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ID PMID Title PublicationDate abstract
21653640 Pathway-driven gene stability selection of two rheumatoid arthritis GWAS identifies and va 2011 Sep 1 Rheumatoid arthritis (RA) is the commonest chronic, systemic, inflammatory disorder affecting ∼1% of the world population. It has a strong genetic component and a growing number of associated genes have been discovered in genome-wide association studies (GWAS), which nevertheless only account for 23% of the total genetic risk. We aimed to identify additional susceptibility loci through the analysis of GWAS in the context of biological function. We bridge the gap between pathway and gene-oriented analyses of GWAS, by introducing a pathway-driven gene stability-selection methodology that identifies potential causal genes in the top-associated disease pathways that may be driving the pathway association signals. We analysed the WTCCC and the NARAC studies of ∼5000 and ∼2000 subjects, respectively. We examined 700 pathways comprising ∼8000 genes. Ranking pathways by significance revealed that the NARAC top-ranked ∼6% laid within the top 10% of WTCCC. Gene selection on those pathways identified 58 genes in WTCCC and 61 in NARAC; 21 of those were common (P(overlap)< 10(-21)), of which 16 were novel discoveries. Among the identified genes, we validated 10 known RA associations in WTCCC and 13 in NARAC, not discovered using single-SNP approaches on the same data. Gene ontology functional enrichment analysis on the identified genes showed significant over-representation of signalling activity (P< 10(-29)) in both studies. Our findings suggest a novel model of RA genetic predisposition, which involves cell-membrane receptors and genes in second messenger signalling systems, in addition to genes that regulate immune responses, which have been the focus of interest previously.
21562776 Combined treatment of etanercept and MTX reverses Th1/Th2, Th17/Treg imbalance in patients 2011 Aug OBJECTIVE: To explore the mechanism of Etanercept in the treatment of rheumatoid arthritis (RA), we investigated whether the Th1/Th2 and Th17/regulatory T cells (Treg) imbalance could be reversed by Etanercept and whether the reversal was related to the improvement of clinical indications. METHODS: We conducted a 12-week study in 40 active RA patients, of whom 20 were given a stable weekly dose of methotrexate (MTX) alone and the other ten received a combined therapy of Etanercept and MTX. Ten healthy donors were chosen as controls. Frequencies of Th1, Th2, Th17, and Treg were quantified using flow cytometry, and related serum cytokines were detected by enzyme-linked immunosorbent assay. The composite 28-joint count Disease Activity Score, erythrocyte sedimentation rate, and C-reactive protein were assessed at each visit. RESULTS: Percentages of IFN-γ(+)Th1 and IL-17(+)Th17 among CD4(+) T cells were significantly higher, while CD4(+)CD25(high)Foxp3(+) Treg were significantly lower in RA patients compared with those in healthy control. After 12 weeks of therapy of MTX single or combination of MTX and Etanercept, the circulating Th17/Treg ratio significantly decreased, while no significant difference was observed in Th1/Th2 ratio. In combined therapy group, the Th17/Treg ratio was positively correlated with the remittance of disease activity. IL-1β, TNF-α, IL-6, IL-17, and IL-23 were significantly decreased, while TGF-β was significantly elevated. The Th17/Treg ratio was positively related to TGF-β, but negatively correlated with IL-6. CONCLUSION: Etanercept in combination with MTX ameliorates RA activity by normalizing the distribution of Th17 and Treg, and their related cytokines, which may partly explain the mechanism of combined therapy of Etanercept plus MTX in RA treatment.
