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ID PMID Title PublicationDate abstract
16463669 Effects of triptolide on the expression and activity of NF-kappaB in synovium of collagen- 2005 The expression and activity of NF-kappaB in the synovium of collagen-induced arthritis (CIA) rats was detected in order to investigate the possible therapeutic effects of triptolide on rheumatoid arthritis (RA). The experimental Wistar rat model of CIA was set up by intradermal injection of emulsion of bovine collagen II and the successful rate of setting-up models was evaluated by arthritis index (AI). Rats were grouped randomly into three groups: normal, model and treatment group. The expression of TNF-alpha and IL-6 in synovial fluid was detected by ELISA, and the expression and activity of NF-kappaB in synovium by immunohistochemistry method and by electrophoretic mobility shift assay (EMSA) respectively. As compared with normal group, the expression of TNF-alpha and IL-6 in synovia (P < 0.05), and the expression and activity of NF-kappaB (P < 0.05) in synovium were increased in model group. There was statistical difference in above-mentioned indexes between model group and treatment group. Triptolide may play a protective role in RA via downregulating the expression and activity of NF-kappaB in synovium.
16261384 Costs in rheumatology: results and lessons learned from the 'Hannover Costing Study'. 2006 Jun The objective of this study is to review the concept of the 'Hannover Costing Study' and to present and discuss the major insights generated during the course of the project. The costing study was performed in conjunction with a randomized controlled prospective trial assessing the effectiveness of a disease management module in rheumatoid arthritis (RA). A full set of clinical and cost data both from patient-reported and payer-derived cost data was developed. In particular the study included (1) the development of a matrix of cost domains which might be used as a common taxonomy in costing studies, (2) the descriptive analysis of payer derived cost data, (3) the analysis of cost data in patients with uncertain diagnosis; (4) the development and validation of a patient-reported costing instrument, and (5) an assessment of productivity costs. The following are the results (1) the developed matrix of cost domains included 16 separate cost domains: 7 outpatient, 3 inpatient, 4 other disease related, and 2 productivity domains; (2) the micro-costing analysis showed total direct costs of 3,815 per patient-year (standard error of mean, SEM: 267) and RA-related direct costs were 2,312 per patient-year; (3) in patients with uncertain diagnosis of RA and no treatment with 'Disease Modifying Antirheumatic Drugs' (DMARD) costs were significantly lower; (4) the comparison of patient-reported with payer-reported cost data generally supports the use of highly aggregated items to assess health care utilization in RA; (5) productivity costs in patients that are gainfully employed and in patients who receive RA-related retirement payments exceed RA-related direct costs. Furthermore, RA-patients reported their productivity losses adequately. The study added some additional insights to the following questions: What costs should be collected, what level of detail is required for that task, what patients should by analyzed, and what data sources should be used in further studies in RA.
16838278 Epitopes of human fibrin recognized by the rheumatoid arthritis-specific autoantibodies to 2006 Aug Formation of the epitopes recognized by the rheumatoid arthritis (RA)-specific autoantibodies to citrullinated proteins (ACPA) on filaggrin and on the alpha- and beta-chains of fibrin, their synovial target, requires conversion of their arginyl residues into citrullyl residues, but is also affected by their amino-acyl environment. Using competition with five citrullinated filaggrin-derived peptides bearing major ACPA epitopes, we confirmed the close cross-reactivity between filaggrin and citrullinated fibrin. To identify the sequential epitopes recognized on fibrin by ACPA, 71 citrullinated 15-mer peptides derived from all the sites of the alpha- and beta-chains of fibrin harboring arginyl residues were tested by ELISA using ACPA-positive RA sera exhibiting different reactivity profiles to the five filaggrin peptides. We identified 18 fibrin-derived peptides bearing ACPA epitopes. Regarding the ability of fibrinogen arginyl residues to be citrullinated in vitro, 11 of the peptides likely correspond to in vivo targeted epitopes. Two out of them bear major epitopes and are located in the central globular domain of the protein. In the synovial tissue, fibrin citrullination and ACPA binding could impair fibrin degradation by plasmin. The immunological conflict between ACPA and fibrin could therefore sustain synovial inflammation not only via pro-inflammatory effector mechanisms but also via impairment of fibrinolysis.
