Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
25084560 Effect of CD95 on inflammatory response in rheumatoid arthritis fibroblast-like synoviocyt 2014 Aug OBJECTIVE: Many CD95-expressing cells don't always undergo apoptosis after stimulation with CD95 ligation. The purpose of this paper is to investigate the role of expression of CD95 (Fas/Apo1) on inflammatory response in fibroblast-like synoviocytes (FLS) obtained from rheumatoid arthritis (RA) and to evaluate the role of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB or Akt) pathways within this process. METHODS: The expression levels of CD95 were monitored by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). Apoptotic cells were detected by in situ apoptosis detection (TUNEL) assay. The RA-FLS were treated with agonistic anti-CD95 antibody or CD95 siRNA. Then the proliferation was detected by CCK-8, and mRNA level of inflammatory cytokines was detected by RT-PCR. After the RA-FLS were treated with agonistic anti-CD95 antibody, the total Akt and pAkt protein expression was analyzed by Western blot, and the changes mentioned above were observed while pre-incubated with the PI3K inhibitor LY294002. RESULTS: A significant increase of CD95 antigen was found in RA compared with osteoarthritis (OA) samples, while apoptosis in RA synovial tissue was not obvious. Low concentrations of agonistic anti-CD95 antibody could promote RA-FLS growth and interleukin-6 (IL-6) mRNA expression, while high concentrations could induce apoptosis. And both of these phenomena could be inhibited by CD95 siRNA. Agonistic anti-CD95 antibody could stimulate the expression of pAkt, and PI3K specific inhibitor LY294002 could induce opposite changes. CONCLUSION: Stimulation of CD95 could promote RA-FLS proliferation and inflammation, and activation of the PI3K/Akt signaling pathway might be the possible mechanism.
25017507 Isolation of healthy individuals' and rheumatoid arthritis patients' peripheral blood neut 2014 Oct In vitro assessment of the functional responses of leukocytes sometimes requires their isolation from blood, joint and tissues. In this study, we compared the efficiency of two procedures - the gelatin method and Ficoll-Hypaque density centrifugation gradient - to isolate peripheral blood neutrophils of healthy individuals and patients with active rheumatoid arthritis (RA). We also assessed whether these procedures affect the neutrophil activation status. Both purification procedures were concluded in 90min, and yielded cell populations with similar degrees of purity (80-90%), number of neutrophils (1-2×10(6) cells per mL of blood), and viability (97-100%). In vitro neutrophil priming with granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly increased the reactive oxygen species producing ability of the cells stimulated with n-formyl-methionyl-leucyl-phenylalanine (n-fMLP), soluble immune complexes (s-ICs), and insoluble immune complexes (i-ICs). Isolated neutrophils not treated with GM-CSF responded to n-fMLP and i-IC, but not to s-IC. Almost all of the neutrophils (98-100%) purified by both methods expressed FcγRII/CD32 and FcγRIII/CD16, but they did not express significant levels of FcγRI/CD64. Similar results were obtained for healthy individuals' and RA patients' neutrophils. In summary, the gelatin method was comparable to Ficoll-Hypaque gradient in terms of purity, yield, and viability of the neutrophil preparations. Both methods neither primed or activated the neutrophils, nor affected their functional responsiveness. Therefore, both methods are suitable to isolate peripheral blood neutrophils of healthy individuals and RA patients.
