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

ID PMID Title PublicationDate abstract
28079986 Establishment of an in vitro three-dimensional model for cartilage damage in rheumatoid ar 2018 Jan Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to progressive joint destruction. To further understand the process of rheumatoid cartilage damage, an in vitro model consisting of an interactive tri-culture of synovial fibroblasts (SFs), LPS-stimulated macrophages and a primary chondrocyte-based tissue-engineered construct was established. The tissue-engineered construct has a composition similar to that of human cartilage, which is rich in collagen type II and proteoglycans. Data generated from this model revealed that healthy chondrocytes were activated in the presence of SFs and macrophages. The activated chondrocytes subsequently displayed aberrant behaviours as seen in a disease state such as increased apoptosis, decreased gene expression for matrix components such as type II collagen and aggrecan, increased gene expression for tissue-degrading enzymes (MMP-1, -3, -13 and ADAMTS-4, -5), and upregulation of inflammatory mediator gene expression (TNF-α, IL-1β, IL-6 and IKBKB). Additionally, the inclusion of SFs and macrophages in the model enabled both cell types to more closely replicate an in vivo role in mediating cartilage destruction. This is evidenced by extensive matrix loss, detected in the model through immunostaining and biochemical analysis. Subsequent drug treatment with celecoxib has shown that the model was able to respond to the therapeutic effects of this drug by reversing cartilage damage. This study showed that the model was able to recapitulate certain pathological features of an RA cartilage. If properly validated, this model potentially can be used for screening new therapeutic drugs and strategies, thereby contributing to the improvement of anti-rheumatic treatment. Copyright © 2017 John Wiley & Sons, Ltd.
28584209 Analysis of Closed Claims in the Clinical Management of Rheumatoid Arthritis in Japan. 2017 Jun 20 BACKGROUND: Despite an increasing awareness of the risk of medical errors, few data sources are available to highlight the characteristics and patterns of medical errors in the clinical management of rheumatoid arthritis (RA). The present study aimed to evaluate medical malpractice claims associated with the management of RA and other autoimmune connective tissue diseases (ACTDs). METHODS: We analyzed 38 ACTD-associated closed claims extracted from a total of 8530 claims processed between July 2004 and June 2014 by the Tokyo headquarters office of Sompo Japan Nipponkoa Incorporated, a leading malpractice insurer in Japan. RESULTS: RA was the most common ACTD assessed in this study, accounting for 20 cases. Although the male-to-female ratio among these cases was 5:15, in accordance with the general demographic distribution of RA, the proportion of patients older than 60 years (77.8%) was relatively high as the general range of RA susceptibility is 30-50 years. The analysis of allegation types among RA cases revealed statistically significant differences from non-RA cases (Fisher's exact test) as well as the following key findings: diagnosis-related allegations were absent (P < 0.01), whereas medication-related allegations were distinctively common (P = 0.02). Clinical processes related to the assessment process were most vulnerable to breakdown and leading to negligence identified with subsequent medication-related allegations, particularly among RA cases. CONCLUSIONS: The characteristics of malpractice claims associated with RA management, including the high frequency of medication-related allegations, breakdowns in the assessment process, and high claim numbers among patients older than 60 years, suggest the importance of caution exercised by physicians when administering immunosuppressants for the clinical treatment of RA.
