TNF-α inhibitors

  • Zuhre Tutuncu
  • Arthur Kavanaugh
Part of the Progress in Inflammation Research book series (PIR)


The development of anti-TNF-α therapy has resulted in the potential to radically alter the course of inflammatory diseasessuch as rheumatoid arthritis (RA). Currently there arethree anti-TNF-α agents available for clinical use: infliximab, a chimeric anti-TNF-α mAb; etanercept, a soluble TNF-receptor construct; and adalimumab (formerly knowas D2E7), a humananti-TNF-α mAb. All three agents block the ability of TNF to bind to the cell and prevent TNF from stimulating the cell to produce the biochemical agents that are ultimately responsible for the clinical markers of RA: inflammation, tissue damage, pain, stiffness, swelling, tenderness, and eventual deformation of the joint and patient disability.


Rheumatoid Arthritis Juvenile Rheumatoid Arthritis Tumor Necrosis Factor Inhibitor Concomitant Methotrexate Rheumatoid Arthritis Trial 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Möhler KM, Torrance DS, Smith CA, Goodwin RG, Stremler KE, Fung VP, Madani H, Widmer MB (1993) Soluble tumor necrosis factor (TNF) receptors are effective theraupetic agents in lethal endothexemia and function simultaneously as both TNF carriers and TNF antagonists. J. Immunol 51: 1548–1561Google Scholar
  2. 2.
    den Broeder AA, Joosten LAB, Saxne T, Heinegard D, Heinegard D, Fenner H, Miltenburg AM, Frasa WL, van Tits LJ, Buurman WA et al (2002) Long term anti-tumour necrosis factor a monotherapy in rheumatoid arthritis: Effect on radiological course and prognosticvalue of markersof cartilage turnover andendothelial activation. Ann Rheum Dis 61: 311–318CrossRefGoogle Scholar
  3. 3.
    Paleolog EM, Hunt M, Elliot MJ, Feldmann M, Maini R, Woody J (1996) Deactivation of vascularendothelium bymonoclonalanti-tumor necrosis factor-α antibody in rheumatoid arthritis. Arthritis Rheum 39: 1082–1091CrossRefPubMedGoogle Scholar
  4. 4.
    Tak PP, Taylor PC, Breedveld FC, Smeets TJM, Daha MR, Smeets TJ, Daha MR, Kluin PM, Meinders AE, Maini RN (1996) Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor a monoclonal antibody treatmentin patients with rheumatoid arthritis. Arthritis Rheum 39: 1077–1081CrossRefPubMedGoogle Scholar
  5. 5.
    Paleolog E, Young S, McClosekey RV et al (1998) Angiogenesis as a therapeutic target in rheumatoid arthritis: serum vascular endothelial growth factor is decreased by anti-TNF a therapy. Clin Exp Rheumatol 16: 232Google Scholar
  6. 6.
    van Vollenhoven R, Harju A, Brannemark S, Klareskog L (2003) Treatment with infliximab (remicade) when etanercept (enbrel) has failed or vice versa: Data from STURE registry showing that switching tumour necrosis factor a blockers can make sense. Ann Rheum Dis 62: 1195–1198CrossRefPubMedGoogle Scholar
  7. 7.
    Maini RN, Breedveld FC, Kalden JR et al (1998) Therapeutic efficacy of multiple intraveneous infusions of anti-tumour necrosis factor-alpha monoclonal antibody combined withlow-dose weekly methotrexatein rheumatoid arthritis. Arthritis Rheum 41: 1552–1563CrossRefPubMedGoogle Scholar
  8. 8.
    Maini R, St Clair EW, Breedweld F, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M et al (1999) Infliximab (chimeric anti-tumour necrosis factor a monoclonalantibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: A randomized phase III trial. Lancet 354: 1932–1939CrossRefPubMedGoogle Scholar
  9. 9.
    Kavanaugh A, St Clair EW, McCune WJ et al (2000) Chimeric anti-tumour necrosis factor a monoclonal antibody treatment of patients with rheumatoidarthritisreceiving methotrexate therapy. J. Rheumatol 27: 841–850PubMedGoogle Scholar
  10. 10.