24574209 Adverse pregnancy outcomes and risk of subsequent rheumatoid arthritis. 2014 Mar OBJECTIVE: Pregnancy and reproductive outcomes have been associated with altered risk of some autoimmune diseases, including rheumatoid arthritis (RA). We sought to determine whether prior pregnancy resulting in a low birth weight (LBW) infant or preterm birth is associated with a risk of subsequent RA in the mother. METHODS: We conducted an analysis of RA risk in parous women from a population-based prospective study of newly diagnosed cases of RA and age-matched healthy controls. The primary outcome measure was disease status (RA versus control), with exposures of prior preterm birth and prior delivery of an infant with LBW (≤2,500 gm), very low birth weight (VLBW; ≤1,500 gm), or extremely low birth weight (ELBW; ≤1,000 gm). A preplanned analysis including only rheumatoid factor (RF)-positive RA cases was also conducted. RESULTS: A total of 202 RA cases and 1,102 controls were analyzed. Prior delivery of an infant with ELBW was associated with RA in the mother (relative risk [RR] 3.7 [95% confidence interval (95% CI) 1.0-13.2]). Prior VLBW (RR 4.0 [95% CI 1.3-11.4]) and ELBW (RR 5.5 [95% CI 1.4-22.5]) infants were associated with RF-positive RA. Prior LBW deliveries and preterm births were more common among RA cases than controls, but the differences were not statistically significant. CONCLUSION: Compared to those with uncomplicated pregnancies, women with a prior VLBW or ELBW delivery had a higher risk of RA, particularly RF-positive RA. This association may reflect common risk factors for pregnancy complications and RA. Alternatively, complicated pregnancy itself may confer risk of subsequent RA.
23537303 A hypersensitive biotin-avidin-TRFIA for quantitative detection of ANA-Ig(GAM) and its cli 2013 We demonstrate herein a novel time-resolved fluoroimmunoassay (TRFIA) with high sensitivity and wide range for quantitative detection of ANA-Ig(GAM) antibodies using a biotin-avidin amplification system. The immunoassay was conducted by following procedures for a typical sandwich immunoreactions with cell nucleus form Hela and the Eu(3+)-labeled biotin combined with biotinylated mouse anti-human Ig(GAM) served as the solid nuclear antigen for ANA and the tracer, respectively. The sensitivity, specificity, and stability of the kit were evaluated and comparison with the classical enzyme-linked immunosorbent assay (ELISA) kit was also made. The average intra-assay and interassay CVs detected by the established ANA-Ig(GAM) biotin-avidin-TRFIA were 4.21% and 6.34%, respectively. The lower detection limit was 2.24 U/mL, and the mean recovery rate was 100.74%. The good measurable range of the established biotin-avidin-TRFIA was within 1.95-64,000 U/mL, while it was only within 32.5-4000 U/mL using an ELISA kit. The values determined by the biotin-avidin-TRFIA and ELISA correlated well (R2 = 0.989). The positive rate of healthy volunteers and patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), primary biliary cirrhosis (PBC), Sjögren's syndrome (SS), scleroderma, and mixed connective tissue disease (MCTD) was 0, 100%, 18.5%, 100%, 37.9%, 90.9%, and 92%, respectively. We conclude that the biotin-avidin-TRFIA we developed gives promise for greater sensitivity and accurate detection for ANA-Ig(GAM) in diagnosing and monitoring autoimmune disorders.
23377198 A biologic pharmacosurveillance program for rheumatoid arthritis: a single-center experien 2013 Jun We have reviewed the experience in a single center of a biologic register for rheumatoid arthritis patients. Over the past decade, the entry demographics show that we are treating patients at an earlier stage and with slightly less severe disease. Our outcomes measured by the percentage in DAS28 remission are comparable with national databases. We were surprised by the small number who were switched from their first biologic to a second (27 %), but this might reflect the lack of a firm "treat to target" approach. Our use of concomitant methotrexate/leflunomide is less than we would have liked and thought, but our use of concomitant corticosteroids is much less than normally seen. A single-center registry can provide useful monitoring and quality assurance data and stimulate change.
