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Objectives Metaanalysis of randomised controlled trials has shown that TNF-inhibitors are effective in RA. These trials however are undertaken in highly selective populations; under an experimental setting that may differ from that of clinical practice, and follow up rarely extend beyond 1 year. In addition all trials were sponsored by the manufacturer. We were asked to extend the review and meta-analysis of RCTs with a review of data from registries to evaluate efficacy and safety of TNF-inhibitors when used in clinical practice (real world). We focused particularly on the following questions: What is the efficacy of TNF-inhibitors when used outside clinical trials? What is the efficacy of TNF-inhibitors after long term use? What adverse events are reported in these studies? What is the risk of malignancies following long term use? What are the experiences concerning use of medication, treatment compliance and change of medication? Methods We searched Medline and Embase June 2006 by combining search terms for registries, cohort studies and databases with terms for TNF-inhibitors and rheumatoid arthritis (RA). We included publications from registries or databases on adalimumab, etanercept and infliximab for treatment of rheumatoid arthritis (RA), ankylosing spondylitis, psoriatic arthritis or juvenile idiopathic arthritis. Manufacturers were also invited to submit data. Outcomes considered were efficacy, safety and medication use. Results The search gave 290 hits, 64 references were retrieved and assessed in full text, and 23 publications finally included. These studies covered patients with RA, in addition we found one study on juvenile idiopathic arthritis. We did not identify relevant studies on ankylosing spondylitis or psoriatic arthritis. The summary of the results from the studies are as follows:1. Effectiveness: We included seven studies from registries and databases reporting clinical effects of TNF-inhibitors. In summary these studies showed that TNFinhibitors were effective also when used in clinical practice. The effect however appeared to be lower compared with RCTs. This could be explained by a more heterogeneous patient population. In addition patients in clinical practice often continued with existing medication, opposed to most clinical trials where patients often discontinued existing medications before enrolling. Although we aimed to 9 assess long-term effectiveness, few patients have been followed beyond 2-3 years of treatment. One study assessed patients with JIA, in this study treatment with TNF-inhibitor (etanercept) led to a significant reduction of the disease activity in most of the patients.2. Combination therapy: Two randomised controlled trials and data from registries evaluated the combination of TNF and MTX treatment. Treatment with TNFinhibitors and methotrexate (MTX) appeared more effective than treatment with TNFinhibitor alone in reducing the disease activity in patients with RA. 3. Cancer: We included six publications that assessed cancer risk following TNFtreatment. A general comments to these studies is that patients have not been followed sufficiently long to allow for conclusions regarding cancer risk. Four studies analysed risk of lymphoma or leukaemia, with inconsistent results. Two studies analysed risk of solid cancer, with inconcistent results. Experiences from transplantation patients shows that cancer usually develops 10-15 years after immunosuppressive medication. Hence, these studies does not give any further information about the risk of developing cancer following treatment with TNF-inhibitors than reported in the randomized controlled trials.4. Infections: Treatment with TNF-inhibitors were associated with increase the risk of infections. In particular, the risk of reactivation of latent tuberculosis. However, routine screening and treatment of tuberculosis prior to TNF-treatment have reduced this risk considerably.5. Compliance: Continuation of treatment with TNF-inhibitors (etanercept og infliximab) after one year was between 62-73 %. This number is lower than compared with RCTs . The reasons for ceasing TNF-treatment were in most cases adverse events or lack of effect. However, it was found that the compliance to TNF-inhibitors was higher then for traditional DMARDs. Conclusion: In conclusion, results from clinical trials and registries show that TNF-inhibitors are effective, also when used on a broader patient population outside the setting of clinical trials. Treatment with TNF-inhibitors is associated with increased risk of infections, in particular tuberculosis. Included studies does not allow for conclusion regarding risk of cancer. Thus, the issue of long term safety is at time being incomplete, with a follow up of 2-3 years in most studies. A national registry for treatment with TNF-inhibitors (and other biologics) in Norway would be a very helpful tool to identify the effect and adverse events after long treatment with TNF-inhibitors.

Tumor necrosis factor --- Rheumatoid arthritis --- Inhibitors. --- Treatment.

