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ID PMID Title PublicationDate abstract
19678909 Rheumatoid arthritis and smoking: putting the pieces together. 2009 Besides atherosclerosis and lung cancer, smoking is considered to play a major role in the pathogenesis of autoimmune diseases. It has long been known that there is a connection between rheumatoid factor-positive rheumatoid arthritis and cigarette smoking. Recently, an important gene-environment interaction has been revealed; that is, carrying specific HLA-DRB1 alleles encoding the shared epitope and smoking establish a significant risk for anti-citrullinated protein antibody-positive rheumatoid arthritis. We summarize how smoking-related alteration of the cytokine balance, the increased risk of infections (the possibility of cross-reactivity) and modifications of autoantigens by citrullination may contribute to the development of rheumatoid arthritis.
20939290 [Effects of resveratrol on proliferation and apoptosis of TNF-alpha induced rheumatoid art 2010 Jul OBJECTIVE: To observe the effect of resveratrol (Res) on in vitro proliferation and apoptosis of TNF-alpha induced rheumatoid arthritis fibroblast-like synoviocytes (RA FLS), and further to investigate the PI3 K/Akt/BAD signal mechanism. METHOD: The inhibition rate of RA FLS was examined by MTT assay. Cell cycle and the amount of apoptotic cells was measured by flow cytometry. PI3K/Akt/BAD signal transduction proteins expression was measured by western blot. RESULT: The living cells measured by MTT dose and time-dependently reduced in Res groups. In Res groups, the fraction of living cells in the S-phase and G2/M-phase decreased respectively, while that in G1-phase increased, the difference was statistically significant compared with the TNF-alpha group (P < 0.05). Flow cytometry demonstrated that the apoptosis rate increased with increased Res concentration. Res inhibited TNF-alpha induced phosphorylation of Akt and BAD in RA FLS. CONCLUSION: Res can inhibit RA FLS proliferation and induce apoptosis through inhibition of PI3K/Akt/BAD signalling pathway. Res may provide a new therapeutic approach in treatment of RA.
20022538 New insights in synovial angiogenesis. 2010 Jan Angiogenesis is the formation of new capillaries from pre-existing vessels. A number of soluble and cell-bound factors may stimulate neovascularization. The perpetuation of angiogenesis involving numerous soluble and cell surface-bound mediators has been associated with rheumatoid arthritis (RA). These angiogenic mediators, among others, include growth factors, primarily vascular endothelial growth factor (VEGF) and hypoxia-inducible factors (HIFs), as well as pro-inflammatory cytokines, various chemokines, cell adhesion molecules, proteases and others. Among the several potential angiogenesis inhibitors, targeting of VEGF, HIF-1, angiopoietin and the alpha(V)beta(3) integrin, as well as some endogenous or synthetic compounds including angiostatin, endostatin, paclitaxel, fumagillin analogues, 2-methoxyestradiol and thalidomide seems to be promising for the management of synovial inflammation and angiogenesis. A complete review of antiangiogenic drugs used in animal models of arthritis or human RA is available in a table.
20524026 Comparison of low-field dedicated extremity magnetic resonance imaging with articular ultr 2010 Dec To compare magnetic resonance imaging (MRI) and ultrasonography (US) in the detection of joint inflammation of rheumatoid arthritis (RA), 6 patients with RA were examined by US and low-field 0.3-T nonenhanced dedicated extremity MRI (compacTscan). All patients were females, with mean age of 50.2 years, mean disease duration of 13.5 years, and mean disease activity score (DAS)28-CRP of 1.78. Each patient was treated with either infliximab, etanercept, adalimumab, or tocilizumab. Intercarpal joints, radioulnar joints, second through fifth proximal interphalangeal (PIP) joints, and first through fifth metacarpophalangeal (MCP) joints (a total of 132 joints, 22 joints in each patient) were assessed by MRI for presence of joint inflammation. A total of 156 joints (24 first interphalangeal and radiocarpal joints plus the above 132 joints), were assessed by grayscale US (GS-US) and power Doppler US (PD-US) for presence of joint inflammation by two trained ultrasonographers. We assessed correlations between joint inflammations on MRI and GS-US/PD-US, and also interobserver correlation between the two ultrasonographers by calculating intraclass correlation coefficients (ICC). Synovial hypertrophy and/or synovial fluid was detected in 74/156 joints on GS-US, and synovitis was detected in 10/156 joints on PD-US and in 38/132 joints on MRI. Using PD-US as a reference, sensitivity of MRI in detection of synovitis was 80%. Using MRI as a reference, sensitivity of PD-US was 21%. Specificity of PD-US was higher than that of MRI. Overall agreement between GS-US and MRI and between PD-US and MRI was 0.56 and 0.76, respectively, suggesting that results of PD-US are close to those of MRI. ICC was 0.545 for GS-US and 0.807 for PD-US, suggesting specificity of PD-US in detecting joint inflammation. Our results show that findings of PD-US correlated with those of MRI. Low-field MRI and PD-US are useful tools for assessment of patients with RA.
