Skip to main content

Advertisement

Log in

Circulating levels of interleukin-6, vascular endothelial growth factor, YKL-40, matrix metalloproteinase-3, and total aggrecan in spondyloarthritis patients during 3 years of treatment with TNFα inhibitors

  • Brief Report
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract

The objectives of the study were to investigate short and long-term changes and relations to treatment response of plasma interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), YKL-40, matrix metalloproteinase-3 (MMP-3), and total aggrecan in patients with spondyloarthritis (SpA) treated with tumor necrosis factor-alpha (TNFα) inhibitors and to compare with levels in healthy subjects. Biomarkers were measured in an observational cohort of 49 SpA patients (ankylosing spondylitis, n = 32, and psoriatic arthritis, n = 17) initiating TNFα inhibitor therapy (infliximab, n = 38; etanercept, n = 8; and adalimumab, n = 3) and compared with levels in healthy subjects. Clinical parameters and biomarkers were measured at baseline, weeks 2, 6, and every 6–12 weeks for up to 3 years. Patients with co-morbidities (n = 4), missing baseline samples (n = 3), and adverse events (n = 5) were excluded. Patients with SpA had compared with healthy subjects elevated IL-6 (median 8.5 ng/l (range, 0.98–64) vs. 1.3 (0.33–26)), VEGF (105 ng/l (22–752) vs. 45 (12–351)), YKL-40 (74 μg/l (14–572) vs. 43 (20–184)), and MMP-3 (43 μg/l (9.1–401) vs. 16 (2.5–47), p ≤ 0.001), whereas total aggrecan was lower (662 μg/l (223–2,219) vs. 816 (399–2,190),p ≤ 0.001). Two weeks after first treatment, all biomarker levels changed towards normal levels (p ≤ 0.03) in clinical responders (n = 24), and persistent reductions over 3 years were found in IL-6, VEGF, YKL-40, and MMP-3. Only MMP-3 decreased (p ≤ 0.02) in non-responders (n = 13). The study demonstrated changes of plasma IL-6, VEGF, YKL-40, MMP-3, and total aggrecan and a potential value for monitoring disease activity and treatment response in SpA patients. Larger prospective studies are required to clarify clinical utility of these biomarkers.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Gladman DD, Antoni C, Mease P, Clegg DO, Nash P (2005) Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis 64:ii14–ii17

    Article  PubMed  Google Scholar 

  2. Sieper J, Braun J, Rudwaleit M, Boonen A, Zink A (2002) Ankylosing spondylitis: an overview. Ann Rheum Dis 61:iii8–iii18

    PubMed  Google Scholar 

  3. Sumer EU, Sondergaard BC, Rousseau JC, Delmas PD, Fosang AJ, Karsdal MA et al (2007) MMP and non-MMP-mediated release of aggrecan and its fragments from articular cartilage: a comparative study of three different aggrecan and glycosaminoglycan assays. Osteoarthritis Cartilage 15:212–221

    Article  CAS  PubMed  Google Scholar 

  4. Maksymowych WP (2009) What do biomarkers tell us about the pathogenesis of ankylosing spondylitis? Arthritis Res Ther 11:101

    Article  PubMed  Google Scholar 

  5. Hetland ML, Lindegaard HM, Hansen A, Podenphant J, Unkerskov J, Ringsdal VS et al (2008) Do changes in prescription practice in patients with rheumatoid arthritis treated with biological agents affect treatment response and adherence to therapy? Results from the nationwide Danish DANBIO Registry. Ann Rheum Dis 67:1023–1026

    Article  CAS  PubMed  Google Scholar 

  6. Pedersen OB, Hansen GO, Svendsen AJ, Ejstrup L, Junker P (2007) Adaptation of the Bath measures on disease activity and function in ankylosing spondylitis into Danish. Scand J Rheumatol 36:22–27

    Article  CAS  PubMed  Google Scholar 

  7. Braun J, Sieper J (2002) Building consensus on nomenclature and disease classification for ankylosing spondylitis: results and discussion of a questionnaire prepared for the International Workshop on New Treatment Strategies in Ankylosing Spondylitis, Berlin, Germany, 18-19 January 2002. Ann Rheum Dis 61:iii61–iii67

    PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Pham T, Guillemin F, Claudepierre P, Luc M, Miceli-Richard C, Fautrel B et al (2006) TNFalpha antagonist therapy in ankylosing spondylitis and psoriatic arthritis: recommendations of the French Society for Rheumatology. Joint Bone Spine 73:547–553

    Article  CAS  PubMed  Google Scholar 

  10. Maksymowych WP, Jhangri GS, Lambert RG, Mallon C, Buenviaje H, Pedrycz E et al (2002) Infliximab in ankylosing spondylitis: a prospective observational inception cohort analysis of efficacy and safety. J Rheumatol 29:959–965

    CAS  PubMed  Google Scholar 

  11. Vandooren B, Kruithof E, Yu DT, Rihl M, Gu J, De Rycke L et al (2004) Involvement of matrix metalloproteinases and their inhibitors in peripheral synovitis and down-regulation by tumor necrosis factor alpha blockade in spondylarthropathy. Arthritis Rheum 50:2942–2953

    Article  CAS  PubMed  Google Scholar 

  12. Visvanathan S, Wagner C, Marini JC, Baker D, Gathany T, Han J et al (2008) Inflammatory biomarkers, disease activity and spinal disease measures in patients with ankylosing spondylitis after treatment with infliximab. Ann Rheum Dis 67:511–517

    Article  CAS  PubMed  Google Scholar 

  13. Kruithof E, De Rycke L, Roth J, Mielants H, Van den Bosch F, De Keyser F et al (2005) Immunomodulatory effects of etanercept on peripheral joint synovitis in the spondylarthropathies. Arthritis Rheum 52:3898–3909