16622024 A critical role for adrenomedullin-calcitonin receptor-like receptor in regulating rheumat 2006 May 1 Rheumatoid arthritis (RA) is characterized by fibroblast-like synoviocyte (FLS) hyperplasia, which is partly ascribable to decreased apoptosis. In this study, we show that adrenomedullin (ADM), an antiapoptotic peptide, is constitutively secreted in larger amounts by FLS from joints with RA (RA-FLS) than with osteoarthritis (OA-FLS). ADM secretion was regulated by TNF-alpha. Peptidylglycine alpha-amidating monooxygenase, the ADM-processing enzyme, was expressed at the mRNA level by both RA-FLS and OA-FLS. Constituents of the ADM heterodimeric receptor calcitonin receptor-like receptor (CRLR)/receptor activity-modifying protein (RAMP)-2 were up-regulated at the mRNA and protein levels in cultured RA-FLS compared with OA-FLS. ADM induced rapid intracellular cAMP production in FLS and reduced caspase-3 activity, DNA fragmentation, and chromatin condensation in RA-FLS exposed to apoptotic conditions, indicating that CRLR/RAMP-2 was fully functional. ADM-induced cAMP production was less marked in OA-FLS than in RA-FLS, suggesting differences in receptor regulation and expression. ADM dose-dependently inhibited RA-FLS apoptosis, and this effect was reversed by the 22-52 ADM antagonist peptide. ADM inhibited RA-FLS apoptosis triggered by extrinsic and intrinsic pathways. Our data suggest that ADM may prevent or reduce RA-FLS apoptosis, via up-regulation of its functional receptor CRLR/RAMP-2. Regulation of ADM secretion and/or CRLR/RAMP-2 activation may constitute new treatment strategies for RA.
17009233 In vitro and in vivo efficacy of a recombinant immunotoxin against folate receptor beta on 2006 Oct OBJECTIVE: To investigate the effects of the recombinant immunotoxin dsFv anti-FRbeta-PE38, which consists of the disulfide-stabilized Fv fragment (dsFv) of the anti-folate receptor beta (anti-FRbeta) antibody and the 38-kd portion of Pseudomonas exotoxin A (PE38), on the activation and proliferation of cells that function in inflammatory and degradative processes in rheumatoid arthritis (RA) synovial tissue. METHODS: The Ig VH-PE38 fusion protein and the Ig VL protein were produced in Escherichia coli, and then joined with a disulfide bond by engineering cysteine residues in the framework regions of these proteins. The effects of dsFv anti-FRbeta-PE38 on the activation and proliferation of cells in RA synovial tissue were investigated by immunohistochemistry; the numbers of cells expressing CD68, vascular cell adhesion molecule 1, angiopoietin 1, CD34, proliferating cell nuclear antigen, and interleukin-6 and the numbers of apoptotic cells were counted in RA synovial tissue engrafted into SCID mice treated or not treated with dsFv anti-FRbeta-PE38. The effects of dsFv anti-FRbeta-PE38 on the generation of osteoclasts from RA adherent synovial mononuclear cells in vitro was investigated by counting the number of resorption pits on dentin slices treated or not treated with dsFv anti-FRbeta-PE38. RESULTS: Administration of dsFv anti-FRbeta-PE38 reduced the numbers of macrophages, activated fibroblast-like cells, endothelial cells, and proliferating cells and increased the numbers of apoptotic cells in RA synovial tissue engrafted into SCID mice. In vitro, the generation of osteoclasts from RA adherent synovial mononuclear cells was largely suppressed by treatment with dsFv anti-FRbeta-PE38. CONCLUSION: Our findings show that dsFv anti-FRbeta-PE38 immunotoxin would be a promising tool for the treatment of RA synovitis, especially when administered intraarticularly.