24912797 Population pharmacokinetic modeling of LY2189102 after multiple intravenous and subcutaneo 2014 Sep Interleukin-1 beta (IL-1β) is an inflammatory mediator which may contribute to the pathophysiology of rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM). Population pharmacokinetics (PK) of LY2189102, a high affinity anti-IL-1β humanized monoclonal immunoglobulin G4 evaluated for efficacy in RA and T2DM, were characterized using data from 79 T2DM subjects (Study H9C-MC-BBDK) who received 13 weekly subcutaneous (SC) doses of LY2189102 (0.6, 18, and 180 mg) and 96 RA subjects (Study H9C-MC-BBDE) who received five weekly intravenous (IV) doses (0.02-2.5 mg/kg). Frequency of anti-drug antibody (ADA) development appears dose-dependent and is different between studies (36.7% in Study H9C-MC-BBDK vs. 2.1% in Study H9C-MC-BBDE), likely due to several factors, including differences in patient population and background medications, administration routes, and assays. A two-compartment model with dose-dependent bioavailability best characterizes LY2189102 PK following IV and SC administration. Typical elimination and distribution clearances, central and peripheral volumes of distribution are 0.222 L/day, 0.518 L/day, 3.08 L, and 1.94 L, resulting in a terminal half-life of 16.8 days. Elimination clearance increased linearly, yet modestly, with baseline creatinine clearance and appears 37.6% higher in subjects who developed ADA. Bioavailability (0.432-0.721) and absorption half-life (94.3-157 h) after SC administration are smaller with larger doses. Overall, LY2189102 PK is consistent with other therapeutic humanized monoclonal antibodies and is likely to support convenient SC dosing.
24187096 Correlation of radiographic progression with the cumulative activity of synovitis estimate 2013 Dec OBJECTIVE: Our prospective study aimed to demonstrate that the cumulative synovial power Doppler (PD) ultrasound scores correlate with radiographic progression better than conventional measures in patients with rheumatoid arthritis (RA). We also investigated the difference between antirheumatic agents. METHODS: Sixty-nine patients with RA who had recently received either methotrexate (MTX; n = 23), tumor necrosis factor (TNF) antagonists (n = 28), or tocilizumab (TCZ; n = 18) were enrolled. Patients underwent clinical, laboratory, and ultrasonographic assessment at baseline, 12 weeks, and 24 weeks. Radiographic damage was evaluated using van der Heijde modified total Sharp score (TSS) at baseline and 24 weeks. RESULTS: Fifty-seven patients continued the same treatment regimen for 24 weeks and completed the study, and 21 patients (36.8%) showed radiographic progression during the study period. In all patients, ΔTSS significantly correlated both with cumulative 28-joint Disease Activity Score-C-reactive protein (DAS28-CRP; ρ = 0.342, p = 0.009) and cumulative total PD scores (ρ = 0.357, p = 0.006). In MTX-treated patients, cumulative total PD scores significantly correlated with ΔTSS (ρ = 0.679, p = 0.004), whereas cumulative DAS28-CRP did not (ρ = 0.487, p = 0.056). However, cumulative total PD scores did not correlate with ΔTSS in TNF antagonist-treated or TCZ-treated patients. CONCLUSION: Our data confirm the evidence that synovial PD activity more accurately reflects active synovial inflammation (which actually causes joint destruction) than do conventional measures in patients treated with MTX. Our data also indicate that TNF antagonists can inhibit short-term radiographic progression in the presence of active synovitis.
23607815 Cigarette smoking and smoking cessation in relation to risk of rheumatoid arthritis in wom 2013 Apr 22 INTRODUCTION: Whereas the overall association between smoking and rheumatoid arthritis (RA) must be regarded as established, considerably less is known about how much smoking is needed to increase the risk of RA, that is, the effect of smoking intensity, duration and cessation. METHODS: The Swedish Mammography Cohort, including 34,101 women aged 54 to 89 years, was followed up from January 1, 2003 through December 31, 2010 (219 RA cases identified). Relative risks (RR) and their 95% confidence intervals (CI) were estimated as rate ratios using Cox proportional hazards model. RESULTS: There was a statistically significant association between smoking intensity (RR comparing 1 to 7 cigarettes/day vs never smoking 2.31 (95% CI: 1.59, 3.36)) as well as duration of smoking (comparing 1 to 25 years vs never smoking RR = 1.60 (95% CI: 1.07, 2.38)) and risk of RA. Compared to never smokers, the risk was still significantly elevated 15 years after smoking cessation (RR = 1.99 (95% CI: 1.23, 3.20)). However, among former smokers, the risk of RA seemed to be decreasing over time since stopping smoking: women who stopped smoking 15 years before the start of the follow-up had 30% lower risk of RA compared to those who stopped only a year before start of the follow-up (RR = 0.70 (95% CI: 0.24,2.02)). CONCLUSIONS: This prospective study highlights that even light cigarette smoking is associated with increased risk of RA in women and that smoking cessation may reduce, though not remove, this risk.
