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ID PMID Title PublicationDate abstract
27026386 [Dyslipidemia and atherogenic risk in patients with rheumatoid arthritis]. 2016 May INTRODUCTION: Dyslipidaemia is one of the main risk factors for atherosclerotic cardiovascular disease. Patients with rheumatoid arthritis have 2-3 times more cardiovascular risk, which is partly due to the pattern of lipids which increase the atherogenic index. METHODS: A descriptive, cross-sectional, observational and prospective study was conducted on 82 patients, selected for their lipid profile. Variables associated with the disease and the drugs used were recorded. Atherogenic risk was calculated, with Chi square being used for categorical variables, and the Mann-Whitney test for the continuous ones. RESULTS: The dyslipidaemia frequency was 54.9%. The most frequent age range of dyslipidaemia was between 51 and 60 years. Patients with type i obesity had a higher frequency of dyslipidaemia. Less dyslipidaemia was found with a lower rate of disease activity. Patients with cyclic citrullinated anti-peptide antibodies and positive rheumatoid factor, erythrocyte sedimentation rate>13mm or CRP>2mg/L had a higher frequency of dyslipidaemia. The mean Castelli atherogenic index was 4.36, the index of Kannel was 2.59, and triglycerides/HDL-c ratio was 3.83.Patients with dyslipidaemia showed a higher frequency of positive rheumatoid factor (P=.0008), and those patients who were taking hydroxychloroquine had a lower frequency of dyslipidaemia P=.03. CONCLUSIONS: Patients with rheumatoid arthritis have a pro-atherogenic lipid profile. It is important to know this and treat it to reduce cardiovascular risk.
26698858 Baseline Serum Osteopontin Levels Predict the Clinical Effectiveness of Tocilizumab but No 2015 OBJECTIVE: To explore the baseline predictors of clinical effectiveness after tocilizumab or infliximab treatment in biologic-naïve rheumatoid arthritis patients. METHODS: Consecutive biologic-naïve patients with rheumatoid arthritis initiating infliximab (n = 57) or tocilizumab (n = 70) treatment were included in our prospective cohort study. Our cohort started in February 2010, and the patients observed for at least 1 year as of April 2013 were analysed. We assessed baseline variables including patients' characteristics (age, sex, disease duration, prednisolone dose, methotrexate dose, other disease-modifying antirheumatic drug use, Clinical Disease Activity Index [CDAI]) and serum biomarker levels (C-reactive protein, immunoglobulin M-rheumatoid factor, anti-cyclic citrullinated protein/peptide antibodies, interferon-γ, interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, IL-17, tumor necrosis factor-α, soluble intercellular adhesion molecule-1, bone alkaline phosphatase, osteonectin, osteopontin) to extract factors associated with clinical remission (CDAI ≤ 2.8) at 1 year using univariate analyses, and the extracted factors were entered into a multivariate logistic regression model. Similar analyses were also performed for Simplified Disease Activity Index (SDAI) remission (≤ 3.3) and Disease Activity Score with 28 joint counts, erythrocyte sedimentation rate (DAS28-ESR) remission (< 2.6). RESULTS: There were no significant differences in the baseline characteristics except for methotrexate use between the groups. In the multivariate analyses, the low baseline osteopontin levels (OR 0.9145, 95% CI 0.8399-0.9857) were identified as predictors of CDAI remission in the tocilizumab group, whereas no predictors of CDAI remission were found in the infliximab group. Similar results were obtained when using SDAI and DAS28-ESR remission criteria. CONCLUSION: Baseline low serum osteopontin levels predict clinical remission 1 year after tocilizumab treatment and not infliximab treatment in biologic-naïve patients with rheumatoid arthritis. Our prediction model provided insights into how to optimize the choice of biologics and warrants external validation in other cohorts.
