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ID PMID Title PublicationDate abstract
21487894 CTLA-4-Ig therapy diminishes the frequency but enhances the function of Treg cells in pati 2011 Aug Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease. Natural T regulatory (nTreg) cells, which constitutively express the CTLA-4 molecule, have an important role in the pathogenesis of autoimmune conditions. Although it has been reported that biological agents are able to modulate the levels or function of Treg lymphocytes, the possible effect of Abatacept (CTLA-4-Ig) therapy on these cells has not been studied in autoimmune conditions. We explored the effect of Abatacept therapy on Treg cells in patients with RA. The number of different subsets of Treg cells was analyzed by flow cytometry in the peripheral blood from 45 patients with RA that were (n = 30) or not (n = 15) under Abatacept therapy as well as in 20 healthy controls. The function of Treg cells was assessed by an assay of inhibition of lymphocyte proliferation. We found that Abatacept therapy was associated with a significant diminution in the levels of CD4+CD25(bright)Foxp3+, and CD4+CTLA-4+ nTreg cells. In contrast, the regulatory function of CD4+CD25+ lymphocytes was significantly enhanced after the administration of Abatacept. Our data suggest that CTLA-4-Ig exerts a complex and interesting effect on Treg cells in patients with RA.
22915056 Severe cardiac failure due to rapidly progressive rheumatoid arthritis-associated valvulop 2012 Aug 12 Cardiac failure due to rapidly progressive valve disease is a rare complication of rheumatoid arthritis (RA) that can be challenging to manage. A patient with severe heart failure secondary to RA who, after failing to respond to medical therapy, underwent high-risk valve surgery and did remarkably well, with dramatic symptomatic improvement and essentially normalised left ventricular size and function as seen on follow-up echocardiography.
23065319 Automated radiofrequency-based US measurement of common carotid intima-media thickness in 2013 Feb OBJECTIVE: To compare the carotid intima-media thickness (IMT) assessed with automated radiofrequency-based US in RA patients treated with synthetic vs synthetic and biologic DMARDs and controls. METHODS: Ninety-four RA patients and 94 sex- and age-matched controls were prospectively recruited at seven centres. Cardiovascular (CV) risk factors and co-morbidities, RA characteristics and therapy were recorded. Common carotid artery (CCA)-IMT was assessed in RA patients and controls with automated radiofrequency-based US by the same investigator at each centre. RESULTS: Forty-five (47.9%) RA patients had been treated with synthetic DMARDs and 49 (52.1%) with synthetic and biologic DMARDs. There were no significant differences between the RA patients and controls in demographics, CV co-morbidities and CV disease. There were significantly more smokers among RA patients treated with synthetic and biologic DMARDs (P = 0.036). Disease duration and duration of CS and synthetic DMARD therapy was significantly longer in RA patients treated with synthetic and biologic DMARDs (P < 0.0005). The mean CCA-IMT was significantly greater in RA patients treated only with synthetic DMARDs than in controls [591.4 (98.6) vs 562.1 (85.8); P = 0.035] and in RA patients treated with synthetic and biologic DMARDs [591.4 (98.6) vs 558.8 (95.3); P = 0.040). There was no significant difference between the mean CCA-IMT in RA patients treated with synthetic and biologic DMARDs and controls (P = 0.997). CONCLUSION: Our results suggest that radiofrequency-based measurement of CCA-IMT can discriminate between RA patients treated with synthetic DMARDs vs RA patients treated with synthetic and biologic DMARDs.