    St Clair E, Wagner C, Fasanmade A, Wang B, Schaible T, Kavanaugh A, Keystone E (2002) Relationship of serum infliximab concentrations to clinical improvementin rheumatoid arthritis. Arthritis Rheum 46: 1451–1459CrossRefGoogle Scholar
  11. 11.
    Korth-Bradley, Abbe SR, Roberta KH, Simcoe DK, Lebsack ME (2000) The pharmacokinetics of Etanercept in healthy volunteers. Ann Pharmacothar 34: 161–164CrossRefGoogle Scholar
  12. 12.
    Jobanputra P, Barton P, Bryan S, Burls A (2002) The effectiveness of infliximab and etanercept for the treatment of rheumatoid arthritis: A systemicreview and economic evaluation. Health Technol Assess 6(21): 1–110PubMedGoogle Scholar
  13. 13.
    Brennan A, Browne KA, Green PA, Jaspar JM, Maini RN, Feldman M (1997) Reduction of serum matrix metalloproteinase 1 and matrix metalloproteinase 3 in rheumatoid arthritis patients following anti-tumour factor-alpha (cA2) therapy. Br J Rheumatol 36: 643–650CrossRefPubMedGoogle Scholar
  14. 14.
    Elliott MJ, Maini RN, Feldman M (1994) Randomized double-blind comparison of chimeric monoclonal antibody to tumor necrosis factoralpha(cA2) versus placeboin rheumatoid arthritis. Lancet 344:1105–1110CrossRefPubMedGoogle Scholar
  15. 15.
    Moreland LW, Margolies G, Heck LW, Saway A, Blosch C, Hanna R, Koopman WJ (1996) Recombinant soluble tumor necrosis factor receptor(p80) fusion protein: toxicity and dose finding trial in refractory rheumatoid arthritis. J. Rheumatol 23: 1849–1855PubMedGoogle Scholar
  16. 16.
    Moreland LW, Baumgartner SW, Schiff MH et al(1997) Treatment of rheumatoid arthritis with a recombinant human tumour necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 337: 141–147CrossRefPubMedGoogle Scholar
  17. 17.
    Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M et al (2000) Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 343: 1594–1602CrossRefPubMedGoogle Scholar
  18. 18.
    Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ, Weaver AL, Keystone EC, Furst DE, Mease PJ et al(1999) Etanercepttherapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med 130: 478–486PubMedGoogle Scholar
  19. 19.
    Weinblatt ME, Kremer KM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, Jackson CG, Lange M, Bürge DJ (1999) A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 340: 253–259CrossRefPubMedGoogle Scholar
  20. 20.
    Genovese MC, Bathon JM, Martin R, Fleischmann R, Tesser JR, Schiff MH, Keystone EC, Wasko MC, Moreland L W, Weaver AL et al (2002) Etanercept versus methotrexate in patients with early rheumatoid arthritis: Two year radiographic and clinical outcomes Arthritis Rheum 46: 1443–1450CrossRefPubMedGoogle Scholar
  21. 21.
    Van de Putte LBA, Rau R, Breedveld FC, Kalden JR et al (2003) Efficacy and safety of the fully human anti-TNF-alpha monoclonal antibody adalimumab (D2E7) in DMARD refractory patients with rheumatoid arthritis: A 12 week, phase II study. Ann Rheum Dis 62: 1168–1177CrossRefPubMedGoogle Scholar
  22. 22.
    Weinblatt M, Keystone E, Furst D, Moreland L W, Weisman MH, Birbara CA, Teoh LA, Fischkoff SA, Chartash EK (2003) Adalimumab, a fully human anti-tumor necrosis factor a monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate. Arthritis Rheum 48: 35–45CrossRefPubMedGoogle Scholar
  23. 23.