28207572 Cross-Reactivity of Chloroquine and Hydroxychloroquine With DRI Amphetamine Immunoassay. 2017 Apr BACKGROUND: Chloroquine and hydroxychloroquine are medical drugs used to treat the chemoprophylaxis of malaria and a second-line anti-inflammatory drug. METHODS: We performed a study of cross-reactivity of chloroquine and hydroxychloroquine in the DRI Amphetamine Assay inspired by a case report of a self-ingestion of chloroquine after a family dispute, that involved the following: (1) an in vitro study with control samples of healthy subjects, (2) an in vivo study with samples of patients with rheumatoid arthritis, and (3) an evaluation of the cross-reactivity of chloroquine and hydroxychloroquine in 3 additional immunoassays. RESULTS: In the case report, the Amphetamine DRI assay resulted positive both at 1000 ng/mL cutoff (1507 and 1137 ng/mL) and at 500 ng/mL cutoff (1178 and 642 ng/mL). Chloroquine urine levels were 103,900 and 100,900 ng/mL at 5 and 9 hours after ingestion. The results with control samples showed a positive cross-reactivity of chloroquine in the DRI Amphetamine Assay (approximately 0.74% and 0.89% at cutoff of 1000 and 500 ng/mL, respectively). Hydroxychloroquine did not cross-react with the DRI Amphetamine Assay up to 1,000,000 ng/mL. In patients treated with chloroquine or hydroxychloroquine, DRI Amphetamine did not produce false-positive results. The comparative assay study showed a positive cross-reactivity of chloroquine in the Emit II Plus Amphetamines Assay with control samples. CONCLUSIONS: Chloroquine can cause false-positive results in the DRI Amphetamine Assay when it is present at high concentrations. Hydroxychloroquine did not produce false-positive results neither in the DRI Amphetamine Assay nor in the others immunoassays evaluated.
29209792 The impact of smoking on disease measures in rheumatoid arthritis: the need for appropriat 2018 Feb In a recent publication, Quintana-Dunque et al. studied patients with early onset rheumatoid arthritis (RA) and showed that baseline smoking status was inversely associated with disease activity and disability at 36 months. The authors conclude that smoking may not be as deleterious as previously considered in RA disease course. However, the authors fail to highlight several limitations of study design and analysis, including time-varying confounding, which may have a direct impact on results and corresponding conclusions.
27465842 CCN1 Promotes VEGF Production in Osteoblasts and Induces Endothelial Progenitor Cell Angio 2017 Jan Angiogenesis is the formation of new capillaries from preexisting vasculature. The perpetuation of angiogenesis plays a critical role in the pathogenesis of various disease states including rheumatoid arthritis (RA). Cysteine-rich 61 (Cyr61 or CCN1) is an important proinflammatory cytokine in RA. Here, we investigated the role of CCN1 in angiogenesis associated with vascular endothelial growth factor (VEGF) production and osteoblasts. We found higher expression of CCN1 and VEGF in synovial fluid from RA patients compared with healthy controls. CCN1 induced VEGF expression in osteoblasts and increased endothelial progenitor cells (EPCs) angiogenesis by inhibiting miR-126 via the protein kinase C-alpha (PKC-α) signaling pathway. CCN1 knockdown inhibited angiogenesis in both in vitro and in vivo models. Inhibition of CCN1 expression with lentiviral vectors expressing short hairpin RNA (shRNA) ameliorated articular swelling, cartilage erosion, and angiogenesis in the ankle joint of mice with collagen-induced arthritis (CIA). Our study is the first to describe how CCN1 promotes VEGF expression in osteoblasts and increased EPCs angiogenesis in RA disease. CCN1 may serve as a potential target for RA treatment. © 2016 American Society for Bone and Mineral Research.
