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ID PMID Title PublicationDate abstract
22113111 Developing potent backbone cyclic peptides bearing the shared epitope sequence as rheumato 2012 Jan 1 Rheumatoid arthritis (RA) is a common human leukocyte antigen-associated disease. Most RA patients have a five-residue sequence motif called the shared epitope (SE) in the DRβ-chain of the HLA-DRB1 protein. The SE was found to activate nitric oxide (NO) production, suggesting a possible mechanism for RA development. The native conformation of the SE is presumed to be an α-helix, thus using cyclic peptides to stabilize this conformation may produce a potent SE mimetic which will have drug-like properties. We present the development of a backbone cyclic SE mimetic that activates NO production in the low nM range. Circular dichroism analysis revealed a conformational change from for the parent linear peptides to the cyclic analogs. The most active cyclic analog is completely stable towards trypsin/chymotrypsin degradation while the linear 15-mer analogs completely degraded within 30 min. The outcome of this study is a potent cyclic peptide with drug-like properties that can be used as a template for drug development.
21415051 Vitamin D receptor regulates TNF-mediated arthritis. 2011 Jun OBJECTIVE: Reduced vitamin D intake has been linked to increased susceptibility to develop rheumatoid arthritis (RA) and vitamin D deficiency is associated with increased disease activity in RA patients. The pathophysiological role of vitamin D in joint inflammation is, however, unclear. METHODS: To determine the influence of absent vitamin D signalling in chronic arthritis, vitamin D receptor (VDR)-deficient mice were crossed with human tumour necrosis factor (TNF) transgenic mice (hTNFtg), which spontaneously develop chronic arthritis. RESULTS: Clinical signs and symptoms of chronic arthritis were aggravated in hTNFtg mice lacking functional VDR signalling. Moreover, synovial inflammation was clearly increased in VDR(-/-)hTNFtg mice as compared to hTNFtg mice and was associated with an increased macrophage influx in inflamed joints. In vitro, VDR-deficient monocytes were proinflammatory and hyper-responsive to TNF stimulation associated with prolonged mitogen-activated protein kinase activation and cytokine secretion. Also, VDR(-/-) monocytes showed enhanced potential to differentiate into bone resorbing osteoclasts in vitro. In line, VDR(-/-)hTNFtg mice had significantly increased cartilage damage and synovial bone erosions. CONCLUSIONS: VDR plays an important role in limiting the inflammatory phenotype in a mouse model of RA. Absent VDR signalling causes a proinflammatory monocyte phenotype associated with increased inflammation, cartilage damage and bone erosion.
21098574 CXCL13: a novel biomarker of B-cell return following rituximab treatment and synovitis in 2011 Mar OBJECTIVES: The B-cell chemokine, CXCL13, is a proposed serum biomarker of synovitis in RA. Its behaviour in the context of B-cell depletion therapy and reconstitution was studied during treatment of RA with rituximab. METHODS: Serum samples from 20 RA patients were analysed for CXCL13, RF-IgM and anti-CCP by ELISA before and 2 and 6 months following rituximab treatment. B cells were monitored by flow cytometry. Gene expression in blood and synovial biopsies was determined by qPCR. RESULTS: Patients with detectable B cells at 6 months had significantly higher levels of CXCL13 and RF-IgM and slightly higher levels of anti-CCP throughout the study, including at baseline, compared with patients with undetectable B cells at 6 months. Conversely, 10 of 12 patients with high baseline CXCL13 had detectable circulating B cells at 6 months, whereas no B cells could be detected at 6 months in patients with low baseline CXCL13. Synovial CXCL13 expression at baseline correlated significantly with serum CXCL13 levels, and the synovium of patients with high serum CXCL13 expressed elevated levels of IL-1β, IL-8, MMP1 and MMP3. In addition, synovial CXCL13 expression correlated significantly with several synovial inflammatory markers. CONCLUSIONS: Serum CXCL13 is predictive of the rate of B-cell repopulation following a course of rituximab in RA. Serum CXCL13 correlates with synovial CXCL13 measured at a single joint, suggesting synovitis as an important source of circulating CXCL13. Within the synovium, CXCL13 expression is highly correlated with markers of synovitis. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00147966.
