Effective serum level of etanercept biosimilar and effect of antidrug antibodies on drug levels and clinical efficacy in Chinese patients with ankylosing spondylitis

  • Yidian Dong
  • Ping Li
  • Tingshuang Xu
  • Liqi BiEmail author
Original Article



To investigate the effective serum level of etanercept biosimilar in Chinese patients with ankylosing spondylitis (AS) who achieve AS Disease Activity Score-C-reactive protein (ASDAS-CRP) < 2.1, and the effect of antidrug antibodies on drug levels and clinical efficacy.


Our study enrolled 60 patients with AS who were treated with etanercept biosimilar. Serum and clinical data were collected at baseline and treatment weeks 4, 12, and 24. Drug levels and antidrug antibody levels were measured using an enzyme-linked immunosorbent assay while tumour necrosis factor (TNF)-α levels were measured using cytometric bead array. A receiver operating characteristic (ROC) curve was used to analyse effective serum level of etanercept biosimilar.


Patients with ASDAS-CRP ≥ 2.1 exhibited significantly lower drug levels than those with ASDAS-CRP < 2.1 did. The cut-off values of effective serum level of patients with AS who achieved ASDAS-CRP < 2.1 at weeks 4, 12, and 24 were 2.32, 2.12, and 2.36 μg/mL, respectively. Patients with drug levels above the cut-off value had lower Bath AS Disease Activity Index (BASDAI) and TNF-α levels. Antidrug antibodies had no effect on the Assessment of Spondylosis Arthritis International Society (ASAS) remission rates, but patients with antidrug antibodies had lower drug levels and higher TNF-α levels.


Detecting serum drug levels and antidrug antibody levels might facilitate estimation of the clinical efficacy and adjustment of medication regimen during etanercept biosimilar therapy in Chinese patients with AS.


Ankylosing spondylitis Biological therapy Drug monitoring Etanercept Pharmacokinetics 



The authors are grateful to the patients who were involved in this study, as well as the nurses and medical doctors for performing clinical assessments.


Yidian Dong contributed to the acquisition, analysis or interpretation of data, and drafting the manuscript. Ping Li contributed to the study conception and design. Tingshuang Xu contributed to the preservation of serum and supervision of the study. Liqi Bi contributed to the study conception and design and final approval of the version published.

Funding information

The authors also thank the support from national key research and development program of China (No. 2017YFC0909002).

Compliance with ethical standards



Ethical statement

This study was conducted in accordance with the ethical standards of the Helsinki Declaration and approved by the Ethical Committee of the China-Japan Union Hospital of Jilin University (approval number, 2015-wjw008). Each patient was selected following a rigorous process and provided written informed consent.

Supplementary material

10067_2018_4424_MOESM1_ESM.pdf (170 kb)
ESM 1 (PDF 169 kb)
10067_2018_4424_MOESM2_ESM.pdf (588 kb)
ESM 2 (PDF 588 kb)
10067_2018_4424_MOESM3_ESM.pdf (531 kb)
ESM 3 (PDF 530 kb)
10067_2018_4424_MOESM4_ESM.pdf (57 kb)
ESM 4 (PDF 56 kb)