27929683 Frequency of Arthritis-Like MRI Findings in the Forefeet of Healthy Volunteers Versus Pati 2017 Feb OBJECTIVE: The objective of the present study is to evaluate arthritis-like findings on MRI studies of the forefeet of healthy volunteers versus patients with symptomatic rheumatoid arthritis (RA) or psoriatic arthritis (PsA). MATERIALS AND METHODS: Two observers analyzed MR images of the forefeet of 31 healthy volunteers, 30 patients with symptomatic RA, and 30 patients with symptomatic PsA, to identify MRI patterns of RA or PsA (e.g., bone marrow edema [BME], erosions, tenosynovitis, joint effusion, periarticular soft-tissue edema, or bony proliferations) on the basis of the Outcome Measures in Rheumatoid Arthritis Clinical Trial RA MRI scoring system and the PsA MRI scoring system. The Mann-Whitney test with Bonferroni correction was used for statistical analysis. RESULTS: Reader 1 found BME in 14 healthy volunteers (45%), whereas reader 2 found BME in 10 volunteers (32%). Tenosynovitis was observed by reader 1 in three healthy volunteers (10%). Joint effusion was found by reader 1 in seven healthy volunteers (23%) and by reader 2 in three volunteers (10%); the mean intensity grades for these findings were low (range, 1-1.33). Erosions, soft-tissue edema, and bony proliferations were not found in the forefeet of healthy volunteers. Reader 1 and reader 2 observed all arthritis-like features on the MR images of patients with RA. The percentages of patients with RA who had such MRI features, as identified by reader 1 and reader 2, respectively, were as follows: BME, 83% and 80%; erosions, 40% and 40%; tenosynovitis, 33% and 17%; effusion, 87% and 53%; soft-tissue edema, 20% and 27%; and bony proliferations, 3% and 3%. The percentages of patients with PsA who were found to have arthritis-like findings on MR images, as determined by reader 1 and reader 2, respectively, were as follows: BME, 70% and 67%; erosions, 20% and 20%; tenosynovitis, 57% and 50%; effusion, 70% and 37%; and soft-tissue edema, 60% and 53%. Bony proliferations were observed by reader 2 only in 7% of patients with PsA. The mean minimum intensity grade was 1 (for tenosynovitis in patients with RA, as observed by reader 2), whereas the maximum intensity grade was 2.53 (for erosions in patients with RA, as observed by reader 1). Tenosynovitis and soft-tissue edema were observed more frequently in patients with PsA than in patients with RA (p = 0.001-0.059). CONCLUSION: On the forefoot of healthy volunteers, mild BME is a common finding, and tenosynovitis and joint effusion are occasional findings. The frequency and intensity of arthritis-like findings on MRI are similar in patients with RA and PsA, with the exception of tenosynovitis and soft-tissue edema, which are more frequently observed in patients with PsA than in patients with RA.
28657833 Serum interleukin-6 and survivin levels predict clinical response to etanercept treatment 2018 Jan OBJECTIVES: To investigate the correlation of nine potential biomarkers with clinical response to etanercept (ETN) therapy in establish rheumatoid arthritis (RA) patients. METHODS: Seventy-three patients with established RA were enrolled in the prospective cohort study. Sixty-nine of 73 cases were included into final analysis for response after 24-week ETN therapy. Serum expression of nine studied proteins was measured by enzyme-linked immunosorbent assay (ELISA). Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-17A, IL-21, IL-34, RANKL, survivin, and COMP were selected as candidate biomarkers. RESULTS: Serum IL-6 level was increased in responders than in nonresponders at baseline, p = .034; to the contrary, serum survivin level was decreased in responders, p = .009. Receiver operating characteristic (ROC) curve illuminated the combination of IL-6 and survivin expressions could predict clinical response with a high AUC 0.875, 95% CI: 0.771-0.976. Furthermore, we found the combination of IL-6 high expression and survivin low expression increased the responding possibility to nearly 20-fold (OR 19.687, 95% CI: 4.087-94.839, p < .001) compared to IL-6 low or survivin high expression by univariate analysis. However, only survivin low expression (p = .002) and CRP (p = .014) high expression were independent predictive factors for achieving clinical response, while IL-6 lack independent predictive value (p = .267). CONCLUSIONS: Comprehensive measurement of IL-6 and survivin in serum could be served as a convincing biomarker for clinical response in ETN-treated patients with established RA.
