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ID PMID Title PublicationDate abstract
22467922 Tocilizumab treatment decreases circulating myeloid dendritic cells and monocytes, 2 compo 2012 Jun OBJECTIVE: Interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) are proinflammatory cytokines involved in inflammatory response. Effective TNF-α blocker treatment is associated with an increase in circulating myeloid dendritic cells (mDC), suggesting their release from inflamed synovium. Currently, in vivo effects of IL-6 inhibition on DC are unknown. We monitored the changes in circulating mDC and plasmacytoid DC (pDC) during tocilizumab (TCZ) therapy in patients with rheumatoid arthritis (RA). METHODS: DC subset levels were evaluated by flow cytometry in patients with RA (n = 43) and in healthy volunteers (n = 20). In patients with RA, these levels were measured before and during TCZ therapy (8 mg/kg every 4 weeks). Response to TCZ therapy was evaluated at 12 weeks. Statistical analysis was based on Mann-Whitney U tests or Wilcoxon signed-rank tests. RESULTS: At baseline, patients with active RA were characterized by a significantly lower level of circulating mDC and pDC compared to healthy donors. However, this difference did not correlate with any disease activity score. TCZ-treated patients who met the European League Against Rheumatism (EULAR) improvement criteria at Week 12 had significant reductions in mDC and monocyte levels as compared with EULAR nonresponders. Levels of pDC, CD4+ T cells, and CD8+ T cells remained stable during the TCZ courses, regardless of treatment response. CONCLUSION: Our study reveals an unexpected reduction of circulating mDC and monocytes in patients with RA in response to TCZ therapy. In accord with reports on neutrophils and platelets decreasing during TCZ therapy, our data suggest an effect of IL-6 inhibition on cells from myeloid lineage.
22447884 Immunity 12 years after alemtuzumab in RA: CD5⁺ B-cell depletion, thymus-dependent T-cel 2012 Aug OBJECTIVES: Lymphocyte depleting therapies have been used to treat refractory autoimmune disease, including RA, but treatment may be associated with long-term lymphopenia. It is unclear whether delayed reconstitution preferentially affects lymphocyte subsets, how this modulates immune challenges and whether thymic function influences the outcome. These questions are now addressed in a detailed analysis of RA patients 12 years after alemtuzumab (anti-CD52) treatment. METHODS: Blood was obtained from 20 RA patients 12 years after alemtuzumab treatment. Lymphocyte subsets were enumerated by flow cytometry. T-cell receptor excision circles (TRECs)/ml were determined to quantify thymic function, and serological responses to neoantigens and recall antigens were assessed. RESULTS: RA patients remained lymphopenic 12 years after their first dose of alemtuzumab. CD5(+) B cells, which may be associated with autoantibody production, were significantly reduced in alemtuzumab-treated patients compared with age-matched disease controls. In addition, naïve and memory CD4(+) T-cell subsets were present in altered proportions in patients who had received alemtuzumab, with increased effector memory CD4(+) T cells, and decreased naïve and central memory CD4(+) T cells. TRECs were detectable in alemtuzumab-treated patients and correlated with CD4(+) lymphocyte counts. Vaccine responses to neoantigens and recall antigens fell within the normal range for an ageing population. CONCLUSIONS: Alemtuzumab therapy resulted in long-term alterations in lymphocyte subsets. The significance of these changes remains uncertain but patients respond normally to antigenic challenges. Thymic function remains an important determinant of T-cell reconstitution even several years after lymphocytotoxic therapy.
