Abstract
The aetiology of systemic, autoimmune, chronic inflammatory diseases — such as rheumatoid arthritis — is not known, and their pathogenesis is complex and multifactorial. However, progress in the characterization of intercellular mediators — proteins that are now known as cytokines — has led to the realization that one cytokine, tumour-necrosis factor (TNF; previously known as TNF-α), has an important role in the pathogenesis of rheumatoid arthritis. This discovery heralded a new era of targeted and highly effective therapeutics for rheumatoid arthritis and, subsequently, other chronic inflammatory diseases.
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References
Taniguchi, T., Ohno, S., Fujii-Kuriyama, Y. & Muramatsu, H. The nucleotide sequence of human fibroblast interferon cDNA. Gene 10, 11–15 (1980).
Nagata, S. et al. Synthesis in E. coli of a polypeptide with human leukocyte interferon activity. Nature 284, 316–320 (1980).
Gray, P. W. et al. Expression of human immune interferon cDNA in E. coli and monkey cells. Nature 295, 503–508 (1982).
Gray, P. W. et al. Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumor-necrosis factor activity. Nature 312, 721–724 (1984).
Pennica, D. et al. Human tumor-necrosis factor: precursor structure expression and homology to lymphotoxin. Nature 312, 724–729 (1984).
Oppenheim, J. J. & Feldmann, M. E. Cytokine Reference, Vol 1: Ligands (Academic Press, London, 2001) http://www.apnet.com/cytokinereference
Cody, J. et al. Recombinant human erythropoietin for chronic renal failure anaemia in pre-dialysis patients. Cochrane Database Sys. Rev. 4, CD003266 (2001).
Morstyn, G., Foote, M. A., Walker, T. & Molineux, G. Filgrastim (r-metHuG-CSF) in the 21st century: SD/01. Acta Haematol. 105, 151–155 (2001).
Coley, W. B. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin. Orthop. 262, 3–11 (1991).
Carswell, E. A. et al. An endotoxin-induced serum factor that causes necrosis of tumors. Proc. Natl Acad. Sci. USA 72, 3666–3670 (1975).
Aggarwal, B. B. et al. Human tumor-necrosis factor production, purification and characterization. J. Biol. Chem. 260, 2345–2354 (1985).
Beutler, B., Milsark, I. W. & Cerami, A. C. Passive immunization against cachectin/tumor-necrosis factor protects mice from lethal effect of endotoxin. Science 229, 869–871 (1985).
Lee, D. M. & Weinblatt, M. E. Rheumatoid arthritis. Lancet 358, 903–911 (2001).
Harris, E. D. Jr. Rheumatoid arthritis. Pathophysiology and implications for therapy. N. Engl. J. Med. 322, 1277–1289 (1990).
Koch, A. E. et al. Vascular endothelial growth factor. A cytokine-modulating endothelial function in rheumatoid arthritis. J. Immunol. 152, 4149–4156 (1994).
Fontana, A. et al. Interleukin-1 activity in the synovial fluid of patients with rheumatoid arthritis. Rheumatol. Int. 2, 49–53 (1982).
Di Giovine, F. S., Malawista, S. E., Nuki, G. & Duff, G. W. Interleukin-1 (IL-1) as a mediator of crystal arthritis. Stimulation of T-cell and synovial fibroblast mitogenesis by urate crystal-induced IL-1. J. Immunol. 138, 3213–3218 (1987).
Buchan, G., Barrett, K., Turner, M., Chantry, D., Maini, R. N. & Feldmann, M. Interleukin-1 and tumour-necrosis factor mRNA expression in rheumatoid arthritis: prolonged production of IL-1α. Clin. Exp. Immunol. 73, 449–455 (1988).
Chu, C. Q., Field, M., Feldmann, M. & Maini, R. N. Localization of tumor-necrosis factor-α in synovial tissues and at the cartilage–pannus junction in patients with rheumatoid arthritis. Arthritis Rheum. 34, 1125–1132 (1991).
Saxne, T., Palladino, M. A. Jr, Heinegard, D., Talal, N. & Wollheim, F. A. Detection of tumor-necrosis factor-α but not tumor-necrosis factor-β in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum. 31, 1041–1045 (1988).
