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The effect of extra-articular manifestations on tumor necrosis factor-α inhibitor treatment duration in patients with ankylosing spondylitis: nationwide data from the Korean College of Rheumatology BIOlogics (KOBIO) registry

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Abstract

Tumor necrosis factor-α inhibitor (TNFi) therapy has shown to be remarkably effective for treating ankylosing spondylitis (AS); however, nearly 30% of AS patients every year either stop TNFi therapy or switch to a different TNFi due to inefficacy or adverse effects. The goal of this study was to identify predictors of TNFi treatment duration, including extra-articular manifestations, using a nationwide registry in Korea. Data obtained from the Korean College of Rheumatology Biologics (KOBIO) registry, a nationwide, multi-center database representing 58 tertiary care hospitals in Korea. Demographics, clinical features, laboratory findings, disease activity indices (BASDAI, ASDAS-ESR, ASDAS-CRP), peripheral arthritis, and extra-articular manifestations (uveitis, enthesitis, dactylitis, psoriasis, and inflammatory bowel disease) were studied in patients with AS during TNFi therapy. We also analyzed treatment duration outcomes for five TNFi agents (etanercept, infliximab, infliximab biosimilar, adalimumab, and golimumab), as well as factors associated with treatment duration, particularly in terms of extra-articular manifestations. Univariable and multivariable Cox regression analyses were performed to verify preliminary results. A total 1482 AS patients starting TNFi drug therapy between Dec. 2012 and Jan. 2017 were included. No differences in demographics, disease activity, or extra-articular manifestations were evident between continued and discontinued TNFi groups at baseline, though baseline differences were detected for gender distribution, CRP, platelet counts, and HLA-B27 positivity. During treatment period, the effects of extra-articular manifestations, including uveitis (unadjusted hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.57 to 1.48, p = 0.74), enthesitis, dactylitis, psoriasis, and inflammatory bowel disease, on TNFi treatment duration were not statistically significant. By contrast, the occurrence of peripheral arthritis was significantly associated with shorter TNFi treatment duration (unadjusted HR 2.21, 95% CI 1.66 to 2.95; adjusted HR 1.38, 95% CI 1.01 to 1.88). Among disease activity indices, higher ASDAS-ESR levels were significantly associated with shortening of the TNFi treatment duration (unadjusted HR 1.87, 95% CI 1.73 to 2.03; adjusted HR 2.23, 95% CI 2.00 to 2.63). Among TNFi drugs, golimumab had a lower discontinuation rate than that of etanercept over a 3-year follow-up period (unadjusted HR 0.46, 95% CI 0.31 to 0.68; adjusted HR 0.65, 95% CI 0.43 to 0.99). In a nationwide KOBIO registry, extra-articular manifestations, including uveitis, were not associated with TNFi treatment duration. Among clinical cofactors, the development of peripheral arthritis during TNFi therapy was associated with a higher risk of TNFi treatment discontinuance in AS patients.

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References

  1. Gorman JD, Sack KE, Davis JC Jr (2002) Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med 346(18):1349–1356. https://doi.org/10.1056/NEJMoa012664

    Article  CAS  PubMed  Google Scholar 

  2. Braun J, Pham T, Sieper J, Davis J, van der Linden S, Dougados M, van der Heijde D (2003) International ASAS consensus statement for the use of anti-tumour necrosis factor agents in patients with ankylosing spondylitis. Ann Rheum Dis 62(9):817–824

    Article  CAS  Google Scholar 

  3. van der Heijde D, Dijkmans B, Geusens P, Sieper J, DeWoody K, Williamson P, Braun J (2005) Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum 52(2):582–591. https://doi.org/10.1002/art.20852

    Article  CAS  PubMed  Google Scholar 

  4. Davis JC Jr, Van Der Heijde D, Braun J, Dougados M, Cush J, Clegg DO, Kivitz A, Fleischmann R, Inman R, Tsuji W (2003) Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheum 48(11):3230–3236. https://doi.org/10.1002/art.11325

    Article  CAS  PubMed  Google Scholar 

  5. van der Heijde D, Kivitz A, Schiff MH, Sieper J, Dijkmans BA, Braun J, Dougados M, Reveille JD, Wong RL, Kupper H, Davis JC Jr (2006) Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 54(7):2136–2146. https://doi.org/10.1002/art.21913

    Article  CAS  PubMed  Google Scholar 

  6. Inman RD, Davis JC Jr, Heijde D, Diekman L, Sieper J, Kim SI, Mack M, Han J, Visvanathan S, Xu Z, Hsu B, Beutler A, Braun J (2008) Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheum 58(11):3402–3412. https://doi.org/10.1002/art.23969