21436364 Ex vivo soft-laser treatment inhibits the synovial expression of vimentin and α-enolase, 2011 May BACKGROUND: Soft-laser therapy has been used to treat rheumatic diseases for decades. The major effects of laser treatment may be dependent not on thermal mechanisms but rather on cellular, photochemical mechanisms. However, the exact cellular and molecular mechanisms of action have not been elucidated. OBJECTIVE: The aim of this study was to investigate the ex vivo effects of low-level laser treatment (with physical parameters similar to those applied previously) on protein expression in the synovial membrane in rheumatoid arthritis (RA). DESIGN: Synovial tissues were laser irradiated, and protein expression was analyzed. METHODS: Synovial membrane samples obtained from 5 people who had RA and were undergoing knee surgery were irradiated with a near-infrared diode laser at a dose of 25 J/cm(2) (a dose used in clinical practice). Untreated synovial membrane samples obtained from the same people served as controls. Synovial protein expression was assessed with 2-dimensional polyacrylamide gel electrophoresis followed by mass spectrometry. RESULTS: The expression of 12 proteins after laser irradiation was different from that in untreated controls. Laser treatment resulted in the decreased expression of α-enolase in 2 samples and of vimentin and precursors of haptoglobin and complement component 3 in 4 samples. The expression of other proteins, including 70-kDa heat shock protein, 96-kDa heat shock protein, lumican, osteoglycin, and ferritin, increased after laser therapy. LIMITATIONS: The relatively small sample size was a limitation of the study. CONCLUSIONS: Laser irradiation (with physical parameters similar to those used previously) resulted in decreases in both α-enolase and vimentin expression in the synovial membrane in RA. Both proteins have been considered to be important autoantigens that are readily citrullinated and drive autoimmunity in RA. Other proteins that are expressed differently also may be implicated in the pathogenesis of RA. Our results raise the possibility that low-level laser treatment of joints affected with RA may be effective, at least in part, by suppressing the expression of autoantigens. Further studies are needed.
22733231 Effects of TNF inhibitor on innate inflammatory and Th17 cytokines in stimulated whole blo 2012 Dec BACKGROUND: Recent studies point to important roles for IL-17 and Th17 cells in sustaining chronic inflammation and articular destruction in rheumatoid arthritis (RA). We investigated the effects of TNF inhibitor on innate inflammatory and Th17 cytokines production by ex vivo lipopolysaccharide (LPS)-stimulated whole blood in patients with RA and the associations of cytokine levels in whole blood cultures with autoantibodies and markers of disease activity. MATERIALS AND METHODS: Whole blood cultures from 18 healthy volunteers and 19 RA patients on etanercept therapy were stimulated with LPS and the production of IL-6, TNF-α, IL-23, IL-17A and IL-21 was measured by ELISA. RESULTS: After stimulation with LPS, the interleukin (IL)-17A (p = 0.020) and IL-21 (p = 0.0001) secretions were significantly higher in patients with RA than in controls, while the TNF-α (p = 0.002) was significantly lower at baseline. Etanercept significantly decreased IL-21 production (p = 0.007), while IL-6 production (p = 0.005) significantly increased after 6 months of therapy. IL-21 significantly correlated with RF (r = 0.917, p < 0.01) and antimutated citrullinated vimentin antibodies (r = 0.770, p < 0.01) at baseline. Logistic regression analysis revealed that baseline IL-21 levels (p = 0.004) were significant predictors of DAS28-ESR at 6 months follow-up. DISCUSSION: Stimulation with LPS increased production of Th17 cytokines in whole blood cultures in patients with RA. Etanercept therapy decreased IL-21 secretion, while the capacity of whole blood cells to produce IL-6 increased. IL-21 production is strongly associated with the levels of autoantibodies. Our findings suggest that IL-21 production in LPS-stimulated whole blood cultures may be predictive of clinical response to etanercept treatment in patients with RA.
22764043 Subclinical femoral atheromatosis in rheumatoid arthritis: comparable prevalence to diabet 2012 Sep OBJECTIVE: Rheumatoid arthritis (RA) is associated with increased coronary artery disease (CAD) and subclinical carotid atheromatosis, reportedly to equal diabetes mellitus (DM). The presence of atheromatic plaques in femoral arteries of RA patients without DM was compared with with DM patients. METHODS: Femoral plaques were recorded in 30 (17 men, age 43.0±12 years, disease duration 9.9±7.1 years) and 60 older RA patients (27 men, age 63.0±7.1 years, disease duration 11.4±7.9 years) matched 1:1 for age, gender and disease duration with DM types 1 and 2 patients, respectively. All were asymptomatic and free of CAD. RESULTS: The number of femoral plaques per patient in either RA subgroup was comparable with DM (0.64±0.82 vs 0.77±0.89 in total respective populations, p=0.340); percentages of patients with femoral plaques were also comparable (RA vs DM type 1 20% and 13%, respectively; RA vs DM type 2 58% and 66%, respectively). Hypertension and dyslipidaemia were significantly more frequent in both DM groups than RA groups. CONCLUSIONS: Subclinical femoral atheromatosis in RA is analogous to DM, further confirming the territorial unrestricted acceleration of the atheromatic process in these patients. Cardiovascular risk stratification based on both carotid and femoral plaque detection in RA should be addressed prospectively.
