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)

Tumor necrosis factor-alpha (TNF-alpha) is a central regulator of inflammation, and TNF-alpha antagonists may be effective in treating inflammatory disorders in which TNF-alpha plays an important pathogenetic role. Recombinant or modified proteins are an emerging class of therapeutic agents. To date, several recombinant or modified proteins which acts as TNF antagonists have been disclosed. In particular, antibodies that bind to and neutralise TNF have been sought as a means to inhibit TNF activity. Inhibition of TNF has proven to be an effective therapy for patients with rheumatoid arthritis and other forms of inflammatory disease including psoriasis, psoriatic arthritis, and ankylosing spondylitis, inflammatory bowel disease. Additionally, the efficacy of preventing septic shock and AIDS has been questioned as a result of recent research. The currently available therapies include a soluble p75 TNF receptor:Fc construct, etanercept, a chimeric monoclonal antibody, infliximab, and a fully human monoclonal antibody, adalimumab. Certolizumab pegol is a novel TNF inhibitor which is an antigen-binding domain of a humanized TNF antibody coupled to polyethylene glycol (PEG) to increase half-life, and thus is Fc-domain-free. In this review, we discuss briefly the present understanding of TNF-alpha-mediated biology and the current therapies in clinical use, and focus on some of the new therapeutic approaches with small-molecule inhibitors. Moreover, we examine recent reports providing important insights into the understanding of efficacy of thalidomide and its analogs, as TNF-alpha activity inhibitories, especially in therapies of several inflammatory diseases within the nervous system.
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PMID:TNF-alpha as a therapeutic target in inflammatory diseases, ischemia-reperfusion injury and trauma. 1968 89

Although the advent of infliximab has changed the treatment paradigm and goals in inflammatory bowel diseases (IBD), it does not provide a cure for IBD and recent evidence has demonstrated that the immunogenicity of this chimeric anti-TNF antibody is associated with secondary loss of response and intolerance. In ulcerative colitis (UC) the efficacy of infliximab was demonstrated in two large clinical trials, but long-term maintenance efficacy data are lacking. Novel biological agents have entered clinical development and pioneering trials have been reported in the last two years. For Crohn's disease (CD) two anti-TNF agents, the fully human IgG1 anti-TNF monoclonal adalimumab and the humanized pegylated Fab-fragment certolizumab-pegol and the humanized anti alpha4 integrin IgG4 antibody both have demonstrated efficacy as maintenance agents. Adalimumab has been approved to treat active rheumatoid arthritis, psoriatric arthritis, and ankylosing spondylitis, and recently moderate-to-severe luminal CD has been added as an indication for this agent both by the FDA and EMEA. Further evidence is needed to establish the therapeutic potential of adalimumab in fistulizing CD and in UC. The benefit to risk ratio of anti-TNF agents in refractory IBD is clearly positive and since most of the toxicity is class specific, adalimumab is expected to have a safety profile similar to that of infliximab except for adverse events related to infusions.
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PMID:Adalimumab in Crohn's disease. 1970 6

Etanercept is a soluble TNF receptor p75 fusion protein which is approved for subcutaneous use (50 mg weekly) in the treatment of patients with active rheumatoid arthritis (RA), juvenile RA, ankylosing spondylitis, and psoriatic arthritis. Etanercept binds to both TNFalpha and lymphotoxin and has quite a short mean half-life (70 hours). Numerous randomized clinical trials have demonstrated its efficacy to improve signs and symptoms in early and established RA and other inflammatory arthritis. Furthermore, etanercept has shown its ability to prevent radiographic progression and to improve health-related quality of life in patients with RA and psoriatic arthritis. A combination of etanercept plus methotrexate was more efficacious than etanercept monotherapy in RA patients but there is currently no evidence that such rheumatic combination is better than monotherapy in other disorders. Etanercept was generally well tolerated both in controlled trials with withdrawal rates being similar to the comparator groups and in large observational studies. Infections and injection-site reactions were the most frequently reported events. Serious infections were slightly increased but the occurrence of tuberculosis seemed less frequent than with anti-TNF monoclonal antibodies (infliximab and adalimumab). The benefit-risk ratio of etanercept appeared to be very positive, and this drug has now emerged as a major therapy in patients with active inflammatory arthritis. Furthermore, it is more frequently considered as an emerging and valuable option in patients with early disease.
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PMID:Update on the use of etanercept across a spectrum of rheumatoid disorders. 1970 51