16033328 TNF-alpha as a promising therapeutic target in chronic asthma: a lesson from rheumatoid ar 2005 Aug TNF-alpha (tumour necrosis factor-alpha) is known to play a critical role in the pathogenic mechanisms of a number of chronic inflammatory diseases, including RA (rheumatoid arthritis), Crohn's disease and psoriasis. The notion that TNF-alpha is released in allergic responses from both mast cells and macrophages via IgE-dependent mechanisms, the demonstration that elevated levels of TNF-alpha are frequently observed in bronchoalveolar fluid of asthmatic subjects undergoing allergen challenge and the results from exposure studies of TNF-alpha in vivo showing increases in airway responsiveness in both normal and asthmatic subjects emphasize the importance of TNF-alpha in the initiation of allergic asthmatic airway inflammation and the generation of airway hyper-responsiveness. Drugs targeting TNF-alpha have been developed to neutralize the deleterious effects of this inflammatory cytokine and have proved to be safe and effective in the treatment of patients with RA, Crohn's disease and psoriasis refractory to conventional treatments. Biological therapies blocking TNF-alpha are likely to constitute a considerable advance in the management of those difficult cases of asthma that are particularly resistant to typical treatment modalities. In this review article, we intend to address the potential role of TNF-alpha in asthma and to put forward the idea that drugs that have been developed to neutralize the deleterious effects of TNF-alpha may also be useful in the management of chronic severe asthma.
16819694 Revision total knee arthroplasty with the total condylar III system: a comparative analysi 2006 Jun BACKGROUND: As revision total knee arthroplasty surgery is becoming more common, it is necessary to evaluate how individual revision prosthesis systems perform in degenerative and inflammatory arthritides. In this study, results of the use of the Total Condylar III (TC III) system in osteoarthritis (55 knees) were compared to results of its use in inflammatory arthritis (16). METHODS: Patients were followed radiographically for 5.9 (3.0-10.2) years and clinically for 3.0 (0.2-6.8) years, using re-revision as the endpoint. RESULTS: At 1 year after revision and at final follow-up, the total Knee Society knee score, function score and range of motion had improved (p < 0.001) with no differences between osteoarthritis and inflammatory arthritis. No knee had definite component loosening, although 23 knees had asymptomatic radiolucent lines. Complications comprised 4 infections, 1 patellar pain syndrome and 1 rupture of the patellar tendon. Using any re-revision of the prosthesis as the endpoint, 5-year survival was 95% and 8-year survival was 94%. INTERPRETATION: Concentration of demanding revision knee arthroplasties to a few hands led to good or excellent knee joint knee score results in four-fifths of the patients, and showed good outcome with the TCIII system. In spite of ligamentous laxity, propensity to develop infections, bone destruction and poor general health, patients with inflammatory arthritis had results similar to those with osteoarthritis.
15909083 [Accelerated atherosclerosis in rheumatic systemic diseases as an example of systemic lupu 2005 May Large increases in mortality related to premature atherosclerosis with coronary artery disease and stroke have been reported during the last few years in patients with systemic lupus erythematosus (SLE). Studies found relative risks of 5 to 7 for myocardial infarction in SLE patients. The traditional risk factors fail to fully account for accelerated atherosclerosis in SLE and APS, in addition prolonged glucocorticoid therapy and long duration of SLE seem to be of importance. The disease SLE per se is an independent risk factor. The current pathogenic hypothesis for atherosclerosis involves an inflammatory response, autoantibodies, immune complexes (containing antibodies to phospholipids, to oxidized LDLs, and to endothelial cells), CD40/CD40 ligand interactions, and bacterial or viral infections responsible for an immune response. The determination of classic and new risk factors, together with specific autoantibody titers and the use of Doppler carotid ultrasound, are useful methods to detect early atherosclerosis. Therapeutic strategies, including early risk factor intervention and effective control of inflammation, are essential to reduce morbidity and mortality and should be incorporated into the management of connective tissue disease with the goal of protecting patients against atherosclerosis.