22906191 Evaluation of sexual dysfunction in women with rheumatoid arthritis: a controlled study. 2012 Oct OBJECTIVE: To evaluate sexual function in women with rheumatoid arthritis (RA) and compare them with healthy controls. MATERIALS AND METHODS: Ninety-five patients with RA and 108 healthy controls were included in the study. Depression levels and sexual functions of all participants were evaluated by the Beck Depression Inventory (BDI) and Index of Female Sexual Function (IFSF), respectively. Morning stiffness in women with RA, pain (Visual Analog Scale--VAS), disability rate (Health Assessment Questionnaire--HAQ), and disease activity score (DAS-28) were defined. RESULTS: Total IFSF and mean of IFSF subgroup scores and significance of sexual life score were lower in patients with RA than controls, whereas mean BDI score was higher. The mean of the total IFSF scores was significantly lower in patients with RA with BDI≥17 than that of patients with BDI<17. The mean of the total IFSF score decreased as disease severity increased. There was a strong negative correlation between total IFSF and DAS-28 scores, a moderate negative correlation between total IFSF score and HAQ, BDI, VAS score, age, and morning stiffness, and weak negative correlation between total IFSF and body mass index. CONCLUSION: RA is observed to have negative effects on sexual functions of women. Presence of depressive symptoms with RA and increased disease severity increase the degree of sexual dysfunction. Women patients with RA should also be asked about their sexual lives while being evaluated.
22325242 Adipogenesis of the mesenchymal stromal cells and bone oedema in rheumatoid arthritis. 2012 May OBJECTIVES: Bone oedema is a pathological change in rheumatoid arthritis (RA) that is detectable by magnetic resonance imaging (MRI). Recent histological analyses revealed that a prominent feature of bone oedema is the replacement of adipose tissue with inflammatory cells. Here, we demonstrate the possible roles of mesenchymal stromal cells (MSCs) in bone oedema formation and the pathogenic potential of the cells in RA. METHODS: Adipogenesis of bone marrow-derived human MSCs was induced by a standard adipogenic induction medium in the presence or absence of cytokines. The cytokine productions from MSCs were screened by an antibody array system and confirmed by ELISA. The migration assay was performed to determine the locomotive abilities of undifferentiated MSCs or MSCs after adipogenesis. The expression of α smooth muscle actin (SMA) and F-actin was examined by immunostaining and phalloidin staining, respectively. RESULTS: TNF-α, interleukin (IL)-1β, IL-6, and TGF-β clearly inhibited the adipogenesis of MSCs. Production of IL-6 was markedly reduced, and IL-8 secretion was augmented in MSCs after adipogenesis. The mobility of MSCs after adipogenesis was clearly reduced in migration assays compared to that of undifferentiated MSCs. Consistent with these findings, SMA and F-actin expressions were clearly suppressed in MSCs committed to adipogenesis. CONCLUSIONS: Our data suggest that the inflammatory milieu promotes bone oedema by blocking adipogenesis of MSCs. In bone oedema, the enhanced IL-6 production and the increased mobility of MSCs may contribute to the progression of RA. Therefore, bone oedema may be an important target lesion in the treatment of RA.
