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ID PMID Title PublicationDate abstract
24628947 Relationship between the IL-4 gene promoter -590C/T (rs2243250) polymorphism and susceptib 2015 Jan OBJECTIVE: Studies investigating the association between interleukin (IL)-4 gene promoter -590C/T (rs2243250) polymorphism and autoimmune diseases report conflicting results. To derive a more precise estimation of the relationship, a meta-analysis was performed. METHODS: A systematic literature search was conducted to identify relevant studies. Pooled odds ratio (OR) with 95% confidence interval (CI) was used to estimate the strength of association. RESULTS: A total of 6001 cases and 6788 controls from 24 studies were analysed. Significant association of the C allele of IL-4 rs2243250 polymorphism with rheumatoid arthritis (RA) was detected (odds ratio (OR) = 0.696, 95% confidence interval (CI) = 0.601-0.807). Stratification by ethnicity indicated an association between the IL-4 rs2243250 polymorphism and RA in Caucasians. Furthermore, the overall ORs of the associations between the C allele and multiple scleorosis (MS) were 1.340 (95% CI = 1.102-1.630). However, we failed to reveal any association between IL-4 rs2243250 polymorphism and systemic lupus erythematosus (SLE), type 1 diabetes (T1D) or Graves' disease (GD). CONCLUSIONS: The present study suggests that the IL-4 rs2243250 polymorphism might be associated with genetic susceptibility to autoimmune diseases, including RA and MS.
23481418 Multifaceted effects of hydroxychloroquine in human disease. 2013 Oct OBJECTIVES: Hydroxychloroquine (HCQ) is a widely used medication for the treatment of rheumatoid arthritis and systemic lupus erythematosus. An increasing body of evidence supports actions of this drug that are not directly related to its immunosuppressive or anti-rheumatic properties. The objective of this systematic review is to characterize the spectrum of conditions that might be responsive to treatment with HCQ. METHODS: PubMed was searched using the MeSH for HCQ with relevant subheadings and the limits of human topics and English language. Four-hundred and fifty-six abstracts from this search were examined individually to exclude those that were not focused on the objectives of this review. The resulting 76 articles were grouped according to topic areas and reviewed in detail. RESULTS: HCQ has been reported to have therapeutic effects in a wide array of conditions, including diabetes mellitus, dyslipidemias, coagulopathies, infectious diseases and malignancies. Mechanisms of action responsible for these effects likely include altered signaling through cellular receptors, post-glycosylation modifications of infectious agents, changes in levels of inflammatory mediators and inhibition of autophagy. Many of the pathways are likely dependent on drug-induced changes in intra-endosomal acidity. CONCLUSIONS: The use of, and interest in, HCQ has spread into many areas of medicine. Actions of this drug may be directly beneficial to patients with non-rheumatic conditions such as diabetes mellitus or viral infections. Further understanding of underlying mechanisms has potential to reveal modifiable pathogenic pathways that might elucidate approaches to the design of more effective therapeutics for many chronic diseases.
23118111 Reliability and longitudinal validity of computer-assisted methods for measuring joint dam 2013 Jan OBJECTIVE: To compare the metric properties of a computer-assisted erosion segmentation volume measurement with scoring using the Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS) in a longitudinal cohort of patients with rheumatoid arthritis (RA). METHODS: Thirty-two sets of baseline and 2-year followup magnetic resonance imaging (MRI) of metacarpal phalangeal 2-5 joints of patients with RA were scored using RAMRIS and segmented using OSIRIS software. The smallest detectable difference (SDD), standardized response mean (SRM), and paired t-test were used to evaluate the sensitivity to change. Eleven of the 32 patients' MRI were segmented by both readers to evaluate interreader agreement. The 28-joint Disease Activity Score (DAS28) and Sharp erosion scores further evaluated construct and longitudinal validity. RESULTS: Reliability of erosion progression by computer-assisted volume measurement was superior to RAMRIS [intrareader interclass correlation coefficient (ICC) 0.97 (0.94-0.99) vs 0.52 (0.22-0.73)] and interreader ICC of volume measurement was 0.85 (0.53-0.96). Computer-assisted volume measurements identified 10 of 32 patients who progressed more than the SDD progression, whereas RAMRIS identified only 4 of 32 patients (p = 0.0013). By a paired t-test, however, all MRI measures progressed significantly over 2 years (irrespective of treatment arm) and there was little difference by SRM. Construct correlational validity of the MRI methods was 0.47-0.90 for status scores and 0.33-0.81 for progression. There was no relationship between the average DAS28 and erosion progression by any imaging method. CONCLUSION: Computer-assisted measurement of erosion volume has good performance metrics. It had excellent intrareader and interreader reliability and was more sensitive to change than RAMRIS in this group of patients. www.ClinicalTrials.gov, NCT00451971.
