Abstract
Tumour necrosis factor (TNF) plays a central part in the pathophysiology of rheumatoid arthritis (RA). TNF initiates signal transduction by interacting with surface bound TNF receptors. Soluble tumour necrosis factor receptors (sTNFRs) act as natural inhibitors of TNF activity. Etanercept, recombinant p75 sTNFR:Fc fusion protein, has received approval from the US Food and Drug Administration for patients with RA and juvenile RA (JRA) who have failed treatment with at least one other drug. Etanercept has demonstrated excellent safety and efficacy in large scale, randomised, double blind, placebo controlled trials of patients with RA and JRA who are refractory to other disease modifying anti-rheumatic drugs. The therapeutic effects mediated by etanercept are rapid and sustained. Combining etanercept with methotrexate was found to be safe and more effective than treatment with methotrexate alone in the treatment of RA. These clinical findings demonstrate that etanercept can result in symptomatic improvement in patients with RA and JRA. Etanercept is an important new addition to the treatment of these diseases.
Full Text
The Full Text of this article is available as a PDF (135.0 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Barrera P., Boerbooms A. M., Janssen E. M., Sauerwein R. W., Gallati H., Mulder J., de Boo T., Demacker P. N., van de Putte L. B., van der Meer J. W. Circulating soluble tumor necrosis factor receptors, interleukin-2 receptors, tumor necrosis factor alpha, and interleukin-6 levels in rheumatoid arthritis. Longitudinal evaluation during methotrexate and azathioprine therapy. Arthritis Rheum. 1993 Aug;36(8):1070–1079. doi: 10.1002/art.1780360807. [DOI] [PubMed] [Google Scholar]
- Bazzoni F., Beutler B. The tumor necrosis factor ligand and receptor families. N Engl J Med. 1996 Jun 27;334(26):1717–1725. doi: 10.1056/NEJM199606273342607. [DOI] [PubMed] [Google Scholar]
- Bertolini D. R., Nedwin G. E., Bringman T. S., Smith D. D., Mundy G. R. Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature. 1986 Feb 6;319(6053):516–518. doi: 10.1038/319516a0. [DOI] [PubMed] [Google Scholar]
- Brennan F. M., Chantry D., Jackson A., Maini R., Feldmann M. Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet. 1989 Jul 29;2(8657):244–247. doi: 10.1016/s0140-6736(89)90430-3. [DOI] [PubMed] [Google Scholar]
- Brennan F. M., Gibbons D. L., Cope A. P., Katsikis P., Maini R. N., Feldmann M. TNF inhibitors are produced spontaneously by rheumatoid and osteoarthritic synovial joint cell cultures: evidence of feedback control of TNF action. Scand J Immunol. 1995 Jul;42(1):158–165. doi: 10.1111/j.1365-3083.1995.tb03639.x. [DOI] [PubMed] [Google Scholar]
- Brockhaus M., Schoenfeld H. J., Schlaeger E. J., Hunziker W., Lesslauer W., Loetscher H. Identification of two types of tumor necrosis factor receptors on human cell lines by monoclonal antibodies. Proc Natl Acad Sci U S A. 1990 Apr;87(8):3127–3131. doi: 10.1073/pnas.87.8.3127. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Butler D. M., Maini R. N., Feldmann M., Brennan F. M. Modulation of proinflammatory cytokine release in rheumatoid synovial membrane cell cultures. Comparison of monoclonal anti TNF-alpha antibody with the interleukin-1 receptor antagonist. Eur Cytokine Netw. 1995 Jul-Dec;6(4):225–230. [PubMed] [Google Scholar]
- Chu C. Q., Field M., Feldmann M., Maini R. N. Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis. Arthritis Rheum. 1991 Sep;34(9):1125–1132. doi: 10.1002/art.1780340908. [DOI] [PubMed] [Google Scholar]
- Cope A. P., Aderka D., Doherty M., Engelmann H., Gibbons D., Jones A. C., Brennan F. M., Maini R. N., Wallach D., Feldmann M. Increased levels of soluble tumor necrosis factor receptors in the sera and synovial fluid of patients with rheumatic diseases. Arthritis Rheum. 1992 Oct;35(10):1160–1169. doi: 10.1002/art.1780351008. [DOI] [PubMed] [Google Scholar]
- Dayer J. M., Beutler B., Cerami A. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med. 1985 Dec 1;162(6):2163–2168. doi: 10.1084/jem.162.6.2163. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fisher C. J., Jr, Agosti J. M., Opal S. M., Lowry S. F., Balk R. A., Sadoff J. C., Abraham E., Schein R. M., Benjamin E. Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med. 1996 Jun 27;334(26):1697–1702. doi: 10.1056/NEJM199606273342603. [DOI] [PubMed] [Google Scholar]
- Hopkins S. J., Humphreys M., Jayson M. I. Cytokines in synovial fluid. I. The presence of biologically active and immunoreactive IL-1. Clin Exp Immunol. 1988 Jun;72(3):422–427. [PMC free article] [PubMed] [Google Scholar]
