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ID PMID Title PublicationDate abstract
16859519 Diagnostic value of antibodies against a modified citrullinated vimentin in rheumatoid art 2006 Antibodies directed against citrullinated vimentin are members of the family of autoantibodies reactive with citrullinated proteins and are among the most specific serological markers for the diagnosis of rheumatoid arthritis (RA). This study was performed to test the diagnostic value of a newly developed enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies against a genetically modified citrullinated vimentin (anti-MCV) in comparison with a second-generation anti-cyclic citrullinated peptides (anti-CCP2) ELISA test system. Blinded sera from 631 patients (409 consecutive out-patients and 222 randomly selected stored sera) with RA (n = 164) and non-RA (osteoarthritis [n = 120], polymyalgia rheumatica/giant cell arteritis [n = 80], spondyloarthritis [n = 36], and other inflammatory rheumatic or non-inflammatory disease [n = 67]) were tested for the presence of anti-MCV and anti-CCP2 antibodies according to the manufacturers' instructions. The diagnostic performance of the anti-MCV was comparable with the anti-CCP2 assay for the diagnosis of RA according to the calculated area under the curve (0.824; 95% confidence interval (CI) 0.778-0.870 versus 0.818; 95% CI 0.767-0.869) as analysed by receiving operating characteristic curve. When categorised with a cutoff value of 20.0 U/ml (as recommended by the manufacturer), sensitivity and specificity of the anti-MCV ELISA were 69.5% (95% CI 61.9%-76.5%) and 90.8% (86.9%-93.8%), respectively, compared with 70.1% (62.5%-77.0%) and 98.7% (96.7%-99.6%) of the anti-CCP2 assay. Using the cutoff values of 19.0 U/ml and 81.5 U/ml for the anti-MCV test to obtain a sensitivity and specificity identical to the anti-CCP2 assay, showed a reduced specificity (89.8%; 85.8%-92.9%) and sensitivity (53.7%; 45.7%-61.5%), respectively, of the anti-MCV ELISA compared with the anti-CCP2 test. In conclusion, the serum ELISA testing for anti-MCV antibodies as well as the anti-CCP-2 assay perform comparably well in the diagnosis of RA. In the high-specificity range, however, the anti-CCP2 assay appears to be superior to the anti-MCV test.
21141568 [The effect of prolactin on the expression of matrix metalloproteinase-9 in the synovium o 2008 Feb AIM: To determine the exact roles of prolactin (PRL) in the pathogenesis of rheumatoid arthritis (RA) and supply experimental basis for clinical treatment of RA, and to investigate the expression of matrix metalloproteinase-9 (MMP-9) in the synovium of adjuvant arthritis rats. METHODS: Forty rats were divided into four groups (n = 10): (1) Normal control group (group A); (2) Adjuvant arthritis control group (group B); (3) Hyperprolactinemic adjuvant arthritis group (group C); (4) Hypoprolactinemic adjuvant arthritis group (group D). The content of PRL in the serum was detected by radio-immunoassay method. The activity of MMP-9 was analyzed by gelatin zymography. The alteration of MMP-9 immunoreactivity were investigated by means of immunohistochemistry in the synovium of all groups. The expressions of MMP-9 were investigated by Western blot in the synovium of all groups. RESULTS: Compared with group A, the activity and expression of MMP-9 of group B in the synovium were highly increased. The activity and expression of MMP-9 in the synovium were the most distinctive in group C. Compared with group B, the activity and expression of MMP-9 in the synovium were decreased in group D, but still higher than group A. CONCLUSION: The present results indicated that PRL might involved in the pathogenesis of RA by regulating the secretion of MMP-9 in the synovium.