23610983 Mitral valve procedure selection and outcomes in patients with rheumatoid arthritis. 2013 Jan BACKGROUND AND AIM OF THE STUDY: Cardiovascular disease is a frequent cause of death in patients with rheumatoid arthritis (RA). Valvular involvement is common, most frequently affecting the mitral valve. Whether RA is an additional risk factor for patients undergoing mitral surgery has not been studied. The study aim was to examine procedure selection and outcome in patients with RA compared to that in patients without RA. METHODS: The 2005-2008 NIS database was searched to identify patients aged > or = 18 years undergoing isolated mitral valve repair or replacement. Patients with and without RA were compared on their baseline characteristics and hospital outcomes. Within the subset of patients with RA, patients undergoing repair and replacement were compared. RESULTS: RA patients comprised 1.0% (710/70,969) of the population, and were older, more likely to be female, and had a higher Charlson comorbidity index. The repair rate for RA patients was lower (37.6% versus 45.5%, p = 0.0401). The hospital length of stay (OR = 1.27, 95% CI 0.88-1.82, p = 0.1946) and hospital mortality (OR = 0.57, 95% CI 0.19-1.72, p = 0.3081) were similar for patients with and without RA. Baseline characteristics were similar between mitral valve repair and replacement subsets. The median LOS was higher for replacement (10 days versus 7 days, p = 0.0242). Hospital mortality was similar for repair versus replacement (OR = 1.17, 95% CI 0.10-13.46, p = 0.8983). CONCLUSION: RA does not appear to be an additional risk factor for adverse outcome following isolated mitral valve surgery. Although repair rates were lower for patients with RA, hospital mortality was similar to that in patients without RA. Within the RA subset, hospital mortality rates between mitral valve repair and replacement were similar.
24028158 Validity of a computer-assisted manual segmentation software to quantify wrist erosion vol 2013 Sep 12 BACKGROUND: To investigate the performance of conventional radiography (CR) for the detection of bone erosions of wrist in rheumatoid arthritis (RA) using multidetector computed tomography (CT) as the reference method and to evaluate the validity of a computer-assisted manual segmentation (outlining) technique to quantify erosion volume on CT scans. METHODS: Twenty five RA patients and six controls underwent CT and radiographic evaluation of the dominant wrist on the same day. CT was performed by using a 64 GE light Speed VCT power. Wrists images were evaluated separately and scored for the presence of erosions according to the Outcome Measures in Rheumatology Rheumatoid Arthritis MRI Scoring System (RAMRIS) and the Sharp/van der Heijde scoring method. Measurements of bone erosion volumes were obtained using OsiriX medical imaging software. The mean value of the volumes of the CT bone erosions detected at two readings was used to calculate inter-rater agreement. RESULTS: The overall sensitivity, specificity and accuracy of radiography for detecting erosions were 25.5%, 98.3% and 70.1%, respectively. Using computer-assisted manual segmentation (outlining) technique, erosion volume on CT measurements per subject was ranged from 0.001 cm³ to 2.01 cm³. Spearman's RAMRIS score of each wrist bones in all subjects (n = 25) were correlated with the total erosion volume on CT (p < 0.0001), with the ratio between erosion volume and the corresponding bone volume on a percentage basis (p < 0.0001). The total Sharp/van der Heijde erosion score of the all wrist bones was correlate with the RAMRIS score (p = 0.008). The intraclass correlation coefficients (ICC) for manual segmentation showed high agreement (ICC = 0.901). CONCLUSIONS: Considering CT as the reference method, CR showed very low sensitivity. A close correlation with CT erosion volumes supports the OMERACT RAMRIS erosion score as a semiquantitative measure of joint damage in RA. Although the computer-assisted manual segmentation can be beneficial for diagnostic decision in cross-sectional CT examinations of the wrist in RA, this technique will require further evaluation in terms of responsiveness.
