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ID PMID Title PublicationDate abstract
19126387 [Effects of TWEAK on the synthesis of MMP-3 in fibroblast-like synoviocytes of rheumatoid 2009 Jan AIM: To investigate the effects of TWEAK on the synthesis of MMP-3 in RA FLS at different concentrations and to discuss the relative mechanism of how TWEAK involves in the destruction of articular bone and cartilage. METHODS: RA FLS were primarily cultured and stimulated with TWEAK. ELISA was used to detect the concentration of MMP-3 in cell-cultured fluid. The gene mRNA expression of MMP-3 was measured by RT-PCR. RESULTS: The level of MMP-3 induced by TWEAK at 50 and 100 microg/L was higher than that in control group, which had significant statistic difference (P<0.05).The expression level of MMP-3mRNA induced by TWEAK at 100 microg/L was 1.26 times higher than that in the control group, which had significant statistic difference (P<0.05).TNF-alpha and IL-1beta had synergetic effect on the synthesis and mRNA expression of MMP-3. The level in the synergetic group was significantly higher than that in the simple TWEAK group , which had significant statistic difference (P<0.05). CONCLUSION: TWEAK can induce RA FLS to synthesize MMP-3 and damage the articular bone and cartilage directly. TNF-alpha, IL-1beta and TWEAK had synergetic effects during the synthesis of MMP-3 in RA FLS.
19635418 Long-term follow-up on 33 TPR ankle joint replacements in 26 patients with rheumatoid arth 2009 BACKGROUND: There exist very few long-term follow-up studies, on total ankle replacement (TAR). In the present study a cohort of rheumatoid arthritic (RA) were followed for up to 23 years. METHODS: Thirty-three TAR were performed in 26 RA patients from 1980 to 1993. Removal of the prostheses and radiolucency was considered endpoints. All patients were followed to prosthesis failure or until death of the patients or until January 2008. RESULTS: Two patients with 3 prostheses were still alive with their prosthesis in place. Eighteen patients with 23 prostheses had died with their prosthesis in place. Two patients had their ipsilateral leg amputated 12 and 14 years after operation of unrelated causes. Five prostheses in 4 patients had been removed. The 10 years prosthesis survival was 85%, when removal is the endpoint. CONCLUSIONS: The long-term survival of this first generation type of TAR adds some optimism to the development of TAR.
20478729 Prediction of response to disease modifying antirheumatic drugs in rheumatoid arthritis. 2010 Dec AIM: To investigate potential predictors of response to conventional DMARDs in RA. METHODS: Study design - 6-month follow-up prospective study. PARTICIPANTS: RA patients with active disease. INTERVENTION AND FOLLOW-UP: Introduction of one DMARD. Response to treatment evaluated at 6 months (ACR20 criteria). ANALYSIS: Potential predictors of response, patients' demographics, disease activity, percentages of PBMC subsets expressing P-gp, serum IL-1β, IL-6, IL-8, IL-10, IL-12, TNF-α levels, were evaluated using univariate and multivariate logistic regression analysis. ROC curve analyses were performed in order to obtain thresholds allowing the prediction of response. RESULTS: Forty-two patients (mean age = 57 ± 13 years, mean disease duration = 5.4 ± 7.2 years) were included. MTX was given to 30. The response to therapy was predicted by the baseline serum level of TNF-α (mean = 30.2 pg/ml ± 18 in non-responders vs. 11.9 pg/ml ± 11.2 in responders). The threshold, which predicted with the best accuracy the response to treatment, was 20.1 pg/ml (sensitivity, specificity, positive and negative predictive values of 75, 78.9, 83.3, and 69.2%, respectively; AUC = 80.3%, 95% CI = 62.8-97.7%). Similar results were obtained in the subgroups of patients treated with MTX and patients with early RA of less than 3 years duration. CONCLUSION: In the present work, the serum concentration of TNF-α was related to further response to DMARDs. Other works are needed for confirmation and to assess whether such biomarker could be used to predict the response to DMARDs at the individual level.