24366321 The safety of biologic therapies in RA-associated interstitial lung disease. 2014 May Interstitial lung disease (ILD) is a common extra-articular manifestation associated with increased morbidity and mortality in patients with rheumatoid arthritis (RA). Early case reports of serious respiratory adverse events (SRAEs) following treatment with anti-TNF agents have led to concerns about biologic therapy in patients with RA-associated ILD (RA-ILD), and a tendency for biologic agents targeting factors other than TNF to be prescribed in such patients. At present, the appropriateness of such decisions is not clear. Given that the therapeutic goal for RA is remission, clinicians increasingly face the challenge of choosing the optimal biologic agent in patients with RA-ILD and uncontrolled joint disease. However, no evidence-based guidelines exist to guide physicians in deciding whether to commence biologic therapy in this setting, or in selecting which drug is most appropriate. Herein, we review the evidence for the comparative pulmonary safety of anti-TNF agents and non-TNF-targeting biologic agents in RA-ILD. In addition, we propose a framework for assessment of baseline disease severity to guide treatment decisions, and for monitoring during therapy. Because of substantial gaps in the available evidence, we also describe a research agenda aimed at obtaining data that will help inform future clinical practice.
24812285 JNK-dependent downregulation of FoxO1 is required to promote the survival of fibroblast-li 2015 Sep BACKGROUND: Forkhead box O (FoxO) transcription factors integrate environmental signals to modulate cell proliferation and survival, and alterations in FoxO function have been reported in rheumatoid arthritis (RA). OBJECTIVES: To examine the relationship between inflammation and FoxO expression in RA, and to analyse the mechanisms and biological consequences of FoxO regulation in RA fibroblast-like synoviocytes (FLS). METHODS: RNA was isolated from RA patient and healthy donor (HD) peripheral blood and RA synovial tissue. Expression of FoxO1, FoxO3a and FoxO4 was measured by quantitative PCR. FoxO1 DNA binding, expression and mRNA stability in RA FLS were measured by ELISA-based assays, immunoblotting and quantitative PCR. FLS were transduced with adenovirus encoding constitutively active FoxO1 (FoxO1ADA) or transfected with small interfering RNA targeting FoxO1 to examine the effects on cell viability and gene expression. RESULTS: FoxO1 mRNA levels were reduced in RA patient peripheral blood compared with HD blood, and RA synovial tissue FoxO1 expression correlated negatively with disease activity. RA FLS stimulation with interleukin 1β or tumour necrosis factor caused rapid downregulation of FoxO1. This effect was independent of protein kinase B (PKB), but dependent on c-Jun N-terminal kinase (JNK)-mediated acceleration of FoxO1 mRNA degradation. FoxO1ADA overexpression in RA FLS induced apoptosis associated with altered expression of genes regulating cell cycle and survival, including BIM, p27(Kip1) and Bcl-XL. CONCLUSIONS: Our findings identify JNK-dependent modulation of mRNA stability as an important PKB-independent mechanism underlying FoxO1 regulation by cytokines, and suggest that reduced FoxO1 expression is required to promote FLS survival in RA.