25787883 Low-Molecular-Weight Fucoidan Inhibits the Viability and Invasiveness and Triggers Apoptos 2015 Oct Fucoidan is a sulfated polysaccharide found mainly in various species of brown algae and brown seaweed. Here, we investigated the effects of low-molecular-weight (LMW) fucoidan (4 kDa) on interleukin-1beta (IL-1β)-stimulated rheumatoid arthritis fibroblast-like synoviocyte (RAFLS). 3-[4,5-Dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay and annexin V/propidium iodide assay were used to assess cell viability and apoptosis, respectively. Transwell assay was performed to evaluate cell invasion. Reverse transcription polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay analysis was done to measure gene expression and secretion. Nuclear factor-kappa B (NF-κB) DNA binding activity was determined by electrophoretic mobility shift assay. LMW fucoidan dose-dependently inhibited the viability and induced apoptosis of IL-1β-treated RAFLS. Fucoidan attenuated IL-1β-induced invasion of RAFLS and decreased the expression and secretion of metalloproteinase (MMP)-1, MMP-3, and MMP-9. Fucoidan suppressed NF-κB binding activity, p65 nuclear translocation, and IκB-α degradation in IL-1β-stimulated RAFLS. Additionally, IL-1β-induced phosphorylation of p38 but not ERK or JNK was significantly impaired by fucoidan treatment. LMW fucoidan reduces the viability, survival, and invasiveness of IL-1β-treated RAFLS, which is associated with inhibition of NF-κB and p38 activation. LMW fucoidan may have therapeutic potential in the treatment of rheumatoid arthritis.
26549160 Association between body composition and disease activity in rheumatoid arthritis. A syste 2016 Jul BACKGROUND: Reports regarding the association between body composition and inflammatory activity in rheumatoid arthritis (RA) have consistently yielded contradictory results. OBJECTIVE: To perform a systematic review on the association between overweight/obesity and inflammatory activity in RA. METHODS: FAST approach: Article search (Medline, EBSCO, Cochrane Library), followed by abstract retrieval, full text review and blinded assessment of methodological quality for final inclusion. Because of marked heterogeneity in statistical approach and RA activity assessment method, a meta-analysis could not be done. Results are presented as qualitative synthesis. RESULTS: One hundred and nineteen reports were found, 16 of them qualified for full text review. Eleven studies (8,147 patients; n range: 37-5,161) approved the methodological quality filter and were finally included. Interobserver agreement for methodological quality score (ICC: 0.93; 95% CI: 0.82-0.98; P<.001) and inclusion/rejection decision (k 1.00, P>.001) was excellent. In all reports body composition was assessed by BMI; however a marked heterogeneity was found in the method used for RA activity assessment. A significant association between BMI and RA activity was found in 6 reports having larger mean sample size: 1,274 (range: 140-5,161). On the other hand, this association was not found in 5 studies having lower mean sample size: 100 (range: 7-150). CONCLUSIONS: The modulation of RA clinical status by body fat mass is suggested because a significant association was found between BMI and inflammatory activity in those reports with a trend toward higher statistical power. The relationship between body composition and clinical activity in RA requires be approached with further studies with higher methodological quality.
27192221 Subclinical ultrasound synovitis in a particular joint is associated with ultrasound evide 2016 Jul OBJECTIVES: The main aim of this study was to investigate the relationship between ultrasound (US) findings indicative of joint inflammation and US features characterising bone erosions at joint level in patients with rheumatoid arthritis (RA) in clinical remission. METHODS: Twenty-four consecutive patients with RA in clinical remission according to EULAR criteria (DAS28<2.6) underwent a complete clinical assessment. An experienced sonographer blind to the clinical data performed the US examinations to detect and score signs of joint inflammation and bone erosions from second to fifth metacarpophalangeal (MCP) joints of both hands. All joints were scanned both on dorsal and volar aspects. The second and fifth MCP joints were scanned also in lateral aspects. RESULTS: The patients were mainly female (79.2%), with a mean age of 63.2 years ±12.3 standard deviation (SD) and a mean disease duration of 114.5 months ±53.9 SD. Half of the patients were rheumatoid factor positive and 45.8% were anti-citrullinated protein antibody positive. A total of 192 MCP joints and 480 aspects were assessed. Of these joints, 105 (54.7%) were found inflamed by grey-scale US, 57 (29.7%) were power Doppler (PD) positive, and bone erosions were detected in 42 (21.7%) joints. PD signal was found in 30 (53.6%) of the 56 eroded aspects and in only 41 (9.7%) out of the 424 aspects without bone erosions. Both the GS and PD mean scores were statistically higher in the joints with US bone erosions compared to those without erosions. CONCLUSIONS: A higher prevalence of PD signal was found in the joints where bone erosions were detected. This is the first study providing evidence supporting the association between US bone erosions and the persistence of subclinical inflammation in RA patients in clinical remission.