19673215 Prospective cardiac gating of carotid three-dimensional ultrasound. 2009 Jul Quantitative measurements of carotid atherosclerosis can be determined using three-dimensional ultrasound (3DUS). This pilot study involved the development of prospective cardiac gating of 3DUS carotid images to reduce cardiac cycle-derived arterial pulsatility. The method developed uses electrocardiograph signal detection of the cardiac cycle R wave with imaging acquisition delayed in time (deltat) after the R wave is detected. Pulsatility of the common carotid artery was measured by calculating the mean percentage change in arterial cross-sectional area (%deltaA) in moderate atherosclerosis (MA) patients (12% +/- 1%) and healthy volunteers (HVs) (16% +/- 3%) and found that %deltaA was significantly higher for HV than for MA (p = 0.016) when no cardiac gating was used. The cardiac gating method was tested with deltat = 250 ms and deltat = 400 ms in young healthy volunteers and rheumatoid arthritis (RA) patients. For all 3DUS measurements acquired without gating, there was a significant association between %deltaA and age (r2 = 0.20, p = 0.035), and mean %deltaA (in HV and RA) was 13% +/- 5% [95% confidence interval (CI) = 10%-17%]. For deltat = 250 ms mean %deltaA was significantly different and decreased to 7% +/- 3% (95% CI = 5%-10%) and for deltat = 400 ms it was significantly different and decreased to 6% +/- 1% (95% CI = 6%-7%) (p = 0.001 for both comparisons). There was no significant difference in mean %deltaA between gating conditions (p = 0.8); however, the 95% CI for %deltaA was decreased for deltat = 400 ms as compared to deltat = 250 ms. Both gating methods also significantly decreased %deltaA to below the reference standard of 12% +/- 1% for MA (p < 0.01 for both comparisons), suggesting that prospective cardiac gating of carotid 3DUS reduces pulsatility effects in HV and RA to levels lower than observed for much older MA patients.
20939892 CXC chemokine receptor 4 expressed in T cells plays an important role in the development o 2010 INTRODUCTION: Chemokines and their receptors are potential therapeutic targets in rheumatoid arthritis (RA). Among these, several studies suggested the involvement of CXC chemokine 4 (CXCR4) and its ligand CXC ligand 12 (SDF-1) in RA pathogenesis. However, the role of these molecules in T-cell function is not known completely because of embryonic lethality of Cxcr4- and Cxcl12-deficient mice. In this report, we generated T cell-specific Cxcr4-deficient mice and showed that the CXCR4 in T cells is important for the development of collagen-induced arthritis (CIA). METHODS: T cell-specific Cxcr4-deficient mice were generated by using the Cre-loxP system. Mice harboring loxP sites flanking exon 2 of the Cxcr4gene (Cxcr4flox/flox) were generated by homologous recombination and crossed with Cre transgenic mice expressing Cre recombinase under the control of Lck promoter (Cxcr4+/+/Lck-Cremice) to generate T cell-specific Cxcr4-deficient mice (Cxcr4flox/flox/Lck-Cre mice). CIA was induced by immunization with chicken type II collagen and Complete Freund's Adjuvant (CFA). RESULTS: The incidence, but not the severity, of CIA was significantly reduced in Cxcr4flox/flox/Lck-Cre mice compared with Cxcr4+/+/Lck-Cre mice. We found that the expression of CXCR4 was enhanced in activated T cells, and the migration of Cxcr4-deficient T cells toward SDF-1 was severely impaired. However, antibody production, cellular proliferative response, and cytokine production on treatment with type II collagen (IIC) were normal in these knockout mice, suggesting that CXCR4 is not involved in T-helper functions. Interestingly, the proportion of CXCR4-expressing T cells was much increased in affected joints compared with that in draining lymph nodes in CIA-induced mice, and distribution of Cxcr4flox/flox/Lck-Cre mouse-derived T cells into affected joints was suppressed compared with that in Cxcr4+/+/Lck-Cre T cells. CONCLUSIONS: These results indicate that CXCR4 expression in T cells is important for the development of CIA, by recruiting activated T cells toward inflammatory sites, and suggest that CXCR4 is a good target for the treatment of RA in humans.
20971419 The reliability of one vs. three trials of pain-free grip strength in subjects with rheuma 2010 Oct STUDY DESIGN: Measurement Reliability. The purpose of the study was to evaluate the test-retest reliability of one vs. the mean of three trials of pain-free grip strength in participants with rheumatoid arthritis (RA). The study used was a repeated-measures, crossover design. Pain-free grip strength was measured with the Biometric E-Link Evaluation System V900S (Unit 25, Nine Mile Point Ind. Est., Gwent UK NP11 7HZ), pain levels recorded before and after grip tests with visual analog scale. High levels of test-retest reliability (intraclass correlation coefficient≥0.91) were found for both one trial and the mean of three trials of pain-free grip strength testing. Median values of grip strength for both methods produced comparable results. Clinically small but statistically significant increases in pain (p≤0.01) were found. One trial of pain-free grip strength is reliable and may save valuable clinical time while reducing the assessment burden placed on patients with RA. LEVEL OF EVIDENCE: N/A.