28431044 Leonurine attenuates fibroblast-like synoviocyte-mediated synovial inflammation and joint 2017 Aug 1 OBJECTIVE: To explore the role of leonurine in the regulation of synovial inflammation and joint destruction inRA. METHODS: Fibroblast-like synoviocytes were isolated from synovial tissue from RA patients. Pro-inflammatory cytokine and MMP expression was evaluated using real-time PCR and a cytometric bead array. Cell migration and invasion in vitro were measured using the Boyden chamber method and the scratch assay, respectively. Protein expression was measured by western blotting. Nuclear factor kappa B (NF-κB) nuclear translocation was detected by immunofluorescence. The in vivo effect of leonurine was evaluated in mice with CIA. RESULTS: Leonurine treatment significantly decreased the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8 and TNFα) and MMPs (MMP-1 and MMP-3) and suppressed the migration and invasion of RA fibroblast-like synoviocytes. The molecular analysis revealed that leonurine impaired TNFα-induced NF-κB signalling by inhibiting the phosphorylation and degradation of inhibitor of NF-κB alpha (IκBα) and subsequently preventing the nuclear translocation of the NF-κB p65 subunit. Leonurine also inhibited the p38 and Jun N-terminal kinase mitogen-activated protein kinases signalling pathways without affecting ERK signalling. Intraperitoneal injection of leonurine reduced synovial inflammation, joint destruction and the serum IL-1β, IL-6 and TNFα levels in mice with CIA. CONCLUSION: Our findings show that leonurine reduces synovial inflammation and joint destruction in RA through the NF-κB and mitogen-activated protein kinases pathways. Leonurine has potential as a therapeutic agent for RA.
29246243 The risk of malignancy and its incidence in early rheumatoid arthritis patients treated wi 2017 Dec 15 BACKGROUND: Treatment with disease-modifying anti-rheumatic drugs (DMARDs) has raised concerns about the risk of malignancies in rheumatoid arthritis (RA) patients. However, the association between biologic DMARDs (bDMARDs) and malignancy in previous reports remains controversial. Therefore we aimed to estimate the incidence of malignancy in early RA patients and to evaluate the relative risk of malignancy with use of bDMARDs. METHODS: A retrospective cohort of incident RA patients was established using the Korean National Claims Database. Among a total of 14,081 RA patients identified, 1684 patients with a history of malignancy were excluded. We calculated the incidence rate of overall and individual malignancies. The standardized incidence ratio (SIR) of malignancies in bDMARD users was compared to that in nonusers. Multivariable logistic regression analysis was used to evaluate the impact of bDMARDs on the development of malignancies in early RA patients. RESULTS: A total of 12,397 early RA patients without a history of malignancy were enrolled. During 41,599 person-years (PY) of follow-up, 725 malignancies developed in 561 patients (174.3/10,000 PY) and 21 hematologic malignancies developed (5.0/10,000 PY). Patients treated with bDMARDs had a significantly lower incidence of overall malignancy compared to those not treated with bDMARDs (SIR 0.45 (95% CI 0.28-0.70)). However, this relationship was not significant with regard to hematologic malignancies (SIR 2.65 (95% CI 0.55-7.76)). On multivariable analysis, bDMARD use was a protective factor against the development of overall malignancy (odds ratio 0.42 (95% CI 0.25-0.73)). However, bDMARD use had no significant protective effect against the development of hematologic malignancies (odds ratio 1.69 (95% CI 0.38-7.59)). CONCLUSIONS: In early RA patients, bDMARD use decreases the overall risk of developing malignancies; however, it does not affect the risk of developing hematologic malignancies.
