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ID PMID Title PublicationDate abstract
20453842 Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk 2010 Jun To identify new genetic risk factors for rheumatoid arthritis, we conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication in an independent set of 6,768 rheumatoid arthritis cases and 8,806 controls. Of 34 SNPs selected for replication, 7 new rheumatoid arthritis risk alleles were identified at genome-wide significance (P < 5 x 10(-8)) in an analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5 and PXK. We also refined associations at two established rheumatoid arthritis risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed rheumatoid arthritis risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P < 0.05, many of which are validated autoimmune risk alleles, suggesting that most represent genuine rheumatoid arthritis risk alleles.
19950280 Inflammatory arthritis in caspase 1 gene-deficient mice: contribution of proteinase 3 to c 2009 Dec OBJECTIVE: Caspase 1, a known cysteine protease, is a critical component of the inflammasome. Both caspase 1 and neutrophil serine proteases such as proteinase 3 (PR3) can process pro-interleukin-1beta (proIL-1beta), a crucial cytokine linked to the pathogenesis of rheumatoid arthritis. This study was undertaken to establish the relative importance of caspase 1 and serine proteases in mouse models of acute and chronic inflammatory arthritis. METHODS: Acute and chronic arthritis were induced in caspase 1-/- mice, and the lack of caspase 1 was investigated for its effects on joint swelling, cartilage metabolism, and histopathologic features. In addition, caspase 1 activity was inhibited in mice lacking active cysteine proteases, and the effects of dual blockade of caspase 1 and serine proteases on arthritis severity and histopathologic features were evaluated. RESULTS: Surprisingly, caspase 1-/- mice, in a model of acute (neutrophil-dominated) arthritis, developed joint swelling to an extent similar to that in wild-type control mice. Joint fluid concentrations of bioactive IL-1beta were comparable in caspase 1-/- mice and controls. In contrast, induction of chronic arthritis (characterized by minimal numbers of neutrophils) in caspase 1-/- mice led to reduced joint inflammation and less cartilage damage, implying a caspase 1-dependent role in this process. In mice lacking neutrophil serine PR3, inhibition of caspase 1 activity resulted in decreased bioactive IL-1beta concentrations in the synovial tissue and less suppression of chondrocyte anabolic function. In addition, dual blockade of both PR3 and caspase 1 led to protection against cartilage and bone destruction. CONCLUSION: Caspase 1 deficiency does not affect neutrophil-dominated joint inflammation, whereas in chronic arthritis, the lack of caspase 1 results in reduced joint inflammation and cartilage destruction. These findings suggest that inhibitors of caspase 1 are not able to interfere with the whole spectrum of IL-1beta production, and therefore such inhibitors may be of therapeutic value only in inflammatory conditions in which limited numbers of neutrophils are present.
19626001 A pharmacodynamic Markov mixed-effects model for determining the effect of exposure to cer 2009 Oct The American College of Rheumatology (ACR) 20% preliminary definition of improvement in rheumatoid arthritis (RA) (ACR20) is widely used in clinical trials to assess response to treatment. The objectives of this analysis were to develop an exposure-response model of ACR20 in subjects receiving treatment with certolizumab pegol and to predict clinical outcomes following various treatment schedules. At each visit, subjects were classified as being ACR20 responders or ACR20 nonresponders or as having dropped out. A Markov mixed-effects model was developed to investigate the effects of the drug on the transitions between the three defined states. Increasing certolizumab pegol exposure predicted an increasing probability of becoming a responder and remaining a responder, as well as a reduced probability of dropping out of treatment. Data from simulations of the ACR20 response rate support the use of dosing regimens of 400 mg at weeks 0, 2, and 4 followed by 200 mg every 2 weeks, or an alternative maintenance regimen of 400 mg every 4 weeks.
19089488 Cost-effectiveness modeling of abatacept versus other biologic agents in DMARDS and anti-T 2009 Apr To assess the cost-effectiveness of abatacept compared to different biologic treatment strategies for moderate to severe rheumatoid arthritis based on current medical practices in Canada. A model was constructed to assess the cost-effectiveness of various biologic treatments over a 2-year time horizon, using two effectiveness endpoints: "low disease activity state" (LDAS) and "remission". Abatacept, as first biologic agent after an inadequate response to DMARDs, provides greater treatment success rate for achieving LDAS (29.4% versus 15.6%) and remission (14.8% versus 5.2%), and appears significantly more cost-effective compared to the sequential use of anti-TNF agents (p<0.001). Abatacept, as second biologic agent after an inadequate response to one anti-TNF agent, provides greater treatment success rate for achieving LDAS (17.1% versus 10.2%) and remission (7.4% versus 3.9%) and appears significantly more cost-effective compared to the sequential use of anti-TNF agents (p<0.001). Abatacept is a cost-effective strategy in patients with an inadequate response to DMARDs or to one anti-TNF agent.