20961415 Identification of a cytokine network sustaining neutrophil and Th17 activation in untreate 2010 INTRODUCTION: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by sustained synovitis. Recently, several studies have proposed neutrophils and Th17 cells as key players in the onset and perpetuation of this disease. The main goal of this work was to determine whether cytokines driving neutrophil and Th17 activation are dysregulated in very early rheumatoid arthritis patients with less than 6 weeks of disease duration and before treatment (VERA). METHODS: Cytokines related to neutrophil and Th17 activation were quantified in the serum of VERA and established RA patients and compared with other very early arthritis (VEA) and healthy controls. Synovial fluid (SF) from RA and osteoarthritis (OA) patients was also analyzed. RESULTS: VERA patients had increased serum levels of cytokines promoting Th17 polarization (IL-1β and IL-6), as well as IL-8 and Th17-derived cytokines (IL-17A and IL-22) known to induce neutrophil-mediated inflammation. In established RA this pattern is more evident within the SF. Early treatment with methotrexate or corticosteroids led to clinical improvement but without an impact on the cytokine pattern. CONCLUSIONS: VERA patients already display increased levels of cytokines related with Th17 polarization and neutrophil recruitment and activation, a dysregulation also found in SF of established RA. 0 Thus, our data suggest that a cytokine-milieu favoring Th17 and neutrophil activity is an early event in RA pathogenesis.
19797512 Effective anti-TNF-alpha therapy can induce rapid resolution and sustained decrease of gas 2009 Nov OBJECTIVE: To examine the effect of anti-tumor necrosis factor-alpha (anti-TNF) therapy in patients with reactive AA amyloidosis associated with rheumatoid arthritis (RA). METHODS: Fourteen patients with reactive AA amyloidosis associated with RA were prospectively evaluated. Four patients were treated with infliximab and 10 with etanercept. The mean period of anti-TNF therapy was 20.1 +/- 13.8 months. Laboratory findings and renal function were examined before and after initiation of anti-TNF therapy. In 9 patients the area of amyloid deposits in serial gastroduodenal mucosal biopsy specimens was examined and image analysis was performed. RESULTS: C-reactive protein and serum amyloid A protein levels were significantly reduced after initiation of anti-TNF therapy. Twenty-four hour creatinine clearance improved in 4 patients, did not change in 5, and deteriorated in 3. Twenty-four hour urinary protein excretion was significantly decreased in 3 patients, not exacerbated in 6, and increased in 3 after initiation of anti-TNF therapy. The biopsy specimens from the 9 patients who underwent serial gastroduodenal biopsies showed significant decreases in the area of amyloid deposits, from 8.8% +/- 6.4% to 1.6% +/- 0.6% (p = 0.003) after initiation of anti-TNF therapy. Four patients showed a sustained decrease in the areas of amyloid deposits in their third biopsy specimens, and amyloid deposits were not detectable in 2. CONCLUSION: Our results indicate a striking effect of anti-TNF therapy for rapid removal and sustained disappearance of amyloid deposits in gastric mucosal tissue with amelioration of renal functions in patients with reactive amyloidosis due to RA.
