Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
19538337 Melatonin inhibits human fibroblast-like synoviocyte proliferation via extracellular signa 2009 Aug The excessive proliferation and migration of synoviocytes are well-characterized phenomena that play key roles in the pathophysiology of rheumatoid arthritis (RA). Melatonin has been shown to have potent anti-proliferative effect in various cancer cells such as breast and prostate cancer cells. In this study, we examined the role of melatonin on synoviocyte proliferation in primary cultured human fibroblast-like synoviocytes (FLSs) by analyzing protein expression of P21(CIP1) (P21) and P27(KIP1) (P27), the cyclin-dependent kinase inhibitors that are important in cell cycle control, and the phosphorylation of mitogen-activated protein kinases (MAPKs). RA-FLS proliferation was determined by a [(3)H]-thymidine incorporation assay. Western blot analysis was applied to examine the underlying mechanisms of melatonin's effect. Melatonin inhibited RA-FLS proliferation in a dose-dependent manner. It reduced proliferation of passage 2 FLSs by 25% at 10 microm and by nearly 40% at 100 microm concentrations. The inhibitory effect of melatonin on RA-FLS proliferation was also observed in passages 4 and 6. Melatonin upregulated the expression levels of P21 and P27 dose-dependently (24 hr), induced the phosphorylation of extracellular signal-regulated protein kinase (ERK) time-dependently (10 microm), but did not affect phosphorylation of P38 in RA-FLSs. In addition, the expression of P21 and P27 triggered by melatonin was inhibited by the pretreatment of the ERK inhibitor, PD98059 (10 microm). The anti-proliferative action of melatonin in RA-FLSs was also blocked by PD98059. Taken together, these results suggest that melatonin exerts the inhibitory effect of the proliferation of RA-FLSs through the activation of P21 and P27 mediated by ERK. Hence we suggest that melatonin could be used as a therapeutic agent for the treatment of RA.
20682671 Hypothalamus-pituitary-adrenal axis function in patients with rheumatoid arthritis treated 2010 Oct OBJECTIVE: To investigate the effects of longterm low-dose chronotherapy with modified-release (MR) prednisone for rheumatoid arthritis (RA) on the hypothalamus-pituitary-adrenal (HPA) axis as part of the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA-1) study. This consisted of a 3-month active-controlled phase and a 9-month open-label extension with MR prednisone including patients previously treated with prednisone (ClinicalTrials.gov number NCT00146640). METHODS: Corticotropin-releasing hormone (CRH) tests were performed on 28 patients at 3 timepoints: at baseline on prestudy immediate-release (IR) prednisone, after the 3-month double-blind phase on either IR prednisone or MR prednisone, and after the 9-month open-label extension on MR prednisone. Changes of cortisol were assessed and compared to individual patients' efficacy and safety data. RESULTS: The increase (mean, SD) of cortisol plasma concentrations after injection of corticorelin was 5.5 (4.37) μg/dl on IR prednisone at baseline (n = 21) and 5.3 (4.07) μg/dl on MR prednisone at 12 months (n = 22). Numbers of normal/suppressed/no response reactions did not differ among treatments. Switching from IR to MR prednisone did not influence responses, nor did longterm treatment of up to 12 months with MR prednisone. No worsening of adrenal impairment was observed on treatment with nighttime-release prednisone in patients with low responsiveness to CRH testing before the treatment with MR prednisone. CONCLUSION: Treatment with nighttime-release prednisone did not change adrenocortical function over 12 months. We presume that chronotherapy with this nighttime-release prednisone may improve the efficacy of longterm low-dose glucocorticoid treatment in patients with RA.