18221983 Use of tumor necrosis factor-alpha inhibitors in patients with chronic hepatitis B infecti 2008 Dec OBJECTIVE: Tumor necrosis factor-alpha (TNF-alpha) inhibitors have emerged as a potent treatment for rheumatoid arthritis (RA), but not without significant risks. In chronic hepatitis B viral infection TNF-alpha is readily produced, and viral clearance is dependent on the amount bioavailable. Limited data suggest that TNF-alpha inhibitors may facilitate uncontrolled hepatitis B viral replication. The purpose of this article was to provide a detailed review of the role of TNF-alpha in controlling hepatitis B viral infection and the clinical impact blockade might have on viral control. METHODS: We describe a patient with chronic hepatitis B viral infection and RA treated with etanercept. We then review case reports, expert opinion, and manufacturer recommendations regarding hepatitis B viral infection, TNF-alpha, and TNF-alpha inhibitors. RESULTS: To date, 13 patients with chronic hepatitis B infection treated with TNF-alpha inhibitors have been reported: 11 with infliximab and 2 with etanercept. Some patients received antiviral therapy for hepatitis B (specifically lamivudine) before, during, or after TNF-alpha inhibitors were started. Clinically apparent reactivation of hepatitis B virus typically occurred 1 month after the 3rd dose of infliximab. Etanercept was not associated with a similar reactivation. The difference between infliximab and etanercept in viral reactivation may be linked to the pharmacologic difference of each medication. CONCLUSIONS: TNF-alpha inhibitors in general should be used cautiously in chronic hepatitis B viral infection. But if necessary, when deciding which agent to use, the clinician should consider the mechanism by which the body clears TNF-alpha.
17207425 Reliability and validity of the American Orthopaedic Foot and Ankle Society Clinical Ratin 2006 Dec BACKGROUND: The use of clinical outcomes instruments is essential for the effective interpretation of individual patient progress as well as the comparison of treatment groups. An outcomes instrument must be reliable and valid to obtain any meaningful data. The purpose of the present study was to examine the reliability and validity of the American Orthopaedic Foot and Ankle Society (AOFAS) clinical rating scale for the hallux metatarsophalangeal-interphalangeal and lesser toes metatarsophalangeal-interphalangeal joints. METHODS: Eleven patients (one man, 10 women) with an average age of 54 (range 40 to 72) years and with classic rheumatoid arthritis not currently treated for foot complaints were enrolled in the present study. The average duration of rheumatoid arthritis was 14 years. Each patient completed a set of two outcomes instruments and had a physical examination by a single clinician at the initial visit and returned at 1 week for completion of the same scales and examination. The outcomes scales used were the AOFAS clinical rating scale for the hallux, the AOFAS clinical rating scale for the lesser toes, and the previously validated Foot Function Index (FFI). Test-retest reliability was evaluated using intraclass correlation coefficients between week 1 and week 2 for the summary scores as well as for the subscales of pain and activity. Consistency between the two instruments was evaluated with Pearson correlation coefficients. RESULTS: The AOFAS clinical rating scale for the hallux and lesser toes is repeatable between 1-week trials (ICC 0.95; p < 0.05; ICC 0.80; p < 0.05, respectively). Moderately strong correlations were found between the mean values for the AOFAS hallux and FFI (r = -0.81; p < 0.05). Weaker correlations were seen between the mean values for the AOFAS lesser toes and FFI scales (r = -0.69; p < 0.05). CONCLUSIONS: The hallux subscale for pain correlates strongly with the FFI subscale for pain, suggesting high content validity (r = -0.94; p < 0.001). Ceiling effects were seen with the AOFAS lesser toe subscale for activity, limiting its usefulness in a general patient population. The AOFAS lesser toe subscale for pain and the AOFAS hallux subscale for activity correlated weakly with the FFI values (r = -0.31; r = -0.37; p > 0.05, respectively). CONCLUSIONS: Although the AOFAS hallux and lesser toe scales were found to be reliable in a rheumatoid patient population, their validity remains in question. These findings must be confirmed with larger subject numbers, with the inclusion of symptomatic patients before recommended routine use of the hallux clinical rating and lesser toe clinical rating scales.