20827783 Alcohol consumption and markers of inflammation in women with preclinical rheumatoid arthr 2010 Dec OBJECTIVE: To examine the association between alcohol consumption and markers of inflammation in preclinical rheumatoid arthritis (RA). METHODS: We studied 174 incident RA cases with stored blood collected 1-16 years prior to RA symptoms (preclinical RA), from the Nurses' Health Study. Alcohol intake was measured using a detailed food frequency questionnaire administered every 4 years, prior to blood collection. Plasma was tested for biomarkers of inflammation, including high-sensitivity C-reactive protein (hsCRP), anti-cyclic citrullinated peptide (anti-CCP) antibodies, interleukin-6 (IL-6), and soluble tumor necrosis factor receptor II (sTNFRII). Generalized additive models were used to identify structure in the relationship between each biomarker and cumulative average alcohol intake. Then general linear models were used for multivariable adjusted analyses with appropriate polynomial terms of alcohol consumption. RESULTS: After controlling for age at blood collection, smoking, parity and duration of breastfeeding, menopausal status, oral contraceptive use, body mass index, and the time between blood collection and RA onset, we found that the daily alcohol consumption showed a U-shaped association with IL-6 levels in RA patients, prior to symptoms. We also found an inverse relationship between alcohol intake and sTNFRII levels, but no associations with hsCRP or anti-CCP levels. CONCLUSION: These results demonstrate an association between alcohol consumption and markers of inflammation, including IL-6 and sTNFRII, in RA patients, prior to the occurrence of symptoms.
19184032 Antibody against mutated citrullinated vimentin: a new sensitive marker in the diagnosis o 2009 Sep The aim of this study was to determine the performance of antibodies against mutated citrullinated vimentin (anti-MCV) in comparison with antibodies to cyclic citrullinated peptides (anti-CCP) in patients with rheumatoid arthritis (RA). Serum levels of anti-MCV and anti-CCP were determined in 193 patients with RA and 332 controls, and sensitivity and specificity were calculated. In a separate analysis of 86 patients, the anti-MCV levels were compared to disease activity. Sensitivity of anti-MCV versus anti-CCP was 71.5 and 69.4%, specificity was 81.3 and 97.6%, respectively. The ROC curves showed higher specificity and an advantage of anti-CCP. In seronegative RA patients the sensitivity of anti-MCV was superior over anti-CCP. Anti-MCV positivities also occurred in systemic lupus erythematosus and Sjoegren's syndrome. In a subgroup of 86 RA patients we found a significant correlation between anti-MCV and disease activity. Anti-MCV appears to be an important marker for the diagnosis of RA, and correlates also with disease activity.
20724433 Increased IL-17 production by peripheral T helper cells after tumour necrosis factor block 2010 Dec OBJECTIVES: The contribution of IL-17-producing Th17 cells to the pathogenesis of T-cell-mediated inflammatory disorders such as RA and atopic dermatitis (AD) has to be viewed in relation to the role of Th1/Th2 cells and long-recognized key cytokines like TNF. We aimed to study the frequency and migration-associated phenotype of peripheral Th17, Th1 and Th2 cells in healthy individuals, RA and AD patients, and to study the influence of anti-TNF therapy in RA. METHODS: Intracellular IL-17, IFN-γ and IL-4 production and CC-chemokine receptor CCR4 and CCR6 expression were analysed flow cytometrically in peripheral memory Th cells from healthy individuals, AD and RA patients. The latter were grouped by disease activity and presence or absence of adalimumab therapy. In RA patients initiating anti-TNF therapy, cytokine production by in vitro-stimulated peripheral mononuclear cells was measured by cytometric bead array. RESULTS: The peripheral Th17 cell frequency is elevated in AD but not in RA. In RA, Th17 cells and IL-17 production increase after anti-TNF therapy, irrespective of disease activity. Th1 cells and IFN-γ production are elevated in remission and under anti-TNF therapy. CCR6 expression is up-regulated in Th17 cells, but RA patients in remission under anti-TNF therapy have significantly lower expression than those with active disease. CONCLUSIONS: The increase in peripheral Th17 cells in RA patients after anti-TNF therapy is accompanied by a decrease in Th17-specific CCR6 expression, which might prevent homing of these potentially pro-inflammatory cells to the synovium.
