Browse

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

ID PMID Title PublicationDate abstract
22750227 RANTES, MCP-1 chemokines and factors describing rheumatoid arthritis. 2012 Oct The MCP-1/CCL2 as well as RANTES/CCL5 chemokines are potent chemoattractants involved in immunoregulatory and inflammatory processes of rheumatoid arthritis. Recent studies demonstrated elevated levels of MCP-1 and RANTES in plasma, synovial fluid, and the synovial tissue of patients with RA. To examine the relationship among MCP-1 and RANTES single nucleotide polymorphisms and circulating levels and rheumatoid arthritis (RA), a total of 156 RA patients and 125 controls were recruited into the study. An association of -855 C/G MCP-1 polymorphism to IgM RF within the RA patients was observed. The lowest circulating levels of RANTES were observed in the AA variant of RANTES -403 G/A polymorphism. Furthermore, an association of -403 AA variant to circulating levels of IL-15 and IL-10 was found. No associations of factors describing rheumatoid arthritis (RFs, ANA, anti-CCP-positive/negative, DAS 28 score and number of swollen joints) with MCP-1 levels, genotype distribution, allelic frequencies and/or frequencies of haplotypes composed of all three studied polymorphisms in promoter region of MCP-1, and RANTES polymorphism were observed. We conclude that the RANTES promoter polymorphism is associated to circulating levels of RANTES, IL15 and IL10. However, our findings suggest that polymorphisms in the MCP-1 and RANTES gene promoters do not contribute significantly to the interindividual RA susceptibility and/or severity in Caucasians.
22174202 Apolipoprotein E gene polymorphisms are strong predictors of inflammation and dyslipidemia 2012 Feb OBJECTIVE: Rheumatoid arthritis (RA), a condition with a strong genetic etiology, is associated with excess cardiovascular disease (CVD). Dyslipidemia in RA may be driven by inflammation and genetic factors. Apolipoprotein E (ApoE) is important for the regulation of lipid levels and CVD risk and immune function in the general population. We compared the frequency of 2 ApoE single-nucleotide polymorphisms (SNP) in patients with RA and controls, and studied the relationship of ApoE genotypes with lipids and inflammation in RA. METHODS: A total of 387 patients with well-characterized RA and 420 non-RA controls were studied. Two ApoE SNP, rs7412 (ApoE2) and rs429358 (ApoE4), were identified. RESULTS: Genotypic (p = 0.908) and allelic (p = 0.894) frequencies did not differ between RA and controls. Within RA, the E2 allele was associated with the lowest and E4 allele with the highest levels of total cholesterol (p = 0.007), low-density lipoproteins (p = 0.004), and apolipoprotein B (p = 0.009). The E4 allele was also associated with lower C-reactive protein (p = 0.007), erythrocyte sedimentation rate (p = 0.001), and Disease Activity Score (p = 0.015) compared to the E3 allele. E2 or E4 alleles were not associated with CVD in RA, although a trend was observed (p = 0.074). CONCLUSION: The frequency of ApoE polymorphisms did not differ between patients with RA and controls. ApoE genotypes are strongly linked to inflammation and lipid levels in RA, raising interest in the prognostic implications of ApoE genotypes.
21575792 Intramedullary vs extramedullary femoral alignment guides: a 15-year follow-up of survivor 2011 Jun The influence of intramedullary (IM) and extramedullary (EM) femoral cutting guides on survivorship of total knee arthroplasty was studied in 6726 total knee arthroplasty guided by either an IM (4993 knees) or EM (1733 knees) system. Fifteen-year survivorship of the 2 cohorts showed no statistically significant difference (EM 97.9% vs IM 98.5%; P = .2500, log rank). Medial bone collapse comprised the highest proportion of all failure modes for both groups (0.35% vs 0.40%, respectively, P = .6731, Cox regression). Mean tibiofemoral (overall) anatomical alignment was statistically more accurate in the IM group (IM 4.6° [± 2.2°] valgus vs EM 5.1° [± 3.1°] valgus; P < .0001). The mean tibial alignment was 90.5° (± 3.0) and 90.3° (± 2.2) (P = .0077). The EM group had a significantly larger tibial component alignment variance (SD(2)) than the IM group. No statistical difference in postoperative Knee Society scores, pain, or stair-climbing abilities was found. The choice of either alignment system should be determined by the patient's anatomy; however, the overall alignment is not as precise using the extramedullary system.