20235187 Association of physical function and physical activity in women with rheumatoid arthritis. 2010 Aug OBJECTIVE: To explore the associations between measures of physical activity (PA) and measures of physical function (PF) in women with rheumatoid arthritis (RA). We hypothesized that the strength of the associations between PA and PF would be moderate, and that after controlling for social and biomedical characteristics, the associations would decrease. METHODS: Women with RA (n = 47, mean +/- SD age 56.5 +/- 7.0 years) participated in the cross-sectional analysis of this study. Social and biomedical characteristics explored included age, ethnicity, disease duration, marital and educational status, height, weight, comorbidity, and disease activity. PF was measured by the self-reported Health Assessment Questionnaire (HAQ) and by a battery of performance-based measures that included self-selected gait speed, the 5 chair rise test, and the single leg stance test. PA was measured by a portable activity monitor worn for 10 days, and was characterized in 2 ways: daily average number of steps and daily energy expenditure during moderate levels of PA. RESULTS: Correlations between measures of PA and PF were small to moderate (zero-order correlations = 0.189-0.479). After controlling for social and biomedical characteristics, the correlations became smaller (semi-partial correlations = 0.095-0.277) and only HAQ score remained significantly associated with PA. CONCLUSION: Associations between measures of PA and measures of PF were explained, in part, by social and biomedical characteristics in women with RA. The results indicate that measures of PF and PA may represent different constructs and support the need to measure PA in rehabilitation research in RA.
21054095 Imaging of normal and pathologic joint synovium using nonlinear optical microscopy as a po 2010 Sep An estimated 1.3 million people in the United States suffer from rheumatoid arthritis (RA). RA causes profound changes in the synovial membrane of joints, and without early diagnosis and intervention, progresses to permanent alterations in joint structure and function. The purpose of this study is to determine if nonlinear optical microscopy (NLOM) can utilize the natural intrinsic fluorescence properties of tissue to generate images that would allow visualization of the structural and cellular composition of fresh, unfixed normal and pathologic synovial tissue. NLOM is performed on rabbit knee joint synovial samples using 730- and 800-nm excitation wavelengths. Less than 30 mW of excitation power delivered with a 40×, 0.8-NA water immersion objective is sufficient for the visualization of synovial structures to a maximum depth of 70 μm without tissue damage. NLOM imaging of normal and pathologic synovial tissue reveals the cellular structure, synoviocytes, adipocytes, collagen, vascular structures, and differential characteristics of inflammatory infiltrates without requiring tissue processing or staining. Further study to evaluate the ability of NLOM to assess the characteristics of pathologic synovial tissue and its potential role for the management of disease is warranted.
20379758 Combined effects of bucillamine and etanercept on a rat type II collagen-induced arthritis 2010 Aug The combined effects of bucillamine (Buc) and etanercept (ETN) on a rat model of type II collagen (CII)-induced arthritis (CIA) after treatment onset were investigated. In the combination treatment, rats received Buc 30 mg/kg orally administered once daily from the onset of arthritis or from 4 days after the onset of arthritis and ETN 0.3 mg/kg subcutaneously administered once on the day of onset. The effects of monotherapy with Buc and ETN, respectively, and of Buc + ETN combination therapy on the resulting polyarthritis were evaluated by histopathological analyses and measurements of hindpaw volumes, serum anti-collagen antibody and immunoglobulin levels, and cytokine levels. The Buc + ETN therapeutic combination reduced hindpaw swelling, synovial proliferation, bone destruction, new bone formation, and inflammatory cell infiltration in CIA. Montherapy with Buc showed a tendency to ameliorate these symptoms, while monotherapy with ETN reduced hindpaw swelling at 4 days after administration but did not maintain treatment efficacy toward the end of the experimental period. Histopathological findings did not reveal any efficacy of the ETN therapy. ETN alone increased the serum immunoglobulin levels, while its combination with Buc reduced these levels. Similar results were obtained for serum anti-CII antibody titers. The Buc + ETN combination treatment also reduced serum interleuking (IL)-1alpha and granulocyte macrophage colony-stimulating factor and tended to reduce serum IL-1beta and IL-6 levels. These results suggest that a combination therapy of Buc and ETN may be effective for the treatment of rheumatoid arthritis (RA).