21296061 NF-κB-mediated anti-inflammatory activity of the sesquiterpene lactone 7-hydroxyfrullanol 2011 Apr 25 Microarray technology can be used to study the molecular mechanisms of new chemical entities with the aim to develop effective therapeutics. 7-Hydroxyfrullanolide (7HF) is a sesquiterpene lactone that was found to be efficacious in multiple animal models of inflammation by suppression of pro-inflammatory cytokines; however, its molecular mechanism of action remains unclear. We investigated the effects of 7HF on lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells using microarray-based gene expression studies and explored the molecular targets affected. Gene expression profiles and pathway analysis revealed that 7HF potently suppressed multiple inflammatory pathways induced by LPS. More importantly, 7HF was found to inhibit NF-κB related transcripts. These transcripts were further validated using freshly isolated synovial cells from rheumatoid arthritis patients, thus clinically validating our findings. Cell-based imaging and subsequent Western blot analysis demonstrated that 7HF inhibited the translocation of NF-κB into the nucleus by directly inhibiting the phosphorylation of IKK-β. Since the transcription of adhesion molecules is regulated by NF-κB, further investigation showed that 7HF dose-dependently suppressed ICAM-1, VCAM-1 and E-selectin expression on LPS-stimulated endothelial cells as well as inhibited the adhesion of monocytes to LPS-stimulated endothelial cells. Taken together, our results reveal that 7HF possesses NF-κB inhibitory potential and suggest a likely molecular mechanism of its anti-inflammatory activity.
21071505 Predictors of the use of physical therapy services among patients with rheumatoid arthriti 2011 Jan BACKGROUND: Although physical therapy is a proven and recommended intervention for managing rheumatoid arthritis (RA), few studies have explored correlates of physical therapy service use among people with RA. OBJECTIVE: The purposes of this study were: (1) to describe physical therapy use among people with RA and (2) to identify biopsychosocial factors associated with physical therapy use. It was expected that use of physical therapy services would be lower than previously reported, considering recent medical advancements, and that including contextual factors may lead to identification of new factors associated with physical therapy use. DESIGN: This was a cohort study. METHODS: Of 1,032 patients prospectively recruited from a large hospital registry, 772 completed baseline and laboratory assessments, received a physical examination, and completed a 1-year follow-up survey regarding physical therapy service use. Measures included: demographics (ie, age, sex, marital status, race, employment, disability status, insurance, income, comorbidities, and education), disease duration, RA medications, self-efficacy (assessed with the Arthritis Self-Efficacy Scale), social support (assessed with the Berkman-Syme Social Network Index), function (assessed with the Multi-Dimensional Health Assessment Questionnaire), and disease activity (assessed with the Rheumatoid Arthritis Disease Activity Index). Self-reported use of physical therapy (yes/no) was assessed at the 1-year follow-up. A staged regression approach, based on a theoretical model, was used to select and enter variables into the regression to develop a parsimonious set of predictors. RESULTS: The patients were well educated and had modestly high incomes, and most had health insurance. Approximately 15.3% of the patients used physical therapy services during the designated follow-up period. Using multivariable modeling, the most significant predictors of physical therapy service use were moderate to high disease activity (odds ratio [OR]=1.4, 95% confidence interval [CI]=1.1-1.8), less than a college education (OR=0.5, 95% CI=0.2-0.8), greater social networks (OR=2.1, 95% CI=1.3-3.5), and being on disability (OR=2.4, 95% CI=1.3-4.6). LIMITATIONS: The limitations of this study were use of a convenience sample and the potential for misclassification of physical therapy service use. CONCLUSIONS: Patients with less than college education were less likely to receive physical therapy services, and those with more active disease, those who were on disability, and those who had greater social networks were more likely to receive physical therapy services.
20300754 Lack of evidence for association of two functional SNPs of CHI3L1 gene (HC-gp39) with rheu 2011 Aug CHI3L1 gene encodes for a glycoprotein (HC-gp39 or YKL40) secreted by synovial fibroblasts, macrophages, neutrophil granulocytes and chondrocytes. Its expression is under the control of NF-kB. It is regarded as an acute phase protein, and its levels are significantly elevated in rheumatic diseases. Furthermore, HC-gp39 has been shown to be recognized by autoreactive T cells in rheumatoid arthritis. In the present study, we have examined two functional variants of the promoter region of CHI3L1 gene (CHI3L1-1 (rs4950928) and CHI3L1-2 (rs10399931) that have been reported earlier to be associated with schizophrenia and sarcoidosis. We used TaqMan allelic discrimination assays to study the genotypes of Hungarian patients with rheumatoid arthritis (n = 182) and of healthy controls (n = 194). No significant association of the investigated SNPs with the disease was found. Here we report that CHI3L1 SNPs, shown to be involved in the predisposition of schizophrenia, are not associated with rheumatoid arthritis.