22576568 [Anti-rheumatic effect of JAK-inhibitors]. 2012 Treatment of rheumatoid arthritis (RA) has dramatically developed with the use of biologics targeting inflammatory cytokines. However, expense and parenteral use can cause issues in the initiation and continuation of the treatment. Therefore a new orally available anti-rheumatic drug has been long-awaited. Recently, small-molecule compounds targeting Janus kinase (JAK) has shown clinical efficacy similar to biologics in clinical trials for active RA. Among the JAK-inhibitors, new drug application for tofacitinib is concurrently under review in western and asian countries and is highly expected to become a new anti-rheumatic drug in the near future. In order to evaluate the mode of action, we utilized peripheral blood and synovium from RA patients. Proliferation and cytokine production of CD4+ T cell was prominently reduced and subsequently inhibited cartilage destruction by the synovium. Our result is in line with the inhibitory effect of tofacitinib on joint destruction in RA patients those who were treated with tofacitinib. Therefore, further clinical efficacy is expected in the in the long-term treatment with tofacitinib.
19844717 Pseudo-pseudo Meigs syndrome developed under the leflunomide therapy. 2011 Apr Pseudo-pseudo Meigs syndrome or Tjalma syndrome is characterized by increased CA-125 level, pleural effusion and ascites in systemic lupus erythematosus (SLE) patients without over tumor. The disorder is relatively rare and it has been reported usually in SLE patients with impaired renal functions. Herein, we present a case of a 47-year-old female patient who developed Tjalma syndrome after administration of leflunomide for rheumatoid arthritis. Surprisingly renal functions of our patient were found in normal limits. This is the first case of Tjalma syndrome that is developed in normal renal functions and the probable role of leflunomide therapy is discussed.
23081991 Serial block-face scanning electron microscopy combined with double-axis electron beam tom 2013 Apr To evaluate the advantages of combination of two advanced electron microscopic technologies such as serial block-face scanning electron microscopy and double-axis electron beam tomography, we analyzed the three-dimensional morphology of cellular relationships between dendritic and plasma cells in the synovial membrane from patients with rheumatoid arthritis, using the combined approach.
21423713 Causal modeling using network ensemble simulations of genetic and gene expression data pre 2011 Mar Tumor necrosis factor α (TNF-α) is a key regulator of inflammation and rheumatoid arthritis (RA). TNF-α blocker therapies can be very effective for a substantial number of patients, but fail to work in one third of patients who show no or minimal response. It is therefore necessary to discover new molecular intervention points involved in TNF-α blocker treatment of rheumatoid arthritis patients. We describe a data analysis strategy for predicting gene expression measures that are critical for rheumatoid arthritis using a combination of comprehensive genotyping, whole blood gene expression profiles and the component clinical measures of the arthritis Disease Activity Score 28 (DAS28) score. Two separate network ensembles, each comprised of 1024 networks, were built from molecular measures from subjects before and 14 weeks after treatment with TNF-α blocker. The network ensemble built from pre-treated data captures TNF-α dependent mechanistic information, while the ensemble built from data collected under TNF-α blocker treatment captures TNF-α independent mechanisms. In silico simulations of targeted, personalized perturbations of gene expression measures from both network ensembles identify transcripts in three broad categories. Firstly, 22 transcripts are identified to have new roles in modulating the DAS28 score; secondly, there are 6 transcripts that could be alternative targets to TNF-α blocker therapies, including CD86--a component of the signaling axis targeted by Abatacept (CTLA4-Ig), and finally, 59 transcripts that are predicted to modulate the count of tender or swollen joints but not sufficiently enough to have a significant impact on DAS28.
22365763 [Present and future of echography in spondyloarthritis]. 2012 Mar Today ultrasound in spondyloarthritis is being developed in three main areas. Joint ultrasound is similar to that described in rheumatoid arthritis and other synovitis, with extensive literature on the matter. Enthesis ultrasound has a growing number of publications that describe the main elementary lesions. Several ultrasound enthesis scores have been developed that provide an overall view of the patient status and this information is useful both in the field of diagnosis and in assessing disease activity. The sacroiliac joints have also received attention and the published sensitivity and specificity could be useful in clinical practice. The future is unknown, but ultrasound has many possibilities that include improving the reliability, the incorporation of enthesis ultrasound assessment to the diagnostic classification criteria as well as the likelyhood developing simplified scores.