    Article  CAS  PubMed  Google Scholar 

  7. Glintborg B, Ostergaard M, Krogh NS, Dreyer L, Kristensen HL, Hetland ML (2010) Predictors of treatment response and drug continuation in 842 patients with ankylosing spondylitis treated with anti-tumour necrosis factor: results from 8 years’ surveillance in the Danish nationwide DANBIO registry. Ann Rheum Dis 69(11):2002–2008. https://doi.org/10.1136/ard.2009.124446

    Article  CAS  PubMed  Google Scholar 

  8. Rosales-Alexander JL, Balsalobre Aznar J, Perez-Vicente S, Magro-Checa C (2015) Drug survival of anti-tumour necrosis factor alpha therapy in spondyloarthropathies: results from the Spanish emAR II study. Rheumatology (Oxford, England) 54(8):1459–1463. https://doi.org/10.1093/rheumatology/kev001

    Article  Google Scholar 

  9. Bearne LM, Byrne AM, Segrave H, White CM (2016) Multidisciplinary team care for people with rheumatoid arthritis: a systematic review and meta-analysis. Rheumatol Int 36(3):311–324. https://doi.org/10.1007/s00296-015-3380-4

    Article  CAS  PubMed  Google Scholar 

  10. Lie E, van der Heijde D, Uhlig T, Mikkelsen K, Rodevand E, Koldingsnes W, Kaufmann C, Kvien TK (2011) Effectiveness of switching between TNF inhibitors in ankylosing spondylitis: data from the NOR-DMARD register. Ann Rheum Dis 70(1):157–163. https://doi.org/10.1136/ard.2010.131797

    Article  CAS  PubMed  Google Scholar 

  11. Glintborg B, Ostergaard M, Krogh NS, Tarp U, Manilo N, Loft AG, Hansen A, Schlemmer A, Fana V, Lindegaard HM, Nordin H, Rasmussen C, Ejstrup L, Jensen DV, Petersen PM, Hetland ML (2013) Clinical response, drug survival and predictors thereof in 432 ankylosing spondylitis patients after switching tumour necrosis factor alpha inhibitor therapy: results from the Danish nationwide DANBIO registry. Ann Rheum Dis 72(7):1149–1155. https://doi.org/10.1136/annrheumdis-2012-201933

    Article  CAS  PubMed  Google Scholar 

  12. Hyrich KL, Watson KD, Silman AJ, Symmons DP (2006) Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford, England) 45(12):1558–1565. https://doi.org/10.1093/rheumatology/kel149

    Article  CAS  Google Scholar 

  13. Elewaut D, Matucci-Cerinic M (2009) Treatment of ankylosing spondylitis and extra-articular manifestations in everyday rheumatology practice. Rheumatology (Oxford, England) 48(9):1029–1035. https://doi.org/10.1093/rheumatology/kep146

    Article  CAS  Google Scholar 

  14. Stolwijk C, van Tubergen A, Castillo-Ortiz JD, Boonen A (2015) Prevalence of extra-articular manifestations in patients with ankylosing spondylitis: a systematic review and meta-analysis. Ann Rheum Dis 74(1):65–73. https://doi.org/10.1136/annrheumdis-2013-203582

    Article  PubMed  Google Scholar 

  15. Guignard S, Gossec L, Salliot C, Ruyssen-Witrand A, Luc M, Duclos M, Dougados M (2006) Efficacy of tumour necrosis factor blockers in reducing uveitis flares in patients with spondylarthropathy: a retrospective study. Ann Rheum Dis 65(12):1631–1634. https://doi.org/10.1136/ard.2006.052092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wendling D, Paccou J, Berthelot JM, Flipo RM, Guillaume-Czitrom S, Prati C, Dernis E, Direz G, Ferrazzi V, Ristori JM (2011) New onset of uveitis during anti-tumor necrosis factor treatment for rheumatic diseases. Semin Arthritis Rheum 41(3):503–510. https://doi.org/10.1016/j.semarthrit.2011.05.005

    Article  PubMed  Google Scholar 

  17. Chorus AM, Miedema HS, Boonen A, Van Der Linden S (2003) Quality of life and work in patients with rheumatoid arthritis and ankylosing spondylitis of working age. Ann Rheum Dis 62(12):1178–1184

    Article  CAS  Google Scholar 

  18. Wu D, Guo YY, Xu NN, Zhao S, Hou LX, Jiao T, Zhang N (2015) Efficacy of anti-tumor necrosis factor therapy for extra-articular manifestations in patients with ankylosing spondylitis: a meta-analysis. BMC Musculoskelet Disord 16:19. https://doi.org/10.1186/s12891-015-0489-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kristensen LE, Karlsson JA, Englund M, Petersson IF, Saxne T, Geborek P (2010) 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 62(10):1362–1369. https://doi.org/10.1002/acr.20258