25187463 [PTPN22 1858C/T polymorphism is associated with rheumatoid arthritis susceptibility in Cau 2014 Jul OBJECTIVE: To investigate the association of 1858C/T polymorphism of protein tyrosine phosphatase nonreceptor type 22 (PTPN22) and rheumatoid arthritis (RA) susceptibility. METHODS: CMB, wanfang (Chinese) and PubMed databases were searched to get the studies on the association between 1858C/T polymorphism and RA susceptibility, and odds ratio (OR) and 95% confidential interval (CI) were calculated under different genetic models. Then heterogeneity, stratified analysis, and publication bias test were conducted in the study. RESULTS: A total of 32 studies (40 separate comparisons) with 25 059 RA patients and 25 466 controls were included in this meta-analysis. No evidence for publication bias was found in these studies. Meta-analysis showed an association between PTPN22 1858C/T polymorphism and RA (OR=1.606, 95%CI: 1.518-1.699, P<0.001). When stratified by ethnicity, T allele of PTPN22 1858C/T polymorphism was a risk allele in Caucasian (OR=1.612, 95%CI: 1.544-1.683, P<0.001); however, the polymorphism was not detected in Asians (or allele frequencies was extremely low). PTPN22 1858C/T polymorphism was associated with rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACCP). CONCLUSION: T allele of PTPN22 1858C/T polymorphism is associated with RA susaptibility in Caucasians. PTPN22 1858C/T polymorphism is significantly more prevalent in RF-positive or ACCP-positive patients than in RF-negative or ACCP-negative patients.
23253692 Evaluation of clinical results and quality of life after surgical reconstruction for rheum 2013 Apr BACKGROUND CONTEXT: The EuroQol (EQ-5D) is a widely used comprehensive measure of health-related quality of life. There has been no study that has evaluated the health-related quality of life before and after the surgical reconstruction of rheumatoid arthritis (RA) cervical spine lesions using EQ-5D. PURPOSE: The present study aimed to evaluate the improvement of quality of life before and after surgical reconstruction of rheumatoid cervical spine using EQ-5D, and the surgical outcomes of cervical spine affected by RA. STUDY DESIGN: A retrospective study of the patients who underwent surgical reconstruction of cervical disorders in RA. PATIENT SAMPLE: Twenty-five patients (seven men, 18 women, mean age 62.2 years) who underwent surgical reconstruction of cervical disorders in RA were enrolled. OUTCOME MEASURES: Japanese Orthopaedic Association (JOA) score and EQ-5D. METHODS: Clinical symptoms were evaluated before surgery and at 2 years after surgery by measuring the JOA score. We also investigated health-related quality of life before surgery and outcome at 2 years after surgery using the EQ-5D questionnaire. RESULTS: Mean observation period was 46.3 months. Mean JOA score significantly improved from 9.1 ± 4.5 points before surgery to 12.4 ± 2.8 at the 2 years after surgery (p=.0001). All the EQ-5D data were improved at the 2 years after surgery, compared with the data before surgery; especially, pain (p=.005), usual activity (p=.005), mobility (p=.008), and anxiety/depression (p=.02) were significantly improved. Utility weight was 0.37 ± 0.27 before surgery and 0.56 ± 0.26 at the 2 years after surgery, showing significant improvement at the 2 years after surgery compared to before surgery (p=.002). CONCLUSIONS: The surgical reconstruction of rheumatoid cervical spine has been demonstrated to improve patients' health-related quality of life.