17276570 Anti-inflammatory and lysosomal stability actions of Cleome gynandra L. studied in adjuvan 2007 Jun The present study was aimed to assess the anti-arthritic nature of Cleome gynandra L. (Cat's whiskers) against Freund's complete adjuvant induced arthritis in rats. The ethanolic extract of C. gynandra was administered orally at a dose of 150 mg/kg body weight for 30 days to the experimental rats after the induction of adjuvant arthritis. The anti-inflammatory activity of C. gynandra leaves was assessed by paw volume measurement, and its capacity to stabilize lysosomal enzyme activities in the plasma and liver of control and experimental rats. The activity of pathophysiological enzymes such as AST, ALT, ALP, cathepsin-D, beta-glucuronidase, N-acetyl-beta-glucosaminidase LDH and the levels of glycoproteins were also estimated in plasma and liver. The increased levels of both lysosomal enzymes and protein-bound carbohydrates in arthritic rats were significantly suppressed to near normal level by the administration of C. gynandra extract. Further, the significantly elevated plasma levels of TNF-alpha found in arthritic rats were found to be significantly restored back to near normal levels by the extract in experimental animals. The membrane stabilizing activity of the extract was further evidenced by histological observations made on the limb tissue. Recently, we have reported the presence of many biologically active phyto chemicals such as triterpenes, tannins, anthroquinones, flavonoids, saponins, steroids, resins, lectins, glycosides, sugars, phenolic compounds, and alkaloids in the extract of C. gynandra and these compounds might be responsible for the anti-arthritic properties observed in the present study. The possible mechanism of action of the C. gynandra extract may be through its stabilizing action on lysosomal membranes and there by preventing the spread of inflammation.
16981801 Review of eight pharmacoeconomic studies of the value of biologic DMARDs (adalimumab, etan 2006 Sep BACKGROUND: Treatment options for the management of rheumatoid arthritis (RA) have expanded from the traditional disease-modifying antirheumatic drugs (DMARDs) to include the biologic DMARDs that inhibit tumor necrosis factoralpha (TNF-a). OBJECTIVE: To assess the medical literature for studies of the economic value of biologic DMARDs, specifically the 3 TNF-a inhibitors (adalimumab, etanercept, and infliximab) used for the management of RA, compared with the traditional DMARDs such as sulfasalazine, antimalarials, penicillamine, gold, methotrexate, azathioprine, leflunomide, and cyclophosphamide. METHODS: A comprehensive search of the MEDLINE and HealthSTAR databases was conducted to identify cost-efficacy, cost-effectiveness, or cost-utility studies published in the English language (from 1966 through November 2004). The search terms and/or MeSH (medical subject headings) titles were cost-benefit analysis, rheumatoid arthritis, antirheumatic agents, antineoplastic and immunosuppressive agents. Studies were critically reviewed and quality was assessed using the Quality of Health Economic Studies instrument. Most studies evaluated the use of biologics among RA patients resistant to DMARDs. Studies were assessed with regard to comparators evaluated, measures of efficacy, perspectives, model duration, treatment duration, and discount rate. RESULTS: From 180 titles identified, 155 were excluded for the following reasons: 89 because they did not consider the drugs of interest, 15 because the population was not RA, 19 because of having the wrong drugs and population, 22 because they were review articles, and 10 because they were general articles. Twentyfive abstracts were accepted for further review. Of these, 13 abstracts were subsequently selected for full-text review. One of the authors identified a study not indexed in MEDLINE. Ultimately, 2 cost-effectiveness and 6 cost-utility studies were selected for this critical review. One study over 6 months reported that triple therapy with DMARDs (methotrexate-hydroxychloroquine-sulfasalazine) was cost effective for methotrexate-resistant patients, which is consistent with American College of Rheumatology (ACR) guidelines that support the use of triple therapy prior to biologics. The incremental cost-effectiveness ratio (ICER) was $1,500 per patient to achieve an ACR20 response for this triple therapy compared with no second-line agent. Overall, biologic therapies cost considerably more than traditional DMARDs but produced more quality-adjusted life-years (QALYs). Despite differences in design and assumptions, published economic models consistently reported ICERs <50,000 dollars per QALY gained for biologics compared with traditional DMARDs, although ICERs of >100,000 dollars were reported from sensitivity analyses. CONCLUSIONS: Clinical guidelines currently recommend the use of biologics as step therapy after failure of traditional DMARDs. Reported ICERs comparing biologics with traditional DMARDs are within a range that is comparable with other accepted medical interventions. The worth of the additional expenditure will ultimately be judged by formulary and policy decision makers because no maximum cost has been defined. Models can be used to inform decision makers, but they must be interpreted and applied carefully. More research is also needed to differentiate the relative economic value of the various biologic agents by therapeutic indication.