22391952 Muscle density in rheumatoid arthritis: associations with disease features and functional 2012 Aug OBJECTIVE: To explore the associations between measures of body composition derived from computed tomography (CT) of the thigh and functional outcomes in patients with rheumatoid arthritis (RA). METHODS: Patients with RA underwent bilateral midfemoral quantitative CT for measurement of thigh fat area (TFA), thigh muscle area (TMA), and thigh muscle density (TMD). The associations of thigh-composition measures with disability and physical performance, as measured with the Health Assessment Questionnaire (HAQ), the Valued Life Activities (VLAs), and the Short Physical Performance Battery (SPPB) instruments, were explored in the total cohort and in the cohort subgrouped by sex, controlling for pertinent demographic, lifestyle, and RA disease and treatment covariates. RESULTS: A total of 152 RA patients were studied. Among the potential determinants of TMD, older age, longer duration of sedentary activity, longer duration of RA, higher tender joint count, higher serum interleukin-6 levels, use of glucocorticoids, and nonuse of hydroxychloroquine were all significantly associated with lower TMD in multivariable models. RA characteristics accounted for 63% of the explainable variability in TMD. When comodeled, higher TFA and lower TMD, but not lower TMA, were significantly and independently associated with higher HAQ scores, lower Short Form 36 health survey physical functioning scores, lower composite SPPB scores, and a greater proportion of affected obligatory VLAs. CONCLUSION: Thigh CT-derived measures of body composition, particularly fat area and muscle density, were strongly associated with disability and physical performance in RA patients, with RA disease features as potential determinants. Efforts to reduce fat and improve muscle quality may reduce disability in this population with impaired physical functioning.
20639266 Predicting arthritis outcomes--what can be learned from the Leiden Early Arthritis Clinic? 2011 Jan OBJECTIVES: In order to allow personalized medicine, adequate prediction of disease outcome is required. In early undifferentiated arthritis (UA), prediction of the development of RA is crucial, and in case of RA predicting the severity of the disease course may guide individualized treatment decisions. METHODS: A total of 570 UA patients and 676 RA patients included in the Leiden Early Arthritis Clinic cohort were studied for baseline characteristics. The disease outcomes studied were fulfillment of the 1987 ACR-RA criteria and arthritis persistence in UA patients and the rate of radiological joint destruction and achieving sustained DMARD-free remission in RA patients. RESULTS: Predictive factors for fulfillment of the 1987 ACR-RA criteria and for persistent arthritis in UA were largely similar. Risk factors for a severe rate of joint destruction were: older age (P<0.001); male gender (P<0.001); longer symptom duration at first visit (P=0.048), involvement of lower extremities (P<0.001); BMI (P<0.001); high acute phase reactants, presence of IgM-RF (P<0.001); anti-CCP2 antibodies (P<0.001); anti-modified citrullinated vimentin antibodies (P<0.001) and HLA-DRB1 shared epitope alleles (P=0.001). A high BMI was associated with a lower rate of joint destruction but with a higher risk of disease persistence. The proportion of variance in joint destruction explained was 32% CONCLUSION: Predictors for RA development, previously used to develop a prediction rule in UA patients, are largely similar to predictors for arthritis persistency. Only part of the joint destruction level in RA is explained by the currently known risk factors. New factors need to be identified in order to guide pharmaceutical intervention at the level of individual RA patients.
23028973 Role of macrophage CCAAT/enhancer binding protein delta in the pathogenesis of rheumatoid 2012 BACKGROUND: The up-regulation of CCAAT/enhancer binding protein delta (CEBPD) has frequently been observed in macrophages in age-associated disorders, including rheumatoid arthritis (RA). However, the role of macrophage CEBPD in the pathogenesis of RA is unclear. METHODOLOGY AND PRINCIPAL FINDINGS: We found that the collagen-induced arthritis (CIA) score and the number of affected paws in Cebpd(-/-) mice were significantly decreased compared with the wild-type (WT) mice. The histological analysis revealed an attenuated CIA in Cebpd(-/-) mice, as shown by reduced pannus formation and greater integrity of joint architecture in affected paws of Cebpd(-/-) mice compared with WT mice. In addition, immunohistochemistry analysis revealed decreased pannus proliferation and angiogenesis in Cebpd(-/-) mice compared with WT mice. CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions. CCL20, IL23A, CXCL1 and TNFAIP6 contributed to the migration and proliferation of synoviocytes, and the latter two proteins were involved in tube formation of endothelial cells. Finally, two anti-inflammatory chemicals, inotilone and rosmanol, reduced the expression of CEBPD and its downstream targets and mitigated the above phenomena. CONCLUSIONS AND SIGNIFICANCE: Collectively, our findings suggest that CEBPD and its downstream effectors could be biomarkers for the diagnosis of RA and potentially serve as therapeutic targets for RA therapy.
