Skip to main content

Advertisement

SpringerLink
Log in

Candidate’s single-nucleotide polymorphism predictors of treatment nonresponse to the first anti-TNF inhibitor in ankylosing spondylitis

  • Original Article
  • Published:
Rheumatology International Aims and scope Submit manuscript

Abstract

The objective of this study is to identify single-nucleotide polymorphisms (SNPs) predictors of treatment nonresponse to the first anti-TNF-alpha agent in ankylosing spondylitis (AS). Patients were classified as “nonresponders” if they failed to achieve improvement ≥50 % of the initial BASDAI. We selected candidate SNPs previously reported, associated with susceptibility or pathogenesis of AS and with other spondylarthropaties (SpAs). The predictors of nonresponse were modeled with multiple logistic regression. The predictive power of the genetic model of nonresponse to treatment was tested with AUC-ROC. One hundred and twenty-one (121) AS patients fulfilled the inclusion criteria. Of the candidate SNPs tested for association with treatment effectiveness, five independent predictors were identified: rs917997, rs755622, rs1800896, rs3740691, and rs1061622. The genetic model of nonresponse to treatment had a predictive power of 0.77 (95 % CI 0.68–0.86). Our study identified several polymorphisms which could be the useful genetic biomarkers in predicting nonresponse to anti-TNF-alpha therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Wright V (1978) Seronegative polyarthritis: a unified concept. Arthritis Rheum 21:619–633

    Article  CAS  PubMed  Google Scholar 

  2. Braun J, Bollow M, Neure L et al (1995) Use of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum 38:499–505

    Article  CAS  PubMed  Google Scholar 

  3. Braun J, Xiang J, Brandt J et al (2000) Treatment of spondyloarthropathies with antibodies against tumor necrosis factor α: first clinical and laboratory experiences. Ann Rheum Dis 59:i85–i89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Maksymowych W (2010) Disease modification in ankylosing spondylitis. Nat Rev Rheumatol 6:75–81

    Article  PubMed  Google Scholar 

  5. van der Heijde D, Dijkmans B, Geusens P et al (2005) Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum 52:582–591

    Article  PubMed  Google Scholar 

  6. Davis JC Jr, van der Heijde D, Braun J et al (2003) Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheum 48:3230–3236

    Article  CAS  PubMed  Google Scholar 

  7. van der Heijde D, Kivitz A, Schiff MH et al (2006) Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 54:2136–2146

    Article  PubMed  Google Scholar 

  8. Braun J, Deodhar A, Inman RD et al (2012) Golimumab administered subcutaneously every 4 weeks in ankylosing spondylitis: 104-week results of the GO-RAISE study. Ann Rheum Dis 71:661–667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Davis JC Jr, van der Heijde DM, Dougados M et al (2005) Baseline factors that influence ASAS 20 response in patients with ankylosing spondylitis treated with etanercept. J Rheumatol 32:1751–1754

    CAS  PubMed  Google Scholar 

  10. Rudwaleit M, Listing J, Brandt J, Braun J, Sieper J (2004) Prediction of a major clinical response (BASDAI 50) to tumour necrosis factor alpha blockers in ankylosing spondylitis. Ann Rheum Dis 63:665–670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Vastesaeger N, van der Heijde D, Inman RD et al (2011) Predicting the outcome of ankylosing spondylitis therapy. Ann Rheum Dis 70:973–981

    Article  PubMed  PubMed Central  Google Scholar 

  12. Rudwaleit M, Claudepierre P, Wordsworth P et al (2009) Effectiveness, safety, and predictors of good clinical response in 1,250 patients treated with adalimumab for active ankylosing spondylitis. J Rheumatol 36:801–810

    Article  CAS  PubMed  Google Scholar 

  13. Lord PA, Farragher TM, Lunt M, Watson KD, Symmons DP, Hyrich KL (2010) Predictors of response to anti-TNF therapy in ankylosing spondylitis: results from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford) 49:563–570

    Article  CAS  Google Scholar 

  14. Arends S, Brouwer E, van der Veer E et al (2011) Baseline predictors of response and discontinuation of tumor necrosis factor-alpha blocking therapy in ankylosing spondylitis: a prospective longitudinal observational cohort study. Arthritis Res Ther 20(13):R94