28678807 Risk of cardiovascular disease in Chinese patients with rheumatoid arthritis: A cross-sect 2017 OBJECTIVE: Though the risk of cardiovascular disease (CVD) in rheumatoid arthritis (RA) has been established in Western population, little is known about the risk in Chinese people with RA. Our objective was to estimate the risk of CVD in Chinese people with RA using hospital medical records data. METHODS: The inpatients medical record database 2005-2015 of Sichuan provincial people's hospital was examined. All individuals with a primary diagnosis of RA were included as cases, and those of osteoarthritis (OA) were included as controls, which consisted of the unmatched dataset. Then, RA cases and OA controls were matched by sex and age at 1:1 ratio, forming the matched dataset. The morbidity of CVD (including ischemia heart disease (IHD), congestive heart failure (CHF), et al), stroke and arthrosclerosis were extracted from the database, so as the demographic data and comorbidities related to CVD. Multiple logistic regression analysis was used to estimate the risk of CVD in RA adjusted for demographics and comorbidities using the unmatched dataset. Sensitivity analysis was conducted 1) considering interaction terms between RA and comorbidities, and 2) using multivariable conditional logistic regression for the matched dataset. RESULTS: The unmatched dataset comprised of 1824RA cases and 1995 OA controls and the matched dataset comprised of 1022 pairs of sex and age matched RA and OA patients. RA exhibited increased odds of prevalent CVD compared with OA, and the adjusted ORs (95%CIs) for CVD, stroke, IHD, CHF, and atherosclerosis were1.86(1.42-2.43), 1.11(0.71-1.74), 1.47(0.97-2.24), 2.09(1.03-4.22), and 2.49 (1.97-3.13), respectively, and was 2.26 (1.29-3.96)for IHD further adjusted for interaction term. The matched dataset analysis found similar results. CONCLUSIONS: Chinese people with RA were approximated 2 times more likely to have CVD, IHD, CHF and atherosclerosis compared with those with OA. The findings justified the need of further longitudinal study to establish the causal-relationship between RA and CVD and to estimate the precise risk in this population.
28957563 Comparing biosimilar SB2 with reference infliximab after 54 weeks of a double-blind trial: 2017 Oct 1 OBJECTIVES: SB2 is a biosimilar to the reference infliximab (INF). Similar efficacy, safety and immunogenicity between SB2 and INF up to 30 weeks were previously reported. This report investigates such clinical similarity up to 54 weeks, including structural joint damage. METHODS: In this phase III, double-blind, parallel-group, multicentre study, patients with moderate to severe RA despite MTX were randomized (1:1) to receive 3 mg/kg of either SB2 or INF at 0, 2, 6 and every 8 weeks thereafter. Dose escalation by 1.5 mg/kg up to a maximum dose of 7.5 mg/kg was allowed after week 30. Efficacy, safety and immunogenicity were measured at each visit up to week 54. Radiographic damage evaluated by modified total Sharp score was measured at baseline and week 54. RESULTS: A total of 584 patients were randomized to receive SB2 (n = 291) or INF (n = 293). The rate of radiographic progression was comparable between SB2 and INF (mean modified total Sharp score difference: SB2, 0.38; INF, 0.37) at 1 year. ACR responses, 28-joint DAS, Clinical Disease Activity Index and Simplified Disease Activity Index were comparable between SB2 and INF up to week 54. The incidence of treatment-emergent adverse events and anti-drug antibodies were comparable between treatment groups. Such comparable trends of efficacy, safety and immunogenicity were consistent from baseline up to 54 weeks. The pattern of dose increment was also comparable between SB2 and INF. CONCLUSION: SB2 maintained similar efficacy, safety and immunogenicity with INF up to 54 weeks in patients with moderate to severe RA. Radiographic progression was comparable at 1 year. TRIAL REGISTRATION: ClinicalTrials.gov (http://clinicaltrials.gov; NCT01936181) and EudraCT (https://www.clinicaltrialsregister.eu; 2012-005733-37).
28169339 DNA methylation governs the dynamic regulation of inflammation by apoptotic cells during e 2017 Feb 7 Efficient clearance of apoptotic cells (AC) is pivotal in preventing autoimmunity and is a potent immunosuppressive stimulus. However, activation of cells prior to apoptosis abolishes their immunoregulatory properties. Here we show using the antigen-induced model of arthritis that the degree of DNA methylation within AC confers their immunomodulatory plasticity. DNA isolated from resting and activated AC mimicked their respective immune effects. Demethylation of DNA abrogated the protective effect of AC whereas remethylation of AC DNA reversed the effects of activation and restored the ability to inhibit inflammation. Disease suppression or lack thereof was associated with TGFβ and IL-6 production respectively. Apoptotic CD4(+) T cells from patients with rheumatoid arthritis and systemic lupus erythematosus were demethylated compared to healthy controls and favoured production of IL-6 when cultured with healthy macrophages, in contrast to the TGFβ produced in response to healthy AC. Our data implicate AC DNA methylation as the molecular switch that imprints their regulatory properties.