26342296 Rheumatoid arthritis patients fulfilling Korean National Health Insurance reimbursement gu 2015 Nov The aim of this study was to compare anti-tumor necrosis factor-α (TNFα) treatment status in rheumatoid arthritis (RA) patients with the Korean National Health Insurance (KNHI) reimbursement eligibility criteria and with American College of Rheumatology (ACR) recommendations, Japan College of Rheumatology (JCR) guidelines and British Society for Rheumatology (BSR) guidelines. Between December 2011 and August 2012, outpatients from 17 South Korean general hospitals diagnosed with RA according to the 1987 ACR criteria were enrolled into a noninterventional, cross-sectional, observational study. Of 1700 patients (1414 female (83.2 %), mean age of 56.6 ± 12.0, mean disease duration 97.9 ± 91.8 months), 306 (18.0 %) had used anti-TNFα agents, and 224 (13.2 %) were currently using an anti-TNFα agent. Of 1394 anti-TNFα-naive patients, 32 (2.3 %) met KNHI reimbursement guidelines, 148 (10.6 %) met ACR recommendations, and 127 (9.1 %) and 126 (9.0 %) were considered eligible for anti-TNFα agents according to JCR and BSR guidelines, respectively. The main discrepancy was the higher active joint count required by the KNHI eligibility criteria. In the opinion of treating rheumatologists, the KNHI reimbursement criteria ineligibility accounted for 15.3 % (n = 213) of the reasons for not initiating anti-TNFα agents in anti-TNFα-naive group. The anti-TNFα user group showed significantly higher disease activity than the anti-TNFα-naive group based on DAS28 score. In comparison with the ACR recommendations and JCR and BSR guidelines, fewer patients met KNHI reimbursement eligibility criteria for anti-TNFα agents. The current amendment of the KNHI criteria based on DAS28 score will improve an access to biologic agents including anti-TNFα treatment for South Korean patients with active RA.
26504820 Is Lipoprotein-Associated Phospholipase A2 a Link between Inflammation and Subclinical Ath 2015 OBJECTIVE: Lipoprotein-associated phospholipase A2 (Lp-PLA2), a marker of vascular inflammation, is associated with cardiovascular disease. This prospective study of an inception cohort aimed to investigate whether the level of Lp-PLA2 is associated with subclinical atherosclerosis in patients with rheumatoid arthritis (RA). METHODS: Patients from northern Sweden diagnosed with early RA were consecutively recruited into an ongoing prospective study. From these, all patients ≤60 years (n = 71) were included for measurements of subclinical atherosclerosis at inclusion (T0) and five years later (T5). Forty age- and sex-matched controls were included. The patients were clinically assessed, SCORE, Reynolds Risk Score, and Larsen score were calculated, and blood samples were drawn from all individuals at T0 and T5. RESULTS: There was no significant difference in the level of Lp-PLA2 between patients with RA and controls (p > 0.05). In simple linear regression models among patients with RA, Lp-PLA2 at T0 was significantly associated with intima media thickness (IMT) at T0 and T5, flow mediated dilation (FMD) at T0 and T5, ever smoking, male sex, HDL-cholesterol (inversely), non-HDL-cholesterol, SCORE, Reynolds Risk Score, and Larsen score (p < 0.05). CONCLUSION. In this cohort of patients with early RA, the concentration of Lp-PLA2 was associated with both subclinical atherosclerosis and disease severity.
26574806 [People with rheumatoid arthritis should be encouraged to engage in physical activity]. 2015 Nov 17 Besides pharmacological treatment regular physical activity is one of the cornerstones of care in rheumatoid arthritis (RA). However, recent research has shown insufficient levels of physical activity in the RA population. This is of concern given the increased risk of cardiovascular disease. There is moderate quality evidence supporting that short-term land-based aerobic exercise on moderate to high intensity results in positive effects on oxygen uptake and pain, but not muscular strength; short-term water-based aerobic exercise on moderate to high intensity results in a positive effect on oxygen uptake; short-term land-based aerobic and strengthening exercise on moderate to high intensity results in positive effects on oxygen uptake and muscular strength, but not pain, and long-term land-based aerobic and strengthening exercise on moderate to high intensity results in positive effects on activity limitation, oxygen uptake and muscular strength.
