Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial adhesion molecules play an important role in the tissue recruitment of leukocytes in inflammatory conditions such as rheumatoid arthritis. We have investigated the effect of the antirheumatic drug gold sodium thiomalate on adhesion molecule protein and mRNA expression in cultured human endothelial cells. Gold sodium thiomalate inhibited cytokine (TNF, IL-1, IL-4)-stimulated expression of vascular cell adhesion molecule-1 and E-selectin but not intercellular adhesion molecule-1 on endothelial cells. Gold sodium thiomalate also suppressed TNF-stimulated increases in vascular cell adhesion molecule-1 and E-selectin mRNA levels but had no effect on intercellular adhesion molecule-1 mRNA. Thiomalate (mercaptosuccinate), but not gold thioglucose or D-penicillamine, mimics the effect of gold sodium thiomalate at equimolar concentrations. We propose that the inhibition of vascular cell adhesion molecule-1 and E-selectin expression by gold sodium thiomalate is due to its thiomalate and not its gold component. Gold sodium thiomalate has a direct effect on endothelial adhesion molecule expression, and this may contribute to its antiinflammatory activity.
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PMID:Effect of gold sodium thiomalate and its thiomalate component on the in vitro expression of endothelial cell adhesion molecules. 752 50

Tumor necrosis factor alpha (TNF alpha) is a cytokine with many biological functions of relevance to inflammatory disease. Although only one of several inflammatory mediators produced in abundance in rheumatoid arthritis (RA), experimental data suggest that it is in a dominant position within a cytokine hierarchy and is therefore a prime target for directed immunotherapy in this disease. We have targeted TNF alpha in vivo using a chimerised monoclonal anti-TNF alpha antibody and have now demonstrated beneficial responses to treatment in three different clinical trials. The results confirm that TNF alpha is of central importance in the inflammatory process in RA and define a new treatment strategy in this disease.
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PMID:TNF alpha blockade in rheumatoid arthritis: rationale, clinical outcomes and mechanisms of action. 754 68

Monoclonal antibodies have been used extensively over the last few years in clinical trials of rheumatoid arthritis (RA). Not only are they potential therapeutic agents, but they are also useful probes into the immunopathogenesis of RA. Anti-tumour necrosis factor alpha (TNF alpha) monoclonal antibodies have been shown to be clinically efficacious. Although they produced rapid disease amelioration, the duration of clinical improvement was limited to 4-6 weeks. Re-treatments were again effective but long-term studies are required to assess their therapeutic role in RA. So far, the therapeutic effects of lymphocyte-depleting antibodies have been disappointing. From the data, it is clear that synovial lymphocytes are more difficult to eliminate than peripheral blood lymphocytes and it is likely that in order to delete all synovial lymphocytes, high doses of depleting antibodies will be required which could lead to severe immunosuppression. Hence, lymphocyte depletion may not be a feasible therapeutic strategy. However, there are a number of clinical trials currently underway attempting to inhibit CD4 lymphocyte function by non-depleting antibodies. In animal models of RA, such antibodies have been shown to induce long-term disease remission. Another possibility is to combine several monoclonal antibodies in order to induce disease remission in RA. This strategy has been used in murine collagen-induced arthritis in which a combination of anti-CD4 and anti-TNF alpha monoclonal antibodies was shown to be synergistic.
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PMID:Therapeutic monoclonal antibodies. 755 52

