Sedentary behaviour is associated with increased long-term cardiovascular risk in patients with rheumatoid arthritis independently of moderate-to-vigorous physical activity

Background Rheumatoid Arthritis (RA) is associated with an increased risk of cardiovascular disease (CVD). The physical dysfunction symptomatic of RA means people living with this disease spend large periods of the day sedentary, which may further elevate their risk of CVD. The primary aim of this study was to investigate relationships between objectively assessed sedentary behaviour patterns and light physical activity (LPA) with 10-year risk of CVD. Secondary aims were to explore the role of sedentary behaviour patterns and LPA for individual CVD risk factors and functional disability in RA. The extent to which associations were independent of moderate-to-vigorous physical activity (MVPA) engagement was also examined. Methods Baseline data from a subsample of participants recruited to the Physical Activity in Rheumatoid Arthritis (PARA) study were used to answer current research questions. Sixty-one patients with RA (mean age (± SD) = 54.92 ± 12.39 years) provided a fasted blood sample and underwent physical assessments to evaluate factors associated with their cardiovascular health. Sedentary behaviour patterns (sedentary time, sedentary bouts, sedentary breaks), LPA and MVPA were measured via 7-days of accelerometry. Ten-year CVD risk was computed (Q-risk-score2), and functional disability determined via questionnaire. Results Regressions revealed significant positive associations between sedentary time and the number of sedentary bouts per day ≥20 min with 10-year CVD risk, with the reverse true for LPA participation. Associations were independent of MVPA engagement. Conclusions Promoting LPA participation and restricting sedentary bouts to <20 min may attenuate long-term CVD risk in RA, independent of MVPA engagement

Autoimmune gastrointestinal complications in patients with Systemic Lupus Erythematosus: case series and literature review

The association of systemic lupus erythematosus (SLE) with gastrointestinal autoimmune diseases is rare, but has been described in the literature, mostly as case reports. However, some of these diseases may be very severe, thus a correct and early diagnosis with appropriate management are fundamental. We have analysed our data from the SLE patient cohort at University College Hospital London, established in 1978, identifying those patients with an associated autoimmune gastrointestinal disease. We have also undertaken a review of the literature describing the major autoimmune gastrointestinal pathologies which may be coincident with SLE, focusing on the incidence, clinical and laboratory (particularly antibody) findings, common aetiopathogenesis and complications

Functional Improvement of Regulatory T Cells From Rheumatoid Arthritis Subjects Induced by Capsular Polysaccharide Glucuronoxylomannogalactan

Objective: Regulatory T cells (Treg) play a critical role in the prevention of autoimmunity, and the suppressive activity of these cells is impaired in rheumatoid arthritis (RA). The aim of the present study was to investigate function and properties of Treg of RA patients in response to purified polysaccharide glucuronoxylomannogalactan (GXMGal). Methods: Flow cytometry and western blot analysis were used to investigate the frequency, function and properties of Treg cells. Results: GXMGal was able to: i) induce strong increase of FOXP3 on CD4+ T cells without affecting the number of CD4+CD25+FOXP3+ Treg cells with parallel increase in the percentage of non-conventional CD4+CD25-FOXP3+ Treg cells; ii) increase intracellular levels of TGF-beta1 in CD4+CD25-FOXP3+ Treg cells and of IL-10 in both CD4+CD25+FOXP3+ and CD4+CD25-FOXP3+ Treg cells; iii) enhance the suppressive activity of CD4+CD25+FOXP3+ and CD4+CD25-FOXP3+ Treg cells in terms of inhibition of effector T cell activity and increased secretion of IL-10; iv) decrease Th1 response as demonstrated by inhibition of T-bet activation and down-regulation of IFN-gamma and IL-12p70 production; v) decrease Th17 differentiation by down-regulating pSTAT3 activation and IL-17A, IL-23, IL-21, IL-22 and IL-6 production. Conclusion: These data show that GXMGal improves Treg functions and increases the number and function of CD4+CD25-FOXP3+ Treg cells of RA patients. It is suggested that GXMGal may be potentially useful for restoring impaired Treg functions in autoimmune disorders and for developing Treg cell-based strategies for the treatment of these diseases

Genetics of rheumatoid arthritis contributes to biology and drug discovery

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological datasets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here, we performed a genome-wide association study (GWAS) meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single nucleotide polymorphisms (SNPs). We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 1012–4. We devised an in-silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci (cis-eQTL)6, and pathway analyses7–9 – as well as novel methods based on genetic overlap with human primary immunodeficiency (PID), hematological cancer somatic mutations and knock-out mouse phenotypes – to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery

Safety and effectiveness of adalimumab in a clinical setting that reflects Canadian standard of care for the treatment of rheumatoid arthritis (RA): Results from the CanACT study

