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)

Soluble receptors for TNF (sTNF-R) are present at elevated concentrations in the synovial fluid of patients with rheumatoid arthritis. They are presumably released by cells of the synovial membrane, including the monocyte-derived synovial macrophages. Cytokines from the synovium, including IL-1 and TNF-alpha, may stimulate release. We therefore examined the release of sTNF-R from monocytes exposed to IL-1 and TNF-alpha. Elutriator-purified human blood monocytes spontaneously released both the p75 and the p55 sTNF-R (1011 +/- 199 and 177 +/- 20 pg/10(6) cells, respectively, mean +/- SEM) during 48 h of in vitro culture. TNF-alpha and IL-1 alpha induced time- and concentration-dependent increases in the release of sTNF-R75 from monocytes, but neither had a measurable effect on the release of sTNF-R55. The release of sTNF-R75 was inhibited by cycloheximide. Neither lymphocytes nor polymorphonuclear leukocytes (PMN) released measurable sTNF-R spontaneously or in response to stimulation with IL-1 alpha, but TNF-alpha stimulated the release of small amounts of sTNF-R75 by PMN. The timing, cycloheximide sensitivity, and selectivity of stimulated release of TNF-R75 by monocytes are consistent with previous observations on other cell types of late (8-20 h) increased synthesis and turnover of cell surface TNF-R75, but not TNF-R55, after stimulation with TNF-alpha or IL-1. These observations help to explain why elevated levels of sTNF-R in synovial fluid coexist with enhanced expression of cell surface TNF-R on synovial macrophages in rheumatoid arthritis.
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PMID:Tumor necrosis factor alpha and interleukin-1 alpha stimulate late shedding of p75 TNF receptors but not p55 TNF receptors from human monocytes. 859 Mar 6

We have previously hypothesized that the pro-inflammatory cytokine TNF alpha has a pivotal role in the pathogenesis of rheumatoid arthritis (RA). It mediates its effects by cross-linking surface p55 TNF receptors (TNF-R), which can be proteolytically cleaved to yield soluble fragments. Upon binding TNF alpha soluble TNF-R (sTNF-R) can inhibit its function. We investigated the enzymatic nature of the proteases involved in TNF-R cleavage, and found that this process is blocked by a synthetic inhibitor of matrix metallo-proteinase activity (MMP), BB-2275. Inhibition of TNF-R cleavage was observed in a number of different cell types, as detected by retention of surface bound TNF receptor and by less sTNF-R released into the cell supernatant. The augmentation of surface TNF-R expression was of biological relevance as TNF alpha-mediated necrosis of human KYM.1D4 rhabdosarcoma cells was enhanced approximately 15-fold in the presence of BB-2275. The addition of BB-2275 to rheumatoid synovial membrane cell cultures totally inhibited MMP activity and also significantly reduced the levels of soluble TNF alpha (P < 0.006), p55 sTNF-R (P < 0.006), and p75 sTNF-R (P < 0.004). Paradoxically, despite the reduction in soluble TNF alpha levels, the production of IL-1 beta, IL-6, and IL-8, cytokines whose production was previously demonstrated to be inhibited by the addition of neutralizing anti-TNF alpha antibody were not down-regulated by BB-2275. These results raise the interesting possibility that a close relationship exits between the enzyme(s) which process membrane-bound TNF alpha, and those involved in surface TNF-R cleavage. Furthermore our observations suggest that hydroxamate inhibitors of MMP activity which block TNF alpha secretion and TNF-R cleavage may not modulate down-stream effects of TNA alpha, and as such suggest that the precise specificity of these compounds will be highly relevant to their clinical efficacy in inflammatory diseases.
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PMID:Paradoxical effects of a synthetic metalloproteinase inhibitor that blocks both p55 and p75 TNF receptor shedding and TNF alpha processing in RA synovial membrane cell cultures. 867 95

Tumor necrosis factor (TNF) induces the production of two forms of soluble receptor (p55 and p75) that are present in human serum at concentrations that increase greatly in inflammatory rheumatic disease, as well as varying among healthy individuals. The purpose of this study was to evaluate the usefulness of soluble TNF receptors in distinguishing different forms of arthritis. Serum from patients with gout, rheumatoid arthritis, and osteoarthritis, and normal control subjects was analyzed for p55, p75, and TNF-alpha by enzyme-linked immunosorbent assay. Patients with gout had the highest level of soluble TNF receptor p55, while there was no significant difference in the level of this receptor between rheumatoid arthritis patients and controls. Both rheumatoid arthritis and gout patients had higher soluble TNF receptor p75 levels than osteoarthritis patients and control subjects, but there was no difference in the p75 level between rheumatoid arthritis and gout patients. Osteoarthritis patients had higher levels of p55 and lower levels of p75 than control subjects. The level of TNF-alpha in rheumatoid arthritis patients was higher than in osteoarthritis patients, gout patients, and control subjects. Determination of soluble TNF receptor levels, especially p55, might enable differentiation of rheumatoid arthritis from osteoarthritis and gout. The level of p75 cannot be utilized to differentiate rheumatoid arthritis and gout, in contrast to the results of previous investigations.
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PMID:Soluble tumor necrosis factor receptor in serum of patients with arthritis. 929 Feb 65