19158815 Two-stage case-control association study of polymorphisms in rheumatoid arthritis suscepti 2009 Jan There is strong evidence for a negative association between schizophrenia and rheumatoid arthritis (RA). However, the mechanism for this association is unknown. We hypothesize that these two diseases share susceptibility genes. Recently, extensive studies have identified some RA susceptibility genes, including NFKBIL1, SLC22A4, RUNX1, FCRL3 and PADI4, in the Japanese population. To assess whether polymorphisms in these RA susceptibility genes are implicated in vulnerability to schizophrenia, we conducted a two-stage case-control association study in Japanese subjects. In a screening population of 534 patients and 559 control subjects, we examined eight polymorphisms in RA susceptibility genes and found a potential association of padi4_94 in PADI4 with schizophrenia. However, we could not replicate this association in a confirmatory population of 2126 patients and 2228 control subjects. The results of this study suggest that these polymorphisms in RA susceptibility genes do not contribute to genetic susceptibility to schizophrenia.
20156953 Standardization of joint examination technique leads to a significant decrease in variabil 2010 Apr OBJECTIVE: To reduce the amount of variability among assessors, we conducted joint examination standardization seminars in conjunction with multicenter clinical trials for patients with rheumatoid arthritis (RA). The examination techniques used were based on the recommendations of the European League Against Rheumatism (EULAR). METHODS: To evaluate the effect of standardization, participants at the seminars examined a given patient with RA before and after they were made familiar with the EULAR examination technique. The number of tender and swollen joints as well as the variance among the examiners before and after the training were compared. Joints were rated positive or negative for tenderness and swelling without grading. RESULTS: Overall, 553 individuals from a variety of countries in Europe, North America, Asia, and Australia participated. Examiners included different kinds of health professionals, mainly physicians and nurses. We found a substantial variance among examiners before the training in the standardized method. This variance could be significantly reduced by the training. We also found that the number of joints considered active was markedly reduced after the training. CONCLUSION: Standardized joint examination training significantly reduces variability among different assessors.
20864908 Optimal treatment of rheumatoid arthritis: EULAR recommendations for clinical practice. 2010 Sep Three important concepts have become standard of care in treating rheumatoid arthritis (RA): 1) development of new drugs: biologic agents; 2) treatment strategies: not an individual drug, but the timely combination of different drugs, given as a specific strategy; 3) treat to target: targeting treatment to the individual patient and adapting treatment when necessary. These concepts led to the development of the European League against Rheumatism recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs. Three so called overarching principles have been formulated, followed by 15 concrete recommendations for the management of RA. These 15 recommendations are described and discussed in this review, with some personal comments. An enormous gain in the development of RA has been achieved, and it is now time to consolidate that gain and make optimal treatment available for every RA patient in Europe. The guidelines described in this article will help physicians to actually do so.
20212387 [MR imaging of the hands in rheumatoid arthritis]. 2010 Jan MRI of the hands in patients with rheumatoid arthritis is becoming routine. It is therefore necessary to develop simple standardized protocols providing fast imaging. It is best to image both hands simultaneously, from distal radioulnar to proximal interphalangeal joints, using a surface coil. Three imaging features are evaluated: synovitis, marrow edema and erosions. These can be quantified with the 'RAMRIS' score based on T1-weighted, fat-suppressed T2-weighted and fat-suppressed contrast material enhanced T1-weighted sequences in 2 planes (coronal and axial). Dynamic imaging provides improved evaluation of synovial inflammation.
