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ID PMID Title PublicationDate abstract
16802349 Regulation of JNK by MKK-7 in fibroblast-like synoviocytes. 2006 Jul OBJECTIVE: JNK regulates matrix metalloproteinase (MMP) gene expression and joint destruction in rheumatoid arthritis (RA). Previous studies demonstrated that the 2 upstream MAPK kinases (MKK-4 and MKK-7) are phosphorylated in RA synovium and form a complex with JNK in fibroblast-like synoviocytes (FLS). However, the functional hierarchy of MKK-4 and MKK-7 in FLS has not been determined. We determined the relative contributions of these MKKs by evaluating the effect of MKK-4 and MKK-7 gene knockdown in cultured FLS. METHODS: FLS were transfected with MKK-4 and/or MKK-7 small interfering RNA, and protein levels were determined by immunoblotting. After stimulation with interleukin-1/beta (IL-1beta), tumor necrosis factor alpha(TNFalpha, or anisomycin, kinase function was determined by in vitro kinase assay. Activator protein 1 (AP-1) binding and transcriptional activity were determined by electrophoretic mobility shift assay and AP-1-luciferase promoter assay, respectively. MMP-3 expression was determined by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. RESULTS: IL-1beta-induced JNK phosphorylation was dependent on MKK-7 but not on MKK-4; however, anisomycin-activated JNK required both kinases. In vitro kinase assay demonstrated that IL-1beta-or TNFalpha induced JNK activity was only MKK-7 dependent, while anisomycin-activated JNK was both MKK-4 and MKK-7 dependent. IL-1beta-induced AP-1 binding activity and AP-1-driven gene expression were strictly MKK-7 dependent. Finally, MMP-3 production only required MKK-7, and there was no effect of MKK-4 deficiency. CONCLUSION: These data indicate that only MKK-7 is required for JNK activation in FLS after cytokine stimulation; however, other forms of cellular stress utilize MKK-4. Thus, JNK function might be modulated by targeting MKK-7 to suppress cytokine-mediated FLS activation while leaving other stress responses intact.
18473972 Anti-interleukin-6 receptor antibody treatment in inflammatory autoimmune diseases. 2006 Sep Tocilizumab (namely MRA), a humanized anti-interleukin (IL)-6 receptor monoclonal antibody, is under development by Roche for the treatment of inflammatory autoimmune diseases such as rheumatoid arthritis (RA), systemic onset juvenile idiopathic arthritis (JIA), adult-onset Still's disease, Castleman's disease and Crohn's disease. Tocilizumab has a long plasma half-life, so it can be administered intravenously biweekly or monthly. Phase I and II clinical trials showed that tocilizumab (2, 4, 5, 8 or 10 mg/kg) reduced disease activity significantly in a dose-dependent manner. Tocilizumab not only improved signs and symptoms, but also normalized inflammatory markers such as C-reactive protein, erythrocyte sedimentation rate (ESR), fibrinogen and serum amyloid A, and reversed joint damage of RA. The efficacy of tocilizumab in the treatment of RA was at least as good as methotrexate. Tocilizumab was generally safe and well tolerated. Some adverse events such as significant rises in total cholesterol and triglyceride levels, liver function disorders, decreases in white blood cell counts, diarrhoea and infection were observed. In summary, preliminary clinical results suggest that tocilizumab is effective and generally well tolerated in the treatment of IL-6-related inflammatory autoimmune diseases. Like other anti-cytokine immunotherapies, caution and close monitoring for the adverse events, especially infection, are necessary in subsequent clinical trials.