27829325 A novel electromechanical autoinjector, AutoTouch™, for self-injection of etanercept: re 2017 Jan OBJECTIVES: We assessed the ability of patients with autoimmune inflammatory diseases to successfully use the investigational AutoTouch™ reusable autoinjector as well as patient preference for AutoTouch™ versus the currently marketed single-use prefilled etanercept SureClick® autoinjector. METHODS: Two multicenter studies were performed: a Home Use Study and a Patient Preference Study. In the Home Use Study, 77 patients with rheumatoid arthritis (RA) or psoriatic arthritis self-administered etanercept once weekly for 5 weeks. The primary end point was successful self-injection of etanercept via AutoTouch™. The Patient Preference Study was an open-label, randomized, 8-week crossover trial (4 weeks for each device) in 216 patients with RA or psoriasis (PsO). The primary end point was preference for AutoTouch™ versus SureClick®. RESULTS: In the Home Use Study, the proportion of successful self-injections with AutoTouch™ during weeks 1 through 5 was 97.8% (95% CI, 96.3‒99.3). In the Patient Preference Study, patients had a preference rate for AutoTouch™ of 41.7% (95% CI, 34.9-48.4) overall, 43.5% (95% CI, 35.5‒51.6) for patients with RA, and 36.8% (95% CI, 24.3‒49.4) for patients with PsO. Needle apprehension was not different at initiation of the autoinjectors, nor was there a difference between the injectors after 4 weeks. Overall, patients preferred AutoTouch™ for ease of self-injecting, ease of pressing the start button, ease of following injection progress, and certainty of knowing when the injection was completed. SureClick® was preferred for fewer steps and experiencing less injection site discomfort or pain. CONCLUSION: The introduction of the AutoTouch™ will give patients a choice between two different autoinjectors for self-administration of etanercept.
28825763 Factors Predicting 2 Years of Remission and Low Disease Activity in Rheumatoid Arthritis P 2017 Aug BACKGROUND: The goals of treatment for rheumatoid arthritis (RA) are remission and low disease activity (LDA). However, many patients do not reach or maintain these targets with regard to disease control. OBJECTIVES: To identify predictive factors of remission/LDA in a cohort of RA patients who started treatment with first line tumor necrosis factor-inhibitors (TNF-i). METHODS: We included 308 RA patients treated with first line TNF-i for 2 years to evaluate remission/LDA based on the 28-joint disease activity score (DAS28). Predictive factors considered for achievement of remission/LDA were: gender, age at the time of TNF-i treatment, early arthritis, baseline C-reactive protein (CRP) and erythrocyte sedimentation rate levels, RF/anti-citrullinated protein antibody positivity, good/moderate European League Against Rheumatism response at 6 months, co-morbidities, and concomitant disease modifying antirheumatic drugs (DMARDs). Intention to treat, receiver operating characteristic curve, and univariate and multivariate analyses by logistic regression were performed. RESULTS: Positive predictors of remission/LDA in both the univariate and the multivariate analyses were: male gender, age at the time of TNF-i treatment ≤ 54 years, negative baseline CRP, and concomitant DMARDs. The presence of any co-morbidity resulted to be a negative predictor of remission/LDA in both the univariate and the multivariate analyses. CONCLUSIONS: Demographic and clinical features were identified as reliable predictors of both the achievement and the maintenance of treatment targets in a cohort of RA patients treated for 2 years with first line TNF-i.