23059810 Anti-TNF-α therapy improves Treg and suppresses Teff in patients with rheumatoid arthriti 2012 Sep Anti-TNF-α therapies have been applied in RA treatment, but the regulatory effect of the drug on immune system is not clear. In this study, we included 33 active RA patients and divided them into two groups. One group received anti-TNF-α mAb+methotrexate for 24 weeks, the other group got placebo+methotrexate for the first 12 weeks and anti-TNF-α mAb+methotrexate for another 12 weeks. Circulatory regulatory T cell (Treg) and effector T cell (Teff) frequency was analyzed pre-therapy and week 12 and week 24 for both group patients by flowcytometry. Our results indicated significantly elevated Treg and decreased Teff at week 24 compared with pre-therapy and week 12 for both group patients, and a little higher Treg and lower Teff frequency in anti-TNF-α therapy group than in placebo therapy patients. Our results demonstrated anti-TNF-α therapy has regulatory effect on immune system of RA patients by promoting Treg proportion increase and suppressing Teff.
21227681 Increased cancer risks among arthroplasty patients: 30 year follow-up of the Swedish Knee 2011 May BACKGROUND: An increasing number of young patients are undergoing knee arthroplasties. Thus, the long-term risks of having a knee prosthesis must be evaluated. This study focuses on the potential carcinogenic effects of the prosthesis; it is a long-term follow-up of all patients in Sweden between 1975 and 2006. METHODS: The incidence of cancer in a total population of operated individuals was compared to the overall national cancer incidence in Sweden by means of standardised incidence ratios. Analysis of cancer latency period was performed to identify potential aetiological factors. RESULTS: For male and female patients with rheumatoid arthritis (RA) or osteoarthritis (OA), the overall cancer risks were elevated, ranging from 1.10 (95% confidence interval (CI): 1.03-1.18) for men with OA to 1.26 (1.23-1.29) for men with RA. The greatest increases in risk were observed for the leukaemia subtypes, myelodysplastic syndromes (MDS) and essential thrombocytosis (ET), ranging from 3.31 (1.24-8.83) for ET in men with OA to 7.38 (1.85-29.51) for ET in women with RA. Increases in risk were also observed for breast cancer, prostate cancer and melanoma. The latency analysis revealed elevated risks late in the study period for both solid and haematopoietic cancers. However, only increases in MDS and possibly prostate cancer and melanoma rates appeared to be connected to the operation. CONCLUSION: This study showed that OA and RA arthroplasty patients have a significantly higher risk of cancer than the general population. Elevated risks of MDS and possibly prostate cancer and melanoma indicated a potential connection to exposure to metals in the implant. The observed excessive incidence of ET was likely associated with the inflammatory disease.
23118111 Reliability and longitudinal validity of computer-assisted methods for measuring joint dam 2013 Jan OBJECTIVE: To compare the metric properties of a computer-assisted erosion segmentation volume measurement with scoring using the Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS) in a longitudinal cohort of patients with rheumatoid arthritis (RA). METHODS: Thirty-two sets of baseline and 2-year followup magnetic resonance imaging (MRI) of metacarpal phalangeal 2-5 joints of patients with RA were scored using RAMRIS and segmented using OSIRIS software. The smallest detectable difference (SDD), standardized response mean (SRM), and paired t-test were used to evaluate the sensitivity to change. Eleven of the 32 patients' MRI were segmented by both readers to evaluate interreader agreement. The 28-joint Disease Activity Score (DAS28) and Sharp erosion scores further evaluated construct and longitudinal validity. RESULTS: Reliability of erosion progression by computer-assisted volume measurement was superior to RAMRIS [intrareader interclass correlation coefficient (ICC) 0.97 (0.94-0.99) vs 0.52 (0.22-0.73)] and interreader ICC of volume measurement was 0.85 (0.53-0.96). Computer-assisted volume measurements identified 10 of 32 patients who progressed more than the SDD progression, whereas RAMRIS identified only 4 of 32 patients (p = 0.0013). By a paired t-test, however, all MRI measures progressed significantly over 2 years (irrespective of treatment arm) and there was little difference by SRM. Construct correlational validity of the MRI methods was 0.47-0.90 for status scores and 0.33-0.81 for progression. There was no relationship between the average DAS28 and erosion progression by any imaging method. CONCLUSION: Computer-assisted measurement of erosion volume has good performance metrics. It had excellent intrareader and interreader reliability and was more sensitive to change than RAMRIS in this group of patients. www.ClinicalTrials.gov, NCT00451971.