21958547 Imidazo[1,5-a]quinoxalines as irreversible BTK inhibitors for the treatment of rheumatoid 2011 Nov 1 Imidazo[1,5-a]quinoxalines were synthesized that function as irreversible Bruton's tyrosine kinase (BTK) inhibitors. The syntheses and SAR of this series of compounds are presented as well as the X-ray crystal structure of the lead compound 36 in complex with a gate-keeper variant of ITK enzyme. The lead compound showed good in vivo efficacy in preclinical RA models.
22466404 Factors influencing sick leave episodes in Mexican workers with rheumatoid arthritis and i 2013 Mar To evaluate impact of working days lost and factors for developing sick leave episodes in Mexicans workers with rheumatoid arthritis (RA). A prospective cohort of 123 patients with RA was followed for 1 year. Factors evaluated for sick leave episodes included: demographics, job characteristics, comorbidity, depressive symptoms, and clinical/therapeutic variables. Rates of sick leave episodes, working days lost, and permanent work disability (PWD) were identified. Statistical analysis included Cox regression models estimating hazard risks (HR) and their 95 % confidence intervals (95% CI). Cumulative time of follow-up for the cohort was 43,380 days, 24 % of workers had at least one episode of sick leave, with a mean of working days lost per patient-year of 18.36; 4.1 % developed PWD. Development of sick leave in the Kaplan-Meier analysis was associated with: age ≥40 years (p = 0.04), having a couple (p = 0.04), performing manual work (p = 0.03), suffering depressive symptoms (p = 0.04), limitations in functioning (p = 0.01), and poor global functional status ≥ III (p = 0.01). Cox regression models identified HAQ-Di ≥ 0.6 as the stronger predictor for sick leave (HR = 4.04, 95 % CI 1.41-11.58, p = 0.009) followed by age (HR = 1.05, 95 % CI 1.01-1.11, p = 0.04), ≥4 risk factors had a HR to 9.4 (95 % CI: 2.1-42.7) for sick leave. In this prospective cohort of Mexican workers with RA, we identified several factors associated with sick leave episodes and working days lost that should be potentially addressed by a multidisciplinary approach, being required to revaluate these strategies with the aim of increasing the work permanence of these patients.
22460626 Joint analysis of binary and quantitative traits with data sharing and outcome-dependent s 2012 Apr We study the analysis of a joint association between a genetic marker with both binary (case-control) and quantitative (continuous) traits, where the quantitative trait values are only available for the cases due to data sharing and outcome-dependent sampling. Data sharing becomes common in genetic association studies, and the outcome-dependent sampling is the consequence of data sharing, under which a phenotype of interest is not measured for some subgroup. The trend test (or Pearson's test) and F-test are often, respectively, used to analyze the binary and quantitative traits. Because of the outcome-dependent sampling, the usual F-test can be applied using the subgroup with the observed quantitative traits. We propose a modified F-test by also incorporating the genotype frequencies of the subgroup whose traits are not observed. Further, a combination of this modified F-test and Pearson's test is proposed by Fisher's combination of their P-values as a joint analysis. Because of the correlation of the two analyses, we propose to use a Gamma (scaled chi-squared) distribution to fit the asymptotic null distribution for the joint analysis. The proposed modified F-test and the joint analysis can also be applied to test single trait association (either binary or quantitative trait). Through simulations, we identify the situations under which the proposed tests are more powerful than the existing ones. Application to a real dataset of rheumatoid arthritis is presented.
21383967 Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthriti 2011 Feb Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P<5 × 10(-8) in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (P(combined) =  1.2 × 10(-12)), rs864537 near CD247 (P(combined) =  2.2 × 10(-11)), rs2298428 near UBE2L3 (P(combined) =  2.5 × 10(-10)), and rs11203203 near UBASH3A (P(combined) =  1.1 × 10(-8)). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5 × 10(-8) (SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases.
21509868 Quantifying synovitis in rheumatoid arthritis using computer-assisted manual segmentation 2011 May PURPOSE: To investigate the reliability, validity and feasibility of a computer-assisted manual segmentation method for determining the synovial membrane volume as a surrogate measure for synovitis in patients with rheumatoid arthritis (RA). MATERIALS AND METHODS: The 3 Tesla (T) MRI scans were acquired in 22 early RA and 16 established RA patients. Synovial membrane volumes in postcontrast T1w axial images at three wrist joint regions were determined by two nonradiologist observers using a computer-assisted manual segmentation method. RESULTS: Intraobserver reliability, measured by intraclass correlation coefficients (ICCs), was excellent in the early (ICC = 0.99) and established (ICC = 0.99) RA cohorts. Interobserver reliability (mean ICC [95% Confidence Interval]) was moderate to excellent in the early and established RA groups (ICCs = 0.87 [0.68,0.94] and 0.88 [0.66, 0.96], respectively). There was a strong correlation between the synovial membrane volumes derived by segmentation and the RA MRI scoring system (RAMRIS) scores for synovitis at all joints in the early (Spearman rho = 0.86-0.96) and established (Spearman rho = 0.85-0.93) RA cohorts. The entire segmentation technique took 19 to 21 min per patient. CONCLUSION: Measurement of MRI synovitis using a computer-assisted manual segmentation method demonstrated excellent intraobserver and very good interobserver reliability, content validity (represented by its strong correlation with RAMRIS synovitis), and moderate feasibility.