16219706 MRI bone oedema predicts eight year tendon function at the wrist but not the requirement f 2006 May OBJECTIVE: To investigate the role of early magnetic resonance imaging (MRI) of the wrist in predicting functional outcome in rheumatoid arthritis. METHODS: MRI scans of the dominant wrist were scored for synovitis, tendon inflammation, bone oedema, and erosion at first presentation (n = 42), at 1 year (n = 42), and at 6 years (n = 31). At 8 years, clinical reassessment (n = 28) was undertaken. Tendon function was graded 0-3 for movement, tendon sheath swelling, and pain on resistance at nine flexor and extensor tendons of the hand. Hand function was also assessed using the Sollerman grip test. The requirement for joint or tendon surgery by 8 years was determined by telephone survey in 39 of the original 42 patients. RESULTS: At 8 years, tendon function was highly correlated with hand function (Sollerman score, R = -0.51, p = 0.005) and global function (health assessment questionnaire score, R = 0.53, p = 0.004). Using a model incorporating baseline and 1 year MRI scores, the MRI bone oedema score was strongly predictive of tendon function at 8 years (chi(2)(2) = 15.3, p = 0.0005), as was the MRI bone erosion score (chi(2)(2) = 9.23, p = 0.01). Hand function was also predicted by the baseline MRI erosion score (p = 0.02). MRI variables did not predict the requirement for surgery, but patients who had surgery were more likely to show progression of MRI bone erosion scores between baseline and 1 year (p = 0.008). CONCLUSIONS: Extensive MRI bone oedema and erosions at the wrist in early rheumatoid arthritis predict tendon dysfunction and impaired hand function in the medium term but not the requirement for joint or tendon surgery.
17009247 Regulation of Mcl-1 expression in rheumatoid arthritis synovial macrophages. 2006 Oct OBJECTIVE: Resistance to apoptosis may be an important mechanism contributing to the persistence of rheumatoid arthritis (RA). This study was undertaken to characterize the expression, regulation, and function of the antiapoptotic Bcl-2 family member Mcl-1 in macrophages isolated from the joints of patients with RA. METHODS: Mononuclear cells were isolated from the synovial fluid (SF) of patients with RA. Mcl-1 expression was documented by intracellular staining of CD14+ cells using flow cytometry, and by real-time polymerase chain reaction or immunoblot analysis of isolated macrophages. The expression of Mcl-1 was suppressed with small interfering RNA (siRNA) or chemical inhibitors of the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt-1 and signal transducer and activator of transcription 3 (STAT-3) pathways. Apoptosis was defined by the loss of mitochondrial transmembrane potential and by DNA fragmentation. RESULTS: The expression of Mcl-1 was increased in CD14+ macrophages from the SF of patients with RA compared with normal in vitro-differentiated macrophages. Inhibition of the PI 3-kinase/Akt-1 or STAT-3 pathways significantly reduced the percentage of CD14+ cells within the SF and resulted in the reduction of Mcl-1 and the induction of apoptosis of synovial macrophages. Transfection of RA synovial macrophages with Mcl-1 siRNA resulted in apoptotic cell death. CONCLUSION: Mcl-1 is critical for the survival of macrophages in the joints of patients with RA, and is therefore a potential therapeutic target in this disease.
16530306 Pathogenesis of neutropenia in large granular lymphocyte leukemia and Felty syndrome. 2006 Sep T-cell large granular lymphocyte leukemia (TLGL) is an atypical chronic lymphoproliferative disorder derived from cytotoxic T-cells (CTL). Unlike most forms of leukemia, the pattern of bone marrow infiltration in TLGL may be subtle and the cytopenias are often lineage specific, with neutropenia dominating. Both granulocytic survival and proliferation defects are observed and are mediated by humoral and cell-mediated mechanisms respectively. Splenic production of immune complexes induces a neutrophil survival defect, where as Fas expression by leukemic CTL results in a marrow based proliferation defect. These humoral and cell-mediated pathways induce granulocytic apoptosis through independent intracellular mechanisms which are not mutually exclusive and may be observed concurrently in individual patients with either TLGL or FS. A variety of therapeutic interventions have been utilized in the management of TLGL and Felty syndrome, including methotrexate, cyclosporine A, cyclophosphamide, glucocorticoids, myeloid colony stimulating factors and splenectomy. Their efficacy and mechanisms of action are reviewed.
17429118 Uncemented primary press-fit total hip arthroplasty: a 3 to 6 years of experience. 2007 Apr PURPOSE: To analyse the 3 to 6 years' clinicoradiological outcome of 45 uncemented total hip arthroplasties performed in 37 patients using cementless Spotorno stem and St Nabor cup. METHODS: The main indications for surgery were avascular necrosis of the femoral head and rheumatoid arthritis. Younger patients with good bone quality and a trumpet-shaped femur were eligible. A single surgeon performed all the operations using a posterolateral approach. Patients were reviewed at 6 weeks, 3 months, 6 months, and yearly thereafter. The clinical status was recorded using the Harris Hip Score. All radiographs were analysed by 2 independent blinded observers on 2 separate occasions. RESULTS: The mean follow-up period was 49 months and the mean Harris Hip Score at the latest follow-up was 94. Osseointegration in the form of trabeculae running from the endosteum to the prosthesis surface along with tropism of the calcar was evident in 73% of the hips. None of the remaining hips showed any continuous radio-opaque lines suggestive of a lack of bone ongrowth. Patients with endosteal condensation had better Harris Hip Scores. Intra-operative stability of the implants could fairly predict outcome. CONCLUSION: Initial clinicoradiological results of uncemented total hip arthroplasty are promising in younger patients with good bone quality and a trumpet-shaped femur.