22530354 May etanercept and PTH (1-34) association heal erosions in early rheumatoid arthritis? A p 2012 Mar INTRODUCTION: Rheumatoid arthritis (RA) is characterized by the formation in the joints of an inflammatory tissue, which causes the appearance of localized erosions on the margins of the joints. The molecular mechanism that causes the bone erosion is multifactorial. Inflammatory cytokines imbalance and OPG-RANK-L system are involved. OBJECTIVE OF THE STUDY: The aim of the study is to evaluate the possibility of inducing healing or reduction in the number of erosions in Rheumatoid Arthritis patients treated with anti-TNF-alpha adding Teriparatide (PTH1-34) to standard treatment with anti-TNF. PATIENTS AND METHODS: Twenty adult patients with active RA diagnosed according to American Rheumatism Association (ARA) criteria at least 6 months before study begin were enrolled. Only patients affected by established RA (6 to 18 months from symptoms beginning) were recruited. Eligible patients were randomized to receive a standard dosage of etanercept (50 mg/week) or etanercept at same dosage with an addition of teriparatide (20 mg). Evaluation of eventual healing of arthritic erosions by magnetic resonance imaging was performed at time zero and then at twelve months. The following evaluation was assessed at baseline and after 12 months according to the Outcome Measures in Rheumatology Clinical Trials (OMERACT) definitions: number of erosion and presence or absence of synovitis, effusion and bone oedema. A comparative examination of quantitative and qualitative assessment of each parameter was applied. Plain radiographs of the hands were obtained at baseline and 52 weeks. Radiographs were scored blindly using the van der Heijde modification of the Sharp method. Safety of each treatment was evaluated by means of the adverse events (AES) evaluation and report. RESULTS: There were no significant differences in baseline characteristics between the groups. The study did not achieve its primary endpoint of healing erosions. In the active arm no healing of erosions was found. At 52 weeks, there were no new MRI erosions in two arms. Bone oedema scores were significantly improved at 52 weeks in favour of both treatments versus baseline scores, without inter-groups differences. X-ray patterns were unchanged in all patients of both groups. No new erosions or previous erosions' healing were observed. No AEs were reported. Patients from both groups demonstrated a significant reduction in the DAS 28 scores at 52 weeks (p < 0.005) if compared with baseline values. CONCLUSIONS: These data confirm rapid control of inflammation and MRI damage benefits after Etanercept administration without a significant improvement in MRI findings after concomitant addition of teriparatide. Even though these results could seem to suggest to avoid the simultaneous use of these two drugs to treat RA erosions, further studies might be suggested to asses if sequential adminstration of an anabolic agent such as Teriparatide, after achieving clinical remission, may be able to improve bone damage.
23815014 [Indications and efficacy of biologics in inflammatory arthritis]. 2012 Oct Major advances in our knowledge of the pathogenesis of inflammatory arthritis during the last 20 years, including the identification of precise targets of joint inflammation, led to the development of biologic targeted therapies. TNF inhibitors were the first such agents to be approved in rheumatoid arthritis, followed by ankylosing spondylitis and psoriatic arthritis. Later, rituximab, an anti-CD20 B lymphocyte antibody ; abatacept, which inhibits the T cell co-stimulatory CD28-CD80 pathway ; and tocilizumab, an interleukin-6 receptor inhibitor, were launched in rheumatoid arthritis. These biologics have dramatically changed the management and mid- to long-term outcomes of patients with rheumatoid arthritis and spondyloarthritis. Current therapeutic strategies are based on disease activity and severity. International societies such as EULAR and ASAS have published precise recommendations for routine management of these patients.
