Tumor necrosis factor, monoclonal antibody rheumatoid arthritis

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. 

Paleolog, E. W., Hunt, M., Elliott, M., Feldmann, M., Maini, R. N., and Woody, J. (1996). Deactivation of vascular endothelium by monoclonal anti tumor necrosis factor a antibody in rheumatoid arthritis. Arthritis Rheum. 39, 1082-1091. 

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). 

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. 

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. 

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. 

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. 

Tak, P. P., Taylor, P. C., Breedveld, F. C., Smeets, T.J., Daha, M. R., Kluin, P. M. etal. (1996). Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor a monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum. 39, 1077-1081. 

Charles PJ, Smeenk RJ, De Jong J, Feldmaim M, Maini RN. Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha findings in open-label and randomized placebo-controlled trials. Arthritis Rheum 2000 43(11) 2383-90. 

Elliot, M.J., Maini, R.N., Feldman, M. etal. (1993). Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor a. Arthritis Rheum. 36, 1681-1690. 

Weinblatt ME, Keystone EC, Furst DE, et al. AdaUmumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for flie treatment of rheumatoid arfluitis in patients taking concomitant mefliotrexate The ARMADA trial [erratum appears in Arfluitis Rheum 2003 48 855]. Arthritis Rheum 2003 48 35 5. 

Answer A. Etanercept binds to tumor necrosis factor (TNF), resulting in the inactivation of this cytokine, which plays a major role in a number of inflammatory disorders including Crohn disease and rheumatoid arthritis. In the synovium, TNF recruits inflammatory cells and leads to neoangiogenesis and joint destruction. Infliximab, a monoclonal antibody, also inactivates TNF. 

Answer C. Interferon-gamma lb (recombinant form) is used in chronic granulomatous disease to decrease infection liability because it increases the formation of tumor necrosis factor (TNF). Infliximab is a monoclonal antibody to TNF used in rheumatoid arthritis, and its use may lead to an increased infection rate. Aldesleukin is a recombinant form of IL-2. 

Infliximab (Remicade) is a chimeric monoclonal antibody against tumor necrosis factor (TNF)-alpha that has shown efficacy in Crohn s disease and rheumatoid arthritis with a disease-modifying activity and rapid onset of action [237]. It is administered intravenously, generally in a schedule with initial infusions at 0, 2, and 6 weeks, followed by administration once every 8 weeks. Infliximab is effective in the treatment of patients with moderately to severely active Crohn s disease with an inadequate response to other treatment options or those with fistulizing disease. In combination with methotrexate, infliximab reduced signs and symptoms and... 

Weisman M FI, Moreland L W, Furst D E, et al. (2003). Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti-tumor necrosis factor-alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant methotrexate A pilot study. Clin. Therapeut. 25 1700-1721. 

---