16849507 Expression of CD44 and L-selectin in the innate immune system is required for severe joint 2006 Aug 1 Proteoglycan (PG)-induced arthritis, a murine model of rheumatoid arthritis, is characterized by autoimmunity against mouse cartilage PG and chronic joint inflammation. L-selectin (CD62L) and CD44 are major adhesion molecules on leukocytes that regulate their homing to lymph nodes and entry into inflamed tissues. In the present study, we studied the requirement for CD44 and CD62L expression for mediating lymphocyte homing, thus permitting the development of autoimmunity vs mediating the entry of leukocytes into the joints, thus allowing inflammation in PG-induced arthritis. We immunized wild-type, CD44 knockout (KO), CD62L KO, and double (CD44/CD62L) KO BALB/c mice with PG and monitored the effects of gene deficiencies on PG-specific immunity, arthritis severity, leukocyte trafficking, and the ability of lymphocytes to adoptively transfer disease to syngeneic SCID mice. Single and double KO mice demonstrated reduced PG-specific spleen cell proliferation, but the production of Th cytokines and autoantibodies was comparable in KO and wild-type mice. KO leukocytes had reduced ability to adhere tightly to the synovial endothelium in arthritic joints. This diminished leukocyte adhesion correlated with the magnitude of granulocyte (neutrophil) influx and the severity of inflammation, which were both reduced in the joints of KO mice. However, transfer of spleen cells from mildly arthritic KO donors to SCID hosts resulted in development of severe arthritis. Our results indicate that CD44 and CD62L expression in the cells of the innate immune system (granulocytes) is important for their efficient influx into the joints and also suggest that granulocytes play a crucial role in arthritis progression.
16049881 [Rheumatoid arthritis]. 2005 Jul 29 The development of novel anti-rheumatic drugs revolutionizes currently therapeutic strategies and diagnostic management of patients with rheumatoid arthritis, facilitating the goal of true remission instead of only symptomatic treatment as in former years. Since early treatment is known to be crucial for the longterm outcome, imaging modalities such as magnetic resonance imaging and high-frequency ultrasonography including Doppler sonography, which allow direct visualization of very early pathologic alterations of synovitis, or even initial destruction, become increasingly important. Besides the established therapy with methotrexate, new drugs such as leflunomide or the use of various combination therapies have been successfully introduced into the therapeutic armamentarium. Especially the introduction of cytokine-antagonists such as TNF-a inhibitors target the aim of remission. In addition, the upcoming therapeutic agents, which influence very effectively the inflammatory and destructive process need also to be integrated into the concert of different therapeutic strategies in the management of patients with rheumatoid arthritis, which includes the mandatory complementary factors such as physiotherapy, ergotherapy and orthopedic surgery.
17178563 Antigen-induced differential gene expression in lymphocytes and gene expression profile in 2006 Dec To explore early signature genes playing critical roles in the initial steps in an autoimmune murine model of rheumatoid arthritis (RA) (proteoglycan (PG)-induced arthritis; PGIA), we performed gene expression profiling of "arthritogenic" spleen cells stimulated with cartilage PG, and compared them to differentially expressed genes, identified in joints prior to the onset of arthritis, and then in the acute and chronic phases of the disease. A total of 280 genes were up-regulated and 226 genes were suppressed in in vitro PG-stimulated lymphocytes at a minimum of 2-fold expression change. Functional gene classification identified several major clusters of biological activity. Expression of immunoglobulin genes (66 transcripts) was downregulated by approximately 3.7-fold, whereas most of the other genes with immune/inflammation-associated functions such as interleukins (IL-1, -2, -4, -6, -10, -12, -16, -17), chemokine receptors and their ligands (Cxcl1, Ccl2, 7, 8, 9, 10, 22, Ccr2, Ccr5), and major components of the complement cascade were upregulated. Using adoptive disease transfer with stimulated lymphocytes into SCID mice, followed by gene expression profiling of SCID paws, indicated that 37 genes were differentially expressed in yet non-inflamed (pre-arthritic) paws; these genes were related mostly to chemokine, IFN-gamma and TNF-alpha signaling. However, the majority of differentially expressed immune response-related genes were silent in pre-arthritic joints, and only 12 genes were found differentially expressed both in antigen (PG)-stimulated lymphocytes and in the synovium prior to the onset of arthritis. Most of these "arthritis-initiation" genes belonged to chemokine mediated cell motility. Transcripts of chemokine receptor 5 (Ccr5), chemokine ligand 7 (Ccl7) and IFN-gamma-inducible proteins (Ifi47) and GTP-ase 1 were expressed at the highest levels in both antigen-stimulated lymphocytes and pre-inflamed synovium, which suggests a key role of these genes in both lymphocyte maturation and arthritis initiation.