21953589 Metabolic effects of high-dose prednisolone treatment in early rheumatoid arthritis: balan 2012 Mar OBJECTIVE: To investigate the dose-related effects of glucocorticoid treatment on glucose tolerance, beta cell function, and insulin sensitivity in patients with early active rheumatoid arthritis (RA). METHODS: A randomized, controlled, single-blind trial was conducted in 41 patients with early active RA. At the beginning of the trial patients had not been treated for their RA, and were randomized to begin treatment with prednisolone at 60 mg/day or 30 mg/day. Before and at the end of 1 week of treatment, a frequently sampled oral glucose tolerance test was performed. The glucose area under the curve (AUC(G) ) was calculated. In addition, beta cell function and insulin sensitivity parameters were computed. RESULTS: Patients (mean ± SD age 55.5 ± 14.8 years and 54.2 ± 12.6 years in the prednisone 60 mg/day and prednisone 30 mg/day groups, respectively; body mass index 24.5 ± 4.1 kg/m(2) and 25.4 ± 4.2 kg/m(2) , respectively) had active disease at baseline (mean ± SD Disease Activity Score in 44 joints 4.1 ± 0.7 and 4.0 ± 0.8, respectively; median C-reactive protein [CRP] level 14 mg/liter [interquartile range 6-34] and 19 mg/liter [interquartile range 3-39], respectively). In addition, 56% of the patients had impaired glucose tolerance at baseline, and 7% were found to have previously unrecognized type 2 diabetes mellitus (DM). Associations of the AUC(G) with erythrocyte sedimentation rate (β = 2.430 [95% confidence interval 0.179-4.681], P = 0.04) and with CRP level (β = 2.358 [95% confidence interval 0.210-4.506], P = 0.03) were demonstrated. Treatment with prednisolone at both dosages reduced CRP levels significantly. The incidence of type 2 DM increased to 24% (P < 0.001) (evenly distributed across the groups). The mean AUC(G) did not change in either treatment arm. Beta cell function improved during prednisone treatment at 60 mg/day (P = 0.02) and at 30 mg/day (P = 0.04). Disease duration was associated with changes in the AUC(G) (β = 3.626 [95% confidence interval 1.077-6.174], P = 0.007) and with deterioration of the glucose state (odds ratio 1.068 [95% confidence interval 1.017-1.122], P = 0.009). CONCLUSION: In this study, short-term treatment with prednisolone 60 mg or 30 mg per day improved disease activity without deterioration of glucose tolerance in patients with active RA. However, due to individual differences, monitoring is recommended.
22870298 Frequency of Th17 CD4+ T cells in early rheumatoid arthritis: a marker of anti-CCP seropos 2012 OBJECTIVE: To examine the frequency and phenotype of Th17 cells in the peripheral blood of early RA (eRA) patients. METHODS: CD4+ T cells were isolated from the peripheral blood of 33 eRA patients, 20 established RA patients and 53 healthy controls (HC), and from the synovial fluid of 20 established RA patients (RASF), by ficoll-hypaque gradient and magnetical negative selection. After polyclonal stimulation, the frequency of Th17 and Th1 cells was determined by flow cytometry and concentrations of IL-17, IFN-γ, TNF-α and IL-10 were measured by ELISA in cell-free supernatants. RESULTS: When all of our eRA patients were analyzed together, a significantly lower percentage of circulating Th17 cells and a lower CD4-derived IL-17 secretion were observed in comparison with HC. However, after stratifying by anti-CCP antibody status, circulating Th17 cells were decreased in anti-CCP(+) but not in anti-CCP(-)-eRA. All Th17 cells were CD45RO+CD45RA- and CCR6+. Dual Th17/Th1 cells were also exclusively decreased in anti-CCP(+)-eRA. Circulating Th17 and Th17/Th1 cells were negatively correlated with anti-CCP titres. When anti-CCP(+)-eRA patients were retested one year after initiating treatment with oral methotrexate, their circulating Th17 frequency was no longer different from HC. Of note, the percentage of circulating Th1 cells and the secretion of CD4-derived IFN-γ, TNF-α and IL-10 were not different between eRA patients and HC. In established RA patients, circulating Th17 and T17/Th1 cell frequencies were comparable to HC. In RASF, both Th17 and Th1 cells were increased when compared with blood of eRA patients, established RA patients and HC. CONCLUSION: Decreased circulating Th17 levels in eRA seem to be a marker of anti-CCP seropositivity, and return to levels observed in healthy controls after treatment with methotrexate.