21953337 Selective involvement of ERK and JNK mitogen-activated protein kinases in early rheumatoid 2012 Mar OBJECTIVES: To investigate the expression and activation of mitogen-activated protein kinases in patients with early arthritis who are disease-modifying antirheumatic drug (DMARD) naïve. METHODS: A total of 50 patients with early arthritis who were DMARD naïve (disease duration <1 year) were prospectively followed and diagnosed at baseline and after 2 years for undifferentiated arthritis (UA), rheumatoid arthritis (RA) (1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism (EULAR) criteria), or spondyloarthritis (SpA). Synovial biopsies obtained at baseline were examined for expression and phosphorylation of p38, extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) by immunohistochemistry and digital analysis. Synovial tissue mRNA expression was measured by quantitative PCR (qPCR). RESULTS: ERK and JNK activation was enhanced at inclusion in patients meeting RA criteria compared to other diagnoses. JNK activation was enhanced in patients diagnosed as having UA at baseline who eventually fulfilled 1987 ACR RA criteria compared to those who remained UA, and in patients with RA fulfilling 2010 ACR/EULAR criteria at baseline. ERK and JNK activation was enhanced in patients with RA developing progressive joint destruction. JNK activation in UA predicted 1987 ACR RA classification criteria fulfilment (R(2)=0.59, p=0.02) after follow-up, and disease progression in early arthritis (R(2)=0.16, p<0.05). Enhanced JNK activation in patients with persistent disease was associated with altered synovial expression of extracellular matrix components and CD44. CONCLUSIONS: JNK activation is elevated in RA before 1987 ACR RA classification criteria are met and predicts development of erosive disease in early arthritis, suggesting JNK may represent an attractive target in treating RA early in the disease process.
21778910 Limited health literacy is a common finding in a public health hospital's rheumatology cli 2011 Aug BACKGROUND: Health literacy (HL) is associated with outcomes in many conditions, but little is known about its impact on arthritic diseases. OBJECTIVES: We sought to determine whether HL is related to disease activity and severity in patients with rheumatoid arthritis (RA). METHODS: English-speaking adult RA patients were recruited for this cross-sectional study. Background information was ascertained by medical record review; Disease Activity Score 28 (DAS-28) scores were determined by providers; subjects completed the Multidimensional Health Assessment Questionnaire (MDHAQ), demographic questionnaires, and validated HL instruments, including the Short Test of Functional Health Literacy in Adults, Rapid Estimate of Adult Literacy in Medicine, and the single-item literacy screener. We used linear regression to assess whether HL was associated with MDHAQ and DAS-28 scores. RESULTS: One hundred ten subjects participated in the study. Limited HL was a common finding, especially among ethnic minorities. The single-item literacy screener results were predictive of lower MDHAQ scores by univariate regression analysis. Similar trends were observed for the Short Test of Functional Health Literacy in Adults and Rapid Estimate of Adult Literacy in Medicine. The relationship between the single-item literacy screener and MDHAQ remained statistically significant in multivariate analysis that controlled for the impact of demographic features and RA disease characteristics. Health literacy scores were not associated with DAS-28 scores. CONCLUSIONS: Health literacy was independently associated with functional impairment in English-speaking RA patients at an urban safety-net clinic. This new finding suggests that RA functional status might be improved by strategies that target limited HL's causal pathways.