20957197 Genetic variation of the Fc gamma receptor 3B gene and association with rheumatoid arthrit 2010 Oct 5 BACKGROUND: Fc gamma receptors (FcγRs) play a crucial role in immunity by linking IgG antibody-mediated responses with cellular effector and regulatory functions. Genetic variants in these receptors have been previously identified as risk factors for several chronic inflammatory conditions. The present study aimed to investigate the presence of copy number variations (CNVs) in the FCGR3B gene and its potential association with the autoimmune disease rheumatoid arthritis (RA). METHODOLOGY/PRINCIPAL FINDINGS: CNV of the FCGR3B gene was studied using Multiplex Ligation Dependent Probe Amplification (MLPA) in 518 Dutch RA patients and 304 healthy controls. Surprisingly, three independent MLPA probes targeting the FCGR3B promoter measured different CNV frequencies, with probe#1 and #2 measuring 0 to 5 gene copies and probe#3 showing little evidence of CNV. Quantitative-PCR correlated with the copy number results from MLPA probe#2, which detected low copy number (1 copy) in 6.7% and high copy number (≥3 copies) in 9.4% of the control population. No significant difference was observed between RA patients and the healthy controls, neither in the low copy nor the high copy number groups (p-values = 0.36 and 0.71, respectively). Sequencing of the FCGR3B promoter region revealed an insertion/deletion (indel) that explained the disparate CNV results of MLPA probe#1. Finally, a non-significant trend was found between the novel -256A>TG indel and RA (40.7% in healthy controls versus 35.9% in RA patients; P = 0.08). CONCLUSIONS/SIGNIFICANCE: The current study highlights the complexity and poor characterization of the FCGR3B gene sequence, indicating that the design and interpretation of genotyping assays based on specific probe sequences must be performed with caution. Nonetheless, we confirmed the presence of CNV and identified novel polymorphisms in the FCGR3B gene in the Dutch population. Although no association was found between RA and FCGR3B CNV, the possible protective effect of the -256A>TG indel polymorphism must be addressed in larger studies.
20934164 Long-term results of computer-assisted posterior occipitocervical reconstruction. 2010 Jun BACKGROUND: Instability of the occipitocervical junction can present challenging surgical problems because of the unique anatomic and biomechanical characteristics of this region. The purpose of this study was to evaluate the long-term surgical results and usefulness of a computed tomography (CT)-based navigation system for the occipitocervical reconstruction. METHODS: Twenty-three patients (10 men, 13 women; mean age at surgery 57.9 years; mean follow-up periods 52.9 months) with occipitocervical junction disorders were treated by occipitocervical reconstruction using pedicle screws, aided by a CT-based navigation system. Roentgenologic measurement and clinical evaluation were performed before surgery and at final follow-up. Postoperative CT and plane radiographs were used to determine the accuracy of screw placement. RESULTS: Mean atlantodental interval and Ranawat value were significantly improved (P<.05), and mean clivoaxial angle was increased after surgery and maintained at final follow-up. Mean Japanese Orthopedic Association score before and at final follow-up was 7.1 ± 4.4 and 11.3 ± 3.5 points, showing significant improvement (P = .005). Fourteen patients (61%) improved more than one Ranawat grade. Six of nine patients (67%) in class IIIB were improved. On the other hand, nine patients (39 %) remained at the same class at final follow-up. A total of 88 pedicle screws were inserted into cervical and upper thoracic pedicles using the navigation system, and only one screw (1.1 %) showed major pedicle wall perforation. Solid union was achieved in all 23 patients. CONCLUSIONS: Occipitocervical reconstruction using pedicle screws provided a high fusion rate and maintained alignment in the occipitocervical region. The computer-assisted navigation system was a useful tool for accurate and safe pedicle screw insertion.