17338291 Mean changes versus dichotomous definitions of improvement. 2007 Feb In recent years, when reporting the results of clinical trials for chronic disease, including rheumatologic conditions, use has been made of dichotomous definitions of improvement, but it is to be expected that continuous definitions would offer improved discrimination between treatment groups. Nevertheless, a well-constructed dichotomous outcome (usually a composite) has advantages of clinical sense and specificity and may, under a variety of realistic conditions, have power that closely approximates that of standard continuous outcome measures. This has been seen for established dichotomous outcome definitions for two rheumatologic conditions, rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Simulation studies performed using multivariate normal generated data that approximates actual trial data for each of RA and AS patients demonstrate the relative power of several dichotomous and continuous outcomes in realistic situations for each of RA and AS. Although the continuous outcomes are typically more powerful than the dichotomous ones, there are some situations in which the power of a well-defined dichotomous outcome approaches or even exceeds that of a continuous outcome based on mean change.
17985407 Disease activity score-28 values differ considerably depending on patient's pain perceptio 2007 Dec OBJECTIVE: To determine if the Disease Activity Index including a 28-joint count (DAS28) is equally applicable for the total population with rheumatoid arthritis (RA). METHODS: Five hundred fifty-seven outpatients with RA [432 women, 125 men; median age 64 yrs (range 0-85), median disease duration 48 mo (range 2-548)] were enrolled consecutively into this cross-sectional study. DAS28, physician's global assessment of disease activity, patient's assessment of pain on visual analog scale, C-reactive protein (mg/dl), rheumatoid factor (RF), and disease duration were recorded. t-tests were applied for all comparisons of DAS28 values. Linear regression analysis was performed for each confounding factor. RESULTS: The mean DAS28 in female patients was 3.66 +/- 0.57 SEM, and in males 3.01 +/- 1.12 (p < 0.001). DAS values in patients with early RA (< 37 mo) were significantly higher than in patients with advanced RA (3.62 +/- 0.67 vs 3.37 +/- 0.81, respectively; p < 0.017). Regression analysis revealed a highly significant relationship between DAS28 score and patient's pain rating (r = 0.592, p < 0.0001). Pain exerted the greatest influence on the DAS28 (p < 0.0001), while of the other factors only age (p < 0.008 for females, p < 0.007 for males) was also significantly correlated with the DAS28 values. CONCLUSION: DAS28 values differ considerably depending primarily on the patient's pain perception and gender and to a lesser degree on patient's age, whereas results for disease duration and RF were inconclusive.
18405783 Clinical and patient-reported outcomes in clinical trials of abatacept in the treatment of 2008 Mar BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic joint inflammation, which if left untreated leads to progressive disability and joint destruction. A combination of antiinflammatory agents, steroids, disease-modifying antirheumatic drugs, and biological agents are used to treat RA. Beyond the use of conventional measures of disease activity, such as American College of Rheumatology (ACR) response rates, the importance of patient-reported outcomes (PROs) in assessing therapeutic benefits is gaining increasing emphasis in clinical trials of RA and other chronic illnesses. Clinical trials testing new RA therapeutics generally include health-related quality of life (HRQoL) measures and assessments of function and disability. Abatacept, a costimulation modulator that selectively targets the activation of T cells and downregulates the immune response, has been approved by the US Food and Drug Administration for the treatment of RA, with or without methotrexate. OBJECTIVE: The aim of this review was to summarize the clinical outcomes and PROs in published trials of abatacept. METHODS: A literature search was performed using the MEDLINE, EMBASE, and BIOSIS databases (restricted to articles posted between January 2000 and September 2007) with the search terms CTLA-4Ig, abatacept, and Orencia to identify published trials of abatacept. Primary clinical trial publications in patients with RA were selected. The ACR response and PROs data presented in the identified publications are summarized in this review. RESULTS: Our search identified 6 studies that met our selection criteria, which included 1 Phase IIa study, 2 Phase IIb studies, and 3 Phase III studies. The Phase IIa study found that abatacept was more effective than placebo and that physical function improved in treated patients compared with placebo. The 2 Phase IIb studies in 339 patients with RA previously treated with methotrexate found statistically significant improvements in HRQoL with abatacept at 6 months and 1 year. Similar findings were noted in the published Phase III trials. Across clinical trials, abatacept has been associated with clinically meaningful and statistically significant improvements in conventional measures of disease activity, HRQoL, and physical function. CONCLUSIONS: These 6 published trials found that abatacept was associated with significant improvements in both conventional measures of disease activity and PROs. Continued assessment of these outcomes will be required to further support the findings of the Phase II and III abatacept clinical trial literature reviewed here.