24241487 Longterm effect of delaying combination therapy with tumor necrosis factor inhibitor in pa 2014 Jan OBJECTIVE: To evaluate the longterm safety of adalimumab administered with or without methotrexate (MTX) and compare the efficacy of combination therapy initialization to adalimumab or MTX monotherapy initialization during the open-label extension (OLE) of the PREMIER trial (ClinicalTrials.gov Identifier:NCT00195663). METHODS: Patients with early rheumatoid arthritis (RA) were randomized to receive blinded adalimumab + MTX, adalimumab alone, or MTX alone for 2 years. Following the double-blinded period, patients enrolling in the OLE were given adalimumab for up to 8 additional years, beginning as monotherapy; investigators could add MTX at their discretion. Results for clinical, functional, and radiographic progression were collected for up to 10 years of treatment. RESULTS: During the PREMIER OLE, 250/497 patients (50.3%) completed the trial without new safety signals arising. Similar proportions of patients discontinued the trial early, although lack of efficacy was reported less often for patients initially randomized to the adalimumab + MTX arm (9.3%; 21.2%, and 23.7% for adalimumab and MTX monotherapies, respectively). Clinical and functional disease control was maintained throughout the trial. Patients initially randomized to adalimumab + MTX displayed better outcomes, particularly in prevention of radiographic progression (modified total Sharp score change = 4.0, 8.8, 11.0 at Year 10 for the initial adalimumab + MTX, adalimumab, and MTX arms, respectively). CONCLUSION: Intensive therapy with adalimumab + MTX combination in patients with early RA has longterm benefits compared to patients initiating with 2-year adalimumab or MTX monotherapy that persists up to 10 years following adalimumab OLE. No new safety findings were observed following longterm adalimumab treatment.
23975674 Non-pharmacological interventions for fatigue in rheumatoid arthritis. 2013 Aug 23 BACKGROUND: Fatigue is a common and potentially distressing symptom for people with rheumatoid arthritis with no accepted evidence based management guidelines. Non-pharmacological interventions, such as physical activity and psychosocial interventions, have been shown to help people with a range of other long-term conditions to manage subjective fatigue. OBJECTIVES: To evaluate the benefit and harm of non-pharmacological interventions for the management of fatigue in people with rheumatoid arthritis. This included any intervention that was not classified as pharmacological in accordance with European Union (EU) Directive 2001/83/EEC. SEARCH METHODS: The following electronic databases were searched up to October 2012, Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; AMED; CINAHL; PsycINFO; Social Science Citation Index; Web of Science; Dissertation Abstracts International; Current Controlled Trials Register; The National Research Register Archive; The UKCRN Portfolio Database. In addition, reference lists of articles identified for inclusion were checked for additional studies and key authors were contacted. SELECTION CRITERIA: Randomised controlled trials were included if they evaluated a non-pharmacological intervention in people with rheumatoid arthritis with self-reported fatigue as an outcome measure. DATA COLLECTION AND ANALYSIS: Two review authors selected relevant trials, assessed risk of bias and extracted data. Where appropriate, data were pooled using meta-analysis with a random-effects model. MAIN RESULTS: Twenty-four studies met the inclusion criteria, with a total of 2882 participants with rheumatoid arthritis. Included studies investigated physical activity interventions (n = 6 studies; 388 participants), psychosocial interventions (n = 13 studies; 1579 participants), herbal medicine (n = 1 study; 58 participants), omega-3 fatty acid supplementation (n = 1 study; 81 participants), Mediterranean diet (n = 1 study; 51 participants), reflexology (n = 1 study; 11 participants) and the provision of Health Tracker information (n = 1 study; 714 participants). Physical activity was statistically significantly more effective than the control at the end of the intervention period (standardized mean difference (SMD) -0.36, 95% confidence interval (CI) -0.62 to -0.10; back translated to mean difference of 14.4 points lower, 95% CI -4.0 to -24.8 on a 100 point scale where a lower score means less fatigue; number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 4 to 26) demonstrating a small beneficial effect upon fatigue. Psychosocial intervention was statistically significantly more effective than the control at the end of the intervention period (SMD -0.24, 95% CI -0.40 to -0.07; back translated to mean difference of 9.6 points lower, 95% CI -2.8 to -16.0 on a 100 point scale, lower score means less fatigue; NNTB 10, 95% CI 6 to 33) demonstrating a small beneficial effect upon fatigue. For the remaining interventions meta-analysis was not possible and there was either no statistically significant difference between trial arms or findings were not reported. Only three studies reported any adverse events and none of these were serious, however, it is possible that the low incidence was in part due to poor reporting. The quality of the evidence ranged from moderate quality for physical activity interventions and Mediterranean diet to low quality for psychosocial interventions and all other interventions. AUTHORS' CONCLUSIONS: This review provides some evidence that physical activity and psychosocial interventions provide benefit in relation to self-reported fatigue in adults with rheumatoid arthritis. There is currently insufficient evidence of the effectiveness of other non-pharmacological interventions.