17207383 Frequency of musculoskeletal conditions among patients referred to Italian tertiary rheuma 2006 Nov OBJECTIVE: To describe the occurrence of different rheumatic diseases and to examine the characteristics of patients referred to six Italian rheumatological units. To compare these data with those from other countries. METHODS: Six Italian rheumatological tertiary referral centers participated in the study. Diagnoses of in- and outpatients aged over 16 years were classified according to the International Classification of Diseases, ninth revision. RESULTS: Three thousand, five hundred and thirty-seven patients with mean age 56 +/- 14.8 years, of which 2604 (73.6%) were women, were studied. Inflammatory joint and spine diseases were diagnosed in 40.4%, connective tissue diseases in 14.4%, degenerative joint and spine diseases in 21.4%, soft tissue rheumatisms in 18.5%, and metabolic bone diseases in 5.3%. There was a significant difference among centers in the frequency of most diagnoses: non-academic centers cared for more patients with arthritis and connective tissue diseases and for less patients with degenerative diseases, soft tissue rheumatisms and metabolic bone diseases. Connective tissue diseases were constantly seen more often in Italian centers, whereas soft tissue rheumatisms were seen more often abroad. CONCLUSION: Our data emphasize the great variability of the diagnostic case-mix in different centers from the same country, an observation that raises some concerns of the results of descriptive multicenter studies. Studies on the breakdown of diagnoses made in rheumatological centers could be helpful to determine the burden of rheumatic diseases on the health system, and for the planning of health interventions by both the national rheumatological societies and health authorities.
16357751 Selective costimulation modulators: a novel approach for the treatment of rheumatoid arthr 2005 Jun T cells have a central role in the orchestration of the immune pathways that contribute to the inflammation and joint destruction characteristic of rheumatoid arthritis (RA). The requirement for a dual signal for T-cell activation and the construction of a fusion protein that prevents engagement of the costimulatory molecules required for this activation has led to a new approach to RA therapy. This approach is mechanistically distinct from other currently used therapies; it targets events early rather than late in the immune cascade, and it results in immunomodulation rather than complete immunosuppression. The fusion protein abatacept is a selective costimulation modulator that avidly binds to the CD80/CD86 ligands on an antigen-presenting cell, resulting in the inability of these ligands to engage the CD28 receptor on the T cell. Abatacept dose-dependently reduces T-cell proliferation, serum concentrations of acute-phase reactants, and other markers of inflammation, including the production of rheumatoid factor by B cells. Recent studies have provided consistent evidence that treatment with abatacept results in a rapid onset of efficacy that is maintained over the course of treatment in patients with inadequate response to methotrexate and anti-tumor necrosis factor therapies. This efficacy includes patient-centered outcomes and radiographic measurement of disease progression. Abatacept has also demonstrated a very favorable safety profile to date. This article reviews the rationale for this therapeutic approach and highlights some of the recent studies that demonstrate the benefits obtained by using abatacept. This clinical experience indicates that abatacept is a significant addition to the therapeutic armamentarium for the management of patients with RA.