<p>Abstract</p> <p>Background</p> <p>This multicenter, open-label, prospective, single cohort study evaluated the effectiveness and safety of adalimumab in a clinical setting reflecting the Canadian standard of care for the treatment of patients with rheumatoid arthritis (RA).</p> <p>Methods</p> <p>Patients ≥ 18 years of age with a history of active RA ≥ 3 months and fulfilling Canadian requirements for biological therapy received adalimumab 40 mg subcutaneously every other week for 12 weeks. Pre-study DMARD treatment regimens, corticosteroids, or NSAIDs were allowed throughout the study. The primary effectiveness outcome measure was the mean change in 28-joint disease activity score (DAS28) from baseline to Week 12. Secondary measures included the proportion of patients achieving joint remission (DAS28 < 2.6) and low-disease activity (DAS28 < 3.2) at Week 12, and European League Against Rheumatism (EULAR: moderate and good) and American College of Rheumatology (ACR: ACR20, 50, and 70) responses, as well as responses in ACR core components at Weeks 4, 8, and 12. Subgroup analysis included a comparison of patients naïve to biological DMARD (BDMARD) therapy versus BDMARD-experienced patients. Safety was assessed in terms of adverse and serious adverse events.</p> <p>Results</p> <p>A total of 879 patients (mean disease duration > 12 years) were enrolled; 772 (87.9%) completed the 12-week period. Adalimumab treatment was associated with rapid and sustained improvements in the signs and symptoms of RA. Significant improvements in mean DAS28 score were observed as early as Week 4. After 12 weeks of adalimumab treatment, 15.3% and 28.9% of patients achieved clinical remission and low-disease activity, respectively. Similarly, significant improvements in ACR core components were observed as early as Week 4, with continued improvements occurring through 12 weeks. Patients naïve to BDMARD therapy demonstrated numerically greater clinical responses when compared with patients who had experienced prior BDMARD therapy, although both subgroups were associated with significant improvements from baseline. The rates and types of adverse events, as well as the results of laboratory measures, demonstrated that adalimumab was generally safe and well-tolerated.</p> <p>Conclusions</p> <p>This study demonstrated that, under conditions reflective of the normal clinical practice in Canada, adalimumab is an effective and safe treatment for patients with RA.</p> <p>Trial registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT00649545">NCT00649545</a>.</p

Histoplasmosis infection in patients with rheumatoid arthritis, 1998-2009

<p>Abstract</p> <p>Background</p> <p>Patients with rheumatic diseases including rheumatoid arthritis (RA) are at increased risk for infections related to both the disease and its treatments. These include uncommonly reported infections due to histoplasmosis.</p> <p>Methods</p> <p>Medical record review of all patients with a diagnosis of RA who developed new histoplasmosis infection in an endemic region between Jan 1, 1998 and Jan 30, 2009 and who were seen at Mayo Clinic in Rochester, Minnesota was performed.</p> <p>Results</p> <p>Histoplasmosis was diagnosed in 26 patients. Most patients were on combination therapies; 15 were on anti-tumor necrosis factor (anti-TNF) agents, 15 on corticosteroids and 16 on methotrexate. Most received more than 6 months of itraconazole and/or amphotericin treatment. Two patients died of causes unrelated to histoplasmosis. Anti-TNF treatment was restarted in 4/15 patients, with recurrence of histoplasmosis in one.</p> <p>Conclusions</p> <p>In this largest single center series of patients with RA and histoplasmosis in the era of immunomodulatory therapy, we found that most patients had longstanding disease and were on multiple immunomodulatory agents. Most cases were pulmonary; typical signs and symptoms of disease were frequently lacking.</p

Blood lipid profiles and peripheral blood mononuclear cell cholesterol metabolism gene expression in patients with and without methotrexate treatment

<p>Abstract</p> <p>Background</p> <p>Methotrexate (MTX) is the most commonly prescribed disease-modifying antirheumatic drug (DMARD) in rheumatoid arthritis. ATP-binding cassette transporter-A1 (ABCA1) and 27-Hydroxylase (HY27) are known antiatherogenic proteins that promote cellular cholesterol efflux. In THP-1 macrophages, MTX can promote the reversal of cholesterol transport, limit foam cell formation and also reverse COX-2 inhibitor-mediated downregulation of ABCA1. Despite its antiatherogenic potential <it>in vitro</it>, the impact of clinical use of low-dose MTX on cholesterol metabolism in humans is unknown. Objective of the study was to examine whether clinical MTX use is associated with altered blood lipids and/or <it>ABCA1/HY27 </it>expressions.</p> <p>Methods</p> <p>In all, 100 rheumatoid arthritis subjects were recruited from a medical center in central Taiwan. Plasma lipid profiles and peripheral blood mononuclear cell <it>HY27 </it>and <it>ABCA1 </it>expressions were compared between subjects taking MTX (MTX+) and other disease-modifying antirheumatic drugs (DMARDs) (MTX-). Dietary intake was assessed by a registered dietician.</p> <p>Results</p> <p>Though no difference observed in the blood lipids between MTX+ and MTX- subjects, the expressions of <it>ABCA1 </it>and <it>HY27 </it>were significantly elevated in MTX+ subjects (n = 67) compared to MTX- subjects (n = 32, p < 0.05). ABCA expression correlated with MTX doses (r = 0.205, p = 0.042), and MTX+ subjects are more likely to have increased <it>HY27 </it>compared to MTX- subjects (OR = 2.5, p = 0.038). Prevalence of dyslipidemia and overweight, and dietary fat/cholesterol intake were lower than that of the age-matched population. Although no differences were observed in the blood lipids, the potential impacts of MTX on cholesterol metabolism should not be overlooked and the atheroprotective effects from MTX induced <it>HY27 </it>and <it>ABCA1 </it>expressions may still be present in those persons with pre-existing dyslipidemia.</p> <p>Conclusions</p> <p>We demonstrated novel findings on the increased gene expressions of atheroprotective protein <it>HY27 </it>and <it>ABCA1 </it>in human peripheral blood mononuclear cells (PBMCs) with clinical use of low-dose MTX. Whether MTX induced <it>HY27 </it>and <it>ABCA1 </it>expressions can protect against cardiovascular disease in patients with chronic inflammation through the facilitation of cholesterol export remains to be established. Further studies on the impacts of low-dose MTX on hypercholesterolemic patients are underway.</p