24708204 Efficacy, safety, pharmacokinetics and immunogenicity of abatacept administered subcutaneo 2014 Nov OBJECTIVE: To evaluate efficacy and safety of subcutaneous (SC) and intravenous (IV) abatacept and background methotrexate (MTX) in Japanese patients with rheumatoid arthritis (RA) and inadequate response to MTX (MTX-IR). METHODS: Double-dummy, double-blind study (NCT01001832); 118 adults with ≥ 10 swollen joints, ≥ 12 tender joints and C-reactive protein (CRP) ≥ 0.8 mg/dL randomized 1:1 to SC abatacept (125 mg weekly) with IV loading (∼10 mg/kg on Day 1), or IV abatacept (∼10 mg/kg monthly) for 169 days, both also receiving MTX (6-8 mg/week). Primary endpoint was Day 169 American College of Rheumatology (ACR)20 response; other efficacy endpoints, safety and immunogenicity were assessed. RESULTS: Similar proportions of patients achieved ACR20 responses at Day 169 with SC (91.5% [95% CI 81.3, 97.2]) and IV abatacept (83.1% [71.0, 91.6]). ACR50/70 responses, adjusted mean changes from baseline in Health Assessment Questionnaire-Disability Index scores and remission rates (28-joint Disease Activity Score [CRP] < 2.6) were also comparable between groups. Serious adverse event frequencies (5.1% vs. 3.4%) were similar with both formulations. One patient per group tested seropositive for immunogenicity. Weekly SC abatacept dosing achieved mean serum concentrations > 10 μg/mL (minimum therapeutic target). CONCLUSIONS: SC abatacept demonstrated comparable efficacy and safety to IV abatacept, with low immunogenicity rates, in MTX-IR Japanese patients with RA.
23565629 Myocardial infarction after rituximab treatment for rheumatoid arthritis: Is there a link? 2014 Rituximab is an anti-CD20 monoclonal antibody often used in the treatment of rheumatoid arthritis (RA). Infusion reactions sometimes develop following rituximab administration. Delayed complications are rare. Acute coronary syndromes are listed as sideeffects of rituximab therapy. We report two cases of acute myocardial infarction following rituximab therapy for RA and review the literature regarding cardiac events in patients treated with rituximab. We would like to raise awareness of this possible complication in patients treated with rituximab.
24854355 Nitrosative modifications of the Ca2+ release complex and actin underlie arthritis-induced 2015 Oct OBJECTIVE: Skeletal muscle weakness is a prominent clinical feature in patients with rheumatoid arthritis (RA), but the underlying mechanism(s) is unknown. Here we investigate the mechanisms behind arthritis-induced skeletal muscle weakness with special focus on the role of nitrosative stress on intracellular Ca(2+) handling and specific force production. METHODS: Nitric oxide synthase (NOS) expression, degree of nitrosative stress and composition of the major intracellular Ca(2+) release channel (ryanodine receptor 1, RyR1) complex were measured in muscle. Changes in cytosolic free Ca(2+) concentration ([Ca(2+)]i) and force production were assessed in single-muscle fibres and isolated myofibrils using atomic force cantilevers. RESULTS: The total neuronal NOS (nNOS) levels were increased in muscles both from collagen-induced arthritis (CIA) mice and patients with RA. The nNOS associated with RyR1 was increased and accompanied by increased [Ca(2+)]i during contractions of muscles from CIA mice. A marker of peroxynitrite-derived nitrosative stress (3-nitrotyrosine, 3-NT) was increased on the RyR1 complex and on actin of muscles from CIA mice. Despite increased [Ca(2+)]i, individual CIA muscle fibres were weaker than in healthy controls, that is, force per cross-sectional area was decreased. Furthermore, force and kinetics were impaired in CIA myofibrils, hence actin and myosin showed decreased ability to interact, which could be a result of increased 3-NT content on actin. CONCLUSIONS: Arthritis-induced muscle weakness is linked to nitrosative modifications of the RyR1 protein complex and actin, which are driven by increased nNOS associated with RyR1 and progressively increasing Ca(2+) activation.