21925447 [Rituximab in rheumatoid arthritis: a systematic review of efficacy and safety]. 2011 Sep INTRODUCTION: The aim of the systematic review was to evaluate the safety and efficacy of rituximab for the treatment of rheumatoid arthritis patients, as part of the Consensus on the use of rituximab in rheumatoid arthritis. A document with evidence based recommendations. METHODS: All papers published from January 2003 to September 2009 were reviewed in a systematic way in Medline, EMBASE and Cochrane Library database. The Mesh terms used were: "Rituximab", "Rheumatoid arthritis", "and Anti-CD20", "Biologics". The abstracts of the EULAR and ACR congress of 2003 to 2009 were also reviewed, as well data of Roche Pharma. Two rheumatologists (BHC y MGH) made the bibliographic review by title and summary of each work. Two authors (BHC y RAA) selected them by quality according the GRADE SCALE after they review. The data were collected in paper. The outcomes evaluated were of efficacy in agreement with OMERACT (Outcome Measurements in Rheumatoid Arthritis Clinical Trials) and The Musculoskeletal Cochrane Study Group. The outcomes of safety evaluated were: mortality, severe infections, severe adverse events, withdraw for any cause, for severe adverse events, and for infusion related reactions. The review was conducted with Cochrane methodology. The odds ratio and relative risk for dichotomist variables; and mean difference between baseline and final measurements for continuous variables, and risk differences were calculated with RevMan 5. The number of patients needed to treat was calculated with Cates' calculator. RESULTS: RTX is an effective drug in three groups of patients with RA: patients who fail to MTX, those who fail anti-TNF and in patients with no prior exposure to MTX. It is necessary to treat 7 (5-10) patients with RTX vs. placebo to obtain an ACR70 response; 9 (6-15) to achieve a DAS28 < 2.6; and 5 (4-8) to achieve a HAQ improvement > 0.2. Safety of the drug was similar to that of placebo except for infusion reactions where 12 (8-26) patients need to be treated with RTX vs. placebo to see a reaction to the first infusion with steroid premedication. Severe adverse events to the infusion had an incidence of 0.7% in patients of the RTX treated group. It was impossible to identify a larger increase in the number of severe infections, probably due to methodological problems, however, the risk of developing infections in patients treated with RTX seems to be comparable to that of other anti-TNF and biologics.
22513132 Interaction between smoking and functional polymorphism in the TGFB1 gene is associated wi 2012 Apr 18 INTRODUCTION: Transforming growth factor-beta1 (TGF-beta1) is a pleiotropic cytokine that plays important roles in immunity and inflammation. Some studies have suggested that polymorphism in the TGFB1 gene is associated with heart disease in the general population. The purpose of the present study was to determine whether common single-nucleotide polymorphisms (SNP) in the TGFB1 gene are associated with ischaemic heart disease (IHD) and/or myocardial infarction (MI) in patients with rheumatoid arthritis (RA), and to investigate the influence of smoking on any association. METHODS: PCR-based assays were used to determine the genotypes of TGFB1 SNPs including TGFB1-509 C/T (rs1800469, in the promoter region), +868 T/C (rs1800470, in exon 1) and +913 G/C (rs1800471, in exon 1) in 414 subjects with established RA. Genotyping for the +868 SNP was also carried out on a second study population of RA patients (n = 259) with early disease. Serum levels of TGF-beta1 were measured using a commercial ELISA kit. Smoking history and IHD/MI status were obtained on each patient. Associations with IHD/MI were assessed using contingency tables and logistic regression analyses. RESULTS: The heterozygous genotype of TGFB+868 was associated with an increased risk of IHD (OR 2.14, 95% CI 1.30 - 3.55) and MI (OR 2.42, 95% CI 1.30-4.50), compared to the homozygous genotypes combined. Smoking was an independent risk for IHD and MI, and evidence of interaction between smoking and TGFB+868 was found. Multivariate analyses indicated that the strongest associations with IHD and MI were due to the combined effect of the TGFB1+868 TC genotype and smoking (OR 2.75, 95% CI 1.59-4.75; and OR 2.58 95% CI 1.33-4.99, respectively), independent of other cardiovascular risk factors. The association of the +868 TC genotype and evidence of +868 TC-smoking interaction with IHD were replicated in a second population of RA patients with early disease. Serum TGF-beta1 levels were not associated with TGFB1 genetic variations, smoking or IHD/MI status. CONCLUSIONS: Interaction between smoking and polymorphism in the TGFB1 gene may influence the risk of IHD and MI in patients with RA.