26649439 Skin Signs of Rheumatoid Arthritis and its Therapy-Induced Cutaneous Side Effects. 2016 Apr Rheumatoid arthritis (RA) is a systemic inflammatory disorder that primarily affects the joints, but may exhibit extra-articular, including cutaneous, manifestations such as rheumatoid nodules, rheumatoid vasculitis, granulomatous skin disorders, and neutrophilic dermatoses. A large burden of cutaneous disease may be an indication of RA disease activity and the need for more aggressive treatment. Many of the therapeutic agents used to treat RA can also result in cutaneous adverse effects, which pose their own diagnostic and therapeutic challenges. Anti-TNFα agents, in particular, have a wide variety of adverse effects including psoraisiform eruptions, granulomatous conditions, and cutaneous connective tissue disorders. Herein we provide an update on the clinical presentations and management of RA-associated cutaneous findings as well as drug-induced cutaneous effects, with particular attention to the adverse effects of biologic disease-modifying agents.
26373925 Serum calprotectin (S100A8/9): an independent predictor of ultrasound synovitis in patient 2015 Sep 15 INTRODUCTION: Calprotectin, a heterodimeric complex of S100A8/9 (MRP8/14), has been proposed as an important serum biomarker that reflects disease activity and structural joint damage in rheumatoid arthritis (RA). The objective of this cross-sectional study was to test the hypothesis that calprotectin is associated with clinical and ultrasound-determined disease activity in patients with RA. METHODS: A total of 37 patients with RA (including 24 females, a mean disease duration of 20 months) underwent a clinical examination and 7-joint ultrasound score (German US-7) of the clinically dominant hand and foot to assess synovitis by grey-scale (GS) and synovial vascularity by power Doppler (PD) ultrasound using semiquantitative 0-3 grading. The levels of serum calprotectin and C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were determined at the time of the ultrasound assessment. We analysed the relationship between serum calprotectin level, traditional inflammatory markers, and ultrasound-determined synovitis. RESULTS: The levels of serum calprotectin were significantly correlated with swollen joint count (r = 0.465, p < 0.005), DAS28-ESR (r = 0.430, p < 0.01), ESR (r = 0.370, p < 0.05) and, in particular, CRP (r = 0.629, p < 0.001). Calprotectin was significantly associated with GS (r = 0.359, p < 0.05) and PD synovitis scores (r = 0.497, p < 0.005). Using multivariate regression analysis, calprotectin, adjusted for age and sex, was a better predictor of PD synovitis score (R(2) = 0.765, p < 0.001) than CRP (R(2) = 0.496, p < 0.001). CONCLUSIONS: The serum levels of calprotectin are significantly associated with clinical, laboratory and ultrasound assessments of RA disease activity. These results suggest that calprotectin might be superior to CRP for monitoring ultrasound-determined synovial inflammation in RA patients.
26725019 Peripheral blood leptin and resistin levels as clinical activity biomarkers in Mexican Rhe 2016 Nov OBJECTIVE: To evaluate the association between the clinical activity of RA patients and serum adipocytokines (Leptin, Adiponectin and Resistin) and inflammatory cytokines. METHODS: All RA patients fulfilled ACR 1987 criteria and were treated with DMARDs. Adipocytokine and inflammatory cytokine levels were evaluated using ELISA. RESULTS: 121 patients were included in the study. Stratifying according to DAS28 (low, moderate and high activity), there were significant differences for Leptin, Resistin, IL-6 and IL-17, however, no differences were seen for Adiponectin, TNFα or IL-1β. Clinical activity positively correlated with Leptin, Resistin, IL-17 and IL-6 levels, but not with Adiponectin, TNFα or IL-1β. Adiponectin levels negatively correlated with TNFα and positively correlated with IL-1β. IL-1β positively correlated with IL-6 and negatively correlated with TNFα and IL-17. CONCLUSION: Circulating Leptin, Resistin, IL-6 and IL-17 levels positively correlate with RA clinical activity in a manner independent of the subject's BMI. Complex relationships between inflammatory cytokines were observed in RA patients suggesting that other metabolic or inflammatory factors could be involved.