23153245 Association of IL-18 polymorphisms with rheumatoid arthritis and systemic lupus erythemato 2012 Nov 15 BACKGROUND: Interleukin (IL)-18, an important proinflammatory cytokine, plays a potential pathological role in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Studies on the relationship of IL-18 gene promoter rs1946518 (-607A/C) polymorphism, rs187238 (-137G/C) polymorphism with RA and SLE are inconclusive. The aim of this study was to get a more precise estimation of the relationship in Asian populations. METHODS: Meta-analysis was conducted on the associations between the IL-18 (-607A/C and -137G/C) polymorphisms and RA and SLE, using; (1) allele contrast, (2) dominant, and (3) recessive models. A total of 11 studies were included in this study. RESULTS: For the relationship of IL-18 rs1946518 polymorphism with RA (additive model: OR=0.752, 95%CI=0.562-1.006; dominant model: OR=0.730, 95%CI =0.479-1.113; recessive model: OR=0.537, 95%CI=0.271-1.064) and SLE (additive model: OR=0.684, 95%CI=0.455-1.028; dominant model: OR=0.645, 95%CI=0.368-1.130; recessive model: OR=0.672, 95%CI =0.447-1.010), no significant association with RA and SLE risk can be found under all genetic models in Asian populations. However, significant associations were observed in Chinese population for both RA ((OR=0.688, 95%CI =0.532-0.889) and SLE (OR=0.606, 95%CI =0.396-0.930) under additive model. For the relationship between IL-18 rs187238 polymorphism and RA or SLE, there was no significant association detected in all genetic models, even in Chinese population. CONCLUSIONS: This meta-analysis indicates that the IL-18-607A/C polymorphism may confer susceptibility to RA and SLE in Chinese population, but not all Asians.
21216819 Interleukin 1 receptor antagonist mediates the beneficial effects of systemic interferon b 2011 May OBJECTIVES: Interferon beta (IFNβ) therapy is effective in multiple sclerosis and murine models of arthritis. Surprisingly, systemic IFNβ treatment induces only minimal improvement in rheumatoid arthritis (RA). To explain this paradox, the authors evaluated the mechanism of IFNβ benefit in passive K/BxN arthritis and the effect of IFNβ treatment on RA synovium. METHODS: Interleukin 10 (IL-10) null, IL-1 receptor antagonist (IL-1Ra) null, IL-1Ra transgenic and wild-type mice were administered K/BxN serum and in some cases treated with IFNβ or normal saline. Clinical response and histological scores were assessed. Gene expression was measured by quantitative PCR. Serum IL-1Ra and IL-6 were measured by ELISA. Paired synovial biopsy specimens from RA patients pre-IFNβ and post-IFNβ treatment (purified natural fibroblast IFNβ (Frone) subcutaneously three times weekly 6 million IU, 12 million IU or 18 million IU) were immunostained for IL-1Ra and IL-10. RESULTS: Il1rn transgenic mice had an attenuated course of arthritis, whereas Il1rn(-/-) and Il10(-/-) mice had more severe serum transfer arthritis than wild-type mice. Daily IFNβ treatment significantly decreased arthritis severity in Il10(-/-) but not Il1rn(-/-) mice. IFNβ treatment did not reduce the histological scores in Il1rn(-/-) mice or gene expression of articular cytokines and chemokines. Paired synovial biopsy specimens from RA patients treated with IFNβ demonstrated a trend towards increased IL-1Ra and reduced IL-10 expression on day 85 levels compared with pretreatment specimens. CONCLUSIONS: The anti-inflammatory effects of IFNβ in passive K/BxN arthritis are dependent on IL-1Ra, but not IL-10. Systemic IFNβ treatment in RA increases synovial IL-1Ra production, but also decreases IL-10 production.