23437951 A threshold hazard model for estimating serious infection risk following anti-tumor necros 2013 Mar 11 Over recent years novel biologic agents have been developed for the treatment of rheumatoid arthritis. The most common type of biologic agent in use in the United Kingdom is the anti-tumor necrosis factor inhibitor class. To fully appreciate the potential risks of anti-tumor necrosis factor therapy in patients, knowledge about the baseline hazard (risk pattern) and the characteristics of patients associated with serious infection is important. We propose a nonproportional hazard model for estimating the infection risk, by including the drug exposure history information into the baseline hazard. We found that the infection risk reaches a peak within 1 month after drug exposure starts and then declines steadily for nearly 2 years before stabilizing out.
24286540 Very different performance of the power Doppler modalities of several ultrasound machines 2013 Oct 24 INTRODUCTION: In many patients with rheumatoid arthritis (RA) subclinical disease activity can be detected with ultrasound (US), especially using power Doppler US (PDUS). However, PDUS may be highly dependent on the type of machine. This could create problems both in clinical trials and in daily clinical practice. To clarify how the PDUS signal differs between machines we created a microvessel flow phantom. METHODS: The flow phantom contained three microvessels (150, 1000, 2000 microns). A syringe pump was used to generate flows. Five US machines were used. Settings were optimised to assess the lowest detectable flow for each US machine. RESULTS: The minimal detectable flow velocities showed very large differences between the machines. Only two of the machines may be able to detect the very low flows in the capillaries of inflamed joints. There was no clear relation with price. One of the lower-end machines actually performed best in all three vessel sizes. CONCLUSIONS: We created a flow phantom to test the sensitivity of US machines to very low flows in small vessels. The sensitivity of the power Doppler modalities of 5 different machines was very different. The differences found between the machines are probably caused by fundamental differences in processing of the PD signal or internal settings inaccessible to users. Machines considered for PDUS assessment of RA patients should be tested using a flow phantom similar to ours. Within studies, only a single machine type should be used.
23838027 The effect of golimumab on haemoglobin levels in patients with rheumatoid arthritis, psori 2013 Oct OBJECTIVE: To evaluate the effect of golimumab on haemoglobin levels in patients with RA, PsA or AS. METHODS: Secondary analysis was performed on integrated data from five randomized controlled studies: three RA, one PsA and one AS (2303 patients total). Golimumab 50 or 100 mg was injected s.c. every 4 weeks with or without MTX. Control groups received placebo injections plus MTX or background therapy. Patients with haemoglobin levels below the age- and sex-specific normal ranges were considered to have anaemia. Ferritin levels were used to distinguish anaemia of mixed aetiology (≥ 15 and <60 ng/ml) and anaemia of inflammation (≥ 60 ng/ml). Changes from baseline to weeks 14 and 24 in haemoglobin level were compared between treatment groups using an analysis of variance on the van der Waerden normal scores. RESULTS: At baseline, 21% of RA patients, 9% of PsA patients and 15% of AS patients had anaemia. Of these, 24%, 57% and 25%, respectively, had anaemia of inflammation. The median increase from baseline to week 14 in the haemoglobin level of anaemic patients was 0.3 g/dl in the control group and 0.9 g/dl in the golimumab group (P < 0.001). Haemoglobin levels improved within the subgroups of patients with anaemia of mixed aetiology (control, 0.4 g/dl vs golimumab, 0.7 g/dl) (P = 0.305) and with anaemia of inflammation (0.2 vs 1.4 g/dl, respectively) (P < 0.001). CONCLUSION: Compared with the control group, patients receiving golimumab treatment had significantly improved haemoglobin levels, particularly among patients with anaemia of inflammation.