15987483 Decreased levels of soluble receptor for advanced glycation end products in patients with 2005 The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily being expressed as a cell surface molecule and binding a variety of ligands. One of these ligands is high-mobility group box chromosomal protein 1, a potent proinflammatory cytokine, expression of which is increased in synovial tissue and in synovial fluid of rheumatoid arthritis (RA) patients. The interaction of high-mobility group box chromosomal protein 1 with cell-surface RAGE leads to an inflammatory response. In contrast, the presence of soluble RAGE (sRAGE) may abrogate cellular activation since the ligand is bound prior to interaction with the surface receptor. Our aim was to analyse to what extent sRAGE is present in patients with chronic joint inflammation (RA) as compared with patients with non-inflammatory joint disease and with healthy subjects, and to assess whether there is an association between sRAGE levels and disease characteristics. Matching samples of blood and synovial fluid were collected from 62 patients with RA with acute joint effusion. Blood from 45 healthy individuals, synovial fluid samples from 33 patients with non-inflammatory joint diseases and blood from six patients with non-inflammatory joint diseases were used for comparison. sRAGE levels were analysed using an ELISA.RA patients displayed significantly decreased blood levels of sRAGE (871 +/- 66 pg/ml, P < 0.0001) as compared with healthy controls (1290 +/- 78 pg/ml) and with patients with non-inflammatory joint disease (1569 +/- 168 pg/ml). Importantly, sRAGE levels in the synovial fluid of RA patients (379 +/- 36 pg/ml) were lower than in corresponding blood samples and correlated significantly with blood sRAGE. Interestingly, a significantly higher sRAGE level was found in synovial fluid of RA patients treated with methotrexate as compared with patients without disease-modifying anti-rheumatic treatment.We conclude that a decreased level of sRAGE in patients with RA might increase the propensity towards inflammation, whereas treatment with methotrexate counteracts this feature.
15580352 The advanced glycation end product pentosidine correlates to IL-6 and other relevant infla 2005 Dec OBJECTIVE: Oxidative stress and inflammatory processes accelerate the formation of advanced glycation end products (AGE), e.g. of pentosidine. The aim of this study was to investigate the relationships between levels of pentosidine in serum and synovial fluid, proinflammatory cytokines, other markers of inflammatory activity, and the state of radiologically visible bone destruction in patients with rheumatoid arthritis (RA). OBJECTIVES: One hundred thirty-three nondiabetic RA patients and 56 age-matched, healthy subjects were included. Serum and synovial fluid pentosidine, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and rheumatoid factor levels were determined. In 30 patients, the proinflammatory cytokines interleukin (IL)-1beta, IL-6, and TNF-alpha and the soluble receptors sIL-2R, sIL-6R, sTNF-alpha, and RI/RII were also measured. RESULTS: Serum levels of pentosidine were on average significantly higher in RA patients than in healthy subjects and correlated significantly to ESR, CRP, and serum levels of IL-6. Serum and synovial fluid pentosidine did not show any differences. Rheumatoid factor-positive RA patients had higher pentosidine levels in the synovial fluid than rheumatoid factor-negative patients. Correlations could not be found between pentosidine and the other cytokines or cytokine receptors measured. CONCLUSION: The binding of AGE on cell receptors induces activation of nuclear factor kappa B, resulting in enhanced synthesis of proinflammatory cytokines. Moreover, AGE generation may also lead to the formation of new, immunologically relevant epitopes at synovial proteins. Both mechanisms could contribute to initiation and perpetuation of the inflammatory and destructive processes in RA.
15743483 Balance between survivin, a key member of the apoptosis inhibitor family, and its specific 2005 Rheumatoid arthritis (RA) is a highly heterogeneous disease with respect to its joint destructivity. The reasons underlying this heterogeneity are unknown. Deficient apoptosis in rheumatoid synovial tissue has been recently demonstrated. We have therefore decided to study the synovial expression of survivin, a key member of the apoptosis inhibitor family. The levels of survivin and antibodies against survivin were assessed by an ELISA in matched blood and synovial fluid samples collected from 131 RA patients. Results were related to joint erosivity at the time of sampling. Monocytes were transfected with survivin anti-sense oligonucleotides and were assessed for their ability to produce inflammatory cytokines. Survivin levels were significantly higher in patients with destructive disease as compared with in RA patients displaying a non-erosive disease. High survivin levels were an independent prognostic parameter for erosive RA. In contrast, high levels of antibodies against survivin were found in patients with non-erosive RA, and were negatively related to erosivity. Survivin levels in RA patients were influenced by treatment, being significantly lower among patients treated with disease-modifying anti-rheumatic drugs. Specific suppression of survivin mRNA resulted in downregulation of IL-6 production. We conclude that survivin determines the erosive course of RA, whereas survivin antibodies lead to a less aggressive course of the disease. These findings together with decreased survivin levels upon disease-modifying anti-rheumatic drug treatment, and the downregulation of inflammatory response using survivin anti-sense oligonucleotides, suggest that extracellular survivin expression mediates the erosive course of joint disease whereas autoimmune responses to the same molecule, manifested as survivin targeting antibodies, mediate protection.