22896020 Cytokine secretion by pathogen recognition receptor-stimulated dendritic cells in rheumato 2012 Oct OBJECTIVE: Interleukin 23 (IL-23) plays a major role in differentiation and survival of IL-17-secreting CD4+ Th17 cells. Having noted a higher frequency of Th17 cells in ankylosing spondylitis (AS) and rheumatoid arthritis (RA) than in healthy donors (HD), we investigated whether IL-23 secretion is increased in these conditions. METHODS: Monocyte-derived dendritic cells (moDC) were obtained from peripheral blood of 17 HD, 16 patients with RA, and 30 patients with AS, and stimulated with ligands for several pathogen recognition receptors. Messenger RNA (mRNA) expression and cytokine secretion were analyzed by real-time polymerase chain reaction and ELISA, respectively. RESULTS: The combination of ligands for Toll-like receptors (TLR) 7/8 and TLR3 led to synergistic secretion of both IL-23 and IL-12p70 from all subjects; similar synergy was seen with TLR2 ligands and curdlan. However, for both combinations, moDC from patients with RA produced significantly lower amounts of IL-23 than moDC from patients with AS; in contrast, IL-12p70 secretion did not differ. Similarly, tumor necrosis factor-α, IL-6, and IL-10 were secreted at comparable levels in all subjects, whereas CXCL8 and CCL3 production was actually enhanced in moDC of patients with RA. Equivalent levels of mRNA for both IL-23p19 and IL-12p35 subunits were found in moDC from all donors, suggesting posttranscriptional regulation of IL-23 production in RA. CONCLUSION: Our observations show that IL-23 production is decreased in RA and maintained in AS. Because increased numbers of CD4+IL-17+ T cells are seen in both diseases, these observations imply that there are different mechanisms underlying chronic inflammation in these 2 forms of inflammatory arthritis.
22807070 Quantitative assessment of foot structure in rheumatoid arthritis by a foot digitizer: det 2012 Nov OBJECTIVE: Foot involvement is a major feature in rheumatoid arthritis (RA), leading to structural deformities. Methods to allow a 3-dimensional (3-D) evaluation of foot structure in RA to be applicable in daily clinical practice have not been evaluated. This study assessed the use of a foot digitizer, a noninvasive 3-D scanner collecting objective quantitative data of the feet, to evaluate the presence of foot structure abnormalities in an RA outpatient cohort. METHODS: Foot digitizer data of RA patients were compared with healthy controls. Subanalyses were performed to find relationships with erosive disease and the presence of swollen and/or tender joints. Linear mixed models were applied with correction, including sex, age, body weight and height, foot length, Disease Activity Score in 28 joints, and disease duration. RESULTS: Forty-one percent of the patients showed >1 abnormal parameter, measured with the 3-D foot scanner. Most differences found were located in the forefoot, the most frequently affected area of the RA foot. Strikingly, even in the absence of joint erosions, marked alterations were found. Comparable differences were also observed between the patients with and without swollen and/or tender joints. Additionally, alterations were not strongly related to foot pain and disability, suggesting the capacity of the foot digitizer to detect early changes in foot structure. CONCLUSION: The results highlight the impact of RA on foot structure, even in the absence of clinical signs of swelling or radiographic erosions. The foot digitizer offers a valuable tool to screen for such foot deformities before the presence of erosions.