23845567 TWEAK promotes osteoclastogenesis in rheumatoid arthritis. 2013 Sep Bone destruction is critical in the functional disability of patients with rheumatoid arthritis (RA). Osteoclasts, specialized bone-resorbing cells regulated by cytokines, such as receptor activator of NF-κB ligand (RANKL), are primarily implicated in bone destruction in RA. The aim of the study was to examine whether tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, has osteoclastogenic activity in patients with RA and in animal models, including mice with collagen-induced arthritis (CIA) and IL-1 receptor antagonist knockout (IL-1RaKO) mice. TWEAK was increased in the synovium, synovial fluid, and serum of patients with RA and in the synovium of CIA mice and IL-1RaKO mice. TWEAK induced RANKL expression in mixed joint cells and splenocytes from CIA mice, IL-1RaKO mice, and fibroblast-like synoviocytes from patients with RA. Both osteoclast precursor cells and osteoclasts express TWEAK receptor fibroblast growth factor-inducible 14. In addition, TWEAK enhanced in vitro osteoclastogenesis without the presence of RANKL-providing cells and by inducing RANKL expression in fibroblast-like synoviocytes. Moreover, treatment with fibroblast growth factor-inducible 14-Fc inhibited RANKL-induced osteoclastogenesis, indicating that endogenous TWEAK also has osteoclastogenic activity. Our data demonstrated that TWEAK promotes osteoclastogenesis in RA, suggesting that therapeutic strategies targeting TWEAK could be effective for treatment of patients with RA, especially in preventing bone destruction.
24998232 False human immunodeficiency virus test results associated with rheumatoid factors in rheu 2014 Jun OBJECTIVE: To investigate if immunological factors associated with rheumatoid arthritis (RA) affect the result of human immunodeficiency virus (HIV) screening by electrochemiluminescence immunoassay (ECLIA) and enzyme-linked immunosorbent assay (ELISA). METHODS: 100 RA cases were enrolled from January 2012 to February 2013 into this study. HIV screening was conducted with ECLIA detecting both HIV-1 p24 antigen, HIV-1 and HIV-2 antibodies, with ELISA and colloidal gold method detecting HIV-1 and HIV-2 antibodies. The samples producing positive results were submitted to the Center for Disease Control for confirmation using Western blotting method. The antibody titers of rheumatoid factors (RF) including RF-IgG, RF-IgM, RF-IgA, and CCP-IgG were analyzed by ELISA. RESULTS: The HIV positive-rate determined by ECLIA was significantly higher than that by ELISA and colloidal gold method (P<0.01). The false-positive rate of HIV screening was associated with antibody titers of RF-IgG, RF-IgM, RF-IgA, and CCP-IgG in RA (P<0.01). CONCLUSIONS: Immunological factors, including RF and anti-CCP antibody, may influence the screening of HIV by ECLIA, producing false-positive result.
22960198 Interleukin-17A promotes rheumatoid arthritis synoviocytes migration and invasion under hy 2013 Mar Both hypoxia and interleukin-17A (IL-17A) promote the migration and invasion of fibroblast-like synoviocytes (FLSs), which are critical for the pathogenesis of rheumatoid arthritis (RA). However, the biochemical pathways regulating IL-17A combined with hypoxia are not well defined. In this study, we found that co-stimulating RA-FLSs with IL-17A and hypoxia did not appear to promote the epithelial-mesenchymal transition (EMT), but did increase cell motility. We further showed that a proinvasive effect of IL-17A on FLSs under hypoxia might be through upregulation of matrix metalloproteinase 2 (MMP2) and MMP9. Moreover, IL-17A-induced expression of MMP2 and MMP9 under hypoxia was accompanied by increased activation of nuclear factor-κB (NF-κB)/hypoxia-inducible factor-1α (HIF-1α). Knockdown or inhibition of HIF-1α and NF-κB by small interfering RNA or specific small molecule inhibitors blocked IL-17A-mediated and hypoxia-mediated MMP2 and MMP9 expression, cell migration, and invasion. In addition, the inhibition of NF-κB led to a marked decrease in the expression of HIF-1α, which indicated that IL-17A activated HIF-1α via the NF-κB pathway in hypoxia. Taken together, our observations suggest a synergetic effect of IL-17A and hypoxia that might contribute to the migration and invasion of RA-FLSs by upregulating the expression of MMP2 and MMP9 by activation of the NF-κB/HIF-1α pathway.