Brennan, F. M., Chantry, D., Jackson, A. M., Maini, R. N. & Feldmann, M. Cytokine production in culture by cells isolated from the synovial membrane. J. Autoimmun. 2, 177–186 (1989).
Feldmann, M., Brennan, F. M. & Maini, R. N. Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 14, 397–440 (1996).
Saklatvala, J., Sarsfield, S. J. & Townsend, Y. Purification of two immunologically different leucocyte proteins that cause cartilage resorption, lymphocyte activation and fever. J. Exp. Med. 162, 1208–1215 (1985).
Brennan, F. M., Chantry, D., Jackson, A., Maini, R. & Feldmann, M. Inhibitory effect of TNF-α antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 2, 244–247 (1989).
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-TNFα antibody with the IL-1 receptor antagonist. Eur. Cytokine Netw. 6, 225–230 (1995).
Alvaro-Garcia, J. M., Zvaifler, N. J., Brown, C. B., Kaushansky, L. & Firestein, G. S. 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 TNFα. J. Immunol. 146, 3365–3371 (1991).
Haworth, C., Brennan, F. M., Chantry, D., Turner, M., Maini, R. N. & Feldmann, M. Expression of granulocyte–macrophage colony-stimulating factor in rheumatoid arthritis: regulation by tumor-necrosis factor-α. Eur. J. Immunol. 21, 2575–2579 (1991).
Holmdahl, R. et al. Type II collagen autoimmunity in animals and provocations leading to arthritis. Immunol. Rev. 118, 193–232 (1990).
Williams, R. O., Feldmann, M. & Maini, R. N. Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc. Natl Acad. Sci. USA 89, 9784–9788 (1992).
Thorbecke, G. J. et al. Involvement of endogenous tumor-necrosis factor-α and transforming growth factor-β during induction of collagen type II arthritis in mice. Proc. Natl Acad. Sci. USA 89, 7375–7379 (1992).
Piguet, P. F. et al. Evolution of collagen arthritis in mice is arrested by treatment with anti-tumour necrosis factor (TNF) antibody or a recombinant soluble TNF receptor. Immunology 77, 510–514 (1992).
Kruys, V., Kemmer, K., Shakhov, A., Jongeneel, V. & Beutler, B. Constitutive activity of the tumor-necrosis factor promoter is cancelled by the 3′ untranslated region in nonmacrophage cell lines; a transdominant factor overcomes this suppressive effect. Proc. Natl Acad. Sci. USA 89, 673–677 (1992).
Keffer, J. et al. Transgenic mice expressing human tumour-necrosis factor: a predictive genetic model of arthritis. EMBO J. 10, 4025–4031 (1991).
Peppel, K., Crawford, D. & Beutler, B. A TNF receptor–IgG heavy chain chimeric protein as a bivalent antagonist of TNF activity. J. Exp. Med. 174, 1483–1489 (1991).
Capon, D. J. et al. Designing CD4 immunoadhesions for AIDS therapy. Nature 337, 525–531 (1989).
Knight, D. M. et al. Construction and initial characterization of a mouse–human chimeric anti-TNF antibody. Mol. Immunol. 30, 1443–1453 (1993).
Feldmann, M. et al. Cytokine production in the rheumatoid joint: implications for treatment. Ann. Rheum. Dis. 49, 480–486 (1990).
Elliott, M. J. et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor-necrosis factor-α. Arthritis Rheum. 36, 1681–1690 (1993).
Elliott, M. J. et al. Repeated therapy with monoclonal antibody to tumour-necrosis factor-α (cA2) in patients with rheumatoid arthritis. Lancet 344, 1125–1127 (1994).
Oudin, J. & Michel, M. A new form of allotype of rabbit γ-globulins apparently correlated with antibody function and specificity. C. R. Acad. Sci. 257, 805–808 (1963).
Maini, R. N. et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor-α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 41, 1552–1563 (1998).
Dresser, D. W. & Mitchison, N. A. The mechanism of immunological paralysis. Adv. Immunol. 8, 129–181 (1968).