Imbalance between pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) and their respective inhibitors is likely to be involved in the pathogenesis of chronic inflammatory disorders such as multiple sclerosis and rheumatoid arthritis. Increasing evidence suggests that the administration of interferon-beta (IFN-beta) displays some efficacy in the treatment of patients with relapsing-remitting multiple sclerosis. The aim of the present study was to determine the effect of IFN-beta on the production of pro-inflammatory cytokines and their inhibitors by stimulated peripheral blood mononuclear cells (PBMC). IFN-beta decreased the production of both IL-1beta and TNF-alpha in a dose-dependent manner, by up to 80% and 55%, respectively. Simultaneously, IFN-beta increased the production of IL-1 receptor antagonist (IL-1Ra) by 37% and did not modulate the release of TNF-soluble receptors (TNF-sRs) p55 and p75. Therefore, by favoring the production of cytokine antagonists over that of pro-inflammatory cytokines, IFN-beta induces an imbalance supporting anti-inflammatory processes. This effect might account for some of the therapeutic benefit of IFN-beta.
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PMID:Interferon-beta not only inhibits interleukin-1beta and tumor necrosis factor-alpha but stimulates interleukin-1 receptor antagonist production in human peripheral blood mononuclear cells. 945 13

Cytokines are signalling glycoproteins mediating acute inflammation, chronic inflammation, and connective tissue destruction. The present study was designed to characterize the profile of cytokine message in normal human articular cartilage and from patients with rheumatoid arthritis (RA) and osteoarthritis (OA), by means of the reverse transcriptase-polymerase chain reaction (RT-PCR). Message RNA (mRNA) was extracted from fresh or frozen cartilage. The results showed expression of mRNA for IL-6, IL-6R, IL-7, IL-8, IL-10, and IL-12 (p35 and p40) exclusively in the RA cartilage. Except for mRNA for IL-8 and IL-10, no other cytokine or cytokine receptor was expressed in OA and control cartilage. mRNA for IL-1beta, IL-4, TNF-alpha, and TNFR-p75, was not detected in any cartilage sample except for one RA specimen expressing IL-1beta mRNA. However, the expression of message for pro-inflammatory cytokines was far more prominent than anti-inflammatory cytokines. This may suggest a disturbed balance of pro- and anti-inflammatory activity in RA cartilage.
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PMID:Detection of cytokine mRNA in human, articular cartilage from patients with rheumatoid arthritis and osteoarthritis by reverse transcriptase-polymerase chain reaction. 950 80

We investigated the serum concentration of the tumour necrosis factor (TNF) family ligands (TNF-alpha and TNF-beta) and their soluble receptors (sTNF-R p55 and sTNF-R p75) in 66 patients with rheumatoid arthritis (RA) and 14 healthy subjects as a control group, using an enzyme-linked immunosorbent assay (ELISA). We examined a possible association between the serum levels of these proteins and RA activity according to the Mallya & Mace scoring system and Ritchie's index. We also evaluated the correlation between the serum levels of ligands and their soluble receptors as well as the ligands and receptors concentration and the duration of the disease. TNF-alpha, sTNF-R p55 and sTNF-R p75 were detectable in the serum of all 66 patients and 14 healthy individuals. In contrast, TNF-beta was measurable in only 14(21.9%) patients with RA and in none of the control subjects. The highest TNF-alpha, sTNF-R p55 and sTNF-R p75 levels were found in those patients in stage 4 of the disease, and the lowest in the control group. We found a positive correlation between sTNF-R p55 and sTNF-R p75 concentrations and Ritchie's index and no correlation with TNF-alpha and TNF-beta. TNF-alpha, sTNF-R p55 and sTNF-R p75 serum levels correlated positively with the duration of the disease, but levels of TNF-beta did not. We observed a positive correlation between the concentrations of TNF-alpha with sTNF-R p55 and with sTNF-R p75, as well as between both soluble receptors. In contrast, we have not observed any correlation between the serum level of TNF-beta with TNF-alpha, sTNF-R p55, and sTNF-R p75. Our studies indicate that TNF-alpha, sTNF-R p55 and sTNF-R p75, but not TNF-beta (lymphotoxin alpha) are good markers of RA activity and that these proteins play an important role in the pathogenesis of this disease.
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PMID:The tumour necrosis factor family of receptors/ligands in the serum of patients with rheumatoid arthritis. 968 90