21943782 Regulatory immune responses induced by IL-1 receptor antagonist in rheumatoid arthritis. 2011 Oct Anakinra, a human recombinant IL-1 receptor antagonist, is approved for the treatment of RA. In this study, 12 patients received the placebo plus MTX treatment, 38 patients received Anakinra combined with MTX treatment. Compared with the placebo plus MTX group, serum levels of IL-17, IFN-γ, IL-21 and IL-1β significantly decreased, the percentages of Th17 cells and Th1 cells were lower and the percentage of Treg cells was higher after receiving Anakinra combined with MTX treatment. The observed regulatory immune responses collectively correlated with clinical improvement in treated patients. A substantial response, ACR 20 at 24 w were consistent with those at 12 w, 16 w and 20 w, and was accompanied by a marked improvement in RA related laboratory parameters. The study reveals that the combination of Anakinra and MTX is safe and well tolerated, which induces regulatory immune responses and significantly provides greater clinical benefit than the placebo plus MTX group.
22505177 Association of ADAMTS12 polymorphisms with rheumatoid arthritis. 2012 Jul a disintegrin and metalloproteinase (ADAM) with thrombospondin type 1 motif 12 (ADAMTS12) is a degradative enzyme that interacts with the degradable fragments of cartilage oligomeric matrix protein, which is a prominent non-collagenous matrix component in articular cartilage. ADAMTS12 has been observed in the cartilage, synovial fluid and serum of arthritic patients, and may play an important role in the pathogenesis of arthritis. In the present study, we investigated whether genetic polymorphisms of ADAMTS12 are associated with rheumatoid arthritis (RA). To observe the association between ADAMTS12 and RA, we genotyped three single nucleotide polymorphisms (SNPs) (rs1364044, intron C/T; rs10461703, intron C/T; rs25754, missense Thr1495Ile) of ADAMTS12 using a direct sequencing method in 303 RA patients and 495 control subjects. Multiple logistic regression models were performed to analyze the genetic data. SNPStats and SNPAnalyzer Pro programs were used to estimate the odds ratios, 95% confidence intervals and p-values. Bonferroni's correction (pc) was conducted to obtain a defined result. Of the three SNPs, the genotype frequency of rs10461703 was associated with the development of RA (pc=0.0024 in the co-dominant model; pc=0.0009 in the dominant model; pc=0.0006 in the log-additive model). The allele frequency of rs10461703 also showed a significant difference between RA and controls (pc<0.0001). The C allele frequency of rs10461703 was lower in the RA group (36.6%) compared to the control group (45.7%), whereas the T allele frequency of rs10461703 in the RA group (63.4%) was higher compared to that in the control group (54.3%). The other two SNPs (rs1364044 and rs25754) were not associated with the development of RA. However, we did not find any association between the three tested SNPs and RA patients according to clinical features, including erythrocyte sedimentation rate, C-reactive protein level, rheumatoid factor (+ and -) and bone erosion (+ and -). Our results suggest that ADAMTS12 may be a susceptibility gene for RA development.
22353668 Analytical and clinical comparison of anti-CCP assays with rheumatoid factor for the diagn 2012 Jun 14 INTRODUCTION: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by chronic joint inflammation and extra-articular manifestations, eventually leading to permanent disability without early therapeutic interventions. METHODS: The analytical and clinical performance of an electrochemiluminescent immunoassay (ECLIA) (Roche Diagnostics, Indianapolis, IN) were determined for cyclic citrullinated peptide antibodies (anti-CCP) in the diagnostic assessment of rheumatoid arthritis compared to a plate-based anti-CCP enzyme immunoassay (EIA) (Inova Diagnostics, Inc.). RESULTS: Imprecision studies on the automated Roche ECLIA demonstrated intra-assay CV's of <3% and inter-assay CV's of <7%. The Inova EIA had intra-assay CV's of <15% and inter-assay CV's of <12%. The limit of quantitation of both assays was acceptable, and both assays showed similar linearity within the manufacturer's defined reportable ranges. Overall, analytical concordance was 62%, with 95.2% positive and 53.2% negative concordance. The clinical specificity in a normal population (n=91) was 98.9% and 100% for Roche ECLIA and Inova EIA, respectively. The clinical specificity in a connective tissue disease population (n=98) was 91.9% (95%CI, 86.0 to 96.5%) and 88.8% (95% CI, 81.0 to 93.6%) for Roche ECLIA and Inova EIA, respectively. CONCLUSION: The Roche ECLIA demonstrated similar analytical performance, although with improved intra-assay precision, in comparison to the Inova EIA. The two methods also demonstrated similar clinical sensitivity and specificity. The Roche automated immunoassay is a viable alternative to the plate-based EIAs with the advantage of being performed on an automated platform.