Chiller, J. M., Habicht, G. S. & Weigle, W. O. Cellular sites of immunologic unresponsiveness. Proc. Natl Acad. Sci. USA 65, 551–556 (1970).
Williams, R. O., Mason, L. J., Feldmann, M. & Maini, R. N. Synergy between anti-CD4 and anti-tumor necrosis factor in the amelioration of established collagen-induced arthritis. Proc. Natl Acad. Sci. USA 91, 2762–2766 (1994).
Genestier, L. et al. Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. J. Clin. Invest. 102, 322–328 (1998).
Feldmann, M. & Maini, R. N. Anti-TNF-α therapy for rheumatoid arthritis: what have we learned? Annu. Rev. Immunol. 19, 163–196 (2001).
Maini, R. N. et al. Randomised phase III trial of infliximab (chimeric anti-TNF-α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate. Lancet 354, 1932–1939 (1999).
Lipsky, P. E. et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N. Engl. J. Med. 343, 1594–1602 (2000).
Lipsky, P. E. et al. 102-week clinical and radiological results from the ATTRACT trial: a two-year, randomized, controlled, phase III trial of infliximab (Remicade) in patients with active rheumatoid arthritis despite methotrexate. Arthritis Rheum. 47, S242 (2000).
Rankin, E. C. et al. A double-blind, placebo-controlled, ascending-dose trial of the recombinant humanised anti-TNF-α antibody CDP571 in patients with rheumatoid arthritis (RA): a preliminary report. Arthritis Rheum. 37, S295 (1994).
Sander, O. et al. Neutralization of TNF by Lenercept (TNFR55–IgG1,Ro 45-2081) in patients with rheumatoid arthritis treated for three months: results of a European phase II trial. Arthritis Rheum. 39, S242 (1996).
Moreland, L. W. et al. Treatment of rheumatoid arthritis with a recombinant human tumor-necrosis factor receptor (p75)–Fc fusion protein. N. Engl. J. Med. 337, 141–147 (1997).
Moreland, L. W. et al. Recombinant soluble tumor-necrosis factor receptor (p80) fusion protein: toxicity and dose-finding trial in refractory rheumatoid arthritis. J. Rheumatol. 23, 1849–1855 (1996).
Kempeni, J. Preliminary results of early clinical trials with the fully human anti-TNF monoclonal antibody D2E7. Ann. Rheum. Dis. 58, I70–I72 (1999).
Edwards, C. K. I. PEGylated recombinant human soluble tumour-necrosis factor receptor type I (r-Hu-sTNF-RI): novel high affinity TNF receptor designed for chronic inflammatory diseases. Ann. Rheum. Dis. 58, I73–81 (1999).
Hazleman, B. et al. Efficacy of a novel PEGylated humanised anti-TNF fragment (CDP870) in patients with rheumatoid arthritis. Rheumatology 39, 87 (2000).
Ulfgren, A. K. et al. Systemic anti-tumor necrosis factor-α therapy in rheumatoid arthritis down-regulates synovial tumor-necrosis factor-α synthesis. Arthritis Rheum. 43, 2391–2396 (2000).
Lacraz, S., Isler, P., Vey, E., Welgus, H. G. & Dayer, J. M. Direct contact between T lymphocytes and monocytes is a major pathway for induction of metalloproteinase expression. J. Biol. Chem. 269, 22027–22033 (1994).
Paleolog, E. M., Hunt, M., Elliott, M. J., Feldmann, M., Maini, R. N. & Woody, J. N. Deactivation of vascular endothelium by monoclonal anti-tumor necrosis factor-α antibody in rheumatoid arthritis. Arthritis Rheum. 39, 1082–1091 (1996).
Ballara, S. et al. Raised serum vascular endothelial growth factor levels are associated with destructive change in inflammatory arthritis. Arthritis Rheum. 44, 2055–2064 (2001).
Davis, D. et al. Anaemia of chronic disease in rheumatoid arthritis: in vivo effects of tumour necrosis factor-α blockade. Br. J. Rheumatol. 36, 950–956 (1997).
Finck, B. et al. A phase III trial of etanercept versus methotrexate (MTX) in early rheumatoid arthritis (Enbrel ERA trial). Arthritis Rheum. 42, S117 (1999).