18957482 Perinatal characteristics, early life infections and later risk of rheumatoid arthritis an 2009 Jul OBJECTIVES: To investigate the importance of birth characteristics and early life infections on the risk of later rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). METHODS: A nationwide register-based case-control study was performed based on prospectively recorded data on individuals born in 1973 or later. Using the Swedish inpatient register and the early arthritis register, cases with RA aged 16 years or above (n = 333) and JIA (n = 3334) were identified. From the Swedish medical birth register (MBR), four controls per case, matched by sex, year and delivery unit were randomly selected. Through linkage to the MBR and to the Swedish inpatient register information on maternal, pregnancy and birth characteristics and infections during the first year of life was identified. Univariate and multivariate odds ratios (OR) were calculated using conditional logistic regression. RESULTS: Overall, infections during the first year of life were associated with increased risks for seronegative (OR 2.6, 95% CI 1.0 to 7.0) but not seropositive (OR 1.2) RA and for JIA (OR 1.9, 95% CI 1.7 to 2.1). Low birth weight (OR 0.7) and being small for gestational age (OR 0.5) were associated with reduced risks of RA of borderline statistical significance. Preterm birth (gestational age < or =258 days) was associated with a non-significantly decreased risk of RA (OR 0.6). Large for gestational age (OR 1.6) and having more than three older siblings (OR 1.4) were non-significantly associated with the risk of RA. CONCLUSION: Infections during the first year of life, and possibly also factors related to fetal growth and timing of birth, may be important in the aetiologies of adult RA and JIA.
19035412 American College of Rheumatology quality indicators for rheumatoid arthritis: benchmarking 2008 Dec 15 OBJECTIVE: To measure how rheumatologists across our health system performed with the American College of Rheumatology (ACR) quality indicators (QIs) for rheumatoid arthritis (RA) and methotrexate (MTX) drug safety, and to develop opportunities for improvement. METHODS: An electronic health record (EHR) review of 1,062 unique RA patients seen by 15 rheumatologists in a 1-year period was performed. Percentage of each QI met, reasons why the metric was not met, and performance of rheumatologists based on years of experience were evaluated. RESULTS: The percentage met was high for QI-2 (RA disease-modifying antirheumatic drug use; 94%), QI-3 (intervention if RA worse; 85%), and QI-4 (MTX risks discussion; 87%). Percentage met was lower for QI-1 (RA core data set; 69%), QI-5 (MTX baseline studies; 41%), and QI-6 (MTX followup studies; 46%). QI-1 and QI-5 were low due to most physicians missing a single test, and QI-6 was low because of few physicians driving the percentage down. Better QI performance was seen in rheumatologists with 10 years of experience for QI-1 (90% versus 64%; odds ratio [OR] 4.21, P = 0.004) and QI-3 (96% versus 82%; OR 4.47, P = 0.019). EHR chart review for this population required 179.3 hours. CONCLUSION: Measurement allows us to better understand the quality of care that we deliver. In this systematic benchmarking of the ACR QIs in a large RA cohort, performance was excellent in RA treatment-related QIs. Significant variability was noted in RA and MTX monitoring measures, which can be addressed using process redesign techniques.
