Immunogenicity of Anti-TNF-α Agents in Autoimmune Diseases

  • Nádia Emi Aikawa
  • Jozélio Freire de Carvalho
  • Clovis Artur Almeida Silva
  • Eloísa Bonfá
Article

Abstract

Prognosis of several autoimmune diseases, especially rheumatoid arthritis (RA), ankylosing spondylitis, Crohn’s disease (CD), and psoriasis, usually refractory to conventional treatment improved considerably with the introduction of tumor necrosis factor alpha (TNF-α) antagonistic agents, which is now available (infliximab, etanercept, and adalimumab). However, a portion of patients persists with active disease, infusion reactions, and relapses even during current biological therapy. One of the reasons for this is the associated immunogenicity to these drugs. The incentive for induction of antibodies against anti-TNF-α agent depends mainly on its constitution. Chimerical drugs have a higher capacity of inducing immunogenicity compared to completely human drugs. Among the three anti-TNF-α agents, this phenomenon has been studied mainly in patients using infliximab, especially in RA and CD. The prevalence of anti-infliximab antibodies in RA varies from 12% to 44% and seems to be inversely proportional to the level of seric infliximab and therapeutic response. The use of etanercept was associated to the development of anti-etanercept antibodies in 0% to 18% of patients, without apparent effect on effectiveness or adverse events. Studies with RA and CD patients show prevalence of anti-adalimumab antibodies from 1% to 87%. Immunosuppressive drug addiction can reduce the induction of anti-TNF-α antibodies.

Keywords

Anti-infliximab Anti-etanercept Anti-adalimumab Anti-HACA Anti-TNF-α Autoimmune disease 