22414257 Proinflammatory and anti-inflammatory cytokines in gingival crevicular fluid and serum of 2013 Jan BACKGROUND: The aim of this study is to evaluate proinflammatory and anti-inflammatory cytokine levels in gingival crevicular fluid (GCF) and serum of rheumatoid arthritis (RA) and chronic periodontitis (CP) patients to assess whether cytokine profiles distinguish patients with RA and patients with CP while using healthy patients as background controls. METHODS: A total of 49 patients, 17 patients with RA (three males and 14 females; mean age: 47.82 ± 10.74 years), 16 patients with CP (10 males and six females; mean age: 44.00 ± 7.00 years), and 16 controls (eight males and eight females; mean age: 28.06 ± 6.18 years) were enrolled. Patients with RA were under the supervision of rheumatologists; 15 of the patients with RA were being treated with methotrexate-sulfasalazine combined therapy, and two of the patients were being treated with leflunomid therapy. Periodontal parameters (plaque index, gingival index, probing depth, and clinical attachment level) were recorded. Interleukin (IL)-1β, IL-4, IL-10, and tumor necrosis factor-α (TNF-α) were determined in GCF and IL-1β and IL-10 in serum by enzyme-linked immunosorbent assay. RESULTS: There were significant differences found among RA, CP, and control groups for all periodontal parameters (P <0.05). The total amount and concentration of GCF IL-1 β, IL-4, IL-10, and TNF-α were similar in RA and CP patients (P >0.05). Although the total amount and concentration of serum IL-10 was not significantly different among the groups (P >0.05), serum IL-1β was significantly lower in the RA group compared to CP patients and controls and was higher in GCF of the RA group compared to the CP group. CONCLUSIONS: Although clinical periodontal disease parameters indicated more severe periodontal disease in CP compared to RA patients, immunologic evaluation did not reveal consistent results regarding proinflammatory and anti-inflammatory cytokine levels. This might be a result of the use of non-steroidal anti-inflammatory drugs and rheumatoid agents by patients with RA.
25142313 Therapeutic uses of anti-interleukin-6 receptor antibody. 2015 Jan Cytokine-targeted therapy has generated a paradigm shift in the treatment of several immune-mediated diseases. Interleukin-6 (IL-6), which was initially identified as B-cell stimulatory factor 2, is a prototypical cytokine with wide-ranging biological effects on immune cells such as B and T cells, on hepatocytes, hematopoietic cells, vascular endothelial cells and on many others. IL-6 is thus crucially involved in the regulation of immune responses, hematopoiesis and inflammation. When infections and tissue injuries occur, IL-6 is promptly synthesized and performs a protective role in host defense against such stresses and traumas. However, excessive production of IL-6 during this emergent process induces potentially fatal complications, including systemic inflammatory response syndrome (SIRS), and dysregulated, persistently high expression of IL-6 causes the onset or development of various chronic immune-mediated disorders. For these reasons, IL-6 blockade was expected to become a novel therapeutic strategy for various diseases characterized by IL-6 overproduction. Indeed, worldwide clinical trials of tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody, have successfully proved its outstanding efficacy against rheumatoid arthritis, juvenile idiopathic arthritis and Castleman disease, leading to the approval of tocilizumab for the treatment of these diseases. Moreover, various reports regarding off-label use of tocilizumab strongly suggest that it will be widely applicable for acute, severe complications such as SIRS and cytokine-release syndrome and other refractory chronic immune-mediated diseases.