17492248 Sick leave and work disability in patients with early arthritis. 2008 Jan We studied the occurrence of sick leave and work disability, the presence of workplace adaptations and the usage of professional guidance related to working problems in patients with early arthritis. Inclusion criteria were arthritis symptoms of less than 2 years duration and a paid job at the time of diagnosis. Assessments were done in connection with an early arthritis clinic (EAC) at entry into the cohort and 12 months thereafter by means of a questionnaire comprising questions on sick leave (absenteeism from work reported to the employer), work disability (receiving a full or partial work disability pension), unemployment, work adaptations and professional guidance related to working problems. Fifty-seven of the 69 participants (83%) had an arthritis symptom duration of <6 months. The number of patients with sick leave due to arthritis in the past 12 months decreased from 28 (41%) at study entry to 18 (26%) after 12 months of follow-up. The number of patients receiving a work disability pension increased from 5 (7%) at study entry to 13 (19%) after 12 months of follow-up (10 partial and 3 full). Sick leave in the 12 months before study entry appeared to be the most important predictor of the institution or increase in a work disability pension (odds ratio, 16.1; 95%CI, 1.8-142.8). Between study entry and follow-up, the number of patients with workplace adaptations increased from 20 (29%) to 28 (42%), whereas the number of patients receiving vocational guidance decreased from 48 (70%) to 36 (52%). In patients with early arthritis and a paid job, arthritis-related sick leave was common and occurred in part before patients entered the EAC and a diagnosis was made. About 20% of the patients became permanently work disabled, with partial work disability being more common than full work disability. Considerable proportions of patients received workplace adaptations and professional guidance with working problems.
17706915 Chronic stress and regulation of cellular markers of inflammation in rheumatoid arthritis: 2008 Jan OBJECTIVES: This study examined whether chronic interpersonal stress is associated with cellular markers of inflammation and regulation of these responses by in vitro doses of glucocorticoids in rheumatoid arthritis (RA) patients. The association between these markers of inflammation and fatigue was also tested. METHODS: Fifty-eight RA patients completed up to 30 daily ratings of the stressfulness of their interpersonal relations. Interleukin-6 (IL-6) production was analyzed in lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cell cultures with and without varying concentrations of the glucocorticoid hydrocortisone. In addition, plasma levels of IL-6 and C-reactive protein (CRP) were analyzed, and subjective ratings of fatigue and pain were obtained on the day of blood sampling. RESULTS: Multilevel modeling showed that higher chronic interpersonal stress was associated with greater stimulated IL-6 production (p<0.05) as well as greater resistance to hydrocortisone inhibition of IL-6 production (p<0.05). These relations were not accounted for by demographic factors, body mass index, or steroid medication use. Stimulated production of IL-6, in turn, was associated with greater levels of self-reported fatigue, controlling for pain (p<0.05). Neither chronic stress ratings nor fatigue symptoms were related to plasma levels of IL-6 or CRP (ps>.05). CONCLUSIONS: Among RA patients, chronic interpersonal stress is associated with greater stimulated cellular production of IL-6 along with impairments in the capacity of glucocorticoids to inhibit this cellular inflammatory response. Moreover, these findings add to a growing body of data that implicate heightened proinflammatory cytokine activity in those at risk for fatigue symptoms.
17224374 Tumor necrosis factor inhibitor-induced pustular psoriasis? 2007 Feb Dialogues in Dermatology, a monthly audio program from the American Academy of Dermatology, contains discussions between dermatologists on timely topics. Commentaries from Dialogues Editor-in-Chief Warren R. Heymann, MD, are provided after each discussion as a topic summary and are provided here as a special service to readers of the Journal of the American Academy of Dermatology.
17171394 [Computer assisted radiological diagnostics of arthritic joint alterations]. 2006 Dec Computer assisted diagnosis (CAD) schemes are currently used in the field of musculoskeletal diseases to quantitatively assess vertebral fractures, joint space narrowing, andr erosion. Most systems work semi-automatically, i.e. they are operator dependent in the selection of anatomical landmarks. Fully automatic programs are currently under development. Some CAD products have already been successfully used in clinical trials.