29067557 Prevalence of Co-existing Autoimmune Disease in Rheumatoid Arthritis: A Cross-Sectional St 2017 Nov INTRODUCTION: Many autoimmune diseases, including rheumatoid arthritis (RA), share common mechanisms; however, population-based studies of the magnitude of multiple autoimmune diseases in patients with RA have not been performed. METHODS: We conducted a cross-sectional study using a US administrative healthcare thcare claims database to screen for prevalence of multiple autoimmune diseases in patients with RA and osteoarthritis (OA). Each patient diagnosed with RA between January 1, 2006 and September 30, 2014 was age- and sex-matched with five patients with OA. The prevalence of 37 pre-specified autoimmune diseases during the 24-month period before and after RA or OA diagnosis was compared. RESULTS: Overall, 286,601 patients with RA and 992,838 matched patients (from 1,421,624 records) with OA were evaluated. During the baseline period, at least one and more than one autoimmune diseases were identified in 24.3% and 6.0% of patients with RA compared with 10.5% and 1.4% of patients with OA, respectively. Highest prevalence rates for patients with RA were for systemic lupus erythematosus (3.8% versus 0.7% for OA) and psoriatic arthritis (3.2% versus 0.4%). Highest odds ratios (ORs) comparing RA with OA were for the prevalence of ankylosing spondylitis (OR 8.0; 95% CI 7.6, 8.5) and psoriatic arthritis (OR 7.8; 95% CI 7.6, 8.1). CONCLUSION: Patients with RA have more concurrent autoimmune diseases than patients with OA. These data suggest that the interrelationship between RA and other autoimmune diseases, and outcomes associated with the occurrence of multiple autoimmune diseases, may play an important role in disease understanding, management, and treatment decisions. FUNDING: Bristol-Myers Squibb.
28651334 TSGSIS: a high-dimensional grouped variable selection approach for detection of whole-geno 2017 Nov 15 MOTIVATION: Identification of single nucleotide polymorphism (SNP) interactions is an important and challenging topic in genome-wide association studies (GWAS). Many approaches have been applied to detecting whole-genome interactions. However, these approaches to interaction analysis tend to miss causal interaction effects when the individual marginal effects are uncorrelated to trait, while their interaction effects are highly associated with the trait. RESULTS: A grouped variable selection technique, called two-stage grouped sure independence screening (TS-GSIS), is developed to study interactions that may not have marginal effects. The proposed TS-GSIS is shown to be very helpful in identifying not only causal SNP effects that are uncorrelated to trait but also their corresponding SNP-SNP interaction effects. The benefit of TS-GSIS are gaining detection of interaction effects by taking the joint information among the SNPs and determining the size of candidate sets in the model. Simulation studies under various scenarios are performed to compare performance of TS-GSIS and current approaches. We also apply our approach to a real rheumatoid arthritis (RA) dataset. Both the simulation and real data studies show that the TS-GSIS performs very well in detecting SNP-SNP interactions. AVAILABILITY AND IMPLEMENTATION: R-package is delivered through CRAN and is available at: https://cran.r-project.org/web/packages/TSGSIS/index.html. CONTACT: hsiung@nhri.org.tw. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
28950911 Assessment of intracranial vessels in association with carotid atherosclerosis and brain v 2017 Sep 26 BACKGROUND: Stroke has been associated with rheumatoid arthritis (RA). We assessed patients with RA and healthy control subjects by transcranial Doppler (TCD), carotid ultrasonography and brain magnetic resonance imaging (MRI). METHODS: Altogether, 41 female patients with RA undergoing methotrexate (MTX) or biologic treatment and 60 age-matched control subjects underwent TCD assessment of the middle cerebral artery (MCA) and basilar artery. Pulsatility index (PI), resistivity (resistance) index (RI) and circulatory reserve capacity (CRC) were determined at rest (r) and after apnoea (a) and hyperventilation (h). The presence of carotid plaques and carotid intima-media thickness (cIMT) were also determined. Intracerebral vascular lesions were investigated by brain MRI. RESULTS: MCA PI and RI values at rest and after apnoea were significantly increased in the total and MTX-treated RA populations vs control subjects. MCA CRC was also impaired, and basilar artery PI was higher in RA. More patients with RA had carotid plaques and increased cIMT. Linear regression analysis revealed that left PI(r) and RI(r) correlated with disease duration and that left PI(r), RI(r), PI(a), PI(h) and basilar PI correlated with disease activity. Right CRC inversely correlated with 28-joint Disease Activity Score. Disease activity was an independent determinant of left PI(a) and right CRC. Compared with long-term MTX treatment alone, the use of biologics in combination with MTX was associated with less impaired cerebral circulation. Impaired cerebral circulation was also associated with measures of carotid atherosclerosis. CONCLUSIONS: To our knowledge, this is the first study to show increased distal MCA and basilar artery occlusion in RA as determined by TCD. Patients with RA also had CRC defects. We also confirmed increased carotid plaque formation and increased cIMT. Biologics may beneficially influence some parameters in the intracranial vessels.
