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ID PMID Title PublicationDate abstract
22350576 Recent trends in use of nonbiologic DMARDs and evaluation of their continuation rates in s 2012 Nov OBJECTIVE: We aim to examine changes in usage of nonbiologic, disease-modifying antirheumatic drugs (DMARDs) and evaluate their continuation rates in Japan. METHODS: We analyzed DMARD treatment data for 3,734 patients with rheumatoid arthritis (RA) from 1998 to 2009 at Juntendo Hospital in Tokyo, Japan. The DMARD usage rate per month was determined to evaluate RA treatment history in the last decade. We also evaluated continuation rates of nonbiologic DMARDs in single and combination therapies and number of nonbiologic DMARD combination therapies used in each patient. RESULTS: We found that nonbiologic DMARD usage has dramatically changed in the last decade, with the most commonly used DMARD shifting from bucillamine to methotrexate (MTX). MTX showed the highest continuation rate; however, much lower continuation rate was observed when used alone rather than in combination treatments. Further, MTX was also used in the highest number of different combination therapies for a particular patient. CONCLUSIONS: These findings indicate that single MTX treatment may be unable to keep patients in clinical remission or lower disease activity compared with several combination therapies. Recent change in permitted maximum dosage of MTX from 8 to 16 mg/week may improve its efficacy and continuation rate in treating Japanese RA patients.
21530170 Rasch analysis informed modifications to the Work Instability Scale for Rheumatoid Arthrit 2011 Nov OBJECTIVE: The Work Instability Scale for Rheumatoid Arthritis (RA-WIS) is a promising prognostic tool for future work disability outcomes. Rasch analysis was conducted to examine the psychometric performance of the RA-WIS in work-related upper limb disorders. STUDY DESIGN AND SETTING: Eligible injured workers (n=396) attending a Shoulder and Elbow Specialty clinic participated in a 1-year study with surveys fielded at four time points. Fit of RA-WIS data (range, 0-23 with 23=highest work instability) to the Guttman structure was evaluated by item-fit, person-fit, item-trait interaction statistics, and the person separation index (PSI). Differential item functioning (DIF) was evaluated by two-way analyses of variance of the residuals across age, sex, location of injury, perceived exertion at work, and repeated testing over time. Unidimensionality was evaluated by principal component analysis of residuals and tests of local independence. RESULTS: RA-WIS data showed significant deviations from the Guttman structure (item-trait interaction χ(2)=181.6, P<0.0001, PSI=0.86). A sequential removal of the six most misfitting items was performed, resulting in a 17-item scale that met all Rasch model expectations (χ(2)=57.5, P=0.007, PSI=0.83), including unidimensionality, local independence of items, and the absence of DIF across all tested factors. CONCLUSION: A new 17-item Upper Limb Work Instability Scale that satisfied assumptions for interval-level scaling was derived.
22427951 PTPN22.6, a dominant negative isoform of PTPN22 and potential biomarker of rheumatoid arth 2012 PTPN22 is a tyrosine phosphatase and functions as a damper of TCR signals. A C-to-T single nucleotide polymorphism (SNP) located at position 1858 of human PTPN22 cDNA and converting an arginine (R620) to tryptophan (W620) confers the highest risk of rheumatoid arthritis among non-HLA genetic variations that are known to be associated with this disease. The effect of the R-to-W conversion on the phosphatase activity of PTPN22 protein and the impact of the minor T allele of the C1858T SNP on the activation of T cells has remained controversial. In addition, how the overall activity of PTPN22 is regulated and how the R-to-W conversion contributes to rheumatoid arthritis is still poorly understood. Here we report the identification of an alternative splice form of human PTPN22, namely PTPN22.6. It lacks the nearly entire phosphatase domain and can function as a dominant negative isoform of the full length PTPN22. Although conversion of R620 to W620 in the context of PTPN22.1 attenuated T cell activation, expression of the tryptophan variant of PTPN22.6 reciprocally led to hyperactivation of human T cells. More importantly, the level of PTPN22.6 in peripheral blood correlates with disease activity of rheumatoid arthritis. Our data depict a model that can reconcile the conflicting observations on the functional impact of the C1858T SNP and also suggest that PTPN22.6 is a novel biomarker of rheumatoid arthritis.