21441823 Hydroxychloroquine use and decreased risk of diabetes in rheumatoid arthritis patients. 2011 Apr BACKGROUND/OBJECTIVES: Several studies have associated hydroxychloroquine use with decreased risk of diabetes mellitus (diabetes) or improved glycemic control in rheumatoid arthritis patients, but the studies were small or used data from self-report. The present study sought to replicate this protective relationship in a health system using electronic health records with laboratory data and physician diagnoses. METHODS: This study is a retrospective cohort of 1127 adults with newly diagnosed rheumatoid arthritis and no diabetes within the Geisinger Health System between January 1, 2003, and March 31, 2008. Patients were classified as ever users (n = 333) or never users (n = 794) of hydroxychloroquine. Incident diabetes cases were defined using 2010 American Diabetes Association criteria. RESULTS: The median follow-up times for the ever and never hydroxychloroquine users were 26.0 and 23.0 months, respectively (P = 0.28). The median duration of hydroxychloroquine exposure was 14.0 months. Of the 48 cases developing diabetes during observation, 3 were exposed to hydroxychloroquine at time of development and 45 were nonexposed, yielding incidence rates of 6.2 and 22.0 per 1000 per year (P = 0.03), respectively. In time-varying Cox proportional hazards regression models adjusting for sex, age, body mass index, positive rheumatoid factor and anti-cyclic citrullinated peptide antibodies, erythrocyte sedimentation rate, and nonsteroidal anti-inflammatory drug, glucocorticoid, methotrexate, and tumor necrosis factor α inhibitor use, the hazard ratio for incident diabetes among hydroxychloroquine users was 0.29 (95% confidence interval, 0.09-0.95; P = 0.04) compared with nonusers. CONCLUSIONS: Our findings support the potential benefit of hydroxychloroquine in attenuating the risk of diabetes in rheumatoid arthritis patients. Further work is needed to determine its potential preventive role in other groups at high risk for diabetes.
21773714 Comparable efficacy of standardized Ayurveda formulation and hydroxychloroquine sulfate (H 2012 Feb Hydroxychloroquine sulfate (HCQS) is a popular disease-modifying antirheumatic drug (DMARD) despite modest efficacy and toxicity. Ayurveda (ancient India medicinal system) physicians treat rheumatoid arthritis (RA) with allegedly safer herbal formulations. We report a head-to-head comparison in an exploratory drug trial. The objective is to compare standardized Ayurvedic formulations and HCQS in the treatment of RA. One hundred twenty-one patients with active moderately severe RA (ACR 1988 classified) were randomized into a 24-week investigator-blind, parallel efficacy, three-arm (two Ayurvedic and HCQS) multicenter drug trial study; polyherb (Tinospora cordifolia and Zingiber officinale based) and monoherb (Semecarpus anacardium). Study measures included joint counts (pain/tenderness and swelling), pain visual analogue scale, global disease assessments, and health assessment questionnaire. Oral meloxicam (fixed-dosage schedule) was prescribed to all patients during the initial 16 weeks. Patients on prednisolone could continue a fixed stable dose (<7.5 mg daily). Rescue oral use of paracetamol was permitted and monitored. All groups matched well at baseline. An intent-to-treat analysis (ANOVA, significance P < 0.05) did not show significant differences by treatment groups. In the polyherb, monoherb, and HCQS arms, 44%, 36%, and 51%, respectively, showed ACR 20 index improvement. Several efficacy measures improved significantly in the HCQS and polyherb groups with no difference between the groups (corrected P). However, the latter was individually superior to monoherb. Only mild adverse events (gut and skin, and none withdrew) were reported with no differences between the groups. Forty-two patients dropped out. This preliminary drug trial controlled for HCQS demonstrated a standardized Ayurvedic polyherb drug to be effective and safe in controlling active RA. A better-designed study with a longer evaluation period is recommended.
21339220 Anti-citrullinated protein antibodies in rheumatoid arthritis: a functional role for mast 2011 Mar Rheumatoid arthritis (RA) is an autoimmune disease characterised by chronic inflammation of the joints. Anti-citrullinated protein antibodies (ACPA) are highly specific for RA and are associated with a more severe disease progression. ACPA have also been shown to have a pathological role in RA. In animal models of RA, ACPA enhances arthritis. Furthermore, in vitro generated immune complexes with ACPA can activate macrophages and the complement system in the human system. Recently, a direct functional and specific response of FcεRI+ immune cells towards citrullinated proteins was demonstrated. Basophils of ACPA+ RA patients are activated by citrullinated proteins that cross link the FcεRI receptor via IgE-ACPA, physiologically bound to the receptor. In addition, synovial mast cells from ACPA+ RA patients show a more activated phenotype than mast cells from ACPA- patients. These findings underline the suggestion that ACPA+ and ACPA- RA are two different disease entities and point to a possible functional role of ACPA and FcεRI+ cells in the pathogenesis of RA.
