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SAT0082 Methotrexate and Anti-TNF-α Treatment Significantly Downregulate Connective Tissue Turnover, Which May Explain the Clinical Benefit
  1. N.S. Gudmann1,
  2. S. Hirata2,
  3. M.A. Karsdal1,
  4. A.C. Bay-Jensen1,
  5. Y. Tanaka2
  1. 1Nordic Bioscience, Herlev, Denmark
  2. 2The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan


Background Rheumatoid arthritis (RA) is characterized by changes in turnover of bone, cartilage and connective tissue of the affected joints. Treatment regimens have improved the last few decades; however not all patients respond adequately to treatment. Thus there is a need for deeper understanding of changes in joint tissue turnover in response to the different treatments.

Objectives To profile the level of connective tissue turnover in patients with short disease duration compared to patients with inadequate response to methotrexate (MTX). Furthermore, we investigated the level of suppression of the turnover in response to MTX and adalimumab (ADA) on a MTX background and the association with changes in disease activity.

Methods 72 Japanese RA patients were included in the study. 23 patients were newly diagnosed (mean disease duration: 6.4 months) and received MTX. The remaining 49 patients were receiving ADA treatment in addition to MTX. Serum samples were drawn along with Sharp/van der Heijde score (SHS) and other clinical data at baseline and again 48 to 60 weeks after initiation of treatment (follow-up). For 41 of the MTX+ADA patients, this was the first biological agent they received. MTX+ADA patients had a mean age of 61 years, mean DAS28-CRP of 4.7 and the mean disease duration of 96months. The MTX patients had in comparison a mean age of 55 years, and a mean DAS28-CRP score of 3.6. Degradation of connective tissue was evaluated by the biomarkers C1M (type I collagen in connective tissue), C3M (type III collagen in connective tissue) and C4M (type IV collagen in basal lamina) respectively. Changes in biomarker levels from baseline to follow-up were evaluated by Wilcoxon matched-pairs rank test. Intergroup correlations were determined by Spearman's rank test.

Results Baseline levels of biomarkers in the MTX group were on average different from the baseline levels in the MTX+ADA group. Baseline C1M level was increased44% in the MTX+ADA group compared to the MTX group (p=0.0194). In contrast, C3M level in MTX+ADA group was 18% lower compared to the MTX group, although not significant. There was less than 5% difference in mean baseline C4M levels between the two groups. C1M, C3M, and C4M were found to be decreased significantly upon treatment with both MTX and ADA (p<0.05). Interestingly, changes in DAS28-CRP correlated with baseline C1M (r=0.57, p=0.008) and C3M (r=0.53, p=0.016) in MTX patients and baseline C3M (r=0.42, p=0.0027) and C4M (r=0.34, p=0.016) in MTX+ADA patients. In addition changes in SHS correlated with C1M (r=0.508, p=0.0133) and C4M (r=0.4547, p=0.0335) in the MTX patients.

Conclusions Baseline levels of C1M in MTX receiving patients were significant lower compared to those initiating MTX+ADA. This may reflect type I collagen degradation as a function of disease duration as wells as prior treatment regiments and thereby an alternative measure of disease activity. Turnover of connective tissue, evaluated by type I, III and IV collagen degradation, was in this study significantly inhibited in response to both MTX and ADA+MTX treatment. In addition the correlation between changes in disease activity and baseline biomarkers levels, suggest that C1M, C3M, C4M may be described as biomarkers of disease activity. C1M and C4M may even predict radiographic progression in early RA.

Disclosure of Interest N. S. Gudmann Employee of: Nordic Bioscience, S. Hirata Consultant for: Abbvie, Bristol-Myers Squibb, Speakers bureau: Abbvie, Bristol-Myers Squibb, M. Karsdal Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, A. Bay-Jensen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, Y. Tanaka Grant/research support from: Mitsubishi-Tanabe, Chugai, MSD, Astellas, Novartis, Speakers bureau: Abbvie, Chugai, Astellas, Takeda, Santen, Mitsubishi-Tanabe, Pfizer, Janssen, Eisai, Daiichi-Sankyo, UCB, GlaxoSmithKline, Bristol-Myers

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