21645693 Selective chemiluminescence method for monitoring of vitamin K homologues in rheumatoid ar 2011 Jul 15 Vitamin K is a fat-soluble vitamin involved in blood coagulation and bone metabolism. The detection and monitoring of vitamin K homologues in rheumatoid arthritis (RA) patients is a challenging problem due to the smaller concentrations of vitamin K and the presence of several interfering medications. Therefore, this study aimed to develop a new highly sensitive and selective chemiluminescence (CL) method designated to quantify vitamin K homologues in plasma of RA patients including phylloquinone (PK, vitamin K(1)), menaquinone-4 (MK-4, vitamin K(2)) and menaquinone-7 (MK-7, vitamin K(2)). The method was based on the unique photochemical properties of vitamin K homologues that were exploited for selective luminol CL reaction. The correlation coefficients of 0.998 or more were obtained in the concentration ranges of 0.1-100 ng mL(-1) vitamin K homologues. The detection limits were 0.03-0.1 ng mL(-1) in human plasma for vitamin K homologues. The developed HPLC-CL system was successfully applied for selective determination of vitamin K homologues in plasma of RA patients. The developed method may provide a useful tool for monitoring vitamin K homologues in different clinical studies such as RA, osteoporosis and hepatocellular carcinoma in which vitamin K is intervented.
23083052 Pulmonary hypertension associated with rheumatic diseases: baseline characteristics from t 2012 Oct OBJECTIVES: The REgistry of Pulmonary Hypertension Associated with Rheumatic Disease (REOPARD) was established in Korea. The baseline data are described from the second year of the registry's operation. METHODS: Patients with a connective tissue disease (CTD) who met the modified definition of the WHO group I pulmonary arterial hypertension (PAH) were enrolled. PAH was defined as a systolic pulmonary arterial pressure> 40 mmHg by echocardiography or mean pulmonary arterial pressure> 25 mmHg by right heart catheterization. Hemodynamic parameters and clinical data such as demographics, functional class, underlying disease, organ involvement, laboratory tests and current treatment were recorded. RESULTS: A total of 321 patients were enrolled during the 2-year study period from 2008 to 2010. The mean age of the patients at registration was 51.9 years and 87.5% were female. Most patients were diagnosed by echocardiography and only 24 patients (7.5%) underwent cardiac catheterization. Exertional dyspnea was present in 63.6% of patients and 31.8% were New York Heart Association class III or IV. Among the patients, systemic lupus erythematosus accounted for 35.3%, systemic sclerosis 28.3%, rheumatoid arthritis 7.8%, overlap syndrome 9.0%, and mixed connective tissue disease 5.9%. There were no significant differences in hemodynamics, functional class, diffusing capacity and N-terminal pro-brain natriuretic peptide levels between the disease subgroups. Treatments consisted of calcium antagonists (57.0%), endothelin antagonists (32.7%), prostanoids (27.1%), phosphodiesterase-5 inhibitors (14.3%) and combinations (37.4%). CONCLUSION: Compared with previous studies, the results showed some differences: underlying diseases, functional status and treatments. This may be due to differences in ethnic background and diagnostic methods of our study.
21572154 Does anti-tumor necrosis factor-α therapy affect risk of serious infection and cancer in 2011 Aug Given the important role tumor necrosis factor-α (TNF-α) antagonists play in managing rheumatoid arthritis and the concern for safety during longterm therapy, we reviewed the latest evidence regarding longterm risk of infection and malignancy with TNF-α antagonists. Our objective was to provide clinicians with information that can be used to counsel and monitor patients who may be candidates for biologic therapy for rheumatoid arthritis (RA). Risk is examined in the context of background infection and malignancy rates in RA. Randomized controlled trial (RCT) data and observational studies summarizing the risk of infection and/or malignancy in RA and specific risks associated with the use of anti-TNF-α biologic agents (adalimumab, infliximab, and etanercept) were identified through a PubMed search. Overall, patients with RA appear to have an approximately 2-fold increased risk of serious infection compared to the general population and non-RA controls, irrespective of TNF-α antagonist use. Although data on infection rates with TNF-α antagonist use are contradictory, caution is merited. Recent analyses suggest that the risk of infection is highest within the first year. Regarding malignancy risk, RCT and observational data are also conflicting; how ever, caution is warranted regarding lymphoproliferative cancers in children and adolescents.