25227901 Clinical trials documenting the efficacy of low-dose glucocorticoids in rheumatoid arthrit 2015 Twelve clinical trials have documented that prednisone or prednisolone in doses of 10 mg/day or less is efficacious to improve function, maintain status and/or slow radiographic progression in patients with rheumatoid arthritis (RA). An early trial reported by de Andrade et al. [Ann Rheum Dis 1964;23:158-162] in 1964 indicated that 5 mg of prednisolone at night was preferred to 5 mg of prednisone in the morning. Harris et al. [J Rheumatol 1983;10:713-721] documented the efficacy of 5 mg/day of prednisone in a non-double-blind trial in 1983. Two important trials in the 1990s by Kirwan [N Engl J Med 1995;333:142-146] using 7.5 mg/day, and the COBRA study by Boers et al. [Lancet 1997;350:309-318] with step-down from 60 mg rapidly tapered to 5 mg/day led to strong advocacy of low-dose glucocorticoids. In 2002, the first Utrecht Study [Ann Intern Med 2002;136:1-12] indicated that 10 mg/day prednisone slowed radiographic progression, a finding confirmed and extended in 2005 by Svensson et al. [Arthritis Rheum 2005;52:3360-3370] with 7.5 mg/day, and Wassenberg et al. [Arthritis Rheum 2005;52:3371-3380] with 5 mg/day of prednisolone. In 2008, Buttgereit et al. [Lancet 2008;371:205-214] reported CAPRA-1, which documented that modified-release prednisone or prednisolone taken at bedtime led to lower morning stiffness and IL-6 levels compared to usual morning prednisone. In 2009, Pincus et al. [Ann Rheum Dis 2009;68:1715-1720] reported a withdrawal clinical trial, in which patients who took 3 mg/day were gradually withdrawn to placebo, and dropped out at a significantly higher rate than control patients who were 'withdrawn' to prednisone. In 2012, a second Utrecht Study [Ann Intern Med 2012;156:329-339], CAMERA-II, documented that 10 mg of prednisone added to a 'treat-to-target' strategy with methotrexate provided incremental slowing of radiographic progression. An Italian study of patients with early RA who received step-up disease-modifying antirheumatic drug therapy over 2 years plus prednisolone or not indicated higher rates of clinical remission and sustained remission associated with 7.5 mg/day of prednisolone [Arthritis Res Ther 2012; 14:R112]. The CAPRA-2 trial [Ann Rheum Dis 2013;72:204-210] documented that modified-release nighttime prednisone or prednisolone was significantly more efficacious than placebo. Taken together, these 12 clinical trials indicate that low-dose glucocorticoids prednisone or prednisolone provides symptomatic relief, improved functional status and slowing of radiographic progression for patients with RA. © 2014 S. Karger AG, Basel.
27129122 PRTX-100 and methotrexate in patients with active rheumatoid arthritis: A Phase Ib randomi 2014 Nov PRTX-100 is a highly-purified preparation of staphylococcal protein A (SpA), with immunologic activity in vitro and in animal models of immune-mediated inflammation. Following single-dose healthy volunteer studies of safety and pharmacokinetics (PK), a multicenter, double-blind, placebo-controlled, sequential dose-escalation, repeated-dose phase I trial was conducted in patients with active rheumatoid arthritis (RA) on methotrexate therapy. Patients were randomized to receive either weekly intravenous PRTX-100 (0.15, 0.45, 0.90, or 1.50 µg/kg) or placebo for 4 weeks. Safety and disease activity were assessed over 16 weeks. Pharmacokinetic profiles were obtained after the first and fourth doses. The most common treatment-related adverse events were nausea, muscle spasms, dizziness, flushing, fatigue, RA flare, and headache. No serious adverse events were considered related to PRTX-100, and none occurred in the highest dose group. Geometric mean values for plasma Cmax (ng/mL) were 4.1, 15.7, 26.5, and 51.2 for doses of 0.15, 0.45, 0.90, and 1.5 µg/kg, respectively. Anti-drug antibodies (ADAs) developed in most PRTX-100 patients, but incidence and titer were not dose-dependent. At the two highest doses, data suggest PRTX-100 may have an effect on RA disease activity, even in patients with ADAs.
