Search

Objective: Endothelium and adhesion molecules are engaged in the pathogenesis of rheumatoid arthritis (RA). This study was undertaken to analyse the effect of etanercept on the levels of soluble cell adhesion molecules (sCAMs) and vascular endothelial growth factor (VEGF) in patients with active RA. Methods: Patients were receiving 50 mg/week of subcutaneous etanercept and 10–25 mg/week of methotrexate (MTX). Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), and VEGF were measured by enzyme-linked immunosorbent assay (ELISA) in 18 RA patients (prior to injection) at 0, 3, 6, 9, and 12 months. Results: A decrease in serum levels of sICAM-1 (p<0.001), sVCAM-1 (p<0.01), sE-selectin (p<0.01), and VEGF (p<0.001) was observed in RA patients after 3 months of treatment with etanercept. Six months of therapy with etanercept prolonged the suppression of serum sICAM-1 (p<0.01) and even more remarkably diminished sVCAM-1, sE-selectin, and VEGF (in all cases p<0.001) concentrations as compared to baseline (month 0). Treatment also effectively diminished sICAM-1, sVCAM-1, and VEGF levels at months 9 and 12 (in all cases p<0.001), and less significantly sE-selectin (p<0.05 at month 9 and p<0.01 at month 12). The Disease Activity Score including a 28-joint count (DAS28) measured at 3, 6, 9, and 12 months decreased significantly compared to baseline (in all cases p<0.001). Conclusion: Our study shows that, besides a rapid suppression of disease activity, serum sCAM and VEGF concentrations are downregulated following anti-tumour necrosis factor alpha (TNFα) therapy combined with MTX. Prolonged treatment with etanercept sustained or even more remarkably diminished the sCAM and VEGF serum concentrations. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to analyse serum concentrations of soluble cell adhesion molecules (CAMs) in patients with early rheumatoid arthritis (RA) before and after 6 months of treatment with methotrexate (MTX). Methods: We studied 32 RA patients, untreated with disease-modifying anti-rheumatic drugs (DMARDs) or corticosteroids, with disease duration less than 3 years. Twenty osteoarthritis (OA) patients constituted the control group. The analysis of serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and E-selectin (sE-selectin) was based on a quantitative sandwich enzyme-linked immunosorbent assay (ELISA). Results: In comparison with OA patients, higher serum concentrations of sICAM-1 (p<0.01), sVCAM-1 (p<0.01), and sE-selectin (p<0.05) were observed in untreated patients with early RA. Six months of treatment with MTX down-regulated serum concentrations of sICAM-1, sVCAM-1, and sE-selectin (in all cases p<0.001) in the RA patients studied. MTX treatment was also followed by a decrease in the clinical markers of RA activity, such as the number of painful and swollen joints, erythrocyte sedimentation rate (ESR), disease activity score (DAS), and C-reactive protein (CRP) levels. Conclusions: Patients with early RA are characterized by high serum concentrations of sICAM-1, sVCAM-1, and sE-selectin. Therapy with MTX resulted in clinical improvement and diminished serum levels of soluble CAMs in the RA patients studied, confirming the effectiveness of MTX in early stages of the disease. [ABSTRACT FROM AUTHOR]