In a recent study from our group, the combination of methotrexate and sulphasalazine (MTX + SASP) seemed superior to MTX alone in the treatment of rheumatoid arthritis (RA). To assess the impact of these therapies on the cytokine cascade, the in vitro production and circulating concentrations of several cytokines and endogenous cytokine antagonists were measured in 30 healthy controls and longitudinally in a subset of 26 patients enrolled in this study. Compared to controls, RA patients had significantly higher circulating concentrations of interleukin-6 (IL-6), soluble receptors for tumour necrosis factor (sTNFR), soluble receptors for interleukin-2 (sIL-2R) and interleukin-1 receptor antagonists (IL-1RA), and their peripheral blood mononuclear cells (PBMNC) showed a higher spontaneous production of interleukin-1 beta (IL-1 beta), tumour necrosis factor alpha (TNF alpha) and IL-1RA (both secreted and cell-associated) and a higher stimulated production of cell-associated TNF alpha, IL-1RA and (to a lesser extent) IL-1 beta. Treatment with MTX alone (n = 12) or combined with SASP (n = 14), resulted in significant reductions of circulating IL-6 and sIL-2R but did not alter IL-1 beta, TNF alpha or IL-1RA concentrations. Decreases in circulating levels of sTNFR and in the in vitro production of cell-associated IL-1 beta and IL-1RA after stimulation were only observed in patients treated with MTX + SASP. The concentrations of IL-1RA and sTNFR in the circulation exceeded moderately those of IL-1 beta and TNF alpha but this is probably insufficient to block IL-1 and TNF alpha activity. In conclusion, therapy with MTX alone or with SASP modulates IL-6 and sIL-2R concentrations in RA. Decreased production of IL-1 beta and IL-1RA and circulating sTNFR levels were only observed during therapy with MTX + SASP. Whether this relates to the better clinical effect observed with the combination therapy remains to be investigated. Circulating levels of IL-6, sIL-2R and sTNFR seem useful markers of disease activity in RA.
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PMID:Effect of methotrexate alone or in combination with sulphasalazine on the production and circulating concentrations of cytokines and their antagonists. Longitudinal evaluation in patients with rheumatoid arthritis. 755 60

In chronic inflammatory diseases, typified by rheumatoid arthritis, we speculated that upregulation and/or disregulation of cytokine production in inflamed tissue might contribute both directly and/or indirectly to the pathology in the synovial joint tissue. This chapter summarises studies performed principally by our own group over the last 9 years or so, but also by others in the field who have investigated the expression of cytokines in RA. From our studies we identified one particular cytokine, tumour necrosis factor alpha (TNF alpha) as an important, 'pivotal', molecule in the disease process. This concept has led to the initiation and completion of the first successful clinical trials in RA patients to verify this hypothesis, using a neutralising antibody to TNF alpha.
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PMID:Cytokine expression in chronic inflammatory disease. 755 70

The recognition that certain monoclonal antibodies have immunosuppressive properties led to the therapeutic application in autoimmune rheumatic diseases, rheumatoid arthritis in particular. The therapeutic potential of monoclonal antibodies directed against cell surface antigens mainly present on T-cells has been suggested by open trials in rheumatoid arthritis but the results of controlled studies are disappointing. Open intervention studies with monoclonal antibodies directed at other antigens relevant for the rheumatoid inflammation such as the intercellular adhesion molecule ICAM-1 or the cytokines IL-6 and TNF alpha provided encouraging clinical improvements. The impressive potential of anti-TNF alpha which was already illustrated by the immediate suppression of the acute phase response in open studies could be confirmed by a recently completed controlled trial. The present overview summarizes the available information on the results of these treatment modalities and discusses the possibilities of monoclonal antibodies as a long term treatment for rheumatic diseases.
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PMID:Monoclonal antibody therapy of inflammatory rheumatic diseases. 755 78

Following many years of research using isolated human tissues and animal models, sufficient knowledge concerning rheumatoid arthritis has accumulated so that novel immunotherapies have been proposed. Biological agents are being tested in clinical trials and include antibodies to T cells and cytokines. Currently the most promising of these is intravenously administered neutralizing anti-TNF antibody. In order to establish disease modification, however, therapy needs to be delivered continuously over the long term. The prospect of delivering cytokine inhibitors as genetic material (naked DNA), viruses or in engineered autologous cells is considered as one option for achieving this goal. We compare two strategies, firstly, using immobile cells such as fibroblasts, myoblasts or keratinocytes, and secondly, the migratory cells of the immune system. The former provides a reservoir of systemic delivery of the therapeutic protein whereas the latter provides targeted delivery determined by the antigen specificity of the immune cells. Early validation has begun in animal models of rheumatoid arthritis.
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PMID:Gene therapy of rheumatoid arthritis via cytokine regulation: future perspectives. 755 79