24283517 Evidence that TNF-β (lymphotoxin α) can activate the inflammatory environment in human c 2013 INTRODUCTION: Inflammatory cytokines play a key role in the pathogenesis of joint diseases such as rheumatoid arthritis (RA). Current therapies target mainly tumor necrosis factor α (TNF-α) as this has proven benefits. However, a large number of patients do not respond to or become resistant to anti-TNF-α therapy. While the role of TNF-α in RA is quite evident, the role of TNF-β, also called lymphotoxin-α (LT-α), is unclear. In this study we investigated whether TNF-β and its receptor play a role in chondrocytes in the inflammatory environment. METHODS: An in vitro model of primary human chondrocytes was used to study TNF-β-mediated inflammatory signaling. RESULTS: Cytokine-induced inflammation enhances TNF-β and TNF-β-receptor expression in primary human chondrocytes accompanied by the up-regulation of inflammatory (cyclooxygenase-2), matrix degrading(matrix metalloproteinase-9 and -13) and apoptotic (p53, cleaved caspase-3) signaling pathways, all known to be regulated by NF-κB. In contrast, anti-TNF-β, similar to the natural NF-κB inhibitor (curcumin, diferuloylmethane) or the knockdown of NF-κB by using antisense oligonucleotides (ASO), suppressed IL-1β-induced NF-κB activation and its translocation to the nucleus, and abolished the pro-inflammatory and apoptotic effects of IL-1β. This highlights,at least in part, the crucial role of NF-κB in TNF-β-induced-inflammation in cartilage, similar to that expected for TNF-α. Finally, the adhesiveness between TNF-β-expressing T-lymphocytes and the responding chondrocytes was significantly enhanced through a TNF-β-induced inflammatory microenvironment. CONCLUSIONS: These results suggest for the first time that TNF-β is involved in microenvironment inflammation in chondrocytes during RA parallel to TNF-α, resulting in the up-regulation of NF-κB signaling and activation of pro-inflammatory activity.
23637326 Use of lipid-lowering agents in rheumatoid arthritis: a population-based cohort study. 2013 Jul OBJECTIVE: Rheumatoid arthritis (RA) is associated with an increased risk of cardiovascular disease and mortality. Lipid-lowering therapy is reportedly underused in patients with RA. Longitudinal cohort studies comparing use of lipid-lowering medications in patients with RA versus the general population are lacking. METHODS: Cardiovascular risk factors, lipid measures, and use of lipid-lowering agents were assessed in a population-based inception cohort of patients with RA and a cohort of non-RA subjects followed from January 1, 1988, to December 31, 2008. The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATPIII) guidelines were assessed at the time of each lipid measure throughout followup. Time from meeting guidelines to initiation of lipid-lowering agents was assessed using Kaplan-Meier methods. RESULTS: The study population included 412 RA and 438 non-RA patients with ≥ 1 lipid measure during followup and no prior use of lipid-lowering agents. Rates of lipid testing were lower among patients with RA compared to non-RA subjects. Among patients who met NCEP ATPIII criteria for lipid-lowering therapy (n = 106 RA; n = 120 non-RA), only 27% of RA and 26% of non-RA subjects initiated lipid-lowering agents within 2 years of meeting the guidelines for initiation. CONCLUSION: There was substantial undertreatment in both the RA and the non-RA cohorts who met NCEP ATPIII criteria for initiation of lipid-lowering agents. Patients with RA did not have as frequent lipid testing as individuals in the general population.
23445730 [Dopamine receptor signaling regulates human osteoclastogenesis]. 2013 Although the central nervous system and the neurotransmitters are known to control not only the immune system but also the homeostasis of bone mass, their pathological relevance to bone disorders remains unclear. Osteoclasts in the synovium of rheumatoid arthritis (RA) play an important role in bone destruction. It is known that increased sympathetic nervous activity increases both differentiation and function of osteoclasts, which leads to bone loss. Dopamine, a major neurotransmitter, transmits signals via five different seven-transmembrane G protein-coupled receptors termed D1 to D5. We previously reported that dopamine plays an important role in IL-6-IL-17 axis and subsequent joint destruction in RA. The major source of dopamine in the synovial tissue of RA was dendritic cells (DCs) that stored and secreted dopamine. Dopamine released by DCs bounded to D1-like dopamine receptors on T cells and induced activation of cAMP and differentiation to Th17 cells via IL-6 production We here overview the interplay among the immune system, bone metabolism and neurologic system shedding light upon dopaminergic signals upon osteoclastogenesis.