Objective: To examine the relation between the serum levels of tumour necrosis factor alpha (TNFalpha), soluble tumour necrosis factor receptors (sTNF-R), and the histological pattern of rheumatoid synovitis.Methods: An enzyme linked immunosorbent assay (ELISA) was used to measure TNFalpha, p55 sTNF-R, and p75 sTNF-R concentrations in the serum of 43 patients with rheumatoid arthritis (RA) and 34 patients with osteoarthritis (OA).Results: Upon histological analysis two variants of rheumatoid synovitis emerged. Twenty six RA specimens presented only diffuse infiltrates of mononuclear cells. In the remaining 17 samples the formation of lymphocytic follicles with germinal centre-like structures was found. Serum concentrations of TNFalpha, p55 and p75 sTNF-R were raised in patients with RA compared with the OA control group (p<0.001 for all comparisons). Levels of TNFalpha, p55 and p75 sTNF-R were higher in the serum of patients with RA with follicular synovitis than in patients with diffuse synovitis (p<0.001, p<0.01, and p<0.05, respectively). Serum concentrations of TNFalpha, p55 and p75 sTNF-R correlated with markers of disease activity.Conclusion: Different histological types of rheumatoid synovitis associated with distinct serum levels of TNFalpha and sTNF-R reflect varying clinical activity of the disease and support the concept of RA heterogeneity. [ABSTRACT FROM AUTHOR]

Chemokines promote leucocyte traffic into the synovium, leading to the initiation and progression of the rheumatoid arthritis (RA). The aim of the study was to determine the effects of etanercept, a soluble tumour necrosis factor receptor (sTNFr), on the serum chemokines levels in patients with active RA. Patients were treated with 50 mg of subcutaneous injection of etanercept per week and methotrexate (10-25 mg/week). Serum levels of interleukin-8 (IL-8), RANTES (regulated upon activation, normal T cell expressed and secreted) and monocyte chemoattractant protein-1 (MCP-1) were assessed by ELISA at months 0, 3, 6, 9 and 12, prior to injection. 3-month treatment with etanercept diminished serum concentrations of IL-8, RANTES and MCP-1 (P < 0.05, P < 0.01 and P < 0.001, respectively). Subsequent etanercept administrations prolonged decrease in serum chemokines levels and in the case of IL-8 even intensified the reduction of its concentration in serum. These changes were accompanied by significant decrease of disease activity score (DAS28) (in all cases P < 0.001). Prior to the first etanercept administration, serum concentrations of studied chemokines correlated with markers of RA activity such as the erythrocyte sedimentation rate (ESR) and DAS28. Following next drug injection such associations were less or not significant. Therapy with etanercept and MTX not only caused a clinical improvement but also diminished serum chemokines levels in RA patients. Further treatment with etanercept sustained chemokines suppression.

Widespread vasculopathy and profound fibrosis are key features of the pathogenesis of systemic sclerosis (SSc). We hypothesized that the TNF-like weak inducer of apoptosis (TWEAK), a recently recognized multifunctional cytokine which regulates angiogenesis and tissue remodeling, may play a role in the development of SSc. The production of TWEAK by the peripheral blood mononuclear cells (PBMC) was investigated, by means of ELISA, in 24 SSc patients and 14 healthy subjects. Moreover, production of TWEAK was correlated with clinical features of SSc. PBMC were isolated using density gradient centrifugation on Histopaque and were cultured in FCS supplemented RPMI medium at 37 degrees C under 5% CO2. Production of TWEAK by PBMC was significantly diminished in patients with more severe microvascular damage, as indicated by the presence of "active" capillaroscopic pattern, compared with SSc patients with less pronounced microangiopathy ("slow" pattern), and healthy subjects. Moreover production of TWEAK correlated inversely with duration of Raynaud's phenomenon. PBMC from patients with scleroderma-related interstitial lung disease tended to produce lower amounts of TWEAK compared with SSc patients without lung involvement but the difference was not significant. The results of our study suggest that diminished production of TWEAK might play a role in the pathogenesis of vascular injury in SSc patients. Whether TWEAK may represent a new therapeutic target in SSc requires further studies.