19811270 Role of CCR5 Delta32 bp deletion in RA and SLE. 2009 May CCR5 and its ligands play important roles in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). A deletion of 32 bp in its gene leads to the production of a non-functional receptor. Although a protective effect of CCR5 Delta32 for the development of RA has been suggested, future study is required to establish the exact role of this deletion for susceptibility to SLE and lupus nephritis. Also, with regard to the association of CCR5 Delta32 with disease severity in RA and SLE, more data are needed to draw firm conclusions. This might become even more relevant as a CCR5 blocking agent is now available.
19723134 Disseminated Salmonella paratyphi infection in a rheumatoid arthritis patient treated with 2010 Jan Anti-tumour necrosis factor (TNF)-alpha treatments are immunosuppressant and represent an important risk factor for developing infections. We report a case of Salmonella paratyphi bacteraemia associated with soft tissue infection in a patient who used infliximab and had recently travelled to India. This case report provides supporting evidence, essentially based only on case reports, that patients receiving anti-TNF-alpha treatments have an increased susceptibility to Salmonella infections, which may develop at unusual and disseminated sites. We emphasize the importance of appropriate counselling of patients undergoing anti-TNF treatment and travelling to areas in which Salmonellae are endemic, as well as the importance of advice to these patients concerning food hygiene.
20211798 Mass customization of foot orthoses for rheumatoid arthritis using selective laser sinteri 2010 Jul Rheumatoid arthritis is an inflammatory joint disease that can lead to pain, stiffness, and deformity, often with marked involvement of the small joints of the foot and ankle. Orthotic devices are commonly prescribed for this condition to lessen symptoms and improve function and mobility, and customized devices are most effective. The work reported in this paper has examined the feasibility of using an additive manufacturing-based approach to manufacture customized orthoses. In order to test feasibility, orthoses have been manufactured using the additive manufacturing technology of selective laser sintering, and have been evaluated through a small-scale patient trial (n = 7). The trial indicated that these orthoses performed as well as the patients' current prescribed customized devices in terms of the observed gait and subjective evaluation of fit and comfort. It is concluded that the feasibility of the additive manufacturing approach has been demonstrated, and further development of a mass customization system to deliver orthoses, together with exploitation of the design freedom offered by the manufacturing method, will give the overall approach significant clinical potential.
21125161 Prospective evaluation of the quality of life in a cohort of patients with early rheumatoi 2010 May INTRODUCTION: Few studies have prospectively assessed the tools used to measure quality of life, both generic and specific, in patients with early rheumatoid arthritis (RA). OBJECTIVE: The objective of this study was to characterize a population of patients with early RA (less than 12 months after symptom onset at the time of the diagnosis) prospectively followed for the pattern of responses to questionnaires addressing quality of life, the Health Assessment Questionnaire (HAQ) and Medical Outcomes Study SF-36 Health Survey (SF-36). PATIENTS AND METHODS: Forty patients with early RA at the time of diagnosis, treated with a standard treatment regimen, were prospectively followed for 3 years. Demographic and clinical data were recorded, and HAQ and SF-36 questionnaires were applied at baseline and after 3, 6, 12, 18, 24, and 36 months. Paired Student t test and Wilcoxon test were used for comparisons (significance level of 5%). RESULTS: The mean age was 45 years, with a prevalence of the female gender (90%). The average score of the initial HAQ was 1.89, with a progressive decline to 0.77 in the third year (P < 0.0001). Most domains of the SF-36 questionnaire presented significant improvement during the three years of follow-up, except for general health and vitality. CONCLUSION: In this population of patients with early RA at the time of diagnosis, the results showed significant impact on quality of life at the time of diagnosis, as measured by HAQ and SF-36 questionnaires. The early treatment of RA seems to be associated with improved health-related quality of life reported by patients.