References

  1. 1.
    Lipsky PE, van der Heijde DM, St Clair EW et al (2000) Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study group. N Engl J Med 343:1594–1602CrossRefPubMedGoogle Scholar
  2. 2.
    Keystone EC, Kavanaugh AF, Sharp JT et al (2004) Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 50:1400–1411CrossRefPubMedGoogle Scholar
  3. 3.
    Weinblatt ME, Keystone EC, Furst DE et al (2003) Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 48:35–45CrossRefPubMedGoogle Scholar
  4. 4.
    van der Laken CJ, Voskuyl AE, Roos JC et al (2007) Imaging and serum analysis of immune complex formation of radiolabelled infliximab and anti-infliximab in responders and non-responders to therapy for rheumatoid arthritis. Ann Rheum Dis 66:253–256CrossRefPubMedGoogle Scholar
  5. 5.
    Caporali R, Pallavicini FB, Filippini M et al (2009) Treatment of rheumatoid arthritis with anti-TNF-alpha agents: a reappraisal. Autoimmun Rev 8:274–280CrossRefPubMedGoogle Scholar
  6. 6.
    Punzi L, Podswiadek M, Sfriso P, Oliviero F, Fiocco U, Todesco S (2007) Pathogenetic and clinical rationale for TNF-blocking therapy in psoriatic arthritis. Autoimmun Rev 6:524–528CrossRefPubMedGoogle Scholar
  7. 7.
    Abe T, Takeuchi T (2001) Rheumatoid arthritis and tumor necrosis factor alpha. Autoimmunity 34:291–303CrossRefPubMedGoogle Scholar
  8. 8.
    Miele E, Markowitz JE, Mamula P, Baldassano RN (2004) Human antichimeric antibody in children and young adults with inflammatory bowel disease receiving infliximab. J Pediatr Gastroenterol Nutr 38:502–508CrossRefPubMedGoogle Scholar
  9. 9.
    Sidiropoulos PI, Boumpas DT (2006) Differential drug resistance to anti-tumour necrosis factor agents in rheumatoid arthritis. Ann Rheum Dis 65:701–703CrossRefPubMedGoogle Scholar
  10. 10.
    Anderson PJ (2005) Tumor necrosis factor inhibitors: clinical implications of their different immunogenicity profiles. Semin Arthritis Rheum 34:19–22CrossRefPubMedGoogle Scholar
  11. 11.
    Haraoui B, Cameron L, Ouellet M, White B (2006) Anti-infliximab antibodies in patients with rheumatoid arthritis who require higher doses of infliximab to achieve or maintain a clinical response. J Rheumatol 33:31–36PubMedGoogle Scholar
  12. 12.
    Dore RK, Mathews S, Schechtman J et al (2007) The immunogenicity, safety, and efficacy of etanercept liquid administered once weekly in patients with rheumatoid arthritis. Clin Exp Rheumatol 25:40–46PubMedGoogle Scholar
  13. 13.
    van de Putte LB, Atkins C, Malaise M et al (2004) Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Ann Rheum Dis 63:508–516CrossRefPubMedGoogle Scholar
  14. 14.
    Suryaprasad AG, Prindiville T (2003) The biology of TNF blockade. Autoimmun Rev 2:346–357CrossRefPubMedGoogle Scholar
  15. 15.
    Valesini G, Iannuccelli C, Marocchi E, Pascoli L, Scalzi V, Di Franco M (2007) Biological and clinical effects of anti-TNF alpha treatment. Autoimmun Rev 7:35–41CrossRefPubMedGoogle Scholar
  16. 16.
    Elkayam O, Burke M, Vardinon N et al (2005) Autoantibodies profile of rheumatoid arthritis patients during treatment with infliximab. Autoimmunity 38:155–160CrossRefPubMedGoogle Scholar
  17. 17.
    Atzeni F, Doria A, Ghirardello A et al (2008) Organ-specific autoantibodies in patients with rheumatoid arthritis treated with adalimumab: a prospective long-term follow-up. Autoimmunity 41:87–91CrossRefPubMedGoogle Scholar
  18. 18.
    Pendley C, Schantz A, Wagner C (2003) Immunogenicity of therapeutic monoclonal antibodies. Curr Opin Mol Ther 5:72–79Google Scholar
  19. 19.
    Maini RN, Breedveld FC, Kalden JR 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 Rheum 41:1552–1563CrossRefPubMedGoogle Scholar
  20. 20.
    Vermeire S, Noman M, Van Assche G, Baert F, D’Haens G, Rutgeerts P (2007) Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease. Gut 56:1226–1231CrossRefPubMedGoogle Scholar
  21. 21.
    Baert F, Noman M, Vermeire S et al (2003) Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med 348:601–608CrossRefPubMedGoogle Scholar
  22. 22.
    Hanauer SB, Wagner CL, Bala M et al (2004) Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn’s disease. Clin Gastroenterol Hepatol 2:542–553CrossRefPubMedGoogle Scholar
  23. 23.
    Radstake TR, Svenson M, Eijsbouts AM et al (2008) Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis, Nov 19. [Epub ahead of print]Google Scholar
  24. 24.
    Ebert EC, Das KM, Mehta V, Rezac C (2008) Non-response to infliximab may be due to innate neutralizing anti-tumour necrosis factor-alpha antibodies. Clin Exp Immunol 154:325–331CrossRefPubMedGoogle Scholar
  25. 25.
    de Vries MK, Wolbink GJ, Stapel SO et al (2007) Decreased clinical response to infliximab in ankylosing spondylitis is correlated with anti-infliximab formation. Ann Rheum Dis 66:1252–1254CrossRefPubMedGoogle Scholar
  26. 26.