20950476 A phase 2 randomized, double-blind study of AMG 108, a fully human monoclonal antibody to 2010 INTRODUCTION: Preclinical work has suggested that IL-1 plays a critical role in the pathogenesis of rheumatoid arthritis (RA). The objective of the present study was to determine the effect of a long-acting IL-1 receptor inhibitor, AMG 108, in a double-blind, placebo-controlled, parallel-dosing study in patients with active RA who were receiving stable methotrexate (15 to 25 mg/week). METHODS: Patients were randomized equally to receive placebo or 50, 125, or 250 mg AMG 108 subcutaneously every 4 weeks for 6 months. The primary efficacy endpoint was a 20% improvement in the American College of Rheumatology response (ACR20) at week 24; other efficacy endpoints included the ACR50, the ACR70, and the RA disease activity score (28-joint count Disease Activity Score) responses, patient-reported outcomes, and pharmacokinetic parameters. Safety endpoints included treatment-emergent adverse events (AEs), infectious AEs, serious AEs, serious infections, injection site reactions, laboratory abnormalities, and antibodies to AMG 108. RESULTS: Of 813 patients enrolled in the study, 204 patients were randomized to the 50 mg group, 203 to the 125 mg group, 203 to the 250 mg group, and 203 to placebo. At week 24, 40.4% of the 250 mg group, 36% of the 125 mg group, 30.9% of the 50 mg group, and 29.1% of the placebo group achieved an ACR20 (P = 0.022, 250 mg vs. placebo). Of the individual ACR components, numerical dose-dependent improvements were only seen in tender joint counts, pain (visual analog scale), and the acute phase reactants, erythrocyte sedimentation rate and C-reactive protein. No dose-related increase was observed in the incidence of treatment-emergent AEs. No deaths were reported, and the incidence of AEs and infections, serious AEs and infections, and withdrawals from study for safety were similar in the AMG 108 and placebo groups. CONCLUSIONS: This large double-blind randomized trial with a long-acting IL-1 receptor blocker, AMG 108, is consistent with the experience of other IL-1 blockers, represents a definitive experiment showing that IL-1 inhibition provides only moderate symptomatic amelioration of arthritis activity in the majority of RA patients, and provides an answer to a question that has been discussed for many years in the rheumatologic community. TRIAL REGISTRATION: ClinicalTrials.gov NCT00293826.
21794792 [Adaptation and validation of the Rheumatoid Arthritis Quality of Life Scale (RAQoL) to Me 2011 Mar OBJECTIVE: To develop and validate the Mexican-Spanish version of the Rheumatoid Arthritis Quality of Life questionnaire (RAQoL). METHODS: The original UK English version of RAQoL was translated into Mexican-Spanish version by a bilingual translation panel. An independent lay panel reviewed the instrument's item phrasing to ensure comprehensiveness and appropriateness in colloquial Mexican-Spanish. Structured cognitive debriefing interviews were conducted with 15 Rheumatoid Arthritis (RA) patients to assess face and content validity. Finally, an independent sample of RA patients completed the RAQoL and additional assessments were performed to assess reproducibility and construct validity. RESULTS: Translation and adaptation was successful as both the lay panel and cognitive debriefing participants considered the new language version to be appropriate. Fifty-seven patients were included in the final evaluation of the Mexican-Spanish version of RAQoL (73.8% female, mean age 52.4 years, SD 14.1, RA duration range 2-27 years). Cronbach's α for the new RAQoL was 0.91 and the test-retest reliability 0.92, indicating that the measure has good internal consistency and low random measurement error. The Mexican-Spanish version of RAQoL could discriminate between patients who differed on their perception of disease activity, general health status, current rating of perceived RA severity and whether or not they were experiencing a disease flare. CONCLUSIONS: The Mexican-Spanish version of RAQoL was well accepted by RA patients. The psychometric quality of the adapted questionnaire shows that it is suitable for use in clinical studies and trials of patients with RA.
19539753 TGF-beta and fibrosis in different organs - molecular pathway imprints. 2009 Aug The action of transforming-growth-factor (TGF)-beta following inflammatory responses is characterized by increased production of extracellular matrix (ECM) components, as well as mesenchymal cell proliferation, migration, and accumulation. Thus, TGF-beta is important for the induction of fibrosis often associated with chronic phases of inflammatory diseases. This common feature of TGF-related pathologies is observed in many different organs. Therefore, in addition to the description of the common TGF-beta-pathway, this review focuses on TGF-beta-related pathogenetic effects in different pathologies/organs, i. e., arthritis, diabetic nephropathy, colitis/Crohn's disease, radiation-induced fibrosis, and myocarditis (including their similarities and dissimilarities). However, TGF-beta exhibits both exacerbating and ameliorating features, depending on the phase of disease and the site of action. Due to its central role in severe fibrotic diseases, TGF-beta nevertheless remains an attractive therapeutic target, if targeted locally and during the fibrotic phase of disease.
