Advertisement

Rheumatology International

, Volume 27, Issue 2, pp 157–161 | Cite as

Association of TNF-alpha –308 G/A polymorphism with responsiveness to TNF-α-blockers in rheumatoid arthritis: a meta-analysis

  • Young Ho Lee
  • Young Hee Rho
  • Seong Jae Choi
  • Jong Dae Ji
  • Gwan Gyu Song
Original Article

Abstract

Tumor necrosis factor (TNF) antagonists are among the most effective therapies for rheumatoid arthritis (RA), yet not all patients show a response. Using meta-analysis, this present study was designed to investigate whether or not the TNF-α promoter –308 A/G polymorphism is associated with responsiveness to anti-TNF therapy in RA patients. We performed an exhaustive search for studies that examined the association of the TNF-α promoter –308 A/G polymorphism and responsiveness of anti-TNF therapy in RA using MEDLINE citations and manual review. Meta-analysis was performed for A allele carrier (genotypes A/A + A/G) between responders to anti-TNF therapy and a non-responder group in a random effects model. A total of 6 studies met the inclusion criteria. The number of patients in individual studies ranged from 33 to 123. There were 311 RA patients who were included in this meta-analysis. There was no heterogeneity between studies (I 2 = 0%, P = 0.42). The overall OR for the A allele carrier status was significantly decreased in the responder group (OR = 0.33, 95% confidence interval = 0.17–0.63, P = 0.0008). The frequency of the A allele carrier was 53/240 (22.1%) in responders and 32/71 (45.1%) in non-responders. Patients not responding to anti-TNF therapy showed an increased frequency of the A allele. The meta-analysis of the available data shows a significant association between the TNF-α promoter –308 A/G polymorphism and responsiveness to anti-TNF therapy, suggesting that the individuals with RA who carry the A allele have a poorer response to anti-TNF therapy than those with the G allele.

Keywords

Rheumatoid arthritis TNF-α inhibitors TNF-α –308 polymorphism Responsiveness 

Reference

  1. 1.
    Harris ED Jr (1990) Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med 322:1277–1289Google Scholar
  2. 2.
    Brennan FM, Maini RN, Feldmann M (1992) TNF alpha–a pivotal role in rheumatoid arthritis? Br J Rheumatol 31:293–298PubMedCrossRefGoogle Scholar
  3. 3.
    Vassalli P (1992) The pathophysiology of tumor necrosis factors. Annu Rev Immunol 10:411–452PubMedCrossRefGoogle Scholar
  4. 4.
    Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M, Harriman GR, Maini RN (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 343:1594–1602PubMedCrossRefGoogle Scholar
  5. 5.
    Allen RD (1999) Polymorphism of the human TNF-alpha promoter–random variation or functional diversity? Mol Immunol 36:1017–1027PubMedCrossRefGoogle Scholar
  6. 6.
    Bouma G, Crusius JB, Oudkerk PM, Kolkman JJ, von Blomberg BM, Kostense PJ, Giphart MJ, Schreuder GM, Meuwissen SG, Pena AS (1996) Secretion of tumour necrosis factor alpha and lymphotoxin alpha in relation to polymorphisms in the TNF genes and HLA-DR alleles. Relevance for inflammatory bowel disease. Scand J Immunol 43:456–463PubMedCrossRefGoogle Scholar
  7. 7.
    Louis E, Franchimont D, Piron A, Gevaert Y, Schaaf-Lafontaine N, Roland S, Mahieu P, Malaise M, De Groote D, Louis R, Belaiche J (1998) Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol 113:401–406PubMedCrossRefGoogle Scholar
  8. 8.
    Mugnier B, Balandraud N, Darque A, Roudier C, Roudier J, Reviron D (2003) Polymorphism at position –308 of the tumor necrosis factor alpha gene influences outcome of infliximab therapy in rheumatoid arthritis. Arthritis Rheum 48:1849–1852PubMedCrossRefGoogle Scholar
  9. 9.
    Padyukov L, Lampa J, Heimburger M, Ernestam S, Cederholm T, Lundkvist I, Andersson P, Hermansson Y, Harju A, Klareskog L, Bratt J (2003) Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis. Ann Rheum Dis 62:526–529PubMedCrossRefGoogle Scholar
  10. 10.
    Balog A, Klausz G, Gal J, Molnar T, Nagy F, Ocsovszky I, Gyulai Z, Mandi Y (2004) Investigation of the prognostic value of TNF-alpha gene polymorphism among patients treated with infliximab, and the effects of infliximab therapy on TNF-alpha production and apoptosis. Pathobiology 71:274–280PubMedCrossRefGoogle Scholar
  11. 11.
    Cuchacovich M, Ferreira L, Aliste M, Soto L, Cuenca J, Cruzat A, Gatica H, Schiattino I, Perez C, Aguirre A, Salazar-Onfray F, Aguillon JC (2004) Tumour necrosis factor-alpha (TNF-alpha) levels and influence of –308 TNF-alpha promoter polymorphism on the responsiveness to infliximab in patients with rheumatoid arthritis. Scand J Rheumatol 33:228–232PubMedCrossRefGoogle Scholar
  12. 12.
    Fonseca JE, Carvalho T, Cruz M, Nero P, Sobral M, Mourao AF, Cavaleiro J, Ligeiro D, Abreu I, Carmo-Fonseca M, Branco JC (2005) Polymorphism at position –308 of the tumour necrosis factor alpha gene and rheumatoid arthritis pharmacogenetics. Ann Rheum Dis 64:793–794PubMedCrossRefGoogle Scholar
  13. 13.
    Kang CP, Lee KW, Yoo DH, Kang C, Bae SC (2005) The influence of a polymorphism at position –857 of the tumour necrosis factor alpha gene on clinical response to etanercept therapy in rheumatoid arthritis. Rheumatology (Oxford) 44:547–552CrossRefGoogle Scholar
  14. 14.
    Egger M, Smith GD, Phillips AN (1997) Meta-analysis: principles and procedures. BMJ 315:1533–1537PubMedGoogle Scholar
  15. 15.
    Davey SG, Egger M (1997) Meta-analyses of randomised controlled trials. Lancet 350:1182Google Scholar
  16. 16.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188PubMedCrossRefGoogle Scholar
  17. 17.
    Feldmann M, Brennan FM, Maini RN (1996) Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 14:397–440PubMedCrossRefGoogle Scholar
  18. 18.
    Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, Teoh LA, Fischkoff SA, Chartash EK (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 48:35–45PubMedCrossRefGoogle Scholar
  19. 19.
    Genovese MC, Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, Wasko MC, Moreland LW, Weaver AL, Markenson J, Cannon GW, Spencer-Green G, Finck BK (2002) Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum 46:1443–1450PubMedCrossRefGoogle Scholar
  20. 20.
    Brinkman BM, Huizinga TW, Kurban SS, van der Velde EA, Schreuder GM, Hazes JM, Breedveld FC, Verweij CL (1997) Tumour necrosis factor alpha gene polymorphisms in rheumatoid arthritis: association with susceptibility to, or severity of, disease? Br J Rheumatol 36:516−521PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Young Ho Lee
    • 1
  • Young Hee Rho
    • 1
  • Seong Jae Choi
    • 1
  • Jong Dae Ji
    • 1
  • Gwan Gyu Song
    • 1
  1. 1.Division of Rheumatology, Department of Internal MedicineKorea University Medical CenterSeoulSouth Korea

Personalised recommendations