21531476 CD8α⁺ dendritic cells improve collagen-induced arthritis in CC chemokine receptor (CCR) 2011 Sep OBJECTIVE: Dendritic cells (DCs) have long been recognized as potential therapeutic targets of rheumatoid arthritis (RA). Increasing evidence has showed that DCs are capable of suppressing autoimmunity by expanding FoxP3⁺ regulatory T cells (T(reg)), which in turn exert immunosuppression by increasing TGFβ-1. In the SKG mice, activated DC prime autoreactive T cells causing autoantibody production and an inflammatory arthritic response. Recently, we reported that CC-chemokine receptor-2 deficient (Ccr2⁻/⁻) mice had impaired DCs migration and reduced CD8α⁺ DCs in the C57Bl/6J mice strain and that these mice were more susceptible to collagen antibody-induced arthritis (CAIA), compared to wild type mice. To examine the mechanism by which DCs contribute to the increased susceptibility of arthritis in Ccr2⁻/⁻ mice, we tested the hypothesis that CD8α⁺ DCs are protective (tolerogenic) against autoimmune arthritis by examining the role of CD8α⁺ DCs in Ccr2⁻/⁻ and SKG mice. METHODS: To examine the mechanism by which DCs defects lead to the development of arthritis, we used two murine models of experimental arthritis: collagen-induced arthritis (CIA) in DBA1/J mice and zymosan-induced arthritis in SKG mice. DBA1/J mice received recombinant fms-like tyrosine kinase 3 ligand (Flt3L) injections to expand endogenous DCs populations or adoptive transfers of CD8α⁺ DCs. RESULTS: Flt3L-mediated expansion of endogenous CD8α⁺ DCs resulted in heightened susceptibility of CIA. In contrast, supplementation with exogenous CD8α⁺ DCs ameliorated arthritis in Ccr2⁻/⁻ mice and enhanced TGFβ1 production by T cells. Furthermore, SKG mice with genetic inactivation of CCR2 did not affect the numbers of DCs nor improve the arthritis phenotype. CONCLUSION: CD8α⁺ DCs were tolerogenic to the development of arthritis. CD8α⁺ DCs deficiency heightened the sensitivity to arthritis in Ccr2⁻/⁻ mice. Ccr2 deficiency did not alter the arthritic phenotype in SKG mice suggesting the arthritis in Ccr2⁻/⁻ mice was T cell-independent.
21305526 Carotid atherosclerosis predicts incident acute coronary syndromes in rheumatoid arthritis 2011 May OBJECTIVE: The role of atherosclerosis in the acute coronary syndromes (ACS) that occur in patients with rheumatoid arthritis (RA) has not been quantified in detail. We undertook this study to determine the extent to which ACS are associated with carotid atherosclerosis in RA. METHODS: We prospectively ascertained ACS, defined as myocardial infarction, unstable angina, cardiac arrest, or death due to ischemic heart disease, in an RA cohort. We measured carotid atherosclerosis using high-resolution ultrasound. We used Cox proportional hazards models to estimate the association between ACS and atherosclerosis, adjusting for demographic features, cardiovascular (CV) risk factors, and RA manifestations. RESULTS: We performed carotid ultrasound on 636 patients whom we followed up for 3,402 person-years. During this time, 84 patients experienced 121 new or recurrent ACS events, a rate of 3.5 ACS events per 100 patient-years (95% confidence interval [95% CI] 3.0-4.3). Among the 599 patients without a history of ACS, 66 incident ACS events occurred over 3,085 person-years, an incidence of 2.1 ACS events per 100 person-years (95% CI 1.7-2.7). The incidence of new ACS events per 100 patient-years was 1.1 (95% CI 0.6-1.7) among patients without plaque, 2.5 (95% CI 1.7-3.8) among patients with unilateral plaque, and 4.3 (95% CI 2.9-6.3) among patients with bilateral plaque. Covariates associated with incident ACS events independent of atherosclerosis included male sex, diabetes mellitus, and a cumulative glucocorticoid dose of ≥ 20 gm. CONCLUSION: Atherosclerosis is strongly associated with ACS in RA. RA patients with carotid plaque, multiple CV risk factors (particularly diabetes mellitus or hypertension), many swollen joints, and a high cumulative dose of glucocorticoids, as well as RA patients who are men, are at high risk of ACS.