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Background Patients with the inflammatory bowel diseases ulcerative colitis and Crohn's disease need lifelong treatment and care. Effect of traditional treatments is varied and may cause serious adverse events. Biological drugs aimed at blocking specific molecular steps in the inflammatory process have been developed. Tumor necrosis factor (TNF)α is a proinflammatory cytokine with a role in the inflammatory process associated with inflammatory bowel disease. Hence, a drug blocking this cytokine might be useful for patients with ulcerative colitis and Crohn's disease. This report includes knowledge of the TNFα-inhibitors infliximab (Remicade(r)), adalimumab (Humira(r)), etanercept (Enbrel(r)) and certolizumab pegol (Cimzia(r)). Method We systematically reviewed and critically appraised available documentation on effect and safety of TNFα-inhibitors. In addition, we have reviewed health economic studies. We identified documentation by a systematic search in Cochrane Library, Medline, Embase, PubMed and NHS Economics Evaluation Database. Our evaluation on efficacy and safety was based on systematic reviews. However, to make sure that all available data was included, we searched for randomized controlled trials published afer the literature seach in the systematic reviews was performed. Results In patients with ulcerative colitis, infliximab was more effective than placebo in achieving improvement of the disease. Data on response and remission are available up to 54 weeks. Infliximab gives a higer proportion of patients with endoscopic remission compared to placebo. None of the other TNFα-inhibitors were tested in patients with ulcerative colitis. In patients with Crohn's disease, infliximab, adalimumab and certolizumab were more effective than placebo in achieving response after induction treatment (1-3 administrations of drug or placebo). Based on patients responding to induction treatment, it has been shown that maintenance treatment with infliximab, adalimumab and certolizumab is more effective than placebo in maintaining the initial response. Infliximab has been showed to be more effective than placebo in achieving fistula closure. Data on etanercerpt in treatment of Crohn's disease is limited. There is no basis to claim that etanercerpt has effect in treatment of Crohn's disease. We identified four economic evaluations in a systematic literature search. All studies were from countries outside Norway and dealt with infliximab treatment of patients with Crohn's disease. Conclusion Infliximab is effective in treatment of ulcerative colitis and Crohn's disease. Adalimumab and certolizumab have documented effect in treatment of Crohn's disease, while studies on patients with ulcerative colitis are lacking. There is too limited data available to conclude regarding safety of long-term treatment with TNFα-inhibitors for both ulcerative colitis and Crohn's disease. Based on results from countries outside Norway, infliximab does not seem to be cost-effective as continuous treatment for patients with Crohn's disease. There might be an exception in the case of patients exhibiting good and long-lasting response. No relevant economic studies were found for ulcerative colitis or for the other TNFα-inhibitors.

Tumor necrosis factor. --- Inflammatory bowel diseases --- Anti-inflammatory agents. --- Treatment.

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It has been established that TNF receptor associated factors (TRAFs) are critical signaling mediators for not only the TNF receptor superfamily, but also the interleukin-1 receptor/Toll-like receptor superfamily and the T-cell receptors. They play important roles in mammalian biology including embryonic development, innate and adaptive immune regulation and maintenance of cellular homeostasis. Agents that manipulate the signaling of these receptors are being used or showing promise towards the treatment and prevention of many human diseases such as rheumatoid arthritis, coronary heart disease, transplantation rejection, insulin resistance, multiple organ failure and cancer. TNF Receptor Associated Factors is the only literature that is entirely devoted to TRAFs. Almost every aspect of TRAF signaling is covered, including the different TRAF family members, their distinct biological functions, the TRAF structures, their modes of receptor recognition, the signaling mechanisms, and the roles of TRAFs in normal cellular functions and in viral infection. TNF Receptor Associated Factors is intended for a wide audience, including researchers in the field of TRAF signaling and students and postdoctoral fellows learning cell biology and cell signal transduction. This exciting new volume is up to date on the most recent advances in TRAF signal transduction.

Tumor necrosis factor --- Cellular signal transduction. --- Receptors. --- Cellular information transduction --- Information transduction, Cellular --- Signal transduction, Cellular --- Bioenergetics --- Cellular control mechanisms --- Information theory in biology --- Cachectin receptors --- Receptors, Tumor necrosis factor --- TNF receptors --- TNFRs (Tumor necrosis factor receptors) --- Tumor necrosis factor receptors --- Cell receptors --- Death receptors --- Cytology. --- Developmental biology. --- Computer security. --- Cell Biology. --- Developmental Biology. --- Systems and Data Security. --- Computer privacy --- Computer system security --- Computer systems --- Computers --- Cyber security --- Cybersecurity --- Electronic digital computers --- Protection of computer systems --- Security of computer systems --- Data protection --- Security systems --- Hacking --- Development (Biology) --- Biology --- Growth --- Ontogeny --- Cell biology --- Cellular biology --- Cells --- Cytologists --- Protection --- Security measures --- Cell biology.