    Wolbink GJ, Vis M, Lems W et al (2006) Development of anti infliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum 54:711–715CrossRefPubMedGoogle Scholar
  27. 27.
    Aybay C, Ozel S, Aybay C (2006) Demonstration of specific antibodies against infliximab induced during treatment of a patient with ankylosing spondylitis. Rheumatol Int 26:473–480CrossRefPubMedGoogle Scholar
  28. 28.
    Svenson M, Geborek P, Saxne T, Bendtzen K (2007) Monitoring patients treated with anti-TNF-alpha biopharmaceuticals: assessing serum infliximab and anti-infliximab antibodies. Rheumatology (Oxford) 46:1828–1834CrossRefGoogle Scholar
  29. 29.
    van der Bijl AE, Breedveld FC, Antoni CE et al (2008) An open-label pilot study of the effectiveness of adalimumab in patients with rheumatoid arthritis and previous infliximab treatment: relationship to reasons for failure and anti-infliximab antibody status. Clin Rheumatol 27:1021–1028CrossRefPubMedGoogle Scholar
  30. 30.
    van den Bemt BJ, den Broeder AA, Snijders GF et al (2008) Sustained effect after lowering high-dose infliximab in patients with rheumatoid arthritis: a prospective dose titration study. Ann Rheum Dis 67:1697–1701CrossRefPubMedGoogle Scholar
  31. 31.
    Bendtzen K, Geborek P, Svenson M, Larsson L, Kapetanovic MC, Saxne T (2006) Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab. Arthritis Rheum 54:3782–3789CrossRefPubMedGoogle Scholar
  32. 32.
    Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T (1997) A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 337:1029–1035CrossRefPubMedGoogle Scholar
  33. 33.
    Hanauer SB, Feagan BG, Lichtenstein GR et al (2002) Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 359:1541–1549CrossRefPubMedGoogle Scholar
  34. 34.
    Farrell RJ, Alsahli M, Jeen YT, Falchuk KR, Peppercorn MA, Michetti P (2003) Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology 124:917–924CrossRefPubMedGoogle Scholar
  35. 35.
    Denton CP, Engelhart M, Tvede N et al (2008) An open-label pilot study of infliximab therapy in diffuse cutaneous systemic sclerosis. Ann Rheum Dis, Sep 9. [Epub ahead of print]Google Scholar
  36. 36.
    Langley RG, Gordon KB (2007) Duration of remission of biologic agents for chronic plaque psoriasis. J Drugs Dermatol 6:1205–1212PubMedGoogle Scholar
  37. 37.
    Stern R, Wolfe F (2004) Infliximab dose and clinical status: results of 2 studies in 1642 patients with rheumatoid arthritis. J Rheumatol 31:1538–1545PubMedGoogle Scholar
  38. 38.
    Ainsworth MA, Bendtzen K, Brynskov J (2008) Tumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn’s disease. Am J Gastroenterol 103:944–948CrossRefPubMedGoogle Scholar
  39. 39.
    Han PD, Cohen RD (2004) Managing immunogenic responses to infliximab: treatment implications for patients with Crohn’s disease. Drugs 64:1767–1777CrossRefPubMedGoogle Scholar
  40. 40.
    Keystone EC, Schiff MH, Kremer JM et al (2004) Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 50:353–363CrossRefPubMedGoogle Scholar
  41. 41.
    Lovell DJ, Giannini EH, Reiff A et al (2000) Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med 342:763–769CrossRefPubMedGoogle Scholar
  42. 42.
    de Vries MK, van der Horst-Bruinsma IE, Nurmohamed MT, Aarden LA, Stapel SO, Peters MJ (2009) Immunogenicity does not influence treatment with etanercept in patients with ankylosing spondylitis (AS). Ann Rheum Dis 68:531–535CrossRefPubMedGoogle Scholar
  43. 43.
    Tyring S, Gordon KB, Poulin Y et al (2007) Long-term safety and efficacy of 50 mg of etanercept twice weekly in patients with psoriasis. Arch Dermatol 143:719–726CrossRefPubMedGoogle Scholar
  44. 44.
    Bender NK, Heilig CE, Dröll B, Wohlgemuth J, Armbruster FP, Heilig B (2007) Immunogenicity, efficacy and adverse events of adalimumab in RA patients. Rheumatol Int 27:269–274CrossRefPubMedGoogle Scholar
  45. 45.
    Bartelds GM, Wijbrandts CA, Nurmohamed MT et al (2007) Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis 66:921–926CrossRefPubMedGoogle Scholar
  46. 46.
    Sandborn WJ, Hanauer SB, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh DG (2007) Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut 56:1232–1239CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • Nádia Emi Aikawa
    • 1
    • 4
  • Jozélio Freire de Carvalho
    • 2
    • 3
    • 4
  • Clovis Artur Almeida Silva
    • 1
    • 4
  • Eloísa Bonfá
    • 2
    • 4
  1. 1.Pediatric Rheumatology Unit of Instituto da CriançaHospital das Clínicas da Faculdade de Medicina da Universidade São Paulo UniversitySão PauloBrazil
  2. 2.Rheumatology DivisionHospital das Clínicas da Faculdade de Medicina da Universidade São Paulo UniversitySão PauloBrazil
  3. 3.Rheumatology DivisionFaculdade de Medicina da Universidade de São PauloSão PauloBrazil
  4. 4.Centro de Dispensação de Medicação de Alto Custo (CEDMAC)Hospital das Clínicas da Faculdade de Medicina da Universidade de São PauloSão PauloBrazil

Personalised recommendations