We undertook this study to evaluate the effects of leflunomide, an oral pyrimidine synthesis inhibitor, on the serum chemokine levels in patients with active rheumatoid arthritis (RA) who were refractory to treatment with methotrexate (MTX) or did not tolerated MTX treatment. RA patients were supposed to receive leflunomide (100 mg/day loading dose for 3 days followed by 20 mg/day orally for the 12 months). Serum concentrations of RANTES (regulated upon activation, normal T cell expressed and secreted), monocyte chemoattractant protein-1 (MCP-1), and interleukin-8 (IL-8) were assessed by enzyme-linked immunosorbent assay before and after 3, 6, 9, and 12 months of treatment with leflunomide. Three months therapy with leflunomide caused reduction in serum RANTES and MCP-1 (in both cases, p < 0.001) levels. Decrease in the concentration of these chemokines persisted until the end of the study period but was less significant. In the case of IL-8, its serum levels significantly diminished after 6 months of therapy with leflunomide (p < 0.01) and remained stable to the end of the study. Changes in serum chemokine levels were accompanied by significant decrease of disease activity score (DAS; p < 0.001). Prior to the first dose of leflunomide, serum concentrations of studied chemokines correlated with marker of RA activity such as the erythrocyte sedimentation rate and IL-8 level with DAS. Furthermore, we demonstrated significant correlations between serum levels of RANTES, MCP-1, and IL-8. During study period, such associations were far less or not significant. Leflunomide, beside a clinical improvement, reduce serum chemokines concentrations in RA patients. Leflunomide seems to be an effective treatment for RA, alternative to current therapies.

Objective: We studied the effects of the multiple infusions of infliximab, a chimeric anti-tumor necrosis factor alpha (anti-TNF-alpha) antibody, on the serum chemokines levels in patients with active rheumatoid arthritis (RA)., Methods: RA patients were supposed to receive 9 infusions of infliximab (3mg/kg) at weeks 0, 2, 6, and every 8 weeks thereafter with the same dose. All patients continued treatment with methotrexate (MTX) (7.5-20mg/week). Serum concentrations of interleukin-8 (IL-8), RANTES (regulated upon activation, normal T cell expressed and secreted) and monocyte chemoattractant protein-1 (MCP-1) were assessed by ELISA at weeks 0, 2, 6, 14, 38, prior to infusion, and additionally at week 62., Results: Initial infusion of infliximab caused reduction in serum IL-8, RANTES and MCP-1 (in all cases p < 0.001) levels. Subsequent infliximab administrations also significantly decreased serum chemokines levels, but was less effective. Prior to the first infliximab infusion serum concentrations of studied chemokines correlated with markers of RA activity such as the erythrocyte sedimentation rate (ESR) or CRP levels, number of swollen joints and disease activity score (DAS). Following next drug infusions such associations were far less significant. Infliximab treatment induced a significant reduction in the number of monocytes observed through the whole study (in all cases p < 0.05)., Conclusion: Anti-TNF-alpha antibody therapy accompanied by MTX, beside a rapid clinical improvement, reduced serum chemokines concentrations in RA patients. Subsequent administrations of infliximab sustained chemokines decrease, although to a lesser extent than the first two dose of infliximab.

Objective: To analyze serum concentrations of matrix metalloproteinases (MMP) MMP-1, MMP-3, MMP-9, MMP-13, tissue inhibitors of MMP (TIMP) TIMP-1 and TIMP-2, and MMP/TIMP ratios in patients with early rheumatoid arthritis (RA) before and after 6 months of treatment with methotrexate (MTX)., Methods: The study group consisted of 30 patients with RA, not treated with disease modifying antirheumatic drugs or corticosteroids, with disease duration < 3 years. Twenty patients with osteoarthritis (OA) served as a control group. Analysis of serum concentrations of MMP and TIMP was based on a quantitative sandwich ELISA., Results: Serum concentrations of MMP-1, MMP-3, MMP-9, and MMP-13 were higher in untreated patients with early RA than in OA patients (p < 0.001 in all cases). Serum levels of TIMP-1 and TIMP-2 dominated in the serum of RA patients compared with controls (p < 0.01 and p < 0.05, respectively). Ratios of MMP to TIMP were significantly higher in patients with early RA versus controls. Six months' treatment with MTX downregulated serum concentrations of MMP-1 (p < 0.001), MMP-3 (p < 0.001), MMP-9 (p < 0.001), MMP-13 (p < 0.01), and TIMP-1 (p < 0.05) in patients with RA. These changes were accompanied by significantly reduced ratios of MMP to TIMP. MTX treatment decreased markers of RA activity such as the number of painful and swollen joints, erythrocyte sedimentation rate, Disease Activity Score, and C-reactive protein., Conclusion: Patients with early RA are characterized by high serum concentrations of tissue-degrading metalloproteinases. Therapy with MTX resulted in clinical improvement and reduced serum MMP levels in patients with RA, confirming effectiveness of MTX in patients in early stages of the disease.

