Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01889 (ankylosing spondylitis)
 5,717 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Up to 2 in 1,000 adults in the UK have ankylosing spondylitis. This chronic inflammatory disease causes pain and stiffness in the spine and sacroiliac and peripheral joints, and may also affect the eyes, heart and ungs. Characteristic features include ankylosis of the spine with a progressive loss of spinal mobility. Treatment with NSAIDs and physical therapy can provide symptomatic relief of pain and stiffness, but does not modify the course of the disease (e.g. slow or prevent ankylosis). In general, disease-modifying antirheumatic drugs (DMARDs), such as gold, methotrexate and sulfasalazine, have little or no effect in ankylosing spondylitis. [symbol: see text]Etanercept (Enbrel--Wyeth) and [symbol: see text]infliximab (Remicade--Schering-Plough), two drugs which block the inflammatory effect of tumour necrosis factor (TNF), are now licensed for the treatment of patients with severe ankylosing spondylitis whose symptoms have not responded adequately to conventional therapy. Here we review the place of these TNF antagonists in the management of such individuals.
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PMID:TNF antagonists for ankylosing spondylitis. 1576 84

Therapeutic options for patients with active and severe spondylarthritis (SpA) have been fairly limited in the past decades. There is now accumulating evidence that biological therapy with agents directed against tumour necrosis factor-alpha (TNF-alpha) is highly efficacious in the spondyloarthritides, especially in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). The TNF blocking agents currently available, infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira), are approved for the treatment of rheumatoid arthritis (RA) in Europe and the USA. In contrast to rheumatoid arthritis (RA) disease-modifying anti-rheumatic drugs (DMARDs) have limited efficacy in SpA. No DMARDs are available for AS patients with active spinal disease. Thus, for AS patients whose condition is not sufficiently controlled with non-steroidal anti-inflammatory drugs (NSAIDs), therapy with TNF blockers may be considered as a first-line treatment. For infliximab, a dose of 3-5 mg/kg seems to be required, and intervals between 6 and 12 weeks are necessary to suppress disease activity continually. The standard dosage of etanercept is 2 x 25 mg subcutaneously (s.c.) per week. There are very few studies with adalimumab (standard dose in RA 20-40 mg s.c. every 1-2 weeks) in SpA. Infliximab and etanercept are now both approved for AS in Europe. There is some evidence that both agents also work in other SpA, especially in PsA. Withdrawal of long-term therapy in AS patients led to relapses of disease after several months. Less radiographic progression after 2 years of continuous treatment with infliximab compared to conventional therapy has been suggested in a small study. Serious adverse events on anti-TNF therapy have remained rare. However, severe infections, including tuberculosis, have been reported. These can be largely prevented by appropriate screening. The benefits of anti-TNF therapy in AS seem to outweigh these shortcomings.
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PMID:Therapy of ankylosing spondylitis. Part II: biological therapies in the spondyloarthritides. 1613 23

Etanercept (Enbrel, Wyeth Pharmaceuticals) is a fusion protein composed of a soluble TNF alpha receptor issued from bio-technology. It is a member of TNF alpha's family with two others marked infliximab (Remicade, Scheringh Plough Laboratory), chimeric monoclonal antibody (25 p. 100 mouse) and adalimumab (Humira, Abbott France Laboratory), humanized monoclonal antibody (100 p. 100 human). In United States, etanercept is approved by Food and Drug Administration, since 1998, to treat rheumatoid arthritis showing an inadequate response to prior therapy with other disease-modifying antirheumatic drugs (DMARDS). In France, the MA (Marketing Authorization) is more recent, in 2000, etanercept to treat active rheumatoid arthritis who showed an inadequate response to others DMARDS (like methotrexate for example), with opportunity, in 2002, to administer etanercept in active, severe RA, in first line treatment without previous use of methotrexate. Others MA have been obtained in ankylosing spondylitis (2004) polyarticular-course juvenile rheumatoid arthritis (2000), and in the treatment of psoriasic arthritis (2002). Request of MA have been realised to treat cutaneous mild to severe psoriasis in adult, which failed to respond, contradication or no tolerance with systemic treatment as methotrexate, cyclosporine or phototherapy. Among the others anti-TNF therapy, only infliximab can be prescribed, in dermatology, to treat psoriatic arthritis in France. Encouraging good results were the subject of cases report, but lacking clinical trial, predicting probably administration of etanercept in others indications in future. TNF alpha is a proinflammatory cytokine and plays an important role in the physiopathology of large inflammatory diseases. Logically, in future, we should increased prescription of biotherapy, particularly anti-TNF alpha. We have to mind short or mild-term adverse events, widely described in the literature, but long-term side effects remained unknown. Moreover, these biotherapic agents have a high cost and should be estimate.
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PMID:[Etanercept]. 1632 16