17101062 MLN51 and GM-CSF involvement in the proliferation of fibroblast-like synoviocytes in the p 2006 Rheumatoid arthritis (RA) is an inflammatory autoimmune disease of unclear etiology. This study was conducted to identify critical factors involved in the synovial hyperplasia in RA pathology. We applied cDNA microarray analysis to profile the gene expressions of RA fibroblast-like synoviocytes (FLSs) from patients with RA. We found that the MLN51 (metastatic lymph node 51) gene, identified in breast cancer, is remarkably upregulated in the hyperactive RA FLSs. However, growth-retarded RA FLSs passaged in vitro expressed small quantities of MLN51. MLN51 expression was significantly enhanced in the FLSs when the growth-retarded FLSs were treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) or synovial fluid (SF). Anti-GM-CSF neutralizing antibody blocked the MLN51 expression even though the FLSs were cultured in the presence of SF. In contrast, GM-CSF in SFs existed at a significant level in the patients with RA (n = 6), in comparison with the other inflammatory cytokines, IL-1beta and TNF-alpha. Most RA FLSs at passage 10 or more recovered from their growth retardation when cultured in the presence of SF. The SF-mediated growth recovery was markedly impaired by anti-GM-CSF antibody. Growth-retarded RA FLSs recovered their proliferative capacity after treatment with GM-CSF in a dose-dependent manner. However, MLN51 knock-down by siRNA completely blocked the GM-CSF/SF-mediated proliferation of RA FLSs. Taken together, our results imply that MLN51, induced by GM-CSF, is important in the proliferation of RA FLSs in the pathogenesis of RA.
18710900 Discordant perspectives of rheumatologists and patients on COBRA combination therapy in rh 2008 Oct OBJECTIVE: The COBRA therapy (combination therapy in early rheumatoid arthritis) has proven to be an effective treatment for early RA, but is rarely prescribed. A survey showed reluctance of Dutch reumatologists to apply COBRA therapy in early RA. The present qualitative study was carried out to further explore the reservation of Dutch rheumatologists towards prescribing COBRA therapy and include patients' view on (components of) COBRA therapy. METHODS: Two focus group discussions were undertaken for rheumatologists (n(1) = 8, n(2) = 7) and two for patients (n(1) = 4, n(2) = 8). In addition, in-depth interviews were conducted with 11 rheumatologists and 1 patient. These were taped and transcribed. Two independent researchers identified themes and these were discussed with three other researchers. RESULTS: Rheumatologists were positive concerning effectiveness of COBRA therapy, but highly concerned about their patients' possible negative reaction to the large amount of pills to be prescribed. In addition, rheumatologists perceived lack of time explaining and prescribing COBRA therapy and felt uncomfortable prescribing high doses of prednisolone. Patients were positive about an aggressive combination therapy such as COBRA, and they had no qualms taking many pills if this could improve their prognosis. Patients associated prednisolone with negative side-effects, but were also aware of the benefits and the need of prednisolone in rough times. A decrease in the amount of pills after intensive treatment was highly appreciated. CONCLUSION: Rheumatologists and patients differed in opinion about the use of COBRA therapy. Rheumatologists were particularly concerned about their patients' reaction towards them prescribing such an aggressive and complex therapy, whereas patients, while aware of the side-effects, were most interested in suppressing illness symptoms and reducing future damage regardless of the amount of pills.
16547695 Serious liver disease induced by infliximab. 2007 Apr Infliximab, a chimeric monoclonal antibody that binds the tumor necrosis factor alpha (TNFalpha), is used in the treatment of rheumatoid arthritis (RA) and Crohn's disease (CD). Previous cases of significant secondary liver disease associated with infliximab treatment have been reported in patients with RA, CD, and psoriatic arthritis. Two additional patients with RA who developed a serious liver disease associated with infliximab treatment are reported here. A 39-year old RA patient was admitted with cholestatic liver disease after 8 months of treatment with infliximab. She had no history of hepatic diseases, exposure to hepatotoxic or illicit drugs, or alcohol abuse. A liver biopsy showed severe ductal proliferation with collapse and enucleation of the hepatocytes. Despite aggressive treatment with oral prednisolone, she developed hepatic failure. On the 45th day, a liver transplant was performed. The second patient, a 54-year old RA patient, was diagnosed with autoimmune hepatitis after 12 infliximab infusions. She fulfilled autoimmune hepatitis type 1 criteria. A liver biopsy disclosed an altered lobulillar structure with chronic inflammation and the formation of collagen bands. She was treated with prednisolone and azatioprine and a complete recovery was noted 1 month later. These cases should alert rheumatologists to the possibility of new adverse reactions (liver injury) associated with the use of TNFalpha blockers in an autoimmune setting.