19693272 Multiparameter phospho-flow analysis of lymphocytes in early rheumatoid arthritis: implica 2009 Aug 20 BACKGROUND: The precise mechanisms involved in the initiation and progression of rheumatoid arthritis (RA) are not known. Early stages of RA often have non-specific symptoms, delaying diagnosis and therapy. Additionally, there are currently no established means to predict clinical responsiveness to therapy. Immune cell activation is a critical component therefore we examined the cellular activation of peripheral blood mononuclear cells (PBMCs) in the early stages of RA, in order to develop a novel diagnostic modality. METHODS AND FINDINGS: PBMCs were isolated from individuals diagnosed with early RA (ERA) (n = 38), longstanding RA (n = 10), osteoarthritis (OA) (n = 19) and from healthy individuals (n = 10). PBMCs were examined for activation of 15 signaling effectors, using phosphorylation status as a measure of activation in immunophenotyped cells, by flow cytometry (phospho-flow). CD3+CD4+, CD3+CD8+ and CD20+ cells isolated from patients with ERA, RA and OA exhibited activation of multiple phospho-epitopes. ERA patient PBMCs showed a bias towards phosphorylation-activation in the CD4+ and CD20+ compartments compared to OA PBMCs, where phospho-activation was primarily observed in CD8+ cells. The ratio of phospho (p)-AKT/p-p38 was significantly elevated in patients with ERA and may have diagnostic potential. The mean fluorescent intensity (MFI) levels for p-AKT and p-H3 in CD4+, CD8+ and CD20+ T cells correlated directly with physician global assessment scores (MDGA) and DAS (disease activity score). Stratification by medications revealed that patients receiving leflunomide, systemic steroids or anti-TNF therapy had significant reductions in phospho-specific activation compared with patients not receiving these therapies. Correlative trends between medication-associated reductions in the levels of phosphorylation of specific signaling effectors and lower disease activity were observed. CONCLUSIONS: Phospho-flow analysis identified phosphorylation-activation of specific signaling effectors in the PB from patients with ERA. Notably, phosphorylation of these signaling effectors did not distinguish ERA from late RA, suggesting that the activation status of discrete cell populations is already established early in disease. However, when the ratio of MFI values for p-AKT and p-p38 is >1.5, there is a high likelihood of having a diagnosis of RA. Our results suggest that longitudinal sampling of patients undergoing therapy may result in phospho-signatures that are predictive of drug responsiveness.
20889600 Quantitative power Doppler ultrasonography is a sensitive measure of metacarpophalangeal j 2010 Dec OBJECTIVE: To investigate the stability over 2 weeks of ultrasonographic assessments of synovial thickness and vascularity in all 10 metacarpophalangeal joints of subjects with rheumatoid arthritis (RA) with a range of disease activities as measured by the validated Disease Activity Score-28 joint score (DAS28-ESR). And in subjects with severe disease activity, to compare the sensitivity of these measurements, acute-phase markers, and vascular endothelial growth factor to change in response to 2 weeks of oral prednisolone (7.5 mg daily). METHODS: A group of 38 subjects with RA were enrolled, 13 (mean DAS28 2.1), 14 (mean DAS28 5.2), and 11 (mean DAS28 5.7) meriting oral corticosteroid treatment. Synovial thickness and vascularity were assessed by ultrasonography at 3 timepoints. Images were ranked by semiquantitative scale. Vascularity was also measured by quantitative determination of the power Doppler area (PDA). RESULTS: In the whole RA cohort, baseline indices of synovial thickness and vascularity correlated with DAS28, as did PDA (r = 0.42, p < 0.05). In the RA groups on stable therapy, synovial thickness and vascularity showed little variation over 2 weeks. In the corticosteroid group, PDA had fold changes of -1.9-fold (p < 0.05) after 1 week and -2.2-fold (p < 0.05) after 2 weeks. These were the largest fold changes of all measured variables. CONCLUSION: Ultrasonographic measures can differentiate disease severity in RA correlating closely with DAS28. Quantitative power Doppler signal was significantly reduced within 1 week of oral prednisolone, a rapid kinetic suggesting that PDA may have value as a sensitive early marker of therapeutic response.
