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
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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.
KeywordsBiomarkers Interleukin-6 Long-term changes Matrix metalloproteinase-3 Spondyloarthritis TNFα inhibitors Total aggrecan Vascular endothelial growth factor YKL-40
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.
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.
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