25123522 Use of magnetic resonance imaging in detecting subclinical synovitis in rheumatoid arthrit 2016 Aug AIM: We studied the usefulness of magnetic resonance imaging (MRI) in detecting subclinical inflammation in patients with asymptomatic RA and tested the hypothesis of interleukin (IL)-18 as a marker of disease activity. METHODS: Thirteen RA patients with Disease Activity Score of 28 joints (DAS28) < 2.6 were evaluated. The patients underwent clinical evaluation, laboratory tests and MRI assessment. Imaging of bilateral hands and wrists was performed using validated acquisition and scoring techniques. Serum IL-18 levels were concurrently measured. RESULTS: MRI assessments showed that 92.3% and 76.9% of patients had synovitis and bone marrow edema, respectively, despite being in clinical remission. Eight out of 12 patients (66.7%) had erosions on MRI which were not visualised on plain radiographs. Of all the 182 joints studied for synovitis on MRI, only one had clinical evidence of joint swelling. Comparison of the total sum scores of synovitis between the right and left hand and wrist joints of individual patients showed a significant difference between the two sides. Measurements of IL-18 indicated that a large proportion (54%) of the patients had undetectable or very low levels of the cytokine. CONCLUSION: MRI is more sensitive in detecting erosions compared with X-rays, and is superior in its ability to detect subclinical inflammation in RA patients. Despite being in clinical remission, a large majority of patients had imaging-detected synovitis and bone marrow edema. Our study highlights the usefulness of MRI for the accurate evaluation of disease activity. In the utility of MRI, it may be important to assess bilateral hands and wrists, instead of limiting to the dominant side.
27445623 Psychological Distress in Out-Patients Assessed for Chronic Pain Compared to Those with Rh 2016 Background. Patients diagnosed with chronic pain (CP) and rheumatoid arthritis (RA) represent two samples with overlapping symptoms, such as experiencing significant pain. Objectives. To compare the level of psychological distress among patients diagnosed CP attending a specialist pain clinic with those attending a specialist RA clinic. Measures. A cross-sectional study was conducted at an academic specialist chronic pain and rheumatology clinic. Participants. 330 participants included a CP group (n = 167) and a RA group (n = 163) completed a booklet of questionnaires regarding demographic characteristics, duration, and severity of their pain. Psychological and personality variables were compared between the CP and RA participants using a Multivariate Analysis of Covariance (MANCOVA). Results. Level of psychological distress based on the subscales of the DASS (depression, anxiety, and stress), PASS (escape avoidance, cognitive anxiety, fear of pain, and physiological anxiety), and PCS (rumination, magnification, and helplessness) was significantly higher in the CP group compared to the RA group. Categorization of individuals based on DASS severity resulted in significant differences in rates of depression and anxiety symptoms between groups, with a greater number of CP participants displaying more severe depressive and anxiety symptoms. Discussion and Conclusions. This study found greater levels of psychological distress among CP individuals referred to an academic pain clinic when compared to RA patients referred to an academic rheumatology clinic.
27356888 Screening of gene signatures for rheumatoid arthritis and osteoarthritis based on bioinfor 2016 Aug The current study aimed to identify gene signatures during rheumatoid arthritis (RA) and osteoarthritis (OA), and used these to elucidate the underlying modular mechanisms. Using the Gene Expression Omnibus database, the present study obtained the GSE7669 mRNA expression microarray data from RA and OA synovial fibroblasts (n=6 each). The differentially expressed genes (DEGs) in RA synovial samples compared with OA samples were identified using the Linear Models for Microarray Analysis package. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed using the Database for Annotation Visualization and Integrated Discovery. A protein‑protein interaction network was constructed and the modules were further analyzed using the Molecular Complex Detection plugin of Cytoscape. A total of 181 DEGs were identified by comparing RA and OA synovial samples (96 up‑ and 85 downregulated genes). The significant DEGs in module 1, including collagen, type I, α 1 (COL1A1), COL3A1, COL4A1 and COL11A1, were predominantly enriched in the extracellular matrix (ECM)‑receptor interaction and focal adhesion pathways. Additionally, significant DEGs in module 2, including radical S‑adenosyl methionine domain containing 2 (RSAD2), 2'‑5'‑oligoadenylate synthetase 2 (OAS2), myxovirus (influenza virus) resistance 1 (MX1) and ISG15 ubiquitin‑like modifier (ISG15), were predominantly associated with immune function pathways. In conclusion, the present study indicated that RSAD2, OAS2, MX1 and ISG15 may be notable gene signatures in RA development via regulation of the immune response. COL3A1, COL4A1, COL1A1 and COL11A1 may be important gene signatures in OA development via involvement in the pathways of ECM-receptor interactions and focal adhesions.
27133494 The Challenge and Opportunity of Capturing Patient Reported Measures of Rheumatoid Arthrit 2016 May Limited health literacy and limited English proficiency are widely prevalent and contribute to rheumatoid arthritis (RA) health care disparities. The RA Patient Global Assessment of Disease Activity often introduces complexity to the health care encounters of patients and research subjects with limited health literacy and limited English proficiency. Important work is being done to ensure that patient-reported outcomes are validated and appropriate for diverse and vulnerable populations.