    Article  Google Scholar 

  15. Can M, Aydın SZ, Niğdelioğlu A, Atagündüz P, Direskeneli H (2012) Conventional DMARD therapy (methotrexate–sulphasalazine) may decrease the requirement of biologics in routine practice of ankylosing spondylitis patients: a real-life experience. Int J Rheum Dis 15:526–530

    Article  CAS  PubMed  Google Scholar 

  16. Chen J, Veras MM, Liu C, Lin J (2013) Methotrexate for ankylosing spondylitis. Cochrane Database Syst Rev 28(2):CD004524

    Google Scholar 

  17. Chen J, Liu C (2005) Sulfasalazine for ankylosing spondylitis. Cochrane Database Syst Rev 18(2):CD004800

    Google Scholar 

  18. Baraliakos X, Brandt J, Listing J et al (2005) Outcome of patients with active ankylosing spondylitis after two years of therapy with etanercept: clinical and magnetic resonance imaging data. Arthritis Rheum 53:856–863

    Article  CAS  PubMed  Google Scholar 

  19. Baraliakos X, Listing J, Fritz C et al (2011) Persistent clinical efficacy and safety of infliximab in ankylosing spondylitis after 8 years-early clinical response predicts long-term outcome. J Rheumatol (Oxford) 50:1690–1699

    Article  CAS  Google Scholar 

  20. Poddubnyy DA, Märker-Hermann E, Kaluza-Schilling W et al (2011) Relation of HLA-B27, tumor necrosis factor-α promoter gene polymorphisms, and T cell cytokine production in ankylosing spondylitis—a comprehensive genotype-phenotype analysis from an observational cohort. J Rheumatol 38:2436–2441

    Article  CAS  PubMed  Google Scholar 

  21. Seitz M, Wirthmu¨ ller U, Moller B, Villiger PM (2007) The −308 tumour necrosis factor-gene polymorphismpredicts therapeutic response to TNF-blockers in rheumatoid arthritis and spondyloarthritis patients. Rheumatology 46:93–96

    Article  CAS  PubMed  Google Scholar 

  22. Collantes E, Zarco P, Munoz E et al (2007) Disease pattern of spondyloarthropathies in Spain: description of the first national registry (REGISPONSER) extended report. Rheumatology (Oxford) 46:1309–1315

    Article  CAS  Google Scholar 

  23. Schiotis R, Font P, Escudero E et al (2011) Usefulness of a centralized system of data collection for the development of an international multicentre registry of spondyloarthritis. Rheumatology (Oxford) 50:132–136

    Article  Google Scholar 

  24. Van der Linden S, Valkenburg HA, Cats A (1984) Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 27:361–368

    Article  PubMed  Google Scholar 

  25. Fan JB, Oliphant A, Shen R et al (2003) Highly parallel SNP genotyping. Cold Spring Harb Symp Quant Biol 68:69–78

    Article  CAS  PubMed  Google Scholar 

  26. Paynter RA, Skibola DR, Skibola CF et al (2006) Accuracy of multiplexed Illumina platform-based single-nucleotide polymorphism genotyping compared between genomic and whole genome amplified DNA collected from multiple sources. Cancer Epidemiol Biomarkers Prev 15:2533–2536

    Article  CAS  PubMed  Google Scholar 

  27. Reich D, Patterson N, De Jager PL et al (2005) A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility. Nat Genet 37:1113–1118

    Article  CAS  PubMed  Google Scholar 

  28. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 15(21):263–265

    Article  Google Scholar 

  29. Glintborg B, Østergaard M, Krogh NS et al (2013) Clinical response, drug survival and predictors thereof in 432 ankylosing spondylitis patients after switching tumour necrosis factor α inhibitor therapy: results from the Danish nationwide DANBIO registry. Ann Rheum Dis 72:1149–1155

    Article  CAS  PubMed  Google Scholar 

  30. Okamura H, Tsutsui H, Kashiwamura S, Yoshimoto T, Nakanishi K (1998) Regulation of interferon-_ production by IL-12 and IL-18. Curr Opin Immunol 10:259–264

