FRI0649 Systemic levels of type vi collagen metabolites are elevated in ra patients and modulated by treatment with anti-il6r therapy
Authors: C. S. Thudium, N. S. Gudmann, M. Karsdal, A.-C. Bay-Jensen
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background:</h3> Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by progressive inflammation systemically and local joint deterioration. Chronic inflammation leads to elevated levels of tissue remodeling and release of extracellular matrix (ECM) metabolites into circulation. Type VI collagen (Col-VI) is found at the interface between the interstitial- and the basement membrane where it binds other matrix proteins and support cell-cell interactions. Blood levels of Col-VI metabolites (C6M) have been associated with increased tissue turnover and disease activity in animal models and clinical studies of lung <sup>1</sup> and liver<sup>2</sup> fibrosis and ankylosing spondylitis<sup>3</sup>. These studies indicate that systemic levels of C6M are released ubiquitously from many organs and may be modulated by anti-inflammatory treatments. Treatment with the αIL-6 receptor agent Tocilizumab (TCZ) results in decreased ECM remodeling <h3>Objectives:</h3> Investigate the modulation of Col-VI metabolites in circulation by TCZ treatment and its association with treatment response. <h3>Methods:</h3> Systemic Col-VI metabolism was measured in the LITHE study (n=740), a one year double blind, placebo controlled phase III parallel group study in patients receiving placebo, 4 mg/kg or 8 mg/kg TCZ in combination with MTX. Col-VI degradation was measured using the C6M assay, measuring a specific MMP generated metabolite at bl, w4 and w16. The odds ratio (OR) of treatment response (ACR20, 50 or 70) at &gt;median decrease was calculated using logistic regression, adjusting for age, sex, BMI, dis. duration (model 1) and treatment (model 2). <h3>Results:</h3> TCZ treatment dose dependently reduced of Col-VI metabolites in serum at w4 in both 4 and 8 mg/kg (9% ns and 46% p&lt;0.0001) doses compared to placebo and the reduction persisted throughout the study. Patients with a high suppression of Col-VI turnover were more likely to respond to treatment compared to patients with low suppression. In patients with high suppression after 4 weeks the OR and ACR20 response at w16 was 1.6 (95% CI, 1.16–2.20), although this was not significant when adjusting for treatment. The OR of ACR50 was 2.2 (95% CI, 1.507–3.296) and for ACR70 2.6 (95% CI, 1.407–4.631). <h3>Conclusions:</h3> Suppression of Col-VI turnover was significantly associated with a higher level of response to TCZ treatment in RA patients after already 4 weeks. We hypothesize that there is an increased systemic connective tissue turnover in RA and connective tissue metabolites may be used as indicators of treatment response. <h3>References</h3> 1. Jenkins RG, Simpson JK, Saini G, et al. <i>Lancet Respir Med</i>. 2015;2600(15):1–11. 2. Leeming DJ, Byrjalsen I, Jiménez W, Christiansen C, Karsdal MA, Liver Int. 2013;33(3):439–447. 3. Bay-Jensen AC, Leeming DJ, Kleyer A, Veidal SS, Schett G, Karsdal MA., Rheumatol Int. 2012;32(11):3565–3572. <h3>Disclosure of Interest:</h3> C. Thudium Employee of: Nordic Bioscience, N. Gudmann Employee of: Nordic Bioscience, M. Karsdal Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, A.-C. Bay-Jensen: None declared