21427177 Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheu 2011 Aug OBJECTIVE: To analyse the clinical relevance of the production of anti-infliximab antibodies (anti-infliximab Abs) in patients with RA undergoing infliximab treatment over a prolonged period of time. METHODS: Clinical characteristics, serum trough infliximab and antibody levels were evaluated in 85 RA patients treated with infliximab for a median of 4.42 (interval 0.4-10.2) years. DAS in 28 joints (DAS-28), EULAR response criteria and survival of treatment were assessed at 3 time points (6 months, 12 months and >4 years). RESULTS: Antibodies against infliximab were detected in 28 (32.9%) patients and were present in all EULAR non-responder patients. Antibody levels were higher in EULAR non-responders throughout the study period (P = 0.05 at 6 months, P = 0.02 at 1 year, P = 0.003 at >4 years) compared with EULAR (good and moderate) responders. Nine (10.5%) patients, all of them with high-serum anti-infliximab Ab levels, developed infusion-related reactions. Patients with anti-infliximab Abs more often required increased infliximab doses (51.7%) (P = 0.032) and median survival time on treatment was shorter (4.15 vs 8.89 years) (P = 0.0006). MTX co-therapy was not associated with lower proportion of anti-infliximab Ab-positive patients, but those receiving both infliximab and MTX had lower levels of anti-infliximab Abs (P = 0.073) and longer survival (P = 0.015) on treatment. CONCLUSION: The formation of anti-infliximab Abs during treatment with infliximab is associated with a loss of clinical response, the appearance of infusion reactions and discontinuation of treatment.
23073787 Associations between interferon regulatory factor 5 polymorphisms and rheumatoid arthritis 2013 Feb The aim of this study was to determine whether interferon regulatory factor 5 (IRF5) polymorphisms confers susceptibility to rheumatoid arthritis (RA) in populations with different ethnicities. We searched the literature using the Pubmed and Embase databases and conducted meta-analyses on associations between the four IRF5 polymorphisms (rs2004640, rs729302, rs752637, and rs2280714) and RA susceptibility, using fixed and random effects models. A total of 12 comparison studies were considered in this meta-analysis, which in total involved 7,916 RA patients and 6,452 controls, and eight European, three Asian, and one Argentinean population. Meta-analysis showed an association between the minor allele of rs2004640 and RA in all subjects (odds ratio [OR] = 0.928, 95 % confidence interval [CI] = 0.865-0.996, P = 0.037). After stratification by ethnicity, analysis indicated that the minor allele was significantly associated with RA in Europeans (OR = 0.889, 95 % CI = 0.839-0.941, P = 5.03 × 10(-6)), but not in Asians (OR = 1.057, 95 % CI = 0.978-1.144, P = 0.164). A direct comparison between anti-citrullinated peptide antibody-positive and -negative patients revealed no difference of the frequency of the rs2004640 minor allele (OR = 1.047, 95 % CI = 0.813-1.348, P = 0.724). Meta-analysis identified a significant association between RA and the minor allele of the rs729302 polymorphism in the overall population (OR = 0.896, 95 % CI = 0.826-0.972, P = 0.009) and in Asians (OR = 0.862, 95 % CI = 0.795-0.935, P = 3.50 × 10(-5)), but not in Europeans (OR = 0.951, 95 % CI = 0.877-1.031, P = 0.225). Meta-analysis showed an association between the minor allele of rs752637 and RA in Europeans (OR = 0.858, 95 % CI = 0.789-0.932, P = 3.03 × 10(-5)), but not in Asians (OR = 1.035, 95 % CI = 0.918-1.168, P = 0.572). No association was found between the rs2280714 polymorphism and RA susceptibility. This meta-analysis confirms that the IRF5 rs2004640, rs729302 and rs752637 polymorphisms are associated with RA susceptibility in different ethnic groups, especially in Europeans and Asians, but further study of this association is required in other ethnic groups.