Rau, R. et al. Long-term treatment with the fully human anti-TNF antibody D2E7 slows radiographic disease progression in rheumatoid arthritis. Arthritis Rheum. 42, S400 (1999).
Waldmann, H. Manipulation of T-cell responses with monoclonal antibodies. Annu. Rev. Immunol. 7, 407–444 (1989).
van Dulleman, H. M. et al. Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 109, 129–135 (1995).
Present, D. H. et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N. Engl. J. Med. 340, 1398–1405 (1999).
Lovell, D. J. et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N. Engl. J. Med. 342, 763–769 (2000).
Brandt, J. et al. Successful treatment of active ankylosing spondylitis with the anti-tumor necrosis factor-α monoclonal antibody infliximab. Arthritis Rheum. 43, 1346–1352 (2000).
Mease, P. J. et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 356, 385–390 (2000).
Chaudhari, U. et al. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 357, 1842–1847 (2001).
Lenercept Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 53, 444–445 (1999).
Cope, A. P. et al. Chronic exposure to tumor necrosis factor (TNF) in vitro impairs the activation of T cells through the T-cell receptor/CD3 complex; reversal in vivo by anti-TNF antibodies in patients with rheumatoid arthritis. J. Clin. Invest. 94, 749–760 (1994).
Deswal, A. et al. Safety and efficacy of a soluble p75 tumor necrosis factor receptor (Enbrel, etanercept) in patients with advanced hear failure. Circulation 99, 3224–3226 (1999).
Keane, J. et al. Tuberculosis associated with Infliximab, a tumor-necrosis factor-α neutralizing agent. N. Engl. J. Med. 345, 1098–1104 (2001).
Feldmann, M., Elliott, M. J., Woody, J. N. & Maini, R. N. Anti-tumor necrosis factor-α therapy of rheumatoid arthritis. Adv. Immunol. 64, 283–350 (1997).
Pisetsky, D. S. & St Clair, E. W. Progress in the treatment of rheumatoid arthritis. JAMA 286, 2787–2790 (2001).
Day, R. Adverse reactions to TNF-α inhibitors in rheumatoid arthritis. Lancet 359, 540–541 (2002).
Brennan, F. M. et al. Evidence that rheumatoid arthritis synovial T cells are similar to cytokine-activated T cells. Arthritis Rheum. 46, 31–41 (2002).
Isler, P., Vey, E., Zhang, J. H. & Dayer, J. M. Cell-surface glycoproteins expressed on activated human T cells induce production of interleukin–1β by monocytic cells: a possible role of CD69. Eur. Cytokine Netw. 4, 15–23 (1993).
Elliott, M. J. et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour-necrosis factor-α (cA2) versus placebo in rheumatoid arthritis. Lancet 344, 1105–1110 (1994).
Paulus, H. E., Egger, M. J., Ward, J. R., Williams, H. J. & Cooperative Systemic Studies of Rheumatic Disease Group. Analysis of improvement in individual rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs, based on the findings in patients treated with placebo. Arthritis Rheum. 33, 477–484 (1990).
Acknowledgements
This history of anti-TNF therapy owes its existence to the research of a great many talented and dedicated scientists, both basic and clinical, all of whose work cannot be cited in this type of review. It also owes its existence to long-term dedicated collaborators, chiefly R. Maini, with whom it has been a great privilege and pleasure to work in this field for 16 years, F. Brennan and many other scientists at KIR, and J. N. Woody of Centocor, but also to many cooperating clinicians. An important group in research is the patients, who are keen to take part in clinical trials, even if it is only for the benefit of future generations of patients. The work that led to the development of the principle of anti-TNF therapy was nearly entirely funded by the Arthritis Research Campaign (ARC) in the United Kingdom. Its long-term investment in this field since 1986 has been rewarded by the benefits to its patient supporters, which will increase following the positive NICE evaluation of anti-TNF therapy.
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Feldmann, M. Development of anti-TNF therapy for rheumatoid arthritis. Nat Rev Immunol 2, 364–371 (2002). https://doi.org/10.1038/nri802
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DOI: https://doi.org/10.1038/nri802
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