Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

The -308 TNFα and the -174 IL-6 promoter polymorphisms associate with effective anti-TNFα treatment in seronegative spondyloarthritis

The Pharmacogenomics Journal volume 16, pages 238–242 (2016)Cite this article

Subjects

Abstract

The genetic predisposition to a long-term efficacy of anti-tumor necrosis factor (TNF)α treatment in seronegative spondyloarthritis (SpA) was investigated by analysing the possible correlation between several single nucleotide gene polymorphisms and the retention rate of anti-TNFα therapies. We compared patients needing to switch the first anti-TNFα (Sw, No. 64) within at least 12 months of follow-up with patients not needing to switch (NSw, No. 123), observing at least 6 months of treatment to establish anti-TNFα failure, leading to treatment change. Response to treatment was evaluated by standardised criteria (BASDAI for axial involvement, DAS28-EULAR for peripheral involvement). The TNFα -308 A allele and the interleukin (IL)-6 -174GG homozygosis resulted as independent biomarkers predicting survival of the first anti-TNFα therapy in SpA patients (P=0.007, odds ratio (OR): 4.4, 95% confidence interval (CI)=1.5–13.1 and P=0.035, OR: 2.1, 95% CI=1.1–4.4). Also, the male gender (P=0.001, OR: 3.4, 95% CI=1.6–7.1) associated with the NSw phenotype, whereas no association was found either with the specific diagnosis or the predominant joint involvement.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. van der Heijde D, Sieper J, Maksymowych WP, Dougados M, Burgos-Vargas R, Landewé R et al. Assessment of SpondyloArthritis international Society. 2010 Update of the international ASAS recommendations for the use of anti-TNF agents in patients with axial spondyloarthritis. Ann Rheum Dis 2011; 70: 905–908.

    Article  PubMed  Google Scholar 

  2. Machado MA, Barbosa MM, Almeida AM, de Araújo VE, Kakehasi AM, Andrade EI et al. Treatment of ankylosing spondylitis with TNF blockers: a meta-analysis. Rheumatol Int 2013; 33: 2199–2213.

    Article  CAS  PubMed  Google Scholar 

  3. Maruotti N, Cantatore FP . Impact of biological therapy on spondyloarthritis. Eur J Clin Pharmacol 2014; 70: 1021–1027.

    Article  CAS  PubMed  Google Scholar 

  4. Saad AA, Ashcroft DM, Watson KD, Hyrich KL, Noyce PR, Symmons DP . Persistence with anti-tumour necrosis factor therapies in patients with psoriatic arthritis: observational study from the British Society of Rheumatology Biologics Register. Arthritis Res Ther 2009; 11: R52.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kievit W, Fransen J, Adang EM, den Broeder AA, Bernelot Moens HJ, Visser H et al. Long-term effectiveness and safety of TNF-blocking agents in daily clinical practice: results from the Dutch Rheumatoid Arthritis Monitoring register. Rheumatology (Oxford) 2011; 50: 196–203.

    Article  CAS  Google Scholar 

  6. Kiltz U, Heldmann F, Baraliakos, Braun J . Treatment of ankylosing spondylitis in patients refractory to TNF-inhibition: are there alternatives? Curr Opin Rheumatol 2012; 24: 252–260.

    Article  CAS  PubMed  Google Scholar 

  7. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW . Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA 1997; 94: 3195–3199.

    Article  CAS  PubMed  Google Scholar 

  8. de Jong BA, Westendorp RG, Bakker AM, Huizinga TW . Polymorphisms in or near tumour necrosis factor (TNF)-gene do not determine levels of endotoxin-induced TNF production. Genes Immunol 2002; 3: 25–29.

    Article  CAS  Google Scholar 

  9. O'Rielly DD, Roslin NM, Beyene J, Pope A, Rahman P . TNF-alpha-308 G/A polymorphism and responsiveness to TNF-alpha blockade therapy in moderate to severe rheumatoid arthritis: a systematic review and meta-analysis. Pharmacogenomics J 2009; 9: 161–167.

    Article  CAS  PubMed  Google Scholar 

  10. Lee YH, Ji JD, Bae SC, Song GG . Associations between tumor necrosis factor-alpha (TNF-alpha) -308 and -238 G/A polymorphisms and shared epitope status and responsiveness to TNF-alpha blockers in rheumatoid arthritis: a meta analysis update. J Rheumatol 2010; 37: 740–746.