    Keystone E, Kavanaugh A, Sharp J, Tannenbaum H et al (2002) Adalimumab (D2E7), a fully human anti-TNFα monoclonal antibody, inhibits the progression of structural damage in patients with active rheumatoid arthritis despite concomitant methotrexate therapy. Arthritis Rheum 46 (suppl 9): S205 Abstract 468Google Scholar
  24. 24.
    Callahan LF (1998) The burden of rheumatoid arthritis: facts and figures. J. Rheumatol (Suppl) 53: 8–12Google Scholar
  25. 25.
    Blair J, Faulds D (1999) Etanercept. A review of its use in rheumatoid arthritis. Drugs 57: 945–966CrossRefGoogle Scholar
  26. 26.
    Nuijten MJ, Engelgriet P, Dujin K, Bruijn G, Wierz D, Koopmanschap M (2001) A costcost study comparing etanercept with infliximab in rheumatoid arthritis. Pharmacoeconomics 19: 1051–1064CrossRefPubMedGoogle Scholar
  27. 27.
    Choi HK, Seeger JD, Kuntz KM (2002) A cost effectivenessanalysis of treatment options for methotrexate-naive rheumatoid arthritis. J. Rheumatol 29: 1156–1165PubMedGoogle Scholar
  28. 28.
    Wong JB, Singh G, Kavanaugh A (2002) Estimating the cost-effectiveness of 54 weeks of infliximab for rheumatoid arthritis. Am J Med 113: 400–408CrossRefPubMedGoogle Scholar
  29. 29.
    Kobelt G, Jönsson, Young A, Eberhardt K (2003) The cost-effectiveness of infliximab (remicade) in the treatment of rheumatoid arthritis in Sweden and United Kingdom based on the ATTRACT study. Rheumatol 42: 326–335CrossRefGoogle Scholar
  30. 30.
    Brennan A, Bansback N, Reynolds A, Conway P (2003) MO’Delling the cost-effectiveness of etanercept in adults with rheumatoid arthritis in the UK. Rheumatol 42:1–13CrossRefGoogle Scholar
  31. 31.
    Kremer JM (2001) Rational use of new and existing disease-modifying agentsin rheumatoid arthritis. Ann Intern Med 134: 695–706PubMedGoogle Scholar
  32. 32.
    Bean AG, Roach DR, Briscoe H, France MP, Korner H, Sedgwick JD, Britton WJ (1999) Structural deficiencies in granuloma formationin TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection. J Immunol 162: 3504–3511PubMedGoogle Scholar
  33. 33.
    Ehlers S, Benini J, Kutsch S, Endres R, Rietschel ET, Pfeffer K (1999) Fatal granuloma necrosis despite intact antibacterial functions in TNFR p55-deficient mice chronically infected with M. Avium. Infect Immun 67: 3571–3579PubMedGoogle Scholar
  34. 34.
    Chen W, Havell EA, Harmsen AG (1992) Importance of endogeneous tumor necrosis factor and gamma interferon in host resistance against Pneumocystis Carinii infection. Infect Immun 60: 1279–1284PubMedGoogle Scholar
  35. 35.
    Allendoerfer R, Deepe GS (1998) Blockade of endogeneous TNF-α exacerbates primary and secondary pulmonary histoplasmosis by differential mechanisms. J. Immunol 160: 6072–6082PubMedGoogle Scholar
  36. 36.
    Rothe J, Lesslauer W, Lotscher H, Lang Y, Koebel P, Kontgen F, Althage A, Zinkernagel R, Steinmetz M, Bluethmann H (1993) Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature 364: 798–802CrossRefPubMedGoogle Scholar
  37. 37.
    Skerret SJ, Bagby GJ, Schmidt RA, Nelson S (1997) Antibody-mediated depletion of tumour necrosis factor impairs pulmonary host defenses to Legionella pneumophila. J Infect Dis 176: 1019–1028CrossRefGoogle Scholar
  38. 38.
    Wolfe F, Mitchell D, Sibley J (1994) The mortality of rheumatoid arthritis. Arthritis Rheum 37: 481–494CrossRefPubMedGoogle Scholar
  39. 39.