21439251 Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoi 2011 Mar BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory condition that typically causes a symmetrical chronic arthritis. Timely use of disease-modifying antirheumatic drugs (DMARDs) is an essential aspect of disease management, but many patients may not respond even when conventional agents are used optimally. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of adalimumab (ADA), etanercept (ETN), infliximab (IFX), rituximab (RTX) and abatacept (ABT) when used in patients with RA who have tried conventional agents and have failed to improve after trying a first tumour necrosis factor (TNF) inhibitor. DATA SOURCES: A systematic review of primary studies was undertaken. Databases searched included the Cochrane Library, MEDLINE (Ovid) and EMBASE up to July 2009. STUDY SELECTION: Two reviewers assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers and screened them against inclusion criteria. STUDY APPRAISAL: Data from included studies were extracted by one reviewer and checked by a second. The quality of included studies was assessed independently by two reviewers, with any disagreements resolved by discussion and consultation with a third reviewer if necessary. RESULTS: Thirty-five studies were included in the systematic review: five randomised controlled trials (RCTs), one comparative study, one controlled study and 28 uncontrolled studies. One RCT (REFLEX) demonstrated the effectiveness of RTX. At 6 months significantly more patients treated with RTX achieved American College of Rheumatology (ACR) 20 [relative risk (RR) = 2.85, 95% confidence interval (CI) 2.08 to 3.91] and ACR70 (RR = 12.14, 95% CI 2.96 to 49.86) compared with those treated with the placebo. Differences between groups in favour of RTX were observed at 6 months for mean change from baseline in Disease Activity Score 28 (DAS28) (mean difference -1.50, 95% CI -1.74 to -1.26) and mean change from baseline in Health Assessment Questionnaire (HAQ) score (mean difference -0.30, 95% CI -0.40 to -0.20). One RCT (ATTAIN) demonstrated the effectiveness of ABT. At 6 months significantly more patients treated with ABT achieved ACR20 (RR = 2.56, 95% CI 1.77 to 3.69) and ACR70 (RR = 6.70, 95% CI 1.62 to 27.80) compared with those treated with placebo. Significant differences between groups in favour of ABT were observed at 6 months for mean change from baseline in DAS28 score (mean difference -1.27, 95% CI -1.62 to -0.93) and mean change from baseline in HAQ score (mean difference -0.34). Twenty-eight uncontrolled studies observed improvement of effectiveness compared with before switching, in patients who switched to ADA, ETN or IFX after discontinued previous TNF inhibitor(s). Four studies were included in the systematic review of cost-effectiveness. Independent economic evaluation undertaken by the assessment group showed that compared with DMARDs, the incremental cost-effectiveness ratios (ICERs) were £34,300 [per quality-adjusted life-year (QALY)] for ADA, £38,800 for ETN, £36,200 for IFX, £21,200 for RTX and £38,600 for ABT. RTX dominates the TNF inhibitors and the ICER for ABT compared with RTX is over £100,000 (per QALY). LIMITATIONS: Paucity of evidence from RCTs for assessing the clinical effectiveness of TNF inhibitors and an absence of head-to-head trials comparing the five technologies. CONCLUSIONS: Evidence from RCTs suggests that RTX and ABT are more effective than supportive care. Data from observational studies suggest that the use of an alternative TNF inhibitor in patients who exhibit an inadequate response to a first TNF inhibitor may offer some benefit, but there remain uncertainties with regard to the magnitude of treatment effects and their cost-effectiveness. Future research should include head-to-head trials comparing the clinical effectiveness and cost-effectiveness of the technologies against each other and emerging biologics. FUNDING: This study was funded by the Health Technology Assessment programme of the National Institute for Health Research.