21087494 Anticitrullinated protein antibody (ACPA) in rheumatoid arthritis: influence of an interac 2010 INTRODUCTION: A deletion polymorphism in glutathione S-transferase Mu-1 (GSTM1-null) has previously been implicated to play a role in rheumatoid arthritis (RA) risk and progression, although no prior investigations have examined its associations with anticitrullinated protein antibody (ACPA) positivity. The purpose of this study was to examine the associations of GSTM1-null with ACPA positivity in RA and to assess for evidence of interaction between GSTM1 and HLA-DRB1 shared epitope (SE). METHODS: Associations of GSTM1-null with ACPA positivity were examined separately in two RA cohorts, the Veterans Affairs Rheumatoid Arthritis (VARA) registry (n = 703) and the Study of New-Onset RA (SONORA; n = 610). Interactions were examined by calculating an attributable proportion (AP) due to interaction. RESULTS: A majority of patients in the VARA registry (76%) and SONORA (69%) were positive for ACPA with a similar frequency of GSTM1-null (53% and 52%, respectively) and HLA-DRB1 SE positivity (76% and 71%, respectively). The parameter of patients who had ever smoked was more common in the VARA registry (80%) than in SONORA (65%). GSTM1-null was significantly associated with ACPA positivity in the VARA registry (odds ratio (OR), 1.45; 95% confidence interval (CI), 1.02 to 2.05), but not in SONORA (OR, 1.00; 95% CI, 0.71 to 1.42). There were significant additive interactions between GSTM1 and HLA-DRB1 SE in the VARA registry (AP, 0.49; 95% CI, 0.21 to 0.77; P < 0.001) in ACPA positivity, an interaction replicated in SONORA (AP, 0.38; 95% CI, 0.00 to 0.76; P = 0.050). CONCLUSIONS: This study is the first to show that the GSTM1-null genotype, a common genetic variant, exerts significant additive interaction with HLA-DRB1 SE on the risk of ACPA positivity in RA. Since GSTM1 has known antioxidant functions, these data suggest that oxidative stress may be important in the development of RA-specific autoimmunity in genetically susceptible individuals.
20725879 [Cartilage quality in finger joints: delayed Gd(DTPA)²-enhanced MRI of the cartilage (dGE 2010 Oct PURPOSE: To evaluate the feasibility of molecular cartilage MRI in finger joints. MATERIALS AND METHODS: Delayed Gd(DTPA)²-enhanced MRI of the cartilage (dGEMRIC) using a variable flip angle approach (VFA) was performed for the metacarpophalangeal (MCP) joints II and III in nine healthy volunteers and eighteen patients with rheumatoid arthritis (RA). The cartilage thickness was measured. Additionally, dGEMRIC was performed on proximal interphalangeal joints (PIP) in two patients with finger osteoarthritis (OA). RESULTS: the dGEMRIC index of the four evaluated cartilage areas was significantly decreased in RA patients compared to healthy subjects. The dGEMRIC index of MCP II phalangeal cartilage was 389.6 ± 85.5 msec vs. 558.7 ± 74.4 msec in healthy subjects. The metacarpal MCP II cartilage dGEMRIC index was 357.3 msec ± 97.1 msec vs. 490.0 ± 86.6 msec. The dGEMRIC indices of MCP III were: phalangeal 436.2 ± 113.6 msec in RA, 558.8 ± 115.5 msec in healthy subjects and metacarpal 398.0 ± 97.6 msec in RA and 529.6 ± 111.0 msec in healthy subjects. Age and cartilage thickness were not significantly different. In PIP joints of finger osteoarthritis patients, low dGEMRIC indices were noted, compared to the controls. CONCLUSION: The dGEMRIC of finger joints is feasible in patients with RA and finger OA. Morphologically normal cartilage shows significantly decreased dGEMRIC values in RA, pointing towards cartilage degeneration on a molecular level. Further studies are needed to establish the usefulness of this technique for early diagnosis, prognosis and therapy monitoring.