16356201 Partial protection against collagen antibody-induced arthritis in PARP-1 deficient mice. 2006 Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear DNA-binding protein that participates in the regulation of DNA repair and maintenance of genomic integrity. In addition, PARP-1 has a role in several models of inflammation disease, where its absence or inactivation confers protection. The aim of this study was to analyze the impact of selective PARP-1 suppression in collagen antibody-induced arthritis. We show that PARP-1 deficiency partially reduces the severity of arthritis, although the incidence of disease was similar in control and deficient mice. Decreased clinical scores were accompanied by partial reduction of histopathological findings. Interestingly, quantitative real-time PCR and ELISA analysis revealed that the absence of PARP-1 down-regulated IL-1beta and monocyte chemotactic protein 1 expression in arthritic joints whereas tumor necrosis factor-alpha transcription was not impaired. Our results provide evidence of the contribution of PARP-1 to the progression of arthritis and identify this protein as a potential therapeutic target for the treatment of rheumatoid arthritis.
17142562 Mechanism of the regulation of organic cation/carnitine transporter 1 (SLC22A4) by rheumat 2007 Mar Recently, it was reported that the organic cation/carnitine transporter 1 (OCTN1, SLC22A4) is associated with chronic inflammatory diseases, such as rheumatoid arthritis (RA) and Crohn's disease. OCTN1 in humans is expressed in synovial tissues of individuals with rheumatoid arthritis. Furthermore octn1 in mice is expressed in inflamed joints with collagen-induced arthritis, a model of human arthritis, but not in the joints of normal mice. OCTN1 should be involved in the inflammatory disease and in the present study, the regulatory mechanism of OCTN1 expression was characterized using the human fibroblast-like synoviocyte cell line MH7A, derived from RA patients. A luciferase-reporter gene assay and gel shift assay demonstrated that RUNX1, which is an essential hematopoietic transcription factor associated with acute myeloid leukemia and is related to RA and Sp1, is involved in the regulation of OCTN1 promoter activity. Inflammatory cytokines such as interleukin-1beta and tumor necrosis factor-alpha increased the expression of OCTN1 mRNA. Furthermore, overexpression of nuclear factor-kappaB (NF-kappaB) activated promoter activity of OCTN1. These results clearly demonstrate that expression of OCTN1 is regulated by various factors, including RUNX1, inflammatory cytokines, and NF-kappaB, all of which are also related to the pathogenesis of RA. Further studies on the physiological substrate(s) of OCTN1 should be done to clarify the roles of OCTN1 in these diseases.
18696397 Tubuloreticular structures in different types of myositis: implications for pathogenesis. 2008 Jul In dermatomyositis (DM) there is strong histopathological evidence of a microvascular pathogenesis, including endothelial microtubular inclusions. In nonspecific myositis, perimysial and perivascular infiltrates in the muscle biopsy similar to DM are found. Microtubular inclusions in endothelial cells were systematically searched for and found in 4 of the 20 muscle biopsies of nonspecific myositis patients (20%). Three had a CTD (SLE, scleroderma, and Sjogren syndrome). Ten patients with DM and 5 patients with sporadic inclusion body myositis served as positive and negative controls, respectively.