  1. 1.
    Davis JC Jr, van der Heijde DM, Braun J et al (2008) Efficacy and safety of up to 192 weeks of etanercept therapy in patients with ankylosing spondylitis. Ann Rheum Dis 67:346–352CrossRefGoogle Scholar
  2. 2.
    Arends S, Brouwer E, Efde M et al (2017) Long-term drug survival and clinical effectiveness of etanercept treatment in patients with ankylosing spondylitis in daily clinical practice. Clin Exp Rheumatol 35:61–68Google Scholar
  3. 3.
    Ruwaard J, l’Ami MJ, Marsman AF et al (2018) Comparison of drug survival and clinical outcome in patients with ankylosing spondylitis treated with etanercept or adalimumab. Scand J Rheumatol 47:122–126CrossRefGoogle Scholar
  4. 4.
    Scheinberg MA, Kay J (2012) The advent of biosimilar therapies in rheumatology—“O brave new world”. Nat Rev Rheumatol 8:430–436CrossRefGoogle Scholar
  5. 5.
    Dörner T, Strand V, Castañeda-Hernández G, Ferraccioli G, Isaacs JD, Kvien TK, Martin-Mola E, Mittendorf T, Smolen JS, Burmester GR (2013) The role of biosimilars in the treatment of rheumatic diseases. Ann Rheum Dis 72:322–328CrossRefGoogle Scholar
  6. 6.
    An Y, Liu T, He D, Wu L, Li J, Liu Y, Bi L, Zhou B, Lin C, He L, Liu X, Li X, Yang N, Zhang Z, Song H, Wei W, Liu J, Bi Y, Li Z (2017) The usage of biological DMARDs and clinical remission of rheumatoid arthritis in China: a real-world large scale study. Clin Rheumatol 36:35–43CrossRefGoogle Scholar
  7. 7.
    De Stefano R, Frati E, De Quattro D, Menza L, Manganelli S (2014) Low doses of etanercept can be effective to maintain remission in ankylosing spondylitis patients. Clin Rheumatol 33:707–711Google Scholar
  8. 8.
    Moghimi J, Sheikhvatan M, Semnani V (2012) The use of low-dose etanercept as an alternative therapy for treatment of ankylosing spondylitis a case series. Rheumatol Int 32:2271–2274CrossRefGoogle Scholar
  9. 9.
    Kneepkens EL, Krieckaert CL, van der Kleij D et al (2015) Lower etanercept levels are associated with high disease activity in ankylosing spondylitis patients at 24 weeks of follow-up. Ann Rheum Dis 74:1825–1829CrossRefGoogle Scholar
  10. 10.
    Jamnitski A, Krieckaert CL, Nurmohamed MT, Hart MH, Dijkmans BA, Aarden L, Voskuyl AE, Wolbink GJ (2012) Patients non-responding to etanercept obtain lower etanercept concentrations compared with responding patients. Ann Rheum Dis 71:88–91CrossRefGoogle Scholar
  11. 11.
    Mok CC, van der Kleij D, Wolbink GJ (2013) Drug levels, anti-drug antibodies, and clinical efficacy of the anti-TNFα biologics in rheumatic diseases. Clin Rheumatol 32:1429–1435CrossRefGoogle Scholar
  12. 12.
    de Vries MK, Brouwer E, van der Horst-Bruinsma IE et al (2009) Decreased clinical response to adalimumab in ankylosing spondylitis is associated with antibody formation. Ann Rheum Dis 68:1787–1788CrossRefGoogle Scholar
  13. 13.
    de Vries MK, Wolbink GJ, Stapel SO, de Vrieze H, van Denderen JC, Dijkmans BAC, Aarden LA, van der Horst-Bruinsma IE (2007) Decreased clinical response to infliximab in ankylosing spondylitis is correlated with anti- infliximab formation. Ann Rheum Dis 66:1252–1254CrossRefGoogle Scholar
  14. 14.
    Arends S, Lebbink HR, Spoorenberg A et al (2010) The formation of autoantibodies and antibodies to TNF-α blocking agents in relation to clinical response in patients with ankylosing spondylitis. Clin Exp Rheumatol 28:661–668Google Scholar
  15. 15.
    Emi Aikawa N, de Carvalho JF, Artur Almeida Silva C, Bonfá E (2010) Immunogenicity of anti-TNF-α agents in autoimmune diseases. Clin Rev Allergy Immunol 38:82–89CrossRefGoogle Scholar
  16. 16.
    de Vries MK, van der Horst-Bruinsma IE, Nurmohamed MT et al (2009) Immunogenicity does not influence treatment with etanercept in patients with ankylosing spondylitis. Ann Rheum Dis 68:531–535CrossRefGoogle Scholar
  17. 17.
    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 27:361–368CrossRefGoogle Scholar
  18. 18.