19685931 Tumour necrosis factor-alpha antagonists in the management of rheumatoid arthritis in the 2009 Rheumatoid arthritis (RA) is a chronic inflammatory disease that frequently affects people aged >or=65 years, causing significant impairment with pain and functional disability. Elderly RA patients have specific problems, including co-morbid diseases, numerous concomitant medications, greater number of damaged joints as a result of longer disease duration and often a more severe disease presentation in elderly-onset RA. These factors, together with an age-related decline in the immune defence mechanisms, make elderly patients more vulnerable. The new era of biologic medications has made intensive treatment of RA patients possible. Anti-tumour necrosis factor-alpha (anti-TNFalpha) agents can cause a dramatic improvement in disease activity and functional capacity, making complete remission of RA a possible target. TNFalpha has been shown to play an important role in both the healthy aging process and age-related diseases such as RA. Targeting this cytokine in elderly patients is therefore reasonable. However, it is not clear whether treatment effects can be reached to the same extent in both elderly and younger patients and whether anti-TNFalpha treatment specifically increases the risk of certain adverse events in elderly RA patients. This review discusses the currently available evidence relating to the efficacy and safety of anti-TNFalpha medication in RA patients aged >or=65 years treated in clinical trials and observational studies. Despite a slightly less robust effect in elderly patients, anti-TNFalpha treatment has a similar long-term efficacy in patients aged >or=65 years and patients aged <65 years. The majority of the study results showed that anti-TNFalpha treatment does not elevate the risk of infections beyond the risk found in age-matched controls. When a moderate increase in risk was found, this occurred equally in elderly and younger patients. Furthermore, whereas anti-TNFalpha agents were found to be relatively safe in the treatment of elderly RA patients, treatment with corticosteroids significantly elevated the risk of serious infections. Corticosteroids are frequently used in elderly patients, but the evidence suggests that preference should increasingly be given to anti-TNFalpha agents, for which the expected benefits will mostly outweigh the modestly increased risks of associated adverse events.
20961791 Cell and cytokine imbalances in rheumatoid synovitis. 2011 May Rheumatoid synovitis is a complex process in which systemic and local homeostatic dysregulation is expressed in the joint. The main genetic susceptibility factors are HLA-DRB1 alleles containing the shared epitope. Environmental factors predominate over genetic factors in the pathogenesis of rheumatoid arthritis (RA), and among them smoking is the most powerful. In RA, disruptions in self-tolerance lead to abnormalities such as recognition of citrullinated antigens by B and T cells. The balance of lymphocyte differentiation in RA is skewed toward the Th1 phenotype, to the detriment of the Th2, Th17, and T regulator (Treg) phenotypes. Imbalances occur in the main cytokine systems including IL-1, TNF, IL-6, IL-18, IL-15, IL-33, IL-22, and IL-13. The joint destruction seen in RA is caused not only by these cytokine imbalances, but also by specific effects of the Wnt system and osteoprotegerin on osteoclasts and by matrix production dysregulation responsible for cartilage damage.
20336460 Pattern-based diagnosis and screening of differentially expressed serum proteins for rheum 2011 Aug The objective of this study was to search for proteomic patterns distinguishing patients with rheumatoid arthritis (RA) from healthy controls, biomarker candidates specific for early RA, and proteins reflecting disease activity, by profiling of serum proteins using magnetic bead-based (MB) separation and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Magnetic chemical affinity beads were used to differentially capture serum proteins prior to MALDI-TOF analysis. Seventy serum samples from patients with RA and 50 from healthy controls were analyzed. The samples were randomly allocated to the training set or test set to develop a pattern by means of decision tree algorithm. ANOVA test was utilized to search for biomarkers for early RA. Pearson correlation analysis was employed to estimate the overexpressed peaks in relation to Disease Activity Score (DAS)28. The algorithm identified a pattern based on 3 peaks (m/z 2,490, 5,910.07, 6,436.73) that, in the training set, separated patients with RA from healthy controls with a sensitivity and specificity of 87.5 and 96.7%, respectively. Blind test data indicated a sensitivity of 86.7% and specificity of 90%. The peaks of m/z 1,014.92 and 1,061.38 were raised significantly in early RA group (disease duration <12 months) compared with those in non-early RA group (disease duration ≥12 months) and healthy controls. A positive correlation was found between the intensity of peak 9,591.47 and DAS28 scores. Using MB separation followed by MALDI-TOF-MS enabled rapid diagnosis of RA according to fingerprint pattern, a method which might also help to assess disease activity and identify early RA.