    Article  CAS  PubMed  Google Scholar 

  11. Song GG, Bae SC, Kim JH, Lee YH . Association between TNF-α promoter -308 A/G polymorphism and rheumatoid arthritis: a meta-analysis. Rheumatol Int 2014; 34: 465–471.

    Article  CAS  PubMed  Google Scholar 

  12. Tong Q, Zhao L, Qian XD, Zhang LL, Xu X, Dai SM et al. Association of TNF-α polymorphism with prediction of response to TNF blockers in spondyloarthritis and inflammatory bowel disease: a meta-analysis. Pharmacogenomics 2013; 14: 1691–1700.

    Article  CAS  PubMed  Google Scholar 

  13. Murdaca G, Gulli R, Spanò F, Lantieri F, Burlando M, Parodi A et al. TNF-α gene polymorphisms: association with disease Susceptibility and response to anti-TNF-α treatment in psoriatic arthritis. J Invest Dermatol 2014; 34: 2503–2509.

    Article  Google Scholar 

  14. Lee YH, Bae SC, Song GG . Functional FCGR3A 158 V/F and IL-6 -174 C/G polymorphisms predict response to biologic therapy in patients with rheumatoid arthritis: a meta-analysis. Rheumatol Int 2014; 34: 1409–1415.

    Article  CAS  PubMed  Google Scholar 

  15. Tutuncu Z, Kavanaugh A, Zvaifler N, Corr M, Deutsch R, Boyle D . Fcgamma receptor type IIIA polymorphisms influence treatment outcomes in patients with infl ammatory arthritis treated with tumor necrosis factor alpha-blocking agents. Arthritis Rheum 2005; 52: 2693–2696.

    Article  CAS  PubMed  Google Scholar 

  16. Morales-Lara MJ, Conesa-Zamora P, García-Simón MS, Pedrero F, Santaclara V, Perez-Guillermo M et al. Association between the FCGR3 A V158F polymorphism and the clinical response to infliximab in rheumatoid arthritis and spondyloarthritis patients. Scand J Rheumatol 2010; 39: 518–520.

    Article  CAS  PubMed  Google Scholar 

  17. Fabbroni M, Cantarini L, Caso F, Costa L, Pagano VA, Frediani B et al. Drug retention rates and treatment discontinuation among anti-TNF-α agents in psoriatic arthritis and ankylosing spondylitis in clinical practice. Mediators Inflamm 2014; 2014: 862969.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Rudwaleit M, van der Heijde D, Landewé R, Akkoc N, Brandt J, Chou CT et al. The Assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann Rheum Dis 2011; 70: 25–31.

    Article  CAS  PubMed  Google Scholar 

  19. Fransen J, Antoni C, Mease PJ, Uter W, Kavanaugh A, Kalden JR et al. Performance of response criteria for assessing peripheral arthritis in patients with psoriatic arthritis: analysis of data from randomised controlled trials of two tumour necrosis factor inhibitors. Ann Rheum Dis 2006; 65: 1373–1378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Braun J, Davis J, Dougados M, Sieper J, van der Linden S, van der Heijde D . First update of the international ASAS consensus statement for the use of anti-TNF agents in patients with ankylosing spondylitis. Ann Rheum Dis 2006; 65: 316–320.

    Article  CAS  PubMed  Google Scholar 

  21. Fabris M, Di Poi E, D'Elia A, Damante G, Sinigaglia L, Ferraccioli G . Tumor necrosis factor-alpha gene polymorphism in severe and mild-moderate rheumatoid arthritis. J Rheumatol 2002; 29: 29–33.

    CAS  PubMed  Google Scholar 

  22. Al-Ansari AS, Ollier WE, Villarreal J, Ordi J, Teh LS, Hajeer AH . Tumor necrosis factor receptor II (TNFRII) exon 6 polymorphism in systemic lupus erythematosus. Tissue Antigens 2000; 55: 97–99.

    Article  CAS  PubMed  Google Scholar 

  23. Fabris M, Quartuccio L, Lombardi S, Saracco M, Atzeni F, Carletto A et al. The CC homozygosis of the -174G>C IL-6 polymorphism predicts a lower efficacy of rituximab therapy inrheumatoid arthritis. Autoimmun Rev 2012; 11: 315–320.

