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

Spondyloarthropathies (SpA) are a group of related disorders. The hallmark symptoms include spondylitis, pauci-articular synovitis and enthesiopathy. In an important number of cases, subclinical gut inflammation with pathological findings resembling Crohn's disease can be found. Some of these patients may eventually develop overt Crohn's disease. Conventional medical therapy in patients with SpA consists of non-steroidal anti-inflammatory drugs (NSAIDs). Sulphasalazin can be co-administered, especially in cases of chronic synovitis or enthesiopathy. Recently, experience with anti-TNF-alpha monoclonal antibodies (infliximab), a new class of biological compounds, has opened new avenues for treating patients with SpA. In particular, infliximab used in two open studies gave significant benefit on the locomotor manifestations in patients with Crohn's disease, in patients with ankylosing spondylitis, undifferentiated SpA and psoriatic arthritis. Etanercept, another TNF-alpha antagonist (soluble receptor), was shown to induce benefit in a placebo-controlled study in patients with psoriatic arthritis. The relationship between SpA and inflammatory bowel disease lead to the hypothesis that interfering with gut inflammation in patients with SpA would yield a potential target for modulating the synovitis in these patients. Thus, besides TNF-alpha blockade, other strategies with potential efficacy can be envisioned, such as IL-10, ICAM-1 antisense or anti-(4)beta(7) antibodies.
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PMID:Current use of biologicals for the treatment of spondyloarthropathies. 1133 71

The traditional approach to the treatment of rheumatoid arthritis (RA) has been the use of nonsteroidal anti-inflammatory drugs usually in combination with a disease-modifying antirheumatic drug (DMARD) such as hydroxychloroquine, gold, sulfasalazine, methotrexate, leflunomide or cyclosporin. Each of these DMARDs has its own distinct toxicities but has also been shown to be effective in reducing signs and symptoms of disease and to some extent, reduce radiological progression. Within the past 10 years, the combination of several traditional DMARDs has been shown to have increased efficacy over monotherapy without a significant increase in toxicity in a majority of studies. Recently, the US Food and Drug Administration has approved infliximab, a chimeric monoclonal antibody to tumour necrosis factor (TNF)-alpha in combination with methotrexate, for the treatment of signs and symptoms of RA, delay of radiological progression of disease and improvement of physical function while anakinra, an interleukin-1 receptor antagonist, has been approved for the treatment of the signs and symptoms of RA either as monotherapy or in combination with methotrexate. Etanercept is the first biological response modifier approved for use in RA in the US. Double-blind, randomised controlled studies have shown etanercept to be effective therapy in patients with RA who have had inadequate response to DMARDs, in combination with methotrexate, and as early monotherapy. Similar results were seen in juvenile and psoriatic arthritis in DMARD nonresponders. Open-label studies have shown efficacy in adult Still's disease, ankylosing spondylitis, progressive systemic sclerosis, Wegener's granulomatosis and chronic uveitis. Safety issues are a concern because of the ubiquitous role of TNF. To date the only consistent adverse event seen with etanercept has been injection site reactions. Infections occur at the same rate and with the same frequency as the placebo population. There should be caution, however, with using etanercept in patients with a serious infection, or recurrent infections or patients with untreated or latent tuberculosis. As of yet there has not been seen an increase of malignancies. Rare neurological and haematological events have been noted. Etanercept has been a significant addition to the armamentarium of medications for the treatment of RA, juvenile and psoriatic arthritis. Preliminary data show that it may be well tolerated and effective in other rheumatic diseases in which there is over production of TNFalpha.
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PMID:Safety and efficacy of disease-modifying anti-rheumatic agents: focus on the benefits and risks of etanercept. 1194 14

There is no reference second-line treatment for patients with rheumatoid arthritis, juvenile chronic arthritis, psoriatic arthropathy or ankylosing spondylitis after failure or intolerance of a slow-acting antirheumatic drug such as methotrexate. Etanercept, a immunosuppressant targeting TNF-alpha (like infliximab), is now approved in France for use in these situations, with the exception of spondylitis. In the second-line treatment of adults with rheumatoid arthritis, the clinical evaluation dossier on etanercept contains data from dose-finding studies and two placebo-controlled trials involving patients in whom several single-agent treatments had failed. At a dose of 25 mg subcutaneously twice a week, etanercept worked partially in about half the patients. Without direct comparisons, the place of etanercept relative to other slow-acting antirheumatic drugs is difficult to establish. From indirect comparisons, etanercept seems a slightly better treatment option than infliximab. In the first-line treatment of rheumatoid arthritis, one trial showed that etanercept worked faster than methotrexate, but there was no significant difference between the two treatments after two years. Little is known about the efficacy of etanercept in patients with juvenile chronic arthritis who do not respond adequately to methotrexate. There are no comparative trials. One double-blind placebo-controlled trial showed that etanercept, when it worked, remained active for at least 7 months. In one trial, etanercept was more effective than placebo in patients with psoriatic arthropathy and ankylosing spondylitis who continued to receive their usual treatment, which included a slow-acting antirheumatic drug in about 50% of cases. More than 50% of patients treated with etanercept have a cutaneous reaction to the injection. These reactions are usually mild or moderate. Active pharmacovigilance is needed, given its mechanism of action, and previous notifications of a wide variety of adverse effects (even though it is sometimes difficult to establish a foolproof link between etanercept and the adverse effect). Long-term studies of large numbers of patients are needed to determine the precise risk of side effects including haematological, infectious, neurological, oncological and immunological effects. In practice, methotrexate remains the first-line treatment for inflammatory arthritis. Etanercept can be a useful second-line treatment, especially in juvenile chronic arthritis.
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PMID:Etanercept: new preparation. Useful after methotrexate failure in inflammatory rheumatism. 1290 20