19445664 Association of common polymorphisms in known susceptibility genes with rheumatoid arthriti 2009 INTRODUCTION: Both genetic and environmental factors contribute to rheumatoid arthritis (RA), a common and complex autoimmune disease. As well as the major susceptibility gene HLA-DRB1, recent genome-wide and candidate-gene studies reported additional evidence for association of single nucleotide polymorphism (SNP) markers in the PTPN22, STAT4, OLIG3/TNFAIP3 and TRAF1/C5 loci with RA. This study was initiated to investigate the association between defined genetic markers and RA in a Slovak population. In contrast to recent studies, we included intensively-characterized osteoarthritis (OA) patients as controls. METHODS: We used material of 520 RA and 303 OA samples in a case-control setting. Six SNPs were genotyped using TaqMan assays. HLA-DRB1 alleles were determined by employing site-specific polymerase chain reaction (PCR) amplification. RESULTS: No statistically significant association of TRAF1/C5 SNPs rs3761847 and rs10818488 with RA was detected. However, we were able to replicate the association signals between RA and HLA-DRB1 alleles, STAT4 (rs7574865), PTPN22 (rs2476601) and OLIG3/TNFAIP3 (rs10499194 and rs6920220). The strongest signal was detected for HLA-DRB1*04 with an allelic P = 1.2*10-13 (OR = 2.92, 95% confidence interval (CI) = 2.18 - 3.91). Additionally, SNPs rs7574865STAT4 (P = 9.2*10-6; OR = 1.71, 95% CI = 1.35 - 2.18) and rs2476601PTPN22 (P = 9.5*10-4; OR = 1.67, 95% CI = 1.23 - 2.26) were associated with susceptibility to RA, whereas after permutation testing OLIG3/TNFAIP3 SNPs rs10499194 and rs6920220 missed our criteria for significance (Pcorr = 0.114 and Pcorr = 0.180, respectively). CONCLUSIONS: In our Slovak population, HLA-DRB1 alleles as well as SNPs in STAT4 and PTPN22 genes showed a strong association with RA.
19404967 Confirmation of STAT4, IL2/IL21, and CTLA4 polymorphisms in rheumatoid arthritis. 2009 May OBJECTIVE: Recent advances have led to novel identification of genetic polymorphisms that are associated with susceptibility to rheumatoid arthritis (RA). Currently, 5 loci (HLA, PTPN22, TRAF1/C5, TNFAIP3, and STAT4) have been consistently reported, whereas others have been observed less systematically. The aim of the present study was to independently replicate 3 recently described RA susceptibility loci, STAT4, IL2/IL21, and CTLA4, in a large Dutch case-control cohort, and to perform a meta-analysis of all published studies to date and investigate the relevance of the findings in clinically well-defined subgroups of RA patients with or without autoantibodies. METHODS: The STAT4, IL2/IL21, and CTLA4 gene polymorphisms (rs7574865, rs6822844, and rs3087243, respectively) were genotyped in 877 RA patients and 866 healthy individuals. A meta-analysis of all published studies of disease association with these polymorphisms was performed using the Mantel-Haenszel fixed-effects method. RESULTS: An association of STAT4, IL2/IL21, and CTLA4 with RA was detected in Dutch patients (odds ratio [OR] 1.19 [P=0.031], OR 0.84 [P=0.051], and OR 0.87 [P=0.041], respectively). Results from the meta-analysis confirmed an association of all 3 polymorphisms with RA in Caucasians (OR 1.24 [P=1.66x10(-11)], OR 0.78 [P=5.6x10(-5)], and OR 0.91 [P=1.8x10(-3)], respectively). The meta-analysis also revealed that STAT4 predisposed to disease development equally in patients with autoantibodies and those without autoantibodies, and that CTLA4 enhanced the development of anti-citrullinated protein antibody (ACPA)-positive RA as compared with ACPA-negative RA. CONCLUSION: Our results replicate and firmly establish the association of STAT4 and CTLA4 with RA and provide highly suggestive evidence for IL2/IL21 loci as a risk factor for RA. Given the strong statistical power of our meta-analysis to confirm a true-positive association, these findings provide considerable support for the involvement of CTLA4 in distinct subsets of RA patients.