23031059 Differential effects of decoy receptor- and antibody-mediated tumour necrosis factor block 2013 Apr Our aim was to clarify if anti-tumour necrosis factor (TNF) drugs have effect on expression of three splice forms of FoxP3 mRNA in blood CD4+ T cells from rheumatoid arthritis (RA) patients compared with healthy controls. Forty-five rheumatoid arthritis patients treated with anti-TNF therapy were investigated in a 12-week prospective cohort study. FoxP3 isoforms, CD25 and CTLA-4 mRNA in blood CD4+ T cells were measured with quantitative real-time PCR. Patients benefitting from the treatment, based on changes in DAS28 scores, revealed a significant decrease in expression of full-length FoxP3 following 12 weeks treatment with TNF receptor 2 fusion protein (Etanercept), but not following treatment with anti-TNF antibodies (Adalimumab or Infliximab). A partial normalization of the CTLA-4/FoxP3fl ratio and a correlation between clinical improvement and change in FoxP3 mRNA expression were also seen in Etanercept responders. These changes were not observed in responsive patients treated with the antibody therapies. Our data suggest that TNF decoy receptor and anti-TNF antibodies differ in their effect on FoxP3 expression in responsive patients. As Etanercept binds both TNF-α and Lymphotoxin-α (LT-α), whereas the antibodies only target TNF-α, LT-α may regulate FoxP3 expression in a subset of RA patients. Our findings support the view that anti-TNF treatment is mainly symptomatic.
22837017 Improvement in insulin resistance after short-term treatment with abatacept: case report a 2012 Sep Insulin resistance, a key feature of type 2 diabetes, is an independent risk factor for developing cardiovascular diseases (CVD), and represents the core of metabolic syndrome (MetS). Actually, an intriguing correlation between MetS and inflammation associated with rheumatoid arthritis (RA) is largely accepted but not yet completely clarified in detail. Recently, the therapeutic arsenal against RA has been enriched of abatacept, a fusion protein (CTLA4 immunoglobulin) designed to modulate the T cell co-stimulatory signal mediated through the CD28-CD80/86 pathway. Here, we report a case of dramatic improvement in insulin resistance, estimated with the surrogate measure HOMA-IR, after treatment with abatacept. Lastly, we shortly review the preclinical evidences supporting a possible role of T lymphocytes in rheumatoid arthritis-associated insulin resistance and how abatacept could improve glucose metabolism by suppressing adipose tissue infiltrating cells.
21715007 Measurement and rates of persistence with and adherence to biologics for rheumatoid arthri 2011 Jul BACKGROUND: Biologics are an important addition to the conventional care of patients with rheumatoid arthritis (RA). Poor persistence with and adherence to biologics can undermine the effectiveness of these medications. There are no standardized methods to track persistence with and adherence to biologics. OBJECTIVE: The goal of this systematic review was to assess the methods of measurement and reported rates of persistence with and adherence to biologic regimens in patients with RA in clinical practice. METHODS: Observational studies that evaluated persistence with and adherence to biologic treatments in patients with RA were identified by searching Medline and SCI-Expanded for observational studies published in English between January 1995 and May 2009, using the following search terms: adalimumab, adherence, arthritis, biologics, compliance, discontinuation, etanercept, infliximab, persistence, RA, treatment retention, and TNF. The articles were independently reviewed to identify relevant studies and abstracted data. RESULTS: Of the 52 studies identified, 73% were based in Europe and 21% were set in the United States. All but 1 study reported measures of persistence, such as median drug survival and rates of discontinuation and retention. Four studies reported on adherence, all of which were conducted in the United States and used administrative claims data. Methods of persistence and adherence measurement were unclear or, if recorded, varied considerably across studies. Although various continuation rates (persistence) were reported across studies, the overall range of continuation at 12 months was 32.0% to 90.9%. Continuation rates were generally higher with the addition of methotrexate or other disease-modifying antirheumatic drugs. CONCLUSION: The data from the available studies on RA treatments suggest a need for better methods for tracking persistence and adherence, for examining prescribing patterns, and for identifying interventions to improve adherence.
21278069 Increased phosphorylation of ezrin/radixin/moesin proteins contributes to proliferation of 2011 Jun OBJECTIVES: Increasing evidence indicates that ezrin/radixin/moesin (ERM) proteins may play a critical role in cell proliferation. This study examined the role of ERM proteins in proliferation of fibroblast-like synoviocytes (FLS) from patients with RA. METHODS: Synovial tissues (STs) were obtained from 18 RA and 6 OA patients. The expression of ERM and its phosphorylated proteins in cultured FLS and ST was assessed by western blots or IF staining. Small interference RNA (siRNA)-mediated ERM knockdown was used to inhibit phosphorylation of ERM. Proliferation of FLS was measured by bromodeoxyuridine (BrdU) incorporation into cell DNA and by PCNA immunoblotting. RESULTS: Our study showed that increased phosphorylation of ERM proteins was found in ST and FLS from patients with RA as compared with OA patients and non-arthritis controls. Treatment with TNF-α, IL-1β or PDGF-induced phosphorylation of ERM proteins in dose- and time-dependent manner by RA FLS, but did not affect the expression of total ERM protein. Rho kinase and p38MAPK signal pathways were involved in TNF-α-induced ERM phosphorylation. We further showed that inhibition of ERM phosphorylation by siRNA-mediated ERM knockdown suppressed TNF-α- or IL-1β-induced BrdU incorporation and PCNA expression in RA FLS. CONCLUSIONS: This study provides the novel evidence that increased phosphorylation of ERM proteins may contribute to proliferation of RA FLS, suggesting that specific inhibition of ERM phosphorylation may be a new therapeutic approach for RA.