22948700 Risk of malignancies in patients with rheumatoid arthritis treated with biologic therapy: 2012 Sep 5 CONTEXT: Concerns exist regarding the potential development of malignancies in patients with rheumatoid arthritis (RA) who are receiving biologic response modifiers (BRMs). OBJECTIVE: To assess the risk of malignancy in patients with RA enrolled in randomized controlled trials (RCTs) of BRMs. DATA SOURCES: Electronic databases, conference proceedings, and websites of regulatory agencies were searched for RCTs evaluating abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab in RA from inception through July 9, 2012. STUDY SELECTION: Independent selection of studies included RCTs that compared the safety of any BRMs used in RA patients with placebo and/or any traditional disease-modifying antirheumatic drugs with a minimum of 24 weeks of follow-up. DATA EXTRACTION: Independent reviewers selected studies and extracted data on quality and outcomes. Pooled estimates and 95% confidence intervals were calculated for each BRM. RESULTS: Sixty-three RCTs with 29,423 patients were analyzed. No statistically significant increased risk of developing malignancy was observed. Of the 29,423 patients, 211 developed a malignancy during the trial (118 solid tumors, 48 skin cancers, 14 lymphomas, 5 hematologic nonlymphomas, and 26 not specified). The incidence rate for any malignancy during the first year of therapy was very low in the BRM plus methotrexate group (0.77%; 95% CI, 0.65%-0.92%), the BRM monotherapy group (0.64%; 95% CI, 0.42%-0.95%), and the controls (0.66%; 95% CI, 0.52%-0.84%). Anakinra plus methotrexate showed lower odds compared with methotrexate alone (Peto odds ratio, 0.11; 95% CI, 0.03-0.45). No statistically significant risk was observed for specific cancer sites, although the Peto odds ratio for lymphoma was 2.1 (95% CI, 0.55-8.4) in patients receiving tumor necrosis factor inhibitors compared with controls. CONCLUSION: The use of BRMs among patients with RA included in RCTs of at least 6 months' duration was not significantly associated with an increased risk of malignancy compared with other disease-modifying antirheumatic drugs or with placebo.
22864384 Simultaneous targeting of TNF and Ang2 with a novel bispecific antibody enhances efficacy 2012 Sep Despite the clinical success of anti-tumor necrosis factor (TNF) therapies in the treatment of inflammatory conditions such as rheumatoid arthritis, Crohn disease and psoriasis, full control of the diseases only occurs in a subset of patients and there is a need for new therapeutics with improved efficacy against broader patient populations. One possible approach is to combine biological therapeutics, but both the cost of the therapeutics and the potential for additional toxicities needs to be considered. In addition to the various mediators of immune and inflammatory pathways, angiogenesis is reported to contribute substantially to the overall pathogenesis of inflammatory diseases. The combination of an anti-angiogenic agent with anti-TNF into one molecule could be more efficacious without the risk of severe immunosuppression. To evaluate this approach with our Zybody technology, we generated bispecific antibodies that contain an Ang2 targeting peptide genetically fused to the anti-TNF antibody adalimumab (Humira®). The bispecific molecules retain the binding and functional characteristics of the anti-TNF antibody, but with additional activity that neutralizes Ang2. In a TNF transgenic mouse model of arthritis, the bispecific anti-TNF-Ang2 molecules showed a dose-dependent reduction in both clinical symptoms and histological scores that were significantly better than that achieved by adalimumab alone.
22791271 Risk factors of severe infections in patients with rheumatoid arthritis treated with leflu 2013 Jul OBJECTIVES: To determine the risk of severe infection requiring or complicating hospitalization associated with leflunomide therapy in patients with rheumatoid arthritis (RA). METHODS: We performed a retrospective study of RA patients who were prescribed leflunomide between 2004 and 2011. Background clinical and laboratory features were compared between patients who suffered severe leflunomide-associated infections and those who did not. RESULTS: Since January 2005, 401 RA patients have started on leflunomide. Among those, 33 (8.2%) developed severe infections: pneumonia, oral candidiasis, pyelonephritis, pulmonary tuberculosis, cellulitis, disseminated herpes zoster, tonsillitis, and pulmonary cryptococcosis. Logistic regression showed that age at entry, the presence of DM, and daily dosage of corticosteroid were associated with development of severe infections. CONCLUSIONS: These results showed that some patients with RA who were taking leflunomide developed severe infections requiring hospitalization, and that older age, DM, and a higher daily dosage of corticosteroid were risk factors associated with leflunomide-associated severe infections.