21125139 Assessing the functional status and quality of life of patients with rheumatoid arthritis. 2010 Jan OBJECTIVES: To assess the impact of Rheumatoid Arthritis (RA) on functional working status, and health-related quality of life (HRQL) of patients. METHODS: This is a descriptive study with 53 patients from a public rheumatology center in Montevideo, Uruguay. A series of instruments were used to assess pain, functional impairment, HRQL, and activity level: P-VAS (Pain Visual Analogue Scale), G-VAS (Global Status Visual Analogue Scale), HAQ (Health Assessment Questionnaire), SF-12 (Medical Outcomes Study Short Form 12), and DAS 28 (Disease Activity Score). Linear regression coeficients, t test, and ANOVA were used to investigate the associations among several independent parameters and the HRQL. Correlations between the assessments of general well-being made by physicians and patients were studied using the intraclass correlation coefficients (ICC). RESULTS: High levels of disease activity (41.5%, severe activity; 26.5%, low activity or remission), severe pain (60%), and impact on global health status (median G-VAS 40, range: 0-100) were observed. More than 70% of the patients had HAQ rates indicating moderate to severe disability. The SF-12 PCS (Physical component Summary) had mean scores of 31.5 points (range 15.2- 59.5; SD=10.1) while those of the MCS (Mental Component Summary) were 37.9 points (range: 15.7 - 66.4; SD=14.6). One or more years of disease evolution and the level of activity were determining factors of HRQL scores. CONCLUSIONS: The study showed that RA is associated with higher disease burden, reflected on pain, impact on global health, and functional and working status, as well as the physical and emotional dimensions of the HRQL. The need for changes in the treatment of this psychologically vulnerable group of patients is paramount.
20300049 Polymorphisms spanning the TNFR2 and TACE genes do not contribute towards variable anti-TN 2010 May The introduction of tumour necrosis factor antagonists (anti-TNF) has greatly improved the treatment of rheumatoid arthritis, however, a significant proportion of patients fail to respond to therapy. We hypothesized that variants spanning the type 2 TNF receptor (TNFR2) and the TNF cleavage enzyme (TACE) genes contribute towards the observed variation in patient response (defined as the absolute change in 28-joint count disease activity score). Twenty-nine single nucleotide polymorphisms (SNPs) were genotyped in a large cohort of patients (n=602) and analysed by multivariate linear regression. Three SNPs (rs520916, rs652625, rs597519) mapping upstream of TNFR2 showed borderline evidence for association (P<0.1) across the complete cohort and, more so, in the etanercept-treated subgroup. However, the evidence of association was neither replicated in an independent cohort (n=377) nor strengthened after combined analysis (n=979). We conclude that common SNPs spanning the TNFR2 and TNF cleavage enzyme (TACE) genes do not have a major effect on the response to anti-TNF therapy in rheumatoid arthritis patients.
20374644 Loss of phosphoinositide 3-kinase gamma decreases migration and activation of phagocytes b 2010 Apr 7 BACKGROUND: Phosphoinositide 3-kinase gamma (PI3Kgamma) has been depicted as a major regulator of inflammatory processes, including leukocyte activation and migration towards several chemokines. This study aims to explore the role of PI3Kgamma in the murine model of antigen-induced arthritis (AIA). METHODS: Development of AIA was investigated in wildtype and PI3Kgamma-deficient mice as well as in mice treated with a specific inhibitor of PI3Kgamma (AS-605240) in comparison to untreated animals. Inflammatory reactions of leukocytes, including macrophage and T cell activation, and macrophage migration, were studied in vivo and in vitro. RESULTS: Genetic deletion or pharmacological inhibition of PI3Kgamma induced a marked decrease of clinical symptoms in early AIA, together with a considerably diminished macrophage migration and activation (lower production of NO, IL-1beta, IL-6). Also, macrophage and neutrophil infiltration into the knee joint were impaired in vivo. However, T cell functions, measured by cytokine production (TNFalpha, IFNgamma, IL-2, IL-4, IL-5, IL-17) in vitro and DTH reaction in vivo were not altered, and accordingly, disease developed normally at later timepoints CONCLUSION: PI3Kgamma specifically affects phagocyte function in the AIA model but has no impact on T cell activation.