21084287 Somatic cell plasticity and Niemann-Pick type C2 protein: fibroblast activation. 2011 Jan 21 A growing body of evidence points toward activated fibroblasts, also known as myofibroblasts, as one of the leading mediators in several major human pathologies including proliferative fibrotic disorders, invasive tumor growth, rheumatoid arthritis, and atherosclerosis. Niemann-Pick Type C2 (NPC2) protein has been recently identified as a product of the second gene in NPC disease. It encodes ubiquitous, highly conserved, secretory protein with the poorly defined function. Here we show that NPC2 deficiency in human fibroblasts confers their activation. The activation phenomenon was not limited to fibroblasts as it was also observed in aortic smooth muscle cells upon silencing NPC2 gene by siRNA. More importantly, activated synovial fibroblasts isolated from patients with rheumatoid arthritis were also identified as NPC2-deficient at both the NPC2 mRNA and protein levels. The molecular mechanism responsible for activation of NPC2-null cells was shown to be a sustained phosphorylation of ERK 1/2 mitogen-activated protein kinase (MAPK), which fulfills both the sufficient and necessary fibroblast activation criteria. All of these findings highlight a novel mechanism where NPC2 by negatively regulating ERK 1/2 MAPK phosphorylation may efficiently suppress development of maladaptive tissue remodeling and inflammation.
20455343 Rheumatoid arthritis: choice of antirheumatic treatment. Methotrexate first. 2010 Feb Various drugs with different risk-benefit balances are claimed to reduce the intensity and frequency of exacerbations and to slow the progression of rheumatoid arthritis. What is the basis for choosing the most appropriate treatment for a given patient? Methotrexate is the best-assessed antirheumatic drug, and the one with which we have the most experience. At doses of 7.5 mg to 25 mg per week, methotrexate relieves pain, reduces the number of affected joints, and provides a functional improvement. It has the adverse effects common to all immunosuppressants, particularly gastrointestinal and haematological disorders. Treatment withdrawals due to adverse effects are infrequent at the doses used in rheumatoid arthritis. Other synthetic antirheumatic drugs such as azathioprine, chloroquine and its derivatives, ciclosporin, cyclophosphamide, D-penicillamine, leflunomide, gold salts and sulfasalazine are no more effective than methotrexate. Some are less effective, and others are more toxic. When used as monotherapy in clinical trials, TNF-alpha antagonists (etanercept and adalimumab) were no more effective than methotrexate on clinical outcome after one or two years. Etanercept and adalimumab seem to have similar risk-benefit balances. In about 10 comparative trials, combination of methotrexate and a TNF-alpha antagonist was more effective than methotrexate monotherapy on functional status and symptoms, especially in initially severe rheumatoid arthritis. Although it has not been proven, the risk of severe adverse effects is likely to be higher with such combinations, and follow-up in comparative trials does not exceed two years. The use of TNF-alpha antagonists is also less convenient, as weekly injections or monthly infusions are necessary. There is no firm evidence that other combinations of antirheumatic drugs are more effective than TNF-alpha antagonist-methotrexate combinations. In patients in whom TNF-alpha antagonists had failed, a combination of rituximab and methotrexate was more effective than methotrexate alone. There is no firm evidence that tocilizumab (an interleukin inhibitor) or abatacept (a drug acting on T lymphocytes) has a better risk-benefit balance than rituximab. The symptomatic efficacy of long-term corticosteroid therapy lasts at least three months but usually less than a year. Efficacy in patients in whom other treatments have failed is uncertain. There is no evidence that introducing methotrexate soon after diagnosis, alone or in combination with a TNF-alpha antagonist, slows the progression of rheumatoid arthritis. In practice, methotrexate is the first-line antirheumatic drug. If methotrexate monotherapy is ineffective, or when rheumatoid arthritis is initially severe, adding a TNF-alpha antagonist can be beneficial. A third-line option is to combine rituximab with methotrexate.
