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)

Tumour necrosis factor (TNF) plays a central part in the pathophysiology of rheumatoid arthritis (RA). TNF initiates signal transduction by interacting with surface bound TNF receptors. Soluble tumour necrosis factor receptors (sTNFRs) act as natural inhibitors of TNF activity. Etanercept, recombinant p75 sTNFR:Fc fusion protein, has received approval from the US Food and Drug Administration for patients with RA and juvenile RA (JRA) who have failed treatment with at least one other drug. Etanercept has demonstrated excellent safety and efficacy in large scale, randomised, double blind, placebo controlled trials of patients with RA and JRA who are refractory to other disease modifying anti-rheumatic drugs. The therapeutic effects mediated by etanercept are rapid and sustained. Combining etanercept with methotrexate was found to be safe and more effective than treatment with methotrexate alone in the treatment of RA. These clinical findings demonstrate that etanercept can result in symptomatic improvement in patients with RA and JRA. Etanercept is an important new addition to the treatment of these diseases.
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PMID:Etanercept: therapeutic use in patients with rheumatoid arthritis. 1057 76

The proinflammatory cytokine, tumour necrosis factor alpha (TNFalpha) has been shown to play a pivotal part in mediating acute and chronic inflammation. The activities of TNFalpha are modulated by the proteolytic shedding of the soluble extracellular domains of the two TNF receptors, p55 sTNF-RI and p75 sTNF-RII. Amgen Inc has cloned and expressed a recombinant form of a natural inhibitor of TNFalpha, referred to as recombinant human soluble TNF receptor type I (r-Hu-sTNF-RI, sTNF-RI). sTNF-RI is an E coli recombinant, monomeric form of the soluble TNF-type I receptor. A high molecular weight polyethylene glycol (PEG) molecule is attached at the N-terminus position to form the molecule intended for clinical evaluations (PEG sTNF-RI). Preclinical studies to date demonstrate that PEG sTNF-RI is efficacious in rodent models of chronic inflammatory disease including rheumatoid arthritis and Crohn's disease at doses as low as 0.3 mg/kg given every other day. This dose results in plasma concentrations of 0.3 to 0.5 microg/ml. Higher doses with correspondingly higher plasma concentrations yield higher efficacy. It has also demonstrated efficacy in E coli lipopolysaccharide, and Staphylococcus enterotoxin B mediated models of acute inflammation in rodents and primates. Pharmacokinetic studies in mice, rats, cynomolgus monkeys, baboons, and chimpanzees have been conducted with PEG sTNF-RI. Absorption from a subcutaneous dose was slow, with the time to reach maximal plasma concentrations of 24-48 hours in rats, and in monkeys, and 3-29 hours in chimpanzees. The initial volume of distribution of PEG sTNF-RI was essentially equivalent to that of plasma (40 ml/kg). This suggests the protein does not appear to extensively distribute from the systemic circulation with a volume of distribution at steady state (Vss) less than 200 ml/kg in all species studied. These results are consistent with previous experience with PEGylated proteins in which PEGylation decreases both the rate of absorption and the plasma clearance of human recombinant proteins in animals and humans. The use of a PEG molecule will probably provide a more advantageous dosing schedule (that is, less frequent dosing) for the patient compared with a non-PEG sTNF-RI.
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PMID:PEGylated recombinant human soluble tumour necrosis factor receptor type I (r-Hu-sTNF-RI): novel high affinity TNF receptor designed for chronic inflammatory diseases. 1057 78

Due to intensive research in the field of cytokines during the last decade the knowledge of cytokine mediated processes has increased intensively. Modulation or even inhibition of the inflammatory cascade gave hope to effective therapeutic possibilities in sepsis or autoimmune diseases, particularly in rheumatoid arthritis (RA). Interestingly the application of biological immunomodulating substances could not increase the prognosis in sepsis, sometimes even deterioration occurred. However, in inflammatory bowel diseases and RA substantial efficacy could be revealed. Since blockade of II-1 or II-2 led to some beneficial results, but also sometimes to significant toxicity, TNF-alpha blockade gave hope to constitute a promising therapeutical target. Since the efficacy of a monoclonal anti-TNF-alpha antibody and a recombinant soluble TNF receptor p75 fusion protein had been demonstrated in animal studies and in vitro, these results could be confirmed in controlled multicenter trials, showing significant improvement of patients according to Paulus and/or ACR criteria. However, a final assessment of therapeutical TNF-alpha blockade in RA cannot be given yet, since the tolerability in long-term application, particularly with respect to the risk of infections and the induction of malignancies and antibodies (e.g. drug induced lupus erythematosus) has to be observed carefully for longer times. Also the cost effectiveness of this new therapeutic approach needs further investigations.
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PMID:[Anti-TNF-alpha therapy as a new option in treatment of rheumatoid arthritis?]. 1063 66