19430165 Rheumatoid arthritis: model of systemic inflammation driving atherosclerosis. 2009 Jun Similarities between the inflammatory pathways in atherosclerosis and rheumatoid arthritis (RA) are striking. Chronic systemic inflammation in RA patients leads to cardiovascular (CV) events beyond traditional cardiac risk factors. Clinicians typically focus on treating the joint manifestations of RA while neglecting to eliminate systemic inflammation, which leaves RA patients vulnerable to adverse CV events. In this review we provide an understanding of how systemic inflammation in RA accelerates atherosclerosis. This knowledge should guide therapeutic targets to minimize CV risk in RA, and may lead to insights into the inflammatory mechanisms of atherosclerosis in general.
19142153 Biologic agents for rheumatoid arthritis: 2008 and beyond. 2009 Jan Rheumatoid arthritis (RA) is a chronic disease with a complex underlying pathology and varied presentation in patients. Several novel biologic disease-modifying antirheumatic drugs have become available for the treatment of RA. Agents in late-stage clinical trials include golimumab and certolizumab, which are anti-tumor necrosis factor (TNF)-alpha agents; ocrelizumab, an anti-CD20 agent; and tocilizumab, an inhibitor of interleukin-6. As treatment options for RA expand, nursing care will play an increasingly important role in empowering patients through interventions such as patient education and adverse effect management.
20012868 Functional capacity in rheumatoid arthritis patients: comparison between Spanish and Brazi 2011 Feb The main objective of this study is to compare Spanish and Brazilian self-reported health-related functional capacity in patients with rheumatoid arthritis (RA). 197 patients diagnosed with RA were studied in Spain (n = 127) and Brazil (n = 70). Pain (Visual analog scale) and functional capacity (Health Assessment Questionnaire/HAQ) were assessed. Patients were questioned about regular exercise practice. Comparisons between groups were performed with Chi-square tests and Student t test. Pearson's correlation coefficient and linear regression models were used to analyze the associations. Brazilian patients were younger (p = 0.013), had worse levels of pain (p = 0.001) and a trend to experience worse functional capacity (p = 0.057) than Spanish ones. Spanish RA patients had higher body mass index (BMI) (p = 0.019) and longer disease duration (p = 0.001). Also, a higher percentage of subjects with RA from the Spanish cohort had been elected to take early retirement when compared with Brazilian patients (p = 0.010). Spanish RA patients had received more drugs than Brazilians (oral corticosteroids p = 0.010, Leflunomide p = 0.023, Methotrexate p = 0.072, non-steroidal anti-inflammatory drugs p = 0.064, biologic therapies p = 0.001). The functional capacity (HAQ) was correlated with age (p = 0.001), disease duration (p = 0.001), age at diagnosis (p = 0.001), pain (p = 0.001) and BMI (p = 0.001) in Spanish patients. In Brazilian, these correlations were only found with disease duration (p = 0.004) and pain (p = 0.001). In conclusion, our data suggest a better management of RA in Spanish when compared with Brazilians. Even with less pain and functional capacity, they receive more drug treatment and a higher percentage of them are retired early.
19208559 Investigating the validity of the minimal disease activity state for patients with rheumat 2009 Feb OBJECTIVE: To validate the definitions of minimal disease activity (MDA) in patients with rheumatoid arthritis (RA) and to compare abatacept to control with respect to patients attaining a state of MDA. METHODS: Two randomized controlled trials comparing abatacept to control in patients with RA were considered: ATTAIN and AIM. Core set measures, Disease Activity Score 28-joint count (DAS28), and, for AIM, radiographic scores were available. The core set and DAS-based definitions for MDA were calculated and the number of patients in the treatment groups meeting the definitions was compared to determine sensitivity of the criteria to treatment differences and patient severity. The number of times achieving MDA was compared to the change in Health Assessment Questionnaire (HAQ), and for the AIM study compared to change in radiographic scores. RESULTS: For both definitions of MDA, the change in radiographic scores showed a continual decrease in progression the more often a patient was in MDA. The change in HAQ, for both studies, showed a similar consistent improvement - the longer a patient was in MDA, then the better the HAQ score. Significantly more patients in the abatacept group met the core set and DAS-based definition of MDA than in the control group. CONCLUSION: The presence and persistence of MDA was associated with slowing of radiographic progression and improvement in the HAQ, providing support for discriminative and predictive validity of the measure. The MDA results were consistent with other efficacy analyses indicating a treatment advantage for abatacept.
