Animal models of RA have been extensively used in the development of anti-arthritic agents. Disease is induced in animals by introduction of arthrogenic antibodies (antibody-induced arthritis or AbIA) or by introduction of antigen (collagen- or mBSA-induced arthritis). These models reflect either the induction or the effector phase of the disease and, therefore, do not recapitulate all aspects of human RA. Subjectivity of clinical scores used to measure disease activity may also limit the utility of these models. Identification of quantitative biomarkers would augment our understanding of the molecular mechanisms underlying animal models and their relevance to human disease. The goal of this study was to use high throughput proteomics technology to identify peripheral blood biomarkers common to both murine models of RA and human disease.
We used multiplex high throughput ELISA technology to screen for peripheral markers associated with RA disease activity in mouse models (AbIA, CIA and mBSA-induced arthritis) and RA patient sera. Disease activity in AbIA and CIA models was assessed using a visual scoring system (scale 0-4), and histophathological scoring was used in mBSA-induced arthritis. Human sera were from 499 patients (70% female, mean age 57.7, 89% Caucasian) with a mean RA disease duration of 14.7 years. DMARDs were used by 67% of patients (MTX 47%; TNFα inhibitors 35%; both treatments 15%). RA disease activity was measured by DAS28-CRP.
We found significantly elevated serum levels of MMP-3 and IL-6 in all three disease models. Both markers correlated strongly with arthritis scores in the AbIA model: MMP-3 R2=0.84, p<0.001; IL-6 R2=0.5, p<0.01. Good correlation between serum concentration and histopathological scores was found in the mBSA model for both MMP-3 (R2=0.82, p=0.0003) and IL-6 (R2=0.6, p=0.01). Correlation between these markers and disease activity in the CIA model was not significant. Analysis of patient sera showed both MMP-3 (OR=1.8, p<0.001) and IL-6 (OR=1.4, p<0.01) to significantly associate with disease activity as assessed by DAS28-CRP.
We have demonstrated that serum levels of MMP-3 and IL-6 are similarly and significantly associated with disease activity in a murine arthritis models and in human RA. These biomarkers hold potential to be a quantitative and objective means of relating disease activity assessment in pre-clinical studies to potential therapeutic impact in human clinical trials.
E.S. Izmailova, Millennium Pharmaceuticals, 3; M. Pickard, Millennium Pharmaceuticals, 3; N. Paz, Millennium Pharmaceuticals, 3; M. Fitzgerald, Millennium Pharmaceuticals, 3; J. Narang, Millennium Pharmaceuticals, 3; N.E. Maher, Millennium Pharmaceuticals, Biogen Idec, 2; A. Healy, Millennium Pharmaceuticals, 3; B. Jaffee, Millennium Pharmaceuticals, 3; N.A. Shadick, Millennium Pharmaceuticals, Biogen Idec, 2; R. Roubenoff, Millennium Pharmaceuticals, Biogen Idec, 3; M.E. Weinblatt, Millennium Pharmaceuticals, Biogen Idec, 5; Millennium Pharmaceuticals, Biogen Idec, 2; A. Parker, Millennium Pharmaceuticals, 3.
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