23194101 A case of urinary incontinence by hydroxychloroquine in a geriatric patient. 2013 Apr WHAT IS KNOWN AND OBJECTIVE: Rheumatoid arthritis is an autoimmune disorder characterized by persistent synovitis and systemic inflammation. Genetic factors account for approximately 50% of cases of rheumatoid arthritis and environmental factors include smoking. Urinary incontinence may occur as a medication adverse effect. We present the first report of a case of hydroxychloroquine-induced urinary incontinence in rheumatoid arthritis. DETAILS OF THE CASE: A 71-year-old female with a history of rheumatoid arthritis developed urinary incontinence as an adverse drug reaction to hydroxychloroquine administered at therapeutic doses. Urinary incontinence remitted with drug withdrawal and reappeared on rechallenge. The Naranjo's algorithm indicated that hydroxychloroquine was a probable cause of this adverse drug reaction. The likely mechanism of this adverse drug is a direct action of the quinolone on the urinary system. WHAT IS NEW AND CONCLUSION: This is the first report of hydroxychloroquine-induced urinary incontinence. The absence of previous reports suggest that the drug rarely causes this adverse effect. Methotrexate is most often used as first-line treatment, and several other drugs are now available to act as Disease-Modifying Antirheumatic Drugs (DMARDs). These drugs may be used alone or combined with methotrexate, most often to increase efficacy and reduce toxicity. The introduction of new biological agents, such as abatacept, rituximab, tocilizumab and inhibitors of tumour necrosis factor, has opened new therapeutic perspectives but are restricted by high costs and risk of infections. Thus, antimalarial drugs, especially the quinolones chloroquine (CQ) and hydroxychloroquine (HCQ), are still in use, and the latter is very efficacious. An advantage of HCQ is its low toxicity compared with other antimalarial drugs. Common side-effects of HCQ and the other antimalarial drugs include gastrointestinal effects such as nausea and vomiting, as well as skin rashes and headache, whereas their most common and severe side-effect is retinopathy. No case of urinopathy has been reported previously with HCQ.
22430029 Obesity and carotid atherosclerosis in African black and Caucasian women with established 2012 Mar 19 INTRODUCTION: Reported findings on the relationship between adiposity and atherosclerotic cardiovascular disease (ACVD) risk in rheumatoid arthritis (RA) are contradictory and originate in developed populations. Approximately 80% of ACVD now occurs in developing countries. We aimed to ascertain the associations of clinical obesity measures with metabolic cardiovascular risk and atherosclerosis in African women with RA from a developing black and developed Caucasian population. METHODS: The associations of body mass index (BMI) as an indicator of overall adiposity and waist circumference and waist-to-height and waist-to-hip ratios as abdominal obesity indices with metabolic risk factors and high resolution B-mode ultrasound-determined carotid artery atherosclerosis were assessed in multivariate regression models in 203 African women with established RA; 108 were black and 95 Caucasian. RESULTS: BMI and waist-to-height ratio were higher in African black compared to Caucasian women (29.9 (6.6) versus 25.3 (4.9) kg/m2, P = 0.002 and 0.59 (0.09) versus 0.53 (0.08), P = 0.01, respectively). Interactions between population origin and anthropometric measures were not related to metabolic risk factors but were associated with atherosclerosis, independent of confounders and individual terms. In all patients, BMI was related to systolic and diastolic blood pressure but not with serum lipid concentrations whereas abdominal obesity indices were associated with serum lipid concentrations but not with blood pressure values; obesity measures that were associated with plasma glucose concentrations comprised BMI, waist circumference and waist-to-height ratio (P < 0.05 in multiple confounder adjusted analysis). In African Caucasian women, BMI was associated with common carotid artery intima-media thickness (standardized β (95% confidence interval (CI)) = 0.21 (0.03 to 0.38)) and waist-to-hip ratio with plaque (odds ratio (OR) (95% CI) = 1.83 (1.03 to 3.25) for one standard deviation (SD) increase). These relationships were independent of multiple non-metabolic risk factors and explained by metabolic risk factors. In African black women with RA, none of the obesity measures was related to atherosclerosis. CONCLUSIONS: Obesity in women with RA from developing groups of black African descent does not as yet translate into atheroma. In Caucasian women with RA that belong to developed populations, BMI and waist-to-hip ratio should be considered in ACVD risk assessment.
