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Lymphotoxin --- Tumor Necrosis Factor --- Tumor necrosis factor --- Congresses. --- Congresses. --- Congresses.

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Psoriasis --- Tumor Necrosis Factor-alpha

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Background and Aims: We have recently identified six adipokines that are oversecreted by omental adipose tissue in obesity: 3 chemokines [Growth-Related Oncogen factor (GRO), Regulated upon Activation Normal T cells Expressed and Secreted (RANTES), Macrophage Inflammatory Protein-1ß (MIP-1ß)], 1 interleukin (IL-7), 1 tissue inhibitor of metalloproteinases (TIMP-1) and 1 growth factor (thrombopoietin, TPO). Enhanced expression of these adipokines in adipocytes did correlate with several features of the metabolic syndrome. The aim of the present study was to examine whether the abnormal hormonal milieu and/or the chronic inflammation state that prevail in obesity could contribute to such dysregulation of adipokine production. We thus examined the effects of some hormones (insulin, glucocorticoids and catecholamines) and the proinflammatory cytokine, TNFα on these adipokines in cultured human omental adipocytes. Because of the potent changes induced by TNF, we more particularly focused on its effects. Results: Treatment of omental adipocytes with hormones induced only a modest increase in some adipokines. By contrast, the addition of TNFα to the medium induced strong changes in the expression of all the adipokines. These changes occurred in a dose-dependent fashion and a ~600 fold increase was observed for some of them (i.e. RANTES). Because TNFα appears to be a main regulator, we characterize in some detail its effects on mature adipocytes from lean and obese subjects. We first confirmed that TNF secretion was higher in stromal-vascular cells (SVC; that contain macrophages) than in adipocytes and enhanced in obesity. We next cultured mature adipocytes in the presence of medium previously conditioned by SVC and obtained a pattern of adipokine expression similar to that induced by TNF. Obese adipocytes exhibited much stronger changes in adipokines in response to TNF than lean adipocytes. Eventually, these changes were fully prevented by TNF-neutralizing antibodies. Conclusions: TNF is a key contributor to adipokine dysregulation in omental adipocytes. In obesity, this proinflammatory cytokine, which is mainly oversecreted by SVC acts on enlarged adipocytes, whiwh are hyper-responsive to that inflammatory triggering signal. This ultimately leads to marked adipokine dysregulation, and further worsening of the inflammatory state and of the metabolic syndrome. Précédemment au laboratoire, Maury et al. ont identifié six adipokines qui sont surexprimées dans le TA omental chez les sujets obèses : 3 chémokines [Growth-Related Oncogen factor (GRO), Regulated upon Activation Normal T cells Expressed and Secreted (RANTES), Macrophage Inflammatory Protein-1β (MIP-1β)], une interleukine (IL-7), une protéase de la matrice extracellulaire [Tissue Inhibitor of Metalloproteinases (TIMP-1)] et un facteur hématopoïétique [thrombopoiétine (TPO)]. L’augmentation de l’expression de ces adipokines dans les adipocytes est corrélée avec plusieurs anomalies du syndrome métabolique. Le but de notre étude était d’examiner si les perturbations hormonales et/ou l’état inflammatoire chronique présents dans l’obésité avaient pu contribuer à la dérégulation de la production d’adipokines. Nous avons donc examiné les effets de certaines hormones (insuline, glucocorticoïdes et catécholamines) et d’une cytokine pro-inflammatoire, le TNF-α, sur nos adipokines d’intérêt dans des cultures d’adipocytes omentaux humains. Le TNF-α ayant induit des modifications très importantes, nous nous sommes donc davantage focalisés sur ses effets. Le traitement des adipocytes par les hormones a induit une augmentation modeste uniquement de certaines adipokines. Par contre, le TNF-α a produit des modifications marquées de l’expression de toutes les adipokines étudiées. Ces modifications se sont produites de manière dose-dépendante et une augmentation jusqu’à ~ 600 fois a été observée, par exemple pour RANTES. Nous avons donc caractérisé en détail le rôle du TNF-α sur des adipocytes matures de sujets minces et obèses. Nous avons tout d’abord montré que la sécrétion du TNF-α était plus élevée dans les SVC que dans les adipocytes et qu’elle était augmentée dans l’obésité. Nous avons ensuite cultivé des adipocytes matures en présence de milieux préalablement conditionnés par des SVC et obtenu un profil d’expression des adipokines similaire à celui induit par le TNF-α. Les adipocytes de sujets obèses présentaient une réponse accrue à ces milieux. Toutes ces modifications ont été entièrement prévenues par des anticorps neutralisant l’activité du TNF-α. En conclusion, le TNF-α joue un rôle-clef dans la dérégulation des adipokines dans les adipocytes omentaux chez le sujet obèse. Dans l’obésité, cette cytokine pro-inflammatoire, principalement sécrétée en excès par les SVC, agit sur les adipocytes hypertrophiés qui y répondent de manière excessive. Cette double perturbation (excès de production et d’action du TNF-α) conduit à une dérégulation de toutes les adipokines, à une aggravation de l’état inflammatoire et du SM.

Tumor Necrosis Factor-alpha --- Adipokines --- Obesity

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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: Treatment with tumour necrosis factor alpha (TNF-α, or simply TNF) inhibitors is considered to be an alternative to the use of traditional disease-modifying anti-rheumatic drugs (DMARDs) in patients with different rheumatic diseases, i.e. rheumatoid arthritis (RA). There are three TNF-inhibitor drugs currently available on the market (brand names in brackets): adalimumab (Humira), etanercept (Enbrel) and infliximab (Remicade). The Norwegian Knowledge Centre for the Health Services has previously summarised the evidence on the drugs' efficacy and safety (in randomised clinical trials and observational studies) while the present report considers cost-effectiveness of the drugs for rheumatoid arthritis. After considerable growth over several years, the aggregate sales of the three drugs amounted to 860 million NOK in 2006. RA is a serious disease, not least from an economic perspective. No cost-of-illness studies have been found for Norway, but studies from Sweden suggest that the costs of the disease are substantial with a large proportion related to loss of work capacity. Methods: We undertook a review of economic evaluations of TNF-inhibitors against RA, and considered an analysis of health-related quality of life data for patients on TNF-inhibitors and DMARD users from a Norwegian observational study. Results: A total of twelve studies from six countries were included in the literature review. The studies were based on health economic models, which were diverse in their characteristics, and therefore the estimates of cost-effectiveness varied significantly. Conclusions: In our review of economic evaluations of TNF-inhibitors, we found significant variation in the type and features of the models used, which led to a wide range of estimates. The potential for direct comparisons of results between the studies, and thus transferability of results into Norwegian setting, is limited. With this in mind, our main conclusions are as follows:1. First line therapy: TNF inhibitors seem not to be cost-effective as first line therapy, based on the one study in which this was considered.2. Second line therapy: We cannot draw any conclusions, since no relevant studies were found.3. Third line therapy: TNF-inhibitors may be cost-effective, particularly in the case of patients in early disease. The drugs are also likely to be more cost-effective for patients who experience a good rather than a moderate response.4. Indirect costs: Prevention of productivity loss may account for considerable savings, but has only been accounted for in a few of the economic evaluations.

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