Rheumatoid arthritis, tumor necrosis factor

HBV, hepatitis B HCV, hepatitis C IAP, inhibitor of apoptosis protein DBM, IAP binding motifs INCA, inhibitory CARD NASH, non-alcoholic steatohepatitis PCD, programmed cell death PCI, pan-caspase inhibitor OA, osteoarthritis RA, rheumatoid arthritis Smac, second mitochondria-derived activator of caspases TRAIL, tumor necrosis factor-related apoptosis-inducing ligand. 

Human tumor necrosis factor (TNF) (Fig. 1) is a hormone-like proinflammatory peptide belonging to the group of cytokines. It is mainly produced by cells of the immune system in response to infection, inflammation, or cell damage. Disregulated TNF is an important factor in many pathological situations, like sqDsis, rheumatoid arthritis, inflammatory bowel disease (Crohn s disease), and Cachexia. The cytotoxic activity of TNF is of interest in development of new antitumoral strategies. 

Feldmann, M., Elliott, M.J., Woody, J.N., Maini, R.N. 1997. Anti-tumor necrosis factor alpha therapy of rheumatoid arthritis. Advances in Immunology 64, 283-350. 

Alvaro-Gracia, J. M., Zvaifler, N. J., Brown, C. B., Kaushansky, K., Firestein, G. S. (1991). Cytokines in chronic inflammatory arthritis VI. Analysis of the synovial cells involved in granulocyte-macrophage colony-stimulating factor production and gene expression in rheumatoid arthritis and its regulation by IL-1 and tumor necrosis factor-a J. Immunol 146,3365-71. 

Tumor Necrosis Factor There are two types of tumor necrosis factor TNF-a and TNF- 8. Of the two, TNF-a has been studied in more detail. TNF-a is a 157 amino acid polypeptide. It is a mediator of immune regulation, including the activation of macrophages and induction of the proliferation of T cells. Another TNF-a function is its cytotoxic effects on a number of tumor cells. Recent research, however, concentrates on its property in the stimulation of inflammation, particularly in the case of rheumatoid arthritis. Clinical trials are being conducted with drugs to block TNF-a with anti-TNF-a monoclonal antibodies. These antibodies target the excessive levels of TNF-a in the synovial fluid of joints and provide relief to sufferers of rheumatoid arthritis (Exhibit 4.10). 

Table 14.4 Pharmacogenetics of the tumor necrosis factor (TNF) antagonists in rheumatoid arthritis (RA)...

Maini, R. N., Breedveld, E. C., Kalden, J. R., et al. (1998) Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis and Rheumatism. 41, 1552-1563. 

Keystone, E. C., Kavanaugh, A. E., Sharp, J. T., et al. (2004) Radiographic, cUnical, and functional outcomes of treatment with adaUmumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy a randomized, placebo-controUed, 52-week trial. Arthritis and Rheumatism. 50, 1400-1411. 

Mugnier, B., Balandraud, N., Darque, A., Roudier, C., Roudier, J., and Reviron, D. (2003) Polymorphism at position -308 of the tumor necrosis factor alpha gene influences outcome of infliximab therapy in rheumatoid arthritis. Arthritis and Rheumatism. 48, 1849-1852. 

Fabris, M., Tolusso, B., Di Poi, E., Assaloni, R., Sinigaglia, L., and Ferraccioli, G. (2002) Tumor necrosis factor-alpha receptor II polymorphism in patients from southern Europe with mild-moderate and severe rheumatoid arthritis. Journal of Rheumatology. 29, 1847-1850. 

Mulcahy, B., Waldron-Lynch, F., McDermott, M. F., et al. (1996) Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis. American Journal of Human Genetics. 59, 676-683. 

Ranganathan, P. (2005) Pharmacogenomics of tumor necrosis factor antagonists in rheumatoid arthritis. Pharmacogenomics. 2, 279-282. 

For rheumatoid arthritis, the pharmacogenomics of three major diseasemodifying antirhenmatic drags (methotrexate, azathioprine, and sulfasalazine) and one class of biologic antirhenmatic drags (the tumor necrosis factor antagonists) are discnssed in detail. 

Tumor necrosis factor-a (TNF-a) is a critical mediator of inflammation in autoimmune diseases like Crohn s disease and rheumatoid arthritis. Infliximab binds TNF-a and prevents its binding to the TNF receptor for treatment of these diseases. 

Tumor necrosis factor (TNF)—One of the cell-damaging proteins involved in inflammation, named because it appeared to kill cancer cells in the laboratory. Drugs for some autoimmune diseases like rheumatoid arthritis and Crohn s disease are designed to target TNF. 