TNF-alpha neutralising agents such as Infliximab (Remicade), Etanercept (Enbrel) and the IL-1 receptor antagonist Anakinra (Kineret), are currently used clinically for the treatment of many inflammatory diseases such as Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, juvenile rheumatoid arthritis, psoriatic arthritis and psoriasis. These protein preparations are expensive to manufacture and administer, need to be injected and can cause allergic reactions. An alternative approach to lowering the levels of TNF-alpha and IL-1beta in inflammatory disease, is to inhibit the enzymes that generate these cytokines using cheaper small molecules. This paper is a broad overview of the progress that has been achieved so far, with respect to small molecule inhibitor design and pharmacological studies (in animals and humans), for the metalloprotease Tumour Necrosis Factor-alpha Converting Enzyme (TACE) and the cysteine protease Caspase-1 (Interleukin-1beta Converting Enzyme, ICE). Inhibitors of these two enzymes are currently considered to be good therapeutic targets that have the potential to provide relatively inexpensive and orally bioavailable anti-inflammatory agents in the future.
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PMID:Inhibitors of TACE and Caspase-1 as anti-inflammatory drugs. 1637 99

CXC chemokines are potent attractants of neutrophil granulocytes, T cells or natural killer cells. Toll-like receptors (TLR) recognize microbial components and are also activated by endogenous molecules possibly implicated in autoimmune arthritis. In contrast to CXC chemokine ligand 8 (CXCL8), no CXC chemokine receptor 3 (CXCR3) ligand (ie CXCL9, CXCL10 and CXCL11) was induced by bacterial TLR ligands in human microvascular endothelial cells (HMVEC). However, peptidoglycan (PGN), double-stranded (ds) RNA or lipopolysaccharide (LPS) (TLR2, TLR3 or TLR4 ligands, respectively) synergized with interferon-gamma (IFN-gamma) at inducing CXCL9 and CXCL10. In contrast, enhanced CXCL11 secretion was only obtained when IFN-gamma was combined with TLR3 ligand. Furthermore, flagellin, loxoribine and unmethylated CpG oligonucleotide (TLR5, TLR7 and TLR9 ligands, respectively) did not enhance IFN-gamma-dependent CXCR3 ligand production in HMVEC. In analogy with TLR ligands, tumor necrosis factor-alpha (TNF-alpha) or interleukin-1beta (IL-1beta), in combination with IFN-gamma, synergistically induced CXCL9 and CXCL11 in HMVEC and human fibroblasts, two fundamental cell types delineating the joint cavity. Etanercept, a humanized soluble recombinant p75 TNF-receptor/IgG(1)Fc fusionprotein, neutralized synergistic CXCL9 production induced by TNF-alpha plus IFN-gamma, but not synergy between IFN-gamma and the TLR ligands PGN or LPS. Synovial chemokine concentrations exemplify the physiopathological relevance of the observed in vitro chemokine production patterns. In synovial fluids of patients with spondylarthropathies (ie ankylosing spondylitis or psoriatic arthritis) or rheumatoid arthritis, significantly enhanced CXCL9, but not CXCL11 levels, were detected compared to concentrations in synovial fluids of patients with metabolic crystal-induced arthritis. Thus, CXCL9 is an important chemokine in autoimmune arthritis.
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PMID:TLR ligands and cytokines induce CXCR3 ligands in endothelial cells: enhanced CXCL9 in autoimmune arthritis. 1684 31