20364358 Prevalence and predictive value of anti-cyclic citrullinated protein antibodies for future 2010 Aug The aim of this study is to evaluate the prevalence and predictive value of anti-cyclic citrullinated protein (CCP) antibodies as a diagnostic marker for future development of rheumatoid arthritis (RA) in a cohort of patients presenting with undifferentiated arthritis (UA). The study comprised 69 patients (22 males and 47 females) presenting with UA, and 66 healthy subjects as control group. For all patients the following parameters were assessed: swollen joint count (SJC), tender joint count (TJC), and duration of morning stiffness in minutes. Baseline laboratory investigations included erythrocyte sedimentation rate (ESR) first hour, C-reactive protein (CRP), complete blood count, complete liver and kidney function tests, urine analysis, anti-nuclear antibodies, rheumatoid factor (RF), and anti-CCP antibodies. Positive correlations were observed between anti-CCP versus SJC, TJC (p = 0.001), duration of morning stiffness (p = 0.04), ESR first hour, and bone erosive changes (p = 0.001). Anti-CCP showed sensitivity of 57%, specificity of 37.9%, positive predictive value of 65.1%, and negative predictive value of 39.3%. Sensitivity and positive predictive values of anti-CCP are close to those observed for RF. In patients presenting with UA, anti-CCP antibodies may allow prediction of RA, thereby allowing early individualized therapeutic decisions.
20496760 [Proteomic analysis of changes in the serum protein profile by anti-TNF-alpha therapy]. 2010 Apr We analyzed the alternation in serum protein by infliximab therapy using proteomics-based technique. More than 50 gel spots were seen to increase or decrease in correlation with clinical improvements of rheumatoid arthritis (RA). Spots of interest were identified by two dimensional electrophoresis and mass spectrometry. Infliximab therapy reduced the inflammatory proteins such as C-reactive protein, serum amyloid protein A, serum amyloid protein P, and alpha1-acid glycoprotein, while the therapy increased Apo A-I, retinol-binding protein, vitamin D-binding protein, and gelsolin. This suggested that infliximab therapy shifted the inflammatory status of serum protein profile of RA patients to normal and modified the extracellular actin-scavenging system as well as vitamin and lipid profile.
19360433 Subjective audiological tests and transient evoked otoacoustic emissions in patients with 2009 Nov We investigated hearing functions in patients with rheumatoid arthritis (RA) using audiological tests and transient evoked otoacoustic emissions (TEOAEs). The study group consisted of 20 adult patients with RA (7 males, 13 females); 20 adult healthy subjects without RA (7 males, 13 females) were recruited as controls. All patients were evaluated by pure tone audiometry, high frequency audiometry, tympanometry and TEOAEs. There were no statistical differences between the study and control groups with respect to the pure tone and high frequency audiometries. TEOAE results of 1.0-2.0 kHz % and of 1.5 and 3.0 kHz amplitude values were significantly lower, and ipsilateral stapes reflex threshold value at 1.0 kHz was significantly higher in the study group when compared to respective values in the control group. In elderly patients and those with longer disease duration, RA nodules and higher methotrexate cumulative doses, hearing thresholds increased and TEOAE values decreased. In active stage of the disease, hearing thresholds diminished and in higher Brinkman Index values, TEOAE values decreased. Compliance values decreased in patients with higher Ritchie Articular Index, C-reactive protein, erythrocyte sedimentation rate and platelet counts, and longer disease duration. Sensorineural hearing loss is generally observed in patients with RA, and this condition may be detected by TEOAEs in an early period of the disease. Inflammation during the active stage of the disease and the subsequent fibrosis may cause conductive hearing loss of varying degrees. In those patients detected as having initiation of TEOAE decrease, vasodilator treatment and antioxidant drugs may be useful in protecting the inner ear.