23253692 Evaluation of clinical results and quality of life after surgical reconstruction for rheum 2013 Apr BACKGROUND CONTEXT: The EuroQol (EQ-5D) is a widely used comprehensive measure of health-related quality of life. There has been no study that has evaluated the health-related quality of life before and after the surgical reconstruction of rheumatoid arthritis (RA) cervical spine lesions using EQ-5D. PURPOSE: The present study aimed to evaluate the improvement of quality of life before and after surgical reconstruction of rheumatoid cervical spine using EQ-5D, and the surgical outcomes of cervical spine affected by RA. STUDY DESIGN: A retrospective study of the patients who underwent surgical reconstruction of cervical disorders in RA. PATIENT SAMPLE: Twenty-five patients (seven men, 18 women, mean age 62.2 years) who underwent surgical reconstruction of cervical disorders in RA were enrolled. OUTCOME MEASURES: Japanese Orthopaedic Association (JOA) score and EQ-5D. METHODS: Clinical symptoms were evaluated before surgery and at 2 years after surgery by measuring the JOA score. We also investigated health-related quality of life before surgery and outcome at 2 years after surgery using the EQ-5D questionnaire. RESULTS: Mean observation period was 46.3 months. Mean JOA score significantly improved from 9.1 ± 4.5 points before surgery to 12.4 ± 2.8 at the 2 years after surgery (p=.0001). All the EQ-5D data were improved at the 2 years after surgery, compared with the data before surgery; especially, pain (p=.005), usual activity (p=.005), mobility (p=.008), and anxiety/depression (p=.02) were significantly improved. Utility weight was 0.37 ± 0.27 before surgery and 0.56 ± 0.26 at the 2 years after surgery, showing significant improvement at the 2 years after surgery compared to before surgery (p=.002). CONCLUSIONS: The surgical reconstruction of rheumatoid cervical spine has been demonstrated to improve patients' health-related quality of life.
22764040 Induced T regulatory cells suppress osteoclastogenesis and bone erosion in collagen-induce 2012 Sep BACKGROUND: Although natural regulatory T cells (nTregs) can suppress osteoclastogenesis, the role of TGF-β-induced CD4+Foxp3+ Tregs (iTregs) in osteoclastogenesis remains unknown. OBJECTIVE: To determine the effects of iTregs on osteoclastogenesis in vitro and on bone erosion in vivo in collagen-induced arthritis (CIA). METHODS: Osteoclastogenesis was induced in bone marrow CD11b+ cells with receptor activator of nuclear factor κ B (NF-κB) ligand (RANKL) and macrophage colony stimulating factor. Graded doses of Tregs were added to inhibit osteoclastogenesis. Transwell and antibody blockade experiments were performed to assess the roles for cell contact and soluble cytokines. NF-κB activation was determined by western blot. iTregs or nTregs were adoptively transferred to mice with CIA to assess in vivo effects on disease incidence and bone erosion, the latter determined by CT scanning. RESULTS: Both nTregs and iTregs greatly suppressed osteoclastogenesis in vitro, but only iTregs sustained this effect when interleukin-6 was present. iTregs, but not nTregs, significantly suppressed development of CIA. Bone erosions in iTregs-treated mice were diminished compared with untreated mice or nTregs-treated mice. Treatment with iTregs, but not with nTregs, dramatically decreased NF-κB p65/p50 levels in osteoclasts in vitro and p65/50 and RANKL expression by synovial tissues in vivo. CONCLUSION: iTregs may be therapeutically beneficial in rheumatoid arthritis and related diseases associated with bone erosions.
21550856 Induction of type B synoviocyte-like cells from plasmacytoid dendritic cells of the bone m 2011 Sep We examined the capacities of bone marrow (BM) plasmacytoid dendritic cells (pDC) to differentiate into type B synoviocyte-like cells. BM aspiration samples were obtained from 24 rheumatoid arthritis (RA) patients and 19 osteoarthritis (OA) patients during joint operations from the iliac crest. CD34+ cells and pDC purified from BM mononuclear cells were cultured with or without SCF, GM-CSF, and TNF-α for 2-4 weeks. RA BM pDC as well as OA BM pDC comparably differentiated into fibroblast-like cells (FLC), expressing cadherin-11 and producing MMP-1, especially in the presence of TNF-α. Of note, depletion of BDCA4+ pDC from RA BM CD34+ cells significantly diminished their capacities to differentiate into FLC, which were restored by addition of BDCA4+cells in a dose-response manner. These results indicate that pDC is one of the progenitors of type B synoviocytes, suggesting that BM pDC might be involved in the pathogenesis of RA and OA.