26714853 Determinants of adherence to disease modifying anti-rheumatic drugs in White British and S 2015 Dec 29 BACKGROUND: Rheumatoid arthritis (RA) is a common chronic inflammatory disease causing joint damage, disability, and reduced life expectancy. Highly effective drugs are now available for the treatment of RA. However, poor adherence to drug regimens remains a significant barrier to improving clinical outcomes in RA. Poor adherence has been shown to be linked to patients' beliefs about medicines with a potential impact on adherence. These beliefs are reported to be different between ethnic groups. The purpose of this study was to identify potential determinants of adherence to disease modifying anti-rheumatic drugs (DMARDs) including an assessment of the influence of beliefs about medicines and satisfaction with information provided about DMARDs and compare determinants of adherence between RA patients of White British and South Asian. METHODS: RA patients of either White British (n = 91) or South Asian (n = 89) origin were recruited from secondary care. Data were collected via questionnaires on patients': (1) self-reported adherence (Medication Adherence Report Scale-MARS); (2) beliefs about medicines (Beliefs about Medicines Questionnaire-BMQ); (3) illness perceptions (Illness Perceptions Questionnaire-IPQ) and (4) satisfaction with information about DMARDs (Satisfaction with Information about Medicines questionnaire-SIMS). In addition, clinical and demographic data were collected. RESULTS: The results revealed that socio-demographic factors only explained a small amount of variance in adherence whereas illness representations and treatment beliefs were more substantial in explaining non-adherence to DMARDs. Patients' self-reported adherence was higher in White British than South Asian patients (median 28 (interquartile range 26-30) vs median 26 (interquartile range 23-30) respectively; P = 0.013, Mann-Whitney test). Patients who reported lower adherence were more dissatisfied with the information they had received about their DMARDs (P < 0.001, Spearman correlation, SIMS action and usage subscale; P < 0.001, Spearman correlation, SIMS potential problems subscale) and had more negative beliefs about their DMARDs and were related to ethnicity with South Asian patients having more negative views about medicines. CONCLUSIONS: Socio-demographic factors were found to explain a small amount of variance in adherence. Illness representations and treatment beliefs were more important in explaining non-adherence to DMARDs. Clinicians managing South Asian patients with RA need to be aware that low adherence may be linked to negative beliefs about medicines and illness representations of RA.
25890314 CYB5A polymorphism increases androgens and reduces risk of rheumatoid arthritis in women. 2015 Mar 11 INTRODUCTION: Rheumatoid arthritis (RA) is characterized by decreased androgen levels, which was the first hormonal abnormality described. Several studies indicated that steroidogenesis is directed towards endogenous glucocorticoids at the expense of androgens. The decisive step governing androgen synthesis is the 17,20-lyase activity of the CYP17A1 gene-encoded enzyme cytochrome P450 17A1. Here, we focused on the role in RA of the critical cofactor for 17,20-lyase activity, cytochrome b5, encoded by the CYB5A gene. METHODS: Data sets of two genome wide RA association studies (GWAS) were screened for single nucleotide polymorphisms (SNP) in the CYB5A gene. Candidate SNPs in CYB5A were studied in a case-control study population of Slovakia. Expression analyses were done in synovial fibroblasts from RA patients by quantitative real-time polymerase chain reaction, and cytochrome b5-expression was detected by immunohistochemistry. Real-life androgen production after steroid conversion was measured using radiolabeled substrates. RESULTS: The study identified the RA-associated intronic SNP rs1790834 in the CYB5A gene in one GWAS and confirmed the same SNP in our study. The minor allele reduced RA risk selectively in women (P=4.1*10(-3); OR=0.63, 95% CI [0.46-0.86]). The protective effect was confined to rheumatoid factor-positive (OR=0.53, [0.37-0.75]) and anti-cyclic citrullinated peptide-positive (OR=0.58, [0.41-0.83]) cases, respectively. The protective allele doubles CYB5A mRNA-expression resulting in 2-3fold activation of steroid 17,20-lyase activity, and protective allele was accompanied by a higher density of cytochrome b5-positive cells in synovial tissue. CONCLUSIONS: CYB5A is the first RA susceptibility gene involved in androgen synthesis. Our functional analysis of SNP rs1790834 indicates that it contributes to the sex bias observed in RA.