21926153 Retreatment with rituximab based on a treatment-to-target approach provides better disease 2011 Dec OBJECTIVE: To assess the efficacy and safety profiles of two different rituximab retreatment regimens in patients with RA. METHODS: Four hundred and ninety-three RA patients with an inadequate response to MTX recruited into rituximab Phase II/III studies received further courses of open-label rituximab based on two approaches: (i) treatment to target (TT): patients assessed 24 weeks after each course and retreated if not in remission [DAS in 28 joints based on ESR (DAS-28-ESR) ≥ 2.6]; (ii) treatment as needed (PRN): patients retreated at the physician's discretion ≥24 weeks following the first course and ≥16 weeks following further courses, if both swollen and tender joint counts were ≥8. All courses consisted of i.v. rituximab 2 × 1000 mg 2 weeks apart plus MTX. Observed data were analysed according to treatment strategy. RESULTS: Multiple courses of rituximab maintained or improved responses irrespective of regimen. TT provided tighter control of disease activity with significantly greater improvements in DAS-28-ESR and lower HAQ-disability index scores vs PRN. TT resulted in significantly more patients achieving major clinical response. PRN resulted in recurrence of disease symptoms between courses, with TT significantly reducing the incidence of RA flares. Despite more frequent retreatment with TT compared with PRN, the rates of serious adverse events and serious infections were comparable between regimens. CONCLUSIONS: Retreatment with rituximab based on 24-week evaluations and to a target of DAS-28-ESR remission leads to improved efficacy and tighter control of disease activity compared with PRN without a compromised safety profile. TT may be the preferable rituximab treatment regimen for patients with RA.
21285165 Evaluation of an inter-professional educational intervention to improve the use of arthrit 2011 May OBJECTIVE: To describe the evaluation of a community-based continuing health education program designed to improve the management of rheumatoid arthritis (RA) and osteoarthritis (OA), and to examine the results by discipline. METHODS: The Getting a Grip on Arthritis(©) program was based on clinical practice guidelines adapted for the primary care environment (best practices). The program consisted of an accredited inter-professional workshop and 6 months of activities to reinforce the learning. Analyses compared best practice scores derived from responses to 3 standardized case scenarios (early and late RA; moderate knee OA) at baseline and 6 months post-workshop using the ACREU Primary Care Survey. RESULTS: In total, 553 primary care providers (nurses/licensed practical nurses 30.9%, rehabilitation professionals 22.5%, physicians 22.5%, nurse practitioners 10.9%, other healthcare providers/non-clinical staff/students 13.1%) attended one of 27 workshops across Canada; 275 (49.7%) completed followup surveys. Best practice scores varied by discipline at baseline (p < 0.05) and improved for all 3 case scenarios, with nurse practitioners and rehabilitation therapists improving the most (p ≤ 0.05). CONCLUSION: Results suggest that inter-professional education may be an effective method for dissemination of guidelines and has potential to improve the delivery of arthritis care, particularly when nurse practitioners and rehabilitation therapists are involved in the care of patients.