Biological agents that inhibit the activity of proinflammatory cytokines are being investigated for use in the treatment of rheumatoid arthritis. Thus far, two of these agents, both of which neutralize tumor necrosis factor alpha (TNF-alpha), have received US Food and Drug Administration approval for the treatment of the disease. Etanercept is a bioengineered fusion protein of the p75 soluble TNF receptor, and infliximab is a chimeric monoclonal antibody to TNF-alpha. Other agents that target proinflammatory cytokines are also being developed. By allowing earlier treatment and better-tolerated long-term therapy, biologics might help slow or prevent disease progression and joint destruction.
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PMID:Cytokines in rheumatoid arthritis: trials and tribulations. 1090 49

Being mediators of immune and inflammatory reactions, abnormal or excessive production of cytokines is often the main cause of the pathology in many types of disease. Targeting cytokines by means of inhibitory drugs may thus offer a valid therapeutic approach in particular diseases. Soluble forms of cytokine receptors (sCR) normally participate in the control of cytokine activity in vivo by inhibiting the ability of cytokines to bind their membrane receptors and from generating a biological response. The ability of sCR to act as cytokine inhibitors, coupled to their specificity, high affinities and low immunogenicities have prompted considerable interest in their use as immunotherapeutic agents. In fact, many types of sCR have been shown to inhibit the biological activity of their cytokines in vitro and in different experimental models. Several sCR, particularly the soluble TNF receptors sTNFR-I (p55) and sTNFR-II (p75), have been modified by linking them to the Fc portion of human immunoglobulin (e.g., 'immunoadhesins') or by the addition of polyethylene-glycol (PEG) (e.g., 'PEGylation'), in order to enhance their affinity and/or biological half-life. These agents have shown significant therapeutic value in clinical trials of patients with rheumatoid arthritis (RA). Indeed, a sTNFR-II:Fc hybrid molecule (etanercept), the first sCR-derived therapeutic agent to receive approval for human use, is already utilised for the treatment of some forms of RA. Additional applications of this drug in other inflammatory conditions are currently being evaluated, while another sCR-derived agent, a human sIL-4R, is undergoing trials for the treatment of asthma. Many other sCR, such as sIL-1R, sIL-5R, sIFNgammaR, may also have significant potential for the treatment of a wide variety of human diseases.
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PMID:Soluble cytokine receptors: novel immunotherapeutic agents. 1106 Jun 91

Rheumatoid arthritis (RA) is the most common chronic autoimmunopathy, clinically leading to joint destruction as a consequence of the chronic inflammatory processes. The pathogenesis of this disabling disease is not well understood, but molecular events leading to tissue inflammation with cartilage and bone destruction are now defined in more detail. Established therapy, slow acting disease-modifying antirheumatic drugs (DMARDs) as with low-dose methotrexate (MTX) are the accepted 'golden standard' therapies and both lead to a significant improvement of disease symptoms, however are unable to stop joint destruction. Due to these disappointing treatment options and the identification of some inflammatory mediators as therapeutic targets, novel therapeutic agents such as monoclonal antibodies (mAbs), cytokine receptor-human immunoglobulin constructs or recombinant human proteins have been tested in RA with some success. In particular, clinical trials testing anti-TNF-alpha agents either alone or in combination with MTX have convincingly demonstrated the feasibility and efficacy of these novel approaches to the therapy of RA. Importantly, a clinical trial testing combination therapy with chimeric (mouse-human) anti-TNF-alpha mAb cA2 (Remicadetrade mark) and MTX could, for the first time in any RA trial, show that average radiological progression in the cA2/MTX groups could be completely prevented over a 12 month observation period. Similar encouraging results might evoke from trials employing other TNF-alpha-directed agents like the fully human mAb D(2)E7 or the p75 TNF-alpha-receptor-Ig construct, etanercept.
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PMID:Biological agents: a novel approach to the therapy of rheumatoid arthritis. 1106 Jul 53