17608745 Validation of an ELISA for the diagnosis of recent Campylobacter infections in Guillain-Ba 2007 Sep Weeks or months following Campylobacter infection, a small proportion of infected individuals develop Guillain-Barré syndrome (GBS) or reactive arthritis (ReA). Stool culture for Campylobacter is often negative in these patients, and serology is therefore the method of choice for diagnosing a recent infection with Campylobacter. This study developed a capture ELISA system to detect anti-Campylobacter IgA and IgM antibodies indicative of a recent infection. The sensitivity of the assay was 82.0% in uncomplicated Campylobacter enteritis patients, 96.2% in GBS patients who were culture-positive for Campylobacter, and 93.1% in culture-positive ReA patients, with a specificity of 93.0%. The assay allows identification of Campylobacter infection in patients with post-infectious neurological and rheumatological complications.
17971849 Therapeutic effect of a poly(ADP-ribose) polymerase-1 inhibitor on experimental arthritis 2007 Oct 31 Poly(ADP-ribose) polymerase-1 (PARP-1) synthesizes and transfers ADP ribose polymers to target proteins, and regulates DNA repair and genomic integrity maintenance. PARP-1 also plays a crucial role in the progression of the inflammatory response, and its inhibition confers protection in several models of inflammatory disorders. Here, we investigate the impact of a selective PARP-1 inhibitor in experimental arthritis. PARP-1 inhibition with 5-aminoisoquinolinone (AIQ) significantly reduces incidence and severity of established collagen-induced arthritis, completely abrogating joint swelling and destruction of cartilage and bone. The therapeutic effect of AIQ is associated with a striking reduction of the two deleterious components of the disease, i.e. the Th1-driven autoimmune and inflammatory responses. AIQ downregulates the production of various inflammatory cytokines and chemokines, decreases the antigen-specific Th1-cell expansion, and induces the production of the anti-inflammatory cytokine IL-10. Our results provide evidence of the contribution of PARP-1 to the progression of arthritis and identify this protein as a potential therapeutic target for the treatment of rheumatoid arthritis.
16925507 Once-daily tramadol in rheumatological pain. 2006 Sep New once-daily formulations of tramadol have been recently marketed in various countries. This review focuses on the matrix systems used in sustained-release formulations to control drug delivery, the pharmacokinetics and pharmacodynamic profile and the available clinical trials on once-daily tramadol. Four controlled clinical studies with a limited number of patients have shown that once-daily tramadol is safe and effective for up to 12 weeks in rheumatological pain treatment, with a favourable side effects profile. Once-daily tramadol has established efficacy superior to that of placebo for pain management and functional improvement in patients with osteoarthritis. Two randomised clinical trials demonstrated similar rates of efficacy between immediate-release and once-daily sustained-release formulation, without significant differences in the use of escape medications and the number of nights woken. Once-daily tramadol offers the advantage of a reduced dosing regimen that improves patient compliance.
17530707 Interleukin-18 induces angiogenic factors in rheumatoid arthritis synovial tissue fibrobla 2007 Jun OBJECTIVE: Interleukin-18 (IL-18) is a proinflammatory cytokine implicated in the pathogenesis of rheumatoid arthritis (RA). This study was undertaken to examine the role of IL-18 in up-regulating secretion of the angiogenic factors stromal cell-derived factor 1alpha (SDF-1alpha)/CXCL12, monocyte chemoattractant protein 1 (MCP-1)/CCL2, and vascular endothelial growth factor (VEGF) in RA synovial tissue (ST) fibroblasts, and the underlying signaling mechanisms involved. METHODS: We used enzyme-linked immunosorbent assays, Western blotting, and chemical inhibitors/antisense oligodeoxynucleotides to signaling intermediates to assess the role of IL-18. RESULTS: IL-18 significantly enhanced the production of SDF-1alpha/CXCL12, MCP-1/CCL2, and VEGF in RA ST fibroblasts, in a time- and concentration-dependent manner. IL-18-induced SDF-1alpha/CXCL12 up-regulation was dependent on JNK, p38 MAPK, phosphatidylinositol 3-kinase (PI3K), and NFkappaB. While IL-18-induced production of SDF-1alpha/CXCL12 was also dependent on protein kinase Cdelta (PKCdelta), production of MCP-1/CCL2 was dependent on PKCalpha, not PKCdelta. Additionally, RA ST fibroblast IL-18-induced MCP-1/CCL2 production was mediated by JNK, PI3K, and NFkappaB. In contrast, IL-18 did not induce secretion of RA ST fibroblast MCP-1/CCL2 or VEGF via p38 MAPK. IL-18-induced RA ST fibroblast production of VEGF was mediated mainly by JNK-2, PKCalpha, and NFkappaB. IL-18 induced phosphorylation of JNK, PKCdelta, p38 MAPK, and activating transcription factor 2 (ATF-2) in RA ST fibroblasts in a time-dependent manner, with JNK-2 being upstream of PKCdelta, ATF-2, and NFkappaB. CONCLUSION: These data support the notion that IL-18 has a unique role in inducing the secretion of angiogenic SDF-1alpha/CXCL12, MCP-1/CCL2, and VEGF in RA ST fibroblasts, via distinct signaling intermediates.
