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)

Dysregulated cytokine production, in particular of the monokines IL-1, IL-6, and TNF, has been implicated in the inflammatory response in rheumatoid arthritis and in promoting the ensuing tissue destruction. The 3-substituted 2-oxindole tenidap has proven anti-inflammatory actions both in vivo and in vitro, among which is the inhibition of TNF and IL-1 production by monocytes following activation by LPS. We have investigated this ability to modulate cytokine activity by studying its effects on cytokine-monocyte interactions and in particular IL-6 production, with the THP-1 monocyte cell line. Tenidap inhibited IL-6 production in a dose-dependent manner when cells were stimulated with a combination of TNF-alpha and IFN-gamma. It also inhibited the priming effect of IFN-gamma, preventing the super-induction of IL-6 production following subsequent stimulation with TNF-alpha and IFN-gamma. These effects occurred under conditions in which the cells were not irreversibly altered with respect to their protein synthetic activity. IFN-gamma-induced up-regulation of HLA-DR was also inhibited by tenidap. Tenidap appears to affect some aspect of the IFN-gamma activation pathway, possibly the differentiation of these immature monocytes to a more mature phenotype. The data presented here indicate that tenidap has the potential to modulate the cytokine network in chronic disease.
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PMID:Tenidap-modulated proinflammatory cytokine activation of a monocyte cell line. 773 Jun 39

This review discusses current concepts of the pathogenesis of rheumatoid arthritis. It is proposed that RA is a T cell mediated disease following which a large number of subsequent inflammatory events are unleashed. Many of the pathogenetic steps are targets for new therapies including biologics. Laboratory, clinical and radiological methods of assessing disease activity are sufficiently sensitive and reproducible to permit their use in multicentre studies capable of detecting a biologic with disease modifying activity. The clinical assessment of the efficacy and toxicity of biologics poses unique problems. These have been illustrated by the example of 3 monoclonal antibodies directed against ICAM-1, CD4 and TNF alpha. The main role of most biologics may be to pinpoint important therapeutic targets which can be attacked by more easily administered and less costly xenobiotic drugs.
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PMID:The pathogenesis of rheumatoid arthritis and the development of therapeutic strategies for the clinical investigation of biologics. 778 87

Pro-inflammatory cytokines such as tumour necrosis factor alpha (TNF alpha) have been implicated in the pathogenesis of rheumatoid arthritis (RA), and have therefore become therapeutic targets. An engineered human antibody, CDP571, that neutralizes human TNF alpha was administered intravenously in single doses of 0.1, 1.0 or 10 mg/kg to patients with active RA (n = 24). The effects of the antibody were compared in a double-blind fashion with those of placebo (n = 12). In an open continuation phase patients were given either 1.0 or 10 mg/kg. We found that CDP571 was well tolerated and caused reductions in markers of disease activity such as erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP): this was confirmed by a reduction in the disease activity score (DAS). There was a reduction in the number of tender joints, maximal in degree and duration after 10 mg/kg. Patients also documented a reduction of pain and relief of arthritis symptoms. The effects of 10 mg/kg CDP571 on ESR, CRP, tender joints, pain and symptom relief compared to placebo were statistically significant at weeks 1 or 2. The continuation phase, although open, confirmed both the safety and the beneficial effects of CDP571 in active RA. In conclusion CDP571, an engineered human anti-TNF alpha antibody, is well tolerated and, after a single dose of 10 mg/kg, provides improvements in symptoms, signs and serological markers of disease activity in patients with active RA.
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PMID:The therapeutic effects of an engineered human anti-tumour necrosis factor alpha antibody (CDP571) in rheumatoid arthritis. 778 47

Although the etiology of rheumatoid arthritis is still unknown, our knowledge of pathophysiologic mechanisms in this disease has markedly increased. Especially the immunological characterization of cells involved in the inflammatory process and their secretory products (cytokines) allowed new experimental therapeutic approaches. Apparently, the cytokines TNF alpha, IL-1, and IL-6, predominantly produced by accessory cells, play an important role in the actual articular and extraarticular inflammation. Therefore, several pilot studies employed various methods to inhibit the effects of these proinflammatory cytokines. This paper provides an overview about initial results of these studies and an outlook with regard to future developments.
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PMID:[Experimental therapy of rheumatoid arthritis with cytokine antagonists]. 779 56