    Doran MF, Crowson CS, Pond GR et al (2002) Frequency of infection in patients with rheumatoid arthritis compared with controls. Arthritis Rheum 46: 2287–2293CrossRefPubMedGoogle Scholar
  40. 40.
    Kavanaugh A, Keystone E (2003) The safety of biologic agents in early rheumatoid arthritis. Clin Exp Rheumatol 21: s203–s208PubMedGoogle Scholar
  41. 41.
    Keane J, Gerbson S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun MM (2001) Tuberculosis associated with infliximab, a tumor necrosis factor neutralizing agent. N Engl J Med 345: 1098–1104CrossRefPubMedGoogle Scholar
  42. 42.
    Charles PJ, Smeenk RJT, De Jong J, Feldmann M, Maini RN (2000) Assessment of antibodies to DsDNA induced in rheumatoid arthritis (RA) patients following treatment with infliximab, a monoclonal antibody to TNF alpha. Arthritis Rheum 43: 2383–2390CrossRefPubMedGoogle Scholar
  43. 43.
    Mohan N, Edwards ET, Cupps TR, Oliverio PJ, Sandberg G, Crayton H, Richert JR, Siegel JN (2001) Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 44: 2862–2869CrossRefPubMedGoogle Scholar
  44. 44.
    van Oosten BW, Barkhof F, Truyen L, Boringa JB, Bertelsmann FW, von Blomberg BM, Woody JN, Hartung HP, Polman CH (1996) Increased MRI activity and immune activation in two multiple sclerosis patients treated withmonoclonal anti-tumor necrosis factor antibody cA2. Neurology 47: 1531–1534PubMedGoogle Scholar
  45. 45.
    The Lenercept Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group (1999)TNF neutralization in MS: Results of a randomized, placebo-controlled multicenter trial. Neurology 53:457–465Google Scholar
  46. 46.
    Moreland LM, Cohen SB, Baumgartner SW, Tindall EA, Bulpitt K, Martin R, Weinblatt M, Taborn J, Weaver A, Burge DJ et al (2001) Long-term safety and efficacy of etanercept in patients with rheumatoid arthritis. J. Rheumatol 28: 1238–1244PubMedGoogle Scholar
  47. 47.
    Lovell DJ, Giannini EH, Reiff A, Cawkwell GD, Silverman ED, Nocton JJ, Stein LD, Gedalia A, Ilowite NT, Wallace CA et al (2000) Etanercept in children with polyarticular juvenile rheumatoid arthritis. N Engl J Med 342: 763–769CrossRefPubMedGoogle Scholar
  48. 48.
    Kietz DA, Pepmueller PH, Moore TL (2002) Therapeutic use of etanercept in polyarticular course juvenile idiopathic arthritis over a two year period. Ann Rheum Dis 61: 171–173CrossRefPubMedGoogle Scholar
  49. 49.
    Brandt J, Haibel H, Reddig J, Sieper J, Braun J (2002) Successful short term treatment of severe undifferentiated spondyloarthropathy with theanti-tumour necrosis factoralpha monoclonal antibody infliximab. J. Rheumatol 29: 118–122PubMedGoogle Scholar
  50. 50.
    Mease PJ, Goffe B S, Metz J, VanderStoep A, Finck B, Buge DJ (2000) Etanercept in the treatment of psoriatic arthritis and psoriasis: Randomizedtrial. Lancet 356: 385–390CrossRefPubMedGoogle Scholar
  51. 51.
    Van den Bosch F, Kruithof E, Baeten D, Herssens A, de Keyser F, Mielants H, Veys EM (2002) Randomized double-blind comparisonof chimeric monoclonal antibody to tumor necrosis factor (infliximab) versus placebo in active spondyloarthropathy. Arthritis Rheum 46: 755–765CrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2005

Authors and Affiliations

  • Zuhre Tutuncu
    • 1
  • Arthur Kavanaugh
    • 1
  1. 1.Division of Rheumatology, Allergy and ImmunologyUniversity of California, San DiegoLa JollaUSA

Personalised recommendations