19950306 Identification of undiagnosed inflammatory arthritis in a community health fair screen. 2009 Dec 15 OBJECTIVE: To identify individuals with undiagnosed inflammatory arthritis (IA) and rheumatoid arthritis (RA) in a community health fair screen, and to establish in a health fair setting the diagnostic accuracy of combinations of the Connective Tissue Disease Screening Questionnaire (CSQ) and autoantibody testing for IA. METHODS: Screening for IA/RA was performed at health fair sites using a combination of the CSQ, joint examination, rheumatoid factor, and anti-cyclic citrullinated peptide (anti-CCP) antibody testing. IA was defined as > or =1 swollen joint suggestive of synovitis on joint examination by a trained clinician. RESULTS: Six hundred one subjects were screened; 51.0% participated because of joint symptoms (pain, stiffness, or swelling). Eighty-four subjects (14.0%) had > or =1 swollen joint, designated as IA on joint examination. Of the 601 subjects screened, 9 (1.5%) had IA and met > or =4 of 7 American College of Rheumatology criteria for RA but had no prior diagnosis of RA, and 15 (2.5%) had IA and RF and/or anti-CCP positivity, suggesting early RA. The diagnostic accuracy of combinations of the CSQ and autoantibody testing for the identification of IA yielded maximal sensitivity, specificity, and positive and negative predictive values of 95.3%, 99.2%, 71.4%, and 97.7%, respectively. CONCLUSION: Health fair screening may be an effective approach for the identification of individuals with undiagnosed IA/RA. A combination of the CSQ and autoantibody testing alone has clinically useful diagnostic accuracy for the detection of IA. Decisions regarding which methodology to use for future health fair IA/RA screening will depend on goals of screening and funding.
20204965 Psychological distress in rheumatoid arthritis patients: an evaluation within the conserva 2010 Jun Rheumatoid arthritis (RA) is a chronic disease, which can lead to considerable psychological distress. The present study evaluated anxiety and depression symptoms for this chronic and painful illness within the framework of the conservation of resources (COR) theory. Coping strategies, coping self-efficacy, religiousness and social support are very important personal resources, which have been found to protect individuals from psychological distress. The aim of the present study was to examine the predictive values of socio-demographic and illness-related variables, perceived social support, ways of coping, religiousness, arthritis self-efficacy and resource loss for psychological distress in a sample of 117 RA patients from Turkey, a secular, Islamic, non-western developing country. The results revealed that RA patients experience considerable anxiety and depressive symptoms. The results of the regression analysis showed that gender, helplessness coping and resource loss are significant predictors of anxiety, whereas arthritis self-efficacy and resource loss are significant predictors of depression. Resource loss appeared as an important predictor for both anxiety and depression. This finding was consistent with the COR theory. The clinical implications of these findings are discussed.
21115235 Cell-specific expression of TLR9 isoforms in inflammation. 2011 Feb Toll-like receptors (TLRs) are key pattern recognition receptors during an immune response. With five isoforms of human TLR9 described, we hypothesised that differential expression of TLR9 isoforms in different cell types would result in variable contributions to the overall input from TLR9 during inflammation. We assessed the molecular expression of the TLR9 isoforms, TLR9-A, -C and -D. In normal peripheral blood mononuclear cells, B-lymphocytes express ∼100-fold more TLR9-A transcript than monocytes or T-lymphocytes, which predominantly express the TLR9-C transcript. Switches in isoform predominance accompany B-lymphocyte development. TLR9 protein expression in rheumatoid inflammatory lesions reflected the TLR9 isoform expression by immune cells. Herein we suggest that B-lymphocytes and plasmacytoid dendritic cells contribute the ∼3-fold higher TLR9-A transcript levels observed in inflamed synovium when compared to subcutaneous rheumatoid nodules. In contrast, macrophages and T-lymphocytes contribute the ∼4-fold higher TLR9-C transcript levels seen in nodules, compared to synovia. From protein sequence, predictions of subcellular localisation suggest TLR9-B may locate to the mitochondria, whereas TLR9-D adopts an opposing orientation in the endoplasmic reticulum. Consistent with this, structure models raise the possibility of alternative ligands for the TLR9-B and TLR9-D variants. Our results highlight differences in the expression of human TLR9 isoforms in normal and inflamed tissues, with differing contributions to inflammation.
