Profiling the expressed kinome in patients with early rheumatoid arthritis
Lead Research Organisation:
University of Birmingham
Department Name: Immunity and Infection
Abstract
Rheumatoid arthritis affects 1-2% of the UK population and is a chronic debiltating disease with high cost to society. Disease modifying drugs, particularly biological therapies, have had a beneficial clinical and health impact on patients. However, there is a need to discover and develop both more clinically and cost effective treatment options. The study propsoed will allow direct analysis of the targets of new classes of DMARDs in relevant human ex vivo systems to allow more informed clinical development.
Technical Summary
Defining robust and reliable predictors of disease outcome in patients at their time of presentation with an inflammatory arthritis remains an elusive goal. Currently the best predictor of disease persistence is time (ie disease duration 3 months). This issue is particularly relevant as there is now emerging evidence that disease specific damage to synovial joints occurs early in Rheumatoid Arthritis (RA) and that early intervention with disease modifying drugs (including biological agents such as the anti TNF-?? agents, infliximab and etanercept), slow the rate of joint damage. We have identified a unique and transient synovial fluid cytokine profile from patients with very early inflammatory synovitis that predicts the subsequent development of rheumatoid arthritis and defines a pathologically unique window for early therapy in inflammatory arthritis destined to become RA.
As this cytokine portrait includes both T cell and fibroblast derived cytokines we now propose to define the profile of expressed kinases in peripheral blood T cells and synovial fibroblasts in patients who present with early inflammatory arthritis in order to assign a core kinome signature (CKS) to patients whose synovitis resolves (good outcome disease) versus those who develop RA (bad outcome disease).
We predict that, patients with early inflammatory arthritis destined to become RA will have a CKS that includes T cell and fibroblast restricted kinases that can predict outcome. If this is the case it will provide a clear rationale and help target the nature of therapy in patients with very early synovitis.
As this cytokine portrait includes both T cell and fibroblast derived cytokines we now propose to define the profile of expressed kinases in peripheral blood T cells and synovial fibroblasts in patients who present with early inflammatory arthritis in order to assign a core kinome signature (CKS) to patients whose synovitis resolves (good outcome disease) versus those who develop RA (bad outcome disease).
We predict that, patients with early inflammatory arthritis destined to become RA will have a CKS that includes T cell and fibroblast restricted kinases that can predict outcome. If this is the case it will provide a clear rationale and help target the nature of therapy in patients with very early synovitis.