    Article  CAS  PubMed  Google Scholar 

  24. Esteve E, Villuendas G, Mallolas J, Vendrell J, López-Bermejo A, Rodríguez M et al. Polymorphism in the interleukin-6 receptor gene are associated with body mass index and with characteristics of the metabolic syndrome. Clin Endocrinol(Oxford) 2006; 65: 88–91.

    Article  CAS  Google Scholar 

  25. Quartuccio L, Fabris M, Pontarini E, Salvin S, Zabotti A, Benucci M et al. The 158VV Fcgamma receptor 3A genotype is associated with response to rituximab in rheumatoid arthritis: results of an Italian multicentre study. Ann Rheum Dis 2014; 73: 716–721.

    Article  CAS  PubMed  Google Scholar 

  26. Sugiura Y, Niimi T, Sato S, Yoshinouchi T, Banno S, Naniwa T et al. Transforming growth factor beta1 gene polymorphism in rheumatoid arthritis. Ann Rheum Dis 2002; 61: 826–828.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Umićević Mirkov M, Janss L, Vermeulen SH, van de Laar MA, van Riel PL, Guchelaar HJ et al. Estimation of heritability of different outcomes for genetic studies of TNFi response in patients with rheumatoid arthritis. Ann Rheum Dis e-pub ahead of print 11 August 2014.

  28. Hreggvidsdottir HS, Noordenbos T, Baeten DL . Inflammatory pathways in spondyloarthritis. Mol Immunol 2014; 57: 28–37.

    Article  CAS  PubMed  Google Scholar 

  29. Panoulas VF, Stavropoulos-Kalinoglou A, Metsios GS, Smith JP, Milionis HJ, Douglas KM et al. Association of interleukin-6 (IL-6)-174G/C gene polymorphism with cardiovascular disease in patients with rheumatoid arthritis: the role of obesity and smoking. Atherosclerosis 2009; 204: 178–183.

    Article  CAS  PubMed  Google Scholar 

  30. Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 1998; 102: 1369–1376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pedersen SJ, Sørensen IJ, Garnero P, Johansen JS, Madsen OR, Tvede N et al. ASDAS, BASDAI and different treatment responses and their relation to biomarkers of inflammation, cartilage and bone turnover in patients with axial spondyloarthritis treated with TNF -inhibitors. Ann Rheum Dis 2011; 70: 1375–1381.

    Article  CAS  PubMed  Google Scholar 

  32. Schoels MM, van der Heijde D, Breedveld FC, Burmester GR, Dougados M, Emery P et al. Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systematic literature review and meta-analysis informing a consensus statement. Ann Rheum Dis 2013; 72: 583–589.

    Article  CAS  PubMed  Google Scholar 

  33. Sieper J, Porter-Brown B, Thompson L, Harari O, Dougados M . Assessment of short-term symptomatic efficacy ot tocilizumab in ankylosing spondylitis: results of randomized, placebo controlled trials. Ann Rheum Dis 2014; 73: 95–100.

    Article  CAS  PubMed  Google Scholar 

  34. Brulhart L, Nissen MJ, Chevallier P, Gabay C . Tocilizumab in a patient with ankylosing spondylitis and Crohn's disease refractory to TNF antagonists. Joint Bone Spine 2010; 77: 625–626.

    Article  PubMed  Google Scholar 

  35. Luc M, Gossec L, Ruyssen-Witrand A, Salliot C, Duclos M, Guignard S et al. C-reactive protein predicts tumor necrosis factor-alpha blocker retention rate in axial ankylosing spondylitis. J Rheumatol 2007; 34: 2078–2081.

    CAS  PubMed  Google Scholar 

  36. Jančić I, Arsenović-Ranin N, Sefik-Bukilica M, Zivojinović S, Damjanov N, Spasovski V et al. -174G/C interleukin-6 gene promoter polymorphism predicts therapeutic response to etanercept in rheumatoid arthritis. Rheumatol Int 2013; 33: 1481–1486.

    Article  PubMed  Google Scholar 

  37. Dávila-Fajardo CL, Márquez A, Pascual-Salcedo D, Moreno Ramos MJ, García-Portales R, Magro C et al. Confirmation of -174G/C interleukin-6 gene promoter polymorphism as a genetic marker predicting antitumor necrosis factor treatment outcome. Pharmacogenet Genomics 2014; 24: 1–5.