Tumor necrosis factor-alpha (TNF-alpha) was first isolated two decades ago as a macrophageproduced protein that can effectively kill tumor cells. TNF-alpha is also an essential component of the immune system and is required for hematopoiesis, for protection from bacterial infection and for immune cell-mediated cytotoxicity. Extensive research, however, has revealed that TNF-alpha is one of the major players in tumor initiation, proliferation, invasion, angiogenesis and metastasis. The proinflammatory activities link TNF-alpha with a wide variety of autoimmune diseases, including psoriasis, inflammatory bowel disease, rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, multiple sclerosis, diabetes and ankylosing spondylitis. Systemic inhibitors of TNF such as etanercept (Enbrel) (a soluble TNF receptor) and infliximab (Remicade) and adalimumab (Humira) (anti-TNF antibodies) have been approved for the treatment inflammatory bowel disease, psoriasis and rheumatoid arthritis. These drugs, however, exhibit severe side effects and are expensive. Hence orally active blockers of TNF-alpha that are safe, efficacious and inexpensive are urgently needed. Numerous products from fruits, vegetable and traditional medicinal plants have been described which can suppress TNF expression and TNF signaling but their clinical potential is yet uncertain.
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PMID:Targeting TNF for Treatment of Cancer and Autoimmunity. 1976 65

Both ankylosing spondylitis (AS) and rheumatoid arthritis (RA) are common, highly heritable conditions, the pathogenesis of which are incompletely understood. Gene-mapping studies in both conditions have over the last couple of years made major breakthroughs in identifying the mechanisms by which these diseases occur. Considering RA, there is an over-representation of genes involved in TNF signalling and the NFKappaB pathway that have been shown to influence the disease risk. There is also considerable sharing of susceptibility genes between RA and other autoimmune diseases such as systemic lupus erythematosus, type 1 diabetes, autoimmune thyroid disease and celiac disease, with thus far little overlap with AS. In AS, genes involved in response to IL12/IL23, and in endoplasmic reticulum peptide presentation, have been identified, but a full genomewide association study has not yet been reported.
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PMID:Genetics of ankylosing spondylitis and rheumatoid arthritis: where are we at currently, and how do they compare? 1982 41

The clinical manifestations of rheumatoid arthritis (RA) and ankylosing spondylitis (AS) differ in many ways. The age of onset in AS is much younger, with an average onset of 28 years compared with 40-50 years in RA, and with a male predominance (3:1) compared with the female predominance in RA. The genetic association with HLA alleles is stronger in AS, with an HLA-B27 antigen in 95% of the patients compared with RA, with 60% HLA DR4 or DR 1 positives. The type and localisation of arthritis is peripheral polyarthritis in RA, especially with involvement of hands and feet, whereas in AS the arthritis is mainly localized in the spine and sacroiliac joints with an oligoarthritis of the larger joints (hips, knees, shoulders). The radiographic signs in RA show bone resorption with erosive changes in contrast with AS where bone formation with vertebral sydesmophytes is present. Extra-articular manifestations can occur in both diseases but again these manifestations differ in the eye (keratoconjuctivitis sicca and scleritis in RA, versus anterior uveitis in AS), heart (pericarditis in RA, conduction disturbances in AS), lungs (pleural lesions or nodules in RA and fibrosis in AS) and gastrointestinal tract (peptic ulcers in RA and colitis in AS).Both diseases respond well to treatment with NSAIDs but DMARDs, which are very important in RA, have limited value in AS. TNF alfa blocking drugs, however, show a high efficacy in both diseases.
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PMID:A systematic comparison of rheumatoid arthritis and ankylosing spondylitis. 1982 45

Rheumatoid arthritis and ankylosing spondylitis are both chronic diseases with inflammation as a hallmark. Both diseases are characterized by structural abnormalities of the peripheral joints (RA) or the spine (AS) that can be visualized on conventional radiographs. RA is associated with destruction (erosions, joint space narrowing) whilst AS is dominated by bone formation (syndesmophytes). The causative relationship between inflammation and structural damage in RA is well established, whilst this relation is largely unknown but certainly less strong in AS. Progression of structural damage in RA is inhibited by disease modifying anti-rheumatic drugs and especially by TNF-blockade, whilst progression of structural damage in AS seems insensitive to TNF-blockade but sensitive to non-steroidal inflammatory drugs.In this article, similarities and dissimilarities with respect to structural damage in RA and AS are discussed and set against a background.
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PMID:A systematic comparison of rheumatoid arthritis and ankylosing spondylitis: structural outcomes. 1982 54