Soluble tumor necrosis factor (TNF) receptor fusion protein (p75) (Enbrel) is a reversible inhibitor of the biologic effects of TNF. Enbrel has been shown in placebo-controlled trials to significantly improve the signs and symptoms of rheumatoid arthritis. Clinical trials are now in progress to assess the safety and efficacy of Enbrel in combination with methotrexate in refractory rheumatoid arthritis along with trials to compare Enbrel to methotrexate in patients with early rheumatoid arthritis.
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PMID:Soluble tumor necrosis factor receptor (p75) fusion protein (ENBREL) as a therapy for rheumatoid arthritis. 971 Aug 88

The US adult rheumatoid arthritis (RA) population numbers approximately 2.1 million, with a greater proportion of cases in women. RA is a disease of the immune system that has no known cure, and current drugs do not affect the underlying cause. The side effects such drugs produce limit their usefulness, and many patients stop responding to these treatments over time. Etanercept, a biologic inflammation modulator, is a novel human recombinant version of the soluble p75 tumor necrosis factor (TNF) receptor that is linked to the Fc receptor of human immunoglobulin G subclass 1. It acts as a competitive inhibitor of the binding of TNF-alpha to cell-surface TNF receptors and thereby inhibits TNF-alpha-induced proinflammatory activity in the joints of RA patients. Etanercept acts as a cytokine "carrier" and TNF-alpha antagonist, rendering TNF-alpha biologically inactive, even though prolonging its half-life. In Phase I, II, and III clinical studies in patients with active, severe RA who had not responded to disease-modifying antirheumatic drug (DMARD) therapy, etanercept treatment decreased disease activity, increased functional activity, and improved health-related quality of life. In a recent 12-month continuation of an earlier 6-month study, 105 patients who received etanercept 25 mg subcutaneously twice weekly demonstrated rapid and sustained improvements in disease activity. The US Food and Drug Administration has approved etanercept for marketing for the treatment of moderately to severely active RA in patients who have not responded adequately to other DMARDs.
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PMID:Etanercept, a novel drug for the treatment of patients with severe, active rheumatoid arthritis. 1009 Apr 26

The armamentarium for the treatment of rheumatoid arthritis (RA) includes several classes of therapeutics that induce symptomatic relief and reduce disease activity. The early addition of disease modifying antirheumatic drugs (DMARD) is now the standard of care in treatment. Methotrexate (MTX) is a cornerstone of contemporary management of RA, and the treatment paradigm for RA includes the early use of MTX and combination DMARD. Unfortunately, second-line treatments alone or in combination rarely induce complete disease remission. Advances in the understanding of the pathogenesis of RA have opened the way for more directed therapy, and new therapies that target the cytokine tumor necrosis factor alpha (TNF-alpha) have demonstrated rapid action and substantial benefit with few adverse effects. This article discusses the pivotal role of MTX in combination with DMARD. The use of leflunomide and cyclosporine as single agents and with MTX is evaluated. The role of TNF-alpha antagonism in the treatment of rheumatologic illnesses is examined, with particular attention to etanercept, a recombinant human TNF receptor (p75)-Fc fusion protein, and infliximab, a chimeric TNF monoclonal antibody (CA2). Data on the efficacy and toxicity of etanercept and infliximab are summarized, including their use in combination therapy with MTX.
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PMID:The role of tumor necrosis factor antagonism in clinical practice. 1032 39

Treatment with a chimeric mAb to TNF-alpha has been shown to suppress inflammation and improve patient well-being in rheumatoid arthritis (RA), but the mechanisms of action of such treatment have not been fully explored. Here we show that in vivo administration of anti-TNF-alpha Ab, using a longitudinal analysis, results in the rapid down-regulation of a spectrum of cytokines, cytokine inhibitors, and acute-phase proteins. Marked diurnal variation in the serum levels of some of these were detected. These results were consistent with the concept of a cytokine-dependent cytokine cascade, and the degree of clinical benefit noted after anti-TNF-alpha therapy is probably due to the reduction in many proinflammatory mediators apart from TNF-alpha, such as IL-6, which reached normal levels within 24 h. Serum levels of cytokine inhibitors such as soluble p75 and p55 TNFR were reduced as was IL-1 receptor antagonist. Reductions in acute-phase proteins occurred after serum IL-6 fell and included serum amyloid A, haptoglobin, and fibrinogen. The latter reduction could be of importance, as it is a risk factor for atherosclerosis, which is augmented in RA patients.
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PMID:Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis. 1041 55


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