19074911 The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who und 2009 Nov OBJECTIVE: To assess the safety, tolerability and efficacy of abatacept in patients with rheumatoid arthritis (RA) who had failed anti-tumour necrosis factor (TNF) therapy and were switched to abatacept directly or after completing washout. METHODS: In this international, 6-month, open-label trial, patients had active RA, an inadequate response to anti-TNF therapy for 3 months or longer and a disease activity score in 28 joints (DAS28 (C-reactive protein; CRP) of 5.1 or greater. "Washout" patients discontinued anti-TNF therapy 2 months or longer pre-screening; "direct-switch" patients began abatacept ( approximately 10 mg/kg) at their next scheduled anti-TNF therapy dose. RESULTS: 1046 patients were treated (449 washout, 597 direct-switch; baseline characteristics were similar between groups). At 6 months, adverse events (AE; 78.0% vs 79.2%), serious AE (11.1% vs 9.9%) and discontinuations due to AE (3.8% vs 4.0%) and serious AE (2.0% vs 1.3%) were comparable in washout versus direct-switch patients. There were no opportunistic infections. At 6 months, in washout versus direct-switch patients, similar clinically meaningful improvements were seen in DAS28 (CRP) (> or =1.2 unit improvement, 59.5% vs 53.6%, respectively; low disease activity state, 22.5% vs 22.3%; DAS28-defined remission, 12.0% vs 13.7%), physical function (health assessment questionnaire disability index > or =0.22 improvement; 46.3% vs 47.1%) and health-related quality of life (mean change in short-form 36 scores: physical component summary, 5.5 vs 6.1; mental component summary, 4.8 vs 5.4). CONCLUSION: Abatacept demonstrated acceptable safety and tolerability and clinically meaningful efficacy over 6 months in patients with inadequate response to anti-TNF therapy. Results were comparable with or without a washout, supporting direct switching from anti-TNF therapy to abatacept as an option in clinical practice. TRIAL REGISTRATION NUMBER: NCT00124982.
18724604 Cardiovascular disease--the silent killer in rheumatoid arthritis. 2008 Aug Rheumatoid arthritis (RA) is a multisystem disease with high rates of morbidity and mortality. In recent years, there has been increasing focus on the growing rates of cardiovascular disease (CVD) in RA, over and above expected levels allowing for 'traditional' risk factors. In this paper the impact of CVD in RA, the relative contributions of traditional risk factors and novel risk factors (including homocysteine, oxidised low-density lipoprotein, high-sensitivity C-reactive protein and leptin), and the need to address cardiovascular risk in the fight against premature death from coronary artery and stroke disease in RA are discussed.
17484112 Quantification of proteins and metabolites by mass spectrometry without isotopic labeling. 2007 We demonstrate the quantification capability and robustness of a new integrated liquid chromatography-mass spectrometry (LC-MS) approach for large-scale profiling of proteins and metabolites. This approach to determine differential expression relies on linearity of signal vs molecular concentration using electrospray ionization LC-MS, reproducibility of sample processing, a novel normalization strategy and associated data analysis software. No isotopic tagging or spiking of internal standards is required. The method is general and applicable to the proteome and metabolome from all biological fluids and tissues. Small or large numbers of samples can be profiled in a single experiment. Differential profiling of 6000 molecular ions per sample by one-dimensional chromatography LC-MS and 30,000 molecular ions per sample by two-dimensional chromatography LC-MS is demonstrated using rheumatoid arthritis patient samples compared with control samples. A new approach to peptide identification is described that involves building libraries of previously identified peptides, circumventing the need to acquire MS/MS data during profiling. Robustness of the platform was tested by repeating sample preparation and LC-MS differential expression analysis after 10 mo, using independent serum aliquots stored at -80 degrees C. To the best of our knowledge, this is the first demonstration of long-term robustness of a platform for quantitative proteomics and metabolomics.
17410521 The construction of standard gamble utilities. 2008 Jan Health effects for cost-effectiveness analysis are best measured in life years, with quality of life in each life year expressed in terms of utilities. The standard gamble (SG) has been the gold standard for utility measurement. However, the biases of probability weighting, loss aversion, and scale compatibility have an inconclusive effect on SG utilities. We determined their effect on SG utilities using qualitative data to assess the reference point and the focus of attention. While thinking aloud, 45 healthy respondents provided SG utilities for six rheumatoid arthritis health states. Reference points, goals, and focuses of attention were coded. To assess the effect of scale compatibility, correlations were assessed between focus of attention and mean utility. The certain outcome served most frequently as reference point, the SG was perceived as a mixed gamble. Goals were mostly mentioned with respect to this outcome. Scale compatibility led to a significant upward bias in utilities; attention lay relatively more on the low outcome and this was positively correlated with mean utility. SG utilities should be corrected for loss aversion and probability weighting with the mixed correction formula proposed by prospect theory. Scale compatibility will likely still bias SG utilities, calling for research on a correction.