    Article  CAS  PubMed  Google Scholar 

  31. de Jager W, Vastert SJ, Beekman JM et al (2009) Defective phosphorylation of interleukin-18 receptor beta causes impaired natural killer cell function in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 60:2782–2793

    Article  PubMed  Google Scholar 

  32. Hunt KA, Zhernakova A, Turner G et al (2008) Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet 40:395–402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhernakova A, Festen EM, Franke L et al (2008) Genetic analysis of innate immunity in Crohn’s disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP. Am J Hum Genet 82:1202–1210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Eder L, Chandran V, Ueng J et al (2010) Predictors of response to intra-articular steroid injection in psoriatic arthritis. Rheumatology (Oxford) 49:1367–1373

    Article  Google Scholar 

  35. Radstake TR, Sweep FC, Welsing P et al (2005) Correlation of rheumatoid arthritis severity with the genetic functional variants and circulating levels of macrophage migration inhibitory factor. Arthritis Rheum 52:3020–3029

    Article  CAS  PubMed  Google Scholar 

  36. Lauten M, Matthias T, Stanulla M, Beger C, Welte K, Schrappe M (2002) Association of initial response to prednisone treatment in childhood acute lymphoblastic leukaemia and polymorphisms within the tumor necrosis factor and the interleukin-10 genes. Leukemia 16:1437–1442

    Article  CAS  PubMed  Google Scholar 

  37. Middleton PG, Taylor PR, Jackson G, Proctor SJ, Dickinson AM (1998) Cytokine gene polymorphisms associating with severe acute graft-versus-host disease in HLA-identical sibling transplants. Blood 92:3943–3948

    CAS  PubMed  Google Scholar 

  38. de Paz B, Alperi-López M, Ballina-García FJ, Prado C, Mozo L, Gutiérrez C, Suárez A (2010) Interleukin 10 and tumor necrosis factor-alpha genotypes in rheumatoid arthritis-association with clinical response to glucocorticoids. J Rheumatol 37:503–511

    Article  PubMed  Google Scholar 

  39. Wajant H, Pfizenmaier K, Scheurich P (2003) Tumor necrosis factor signaling. Cell Death Differ 10:45–65

    Article  CAS  PubMed  Google Scholar 

  40. Grell M, Douni E, Wajant H et al (1995) The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell 83:793–802

    Article  CAS  PubMed  Google Scholar 

  41. Kim EY, Priatel JJ, Teh SJ, Teh HS (2006) TNF receptor type 2 (p75) Functions as a costimulator for antigen-driven T cell responses in vivo. J Immunol 176:1026–1035

    Article  CAS  PubMed  Google Scholar 

  42. Cope AP, Aderka D, Doherty M et al (1992) Increased levels of soluble tumor necrosis factor receptors in the sera and synovial fluid of patients with rheumatic diseases. Arthritis Rheum 35:1160–1169

    Article  CAS  PubMed  Google Scholar 

  43. Deleuran BW, Chu C-Q, Field M et al (1992) Localization of tumor necrosis factor receptors in the synovial tissue and cartilage-pannus junction in patients with rheumatoid arthritis: implications for local actions of tumor necrosis factor. Arthritis Rheum 35:1170–1178

    Article  CAS  PubMed  Google Scholar 

  44. Tolusso B, Sacco S, Gremese E, La Torre G, Tomietto P, Ferraccioli GF (2004) Relationship between the tumor necrosis factor receptor II (TNF-RII) gene polymorphism and sTNF-RII plasma levels in healthy controls and in rheumatoid arthritis. Hum Immunol 65:1420–1426

    Article  CAS  PubMed  Google Scholar 

  45. Glossop JR, Dawes PT, Nixon NB, Mattey DL (2005) Polymorphism in the tumour necrosis factor receptor II gene is associated with circulating levels of soluble tumour necrosis factor receptors in rheumatoid arthritis. Arthritis Res Ther 7:R1227–R1234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Fabris M, Tolusso B, Di Poi E, Assaloni R, Sinigaglia L, Ferraccioli G (2002) Tumor necrosis factor-alpha receptor II polymorphism in patients from southern Europe with mild-moderate and severe rheumatoid arthritis. Rheumatology 29:1847–1850