19950324 A prospective approach to investigating the natural history of preclinical rheumatoid arth 2009 Dec 15 OBJECTIVE: To describe a large, multicenter prospective cohort study of first-degree relatives (FDRs) of probands with rheumatoid arthritis (RA), and outline the use of such a study in investigating the natural history of RA development. METHODS: A total of 1,058 FDRs, none of whom met the American College of Rheumatology criteria for RA, were enrolled in a prospective study investigating genetic and environmental influences on the development of RA-related autoimmunity. Demographic, epidemiologic, genetic, autoantibody, and physical examination data from the initial study enrollment visit were described for these FDRs, and the relationship was examined between genetic factors, autoantibodies, inflammation, and joint disease. RESULTS: Fifty-five percent of the FDRs had > or =1 copy of the shared epitope, 20% had > or =1 copy of the PTPN22 polymorphism, and approximately 16% were positive for rheumatoid factor (RF; including isotypes) and/or anti-cyclic citrullinated peptide antibody. IgM-RF positivity is associated with > or =1 tender joint on examination (odds ratio [OR] 2.50, 95% confidence interval [95% CI] 1.27-4.89; P < 0.01) and elevated C-reactive protein (CRP) levels (OR 5.31, 95% CI 1.45-19.52; P = 0.01). CONCLUSION: FDRs without RA demonstrate high prevalences of genetic risk factors and RA-related autoantibodies. Additionally, an RF association with tender joints and elevated CRP levels suggests that autoantibodies are a valid intermediate marker of RA-related autoimmunity in this cohort. This prospective FDR cohort will be a valuable resource for evaluating the relationship between genetic and epidemiologic factors and the development of RA-related autoimmunity.
20142812 Tumor necrosis factor blockade and the risk of viral infection. 2010 Mar Tumor necrosis factor (TNF) blockers are widely used to treat rheumatoid arthritis and other chronic inflammatory diseases. Many studies have demonstrated an increased risk of opportunistic infections such as tuberculosis and fungal infection in patients treated with TNF blockers, which is thought to be related to the primary role of TNF both in host defense and in the immune response. Little is known, however, about the association between TNF blockade and the development of viral infection. Owing to the critical role of TNF in the control of viral infection, depletion of this cytokine with TNF blockers could facilitate the development or reactivation of viral infection. A number of large observational studies have found an increased risk of herpes zoster in patients receiving TNF blockers for the treatment of rheumatoid arthritis. This Review draws attention to the risk of several viral infections, including HIV, varicella zoster virus, Epstein-Barr virus, cytomegalovirus, and human papillomavirus, in patients receiving TNF-blocking therapy for chronic inflammatory conditions. In addition, implications for clinical practice and possible preventative approaches are discussed.
21253435 Rodent preclinical models for developing novel antiarthritic molecules: comparative biolog 2011 Rodent models of immune-mediated arthritis (RMIA) are the conventional approach to evaluating mechanisms of inflammatory joint disease and the comparative efficacy of antiarthritic agents. Rat adjuvant-induced (AIA), collagen-induced (CIA), and streptococcal cell wall-induced (SCW) arthritides are preferred models of the joint pathology that occurs in human rheumatoid arthritis (RA). Lesions of AIA are most severe and consistent; structural and immunological changes of CIA best resemble RA. Lesion extent and severity in RMIA depends on experimental methodology (inciting agent, adjuvant, etc.) and individual physiologic parameters (age, genetics, hormonal status, etc.). The effectiveness of antiarthritic molecules varies with the agent, therapeutic regimen, and choice of RMIA. All RMIA are driven by overactivity of proinflammatory pathways, but the dominant molecules differ among the models. Hence, as with the human clinical experience, the efficacy of various antiarthritic molecules differs among RMIA, especially when the agent is a specific cytokine inhibitor.
20066426 Mean platelet volume in patients with rheumatoid arthritis: the effect of anti-TNF-α ther 2010 Jun A number of mediators are involved in the inflammatory processes that affect joints and vascular wall of patients with rheumatoid arthritis (RA). Tumour necrosis factor alpha (TNFa) is one such mediator, and it is widely regarded as an important target for anti-rheumatic treatment. Most recent studies show that anti-TNFa medication suppresses inflammation and reduces overall activity of RA. The aim of the current study was to investigate changes of mean platelet volume (MPV) in response to the 3-month anti-TNFa therapy in RA. Twenty-one RA patients without established cardiovascular disease were recruited for anti-TNFa therapy and underwent thorough clinical and laboratory evaluation at baseline, 2 weeks, and 12 weeks. Anti-TNFa therapy resulted in a significant (p = 0.01) increase in MPV over the duration of the study (7.7 +/- 0.9, 7.8 +/- 1.1, and 8.4 +/- 1.1 fL at baseline, 2 weeks, and 12 weeks, respectively). The results of the study expand perspectives of the use of MPV in conditions associated with high-grade inflammation, particularly RA, for monitoring anti-inflammatory treatment. More prospective studies with large numbers of patients are warranted to ascertain associations of high and low values of MPV with diverse markers of inflammation and vascular pathology.