Antagonists of tumor necrosis factor (TNF) have revolutionized the treatment of selected inflammatory diseases. In rheumatology, this has been most notable for ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis. Despite their specificity for TNF, these agents, which include the soluble p75 receptor etanercept and the anti-TNF antibodies adalimumab and infliximab, have demonstrated differential clinical efficacy in studies of rheumatoid arthritis; patients who do not respond to one antagonist often respond to another. Therapeutic disparity of these agents is also seen in specific diseases, most notably Crohn's disease. Differences in pharmacodynamics, pharmacokinetics and mechanisms of action, as well as disease heterogeneity, have been proposed to account for these effects. Reverse signaling by transmembrane TNF in response to anti-TNF antibodies, but not soluble receptor, might also influence the therapeutic response.
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PMID:Drug insight: different mechanisms of action of tumor necrosis factor antagonists-passive-aggressive behavior? 1739 8

Etanercept (Amgen Inc, Thousand Oaks, CA) is a human soluble p75 tumor necrosis factor (TNF) receptor-human-IgG1 (hup75 TNFR-huIgG1) fusion protein used in the treatment of chronic inflammatory diseases in humans, including rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and psoriasis. To be able to study the effects of the soluble receptor fusion protein in mouse models, including those that mimic human granulomatous infections, a murine soluble p75-TNF receptor-murine IgG1 (murine p75-murine IgG1) fusion protein had to be constructed. This article discusses the generation, large-scale production, and purification of this molecule.
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PMID:Construction and purification of the murine p75-murine IgG1 fusion protein. 1750 70

Etanercept is a dimeric fusion protein based on the p75 TNF-alpha receptor. It binds to TNF-alpha and blocks its biologic activity. In randomized, double-blind, placebo-controlled trials, etanercept has therapeutic activity in rheumatoid arthritis, psoriatic arthritis, polyarticular-course juvenile idiopathic arthritis and ankylosing spondylitis. Etanercept improves joint inflammation, physical function and slows/halts structural damage, especially when combined with methotrexate. A sustained response is observed in a substantial percentage of patients. Although some safety issues should be considered before starting etanercept treatment, in general terms, etanercept is a well tolerated drug with an acceptable safety profile. The use of any TNF-alpha antagonist must be in agreement with the National Recommendations for Biologic Therapy, and in difficult clinical situations, a balance between risk/benefit needs to be obtained.
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PMID:Etanercept: long-term clinical experience in rheumatoid arthritis and other arthritis. 1756 71

Etanercept (Enbrel), a recombinant, dimeric, soluble tumour necrosis factor (TNF) receptor protein, is approved in various countries for the treatment of adult patients with ankylosing spondylitis or psoriatic arthritis. Monotherapy with subcutaneous etanercept 25mg twice weekly or 50mg once weekly was effective and generally well tolerated in patients with ankylosing spondylitis or psoriatic arthritis participating in several large, well designed clinical studies. Treatment with etanercept was more effective than placebo in reducing disease activity and improving health-related quality of life (HR-QOL) in both patient populations, and in delaying structural disease progression in patients with psoriatic arthritis. The beneficial response to etanercept achieved with shorter-term treatment was sustained in studies of up to 4 years' total duration. Randomised, well designed, head-to-head comparisons, including pharmacoeconomic analyses, with other anti-TNF biological modulators are required to accurately position etanercept and fully establish its cost effectiveness. In the meantime, etanercept is a valuable treatment option for patients with ankylosing spondylitis or psoriatic arthritis who are suitable candidates for therapy.
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PMID:Etanercept: a review of its use in the management of ankylosing spondylitis and psoriatic arthritis. 1803 93

New pathogenetic insights have identified the key role of TNF-alpha in inflammatory rheumatic diseases and have revolutionized the therapy of spondyloarthritides. TNF-alpha-antagonists specifically inhibit the pro-inflammatory effects of TNF-alpha. Clinical studies with infliximab (Remicade), Etanercept (Enbrel) or Adalimumab (Humira) in ankylosing spondylitis or related diseases demonstrate superior efficacy to conventional drugs like non-steroidal antirheumatic drugs or traditional disease modifying antirheumatic drugs.
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PMID:[Biologics in the early treatment of ankylosing spondylitis and related forms of spondyloarthritis]. 1850 Apr 71


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