22357358 Novel small-molecular therapeutics for rheumatoid arthritis. 2012 May PURPOSE OF REVIEW: Since the introduction of biologic therapies into the treatment paradigm of rheumatoid arthritis (RA), there has been hope that oral small molecule immune modulators would be developed that would have a risk : benefit profile at least similar to biologic therapies, be more convenient for the patient and, hopefully, be less expensive. This article reviews the progress made in the development of these compounds over the past year. RECENT FINDINGS: Additional information has become available in the past year on five oral compounds including kinase inhibitors (tofacitinib, fostamatinib, VX-509), an S1P lyase inhibitor (LX 3305) and a chemokine receptor-1 antagonist (CCX354-C). Efficacy has been shown in phase III with tofacitinib and in phase II with fostamatinib and VX-509; safety was the primary endpoint of the trials of CCX354-C and LX3305. Regarding side effects, liver test elevation and neutropenia occurred with tofacitinib, VX-509 and fostamatinib; lipid elevation with tofacitinib and VX-509; creatinine elevation and anemia with tofacitinib, and hypertension and diarrhea with fostamatinib. SUMMARY: Compounds that inhibit tyrosine kinase pathways involved in cellular signalling have been shown to be effective in the treatment of RA with a reasonable risk : benefit ratio. It is too early to tell about inhibitors of other pathways.
21985166 Rheumatoid arthritis and pregnancy: safety considerations in pharmacological management. 2011 Oct 22 Pregnancy can pose a challenge to the physician caring for women with rheumatoid arthritis (RA). While many women with RA experience a spontaneous improvement in joint pain and inflammation during pregnancy, in others it remains active and they continue to need ongoing therapy. It is important to tailor the treatment regimen so that the disease is stabilized prior to conception and to use medications that are safe throughout pregnancy and lactation. The use of immunomodulating medications considered low risk during pregnancy allows for optimal outcomes. NSAIDs should be avoided in the third trimester. Corticosteroids may be used throughout pregnancy in the lowest effective dose. Antimalarial agents, sulfasalazine and azathioprine are safe options, but methotrexate and leflunomide are contraindicated as they are teratogenic and must, therefore, be withdrawn before a planned pregnancy. The risk for some of the newer biological therapies for RA is not necessarily their proven teratogenicity, but the absence of proven safety for the fetus. As such, it is recommended that abatacept, rituximab and tocilizumab be withheld prior to pregnancy; however, tumour necrosis factor inhibitors and anakinra may be continued until conception. In this review, we provide an overview of the RA treatment issues pre-conception, during pregnancy and in the post-partum period with respect to breastfeeding, and we provide guidelines for drugs that may be used relatively safely for RA management in pregnant women. Where available, pre-conception guidelines for men using these medications for RA are also discussed.
21778735 A non-parametric method for building predictive genetic tests on high-dimensional data. 2011 OBJECTIVE: Predictive tests that capitalize on emerging genetic findings hold great promise for enhanced personalized healthcare. With the emergence of a large amount of data from genome-wide association studies (GWAS), interest has shifted towards high-dimensional risk prediction. METHODS: To form predictive genetic tests on high-dimensional data, we propose a non-parametric method, called the 'forward ROC method'. The method adopts a computationally efficient algorithm to search for environment risk factors, genetic predictors on the entire genome, and their possible interactions for an optimal risk prediction model, without relying on prior knowledge of known risk factors. An efficient yet powerful procedure is also incorporated into the method to handle missing data. RESULTS: Through simulations and real data applications, we found our proposed method outperformed the existing approaches. We applied the new method to the Wellcome Trust rheumatoid arthritis GWAS dataset with a total of 460,547 markers. The results from the risk prediction analysis suggested important roles of HLA-DRB1 and PTPN22 in predicting rheumatoid arthritis. CONCLUSION: We proposed a powerful and robust approach for high-dimensional risk prediction. The new method will facilitate future risk prediction that considers a large number of predictors and their interaction for improved performance.