Objective: Studies indicate the genetic, biological, and clinical heterogeneity of rheumatoid arthritis (RA). Recently the histological diversity of RA has been postulated. We investigated whether serum concentrations of interleukin 8 (IL-8), RANTES (regulated upon activation normal T cell expressed and secreted), and monocyte chemoattractant protein-1 (MCP-1) are correlated with histological appearance of the rheumatoid synovitis., Methods: Using ELISA we assessed IL-8, RANTES, and MCP-1 concentrations in serum of 47 patients with RA and 30 patients with osteoarthritis (OA)., Results: Morphological analysis of synovial specimens distinguished 2 types of rheumatoid synovitis. Twenty-eight RA samples presented diffuse infiltrates of mononuclear cells with no specific microanatomical organization and were categorized as diffuse synovitis. In the remaining 19 specimens, classified as follicular synovitis, formation of lymphocytic follicles with germinal center-like structures was observed. Serum levels of studied chemokines were increased in patients with RA compared to the OA control group (p < 0.001 for all comparisons). Concentrations of IL-8, RANTES, and MCP-1 were highest in serum of RA patients with follicular synovitis in comparison with patients with diffuse synovitis (p < 0.01, p < 0.01, and p < 0.05, respectively) and could distinguish RA patients with these 2 histological disease patterns. Serum levels of chemokines correlated with markers of disease activity such as erythrocyte sedimentation rate, C-reactive protein concentrations, and Disease Activity Score., Conclusion: Distinct histological variants of rheumatoid synovitis associated with different serum levels of IL-8, RANTES, and MCP-1 reflect clinical activity of the disease and confirm the concept of RA heterogeneity.

Objective: Matrix metalloproteinases (MMP) are involved in the articular tissue destruction processes in the pathogenesis of rheumatoid arthritis (RA). We investigated the effects of multiple infusions of infliximab, a chimeric anti-tumor necrosis factor-a (anti-TNF-a) antibody, on concentrations of serum MMP and tissue inhibitors of metalloproteinases (TIMP) in patients with active RA., Methods: Patients with RA were scheduled to receive 9 infusions of infliximab (3 mg/kg) at Weeks 0, 2, 6, and every 8 weeks thereafter. The therapy was combined with methotrexate (MTX) (7.5-20 mg/week). Serum concentrations of interstitial collagenase (MMP-1), stromelysin-1 (MMP-3), gelatinase B (MMP-9), TIMP-1, and TIMP-2 were measured by ELISA prior to infusion at Weeks 0, 2, 6, 14, 38, and 62., Results: The initial infusion of infliximab downregulated serum levels of MMP-1 (p < 0.001), MMP-3 (p < 0.001), MMP-9 (p < 0.001), TIMP-1 (p < 0.01), and TIMP-2 (p < 0.05). The second drug administration caused even more remarkable reduction of measured MMP (p < 0.001 in all cases) but not of TIMP levels. These changes were accompanied by decreased ratios of measured MMP to TIMP. Further infliximab therapy also significantly suppressed serum MMP levels, but was less effective. Before the first infliximab infusion serum concentrations of MMP and TIMP correlated with markers of RA activity such as the Disease Activity Score and C-reactive protein levels. After further drug administrations such associations, although less significant, were also noted., Conclusion: Anti-TNF-a antibody therapy combined with MTX resulted in rapid clinical improvement and reduced serum MMP concentrations in patients with RA. Further infusions of infliximab maintained the decrease of MMP, although to a lesser extent than the first and second doses.