23237239 The allogeneic umbilical cord mesenchymal stem cells regulate the function of T helper 17 2012 Dec 13 BACKGROUND: Previous in vivo studies have shown that mesenchymal stem cell (MSC) transplantation significantly improves the condition of a number of autoimmune diseases including autoimmune cerebrospinal meningitis, multiple sclerosis, glomerulonephritis and systemic lupus erythematosus. METHODS: To investigate the immunoregulatory effect of stem cell transplantation, human umbilical cord MSCs were co-cultured with peripheral blood mononuclear cells (PBMCs) from patients with rheumatoid arthritis (RA). Orphan nuclear receptor gamma (ROR-γ) mRNA and protein expression was detected with real-time PCR and Western blotting. Interleukin (IL)-17, IL-6 and tumor necrosis factor (TNF-α) in the cell culture supernatant were measured using a flow cytometric bead capture method. RESULTS: After 72 hours of co-culture, the mRNA and protein expression levels of ROR-γ in co-cultured PBMCs were decreased compared with that in PBMC of RA patients cultured alone (p < 0.05). Moreover, the decrement was positively related to the disease activity of RA (p < 0.05). Decreased secretion of IL-17, TNF-α and IL-6 were also found in co-culture supernatants of PBMCs from patients with severe and moderate disease activity, but not in supernatant from PBMCs cultured alone. The decreased cytokine expression levels were positively correlated to the concentrations of MSCs. In contrast, PBMCs from healthy controls or patients with mild RA did not show significant differences in ROR-γ expression or cytokine secretion following co-culture with MSCs as compared with those cultured alone. CONCLUSIONS: In vitro co-culture with MSCs down-regulated the inflammatory response of PBMCs from RA patients with severe disease activity, but had no significant effect on PBMCs from healthy controls or patients with mild disease activity, suggesting that the immunoregulatory role of MSCs may associate with the occurrence of inflammatory mediators.
21592391 Causal graph-based analysis of genome-wide association data in rheumatoid arthritis. 2011 May 18 BACKGROUND: GWAS owe their popularity to the expectation that they will make a major impact on diagnosis, prognosis and management of disease by uncovering genetics underlying clinical phenotypes. The dominant paradigm in GWAS data analysis so far consists of extensive reliance on methods that emphasize contribution of individual SNPs to statistical association with phenotypes. Multivariate methods, however, can extract more information by considering associations of multiple SNPs simultaneously. Recent advances in other genomics domains pinpoint multivariate causal graph-based inference as a promising principled analysis framework for high-throughput data. Designed to discover biomarkers in the local causal pathway of the phenotype, these methods lead to accurate and highly parsimonious multivariate predictive models. In this paper, we investigate the applicability of causal graph-based method TIE* to analysis of GWAS data. To test the utility of TIE*, we focus on anti-CCP positive rheumatoid arthritis (RA) GWAS datasets, where there is a general consensus in the community about the major genetic determinants of the disease. RESULTS: Application of TIE* to the North American Rheumatoid Arthritis Cohort (NARAC) GWAS data results in six SNPs, mostly from the MHC locus. Using these SNPs we develop two predictive models that can classify cases and disease-free controls with an accuracy of 0.81 area under the ROC curve, as verified in independent testing data from the same cohort. The predictive performance of these models generalizes reasonably well to Swedish subjects from the closely related but not identical Epidemiological Investigation of Rheumatoid Arthritis (EIRA) cohort with 0.71-0.78 area under the ROC curve. Moreover, the SNPs identified by the TIE* method render many other previously known SNP associations conditionally independent of the phenotype. CONCLUSIONS: Our experiments demonstrate that application of TIE* captures maximum amount of genetic information about RA in the data and recapitulates the major consensus findings about the genetic factors of this disease. In addition, TIE* yields reproducible markers and signatures of RA. This suggests that principled multivariate causal and predictive framework for GWAS analysis empowers the community with a new tool for high-quality and more efficient discovery. REVIEWERS: This article was reviewed by Prof. Anthony Almudevar, Dr. Eugene V. Koonin, and Prof. Marianthi Markatou.
20063189 Disseminated cutaneous and visceral Kaposi sarcoma in a woman with rheumatoid arthritis re 2012 Apr Kaposi sarcoma (KS) is a vascular neoplasm mainly affecting the skin of the limbs that has previously been associated with rheumatoid arthritis (RA). When compared with the RA patients treated with corticosteroids and immunosuppressive drugs, the reported number of KS in RA patients was very rare. Although the exact mechanisms of developing KS in RA patients are unclear, some drugs which include corticosteroid have been suggested as an etiological factor in previous case reports of RA and KS. We report, here in, another case of KS associated with the initiation of leflunomide in a patient with RA.