- Husby G., Williams R. C., Jr Synovial localization of tumor necrosis factor in patients with rheumatoid arthritis. J Autoimmun. 1988 Aug;1(4):363–371. doi: 10.1016/0896-8411(88)90006-6. [DOI] [PubMed] [Google Scholar]
- Jones E. Y., Stuart D. I., Walker N. P. Structure of tumour necrosis factor. Nature. 1989 Mar 16;338(6212):225–228. doi: 10.1038/338225a0. [DOI] [PubMed] [Google Scholar]
- Keffer J., Probert L., Cazlaris H., Georgopoulos S., Kaslaris E., Kioussis D., Kollias G. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 1991 Dec;10(13):4025–4031. doi: 10.1002/j.1460-2075.1991.tb04978.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lader C. S., Flanagan A. M. Prostaglandin E2, interleukin 1alpha, and tumor necrosis factor-alpha increase human osteoclast formation and bone resorption in vitro. Endocrinology. 1998 Jul;139(7):3157–3164. doi: 10.1210/endo.139.7.6085. [DOI] [PubMed] [Google Scholar]
- Mohler K. M., Torrance D. S., Smith C. A., Goodwin R. G., Stremler K. E., Fung V. P., Madani H., Widmer M. B. Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J Immunol. 1993 Aug 1;151(3):1548–1561. [PubMed] [Google Scholar]
- Moreland L. W., Baumgartner S. W., Schiff M. H., Tindall E. A., Fleischmann R. M., Weaver A. L., Ettlinger R. E., Cohen S., Koopman W. J., Mohler K. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med. 1997 Jul 17;337(3):141–147. doi: 10.1056/NEJM199707173370301. [DOI] [PubMed] [Google Scholar]
- Moreland L. W., Schiff M. H., Baumgartner S. W., Tindall E. A., Fleischmann R. M., Bulpitt K. J., Weaver A. L., Keystone E. C., Furst D. E., Mease P. J. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med. 1999 Mar 16;130(6):478–486. doi: 10.7326/0003-4819-130-6-199903160-00004. [DOI] [PubMed] [Google Scholar]
- Nawroth P. P., Bank I., Handley D., Cassimeris J., Chess L., Stern D. Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1. J Exp Med. 1986 Jun 1;163(6):1363–1375. doi: 10.1084/jem.163.6.1363. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Neidel J., Schulze M., Lindschau J. Association between degree of bone-erosion and synovial fluid-levels of tumor necrosis factor alpha in the knee-joints of patients with rheumatoid arthritis. Inflamm Res. 1995 May;44(5):217–221. doi: 10.1007/BF01782262. [DOI] [PubMed] [Google Scholar]
- Okamoto H., Yamamura M., Morita Y., Harada S., Makino H., Ota Z. The synovial expression and serum levels of interleukin-6, interleukin-11, leukemia inhibitory factor, and oncostatin M in rheumatoid arthritis. Arthritis Rheum. 1997 Jun;40(6):1096–1105. doi: 10.1002/art.1780400614. [DOI] [PubMed] [Google Scholar]
- Pennica D., Nedwin G. E., Hayflick J. S., Seeburg P. H., Derynck R., Palladino M. A., Kohr W. J., Aggarwal B. B., Goeddel D. V. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984 Dec 20;312(5996):724–729. doi: 10.1038/312724a0. [DOI] [PubMed] [Google Scholar]
- Roux-Lombard P., Punzi L., Hasler F., Bas S., Todesco S., Gallati H., Guerne P. A., Dayer J. M. Soluble tumor necrosis factor receptors in human inflammatory synovial fluids. Arthritis Rheum. 1993 Apr;36(4):485–489. doi: 10.1002/art.1780360408. [DOI] [PubMed] [Google Scholar]
- Saklatvala J. Tumour necrosis factor alpha stimulates resorption and inhibits synthesis of proteoglycan in cartilage. Nature. 1986 Aug 7;322(6079):547–549. doi: 10.1038/322547a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Saxne T., Palladino M. A., Jr, Heinegård D., Talal N., Wollheim F. A. Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum. 1988 Aug;31(8):1041–1045. doi: 10.1002/art.1780310816. [DOI] [PubMed] [Google Scholar]
- Tetta C., Camussi G., Modena V., Di Vittorio C., Baglioni C. Tumour necrosis factor in serum and synovial fluid of patients with active and severe rheumatoid arthritis. Ann Rheum Dis. 1990 Sep;49(9):665–667. doi: 10.1136/ard.49.9.665. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tucci M. A., Baker R., Mohamed A., Tsao A. K., Hughes J. Synovial tissues collected from rheumatoid patients undergoing total joint arthroplasty express markers for acute inflammation. Biomed Sci Instrum. 1997;34:169–174. [PubMed] [Google Scholar]
- Van Zee K. J., Kohno T., Fischer E., Rock C. S., Moldawer L. L., Lowry S. F. Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4845–4849. doi: 10.1073/pnas.89.11.4845. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weinblatt M. E., Kremer J. M., Bankhurst A. D., Bulpitt K. J., Fleischmann R. M., Fox R. I., Jackson C. G., Lange M., Burge D. J. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999 Jan 28;340(4):253–259. doi: 10.1056/NEJM199901283400401. [DOI] [PubMed] [Google Scholar]