CLASSICAL DATA: Spondyloarthropathies regroup several rheumatological entities (ankylosing spondylitis, reactive arthritis, psoriatic rheumatism, entero-colopathic disease rheumatism, undifferentiated spondyloarthropathies ) with validated diagnosis criteria. Drug therapy is based upon NSAIDs (non-steroidal antiinflammatories). Refractory forms may lead to severe functional impairment, raising the need of more effective treatments. IN FAVOUR OF ANTI-TNF-ALPHA AGENTS: Several arguments (TNF-alpha serum levels, elevated levels of mRNA, TNF messengers, in sacro iliac biopsies, efficacy of anti TNF-alpha agents in Crohn's disease ) justify the use of anti-TNF-alpha agents in the treatment of spondyloarthropathies. Two biologic agents have been assessed in these circumstances: a monoclonal antibody (Infliximab) and a soluble form of the TNF receptor (Etanercept). EFFICACY AND SAFETY: Results of open and controlled studies, although on small series, demonstrated the significant efficacy of anti-TNF-alpha agents on the various clinical, biological, functional and quality of life parameters, and confirmed by imaging (MRI ). Tolerance is fair, but two cases of diffuse tuberculosis have been reported with Infliximab. THERAPEUTIC PROGRESS: Even if additional studies are required to answer some questions (long term efficacy and safety, treatment modalities), anti TNF agents appear as a therapeutic progress in refractory spondyloarthropathies, for which few validated options have existed up till now.
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PMID:[Therapeutic use of anti-TNF-alpha agents in spondyloarthropathies]. 1453 71

Tumour necrosis factor (TNF) is a pro-inflammatory cytokine with a role in the pathogenesis of a number of conditions including rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and Crohn's disease. Etanercept (Enbrel; Immunex Corp., Seattle, WA, USA) is a recombinant soluble fusion protein of TNF-alpha type II receptor and IgG which acts by blocking the action of TNF-alpha. It is licensed for use in rheumatoid arthritis and juvenile chronic arthritis. A number of studies report the development of antinuclear and anti-double-stranded DNA antibodies in patients treated with TNF antagonists for rheumatoid arthritis. There are few reports of the development of clinical features of discoid, subacute or systemic lupus erythematosus. We present one of the first reported cases of etenercept-induced systemic lupus erythematosus and review the literature of lupus and TNF antagonists.
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PMID:Etanercept-induced systemic lupus erythematosus. 1461 25

Etanercept, a soluble recombinant human tumor necrosis factor receptor (TNFr) fusion protein, is effective and well tolerated in the treatment of rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JRA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). The primary objective of this study was to investigate the potential pharmacokinetic and pharmacodynamic interaction between a single dose of R- and S-enantiomers of warfarin and multiple doses of etanercept after administration of warfarin and etanercept alone and together. In a nonrandomized, three-period study, 12 healthy male subjects received a single oral 25-mg dose of warfarin after an overnight fast, followed by twice-weekly 25-mg subcutaneous doses of etanercept for seven doses. The last dose of etanercept was administered concurrently with a second dose of warfarin. Serial blood samples for plasma warfarin concentration measurement and international normalized ratio (INR) assessment were collected before and up to 144 hours after dose administration. Serial blood samples for serum etanercept concentration measurement were collected before and up to 60 hours after the sixth dose and 264 hours after the seventh dose. Etanercept did not affect the pharmacokinetics and pharmacodynamics of warfarin. All ratios of maximum serum concentration (C(max)) and area under the serum concentration versus time curve (AUC) for pharmacokinetics (R- and S-enantiomers of warfarin) and INR fell within the confidence interval of 0.8 to 1.25. Warfarin also did not cause a clinically significant alteration in the pharmacokinetics of etanercept. In conclusion, coadministration of etanercept and warfarin would not be expected to change the pharmacokinetics of either medication; therefore, no dosage adjustment is needed in cases in which warfarin and etanercept are coadministered.
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PMID:Absence of a pharmacokinetic interaction between etanercept and warfarin. 1510 76