21131423 Profiling of CD4+ T cells with epigenetic immune lineage analysis. 2011 Jan 1 Proper transcriptional control of pro- and anti-inflammatory responses of the immune system is important for a fine-tuned balance between protection and tolerance. Emerging evidence suggests a key role for epigenetic regulation in governing the Th cell differentiation, where effector cytokines direct the overall immune response. In this study, we describe a method to pinpoint the location of isolated human CD4(+) T cells on any T cell effector axis based on specific CpG methylation of cytokine and transcription factor loci. We apply the method on CD4(+) cells obtained from rheumatoid arthritis and multiple sclerosis patients and show that synovial fluid infiltrating CD4(+) T cells are committed toward both Th1 and regulatory T cell phenotype, whereas the Th2 response is suppressed. Furthermore, we show that the IL-17A gene is regulated by promoter methylation and that Th17 commitment is not a common feature in the inflamed joints of rheumatoid arthritis patients. We conclude that the method described in this paper allows for accurate profiling of Th lineage commitment in ex vivo-isolated CD4(+) T cells.
22455469 Reliability of the Fox-walk test in patients with rheumatoid arthritis. 2012 PURPOSE: The Fox-walk test is a new method used to estimate aerobic capacity outside a clinical environment, which may be useful in the implementation of daily health-enhancing physical activity. The aim of our study was to investigate the reliability of the test in people with rheumatoid arthritis (RA). METHOD: Fifteen participants performed the Fox-walk test three times with weekly intervals. The intraclass correlation coefficient (ICC), the standard error of measurement (SEM) and the smallest detectable change (SDC) were used to estimate the reliability. General health perception, lower limb pain and fatigue were measured to determine their potential influence on the reliability. RESULTS: There were no systematic differences between the three test occasions (p = 0.190) and the reliability was almost perfect (ICC = 0.982). None of the covariates influenced the reliability. The SEM was 0.999 ml/kg/min or 3.4% and the SDC was 2.769 ml/kg/min or 9.4%. CONCLUSIONS: These findings demonstrate that the Fox-walk test is reliable in people with RA and enables differentiation between people with RA and monitoring progress. The validity of the test among people with RA is still to be determined. IMPLICATIONS FOR REHABILITATION: • The Fox-walk test is a new method to estimate aerobic capacity and could be performed walking or running. • The test is self administered without expensive equipment and is available in 150 public places in Sweden and several other European countries. • The Fox-walk test is a reliable test for use among people with rheumatoid arthritis monitoring the progress of their physical activity.
22820172 Efficacy of concurrent administration of cilostazol and methotrexate in rheumatoid arthrit 2012 Sep 17 AIMS: This study aimed to assess the beneficial effects of the concurrent administration of cilostazol and methotrexate (MTX) on the synovial fibroblasts obtained from patients with rheumatoid arthritis (RA), and in a mouse model of collagen-induced arthritis (CIA). MAIN METHODS: Production of TNF-α, IL-1β, IL-6 and MCP-1 on synovial fibroblasts from RA patients was determined by RT-PCR. Cell proliferation, viability and apoptosis were measured. Anti-arthritic effects were evaluated in CIA mice. KEY FINDING: Concurrent use of cilostazol and MTX effectively suppressed proliferation and cell viability associated with enhanced apoptosis of synovial fibroblasts and significantly suppressed cytokine production, including TNF-α, IL-1β, IL-6, and MCP-1 in an additive manner. In line with these findings, LPS-induced increased expression of NURR1 mRNA and protein were suppressed by cilostazol and MTX in accordance with suppression of NF-κB p65 activity. These suppressed effects were reversed by KT5720 (cAMP-protein kinase inhibitor) and ZM 241385 (A(2A) receptor antagonist), respectively. In CIA mice, treatment with cilostazol, MTX and their combination significantly decreased clinical signs with improvement of histopathological status in the paw of mice, accompanied by reduced serum cytokine levels. Likewise, following concurrent administration, CD68 (+)-cell recruitment, proteoglycan depletion and osteoclast formation were significantly suppressed in association with repressed RANKL expression in the joints of CIA mice. SIGNIFICANCE: In conclusion, a combination of cilostazol and MTX may provide an effective therapeutic strategy for the suppression of inflammation and the prevention of joint damage in RA via activation of the cAMP-dependent protein kinase in the synovial fibroblasts.