23218430 The issue of comparators in economic evaluations of biologic response modifiers in rheumat 2012 Oct INTRODUCTION: Over the last decade, a number of biologic response modifiers (BRMs) have emerged and transformed rheumatoid arthritis (RA) management. Due to their relatively high costs, economic evaluations have attempted to determine their place in the RA treatment armamentarium. This article reviews three key areas where changes to the treatment paradigm challenges findings of existing economic evaluations. METHODS: We performed a literature search of economic evaluations examining BRMs approved for use in North America for RA. Only economic evaluations that examined relevant direct costs and health outcomes were included. Data were extracted and summarised, then stratified by patient population and comparators. Reported incremental cost-effectiveness ratios (ICERs) were compared across studies. RESULTS: It appears that tumour necrosis factor (TNF) alpha inhibitors are less cost effective compared to disease-modifying anti-rheumatic drugs (DMARDs) for first-line treatment. In addition, it appears that treatment with a TNF alpha inhibitor in patients who were refractory to previous DMARD therapies is more cost effective, compared to switching to another DMARD. Finally, after an inadequate response to a TNF alpha inhibitor, it appears that therapy with rituximab is more cost effective than treatment with another TNF alpha inhibitor or abatacept. DISCUSSION: It is important to acknowledge that cost effectiveness depends on which comparators are included in the analyses and the evidence for the comparators. The most typical comparator in the studies was traditional DMARDs, mainly methotrexate. However, as more BRMs come into the market and new clinical evidences emerge on the comparative effectiveness of BRMs, new economic evaluations will need to incorporate this information such that reimbursement decisions can be fully informed regarding relative value.
21820934 Associations of vitamin D receptor gene polymorphisms FokI and BsmI with susceptibility to 2012 Mar OBJECTIVES: Reports of immunomodulating effects of vitamin D suggest a need for examining allele and genotype frequencies of the vitamin D nuclear receptor gene (VDR) in patients with autoimmune diseases. T-helper-1 (Th1) counts in peripheral blood are increased in both rheumatoid arthritis (RA) and Behçet's disease (BD). We studied VDR polymorphisms in patients with these two diseases in Tunisia. METHODS: In 108 patients with RA, 131 patients with BD, and 152 controls, we studied FokI and BsmI VDR polymorphisms, using the restriction fragment length polymorphism technique. RESULTS: The FokI polymorphism alleles and genotype were significantly more common in the RA group than in the controls (P=0.001 and P=0.005, respectively). The FokI F allele and F/F genotype were significantly associated with BD (P=0.0003 and P=0.002, respectively). Furthermore, in the group with BD, the FokI polymorphism was significantly associated with the presence of vascular manifestations (P=0.006). In patients with RA, the FokI polymorphism was significantly associated with female gender (P=0.003). No significant associations were found between the Bsm1 polymorphism and RA or BD. CONCLUSION: The VDR F allele is associated with RA and BD in Tunisians.
23092868 Mixed treatment comparison of the treatment discontinuations of biologic disease-modifying 2012 Nov BACKGROUND: Introduction of biologic disease-modifying antirheumatic drugs (DMARDs) has considerably changed treatment options for rheumatoid arthritis (RA) over the past decade. Very little information is available on comparative discontinuation rates of the biologics. OBJECTIVE: To compare treatment discontinuations for 9 biologic DMARDs in adults with RA. METHODS: We searched electronic databases through May 2012 to retrieve randomized controlled trials (RCTs) of patients with RA that compared biologic DMARDs with placebo or another biologic DMARD. The primary outcome was treatment discontinuation during the blinded phase of the trials, measured as overall withdrawals, withdrawals resulting from lack of efficacy, and withdrawals resulting from adverse events. Random-effects meta-analysis estimated the effect size for individual agents, and adjusted indirect comparisons were made between biologics using mixed treatment comparisons (MTC) meta-analysis. RESULTS: Forty-four trials were included in the analysis. In comparison with placebo, biologics were less likely to be withdrawn because of lack of efficacy (OR 0.22, 95% CI 0.17 to 0.27) and more likely to be withdrawn because of an adverse event (OR 1.41, 95% CI 1.16 to 1.70). Based on the MTC, certolizumab had the most favorable overall withdrawal profile, followed by etanercept and rituximab. Certolizumab had lower relative withdrawal rates resulting from lack of efficacy than adalimumab, anakinra, and infliximab. Anakinra had higher relative withdrawal rates resulting from lack of efficacy than most other biologics. Certolizumab and infliximab had more, while etanercept had fewer, withdrawals because of adverse events than most other drugs. CONCLUSIONS: Based on MTC using data from RCTs, differences in discontinuation rates were observed, generally favoring certolizumab, etanercept, and rituximab over other biologic DMARDs. These potential differences need to be further explored in head-to-head trials or well-conducted observational studies.