19720679 Hand deformities are important signs of disease severity in patients with early rheumatoid 2009 Nov OBJECTIVES: The aim of this study was to investigate the occurrence and significance of hand deformities during the first 10 years of RA. METHODS: One hundred and eighty-three early RA patients were included in the study during 1985-89. Mean +/- S.D. of age at onset was 51.4 +/- 12.4 years, and mean duration of symptoms before inclusion 12 +/- 7 months; 64% were women. The patients were followed annually. Assessment of hand deformities was standardized. Hand mobility was measured by signals of functional impairment (SOFI), disability by HAQ and hand HAQ, disease activity by ESR and radiographic changes by the Larsen method. RESULTS: One hundred and eight (59%) patients developed at least one hand deformity during the study time. The majority occurred during the first years. After 10 years, the rate of ulnar deviation, button hole deformity and swan neck deformity was 44, 24 and 23.5%, respectively. The deformity group showed significantly higher disease activity during the first 5 years, and significantly more hand impairment, more disability and more severe radiographic changes throughout the study. Presence of a deformity after 1 year increased the risk of developing a Larsen score above median after 5 years. Odds ratio (95% CI) was 2.1 (1.023, 4.385). CONCLUSIONS: More than half of the patients in this early RA cohort had developed hand deformities after 10 years. Most deformities occurred during the first year of the disease. Presence of hand deformities had an impact on daily life function and added useful prognostic information, being an early sign of a more severe disease.
18986219 Clinical responses to gene therapy in joints of two subjects with rheumatoid arthritis. 2009 Feb This paper provides the first evidence of a clinical response to gene therapy in human arthritis. Two subjects with rheumatoid arthritis received ex vivo, intraarticular delivery of human interleukin-1 receptor antagonist (IL-1Ra) cDNA. To achieve this, autologous synovial fibroblasts were transduced with a retrovirus, MFG-IRAP, carrying IL-1Ra as the transgene, or remained as untransduced controls. Symptomatic metacarpophalangeal (MCP) joints were injected with control or transduced cells. Joints were clinically evaluated on the basis of pain; the circumference of MCP joint 1 was also measured. After 4 weeks, joints underwent surgical synovectomy. There were no adverse events in either subject. The first subject responded dramatically to gene transfer, with a marked and rapid reduction in pain and swelling that lasted for the entire 4 weeks of the study. Remarkably, joints receiving IL-1Ra cDNA were protected from flares that occurred during the study period. Analysis of RNA recovered after synovectomy revealed enhanced expression of IL-1Ra and reduced expression of matrix metalloproteinase-3 and IL-1beta. The second subject also responded with reduced pain and swelling. Thus, gene transfer to human, rheumatoid joints can be accomplished safely to produce clinical benefit, at least in the short term. Using this ex vivo procedure, the transgene persisted within the joint for at least 1 month. Further clinical studies are warranted.
19604443 Impact of short-term therapies with biologics on prothrombotic biomarkers in rheumatoid ar 2009 May BACKGROUND: Imbalance of haemostasis in patients with rheumatoid arthritis (RA) contributes to future risk of cardiovascular diseases (CVD). Prothrombotic molecules, e.g. fibrinogen, D-dimer, and tPA are elevated in plasma of RA patients, being associated to CVD. There is no imformation about the influence of biological drugs, e.g. anti-CD20 and tumor necrosis factor (TNF) antibodies on these prothrombotic molecules. OBJECTIVE: To assess whether anti-TNF and anti-CD20 therapies modify the profiles of cardiovascular risk factors in patients with RA. METHODS: The expression of prothrombotic molecules in plasma was investigated in 10 RA patients before and after treatment with TNF-alpha antibodies and in another 12 RA patients before and after anti-CD20 treatment. RESULTS: Both anti-TNF and anti-CD20 infusions gave rise to clear clinical improvement. However, only anti-CD20 infusion significantly (p=0.05) reduced concentration of fibrinogen (p=0.05), D-dimer (p<0.001), as well as tPA levels (p<0.01). In contrast, in TNF antibody treated patients only tPA levels were significantly decreased following the treatment (p<0.05). CONCLUSIONS: Infusion of CD20 antibodies to the patients with active RA led to a clearly reduced plasma levels of predictors of CVD indicating that this treatment, apart from its anti-inflammatory properties, may reduce the risk for future CVD in RA.
