Background Turnover of bone, cartilage and connective tissue is widely affected in Rheumatoid arthritis (RA) joints. Although treatment regimens have improved there is still no treatment that fits all patients. Thus there is a need for broaden the understanding of how the turnover of connective tissue in the affected joints is altered in response to different treatment regiments. Connective tissue turnover can be quantified by measurement of neo-epitopes of collagen type I, III and IV, released upon upregulation of active matrix metalloproteinases (MMP).
Objectives To investigate changes in connective tissue turnover by quantification of collagen specific neo-epitopes in blood of RA patients as an effect of Tocilizumab (TCZ, IL-6R) or Tofacitinib (TOF, JAK inhibitor) treatment, both of which blocks the JAK/STAT cascade.
Methods 77 RA patients were included in the study of them 50 patients were treated with TCZ and 27 patients with TOF. The TCZ group was on average 56.3 years old, had a disease activity score (DAS28-CRP) at 4.8, and 12% were males. TOF treated patients were on average 53.3 years old, had a DAS28-CRP at 5.6 and 14.8% were males. Patients in the TOF group were biologic naïve, whereas most patients in the TCZ group had received other kinds of biologics before. Collagen specific neo-epitopes were quantified in serum of all patients at baseline and follow-up (48-60 weeks) by means of the biomarkers: C1M, C3M and C4M measuring MMP degradation of type I, III and IV collagen, respectively. Changes in biomarker levels at follow-up were calculated by Wilcoxon matched-pairs rank test. Inter-group correlations were determined by Spearman's rank test. A multiple regression model, with backwards calculations, was applied to evaluate whether the change in disease activity (DAS28-CRP) was dependent of baseline values of biomarkers, age, sex and disease duration. Log transformations were applied for variables, in a multiple regression model that did not meet the criteria of normality.
Results Serum levels of C1M, C3M and C4M were significantly decreased at follow-up after initiation of either TOCI or TOFA treatment (see figure). Baseline levels of C1M were correlated with C3M (r=0.543, p≤0.0001) and C4M (r=0.510, p≤0.0001). Additionally C3M correlated with C4M (r=0.661, p≤0.0001). Serum C1M (r=473, p≤0.0001), C3M (r=0.303, p=0.0075) and C4M (r=0.432, p≤0.0001) were all correlated significantly with the disease activity, DAS28-CRP. Moreover levels of C1M and C4M were correlated with change in DAS28-CRP (r=0.429, p=0.0002 and, r=0.449, P≤0.0001 respectively).
The multiple regression model revealed that changes in DAS28-CRP were associated with, log transformed values of, disease duration (r=-0.559, p=0.0467), C1M (r=0.294, p=0.0121), C3M (r=-0.205, p=0.0847) and C4M (r=4.177, p=0.0009). Age and gender did not contribute significantly to the regression equation.
Conclusions Based on the measured biomarkers it was found that degradation of type I, III and IV collagen of the connective tissue was inhibited after treatment targeting the JAK/STAT pathway either by inhibiting the IL6 receptor (TCZ) or JAK (TOF). Correlations between change in DAS28-CRP and baseline values of both C1M, and C4M suggest that these biomarkers may have a value as predictors of treatment response.
Disclosure of Interest S. Hirata Consultant for: Abbvie, Eisai, Bristol-Myers Squibb, Speakers bureau: Abbvie, Eisai, Bristol-Myers Squibb, N. Gudmann Employee of: Nordic Bioscience, 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, Consultant for: Abbvie, Chugai, Astellas, Takeda, Santen, Mitsubishi-Tanabe, Pfizer, Janssen, Eisai, Daiichi-Sankyo, UCB, GlaxoSmithKline, Bristol-Myers, Speakers bureau: Abbvie, Chugai, Astellas, Takeda, Santen, Mitsubishi-Tanabe, Pfizer, Janssen, Eisai, Daiichi-Sankyo, UCB, GlaxoSmithKline, Bristol-Myers