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Death receptors play a central role in directing apoptosis in mammalian cells. This process of active cell death is important for a number of biological processes, e.g. for the regulation of the immune system. Death receptors are cell surface receptors that transmit apoptotic signals initiated by corresponding death ligands. Many complex signaling pathways are activated and apoptosis is the final result of a complex biochemical cascade of events. Besides their role in the induction of cell death, evidence now exists that death receptors are able to activate several non-apoptotic signaling pathways which, depending on cellular context, may lead to apoptosis resistance, secretion of pro-inflammatory proteins, proliferation and invasive growth of cancer cells. This book looks at the molecular basis of death receptor signaling and the role of death receptors in cancer development.

Cancer -- Treatment. --- Carcinogenesis -- Molecular aspects. --- Death receptors -- Molecular aspects. --- Neoplasms -- Etiology. --- Neoplasms -- Therapy. --- Receptors, Death Domain -- Physiology. --- Receptors, Tumor Necrosis Factor -- Physiology. --- Tumor necrosis factor -- Physiological effect. --- Tumor necrosis factor -- Receptors -- Physiological effect. --- Cell receptors --- Carcinogenesis --- Cancer --- Tumor necrosis factor --- Diseases --- Receptors, Cytokine --- Receptors, Cell Surface --- Biological Science Disciplines --- Receptors, Death Domain --- Physiology --- Receptors, Tumor Necrosis Factor --- Neoplasms --- Membrane Proteins --- Receptors, Immunologic --- Natural Science Disciplines --- Disciplines and Occupations --- Proteins --- Amino Acids, Peptides, and Proteins --- Chemicals and Drugs --- Medicine --- Biology --- Cytology --- Oncology --- Microbiology & Immunology --- Health & Biological Sciences --- Physiological effect --- Molecular aspects --- Treatment --- Receptors --- Ligands (Biochemistry) --- Cancer. --- Cell death. --- Cell receptors. --- Apoptosis. --- Cellular signal transduction. --- Cellular information transduction --- Information transduction, Cellular --- Signal transduction, Cellular --- Cell membrane receptors --- Cell surface receptors --- Receptors, Cell --- Cell degeneration --- Cancers --- Carcinoma --- Malignancy (Cancer) --- Malignant tumors --- Medicine. --- Cancer research. --- Molecular biology. --- Oncology. --- Biochemistry. --- Cell biology. --- Biomedicine. --- Cancer Research. --- Cell Biology. --- Molecular Medicine. --- Biochemistry, general. --- Cell death --- Binding sites (Biochemistry) --- Cell membranes --- Cells --- Death (Biology) --- Tumors --- Bioenergetics --- Cellular control mechanisms --- Information theory in biology --- Biochemistry

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Over the last decade, the advent of biologic agents has greatly revolutionized therapeutic medicine in the management of chronic inflammatory diseases, such as rheumatoid arthritis, Crohn’s disease, and psoriasis. Elucidation of the complex web of cytokine network and the roles of these cytokines in the pathogenesis of inflammatory disorders provided one of the key catalysts for the advancement of targeted biologic therapy in autoimmune and inflammatory diseases. TNF-alpha is known to play a crucial role in the pathogenesis of many chronic inflammatory diseases. Elevated levels of TNF-alpha have been demonstrated in Crohn’s disease, psoriasis, psoriatic arthritis, and rheumatoid arthritis, suggesting a role for TNF-alpha in their pathogenesis. Although TNF-alpha plays a critical role in the activation of innate and acquired immune responses, the persistence of the immune response and inappropriate production of TNF-alpha can produce pathological changes resulting from chronic inflammation and tissue damage. This volume provides a comprehensive overview of the development, pharmacology, efficacy, and safety of the currently available TNF-alpha inhibitors – etanercept, infliximab, and adalimumab. The most recent preclinical and clinical data is presented on this topic, which should be of interest to the preclinical researcher, the clinician, and the patient who wants to learn more about these therapies.

Tumor necrosis factor --- Anti-inflammatory agents. --- Inhibitors. --- Anti-inflammatories --- Antiinflammatory agents --- Antiphlogistics --- Antipyretics --- Inflammation --- Cachectin --- Lymphotoxin --- TNF (Immunology) --- Cytokines --- Glycoproteins --- Growth factors --- Macrophages --- Immunology. --- Rheumatology. --- Dermatology. --- Toxicology. --- Gastroenterology. --- Pharmacology/Toxicology. --- Internal medicine --- Digestive organs --- Chemicals --- Medicine --- Pharmacology --- Poisoning --- Poisons --- Skin --- Connective tissues --- Joints --- Immunobiology --- Life sciences --- Serology --- Diseases --- Toxicology --- Pharmacology. --- Gastroenterology . --- Drug effects --- Medical pharmacology --- Medical sciences --- Chemotherapy --- Drugs --- Pharmacy --- Physiological effect