27225300 Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis. 2016 Jul Synovial proliferation, neovascularization and leukocyte extravasation transform the normally acellular synovium into an invasive tumour-like 'pannus'. The highly dysregulated architecture of the microvasculature creates a poor oxygen supply to the synovium, which, along with the increased metabolic turnover of the expanding synovial pannus, creates a hypoxic microenvironment. Abnormal cellular metabolism and mitochondrial dysfunction thus ensue and, in turn, through the increased production of reactive oxygen species, actively induce inflammation. When exposed to hypoxia in the inflamed joint, immune-inflammatory cells show adaptive survival reactions by activating key proinflammatory signalling pathways, including those mediated by hypoxia-inducible factor-1α (HIF-1α), nuclear factor κB (NF-κB), Janus kinase-signal transducer and activator of transcription (JAK-STAT) and Notch, which contribute to synovial invasiveness. The reprogramming of hypoxia-mediated pathways in synovial cells, such as fibroblasts, dendritic cells, macrophages and T cells, is implicated in the pathogenesis of rheumatoid arthritis and other inflammatory conditions, and might therefore provide an opportunity for therapeutic intervention.
26990995 Association of Improvement in Pain With Therapeutic Response as Determined by Individual I 2016 Nov OBJECTIVE: To use statistical methods to establish a threshold for individual response in patient-reported outcomes (PROs) in patients with rheumatoid arthritis. METHODS: We used an analysis of variance model in patients on stable therapy (discovery cohort) to establish critical differences (d(crit) ) for the minimum change associated with a significant individual patient response (beyond normal variation) in the PRO measures of pain (0-10), fatigue (0-10), and function (Funktionsfragebogen Hannover questionnaire; 0-100). We then evaluated PRO responses in patients initiating adalimumab in a noninterventional study (treatment cohort). RESULTS: In the discovery cohort (n = 700), PROs showed excellent long-term retest reliability. The minimum change that exceeded random fluctuation was conservatively determined to be 3 points for pain, 4 points for fatigue, and 16 points for function. In the treatment cohort (n = 2,788), 1,483 patients (53.2%) achieved a significant individual therapeutic response as assessed by Disease Activity Score in 28 joints (DAS28)-d(crit) (≥1.8 points) after 12 months of adalimumab treatment; 68.5% of patients with a DAS28-d(crit) response achieved a significant improvement in pain, whereas approximately 40% achieved significant improvements in fatigue or function. Significant improvements in all 3 PROs occurred in 22.7% of patients; 22.8% did not have any significant PRO responses. In contrast, significant improvements in all 3 PROs occurred in only 4.4% of 1,305 patients who did not achieve a DAS28-d(crit) response at month 12, and 59.1% did not achieve any significant PRO responses. CONCLUSION: The establishment of critical differences in PROs distinguishes true responses from random variation and provides insights into appropriate patient management.
26615796 HLA-DRB1 gene polymorphisms and its associations with rheumatoid arthritis in Chinese Han 2016 Feb Rheumatoid arthritis (RA) is a common chronic autoimmune disease characterized by symmetric polyarthritis. This study was designed to investigate the associations between HLA-DRB1 gene polymorphisms and RA in the Chinese Han population of Shaanxi province, northwest of China. In total, we identified 31 high-resolution HLA-DRB1 alleles in 109 patients with RA. Compared with the controls, the AF of HLA-DRB1*04:05 (P = 0.000, Pc = 0.007, OR = 3.462, 95%CI: 1.749-6.852) was significantly higher in patients with RA. In addition, the patients with RA had higher allele frequency (AF) of the HLA-DRB1*04:03 (P = 0.030, Pc = NS, OR = 4.737, 95%CI: 1.012-22.180); DRB1*04:06 (P = 0.018, Pc = NS, OR = 5.288, 95%CI: 1.145-24.422) and the shared epitope (SE) alleles (P = 0.004, Pc = NS, OR = 2.166, 95%CI: 1.279-3.667), respectively. Moreover, positive possibilities of RF and anti-CCP were significant higher in SE-positive patients compared to SR-negative patients (OR = 4.787, 95%CI: 1.101-20.824; OR = 3.775, 95%CI: 1.106-12.876, respectively). Our results indicated that HLA-DRB1*04:05, *04:03, *04:06 and SE alleles might be susceptibility allele for RA in Chinese Han population of Shaanxi province, northwest of China.