23194301 Targeted chemo-photothermal treatments of rheumatoid arthritis using gold half-shell multi 2013 Jan 22 We have developed RGD-attached gold (Au) half-shell nanoparticles containing methotrexate (MTX) for the treatment of rheumatoid arthritis (RA), where MTX is the most widely used disease-modifying anti-rheumatic drug (DMARD) for the treatment of RA, and RGD peptide is a targeting moiety for inflammation. Upon near-infrared (NIR) irradiation, heat is locally generated due to Au half-shells, and the drug release rate is enhanced, delivering heat and drug to the inflamed joints simultaneously. RA is a chronic inflammatory disease characterized by synovial inflammation in multiple joints within the penetration depth of NIR light. When combined with NIR irradiation, these nanoparticles containing a much smaller dosage of MTX (1/930 of MTX solution) showed greater therapeutic effects than that of a conventional treatment with MTX solution in collagen-induced arthritic mice. This novel drug delivery system is a good way to maximize therapeutic efficacy and minimize dosage-related MTX side effects in the treatment of RA. Furthermore, these multifunctional nanoparticles could be applied to other DMARDs for RA or other inflammatory diseases.
21417950 Hydroxychloroquine in systemic lupus erythematosus and rheumatoid arthritis and its safety 2011 Sep INTRODUCTION: The antimalarial drug hydroxychloroquine (HCQ) is widely used to treat various rheumatic diseases. Many autoimmune diseases occur in women of child-bearing age who may become pregnant while on therapy, which raises concerns regarding the teratogenicity of HCQ and its effect on the outcome of the pregnancy. There is a lack of data regarding the safety of HCQ during pregnancy. AREAS COVERED: In this review, the authors attempt to identify relevant publications by searching MEDLINE, Cochrane database, Ovid-Currents Clinical Medicine, Ovid-Embase:Drugs and Pharmacology, EBSCO, Web of Science and SCOPUS using the search terms HCQ and/or pregnancy. A basis for the mechanism of action of HCQ is provided. EXPERT OPINION: HCQ has been shown by numerous studies over the past 15 years to be efficacious in the treatment of autoimmune diseases, including systemic lupus erythematosus, discoid lupus erythematosus and rheumatoid arthritis. HCQ does not appear to be associated with any increased risk of congenital defects, spontaneous abortions, fetal death, prematurity or decreased numbers of live births in patients with autoimmune diseases. Therefore, in the author's opinion, HCQ is safe for the treatment of autoimmune diseases during pregnancy.
21121872 Clinical safety of tocilizumab in rheumatoid arthritis. 2011 Jan IMPORTANCE OF THE FIELD: Tocilizumab is a new biologic disease-modifying antirheumatic drug directed against the activity of IL-6, a key pro-inflammatory cytokine in the pathogenesis of rheumatoid arthritis (RA). This drug has proved highly effective in RA patients, including those who had previously not responded to anti-TNFs. As side effects are a major cause for discontinuing biologic therapy, the present article focuses on the tolerability profile of tocilizumab. AREAS COVERED IN THIS REVIEW: This review describes the adverse events (AEs) reported in RA patients treated with tocilizumab. Most data are derived from controlled clinical trials and their open-label extensions. WHAT THE READER WILL GAIN: The reader will gain a comprehensive review of treatment-emergent AEs associated with tocilizumab therapy. These AEs include infections, including opportunistic infections, infusion and hyper-sensitivity reactions, gastrointestinal perforation, and laboratory test abnormalities, especially hepatic transaminase elevations, altered lipid profile and neutropenia. TAKE HOME MESSAGE: Based on current data, tocilizumab appears to have an acceptable safety profile inasmuch as most AEs were manageable or controllable. However, results from large scale pharmacoepidemiological investigations and appropriate post-marketing surveillance are awaited to identify the full spectrum of AEs and define the true benefit:risk ratio of tocilizumab.