22340996 Prevalence of traditional modifiable cardiovascular risk factors in patients with rheumato 2012 Feb OBJECTIVE: Despite the recognized risk of accelerated atherosclerosis in patients with rheumatoid arthritis (RA), little is known about cardiovascular risk management in contemporary cohorts of these patients. We tested the hypotheses that major modifiable cardiovascular risk factors were more frequent and rates of treatment, detection, and control were lower in patients with RA than in non-RA controls. METHODS: The prevalence of hypertension, diabetes, elevated low-density lipoprotein (LDL) cholesterol, elevated body mass index, smoking, moderate-high 10-year cardiovascular risk and the rates of underdiagnosis, therapeutic treatment, and recommended management were compared in 197 RA patients and 274 frequency-matched control subjects, and their associations with clinical characteristics were examined. RESULTS: Eighty percent of RA patients and 81% of control subjects had at least 1 modifiable traditional cardiovascular risk factor. Hypertension was more prevalent in the RA group (57%) than in controls [42%, P = 0.001]. There were no statistically significant differences in the frequency of diabetes, elevated body mass index, smoking, intermediate-high 10-year coronary heart disease risk, or elevated LDL in patients with RA versus controls. Rates of newly identified diabetes, hypertension, and hyperlipidemia were similar in RA patients versus controls. Rates of therapeutic interventions were low in both groups but their use was associated with well-controlled blood pressure (OR = 4.55, 95% CI: 1.70, 12.19) and lipid levels (OR = 9.90, 95% CI: 3.30, 29.67). CONCLUSIONS: Hypertension is more common in RA than in controls. Other traditional cardiovascular risk factors are highly prevalent, underdiagnosed, and poorly controlled in patients with RA, as well as controls.
21998120 The ACPA recognition profile and subgrouping of ACPA-positive RA patients. 2012 Feb OBJECTIVE: Anticitrullinated protein antibodies (ACPA) are the most predictive factor for the development of rheumatoid arthritis (RA). Epitope spreading towards more citrullinated epitopes occurs before the onset of RA. Here, the authors investigated whether specific epitope recognition allows the identification of specific RA subgroups and whether it is associated with clinical features of RA. METHODS: The reactivity of 661 patients with RA from the Leiden Early Arthritis Clinic against several citrullinated antigens was determined by ELISA. Cluster analyses were performed to identify subgroups of patients on the basis of their ACPA recognition profile. The association of the specific reactivities with clinical characteristics was studied. RESULTS: ACPA-positive patients displayed a heterogeneous ACPA recognition profile. After performing cluster analyses, no apparent clustering of patients was found, and on the basis of the reactivities analysed, 64 different subgroups could already be identified. The extent of epitope recognition was associated with anticyclic citrullinated peptide-2 levels. The recognition of specific citrullinated epitopes was not associated with baseline characteristics. Likewise, patients with an extended fine specificity repertoire did not display differences in baseline characteristics or joint damage after 7 years of follow-up using cyclic citrullinated peptide-2 levels as a proxy, compared to ACPA-positive patients recognising fewer peptides. CONCLUSION: These data show that the ACPA response is highly diverse with respect to recognition of specific citrullinated epitopes. Furthermore, the authors' data indicate that clinical correlates in established ACPA-positive RA are independent from the specific (group of) citrullinated peptides recognised.
23270711 Inflammatory lesions in the bone marrow of rheumatoid arthritis patients: a morphological 2012 Dec 27 The synovial tissue stands at the epicenter of joint pathology in rheumatoid arthritis (RA). As a primary target of the disease, studies on the synovium have provided invaluable insights into the mechanisms involved in disease pathogenesis. Recent work has, however, revealed the importance of a previously unseen anatomic compartment in direct contact with the joint space, namely the subchondral bone marrow. Bone marrow edema (BME) visible on magnetic resonance imaging (MRI) is clinically meaningful in both early and late RA as it associates with future development of bone erosions and poor functional outcomes. Although the histopathologic correlates of MRI-based BME in early RA remain obscure, studies in advanced disease are consistent in describing lymphocytic inflammatory infiltrates within the subchondral marrow cavity of affected joints. In this review, we discuss the nature of bone marrow lesions in patients with RA, analyze their relationship with synovitis, and explore their potential contribution to the pathological processes of the disease.
