Background: Rheumatoid arthritis (RA) is an inflammatory systemic autoimmune (AI) disorder of the joints. We have developed an RA QSP model comprising multiple cell types & cytokines and calibrated to clinical readouts of standard therapies. The model can be used for its predictive power to test new trial designs to support drug development as multiple pathways are continually being studied as potential therapeutic targets Methods: The Vantage RA QSP model [1] represents an inflamed joint at steady state. Modular design approaches are used to set up immunological subsystems (cell lifecycle & cytokine effects). Ordinary Differential Equations (ODEs) capture the interactions of key cell types & pro and anti-inflammatory cytokines. The model parameters are constrained by clinical trial data (“top-down” constraints) & by “bottom-up” data (cell proliferation rate, cytokine secretion rate). DAS-28 score in Virtual Population (VPop) are calibrated to match clinical trials for Methotrexate, Adalimumab (anti-TNF-α therapy) & Tocilizumab. The modeling approach considers specific features of AI trial design like the placebo effect, & the link between physiological variables & clinical scores. Results: The Vantage RA QSP model captures multiple pathways in RA and therapy effects on clinical scores. The VPop is calibrated to capture the mean baseline DAS-28 score along with the remission & response percentages reported in Williams et al. 1985 [2], OPTIMA & ROSE trials. Conclusion: The Vantage RA QSP model captures the physiology and clinical outcomes of RA, including response to three therapies. The modular model design allows model repurposing to other AI disorders. The model can be used to test new trial designs for mono & combination therapies or identify distinctive features of responders to treatment.
[1] Tamara Ray, Madhav Channavazzala, Dinesh Bedathuru, Maithreye Rengaswamy, Rukmini Kumar. QSP Model of Rheumatoid Arthritis, capturing range of clinical responses to Methotrexate and anti-TNF-a therapies. Poster presented at: PAGE 28 (2019), Stockholm, Sweden. [2] Williams, H. J., et al. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology, 28(7), 721-730.