Paid work is associated with improved health-related quality of life in patients with rheumatoid arthritis

Numerous patients with rheumatoid arthritis (RA) end their working career due to consequences of the disease. No publication has reported whether there is an independent association between patients' health-related quality of life (HRQOL) and employment status. The objective of the study was to investigate the association of paid work and HRQOL in patients with RA whilst controlling for demographics and disease severity. This was a cross-sectional study. Three hundred and ten patients were consecutively recruited from two Norwegians hospitals when commencing disease modifying anti-rheumatic drug treatment. Data on demographics, employment status, disease activity (DAS28-3), physical functioning, pain, tiredness, and HRQOL (SF-36) were collected. HRQOL were compared between 123 patients working full- or part-time and 187 patients not working due to disability pension, retirement, being students or “home workers”. The regression analyses showed an independent positive association between paid work and the physical (p = 001) and the mental component (p = 012) of the SF-36 when controlling for demographics and disease severity. Paid work was statistically significantly associated with better HRQOL in patients with RA. The positive association of performing paid work and HRQOL imply that health care providers should thoroughly evaluate the possibilities for the patients to continue with paid work

Association between AIRE gene polymorphism and rheumatoid arthritis: a systematic review and meta-analysis of case-control studies.

Autoimmune regulator (AIRE) is a transcription factor that functions as a novel player in immunological investigations. In the thymus, it has a pivotal role in the negative selection of naive T-cells during central tolerance. Experimental studies have shown that single nucleotide polymorphism (SNP) alters transcription of the AIRE gene. SNPs thereby provide a less efficient negative selection, propagate higher survival of autoimmune T-cells, and elevate susceptibility to autoimmune diseases. To date, only rheumatoid arthritis (RA) has been analysed by epidemiological investigations in relation to SNPs in AIRE. In our meta-analysis, we sought to encompass case-control studies and confirm that the association between SNP occurrence and RA. After robust searches of Embase, PubMed, Cochrane Library, and Web of Science databases, we found 19 articles that included five independent studies. Out of 11 polymorphisms, two (rs2075876, rs760426) were common in the five case-control studies. Thus, we performed a meta-analysis for rs2075876 (7145 cases and 8579 controls) and rs760426 (6696 cases and 8164 controls). Our results prove that rs2075876 and rs760426 are significantly associated with an increased risk of RA in allelic, dominant, recessive, codominant heterozygous, and codominant homozygous genetic models. These findings are primarily based on data from Asian populations

Protein tyrosine phosphatase non-receptor 22 and C-Src tyrosine kinase genes are down-regulated in patients with rheumatoid arthritis

Several protein tyrosine phosphatase non-receptor 22 (PTPN22) single-nucleotide polymorphisms (SNPs) have been significantly related with rheumatoid arthritis (RA) susceptibility. Nevertheless, its potential influence on PTPN22 expression in RA has not been completely elucidated. Furthermore, PTPN22 binds to C-Src tyrosine kinase (CSK) forming a key complex in autoimmunity. However, the information of CSK gene in RA is scarce. In this study, we analyzed the relative PTPN22 and CSK expression in peripheral blood from 89 RA patients and 43 controls to determine if the most relevant PTPN22 (rs2488457, rs2476601 and rs33996649) and CSK (rs34933034 and rs1378942) polymorphisms may influence on PTPN22 and CSK expression in RA. The association between PTPN22 and CSK expression in RA patients and their clinical characteristics was also evaluated. Our study shows for the first time a marked down-regulation of PTPN22 expression in RA patients carrying the risk alleles of PTPN22 rs2488457 and rs2476601 compared to controls (p?=?0.004 and p?=?0.007, respectively). Furthermore, CSK expression was significantly lower in RA patients than in controls (p?<?0.0001). Interestingly, a reduced PTPN22 expression was disclosed in RA patients with ischemic heart disease (p?=?0.009). The transcriptional suppression of this PTPN22/CSK complex may have a noteworthy clinical relevance in RA patients