disease primarily targeting the joints. The three PTMs mainly involved in this disease are glycosylation, citrullination, and carbamylation. Glycosylation is essential for antigen processing and presentation and can modulate immunoglobulin activity. Citrullination of self-antigens is strongly associated with RA, as demonstrated by the presence of antibodies directed to anti-citrullinated proteins in patients' sera. Carbamylation and its dysregulation have been recently associated with RA. Aim of this review is to illustrate the most significant alterations of these PTMs in RA and to evaluate their possible involvement in the pathogenesis of the disease.
26753210 [Treat-to-target in rheumatology]. 2015 The treat-to target concept has been widely used in many chronic devastating disorders (like hypertension, diabetes meilitus, caraiovascuiar diseases) for many years. It has been initiated in the cardiovascular diseases treatment where, based on vast clinical databases, it had been proven that the achievement of certain therapeutical results (e.g. blood pressure lowering<140/90; target for HbAlc less than 7%; normalization of lipid concentration) lead to significant reduction of cardiovascular accidents and improved long-term prognosis.The main principles of treat-to-target concept are deeply rooted in the humanistic tradition and nature of medical science including: cooperation between doctor and patient based on mutual understanding, achievement of remission due to effective treatment, avoidance of damage and improvement of patient's quality of life. The principles of T2T were first applied in rheumatic diseases in 2010 to plan the treatment of rheumatoid arthritis. The application of T2T in rheumatoid arthritis treatment, where the achievement of remission or low disease activity can be quite accurately quantified, is now quite widespread. The principles forT2T application within ankylosing spondylitis, psoriatic arthritis and lately systemic lupus erythematosus have been desianed. This study is aimed at making the readers familiar with T2T concept and suggesting the ways of its clinical application.
25118313 Methotrexate-mediated inhibition of nuclear factor κB activation by distinct pathways in 2015 Jan OBJECTIVES: Nuclear factor κB (NF-κB) is a critical activator of inflammatory processes and MTX is one of the most commonly prescribed DMARDs for treatment of RA. We sought to determine whether MTX inhibited NF-κB activity in RA and in lymphocytes and fibroblast-like synoviocytes (FLSs) and to define underlying mechanisms of action. METHODS: An NF-κB luciferase reporter plasmid was used to measure NF-κB activation across experimental stimuli. Flow cytometry was used to quantify changes in intracellular protein levels, measure levels of reactive oxygen species and determine apoptosis. Quantitative RT-PCR was used to identify changes in MTX target genes. RESULTS: In T cell lines, MTX (0.1 μM) inhibited activation of NF-κB via depletion of tetrahydrobiopterin (BH4) and increased Jun-N-terminal kinase (JNK)-dependent p53 activity. Inhibitors of BH4 activity or synthesis also inhibited NF-κB activation and, similar to MTX, increased JNK, p53, p21 and JUN activity. Patients with RA expressed increased levels of phosphorylated or active RelA (p65) compared with controls. Levels of phosphorylated RelA were reduced in patients receiving low-dose MTX therapy. In contrast, inhibition of NF-κB activation by MTX was not mediated via BH4 depletion and JNK activation in FLSs, but rather was completely prevented by adenosine receptor antagonists. CONCLUSION: Our findings support a model whereby distinct pathways are activated by MTX in T cells and FLSs to inhibit NF-κB activation.
27481132 GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbate 2016 Aug 22 When SUCNR1/GPR91-expressing macrophages are activated by inflammatory signals, they change their metabolism and accumulate succinate. In this study, we show that during this activation, macrophages release succinate into the extracellular milieu. They simultaneously up-regulate GPR91, which functions as an autocrine and paracrine sensor for extracellular succinate to enhance IL-1β production. GPR91-deficient mice lack this metabolic sensor and show reduced macrophage activation and production of IL-1β during antigen-induced arthritis. Succinate is abundant in synovial fluids from rheumatoid arthritis (RA) patients, and these fluids elicit IL-1β release from macrophages in a GPR91-dependent manner. Together, we reveal a GPR91/succinate-dependent feed-forward loop of macrophage activation and propose GPR91 antagonists as novel therapeutic principles to treat RA.
25641887 Urinary albumin excretion is increased in patients with rheumatoid arthritis and associate 2015 Apr OBJECTIVE: Rheumatoid arthritis (RA) is associated with increased risk of cardiovascular disease (CVD). High urinary albumin excretion is a risk factor for CVD in the general population, but its role in atherosclerosis in patients with RA is not well defined. METHODS: We determined the urine albumin to creatinine ratio (UACR) in 136 patients with RA and 79 controls. Individuals with diabetes or a clinical history of CVD were excluded. We measured coronary artery calcium (CAC) with electron beam computer tomography and augmentation index (AIx) using pulse wave analysis. In patients with RA, erythrocyte sedimentation rate and concentrations of vascular cell adhesion protein-1 (VCAM-1), interleukin 10 (IL-10), C-reactive protein, IL-6, tumor necrosis factor-α, and cystatin-C were measured and results correlated with UACR. RESULTS: Patients with RA had higher UACR [median (interquartile range): 7.6 (4.0-15.5) mg/g] than control subjects: 5.6 (3.3-9.0) mg/g; p = 0.02. The presence of CAC was not associated with UACR in RA or control subjects. In patients with RA, UACR was significantly correlated with AIx (rho = 0.24, p = 0.01), higher levels of VCAM-1 (rho = 0.2, p = 0.01), and lower levels of IL-10 (rho = -0.2, p = 0.02). The association between AIx and higher UACR remained significant in multivariate analysis [β coefficient of 1.5 (95% CI 0.1-2.8), p = 0.03 that adjusted for age, sex, and race]. CONCLUSION: Urinary albumin excretion was higher in patients with RA than controls and correlated with increased arterial stiffness, higher VCAM-1, and lower IL-10 concentrations.
25895821 Advances in use of immunomodulatory agents--a rheumatology perspective. 2015 Jun With the advent of biologic agents such as TNF inhibitors, the treatment paradigm for autoimmune systemic inflammatory diseases has progressed tremendously. Despite some distinct treatments, similarities exist in several aspects of the treatment of autoimmune inflammatory diseases such as rheumatoid arthritis (RA), IBD and psoriasis. With a so-called treat-to-target strategy aiming at remission, the intensive and early application of disease-modifying antirheumatic drugs within a 'window of opportunity', and in combination with TNF inhibitors, has become the overarching principle of RA therapy. In this Perspective, the concept of treatment approaches using immunomodulatory agents and the latest advances of therapies in autoimmune systemic inflammatory diseases, especially RA, are overviewed from a rheumatology perspective to provide insights into possible approaches to the treatment of inflammatory gastrointestinal disease.