29158080 Risk-stratified management strategies for HBV reactivation in RA patients receiving biolog 2019 Feb It is estimated that more than two billion people around the world have been infected by Hepatitis B virus (HBV). Reactivation of HBV (rHBV) is a potentially fatal complication after biological therapy. With the increasing use of biologics and targeted therapy in rheumatoid arthritis (RA) patients who are refractory to conventional synthetic disease-modifying anti-rheumatic drugs, rHBV in those with past infection has become increasingly problematic, especially in HBV-endemic regions. Among those receiving biological therapy, the risk of rHBV varies according to the status of HBV infection and the degree of biologic-related immunosuppression. As rHBV is largely preventable, it is imperative that the risk status of rHBV in RA patients receiving biological and targeted therapy be stratified. Therefore, the aim of this review was to summarize the reported data on rHBV, and propose management strategies for RA patients with different risks of rHBV based on evidence presented in the current literature.
28550307 Therapeutic effects of matrine derivate MASM in mice with collagen-induced arthritis and o 2017 May 26 MASM is a matrine derivate that exhibits a number of pharmacological effects, including immunosuppressive activity and anti-inflammatory properties. In this study, the mechanisms underlying the therapeutic efficacy of MASM in the treatment of rheumatoid arthritis were investigated using DBA/1 mice with collagen-induced arthritis (CIA) and fibroblast-like synoviocytes derived from rheumatoid arthritis patients (RA-FLS). We demonstrated that MASM markedly attenuated the severity of arthritis in CIA mice. The therapeutic effects were associated with ameliorated joint swelling and reduced bone erosion and destruction. Furthermore, the administration of MASM suppressed the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). In vitro, MASM inhibited the expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-8) and matrix metalloproteinases (MMP-1, MMP-3 and MMP-13) by inhibiting both the phosphorylation of MAPKs and the activation of NF-κB in IL-1β-stimulated RA-FLS. Additionally, MASM could induce apoptosis of RA-FLS via mitochondrial and Akt signaling pathways in human RA-FLS. These findings suggest that MASM could attenuate arthritis severity in CIA mice at least partially by blocking the phosphorylation of MAPKs and the activation of NF-κB and by inducing apoptosis in RA-FLS. MASM could be a potent therapeutic agent for the treatment of RA.
25401225 Hepatosplenic Hodgkin lymphoma without lymphadenopathy following reversible methotrexate-a 2017 Mar Lymphoproliferative disorders (LPDs) occur more frequently in rheumatoid arthritis (RA) patients treated with immunosuppressive agents than in the non-RA population. However, the various forms of disease progression have not yet been elucidated in detail. We encountered a case of Epstein-Barr virus (EBV)-positive atypical polymorphous LPD in the cervical and intraabdominal lymph nodes with hepatosplenomegaly in an 88-year-old female with RA who had taken infliximab and methotrexate (MTX) for six years. Although spontaneous remission occurred following the withdrawal of infliximab and MTX, reversible LPD evolved into hepatosplenic Hodgkin lymphoma without lymphadenopathy presenting as a cholestatic febrile illness. Our findings suggest that the recurrent lesions of MTX-associated LPDs may not always coincide with the primary lesion and may present unexplained findings based on various extranodal diseases.