Feldmann, M. et al. (1997). Anti-tumor necrosis factor-a therapy of rheumatoid arthritis. Adv. Immunol. 64, 283-350. Hohlfeld, R. (1997). Biotechnological agents for the immunotherapy of multiple sclerosis — principles, problems and... 

Etanercept is a recombinant human soluble tumor necrosis factor-alpha (TNFo ) receptor fusion protein that binds to TNFo and decreases its role in disorders involving excess inflammation. It is approved for subcutaneous use in the treatment of patients with moderate to severe active rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing arthritis and plaque psoriasis. To the adverse reactions mentioned for infliximab, rare reports of congestive heart failure should be added. 

Mecfianism of Action A monoclonal antibody that binds specifically to tumor necrosis factor (TNF) alpha, blocking its interaction with cell surface TNF receptors, Tfier-apeutic Effect Reduces inflammation, tenderness, and swelling of joints slows or prevents progressive destruction of joints in rheumatoid arthritis. 

Mechanism of Action Aprotein that binds to tumor necrosis factor (TNF), blocking its interaction with cell surface receptors. Elevated levels of TNF, which is involved in inflammatory and immune responses, are found in the synovial fluid of rheumatoid arthritis patients. Therapeutic Effect Relieves symptoms of rheumatoid arthritis. Pharmacokinetics Well absorbed after subcutaneous administration. Half-life 115 hr. 

The same principle was later applied by scientists at Immunex to enhance the pharmaceutical properties of the tumor necrosis factor receptor (TNFr), which, like CD4, is rapidly cleared from blood. The hybrid TNFr-Fc molecule (-150 kDa), which is now known as Enbrel, is used to reduce the inflammatory responses of rheumatoid arthritis [33,34]. The hybrid TNFr-Fc bas extended the plasma half-life of TNFr from several minutes to 190 hours. 

B. Indications and use Kineret is indicated for the reduction in signs and symptoms of moderately to severely active rheumatoid arthritis in patients 18 years of age or older who have failed one or more disease-modifying antirheumatic drugs (DMARDs). Kineret can be used alone or in combination with DMARDs other than tumor necrosis factor (TNF) blocking agents. 

Murray, K.M., and S.L. Dahl, Recombinant human tumor necrosis factor receptor (p75) Fc fusion protein (TNFR Fc) in rheumatoid arthritis. Ann Pharmacother, 1997. 31(11) 1335-8. 

Genovese MC et al Abatacept for rheumatoid arthritis refractory to tumor necrosis factor a inhibition. N Engl J Med 2005 353 1114. [PMID 16162882]... 

Jones RE, Moreland LW Tumor necrosis factor inhibitors for rheumatoid arthritis. Bull Rheum Dis 1999 48 14. 

Some drugs situations are frankly confusing and need to be explored in greater depth. For example, tumor necrosis factor (TNF) is produced in the body as a natural defense against the many spontaneous tumors that arise in the body and has been suggested as a treatment for cancer, which may very well be effective under some conditions. However, TNF is also believed to be involved in the pain associated with rheumatoid arthritis, and monoclonal antibodies with specific activity against TNF are now on the market. The use of TNF is therefore a complex issue and needs to be evaluated with considerable care. 

Camussi G, Lupia E (1998) The future role of anti-tumor necrosis factor (TNF) products in the treatment of rheumatoid arthritis. Drugs 55(5) 613—620... 

Maini, R., St. Clair, E. W., Breedveld, F., Furst, D., Kalden, J., Weisman, M., Smolen, J., Emery, P. 1999. Infliximab (chimeric anti-tumor necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate a randomised phase HI trial. Attract study group. Lancet 354 1932-1939. 

In addition to direct effects on genes regulating inflammation, glucocorticoids also inhibit the transcription factors that initiate synthesis of pro-inflammatory cytokines (e.g., interleukin-1, tumor necrosis factor), enzymes (e.g., COX-2, nitric oxide synthase), and receptor proteins (e.g., natural killer receptors).17,87,89 Glucocorticoids may also exert some of their effects via a membrane-bound receptor that regulates activity of macrophages, eosinophils, T lymphocytes, and several other types of cells involved in the inflammatory response.89 Consequently, glucocorticoids affect many aspects of inflammation, and their powerful anti-inflammatory effects in rheumatoid arthritis result from their ability to blunt various cellular and chemical components of the inflammatory response. 

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