21359555 [Patient/rheumatologist evaluation of infusion treatment for rheumatoid arthritis]. 2011 Apr OBJECTIVES: The various biologic agents currently available for the treatment of RA can be administered subcutaneously (s.c.) or via intravenous (i.v.) infusion with variable intervals depending on the drug. This investigation aims to identify the preferences and concerns of affected patients and their physicians. METHODS: We conducted a survey of 102 patients with RA currently receiving Rituximab (RTX) therapy. They were asked about different aspects of their current and previous RA therapy, including overall satisfaction, tolerability, mode of drug administration, as well as duration and intervals. In addition, 17 rheumatologists were asked about different aspects of s.c. or i.v. drug administration, their preference and the suspected preference of their patients. RESULTS: The mean age of our patients was 59 ± 11.2 years. Patients had failed ≥2 DMARD therapies and ≥ 1 biologic treatment. The impact of RTX infusions on planning different activities including job, hobbies or travelling was considered as low or very low in 76% of the respondents. Interestingly, 63.4% of patients would prefer an infusion every 6-9 months as RA therapy, whereas 21.5% would prefer tablets only; 12.9% of our patient cohort would prefer s.c. injections every second week, and only 2% would prefer an infusion every month. In all, 92% of patients questioned would choose RTX therapy again. In contrast, 88% of rheumatologists preferred s.c. injection and even 94% of them assumed that their patients would do so as well if they had the choice. The suggested reasons included greater flexibility, convenience and independence during s.c. therapy. CONCLUSION: Contrary to the assumption of rheumatologists, we have demonstrated a preference among RTX patients for i.v. drug administration every 6-9 months over other methods of administration.
23039928 Detection for gene-gene co-association via kernel canonical correlation analysis. 2012 Oct 8 BACKGROUND: Currently, most methods for detecting gene-gene interaction (GGI) in genomewide association studies (GWASs) are limited in their use of single nucleotide polymorphism (SNP) as the unit of association. One way to address this drawback is to consider higher level units such as genes or regions in the analysis. Earlier we proposed a statistic based on canonical correlations (CCU) as a gene-based method for detecting gene-gene co-association. However, it can only capture linear relationship and not nonlinear correlation between genes. We therefore proposed a counterpart (KCCU) based on kernel canonical correlation analysis (KCCA). RESULTS: Through simulation the KCCU statistic was shown to be a valid test and more powerful than CCU statistic with respect to sample size and interaction odds ratio. Analysis of data from regions involving three genes on rheumatoid arthritis (RA) from Genetic Analysis Workshop 16 (GAW16) indicated that only KCCU statistic was able to identify interactions reported earlier. CONCLUSIONS: KCCU statistic is a valid and powerful gene-based method for detecting gene-gene co-association.
21444233 Optimizing methotrexate therapy in rheumatoid arthritis: a systematic literature review. 2011 Dec OBJECTIVE: To describe the means of optimizing methotrexate therapy for rheumatoid arthritis in daily clinical practice, based on a systematic literature review. METHODS: We systematically reviewed the literature by searching the PubMed, Embase, and Cochrane databases and reviewing communications to ACR and EULAR meetings for studies on methotrexate starting dosages, dosage increment sizes and intervals, maximum dosages, and routes of administration in patients with rheumatoid arthritis. We used an appropriate scoring system to assess the methodological quality of each selected study. RESULTS: We identified 519 studies of which 11 were selected based on the titles and abstracts then on the full-length articles. Methotrexate was optimally effective when started in a high dosage (more than 10mg/week orally) that was subsequently increased by 5mg/month up to 25-30mg/week,(1) with appropriate adjustments based on clinical disease activity and tolerance of each patient. For a given methotrexate dosage, parenteral administration was more effective and produced fewer gastrointestinal adverse effects than oral administration. CONCLUSION: The information supplied by this systematic review support higher starting dosage, an intensive dosage increase schedule and recourse to parenteral administration in case of unresponsiveness or intolerance to oral methotrexate. They should improve the management of patients given methotrexate therapy for rheumatoid arthritis.