25367151 Down-regulating peroxisome proliferator-activated receptor-gamma coactivator-1 beta allevi 2014 Oct 24 INTRODUCTION: Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction and disability. Peroxisome proliferator-activated receptor-gamma coactivator-1 beta (PGC-1β) is a transcriptional coactivator that plays important roles in regulating multiple aspects of energy metabolism and cytokine signaling pathways. PGC-1β overexpression leads to the attenuation of macrophage-mediated inflammation. In this study, we aimed to determine the expression of PGC-1β in RA synovium and fibroblast-like synoviocytes (FLS), and explore the mechanisms of PGC-1β on both the proinflammatory effects and apoptosis in RA-FLS. METHODS: Synovium was obtained from 31 patients with active RA, as well as 13 osteoarthritis (OA) and 10 orthopedic arthropathies (Orth.A) as "less inflamed" disease controls. FLS were then isolated and cultured. Synovial PGC-1β expression was determined by immunohistochemistry staining, while FLS PGC-1β expression was detected by immunofluorescence staining, quantitative real-time PCR (qPCR) assay and western blot. PGC-1β was depleted by lentivirus sh-RNA, and up-regulated by pcDNA3.1- PGC-1β. The expression of proinflammatory cytokines, matrix metalloproteinases and receptor activator of nuclear factor-kappaB ligand was analyzed by qPCR, cytometric bead array and western blot. The expression of mitogen-activated protein kinases and nuclear factor-kappaB (NF-κB) was determined by qPCR and western blot. Besides, cell apoptosis was examined using flow cytometry. The interaction between PGC-1β and NF-κB was performed by dual-luciferase reporter gene assays. RESULTS: (A) Synovial PGC-1β was over-expressed in RA patients compared with OA or Orth.A patients. (B) PGC-1β expression significantly increased in RA-FLS compared with OA-FLS. (C) PGC-1β mediated the expression of proinflammatory cytokines and apoptosis through extracellular signal-regulated kinase (ERK), p38 and NF-κB in RA-FLS. (D) PGC-1β mediated NF-κB transcription in RA-FLS, but did not affect ERK and p38. CONCLUSION: The results indicate that PGC-1β may play important roles in the proinflammatory effects and apoptosis of RA-FLS.
23778483 Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rh 2013 Jun OBJECTIVES: Hydroxychloroquine is an antimalarial agent that has been used in systemic lupus erythematosus and rheumatoid arthritis treatment for many years. Recently, novel mechanisms of action have been proposed, thereby broadening the therapeutic perspective of this medication. The purpose of this study was to evaluate the immunomodulatory activity of hydroxychloroquine in T helper 17 (Th17) cytokines in healthy individuals and patients. METHODS: Eighteen female patients with systemic lupus erythematosus (mean age 39.0±12.9 years) and 13 female patients with rheumatoid arthritis (mean age 51.5±7.7 years) were recruited from Universidade Federal de Pernambuco-Brazil. The patients were included after fulfilling four classification criteria for systemic lupus erythematosus or rheumatoid arthritis from the American College of Rheumatology. After being stimulated with phorbol 12-myristate 13-acetate and ionomycin in the absence or presence of different concentrations of hydroxychloroquine, the interleukin 6, 17 and 22 levels were quantified with an enzyme-linked immunosorbent assay in culture supernatants of peripheral blood mononuclear cells from healthy individuals and patients. RESULTS: We demonstrated that in peripheral blood mononuclear cells from healthy volunteers and in systemic lupus erythematosus and rheumatoid arthritis patients, there was a significant reduction in the IL-6, IL-17 and IL-22 supernatant levels after adding hydroxychloroquine. CONCLUSIONS Our in vitro results demonstrated that hydroxychloroquine inhibits IL-6, IL-17 and IL-22 production and contributes to a better understanding of the mechanism of action of this medication.
23324173 Disease severity in K/BxN serum transfer-induced arthritis is not affected by IL-33 defici 2013 Jan 16 INTRODUCTION: Interleukin (IL)-33 is a cytokine of the IL-1 family, which signals through the ST2 receptor. Previous work suggested implication of the IL-33/ST2 axis in the pathogenesis of human and mouse arthritis. Here, we directly investigated the role of endogenous IL-33 in K/BxN serum transfer-induced arthritis by using IL-33 knockout (KO) mice. METHODS: Arthritis was induced by injection of complete K/BxN serum or purified IgG. Disease severity was monitored by clinical and histological scoring. RESULTS: K/BxN serum transfer induced pronounced arthritis with similar incidence and severity in IL-33 KO and wild-type (WT) mice. In contrast, disease development was significantly reduced in ST2 KO mice. IL-33 expression in synovial tissue was comparable in arthritic WT and ST2 KO mice, and absent in IL-33 KO mice. Transfer of purified arthritogenic IgG instead of complete K/BxN serum also resulted in similar arthritis severity in IL-33 KO and WT mice, excluding a contribution of IL-33 contained in the serum of donor mice to explain this result. We investigated additional potential confounding factors, including purity of genetic background, but the mechanisms underlying reduced arthritis in ST2 KO mice remained unclear. CONCLUSIONS: The data obtained with IL-33 KO mice indicate that endogenous IL-33 is not required for the development of joint inflammation in K/BxN serum transfer-induced arthritis. On the contrary, arthritis severity was reduced in ST2 KO mice. This observation might relate to IL-33 independent effects of ST2, and/or reveal the existence of confounding variables affecting the severity of joint inflammation in these KO strains.