21905006 Protease-activated receptor 2, rather than protease-activated receptor 1, contributes to t 2012 Jan OBJECTIVE: To investigate whether protease-activated receptor 1 (PAR-1) and/or PAR-2 promotes the invasiveness/proliferation of synovial fibroblasts (SFs) and to determine the signaling mechanisms of these pathways. METHODS: SFs were isolated from the synovial tissue of patients with rheumatoid arthritis (RA), patients with osteoarthritis (OA), and PAR-1- or PAR-2-knockout (KO) mice. Expression of PAR-1 and PAR-2 was detected by immunofluorescence and Western blotting. The invasion and proliferation of SFs were measured by invasion assay and MTT assay, respectively. Matrix metalloproteinase 2 (MMP-2) and MMP-9 were detected by zymography, and cytokines were measured by enzyme-linked immunosorbent assay. RESULTS: PAR-1 and PAR-2 were colocalized with SFs in RA and OA synovium and, to a considerably lesser extent, in normal synovium. Inhibition of PAR-2 by small interfering RNA (siRNA) inhibited RASF invasion and proliferation, whereas blocking of PAR-1 by siRNA had the reverse effects. SFs from PAR-2-KO mice exhibited slower rates of proliferation and invasion. SFs from PAR-1-KO mice produced less MMP-2 and, in response to tumor necrosis factor α (TNFα) stimulation, had increased MMP-9 secretion when compared to SFs from wild-type and PAR-2-KO mice. Inhibition of PAR-1, but not PAR-2, stimulated the secretion of interleukin-17 (IL-17) and TNFα by RASFs. Furthermore, PAR-1 and PAR-2 had opposing effects on the activation of ERK, p38, and NF-κB. CONCLUSION: Activation of PAR-1 stimulates MMP-2 secretion, inhibits RASF growth and invasion, and decreases production of IL-17 and TNFα by RASFs, whereas activation of PAR-2 stimulates RASF growth and invasion and increases production of TNFα. Thus, although PAR-1 and PAR-2 are coexpressed by RASFs, PAR-2 alone appears to be responsible for the aggressive properties of RASFs and is likely to contribute to the pathologic progression of RA.
22262513 Comparative responsiveness of the EuroQol-5D and Short Form 6D to improvement in patients 2012 Jun OBJECTIVE: For cost-utility analyses of health technologies, utilities are commonly measured with the EuroQol-5D (EQ-5D) or the Short Form 6D (SF-6D). Although most studies in rheumatoid arthritis (RA) found the SF-6D to be more responsive than the EQ-5D, evidence is not convincing. The aim of this study was to compare the responsiveness of the EQ-5D and SF-6D to improvement in RA patients treated with tumor necrosis factor (TNF) blockers. METHODS: Data from 278 RA patients included in the Dutch Rheumatoid Arthritis Monitoring registry were used. Internal responsiveness over 1 year was evaluated by using standardized response means (SRMs). External responsiveness was evaluated by using receiver operating characteristic curves based on perceived health change (self-reported health transition item Short Form 36) and change in disease activity (European League Against Rheumatism response criteria based on the Disease Activity Score in 28 joints). RESULTS: The scores of the EQ-5D and SF-6D changed moderately over 1 year (SRMs 0.50 and 0.67, respectively). The SF-6D was significantly more responsive to treatment than the EQ-5D. The EQ-5D and SF-6D were moderately able to correctly classify patients according to health transition (areas under the curve [AUCs] 0.67 and 0.72, respectively) and change in disease activity (AUCs 0.71 and 0.65, respectively). CONCLUSION: The EQ-5D and SF-6D were only moderately responsive to improvement in RA patients treated with TNF blockers. Overall, the SF-6D was more responsive than the EQ-5D.
21767687 An evaluation of a biopsychosocial framework for health-related quality of life and disabi 2011 Aug OBJECTIVE: To examine the relationships between physical, psychological, and social factors and health-related quality of life (HRQOL) and disability in rheumatoid arthritis (RA). METHODS: A sample of 106 patients with rheumatoid arthritis (RA) completed measures of self-reported disease activity and psychosocial functioning, including coping, personal mastery, social network, perceived stress, illness beliefs, the SF-36 and Health Assessment Questionnaire Disability Index (HAQ-DI). In addition, physician-based assessment of disease activity using the Disease Activity Scale (DAS-28) was obtained. Hierarchical multiple regression analyses were used to evaluate the relationships between psychosocial factors and scores on the SF-36 and HAQ-DI. RESULTS: Lower self-reported disease activity was associated with higher SF-36 physical functioning scores, while the contribution of active coping, passive coping, and helplessness was significant only as a block. Lower self-reported disease activity, higher personal mastery, and lower perceived stress contributed to higher SF-36 mental health functioning, and higher self-reported disease activity and lower helplessness were associated with greater disability, as indexed by the HAQ-DI. The DAS-28, an objective of measure of disease activity, was unrelated to any of these outcomes. CONCLUSIONS: The findings highlight the importance of targeting psychological factors to enhance HRQOL and disability in the clinical management of RA patients.