    Article  CAS  Google Scholar 

  20. Kang JH, Park DJ, Lee JW, Lee KE, Wen L, Kim TJ, Park YW, Lee SS (2014) Drug survival rates of tumor necrosis factor inhibitors in patients with rheumatoid arthritis and ankylosing spondylitis. J Korean Med Sci 29(9):1205–1211. https://doi.org/10.3346/jkms.2014.29.9.1205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Arends S, Brouwer E, van der Veer E, Groen H, Leijsma MK, Houtman PM, Th AJTL, Kallenberg CG, Spoorenberg A (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 13(3):R94. https://doi.org/10.1186/ar3369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gulyas K, Bodnar N, Nagy Z, Szamosi S, Horvath A, Vancsa A, Vegh E, Szabo Z, Szucs G, Szekanecz Z, Szanto S (2014) Real-life experience with switching TNF-alpha inhibitors in ankylosing spondylitis. The European journal of health economics : HEPAC : health economics in prevention and care 15(Suppl 1):S93–S100. https://doi.org/10.1007/s10198-014-0598-0

    Article  PubMed  Google Scholar 

  23. Ciurea A, Exer P, Weber U, Tamborrini G, Steininger B, Kissling RO, Bernhard J, Scherer A (2016) Does the reason for discontinuation of a first TNF inhibitor influence the effectiveness of a second TNF inhibitor in axial spondyloarthritis? Results from the Swiss Clinical Quality Management Cohort. Arthritis Res Ther 18:71. https://doi.org/10.1186/s13075-016-0969-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fisher A, Bassett K, Goel G, Stanely D, Brookhart MA, Freeman HR, Wright JM, Dormuth CR (2016) Heterogeneity in comparisons of discontinuation of tumor necrosis factor antagonists in rheumatoid arthritis—a meta-analysis. PLoS One 11(12):e0168005. https://doi.org/10.1371/journal.pone.0168005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Souto A, Maneiro JR, Gomez-Reino JJ (2016) Rate of discontinuation and drug survival of biologic therapies in rheumatoid arthritis: a systematic review and meta-analysis of drug registries and health care databases. Rheumatology (Oxford, England) 55(3):523–534. https://doi.org/10.1093/rheumatology/kev374

    Article  CAS  Google Scholar 

  26. Corbett M, Soares M, Jhuti G, Rice S, Spackman E, Sideris E, Moe-Byrne T, Fox D, Marzo-Ortega H, Kay L, Woolacott N, Palmer S (2016) Tumour necrosis factor-alpha inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis: a systematic review and economic evaluation. Health technology assessment (Winchester, England) 20(9):1–334, v-vi. https://doi.org/10.3310/hta20090

    Article  Google Scholar 

  27. Thygesen LC, Ersboll AK (2014) When the entire population is the sample: strengths and limitations in register-based epidemiology. Eur J Epidemiol 29(8):551–558. https://doi.org/10.1007/s10654-013-9873-0

    Article  PubMed  Google Scholar 

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Acknowledgements

The data was provided from the Clinical Research Committee of the Korean College of Rheumatology and thanks to all participating hospitals.

Funding

This study is supported by fund of the Soonchunhyang University.

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Authors and Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea

    Yunsuek Kim & Hyun-Sook Kim

  2. Department of Biostatistics, College of Medicine, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea

    Suyeon Park

  3. Division of Rheumatology, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, 59 Daesagwan-ro, Yongsan-gu, Seoul, 04401, Republic of Korea

    Hyun-Sook Kim

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  1. Yunsuek Kim
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Correspondence to Hyun-Sook Kim.

Ethics declarations

This research complied with the Helsinki Declaration. Informed consent was obtained from all enrolled participants. The same informed consent form (ICF) and study protocol were provided to the independent institutional review boards/ethics committees (IRB/EC) at each medical center, and each IRB/EC reviewed the appropriateness of the protocol, risks, and benefits to the study participants. Ultimately, the IRB/EC independently approved this study without revision of the ICF or study protocol.

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Kim, Y., Park, S. & Kim, HS. The effect of extra-articular manifestations on tumor necrosis factor-α inhibitor treatment duration in patients with ankylosing spondylitis: nationwide data from the Korean College of Rheumatology BIOlogics (KOBIO) registry. Clin Rheumatol 37, 3275–3284 (2018). https://doi.org/10.1007/s10067-018-4290-0

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