    CAS  Google Scholar 

  47. Pedersen SJ, Sørensen IJ, Garnero P et al (2011) ASDAS, BASDAI and different treatment responses and their relation to biomarkers of inflammation, cartilage and bone turnover in patients with axial spondyloarthritis treated with TNFα inhibitors. Ann Rheum Dis 70:1375–1381

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Authors would like to thank Pedro Zarco Montejo, Hospital FUNDACION ALCORCÓN, Jordi Gratacós Masmitjá, Hospital PARC TAULÍ, Xavier Juanola Roura Hospital BELLVITGE, Enrique Batlle Gualda, University Hospital ALICANTE, Pilar Fernández Dapica Hospital DOCE DE OCTUBRE, Luis F. Linares Ferrando Hospital VIRGEN DE LA ARRIXACA, Mª Elia Brito Brito Hospital RAMÓN Y CAJAL, Eduardo Cuende Quintana University Hospital PRÍNCIPE DE ASTURIAS, Carlos Vázquez Galeano Hospital SAN JORGE, Enrique Calero Secall University Hospital CARLOS HAYA, Carlos Rodríguez Lozano Hospital DOCTOR NEGRÍN, Rubén Queiro Silva University Hospital CENTRAL DE ASTURIAS, Antonio Juan Más Hospital. FUNDACIÓN SON LLATZER, Cristina Medrano Le Quement Hospital. INTERNACIONAL MERIMAR, Enrique Ornilla University Hospital NAVARRA, Carlos Montilla Morales University Hospital VIRGEN DE LA VEGA, Teresa Clavaguera Poch Hospital PALAMÓS, Mª Cruz Fernández Espartero Hospital MÓSTOLES, for providing helpful information about the patients included in REGISPONSER-AS cohort. This work was supported by the Spanish Ministry of Science and Innovation (Project PSE-01000-2006-1) and by Progenika Biopharma S.A. The author SR wishes to thank Prof. Simion Simon, PhD at University Babes Bolyai, Cluj-Napoca, for the internship at University Hospital, “Reina Sofia”, Cordoba, Spain provided from program cofinanced by The SECTORAL OPERATIONAL PROGRAMME HUMAN RESOURCES DEVELOPMENT, Contract POSDRU 6/1.5/S/3— “Doctoral studies: through science toward society”.

Conflict of interest

MS., N.B., M.A., A.M. and D.T. are currently employees of Progenika Biopharma, SA. A.S. is supported by an unrestricted Grant from Pfizer. This does not alter our compliance with all the policies on sharing data and materials. All the other authors have no conflicts of interest to declare.

Author information

Authors and Affiliations

  1. Department of Pharmacology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania

    Ruxandra Schiotis & Anca Buzoianu

  2. Department of Rheumatology, “Reina Sofia” Universitary Hospital, Instituto Maimónides de Investigación Biomedica de Córdoba (IMIBIC), University of Córdoba, Córdoba, Spain

    Ruxandra Schiotis, Alejandro Escudero, Pilar Font & Eduardo Collantes-Estévez

  3. Department of Rheumatology, “Puerta de Hierro Majadahonda” University Hospital, Madrid, Spain

    Alejandra Sánchez & Juan Mulero

  4. Department of R+D, Progenika Biopharma SA, Derio, Vizcaya, Spain

    Nerea Bartolomé, Magdalena Szczypiorska, Antonio Martínez, Diego Tejedor & Marta Artieda

Authors
  1. Ruxandra Schiotis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alejandra Sánchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alejandro Escudero
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nerea Bartolomé
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Magdalena Szczypiorska
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pilar Font
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Antonio Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Diego Tejedor
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marta Artieda
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Juan Mulero
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Anca Buzoianu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Eduardo Collantes-Estévez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ruxandra Schiotis.

Additional information

This study was carried out on behalf of the REGISPONSER Study Group.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schiotis, R., Sánchez, A., Escudero, A. et al. Candidate’s single-nucleotide polymorphism predictors of treatment nonresponse to the first anti-TNF inhibitor in ankylosing spondylitis. Rheumatol Int 34, 793–801 (2014). https://doi.org/10.1007/s00296-013-2913-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-013-2913-y

Keywords

Search

Navigation