21336817 Radiosynovectomy using yttrium-90, phosphorus-32 or rhenium-188 radiocolloids versus corti 2011 Jun BACKGROUND: Radiosynovectomy (RSO) is widely used in rheumatoid arthritis (RA). Commercially available radiopharmaceuticals are costly, and therefore new agents may be of interest. Radiocolloids labelled with less costly and more accessible radionuclides are of interest to developing countries. We investigated the efficacy of different formulations in RA. METHODS: In a multicentre effort, a cohort of 99 RA patients with knee involvement underwent RSO. Sixty-eight patients were treated with 184 ± 4 MBq Y-90 silicate (Y-90), 15 patients with 53 ± 11 MBq P-32 colloid (P-32), and 16 patients with 451 ± 110 MBq of Re-188 tin colloid (Re-188). Corticosteroid group (CSG) consisting of 46 patients received an intra-articular instillation of 20-40 mg triamcinolone. Pain response was evaluated by a 10-step visual analogue scale (VAS) before, 1 month, 3 months, 6 months and 12 months following the procedure. RESULTS: In the RSO group (n = 99), pain relief by VAS from 6 ± 2 before to 5 ± 3, 4 ± 2, 3 ± 2 and 4 ± 2 at 1, 3, 6, 12 months after RSO was documented (Y-90 group: 6 ± 2 to 3 ± 2; P-32: 5 ± 2 to 3 ± 2, Re-188: 7 ± 2 to 4 ± 2 before vs. 6 months after therapy, respectively). The CSG VAS values were 6 ± 2 before and 5 ± 2, 4 ± 3, 5 ± 2 and 6 ± 2 at 1, 3, 6 and 12 months after corticosteroid instillation, respectively. Pain relief achieved with the three radiocolloid formulations did not differ significantly (P > 0.1). Pain relief at 12 months was more durable in RSO compared to CSG, P < 0.05. At 3 months, pain relief (>2 steps) was reported by 86% of RSO versus 67% of CSG, at 6 months 72 versus 46% and at 12 months 46 versus 21%. Side effects, i.e. swelling or transient pain increase, were recorded in 16% of patients but resolved within 1 month. CONCLUSION: Therapeutic efficacy of RSO for RA of the knee applying either P-32, Re-188 or Y-90 provides comparable results. Pain relief by RSO is longer lasting as compared to corticosteroid instillation.
21547893 Synovial fibroblast hyperplasia in rheumatoid arthritis: clinicopathologic correlations an 2011 Sep OBJECTIVE: Synovial fibroblast (SF) hyperplasia contributes to the pathogenesis of rheumatoid arthritis (RA), but quantitative information on this process is scarce. This study was undertaken to evaluate the fibroblast-specific marker Hsp47 as a quantitative marker for SFs and to analyze its clinicopathologic correlates and evolution after anti-tumor necrosis factor α (anti-TNFα) therapy. METHODS: Synovial biopsy samples were obtained from 48 patients with RA and 20 controls who were healthy or had osteoarthritis (OA). Twenty-five RA patients who had active disease at the time of biopsy underwent a second biopsy after anti-TNFα therapy. Immunolabeling for Hsp47, inflammatory cells, and vascular cell markers was performed. Hsp47-positive lining and sublining fractional areas were quantified, and their correlation with clinicopathologic variables was analyzed. RESULTS: In normal and diseased synovial tissue, Hsp47 was specifically and uniformly expressed by lining, sublining, and perivascular fibroblasts. Lining SF area was significantly increased in both RA and late OA tissue compared to normal tissue. Sublining SF area was increased in RA tissue but not in late OA tissue compared to normal tissue. Lining SF area was positively correlated with macrophage density, Disease Activity Score in 28 joints, and RA disease duration. In contrast, sublining SF area was negatively correlated with RA disease duration and activity. A significant reduction in lining SF area but not sublining SF area was observed after anti-TNFα therapy. CONCLUSION: Our findings indicate that Hsp47 is a reliable marker for quantifying SFs in human synovial tissue. Our data suggest that lining and sublining SFs undergo different dynamics during the course of the disease. Lining SF expansion parallels the activity and temporal progression of RA and can be partially reversed by anti-TNFα therapy.