17804836 TRAF1-C5 as a risk locus for rheumatoid arthritis--a genomewide study. 2007 Sep 20 BACKGROUND: Rheumatoid arthritis has a complex mode of inheritance. Although HLA-DRB1 and PTPN22 are well-established susceptibility loci, other genes that confer a modest level of risk have been identified recently. We carried out a genomewide association analysis to identify additional genetic loci associated with an increased risk of rheumatoid arthritis. METHODS: We genotyped 317,503 single-nucleotide polymorphisms (SNPs) in a combined case-control study of 1522 case subjects with rheumatoid arthritis and 1850 matched control subjects. The patients were seropositive for autoantibodies against cyclic citrullinated peptide (CCP). We obtained samples from two data sets, the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA). Results from NARAC and EIRA for 297,086 SNPs that passed quality-control filters were combined with the use of Cochran-Mantel-Haenszel stratified analysis. SNPs showing a significant association with disease (P<1x10(-8)) were genotyped in an independent set of case subjects with anti-CCP-positive rheumatoid arthritis (485 from NARAC and 512 from EIRA) and in control subjects (1282 from NARAC and 495 from EIRA). RESULTS: We observed associations between disease and variants in the major-histocompatibility-complex locus, in PTPN22, and in a SNP (rs3761847) on chromosome 9 for all samples tested, the latter with an odds ratio of 1.32 (95% confidence interval, 1.23 to 1.42; P=4x10(-14)). The SNP is in linkage disequilibrium with two genes relevant to chronic inflammation: TRAF1 (encoding tumor necrosis factor receptor-associated factor 1) and C5 (encoding complement component 5). CONCLUSIONS: A common genetic variant at the TRAF1-C5 locus on chromosome 9 is associated with an increased risk of anti-CCP-positive rheumatoid arthritis.
17980044 Acupuncture in the treatment of rheumatoid arthritis: a double-blind controlled pilot stud 2007 Nov 3 BACKGROUND: In planning a randomized controlled trial of acupuncture, we conducted a pilot study using validated outcome measures to assess the feasibility of the protocol, and to obtain preliminary data on efficacy and tolerability of 3 different forms of acupuncture treatment as an adjunct for the treatment of chronic pain in patients with Rheumatoid arthritis (RA). METHODS: The study employs a randomized, prospective, double-blind, placebo-controlled trial to evaluate the effect of electroacupuncture (EA), traditional Chinese acupuncture (TCA) and sham acupuncture (Sham) in patients with RA. All patients received 20 sessions over a period of 10 weeks. Six acupuncture points were chosen. Primary outcome is the changes in the pain score. Secondary outcomes included the changes in the ACR core disease measures, DAS 28 score and the number of patients who achieved ACR 20 at week 10. RESULTS: From 80 eligible patients, 36 patients with mean age of 58 +/- 10 years and disease duration of 9.3 +/- 6.4 years were recruited. Twelve patients were randomized to each group. Twelve, 10 and 7 patients from the EA, TCA and Sham group respectively completed the study at 20 weeks (p < 0.03); all except one of the premature dropouts were due to lack of efficacy. At week 10, the pain score remained unchanged in all 3 groups. The number of tender joints was significantly reduced for the EA and TCA groups. Physician's global score was significantly reduced for the EA group and patient's global score was significantly reduced for the TCA group. All the outcomes except patient's global score remained unchanged in the Sham group. CONCLUSION: This pilot study has allowed a number of recommendations to be made to facilitate the design of a large-scale trial, which in turn will help to clarify the existing evidence base on acupuncture for RA. TRIAL REGISTRATION: ClinicalTrials.gov NCT00404443.