16869000 Regeneration of B cell subsets after transient B cell depletion using anti-CD20 antibodies 2006 Aug OBJECTIVE: Transient B cell depletion with the monoclonal anti-CD20 antibody rituximab has resulted in favorable clinical responses in patients with rheumatoid arthritis (RA). However, little is known about the regeneration profile of different peripheral B cell subpopulations. The aim of this study was to delineate the regeneration profile of different B cell subsets in the peripheral blood after selective anti-CD20-mediated B cell depletion. METHODS: Seventeen patients with RA refractory to standard therapy were treated with rituximab. Patients 1-6 received 4 weekly infusions of rituximab at a dose of 375 mg/m2, and patients 7-17 received 2 infusions of rituximab (1,000 mg), 2 weeks apart. Four-color staining was performed at several time points, using CD38, IgD, and CD27 in addition to other cell surface markers. In one patient, the mutational status of the immunoglobulin receptor was examined. RESULTS: The analysis revealed a distinct pattern of B cell regeneration. The first wave of repopulating B cells were immature B cells (CD38high,IgD+,CD10+,CD24high), the immunoglobulin receptors of which were not yet somatically mutated. In parallel, a recirculation of plasma cells was observed. Later, the number of naive B cells increased, and these cells predominated in the peripheral blood B cell pool. CD27+ memory B cells showed a slow and delayed repopulation, and the level of these cells stayed significantly reduced (<50%) compared with baseline values, for more than 2 years. CONCLUSION: Our findings provide evidence for a characteristic regeneration pattern of B cell subpopulations, with long-lasting modulation of B cell subset composition, after selective anti-CD20-mediated B cell depletion.
16859515 Diagnostic value of anti-human citrullinated fibrinogen ELISA and comparison with four oth 2006 We studied the diagnostic performance of the anti-human citrullinated fibrinogen antibody (AhFibA) ELISA for rheumatoid arthritis (RA) in a consecutive cohort (population 1) and evaluated the agreement between the AhFibA ELISA and four other assays for anti-citrullinated protein/peptide antibodies (ACPAs) as well as rheumatoid factor in patients with longstanding RA (population 2). Population 1 consisted of 1024 patients with rheumatic symptoms; serum samples from these patients were sent to our laboratory for ACPA testing within the context of a diagnostic investigation for RA. Ninety-two of these patients were classified as having RA according to the American College of Rheumatology criteria and 463 were classified as non-RA patients. Population 2 consisted of 180 patients with longstanding RA and was used to assess agreement and correlations between five ACPA assays: anti-cyclic citrullinated peptide (CCP)1 and anti-CCP2 antibodies were detected using a commercially available ELISA, AhFibA using ELISA, and anti-PepA and anti-PepB antibodies using line immunoassay. Applying previously proposed cut-offs for AhFibA, we obtained a sensitivity of 60.9% and a specificity of 98.7% in population 1. Receiver operating characteristic curve analysis could not detect a significant difference in diagnostic performance between the AhFibA ELISA and anti-CCP2 assay. Performing a hierarchical nearest neighborhood cluster analysis of the five different ACPA assays in population 2, we identified two clusters: a cluster of anti-pepA, anti-pepB and anti-CCP1, and a cluster of AhFibA and anti-CCP2. In conclusion, we found that AhFibA and anti-CCP2 antibodies had similar diagnostic performance. However, disagreement between ACPA tests may occur.