There are clear differences in the clinical picture and in the pathogenesis between rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Biologic agents targeting TNF-alpha are efficacious in both diseases, with some tendency to work even better in spondyloarthritides (SpA) on a clinical basis. However, anti-TNF therapy was shown to inhibit radiographic progression in RA but not in AS. This is probably due to the outstanding difference in pathogenesis: while in RA osteodestructive lesions such as erosions predominate, AS patients will rather develop osteoproliferative changes such as syndesmophytes. There is some evidence that anti-TNF agents may show longterm efficacy and acceptable safety profiles over 5-10 years. There are some differences between the agents.Whether the recent developments of targeted therapies in RA with agents such as rituximab, abatacept and tocilizumab will also work for AS is unknown at present.
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PMID:Biologics in the treatment of rheumatoid arthritis and ankylosing spondylitis. 1982 66

Joint involvement associated with inflammatory bowel disease (IBD) belongs to the concept of spondyloarthritis (SpA) and includes two types of arthritis: a peripheral arthritis characterized by the presence of pauciarticular asymmetrical arthritis affecting preferentially joints of lower extremities and an axial arthropathy including inflammatory back pain, sacroiliitis and ankylosing spondylitis (AS). Treatment of arthritis includes a short-term use of NSAIDs associated with optimized treatment of gut inflammation. Safety concerns mean that long-term treatment with NSAIDs is best avoided if possible. Salazopyrine can be recommended for treatment of peripheral arthritis. Methotrexate and azathioprine are generally ineffective. Finally, efficacy of anti-TNF therapy (infliximab and adalimumab) is well established. However, use of etanercept is not recommended because of the increased risk for intestinal disease relapse. Pathogenesis of gut-joint iteropathy is not elucidated. Both inflammations are tightly related as suggested by human evidence of gut inflammation in patients with other forms of SpA and animal evidence of gut and joint inflammation in HLA-B27/human beta(2)-microglobulin transgenic rat model and TNF(DeltaARE) mice. Several clues for the linkage between gut and joint inflammation have been put forward including an altered recognition and handling of bacterial antigens, an aberrant trafficking of CD8+ T cells with an impaired T-helper type 1 cytokine profile and expression of aEb7 integrin, an altered trafficking of macrophages expressing CD163 and evidence of an increased angiogenesis. A transcriptome analysis of mucosal biopsies identified a set of 95 genes that are differentially expressed in both CD and SpA as compared with healthy controls suggesting common pathways. TNF plays a key role in the pathogenesis of various arthritic diseases and IBD. Mesenchymal/myofibroblast-like cells may represent the local primary targets of TNF in the induction of gut and joint pathology. Selective expression of TNFRI on these cells seems to be sufficient to orchestrate the complete development of SpA-related pathologies at least in TNF(DeltaARE) mice. Finally, genetic susceptibility is probably required to develop these pathologies. Genotyping of AS patients provided evidence for an important overlap between determinants of inherited predisposition to CD and AS. The best documented common association is with an IL-23R polymorphism, although the exact role remains unexplored. In addition, evidence suggests that a number of recently identified CD-susceptibility loci are associated with AS. Clinical, genetical, immunological and therapeutic evidence support the tight junction between gut and joint inflammation in two linked diseases, IBD and SpA, belonging to the 'immune-mediated inflammatory diseases'.
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PMID:Joint involvement associated with inflammatory bowel disease. 1989 67

Etanercept is singular among anti-tumor necrosis factor alpha (TNF-alpha) agents, for being a soluble antibody to both TNF and lymphtoxin-alpha. The long-term neutralization of two cachexins by etanercept would theoretically compromise early detection of malignancy. This case reports a patient who was treated by etanercept for 21 months due to ankylosing spondylitis. Metastatic malignancy of unknown origin developed, and silently led the patient to lethal hepatic rupture. With an example of a malignancy masking effect of soluble TNF receptor, this article questions a need for vigilant attention to de novo carcinoma during the therapy, and calls for refined strategies in modulating autoimmune diseases.
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PMID:The silent progression of metastatic malignancy during the treatment with soluble tumor necrosis factor receptor. 1989 39


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