Rheumatoid arthritis is a common cause of chronic disability for which current therapies are of limited value in controlling the disease process and outcome. Our initial approach to understanding the pathogenesis of RA and defining a novel therapeutic target was to investigate the role of cytokines by blocking their action with antibodies on cultured synovial-derived mononuclear cells in vitro. These investigations suggested that neutralization of TNF alpha with antibodies significantly inhibited the generation of other pro-inflammatory cytokines also over-produced, such as, IL-1, GM-CSF, IL-6 and IL-8. The implication that blockade of a single cytokine, TNF alpha might have far-reaching effects on multiple cytokines and thereby exert significant anti-inflammatory and protective effects on cartilage and bone of joints, was tested in arthritic DBA/1 mice immunized with collagen II. Impressive amelioration of joint swelling and joint erosions in this model encouraged clinical trials with a monoclonal anti-TNF alpha antibody. The cA2 chimeric anti-TNF alpha high-affinity antibody was initially tested in an open-label study at a dose of 20 mg/kg on 20 patients, with substantial and universal benefit. Subsequently, a randomized placebo-controlled double-blind trial was performed on 73 patients comparing a single intravenous injection of placebo (0.1% human serum albumin) with two doses of cA2. Using a composite disease activity index, at 4 weeks post infusion, 8% of patients receiving placebo improved compared with 44% receiving 1 mg/kg cA/2 and 79% receiving 10 mg/kg. Between 2 to 4 repeated cycles of cA2 were administered to 7 patients and all patients showed improvement of a similar magnitude with each cycle. These data support our proposition that TNF alpha is implicated in the pathogenesis of RA, and is thus a key therapeutic target. Monoclonal anti-TNF alpha antibodies control disease flares and are candidate agents for longer-term control of RA, although repeated therapy with cA2 is associated with anti-idiotypic responses in 50% of patients and a trend toward shortening of the duration of response. In the DBA/1 arthritic mice, synergy of action of anti-TNF and anti-CD4 is observed together with suppression of an anti-globulin response, indicating one way in which benefit might be augmented in the future.
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PMID:Monoclonal anti-TNF alpha antibody as a probe of pathogenesis and therapy of rheumatoid disease. 759 Aug 14

Pregnancy exerts suppressive effects on a number of chronic inflammatory conditions, particularly rheumatoid arthritis. We isolated peripheral blood polymorphonuclear leukocytes (PMN) from pregnant women at 30 to 34 wk (n = 34) and showed significant reductions in respiratory burst activity compared with nonpregnant controls (n = 34), as determined by lucigenin-enhanced chemiluminescence (LUCL). Responses to FMLP were reduced by 54% (p = 0.0046) and to zymosan-activated serum (ZAS) by 69% (p = 0.0043). Following LUCL responses to these agonists in women throughout the course of their pregnancy (n = 7) revealed significantly reduced responses by the second and third trimesters (p < 0.005). Intracellular H2O2 production in PMN at 30 to 34 wk gestation was significantly reduced (p = 0.0454) in response to FMLP, compared with the nonpregnant controls. Investigation of adhesion molecule expression revealed no differences in CD11b or CD18. However, loss of CD62L from the PMN surface in response to FMLP and ZAS was significantly reduced at 30 to 34 wk, as compared with controls (FMLP, p = 0.049; ZAS, p = 0.01; n = 34). There were no significant differences in cell surface formyl peptide receptor expression, although there were statistical differences in LUCL responses to all concentrations of FMLP used (p < 0.05). Incubating PMN with TNF, IL-8, and granulocyte-macrophage CSF increased formyl peptide receptor expression but revealed no differences between the two groups. Priming of pregnancy PMN with the same cytokines gave significantly reduced LUCL when cells were subsequently stimulated with FMLP (p < 0.05; n = 6). Our results show a reduction in PMN NADPH-oxidase activity during pregnancy and may offer a partial explanation for the remission of symptoms observed in rheumatoid arthritis.
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PMID:The effect of pregnancy on polymorphonuclear leukocyte function. 759 61

The frequency of the uncommon allele (TNF2) of a polymorphism in the promoter region of the tumour necrosis factor alpha (TNF alpha) gene in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) was found to be 3 times that of the normal anglo-saxon population. In SLE patients, this allele was strongly associated with HLA-DR3 expression and was also more frequent in patients who did not have malar rash. Functional studies of normal monocyte cytokine production in vitro showed that this genotype was associated with increased IL-1 alpha protein production but there were no differences in the production of TNF alpha protein.
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PMID:Increased frequency of the uncommon allele of a tumour necrosis factor alpha gene polymorphism in rheumatoid arthritis and systemic lupus erythematosus. 761 82


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