18417067 Rheumatoid arthritis and cardiovascular disease. 2008 Apr Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease affecting approximately 1% of the adult general population. Cardiovascular disease is recognized as the leading cause of death in RA patients, accounting for nearly 40% of their mortality. Patients with RA are at a twofold increased risk for myocardial infarction and stroke, with risk increasing to nearly threefold in patients who have had the disease for 10 years or more. Congestive heart failure appears to be a greater contributor to excess mortality than ischemia. This increased cardiovascular disease risk in RA patients seems to be independent of traditional cardiovascular risk factors. Pathogenic mechanisms include pro-oxidative dyslipidemia, insulin resistance, prothrombotic state, hyperhomocysteinemia, and immune mechanisms such as T-cell activation that subsequently lead to endothelial dysfunction, a decrease in endothelial progenitor cells, and arterial stiffness, which are the congeners of accelerated atherosclerosis observed in RA patients. This paper discusses pathogenic mechanisms, effects of methotrexate, tumor necrosis factor antagonists, steroids, and statins, with a perspective on therapy.
17696278 Peripheral blood expression of nuclear factor-kappab-regulated genes is associated with rh 2007 Sep OBJECTIVE: To evaluate peripheral blood expression of genes regulated by nuclear factor-kappaB (NF-kappaB), a key mediator of tumor necrosis factor-alpha (TNF-alpha) signaling, in patients with rheumatoid arthritis (RA) before and during treatment with anti-TNF-alpha or methotrexate (MTX). We analyzed association of gene expression with disease activity, rheumatoid factor (RF), age, sex, disease duration, treatment modality, and clinical response. METHODS: Sixty patients consented for RNA analysis at baseline and after 2 and 6 weeks of treatment. Disease activity was quantified using Disease Activity Score (DAS28) and C-reactive protein (CRP). Expression of 67 TNF-alpha-responsive, NF-kappaB-regulated genes was measured using Affymetrix arrays and RT-PCR. RESULTS: Expression of 34 genes was associated with DAS28-CRP, notably S100A12/calgranulin C, IL7R, and aquaporin 3. No association was observed with age, sex, RF, or disease duration. Expression of 16 genes changed in a manner that differed significantly between treatment groups. Eleven were reduced in anti-TNF-alpha-treated patients relative to MTX, while 5 were increased. The majority of these observations were confirmed using RT-PCR. Gene expression was not associated significantly with change in disease activity. CONCLUSION: NF-kappaB-dependent gene expression in peripheral leukocytes is highly correlated with RA activity as measured by DAS28-CRP. Expression of many genes responds differentially to anti-TNF-alpha versus MTX, suggesting fundamentally different effects on the NF-kappaB pathway. This peripheral blood expression signature provides candidate markers that could lead to development of a simple, minimally invasive pharmacodynamic assay for RA treatments directed at the NF-kappaB pathway. Combination of gene expression data with clinical scores and serum markers may provide more sensitive and predictive measures of RA disease activity.