Anaemia of chronic disease (ACD) is a common extra-articular manifestation of rheumatoid arthritis (RA). Tumour necrosis factor alpha (TNF alpha) plays an important role in the development of ACD. The objective of the present study was to assess inhibition of in vitro colony-forming unit erythrocyte (CFUe) and blast-forming unit erythrocyte (BFUe) growth by TNF alpha and to examine whether this suppression could be counteracted by adding increasing concentrations of recombinant human erythropoietin (EPO) (r-h-EPO) to bone marrow cultures of RA patients with ACD and without anaemia (controls). Bone marrow cells of RA patients with ACD and control patients were cultured. The cultures were incubated with increasing concentrations of r-h-EPO (0.25; 0.5; 1; 2 U/ml), each in combination with increasing quantities of TFN alpha (0; 50; 100; 200; 400 U/ml). CFUe and BFUe were assessed after 7 and 14 days, respectively. Dose-dependent inhibition of BFUe and CFUe by increasing concentrations of TNF alpha was observed in ACD and controls. Regarding CFUe (ACD patients) incubated with 0.25 U/ml EPO, 50 U/ml TNF alpha caused 28% suppression compared to cultures without TNF alpha. Increasing the concentration of r-h-EPO from 0.25 U/ml to 2 U/ml completely restored the number of CFUe. A similar pattern was observed in BFUe growth in both groups. These data demonstrated the suppressive effects of TNF alpha on erythropoiesis in vitro and that the suppressed erythropoiesis could be partly corrected by the addition of excess r-h-EPO to the cultures. No significant differences were observed between ACD and control RA patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:R-h-erythropoietin counteracts the inhibition of in vitro erythropoiesis by tumour necrosis factor alpha in patients with rheumatoid arthritis. 783 70

This review has summarized information published over the last 5 years on the presence and pathophysiologic role of IL-1 and TNF alpha in RA. The evidence to date shows that 5 of 6 criteria for identifying mediators of tissue damage in human autoimmune diseases are satisfied (Table 1). The last criterion, prevention of clinical progression in patients with RA, is currently being evaluated. Many new therapeutic approaches are currently being developed, including the use of soluble receptors to IL-1 or TNF, monoclonal antibodies to TNF alpha, a specific IL-1 receptor antagonist, and gene therapy with the latter molecule. It should be emphasized that both IL-1 and TNF alpha play important roles in normal host defense; the possible complications of blocking their production or effects need to be carefully evaluated in long-term studies. A recent review has emphasized that although IL-1 and TNF alpha have many overlapping biologic properties, each may exhibit distinct effects in joint disease (99). Anti-TNF treatment may be primarily antiinflammatory but blocking IL-1 may be more effective in preventing cartilage destruction (100). The possibility exists that simultaneous inhibition of TNF alpha and IL-1 may be more therapeutically efficacious than blockade of either agent alone, as was recently demonstrated with IL-1ra and soluble TNF receptors in bacterial cell wall-induced arthritis in rats (101). The next level of clinical studies in rheumatoid arthritis should include the use of two biologic response modifiers together, or one agent combined with a more traditional form of therapy.
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PMID:Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis. 784 4

Studies done over the last few years have demonstrated that interleukin-1 and tumor necrosis factor alpha, which are produced mainly by monocyte-macrophages, are the key mediators of inflammation and tissue destruction in rheumatoid arthritis. The synergistic effects of these factors lead to the production of large amounts of metalloproteases by the synovial cells, chondrocytes, and bone-derived cells. Direct membrane-to-membrane contact between activated lymphocytes and monocyte-macrophages is one of the main factors activating the production of interleukin-1 and tumor necrosis factor alpha. This activation involves several glycoproteins expressed at the surface of activated lymphocytes (CD11, CD69). Antibodies can partially block this lymphocyte-monocyte interaction. Recent studies have identified two mechanisms capable of inhibiting macrophage and synovial cell activation. One calls into play the antiinflammatory cytokines, such as interleukin-4 and interleukin-10, which are potent inhibitors of the production of interleukin-1, tumor necrosis factor alpha, and the metalloproteases. Interleukin-10 also activates the tissue inhibitor of metalloproteases. The second mechanism, which is more specific, involves antagonists such as the interleukin-1 receptor antagonist and inhibitory soluble fragments derived from the extramembranous portion of the two receptors for tumor necrosis factor alpha (TNF-sR55 and TNF-sR75). These molecules, which we first studied in their naturally-occurring form, have been cloned and are being tested in several conditions including rheumatoid arthritis. Similar soluble fragments of the receptors for interleukin-1 alpha and beta can inhibit interleukin-1.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Cytokines and anti-cytokines in inflammatory rheumatism]. 785 69