Etanercept is a dimeric fusion protein based on the p75 tumor necrosis factor (TNF) receptor. It binds to TNFalpha and blocks its biological activity. Subcutaneous etanercept is effective in the treatment of rheumatoid arthritis, psoriatic arthritis, and polyarticular-course juvenile rheumatoid arthritis. More recently, etanercept has shown efficacy in the treatment of adults with ankylosing spondylitis. In randomized, double-blind, placebo-controlled trials, subcutaneous etanercept 25mg twice weekly for 6-24 weeks significantly reduced disease activity in patients with active ankylosing spondylitis. In the largest trial, etanercept produced a response rate of 57% compared with 22% for placebo after 24 weeks (response was determined via the validated ASAS 20 response criteria developed by the Assessments in Ankylosing Spondylitis [ASAS] Working Group). Etanercept therapy significantly improved health-related quality of life in patients with ankylosing spondylitis compared with placebo. The greatest improvements in a 16-week study were seen in the domains of physical functioning, physical role, bodily pain, vitality, and social functioning. Etanercept was generally well tolerated, with few serious adverse events or treatment withdrawals. The most common adverse events were injection-site reactions and minor upper respiratory tract infections.
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PMID:Etanercept: in ankylosing spondylitis. 1516 37

Etanercept is effective in the treatment of rheumatoid arthritis (RA)when used as monotherapy and in combination with methotrexate(MTX). Radiographic progression of disease was slowed significantly when the drug was used for a 24-month period and was statistically significantly better than MTX. In addition to its use in RA,etanercept is approved by the U.S. Food and Drug Administration for other rheumatologic conditions, including psoriatic arthritis,ankylosing spondylitis, and juvenile chronic arthritis.
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PMID:Treatment of rheumatoid arthritis with etanercept. 1517 43

Etanercept is a self-administered medication that has FDA approval for the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Etanercept is a human fusion protein of the tumor necrosis factor receptor (TNFR) and the Fc region of IgG1 that binds to and presumably inhibits the pro-inflammatory and pro-proliferative activity of the tumor necrosis factor (TNF). A recent multisite, randomized, double-blind, placebo-controlled study conclusively demonstrates that etanercept as monotherapy effectively treats patients with moderate-to-severe plaque psoriasis. This effect is dose-responsive, with the etanercept 50 mg twice-weekly dose significantly more effective than the 25 mg twice-weekly dose in reducing the Psoriasis Area and Severity Index (PASI) score over both 12 and 24 weeks of continuous therapy. Nevertheless, clinical trials do not instruct the dermatologist on how to practically integrate etanercept into a patient's pre-existing treatment regimen. Many psoriasis patients are already on other systemic therapies or have a medical history that necessitates a tailored approach to their therapy. Further, in some patients, etanercept at 25 mg twice weekly is ineffective in maximally clearing a patient of psoriasis. Below are cases that demonstrate how etanercept can be combined with other medications in order to both maximize clinical efficacy and minimize potential risk.
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PMID:Etanercept for the treatment of psoriasis: combination therapy with other modalities. 1517 61

Rheumatoid arthritis is a severe, debilitating condition for which existing therapies are of limited efficacy. In addition, the most common structure of treatment for patients with rheumatoid arthritis has recently been called into question, and many believe it should be reversed so that stronger treatments are administered earlier in the progression of the disease. Pivotal to the changes in rheumatoid arthritis treatment is the introduction of the pro-inflammatory tumor necrosis factor (TNF) antagonists. Overexpression of cytokines in inflamed joints plays an important role in joint inflammation and tissue damage, and the place of cytokines in the pathology of rheumatoid arthritis has offered hope that their antagonism will reduce symptoms and slow the advancement of the condition. With this in mind, etanercept, a fully human soluble TNF receptor fusion protein, was developed. The potency of this novel drug in blocking TNF activity has been shown in animal models and in clinical trials. The latter have demonstrated a positive safety profile and efficacy in reducing pain and the number of tender and swollen joints in rheumatoid arthritis patients. The effects of etanercept have also been observed soon after administration and have been sustained over several years. Etanercept has offered encouragement for those seeking new, more efficacious and less toxic methods of treating rheumatoid arthritis in children, adults and the elderly. In addition to the treatment of adult and juvenile rheumatoid arthritis, etanercept has also demonstrated utility in treating ankylosing spondylitis and psoriatic arthritis.
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PMID:The soluble tumor necrosis factor receptor etanercept: a new strategy for the treatment of autoimmune rheumatic disease. 1519 Mar 85


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