16446172 Could single-nucleotide polymorphisms (SNPs) affecting the tumour necrosis factor promoter 2006 Tumour necrosis factor (TNF), a cytokine mainly produced by macrophages, is associated with a broad spectrum of biological effects, mainly associated with the host defense against microbes. The TNF gene is located on chromosome six within the major histocompatibility complex (MHC). Rheumatoid arthritis (RA) is a systemic autoimmune disease where TNF plays a central role in its etiology and pathogenesis. Written medical evidence of RA can be traced at least as far back as the 17th century, while human paleopathological studies appear to show the presence of RA prior to this period. The fact that RA has experienced an increment both in severity and mortality could be explained by many causes, particularly the crucial role of the immune system. Single-nucleotide polymorphisms (SNPs) are the most common genetic variations and occur at a frequency of approximately 1 in 1000 bp throughout the genome. The -308 TNF SNP is a mutation that affects the promoter region of the TNF gene. It defines the TNF1 and TNF2 alleles, determining low and high levels of TNF expression, respectively. The presence of the TNF2 allele has also been linked to increased susceptibility to and severity in a variety of autoimmune and inflammatory disorders, including RA, systemic lupus erythematosus, and ankylosing spondylitis. Studies on the functional significance of -308 SNP have detected higher levels of TNF production by cells from TNF2-carrying individuals than cells from TNF1 individuals. This difference does not appear to be due to other genes lying within the MHC region. Since the presence of the TNF2 allele may increase the host's resistance to local infection, by increasing local production of TNF at the infection site, we may suggest that such a mutation has emerged as a selective advantage to carriers of the TNF2 allele. This hypothesis may prove itself by observing the high incidence of tuberculosis and other infectious processes in those patients treated with anti-TNF therapy. Since the human lifespan has increased, the persistence of the TNF2 allele at high frequency in the population now confers what appears to be a marked survival disadvantage. As a result of the disregulation of the immune system, the genetically-predisposed host expresses larger amounts of TNF, leading to chronic inflammatory processes and autoimmune diseases, currently more prevalent. We suggest that RA, a relatively new and increasingly frequent disease, is favored by the presence of the -308 TNF promoter polymorphism, responsible for increased TNF production.
16980401 Test of association between haplotypes and phenotypes in case-control studies: examination 2006 Nov The use of haplotype information in case-control studies is an area of focus for the research on the association between phenotypes and genetic polymorphisms. We examined the validity of the application of the likelihood-based algorithm, which was originally developed to analyze the data from cohort studies or clinical trials, to the data from case-control studies. This algorithm was implemented in a computer program called PENHAPLO. In this program, haplotype frequencies and penetrances are estimated using the expectation-maximization algorithm, and the haplotype-phenotype association is tested using the generalized likelihood ratio. We show that this algorithm was useful not only for cohort studies but also for case-control studies. Simulations under the null hypothesis (no association between haplotypes and phenotypes) have shown that the type I error rates were accurately estimated. The simulations under alternative hypotheses showed that PENHAPLO is a robust method for the analysis of the data from case-control studies even when the haplotypes were not in HWE, although real penetrances cannot be estimated. The power of PENHAPLO was higher than that of other methods using the likelihood-ratio test for the comparison of haplotype frequencies. Results of the analysis of real data indicated that a significant association between haplotypes in the SAA1 gene and AA-amyloidosis phenotype was observed in patients with rheumatoid arthritis, thereby suggesting the validity of the application of PENHAPLO for case-control data.
18759306 Replication of the tumor necrosis factor receptor-associated factor 1/complement component 2008 Sep OBJECTIVE: We recently showed, using a candidate gene approach in a case-control association study, that a 65-kb block encompassing tumor necrosis factor receptor-associated factor 1 (TRAF1) and C5 is strongly associated with rheumatoid arthritis (RA). Compared with case-control association studies, family-based studies have the added advantage of controlling potential differences in population structure and are not likely to be hampered by variation in population allele frequencies, as is seen for many genetic polymorphisms, including the TRAF1/C5 locus. The aim of this study was to confirm this association in populations of European origin by using a family-based approach. METHODS: A total of 1,356 western European white individuals from 452 "trio" families were genotyped for the rs10818488 polymorphism, using the TaqMan allelic discrimination assay. RESULTS: We observed evidence for association, demonstrating departure from Mendel's law, with an overtransmission of the rs10818488 A allele (A = 55%; P = 0.036). By taking into consideration parental phenotypes, we also observed an increased A allele frequency in affected versus unaffected parents (A = 64%; combined P = 0.015). Individuals carrying the A allele had a 1.2-fold increased risk of developing RA (allelic odds ratio 1.24, 95% confidence interval 1.04-1.50). CONCLUSION: Using a family-based study that is robust against population stratification, we provide evidence for the association of the TRAF1/C5 rs10818488 A allele and RA in populations of European descent, further substantiating our previous findings. Future functional studies should yield insight into the biologic relevance of this locus to the pathways involved in RA.