24286116 Comparative evaluation of the effects of treatment with tocilizumab and TNF-α inhibitors 2013 Oct 2 INTRODUCTION: Anemia of inflammation (AI) is a common complication of rheumatoid arthritis (RA) and has a negative impact on RA symptoms and quality of life. Upregulation of hepcidin by inflammatory cytokines has been implicated in AI. In this study, we evaluated and compared the effects of IL-6 and TNF-α blocking therapies on anemia, disease activity, and iron-related parameters including serum hepcidin in RA patients. METHODS: Patients (n = 93) were treated with an anti-IL-6 receptor antibody (tocilizumab) or TNF-α inhibitors for 16 weeks. Major disease activity indicators and iron-related parameters including serum hepcidin-25 were monitored before and 2, 4, 8, and 16 weeks after the initiation of treatment. Effects of tocilizumab and infliximab (anti-TNF-α antibody) on cytokine-induced hepcidin expression in hepatoma cells were analyzed by quantitative real-time PCR. RESULTS: Anemia at base line was present in 66% of patients. Baseline serum hepcidin-25 levels were correlated positively with serum ferritin, C-reactive protein (CRP), vascular endothelial growth factor (VEGF) levels and Disease Activity Score 28 (DAS28). Significant improvements in anemia and disease activity, and reductions in serum hepcidin-25 levels were observed within 2 weeks in both groups, and these effects were more pronounced in the tocilizumab group than in the TNF-α inhibitors group. Serum hepcidin-25 reduction by the TNF-α inhibitor therapy was accompanied by a decrease in serum IL-6, suggesting that the effect of TNF-α on the induction of hepcidin-25 was indirect. In in vitro experiments, stimulation with the cytokine combination of IL-6+TNF-α induced weaker hepcidin expression than did with IL-6 alone, and this induction was completely suppressed by tocilizumab but not by infliximab. CONCLUSIONS: Hepcidin-mediated iron metabolism may contribute to the pathogenesis of RA-related anemia. In our cohort, tocilizumab was more effective than TNF-α inhibitors for improving anemia and normalizing iron metabolism in RA patients by inhibiting hepcidin production.
25205016 Identical subchondral bone microarchitecture pattern with increased bone resorption in rhe 2014 Dec OBJECTIVES: To analyze the differences in microarchitecture and bone remodeling of subchondral bone in femoral heads from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). DESIGNS: Peri-articular bone samples, including subchondral trabecular bone (STB) and deeper trabecular bone (DTB) were extracted from the load-bearing region of femoral heads from 20 patients with RA and 40 patients with OA during hip replacement surgery. Micro-CT, histomorphometry and backscatter scanning electron microscopy (BSEM) were performed to assess microarchitecture and bone histology parameters. RESULTS: In both RA and OA, STB showed more sclerotic microarchitecture and more active bone remodeling, compared to DTB. RA and OA showed similar microarchitecture characteristics in both STB and DTB, despite STB in RA exhibiting higher bone resorption. In addition, there was no difference in the frequency of bone cysts in STB between RA and OA. In STB, the trabecular bone surrounding subchondral bone cysts (Cys-Tb) was more sclerotic than the trabecular bone found distant to cysts (Peri-Tb), with a higher level of bone remodeling. Both Cys-Tb region and Peri-Tb region were detected to have similar microarchitectural and bone remodeling characteristics in RA and OA. CONCLUSIONS: Apart from higher bone resorption in the general subchondral bone of RA samples, the peri-articular bone exhibited similar microarchitectural and bone remodeling characteristics in RA and OA.