21917824 Evaluation of abatacept administered subcutaneously in adults with active rheumatoid arthr 2012 Jan OBJECTIVES: To assess the effect of a temporary interruption in subcutaneous (SC) abatacept on immunogenicity, safety and efficacy in patients with active rheumatoid arthritis despite methotrexate in a phase III trial. METHODS: Following a 12-week open-label introduction (period I; intravenous abatacept loading dose and weekly fixed-dose SC abatacept 125 mg), patients were randomised 2:1 to double-blind SC placebo or SC abatacept for 12 weeks (period II). At the end of period II, patients receiving SC abatacept continued treatment and patients on placebo were reintroduced to SC abatacept (12-week open-label period III). The co-primary end points were ELISA-detected immunogenicity rate and safety at the end of period II. Efficacy was also monitored. RESULTS: Of 167 patients entering period I, 72% qualified for period II; during periods II and III, three patients discontinued treatment. Mean (SD) disease duration was 6.6 (6.5) years and Disease Activity Score 28 was 4.8 (0.8). The primary end point was met, with a non-significant increase in immunogenicity upon withdrawal (7/73 placebo vs 0/38 abatacept in period II; p=0.119) which was reversed upon reintroduction of SC abatacept (2/73 vs 1/38, end period III). Safety was comparable regardless of withdrawal, with no unexpected events upon reintroduction. Two patients experienced reactions at the SC injection site. On withdrawal, patients experienced slight worsening in efficacy which improved following reintroduction. CONCLUSIONS: Overall immunogenicity to SC abatacept is low, consistent with intravenous abatacept, and is not significantly affected by a 3-month interruption and reintroduction. This stop-start schedule was well tolerated, with little impact on safety and efficacy. These are important considerations for the clinical use of SC abatacept. CLINICALTRIALS: gov Identifier NCT00533897.
22006448 Disorders in angiogenesis and redox pathways are main factors contributing to the progress 2012 Apr OBJECTIVE: To clarify the pathogenesis of rheumatoid arthritis (RA) by comparing protein expression in fibroblast-like synoviocytes (FLS) from patients with RA with that in FLS from normal subjects, using proteomics analysis. METHODS: Proteins extracted from primary cultures of FLS obtained from 50 patients with RA and 10 normal subjects were analyzed by automated 2-dimensional nano-electrospray ionization liquid chromatography tandem mass spectometry. Differentially expressed proteins were screened by 2-sample t-test (P < 0.05) and fold change (>1.5), based on the bioinformatics analysis. The expression of vasculature development-related proteins (Thy-1, connective tissue growth factor [CTGF], and thrombospondin 1 [TSP-1]) and redox-related proteins (superoxide dismutase 2 [SOD2]) in synovial tissue was confirmed by real-time polymerase chain reaction and Western blotting. The effect of Thy-1 and CTGF knockdown on Thy-1, CTGF, TSP-1, and vascular endothelial growth factor (VEGF) was analyzed by RNA interference experiments. RESULTS: According to the criteria of having >1 unique peptide per protein present and a false discovery rate of ≤5%, 1,060 proteins were identified from patients with RA, and 1,292 proteins were identified from normal subjects, from which 100 differentially expressed proteins were screened out from the RA proteins. Of these, 46 proteins were up-regulated, and the remaining 54 proteins were down-regulated. Gene ontology and pathway analyses showed that 6 vasculature development-related proteins were up-regulated, including Thy-1, CTGF, and TSP-1, while 11 redox-related proteins were down-regulated, including SOD2. The results were consistent with those obtained using mass spectrometry. Thy-1, VEGF, CTGF, and TSP-1 were down-regulated after Thy-1 knockdown, and VEGF and CTGF were down-regulated after CTGF knockdown. Recombinant human CTGF could enhance proliferation and Transwell migration of human umbilical vein endothelial cells. CONCLUSION: Up-regulation of vasculature development-related proteins and down-regulation of redox-related proteins in FLS are predominant factors that may contribute to the pathogenesis of RA.