22149896 Comparative study of normal and rheumatoid arthritis fibroblast-like synoviocytes prolifer 2012 Fibroblast-like synoviocytes (FLSs) are one of the main contributors of prostaglandin E(2) (PGE(2)) in the hyperplastic synovium of rheumatoid arthritis (RA) patients. cyclooxygenase-2 (COX-2)/PGE(2) pathway is involved in the proliferation of several cell types. We have previously shown that mechanical stretch affects COX-2 and PGE(2) production in human RA FLSs; however, its role in cell proliferation remains to be elucidated. In this study, a comparison is drawn between human RA and normal FLSs to understand the role of mechanical stretch and PGE(2) on the proliferation of FLSs. The results showed that physiological level (6%, 1 Hz) of cyclic mechanical stretch significantly decreased the proliferation of RA FLSs but not normal FLSs, while the induction of apoptosis was not observed by stretch in either RA or normal FLSs. IL-1β (5 ng/ml)-induced COX-2/PGE(2) levels are downregulated by stretch in RA FLSs only. Further investigation showed that high concentration (100 and 500 ng/ml) of PGE(2) significantly induced cell proliferation only in RA FLSs, and this induction failed to be suppressed by stretch. In conclusion, this study demonstrated that elevated levels of PGE(2) in the synovial cavity are involved in the proliferation of RA FLSs, and cyclic mechanical stretch regulates the RA synovial hyperplasia.
22867979 Different risk factors between interstitial lung disease and airway disease in rheumatoid 2012 Nov OBJECTIVE: To identify clinical and genetic risk factors for interstitial lung disease (ILD) or airway disease (AD) in patients with rheumatoid arthritis (RA) and to evaluate differences between the associations of these factors with ILD and AD. METHODS: We reviewed high-resolution computed tomography (HRCT) images and clinical data of 356 RA patients obtained at their first visit. The diagnosis of ILD and AD was based on abnormal HRCT findings. Multinomial logistic regression analysis and likelihood ratio tests were performed. RESULTS: High titers of rheumatoid factor are similarly associated with increased risks of ILD (relative risk ratio, 3.1; p = 0.02) and AD (relative risk ratio, 3.0; p = 0.02). High levels of anti-cyclic citrullinated peptide antibodies were associated strongly with AD (relative risk ratio, 3.8; p = 0.005) and less strongly with ILD (relative risk ratio, 2.7; p = 0.07). Age was the potent risk factor for ILD (relative risk ratio, 4.6; p = 0.003), while that for AD was advanced stage (relative risk ratio, 11.5; p < 0.0005). The carriage of HLA-DRB1*1502 had opposite influences on the two conditions: relative risk ratio = 4.02 for ILD (p = 0.013) and relative risk ratio = 0.15 for AD (p = 0.08). This difference was statistically significant (p = 0.0005). Associations of sex and smoking history with ILD disappeared in the multinomial logistic regression analysis. CONCLUSIONS: The differential associations of ILD and AD with various clinical and genetic factors suggest that ILD and AD have distinct etiologies in RA.
