Autoimmune arthritis, in the form of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), is the most common rheumatic condition worldwide, and manifests as chronic joint inflammation that results in significant morbidity and disability. Methotrexate (MTX) continues to be the most widely used disease-modifying drug in the treatment of autoimmune arthritis, but is characterized by a slow onset of action along with an unpredictable response profile resulting in inadequate efficacy in approximately 1 out of every 3 patients treated. As a result, the treatment of RA and JIA frequently requires individual tailoring of drug therapy and is characterized by a 'trial-and-error' approach to therapy. Recognizing that early control of disease activity is a positive predictor of long-term outcomes, there remains a critical need to identify biomarkers to guide clinicians in the early selection and optimization of drug therapy in these patients. The goal of this project is to apply a translational metabolomics approach to identify molecular biomarkers of disease activity and MTX response in autoimmune arthritis. We hypothesize that both RA and JIA result in metabolic dysregulation with corresponding changes in metabolomic profiles that are associated with response to MTX, which therefore represent molecular markers that can be utilized to guide therapy in these patients. To test this hypothesis, we will utilize patient samples in combination with advanced techniques in metabolomics and biomarker assay development to address the following aims: 1) identify circulating metabolomic markers of disease in autoimmune arthritis, 2) identify circulating metabolomic markers of MTX response in autoimmune arthritis, and 3) develop a chip-based assay for the quantitation of molecular markers of MTX response in autoimmune arthritis. The candidate is a clinical pharmacologist with a proven commitment to the conduct of translational science to drive the mission of precision medicine in the treatment of autoimmune arthritis. The skills in metabolomics and bioanalytical assay development acquired through this proposal will facilitate the candidate's long-term goal to improve the safety and efficacy of drug therapies in the treatment of autoimmune arthritis through the establishment of a research program investigating the application of pharmaco-metabolomics as a strategy to personalize drug therapy in the treatment of RA and JIA.
Although methotrexate is widely used in the treatment of arthritis, it is ineffective in 1 out of every 3 patients treated. In this research we will identify metabolic biomarkers of disease activity and drug response towards the development of diagnostic tools to guide clinicians in the early optimization of drug therapy in the treatment of arthritis.
