Executive Summary : | Rheumatoid arthritis (RA) is complex autoimmune disease with unpredictable response to Disease Modifying Anti Rheumatic drugs. Methotrexate (MTX) is the anchor drug and “Treat to Target” being the essence of current RA management theme, it is imperative that physicians should be able to predict, which patients will respond favorably to MTX. Peripheral Blood Mononuclear Cells Methotrexate- Polyglutamates (PBMC MTX-PGs) can be used for measuring bioactive MTX target cell concentration while Multi-biomarker disease activity (MBDA) measurement is used for immune profile/ disease activity & pharmacogenomics for guiding baseline response prediction. Prediction of disease response to treatment is the holy grail for most debilitating chronic medical disorders such as RA, and this study aspires to work in that direction, where a precision medicine model can be developed combining PBMC MTX-PGs with MBDA measurements for disease immune profile & pharmacogenetics to improve response rates to Methotrexate and prognosis in RA patients. Although the pharmacogenomics, cytokines and MTX pharmacokinetics in RA patients have been studied separately in several studies. Parallel measurements of drug bioavailability, inflammatory biomarkers and single nucleotide polymorphisms of genetic variants related to efficacy and toxicity of MTX regulating transporters, folate, purine metabolism and inflammatory mediator genes & their correlation with clinical response is the innovative aspect of this study . A pharmacogenomic model of MTX transport and metabolism should reflect with MTX- PGs in PBMCs & that for pharmaco-dynamics of MTX should correlate with inflammatory biomarkers. Similarly inflammatory biomarkers should be correlated with clinical response. In addition no single biomarker is yet reliably predictive of disease activity, hence we are using multiple biomarkers and exploring newer biomarkers like serum lactoferrin in this pursuit. Successful completion of the study will identify potential pharmacogenomic and metabolic biomarkers of disease activity and drug response, towards the development of future diagnostic tools to guide clinicians for the early optimization of drug therapy in the treatment of rheumatoid arthritis. |
Co-PI: | Dr. Rupinder Kaur Kanwar, All India Institute Of Medical Sciences (AIIMS) Bhopal, Madhya Pradesh-462020, Dr. John Ashutosh Santoshi, All India Institute Of Medical Sciences (AIIMS) Bhopal, Madhya Pradesh-462020, Dr. Murali Munisamy, All India Institute Of Medical Sciences (AIIMS) Bhopal, Madhya Pradesh-462020, Dr. Abhishek Singhai, All India Institute Of Medical Sciences (AIIMS) Bhopal, Madhya Pradesh-462020, Prof. Jagat Rakesh Kanwar, All India Institute Of Medical Sciences (AIIMS) Bhopal, Madhya Pradesh-462020 |