21125264 Power estimation using a population pharmacokinetics model with optimal design by clinical 2011 Mar OBJECTIVES: The aim of this article was to determine the power for pharmacokinetic interaction investigations using population a pharmacokinetic modelling approach with optimal sampling designs and clinical trial simulations. METHODS: A clinical trial simulation approach was proposed to estimate the power for pharmacokinetic effects in drug-drug interaction (DDI) studies. This approach consisted of: (1) population pharmacokinetic (PK) model(s) was characterised for the drug(s) studied; (2) D-optimal design strategy was applied based on these model(s) to determine optimal sampling times for DDI investigation; (3) clinical trial simulations under particular study designs, for example a randomised parallel design, were used to evaluate the sample size needed for studying PK interaction. The approach was described using an example investigating the impact of a new anti-inflammatory drug on methotrexate (MTX) exposure in rheumatoid arthritis (RA) patients. RESULTS: The power for evaluating PK interaction largely depended on the interindividual variability (IIV) in PK parameters. Residual variability was also influential to a lesser degree in the sample size determination using the proposed approach. It required 40-60 participants for scenarios where IIV was relatively low in order to achieve 90% power. However, a sample size of 80 individuals was required to reach 90% power where both IIV and residual variances were high. Under the same IIV assumptions, the proposed approach in general required a smaller sample size compared with the standard noncompartmental analysis method with intensive blood samples to attain the target power. When IIV was low, the difference in the power between the two approaches was relatively small. CONCLUSIONS: Population PK modelling with optimal design and clinical trial simulation to determine sample size when designing drug-drug interaction studies was efficient and cost effective.
20621086 7-hydroxyfrullanolide, a sesquiterpene lactone, inhibits pro-inflammatory cytokine product 2010 Oct 10 A promising therapeutic approach to reduce pathological inflammation is to inhibit the increased production of pro-inflammatory cytokines (e.g., TNF-alpha, IL-6). In this study, we investigated the anti-inflammatory potential of 7-hydroxyfrullanolide (7HF). 7HF is an orally bioavailable, small molecule sesquiterpene lactone isolated from the fruit of Sphaeranthus indicus. 7HF significantly and dose-dependently diminished induced and spontaneous production of TNF-alpha and IL-6 from freshly isolated human mononuclear cells, synovial tissue cells isolated from patients with active rheumatoid arthritis and BALB/c mice. Oral administration of 7HF significantly protected C57BL/6J mice against endotoxin-mediated lethality. In the dextran sulfate sodium (DSS) model of murine colitis, oral administration of 7HF prevented DSS-induced weight loss, attenuated rectal bleeding, improved disease activity index and diminished shortening of the colon of C57BL/6J mice. Histological analyses of colonic tissues revealed that 7HF attenuated DSS-induced colonic edema, leukocyte infiltration in the colonic mucosa and afforded significant protection against DSS-induced crypt damage. 7HF was also significantly efficacious in attenuating carrageenan-induced paw edema in Wistar rats after oral administration. In the collagen-induced arthritis in DBA/1J mice, 7HF significantly reduced disease associated increases in articular index and paw thickness, protected against bone erosion and joint space narrowing and prominently diminished joint destruction, hyperproliferative pannus formation and infiltration of inflammatory cells. Collectively, these results provide evidence that 7HF-mediated inhibition of pro-inflammatory cytokines functionally results in marked protection in experimental models of acute and chronic inflammation.
21088969 [Diagnostic spectrum, treatment indication and symptom duration in initial referrals to th 2010 Dec There is evidence that early initiation of therapy in inflammatory rheumatic diseases, in particular rheumatoid arthritis (RA), has a positive effect on disease course.To investigate referral procedures, 198 German rheumatologists reported over a 3-month period and for each patient seen for the first time on: patient characteristics, specialization of the referring physician, symptom duration, time interval between making the appointment and the first visit, diagnoses and relevant drug history. Multivariate logistic regression analyses were performed to investigate the odds ratios for a first consultation within 3 months after symptom onset.The 17,908 newly referred adult patients were 54 years old on average and 72% were women. Inflammatory rheumatic disease was diagnosed in 53%. Mean disease duration was 30 ± 57 months (median 7.3 months). There was no apparent association between patient age, education, disease severity or specialisation of the referring physician; however, there was a clear association with waiting times to first consultation.A higher number of early arthritis clinics could significantly shorten the time to first rheumatological consultation. Therefore, more efforts need to be made to fast-track referrals from primary care physicians to rheumatologists as well as to optimise rheumatologists' appointment regulations for new patients. However, these efforts can only succeed with a significant increase in the number of rheumatologists, while ensuring a firm economic basis.