    Article  PubMed  Google Scholar 

  38. Cañete JD, Suárez B, Hernández MV, Sanmartí R, Rego I, Celis R et al. Influence of variants of Fc gamma receptors IIA and IIIA on the American College of Rheumatology and European League Against Rheumatism responses to anti-tumour necrosis factor alpha therapy in rheumatoid arthritis. Ann Rheum Dis 2009; 68: 1547–1552.

    Article  PubMed  Google Scholar 

  39. Ramírez J, Fernández-Sueiro JL, López-Mejías R, Montilla C, Arias M, Moll C et al. FCGR2A/CD32A and FCGR3A/CD16A variants and EULAR response to tumor necrosis factor-α blockers in psoriatic arthritis: a longitudinal study with 6 months of followup. J Rheumatol 2012; 39: 1035–1041.

    Article  PubMed  Google Scholar 

  40. Kristensen LE, Karlsson JA, Englund M, Petersson IF, Saxne T, Geborek P . Presence of peripheral arthritis and male sex predicting continuation of anti-tumor necrosis factor therapy in ankylosing spondylitis: an observational prospective cohort study from the South Swedish Arthritis Treatment Group Register. Arthritis Care Res 2010; 62: 1362–1369.

    Article  CAS  Google Scholar 

  41. Zufferey P, Ghosn J, Becce F, Ciurea A, Aubry-Rozier B, Finckh A et al. Anti-tumor necrosis factor drug survival in axial spondyloarthritis is independent of the classification criteria. Rheumatol Int 2014; 35: 295–302.

    Article  PubMed  Google Scholar 

  42. Paramarta JE, De Rycke L, Ambarus CA, Tak PP, Baeten D . Undifferentiated spondyloarthritis vs ankylosing spondylitis and psoriatic arthritis: a real-life prospective cohort study of clinical presentation and response to treatment. Rheumatology (Oxford) 2013; 52: 1873–1878.

    Article  CAS  Google Scholar 

  43. Baeten D, Breban M, Lories R, Schett G, Sieper J . Are spondylarthritides related but distinct conditions or a single disease with a heterogeneous phenotype? Arthritis Rheum 2013; 65: 12–20.

    Article  PubMed  Google Scholar 

  44. Wendling D, Guillot X, Prati C . The IL-23/Th17 pathway in spondyloarthritis: The Royal Road? Joint Bone Spine 2014; 65: 1–4.

    Google Scholar 

Download references

Acknowledgements

Dr CF is currently receiving a fellowship from the University-Hospital of Udine.

Author information

Author notes

  1. M Fabris and L Quartuccio: MF and LQ contributed equally to this study.

Authors and Affiliations

  1. Clinical Pathology,

    M Fabris & F Curcio

  2. , University-Hospital of Udine, Udine, Italy

    M Fabris & F Curcio

  3. Department of Medical and Biological Sciences, University of Udine, Udine, Italy

    M Fabris, L Quartuccio, F Curcio & S De Vita

  4. Rheumatology, University-Hospital of Udine, Udine, Italy

    L Quartuccio, C Fabro, S Sacco & S De Vita

  5. Institute of Physical Medicine and Rehabilitation ‘Gervasutta’, Udine, Italy

    S Lombardi

  6. Department of Medicine, Rheumatology Unit, University of Padova, Padova, Italy

    R Ramonda & D Punzi

  7. Department of Medicine, Section of Rheumatology, University of Verona, Verona, Italy

    D Biasi & S Adami

  8. Rheumatology Department of Lucania, San Carlo Hospital of Potenza, Potenza, Italy

    I Olivieri

Authors
  1. M Fabris
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Quartuccio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Fabro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Sacco
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Lombardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R Ramonda
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D Biasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D Punzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S Adami
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. I Olivieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. F Curcio
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. S De Vita
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S De Vita.

Ethics declarations

Competing interests

The authors delare no conflicts of intrest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fabris, M., Quartuccio, L., Fabro, C. et al. The -308 TNFα and the -174 IL-6 promoter polymorphisms associate with effective anti-TNFα treatment in seronegative spondyloarthritis. Pharmacogenomics J 16, 238–242 (2016). https://doi.org/10.1038/tpj.2015.49

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2015.49

This article is cited by

Search

Advanced search

Quick links