    Garrett S, Jenkinson T, Kennedy LG et al (1994) A new approach to defining disease status in ankylosing spondylitis the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol 21:2286–2291Google Scholar
  19. 19.
    Braun J, Pham T, Sieper J, Davis J, van der Linden S, Dougados M, van der Heijde D, ASAS Working Group (2003) International ASAS consensus statement for the use of anti-tumour necrosis factor agents in patients with ankylosing spondylitis. Ann Rheum Dis 62:817–824CrossRefGoogle Scholar
  20. 20.
    Sieper J, Rudwaleit M, Baraliakos X et al (2009) The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis 68:1–44Google Scholar
  21. 21.
    Machado P, Landewé R, Lie E et al (2011) Ankylosing Spondylitis Disease Activity Score (ASDAS): defining cut-off values for disease activity states and improvement scores. Ann Rheum Dis 70:47–53CrossRefGoogle Scholar
  22. 22.
    van der Heijde D, Landewé R, Feldtkeller E (2008) Proposal of a linear definition of the Bath ankylosing spondylitis metrology index (BASMI) and comparison with the 2-step and 10-step definitions. Ann Rheum Dis 67:489–493CrossRefGoogle Scholar
  23. 23.
    Rojas JR, Taylor RP, Cunningham MR, Rutkoski TJ, Vennarini J, Jang H, Graham MA, Geboes K, Rousselle SD, Wagner CL (2005) Formation, distribution,and elimination of infliximab and anti-infliximab immune complexes in cynomolgus monkeys. J Pharmacol Exp Ther 313:578–585CrossRefGoogle Scholar
  24. 24.
    Kui R, Gál B, Gaál M, Kiss M, Kemény L, Gyulai R (2016) Presence of antidrug antibodies correlates inversely with the plasma tumor necrosis factor (TNF)-α level and the efficacy of TNF-inhibitor therapy in psoriasis. J Dermatol 43:1018–1023CrossRefGoogle Scholar
  25. 25.
    Schulz M, Dotzlaw H, Neeck G (2014) Ankylosing spondylitis and rheumatoid arthritis serum levels of TNF-α and its soluble receptors during the course of therapy with etanercept and infliximab. Biomed Res Int 2014:675108CrossRefGoogle Scholar
  26. 26.
    Zou J, Rudwaleit M, Brandt J, Thiel A, Braun J, Sieper J (2003) Up regulation of the production of tumour necrosis factor alpha and interferon gamma by T cells in ankylosing spondylitis during treatment with etanercept. Ann Rheum Dis 62:561–564CrossRefGoogle Scholar
  27. 27.
    Batycka-Baran A, Flaig M, Molin S, Ruzicka T, Prinz JC (2012) Etanercept-induced injection site reactions: potential pathomechanisms and clinical assessment. Expert Opin Drug Saf 11:911–921CrossRefGoogle Scholar
  28. 28.
    Lie E, Lindström U, Zverkova-Sandström T, Olsen IC, Forsblad-d’Elia H, Askling J, Kapetanovic MC, Kristensen LE, Jacobsson LTH (2017) Tumour necrosis factor inhibitor treatment and occurrence of anterior uveitis in ankylosing spondylitis: results from the Swedish biologics register. Ann Rheum Dis 76:1515–1521CrossRefGoogle Scholar
  29. 29.
    Wu B, Song Y, Leng L, Bucala R, Lu LJ (2015) Treatment of moderate rheumatoid arthritis with different strategies in a health resource-limited setting: a cost-effectiveness analysis in the era of biosimilars. Clin Exp Rheumatol 33:20–26Google Scholar
  30. 30.
    Olivieri I, D’Angelo S, Padula A, Leccese P, Nigro A, Palazzi C (2013) Can we reduce the dosage of biologics in spondyloarthritis? Autoimmun Rev 12:691–693CrossRefGoogle Scholar
  31. 31.
    Li J, Wang X, Han Z, Zhang Y, Wang Y, Zhang Y (2016) Dose reduction of recombinant human tumor necrosis factor inhibitors (etanercept) can be effective in ankylosing spondylitis patients with synovitis of the hip in a Chinese population. Int J Immunopathol Pharmacol 29:510–515CrossRefGoogle Scholar
  32. 32.
    Park JW, Yoon YI, Lee JH et al (2016) Low dose etanercept treatment for maintenance of clinical remission in ankylosing spondylitis. Clin Exp Rheumatol 34:592–599Google Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2019

Authors and Affiliations

  1. 1.Department of Rheumatology and ImmunologyChina-Japan Union Hospital of Jilin UniversityChangchunChina

Personalised recommendations