Objective: The present study was conducted to investigate whether the serum levels of interleukin 6 (IL-6), soluble IL-2 receptor (sIL-2R) and sIL-6R are associated with the morphological appearance of rheumatoid arthritis (RA)., Methods: Using the ELISA technique we measured the IL-6, sIL-2R and sIL-6R concentrations in the serum of 34 patients with RA and 28 patients with osteoarthritis (OA). Histological analysis of synovial samples distinguished 2 types of rheumatoid synovitis. Twenty-one RA specimens presented diffuse infiltrates of mononuclear cells without any specific microanatomical organization. In remaining 13 samples the formation of lymphocytic follicles with germinal center-like structures was found., Results: Serum levels of IL-6, sIL-2R and sIL-6R were elevated in patients with RA compared to the OA control group (p < 0.001, p < 0.001 and p < 0.05 respectively). Concentrations of IL-6 and sIL-2R were highest in the serum of RA patients with follicular synovitis in comparison to patients with diffuse synovitis (p < 0.001 and p < 0.01 respectively) and could distinguish RA patients with these two histological variants of the disease. Serum levels of IL-6 and sIL-2R correlated with markers of disease activity such as ESR and CRP levels. In addition, the clinical data suggest a more severe disease among RA patients with follicular synovitis., Conclusion: Distinct histological types of rheumatoid synovitis associated with unique serum concentrations of IL-6 and sIL-2R reflect levels of disease activity and confirm the concept of RA heterogeneity.

Objective: Rheumatoid arthritis (RA) is characterized by an invasive and tissue destructive infiltrate of lymphocytes, macrophages, and synoviocytes formed in the joints. Its etiopathogenesis and the role of the particular morphological components of synovitis remain unclear. There is evidence that its histological heterogeneity is correlated with synovium cytokine transcription. We investigated whether the serum cytokine profile is associated with the morphological appearance of the disease., Methods: Tissue and serum samples were collected from 25 patients with clinically active RA and 25 with osteoarthritis (OA) as a control group. After histological analysis RA synovial biopsies were divided into 2 distinct types; 16 samples were characterized by diffuse lymphocyte infiltrates with no additional microanatomical organization. Lymphocytic aggregates with germinal center-like structures were found in 9 specimens. Serum concentrations of interferon-gamma (IFN-gamma), interleukin 12 (IL-12, p70 heterodimer), tumor necrosis factor-alpha (TNF-alpha), and IL-15 were measured by ELISA., Results: Low concentrations of IFN-gamma (p < 0.01) and IL-12 (NS) were found in RA patients' serum compared with OA controls. RA patients with follicular synovitis had lower serum concentration of IFN-gamma (p < 0.05) and IL-12 (p < 0.05) than patients with diffuse infiltrates. High concentration of TNF-alpha and IL-15 characterized RA patient serum in comparison with controls (respectively, p < 0.001 and p < 0.01). In the serum of RA patients with follicular synovitis TNF-alpha was a dominant cytokine (p < 0.01) compared to patients with diffuse disease. At TNF-alpha level > or = 44 pg/ml, 5 (56%) of 9 patients with follicular RA had such elevated values vs one of 16 diffuse patients (< 10%; p < 0.02). Only serum concentrations of TNF-alpha could effectively differentiate between patients with OA and subgroups of RA. Analysis of clinical data suggested that activity of rheumatoid disease in patients with follicular synovitis was more severe than in those with diffuse infiltrates., Conclusion: The association between distinct histological appearance of rheumatoid synovitis and serum cytokine profile and diverse clinical activity of disease seems to confirm its heterogeneity.