20690084 No association of polymorphisms in the suppressor of cytokine signaling (SOCS)-3 with rheu 2010 Aug 3 Suppressor of cytokine signaling (SOCS)-3 is a key negative regulator of cytokine signaling that inhibits the JAK/STAT signal transduction pathway; there are reports describing its role in attenuating arthritis through SOCS-3 overexpression. We examined the relationship between polymorphisms in the coding sequence and promoter region of SOCS-3 and rheumatoid arthritis (RA) in a Chinese Han population. Two single-nucleotide polymorphisms in the SOCS-3 5' region: -1044 C>A within the promoter region and rs12953258 (-920 C>A) in the 5'UTR (exon 2) of SOCS-3 were studied by restriction fragment length polymorphism analysis and tetra-ARMS-PCR in 100 RA patients and 100 healthy adults. The prevalence of the homozygous genotype -1044 CC was 100% in both RA and control groups. The heterozygous genotype (-920 C>A) was present in 89% of RA and in 82% of the control group, which is significantly different from the distribution in Western people. There was no transmission disequilibrium between these two SNPs (r(2) = 0.000). We did not detect significant differences in allele or genotype frequencies for either of these SNPs between the RA group and controls (P > 0.05). There was no association between rheumatoid factor and SOCS-3 SNP rs12953258 (P = 0.258). We conclude that SOCS-3 polymorphism is not a genetic risk factor for RA in Chinese patients.
20363004 [Tumour necrosis factor alpha antagonists in established rheumatoid arthritis: effectivene 2010 May 22 BACKGROUND AND OBJECTIVE: Knowing the differences in the effectiveness between three tumour necrosis factor alpha antagonists (anti-TNF alpha) in rheumatoid arthritis (RA) has important clinical implications. The aim of this study was to assess anti-TNF alpha effectiveness and to study possible differences in outcomes between them. PATIENTS AND METHOD: We included all patients with rheumatoid arthritis (RA) attended in consulting room from Zaragoza Area II between May 2000 and December 2006 who completed a year with anti-TNF alpha treatment. Several demographic and clinical parameters at the beginning and after a year with three different agents were analysed and compared. RESULTS: 119 patients completed a year with anti-TNF alpha, 28 with infliximab, 44 with etanercept and 37 with adalimumab. After a year with treatment, DAS 28 descended 1,82 (1,42) points and HAQ 0,3 (0,58) (p<0,05). Comparing the clinical parameters after a year DAS 28 was 3,8 in the three groups. HAQ was 1,2 for patients in treatment with infliximab and 0,9 for patients with etanercept and adalimumab. There were no significant differences in effectiveness between the 3 drugs. CONCLUSIONS: Anti-TNF alpha drugs are effective to treat RA and the effectiveness is similar in all them.
20235213 Reliability of patient self-evaluation of swollen and tender joints in rheumatoid arthriti 2010 Aug OBJECTIVE: Swollen and tender joints, important in assessing rheumatoid arthritis (RA) activity, have traditionally been evaluated by health professionals. Whether patients can accurately evaluate joints is uncertain. This study evaluated 1) the reliability of patient-assessed swollen joint counts (SJCs) and tender joint counts (TJCs) versus those assessed by a physician, nurse, and B-mode ultrasonography (US) and 2) patient-derived Disease Activity Score in 28 joints (DAS28) compared with physician-, nurse-, and US-derived DAS28. METHODS: Fifty RA patients self-assessed 28 joints (shoulders, elbows, wrists, metacarpophalangeal, proximal interphalangeal, and knees) for swelling and tenderness. They were then assessed separately by a physician, a nurse, and an ultrasonographer. Nine patients were tested twice (intraobserver reliability), and reliability was assessed at the patient level (28 joints) by intraclass correlation coefficients (ICCs) and at the joint level by prevalence-adjusted bias-adjusted kappa. RESULTS: TJC reliability was good for patient versus physician (ICC 0.85 [95% confidence interval (95% CI) 0.65, 0.94]) and patient versus nurse (ICC 0.76 [95% CI 0.47, 0.90]). However, SJC reliability was poor for patient versus physician (ICC 0.41 [95% CI -0.05, 0.72]) and patient versus nurse (ICC 0.44 [95% CI -0.005, 0.74]). SJC reliability was poor in all assessors compared with B-mode US, particularly patient-assessed SJC (ICC 0.22 [95% CI -0.25, 0.61]). However, patient-derived DAS28 correlated well with US-derived DAS28 (ICC 0.95 [95% CI 0.87, 0.98]). Intraobserver reliability was good for all assessors for TJC, but was lower for SJC. CONCLUSION: Patient-derived DAS28 is at least as reliable as physician-, nurse-, or US-derived DAS28, despite poor reliability in patient-assessed SJC.