There is accumulating evidence that tumour necrosis factor (TNF) plays a major role in the pathogenesis of rheumatoid arthritis (RA). Recent biotechnological advances have allowed for the development of agents that directly target TNF, a pro-inflammatory cytokine. In the last 2 years, the US FDA and the EU's Commission of the European Communities have approved two biological agents for the treatment of refractory RA, etanercept and infliximab. Etanercept is a fusion protein, composed of the Fc portion of IgG1 and the extracellular domain of the TNF receptor (p75). Infliximab is a chimeric monoclonal antibody (mAb) composed of murine variable and human constant regions. In placebo-controlled trials, both agents have proven to be effective and well-tolerated in RA patients. This review evaluates the available TNF inhibitors, summarises pertinent clinical trials and underscores differences between the two agents in terms of molecular structure, efficacy, safety data, antigenicity and pharmacokinetics.
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PMID:TNF blockade in the treatment of rheumatoid arthritis: infliximab versus etanercept. 1133 70

In recent years, new disease modifying agents including leflunomide and tumour necrosis factor (TNF) antagonists have been used to treat patients with rheumatoid arthritis (RA). Leflunomide prevents proliferation of activated lymphocytes by inhibiting dihydroorotate dehydrogenase, a critical step in de novo pyrimidine synthesis. Leflunomide has been shown to be as effective as sulfasalazine and methotrexate (MTX) in placebo-controlled trials. It also improves physical function, quality of life measures and retards radiographic progression. TNF antagonists include infliximab and etanercept. Infliximab is a chimeric TNF monoclonal antibody. Repeated infusions of low dose infliximab (1 mg/kg) are ineffective if given alone. Addition of MTX to infliximab has been shown to prolong the duration of clinical response. Etanercept is a human TNF receptor p75 Fc fusion protein. In active RA patients with suboptimal response to MTX, additional clinical benefit was obtained by the addition of infliximab or etanercept to MTX. The main side effect of etanercept is injection site reaction. However, the long-term effect of TNF antagonists in the development of infection, malignancy and autoimmune disease remains unknown.
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PMID:New disease modifying agents in adult rheumatoid arthritis. 1137 15

Most disease modifying antirheumatic drugs (DMARD) are discontinued within 5 years because of loss of clinical efficacy or toxicity. As a result, there has been a concerted effort to develop new immunomodulatory agents, particularly biological agents, that block the putative proinflammatory cytokines. Among the agents developed thus far, inhibitors of tumor necrosis factor (TNF) have shown perhaps the greatest promise as therapeutic agents for rheumatoid arthritis (RA). Two TNF-blocking agents, etanercept (Enbrel) and infliximab (Remicade), have been approved in the US and more recently in Europe, for the treatment of patients with RA. The results of randomized placebo controlled trials have shown that both agents significantly decrease the intensity of synovitis and prevent or retard the progression of cartilage destruction, especially when combined with methotrexate. Their side effect profiles appear to be acceptable, although rare cases of lupus-like diseases and of severe infections have been reported. Although the early clinical experience with these agents has been encouraging, their longterm safety and continuing efficacy in the general population with RA, as well as in high risk patient subsets (i.e., patients with malignancies or chronic infections), remain to be determined. In addition, the costs of these newer agents must be justified on clinical grounds. Because of the questions still surrounding these new treatment principles, several consensus conferences have been held in Europe and the US to address the role of the new biologicals in the current RA armamentarium.
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PMID:How do the biologics fit into the current DMARD armamentarium? 1140 55

Etanercept, a recombinant tumor necrosis factor receptor (p75)-Fc fusion protein competitively inhibits tumor necrosis factor-alpha (TNF). Etanercept has been successfully used in patients with rheumatoid arthritis, where it reduces pain and inflammation. Because locally produced proinflammatory cytokines play a role in pain after nerve injury, we investigated whether etanercept can reduce pain and hyperalgesia in an animal model of painful neuropathy, the chronic constriction injury of the sciatic nerve. C57BL/6 mice received etanercept or sham treatment by local near-nerve injection to the injured nerve or by systemic application. Treatment with etanercept reduced thermal hyperalgesia and mechanical allodynia significantly in both modes of application. The effect of etanercept was present in animals that were treated from the time of surgery and in those that were treated from day 6, when hyperalgesia was already present. These results suggest the potential of etanercept as a treatment option for patients with neuropathic pain.
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PMID:Etanercept reduces hyperalgesia in experimental painful neuropathy. 1144 85


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