A radioreceptor assay for tumour necrosis factor alpha (TNF alpha)-binding proteins was development that is suitable for use with synovial fluids and sera. This assay, an alternative to the commonly used enzyme-linked immunosorbent assays (ELISAs), is not specific for soluble tumour necrosis factor alpha receptors (sTNF-R), but detects any molecules that might compete with TNF alpha for receptor binding. It also detects molecules that might bind TNF alpha and thereby interfere with subsequent binding to receptor. In a preliminary study, the assay was used to determine levels of TNF alpha-binding activity in a test group of synovial fluids from patients with rheumatoid arthritis (RA), osteoarthritis (OA) or psoriatic arthritis (PA). Levels of binding activity were much higher than those reported for sTNF-R alone in other studies [1, 2]. Our results indicated that there may be other molecules associated with the inflamed synovium that can interfere with the binding of TNF to its receptors and so attenuate its effect in diseases such as RA.
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PMID:A radioreceptor assay for TNF alpha-binding proteins. 787 33

There is increasing evidence that TNF-alpha is a cytokine of major importance in the pathogenesis of rheumatoid arthritis. Since TNF-alpha mediates its effects via high affinity receptors, we were interested in investigating their expression and function in cells from rheumatoid tissue. Synovial fibroblasts derived from rheumatoid synovial tissue are stimulated by TNF-alpha to proliferate and release cytokines, prostaglandins, proteases and protease inhibitors. We have evaluated through which receptor stimulation of DNA synthesis and the release of the proinflammatory agents, IL-6, IL-8 and PGE2 are induced. It was found that rheumatoid synovial fibroblasts express both the p55 and p75 TNF receptor, in a ratio of 4:1. TNF-alpha-stimulated synovial fibroblast DNA synthesis and the release of IL-6, IL-8 and PGE2 was inhibited by antagonist monoclonal antibodies against either the p55 or the p75 TNF receptor, although the blockade of the p55 TNF receptor had a more potent effect than inhibition of the p75 TNF receptor alone. Similarly, specific monoclonal antibodies, agonistic for either the p55 or p75 TNF receptor stimulated synovial fibroblast DNA synthesis, as well as IL-6, IL-8 and PGE2 release. Both p55 and p75 TNF receptors on dermal and gingival fibroblasts were also involved in TNF-alpha-mediated DNA synthesis and IL-6, IL-8 and PGE2 release, although differences in the levels of DNA synthesis and release of inflammatory cytokines and PGE2 were observed between the three fibroblast types.
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PMID:p55 and p75 tumor necrosis factor receptors are expressed and mediate common functions in synovial fibroblasts and other fibroblasts. 788 Sep 74

Rheumatoid arthritis (RA) is an autoimmune disease with inflammatory manifestations in the peripheral synovial joints, which are infiltrated by activated T cells, macrophages, and plasma cells. We have investigated the role of cytokines in RA and have proposed that tumour necrosis factor has a pivotal role in the pathogenesis of this disease. This chapter describes those studies, which led to the first clinical trial in RA patients using a chimeric anti TNF alpha antibody. In addition to pro-inflammatory cytokine production, at sites of inflammation such as the RA synovial joint, there is also evidence for homeostatic immunoregulatory mechanisms which include the production of cytokine inhibitors, such as soluble TNF-R and the IL-1 receptor antagonist, and cytokines with immunoregulatory properties like IL-10. The evidence for these inhibitors in RA is presented, and the relevance of this homeostatic mechanism in relation to chronic inflammatory diseases is discussed.
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PMID:TNF alpha as a therapeutic target in rheumatoid arthritis. 789 23


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