19818132 The ITGAV rs3738919 variant and susceptibility to rheumatoid arthritis in four Caucasian s 2009 INTRODUCTION: Angiogenesis is an important process in the development of destructive synovial pannus in rheumatoid arthritis (RA). The ITGAV +gene encodes a cell cycle-associated antigen, integrin alphanubeta 3, which plays a role in RA angiogenesis. Previously, two independent studies identified an association between the major allele of the ITGAV single-nucleotide polymorphism (SNP) rs3738919 and RA. We therefore tested this association in an independent study using New Zealand (NZ) and Oxford (UK) RA case control samples. METHODS: We compared genotype frequencies in 740 NZ Caucasian RA patients and 553 controls genotyped for rs3738919, using a polymerase chain reaction-restriction fragment length polymorphism assay. A TaqMan genotyping SNP assay was used to type 713 Caucasian RA patients and 515 control samples from Oxford for the rs3738919 variant. Association of rs3738919 with RA was tested in these two sample sets using the chi-square goodness-of-fit test. The Mantel-Haenszel test was used to perform a meta-analysis, combining the genetic results from four independent Caucasian case control cohorts, consisting of 3,527 cases and 4,126 controls. Haplotype analysis was also performed using SNPs rs3911238, rs10174098 and rs3738919 in the Wellcome Trust Case Control Consortium, NZ and Oxford case control samples. RESULTS: We found no evidence for association between ITGAV and RA in either the NZ or Oxford sample set (odds ratio [OR] = 0.88, P(allelic) = 0.11 and OR = 1.18, P(allelic) = 0.07, respectively). Inclusion of these data in a meta-analysis (random effects) of four independent cohorts (3,527 cases and 4,126 controls) weakens support for the hypothesis that rs3738919 plays a role in the development of RA (OR(combined) = 0.92, 95% confidence interval 0.80 to 1.07; P = 0.29). No consistent haplotype associations were evident. CONCLUSIONS: Association of ITGAV SNP rs7378919 with RA was not replicated in NZ or Oxford case control sample sets. Meta-analysis of these and previously published data lends limited support for a role for the ITGAV in RA in Caucasians of European ancestry.
20070642 Effects of method of translation of patient-reported health outcome questionnaires: a rand 2010 Jun AIMS: To compare two versions of a questionnaire translated using forward-backward (FB) translation and dual-panel (DP) methodologies regarding preference of wording and psychometric properties. METHODS: The Rheumatoid Arthritis Quality of Life instrument was adapted into Swedish by two independent groups using FB and DP methodologies, respectively. Seven out of thirty resulting items were identical. Nonidentical items were evaluated regarding preference of wording by 23 bilingual Swedes, 50 people with rheumatoid arthritis (RA), and 2 lay panels (n = 11). Psychometric performance was assessed from a postal survey of 200 people with RA randomly assigned to complete one version first and the other 2 weeks later. RESULTS: Preference did not differ among the 23 bilinguals (P = 0.196), whereas patients and lay people preferred DP over FB item versions (P < 0.0001). Postal survey response rates were 74% (FB) and 75% (DP). There were more missing item responses in the FB than the DP version (6.9% vs. 5.6%; P < 0.0001). Floor/ceiling effects were small (FB, 6.1/0%; DP, 4.4/0.7%) and reliability was 0.92 for both versions. Construct validity was similar for both versions. Differential item functioning by version was detected for five items but cancelled out and did not affect estimated person measures. CONCLUSIONS: The DP approach showed advantages over FB translation in terms of preference by the target population and by lay people, whereas there were no obvious psychometric differences. This suggests advantages of DP over FB translation from the patients' perspective, and does not support the commonly held view that FB translation is the "gold standard."