22426662 Granulomatous meningitis due to rheumatoid arthritis. 2012 Jun Meningoencephalitis is a rare but aggressive complication of rheumatoid arthritis (RA). The most common complications of RA occur in the severe and chronic stages of the disease. Only a few cases have been reported in the literature. The symptoms are usually nonspecific, and arthralgia may be missing. Brain MRI and CSF analysis are useful to guide the diagnosis. However, a biopsy is required to demonstrate the existence of granulomatous lesions and the lack of mycobacterium infection. Early detection is essential to prevent neurological complications. Treatment consists of intravenous high doses of corticoid followed by oral tapered doses associated with immunosuppressive therapy. The present case is remarkable by the presence of granulomatous lesions in the lung and meninges and the dramatic improvement after immunosuppressive therapy.
21859704 Development of the Birmingham Rheumatoid Arthritis Model: past, present and future plans. 2011 Sep The Birmingham Rheumatoid Arthritis Model (BRAM) has been developed over a number of years to inform several appraisals of biologic drugs by the Technology Appraisals Committee of the UK National Institute for Health and Clinical Excellence. This article describes the processes used in the construction of the different versions of the BRAM.
21750959 Pregnancy and rheumatoid arthritis: insights into the immunology of fetal tolerance and co 2011 Oct It has long been recognized that symptoms and signs of rheumatoid arthritis (RA) frequently improve spontaneously during pregnancy, only to flare postpartum. Although the mechanisms behind this phenomenon remain poorly understood, there is growing interest in the immunologic changes that occur during healthy pregnancy as a possible explanation. Because the maternal immune system must adapt during pregnancy to accept the semi-allogeneic fetus, it has been hypothesized that these natural changes induced by pregnancy on maternal immune regulatory cells may have the additional benefit of controlling the immunopathology driving disease activity in RA. Here, we review our current understanding on the effects of pregnancy on RA and highlight some of the recent literature related to advancing our understanding on the immunology of pregnancy as well as the immunologic changes in RA during pregnancy.
23164197 Matrix to predict rapid radiographic progression of early rheumatoid arthritis patients fr 2012 Nov 19 INTRODUCTION: Early rheumatoid arthritis (RA) patients may show rapid radiographic progression (RRP) despite rapid initiation of synthetic disease-modifying anti-rheumatic drugs (DMARDs). The present study aimed to develop a matrix to predict risk of RRP despite early DMARD initiation in real life settings. METHODS: The ESPOIR cohort included 813 patients from the community with early arthritis for < 6 months; 370 patients had early RA and had received methotrexate or leflunomide during the first year of follow-up. RRP was defined as an increase in the van der Heijde-modified Sharp score (vSHS) ≥ 5 points at 1 year. Determinants of RRP were examined first by bivariate analysis, then multivariate stepwise logistic regression analysis. A visual matrix model was then developed to predict RRP in terms of patient baseline characteristics. RESULTS: We analyzed data for 370 patients. The mean Disease Activity Score in 28 joints was 5.4 ± 1.2, 18.1% of patients had typical RA erosion on radiographs and 86.4% satisfied the 2010 criteria of the American College of Rheumatology/European League Against Rheumatism. During the first year, mean change in vSHS was 1.6 ± 5.5, and 41 patients (11.1%) showed RRP. A multivariate logistic regression model enabled the development of a matrix predicting RRP in terms of baseline swollen joint count, C-reactive protein level, anti-citrullinated peptide antibodies status, and erosions seen on radiography for patients with early RA who received DMARDs. CONCLUSIONS: The ESPOIR matrix may be a useful clinical practice tool to identify patients with early RA at high risk of RRP despite early DMARD initiation.