20039418 Inhibition of NF-kappaB signaling by fasudil as a potential therapeutic strategy for rheum 2010 Jan OBJECTIVE: Rheumatoid arthritis (RA) is the most common systemic autoimmune disease and is characterized mainly by symmetric polyarticular joint disorders. The pathologic processes are mediated by a number of cytokines, chemokines, cell adhesion molecules, and matrix metalloproteinases. The expression of most of these molecules is controlled at the transcriptional level. In addition, activation of NF-kappaB is involved in RA pathogenesis. This study was performed to explore the role of a novel serine/threonine kinase inhibitor, fasudil, in the control of the NF-kappaB activation pathway and to investigate the therapeutic effects of fasudil on arthritis development in a rat model of RA. METHODS: Fibroblast-like synoviocytes (FLS) from RA patients and human endothelial cells (ECs) were established and maintained. To study the role of fasudil on cytokine expression, various cytokines expressed in the RA FLS and human ECs were measured by enzyme-linked immunosorbent assay following stimulation of the cells with interleukin-1beta (IL-1beta) in the presence of various concentrations of fasudil. The role of fasudil on NF-kappaB activation was studied using a reporter gene assay, Western blotting of IkappaBalpha, immunofluorescence analysis of the p65 subunit of NF-kappaB, and electrophoretic mobility shift assay. The in vivo effects of fasudil on arthritis were studied in a rat adjuvant-induced arthritis (AIA) model. RESULTS: Fasudil inhibited cytokine expression in RA FLS and human ECs and also inhibited the activation of ECs, in a dose-dependent manner. Fasudil inhibited IL-1beta-induced activation of NF-kappaB independent of the inhibition of IkappaBalpha degradation and nuclear translocation of NF-kappaB, and inhibited IL-1beta-induced DNA binding of NF-kappaB. Finally, in vivo, fasudil ameliorated arthritis in rats with AIA, without any adverse effects. CONCLUSION: Serine/threonine kinase inhibitor fasudil inhibits the development of arthritis in a rat model of RA, and also inhibits the NF-kappaB signaling required for binding of NF-kappaB to specific DNA sequences through, for example, the phosphorylation of p65, suggesting that a specific target of fasudil might be a novel NF-kappaB kinase. Thus, fasudil serves as a novel strategy for the treatment of RA.
19333990 Measuring finger joint cartilage by ultrasound as a promising alternative to conventional 2009 Apr 15 OBJECTIVE: To evaluate the reliability and validity of a novel ultrasound (US) imaging method to measure metacarpophalangeal (MCP) and proximal interphalangeal (PIP) finger joint cartilage. METHODS: We examined 48 patients with rheumatoid arthritis (RA), 18 patients with osteoarthritis (OA), 24 patients with unclassified arthritis of the finger joints, and 34 healthy volunteers. The proximal cartilage layer of MCP and PIP joints for fingers 2-5 was bilaterally visualized from a posterior view, with joints in approximately 90 degrees flexion. Cartilage thickness was measured with integrated tools on static images. External validity was assessed by measuring radiologic joint space width (JSW) and a numeric joint space narrowing (JSN) score in patients with RA. RESULTS: Precise measurement was possible for 97.5% of MCP and 94.2% of PIP joints. Intraclass correlation coefficients for bilateral total joint US scores were 0.844 (95% confidence interval [95% CI] 0.648-0.935) for interobserver comparisons and 0.928 (95% CI 0.826-0.971) for intraobserver comparisons (using different US devices). The US score correlated with JSN for both hands (adjusted R(2) = 0.513, P < 0.001) and JSW of the same finger joints (adjusted R(2) = 0.635, P < 0.001). Reduced cartilage shown by US allowed discrimination of early symptomatic OA versus early RA and healthy joints. In patients with RA, US scores correlated with duration of treatment-resistant, progressive RA. CONCLUSION: The US method of direct visualization and quantification of cartilage in MCP and PIP joints is objective, reliable, valid, and can be useful for diagnostic purposes in patients with arthritis.