    Article  CAS  PubMed  Google Scholar 

  14. Maksymowych WP, Poole AR, Hiebert L, Webb A, Ionescu M, Lobanok T et al (2005) Etanercept exerts beneficial effects on articular cartilage biomarkers of degradation and turnover in patients with ankylosing spondylitis. J Rheumatol 32:1911–1917

    CAS  PubMed  Google Scholar 

  15. Appel H, Janssen L, Listing J, Heydrich R, Rudwaleit M, Sieper J (2008) Serum levels of biomarkers of bone and cartilage destruction and new bone formation in different cohorts of patients with axial spondyloarthritis with and without tumor necrosis factor-alpha blocker treatment. Arthritis Res Ther 10:R125

    Article  PubMed  Google Scholar 

  16. Maksymowych WP, Rahman P, Shojania K, Olszynski WP, Thomson GT, Ballal S et al (2008) Beneficial effects of adalimumab on biomarkers reflecting structural damage in patients with ankylosing spondylitis. J Rheumatol 35:2030–2037

    CAS  PubMed  Google Scholar 

  17. Braun J, Deodhar A, Dijkmans B, Geusens P, Sieper J, Williamson P et al (2008) Efficacy and safety of infliximab in patients with ankylosing spondylitis over a two-year period. Arthritis Rheum 59:1270–1278

    Article  CAS  PubMed  Google Scholar 

  18. Dijkmans B, Emery P, Hakala M, Leirisalo-Repo M, Mola EM, Paolozzi L et al (2009) Etanercept in the longterm treatment of patients with ankylosing spondylitis. J Rheumatol 36:1256–1264

    Article  CAS  PubMed  Google Scholar 

  19. Van Der Heijde D, Schiff MH, Sieper J, Kivitz A, Wong RL, Kupper H et al (2008) Adalimumab effectiveness for the treatment of ankylosing spondylitis is maintained for up to 2 years: long-term results from the ATLAS trial. Ann Rheum Dis 68:922–929

    Article  PubMed  Google Scholar 

  20. Antoni CE, Kavanaugh A, Van Der Heijde D, Beutler A, Keenan G, Zhou B et al (2008) Two-year efficacy and safety of infliximab treatment in patients with active psoriatic arthritis: findings of the Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT). J Rheumatol 35:869–876

    CAS  PubMed  Google Scholar 

  21. Mease PJ, Ory P, Sharp JT, Ritchlin CT, Van Den Bosch F, Wellborne F et al (2009) Adalimumab for long-term treatment of psoriatic arthritis: 2-year data from the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT). Ann Rheum Dis 68:702–709

    Article  CAS  PubMed  Google Scholar 

  22. Briot K, Roux C, Gossec L, Charni N, Kolta S, Dougados M et al (2008) Effects of etanercept on serum biochemical markers of cartilage metabolism in patients with spondyloarthropathy. J Rheumatol 35:310–314

    CAS  PubMed  Google Scholar 

  23. Davis JC Jr, van der Heijde DM, Dougados M, Braun J, Cush JJ, Clegg DO 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 

  24. Rudwaleit M, Schwarzlose S, Hilgert ES, Listing J, Braun J, Sieper J (2008) MRI in predicting a major clinical response to anti-tumour necrosis factor treatment in ankylosing spondylitis. Ann Rheum Dis 67:1276–1281

    Article  CAS  PubMed  Google Scholar 

  25. Rudwaleit M, Claudepierre P, Wordsworth P, Cortina EL, Sieper J, Kron M et al (2009) Effectiveness, safety, and predictors of good clinical response in 1250 patients treated with adalimumab for active ankylosing spondylitis. J Rheumatol 36:801–808

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The YKL-40 ELISA kits were provided by Quidel Corporation (San Diego, CA, USA) and the total aggrecan ELISA kits by IDS Nordic (Boldon, UK). Quidel and IDS Nordic had no role in (1) the design of the study; (2) the data collection, analysis, and interpretation; (3) the preparation of the manuscript; and (4) no rights to approve, delay, or disapprove of publication of the work. Furthermore, we thank the Faculty of Health Sciences, University of Copenhagen, Denmark, for a Ph.D. grant (3 years salary) to Susanne Juhl Pedersen. In addition, we thank Dr. Ole Slot, Dr. Ole Majgaard, and Dr. Ulrik Birk Lauridsen who treated the patients included in the study; laboratory technician Teresa Rozenfeld for analyzing the biomarkers; and the staff at the Department of Clinical Immunology at Nykøbing Falster County Hospital for providing blood samples from healthy volunteer blood donors.

Disclosures

SJ Pedersen, none; ML Hetland has received consulting fees and/or research grants from Abbott, Bristol-Meyer Squibb, Centocor, Pfizer, Novartis, Roche, Schering-Plough, UCB, and Wyeth; IJ Sørensen has received consulting fees and speaking fees from Abbott, Bristol-Myers Squibb, Schering-Plough, and Wyeth; M Østergaard has received consulting fees and/or research grants from Abbott, Amgen, Bristol-Meyer Squibb, Centocor, Genmab, Glaxo-Smith-Kline, Leo, Novo, Pfizer, Novartis, Roche, Schering-Plough, UCB, and Wyeth; HJ Nielsen, none; and JS Johansen, none.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Susanne Juhl Pedersen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pedersen, S.J., Hetland, M.L., Sørensen, I.J. et al. Circulating levels of interleukin-6, vascular endothelial growth factor, YKL-40, matrix metalloproteinase-3, and total aggrecan in spondyloarthritis patients during 3 years of treatment with TNFα inhibitors. Clin Rheumatol 29, 1301–1309 (2010). https://doi.org/10.1007/s10067-010-1528-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-010-1528-x

Keywords

Navigation