22294635 Inflamed target tissue provides a specific niche for highly expanded T-cell clones in earl 2012 Jun OBJECTIVE: To profile quantitatively the T-cell repertoire in multiple joints and peripheral blood of patients with recent onset (early) or established rheumatoid arthritis (RA) using a novel next-generation sequencing protocol to identify potential autoreactive clones. METHODS: Synovium of patients with recent onset (early) RA (<6 months) (n=6) or established RA (>18 months) (n=6) was screened for T-cell clones by sequencing over 10 000 T-cell receptors (TCR) per sample. T cells from paired blood samples were analysed for comparison. From two patients synovial T cells were obtained from multiple inflamed joints. The degree of expansion of each individual clone was based on its unique CDR3 sequence frequency within a sample. Clones with a frequency of over 0.5% were considered to be highly expanded clones (HEC). RESULTS: In early RA synovium, the T-cell repertoire was dominated by 35 HEC (median, range 2-70) accounting for 56% of the TCR sequenced. The clonal dominance in the synovium was patient specific and significantly greater than in established RA (median of 11 HEC (range 5-24) in established RA synovium accounting for 9.8% of T cells; p<0.01). 34% (range 28-40%) of the most expanded T-cell clones were shared between different joints in the same patients, compared with only 4% (range 0-8%) between synovium and blood (p=0.01). CONCLUSIONS: In RA, a systemic autoimmune disease, the inflamed synovium forms a niche for specific expanded T-cell clones, especially in early disease. This suggests that, at least in RA, autoreactive T cells should be addressed specifically in the inflamed tissue, preferably in the early phase of the disease.
21482536 Acute serum amyloid A regulates cytoskeletal rearrangement, cell matrix interactions and p 2011 Jul OBJECTIVE: Serum amyloid A (A-SAA) is an acute-phase protein with cytokine-like properties implicated in the pathogenesis of rheumatoid arthritis (RA), atherosclerosis, diabetes and Alzheimer's disease. This study characterises the mechanism of A-SAA-induced cytoskeletal rearrangement and migration in synovial fibroblasts and microvascular endothelial cells (human dermal endothelial cells; HDEC). METHODS: Immunohistology and immunofluorescence were used to examine αvβ3 and β1-integrins, filamentous actin (F-actin) and focal adhesion expression in rheumatoid arthritis synovial tissue (RAST) and rheumatoid arthritis synovial fibroblast cells (RASFC). A-SAA-induced αvβ3 and β1-integrin binding was measured by adhesion assay. Cytoskeletal rearrangement and ρ-GTPase activation following A-SAA stimulation was examined using dual immunofluorescent staining for F-actin/vinculin staining, pull down assays and immunoblotting for Cdc42 and RhoA. Cell growth, invasion/migration, angiogenesis and actin formation were examined in the presence or absence of specific Rac1 and Cdc42 inhibitors (NSC23766 and 187-1). RESULTS: αvβ3, β1-integrin and F-actin predominantly localised to vascular endothelium and lining layer cells in RAST, compared with osteoarthritis and normal control synovial tissue. A-SAA significantly increased αvβ3 and β1 binding in RASFC. A-SAA induced cytoskeletal disassembly, loss of focal adhesions and filopodia formation in RASFC and HDEC. A-SAA significantly induced Cdc42 activation but failed to promote RhoA activation in HDEC and synovial fibroblast cells. Blockade of Rac-1 and Cdc42 inhibited A-SAA-induced cell growth, invasion/migration, actin cytoskeletal rearrangement and angiogenesis. CONCLUSIONS: These data show a novel mechanism for A-SAA-induced cell migrational events in RA mediated via cytoskeletal signalling pathways.
23138614 Do anti-TNF-α drugs increase cancer risk in rheumatoid arthritis patients? 2013 Apr Concern has been raised about an increased risk of lymphoma and skin cancers in patients with rheumatoid arthritis due to administration of anti-TNF-α drugs. Meta-analysis of observational data from registries as well as from randomized controlled trials has failed to show a significant increase in the risk of lymphoma when the sample size has been sufficiently large; skin cancer risk may represent a valid concern. Issues relating to interpretation of these data are discussed.