20635122 A latent variable approach for modeling categorical endpoints among patients with rheumato 2010 Aug The need for accurate exposure-response modeling is critical in the drug development process. Few methods are available for linking discrete endpoints, especially ordered categorical variables, to mechanistic (e.g., indirect response) models. Here we describe a latent-variable approach that is proposed in conjunction with an inhibitory indirect response model to link the placebo/comedication effect and drug exposure to the endpoints. The model is parsimonious, with desirable characteristics at initial timepoints, and allows simultaneous modeling of multiple endpoints that are categorically ordered. Application of the model is demonstrated with data from a phase 3 clinical trial of golimumab, a human IgG1kappa monoclonal antibody that binds with high affinity and specificity to tumor necrosis factor (TNF)-alpha, in patients with rheumatoid arthritis. The efficacy endpoints were 20, 50, and 70% improvement in the American College of Rheumatology criteria (ACR20, ACR50, and ACR70, respectively) as measures of improvement in disease severity. The modeling results were shown to be consistent by using either a sequential or simultaneous pharmacokinetic/pharmacodynamic modeling approach. The suitability of likelihood profiling and proper use of bootstrap methods in assessing parameter estimation precision are also presented. More accurate, parsimonious models with appropriately quantified uncertainty can facilitate better drug development decisions.
20549275 Constitutional symptoms at the onset of rheumatoid arthritis and subsequent arterial stiff 2010 Oct The onset of rheumatoid arthritis (RA) can be associated with constitutional symptoms. Systemic inflammation may be a common factor behind such symptoms and the subsequent development of arterial disease. The aim of this study was to determine if a relationship exists between constitutional symptoms and arterial stiffness. We recruited 103 ambulatory RA patients (85 female) without overt arterial disease aged between 40 and 65 years attending hospital clinics. A research nurse measured arterial stiffness (heart rate standardised augmentation index, AIX) using the 'SphygmoCor' device, fasting lipids and erythrocyte sedimentation rate (ESR). Assessment included patient recall of constitutional symptoms at arthritis onset (aching muscles, tiredness, generalised weakness, low mood/depression, fever, loss of weight, loss of appetite) and a detailed medical record review. Regression analysis was used to adjust mean differences in AIX in the presence/absence of constitutional symptoms for current age, sex, arthritis duration, age arthritis onset, study ESR, ever smoked, mean arterial blood pressure (BP), treated hypertension and cholesterol. Mean age was 54 years (age arthritis onset 42 years), brachial BP 125/82 mmHg, cholesterol 5.4 mmol/L, ever smoked 59%, median RA duration 9 years, median ESR 16 mm/h and mean AIX 31.7 (SD 7.8). Unadjusted mean difference in AIX was -0.7 (95%CI -4.5 to 3.1; p = 0.72) in the presence of constitutional symptoms and the adjusted mean difference was -0.1 (-3.2 to 2.9; p = 0.93). No individual symptoms were significantly associated with increased arterial stiffness. In conclusion, we found no convincing association between constitutional symptoms at the onset of arthritis and subsequent arterial stiffness.