22133625 Tumor necrosis factor blockade differentially affects innate inflammatory and Th17 cytokin 2012 Jan OBJECTIVE: To evaluate the effect of a tumor necrosis factor-α (TNF-α) inhibitor (etanercept) on innate inflammatory and Th17 cytokines in patients with rheumatoid arthritis (RA). METHODS: Serum samples were collected from 40 patients with active RA refractory to conventional disease-modifying antirheumatic drugs who initiated therapy with etanercept plus methotrexate (MTX). Treatment response was assessed at Week 24 according to the European League Against Rheumatism response criteria. Serum levels of interleukin 6 (IL-6), TNF-α, IL-32, IL-23, IL-17A, IL-21, and IL-22 were measured in patients with RA and 25 healthy controls. RESULTS: Patients with RA had increased levels of IL-6 (p < 0.001), IL-32 (p < 0.001), IL-23 (p < 0.001), and a trend toward increased IL-21 in the sera compared to controls. At 24 weeks' posttreatment, followup serum samples of etanercept responders had decreased levels of IL-6 (p < 0.001) and increased IL-21 (p < 0.05) and IL-32 (p < 0.001), while there were no differences in cytokine levels in non-responders. Serum IL-6 levels were positively correlated with levels of erythrocyte sedimentation rate (r = 0.458, p < 0.01), C-reactive protein (r = 0.593, p < 0.01), and 28-joint Disease Activity Score (r = 0.432, p < 0.01) at baseline. Serum IL-21 levels were positively correlated with levels of rheumatoid factor (r = 0.513, r = 0.633, both p < 0.01) and antimutated citrullinated vimentin antibodies (r = 0.515, p < 0.01; r = 0.428, p < 0.05) at baseline and after 24 weeks of treatment with etanercept. CONCLUSION: Multiple inflammatory pathways contribute to persistent chronic inflammation in RA. In contrast to nonresponders, etanercept therapy modulated serum cytokine levels and caused a marked decrease of IL-6 levels in responders. IL-21 might be involved in the regulation of autoantibody production in RA.
22565169 Lymphocytes from rheumatoid arthritis patients have elevated levels of intracellular perox 2012 Aug Peroxiredoxin 2 has immune regulatory functions, but its expression in human peripheral blood lymphocytes and levels in extracellular fluid in healthy subjects and rheumatoid arthritis patients are poorly described. In the present study, the median intracellular peroxiredoxin 2 protein content of lymphocytes from rheumatoid arthritis patients was more than two-fold higher compared with healthy subjects' lymphocytes. Intracellular peroxiredoxin 3 levels were similar in healthy and rheumatoid arthritis lymphocytes. Flow cytometry detected peroxiredoxin 2 on the surface of ca. 8% of T cells and ca. 56% of B cells (median % values) of all subjects analyzed. Exofacial thioredoxin-1 was also observed. In the total lymphocyte population from rheumatoid arthritis patients, few cells (median, 6%) displayed surface peroxiredoxin 2. In contrast, a significantly increased proportion of interleukin-17(+ve) lymphocytes were exofacially peroxiredoxin 2(+ve) (median, 39%). Prdx2 was also detected in human extracellular fluids. We suggest that crucial inflammatory cell subsets, i.e. interleukin-17(+ve) T cells, exhibit increased exofacial redox-regulating enzymes and that peroxiredoxin 2 may be involved in the persistence of pro-inflammatory cells in chronic inflammation.
22898219 A questionnaire survey of patient experience with the Rheumatology Monitoring Clinic in Si 2012 Aug AIM: The concept of a pharmacist/advanced practice nurse (APN)-led Rheumatology Monitoring Clinic (RMC) is a novel service in Singapore; we therefore conducted a questionnaire survey of patient experience. METHODS: Patients attending the RMC were provided with a set of questionnaires. As a substudy, a separate questionnaire was given to the rheumatologists and therapists conducting the RMC. RESULTS: Of the 105 patients surveyed, a total of 97 (92.4%) patients were satisfied/strongly satisfied with the overall service, and none were dissatisfied; 96% felt that the pharmacists/APNs provided clear, detailed information about their disease and medication, while 92% of patients were confident they knew what side-effects were possible. Ninety-two percent and 93% of patients were more likely to adhere to treatment, and were willing to come back for follow-up at the RMC, respectively. There was no difference in patient satisfaction in the average Likert summed scores, between the pharmacists and APNs. Age, gender, ethnicity and underlying disease did not exert any influence on the responses. All the rheumatologists surveyed were satisfied with the patients' management and the professionalism of the therapists. They opined that the RMC freed up time for them to see more complex cases. All the pharmacists/APNs concurred that the referrals were appropriately selected. CONCLUSIONS: We established the acceptability of a non-physician-led clinic in our local setting and highlighted the usefulness of having a routine clinic for monitoring medication toxicity and patient education. The RMC received positive feedback from patients, rheumatologists and allied health therapists, with a high degree of satisfaction among the respondents.