Presenter Status
Fellow
Abstract Type
Research
Primary Mentor
Laura Ramsey
Start Date
16-5-2025 11:30 AM
End Date
16-5-2025 1:30 PM
Presentation Type
Poster Presentation
Description
Background: Methotrexate (MTX) is the cornerstone disease-modifying anti-rheumatic drug for the treatment of Juvenile Idiopathic Arthritis (JIA). While most patients receiving MTX have a favorable outcome, approximately 30% do not respond, and several experience toxic events, suggesting interindividual difference. Furthermore, evaluation of MTX response takes several months, with the risk of missing the early “window of opportunity” for treatment. Predicting MTX response prior to administration would greatly benefit these patients and their treating physicians by saving valuable time during the early stages of the disease onset. MTX is a folate antagonist and, similar to folate, it undergoes polyglutamation inside the cell (MTXGlu(n)). Long chain MTXGlu3-5 have been shown to correlate with clinical response in JIA and RA patients. Therefore, levels of MTXGlu(n) could be used as a biomarker for MTX response prediction.
Objectives/Goal: The goal of this study is to elucidate the pharmacogenomic predictors of methotrexate pharmacokinetics and pharmacodynamics, aiming to optimize personalized treatment strategies for JIA patients.
Methods/Design: We recruited JIA patients from three participating clinical sites in two countries (Kansas City, Cincinnati, and Italy) and from the CARRA Registry. JIA patients were diagnosed with polyarticular JIA by a trained rheumatologist and treated with MTX. Blood samples were collected after 6 months of treatment using the mitra microsampling (MMS) method. MTXGlu(n) was measured using an established a published LC/MS/MS method. Red blood cell (RBC) MTXGlu(n) levels were reported as individual glutamate concentrations, total (summed) MTXGluTOT concentration, "short chain" MTXGlu1+2, "long chain" MTXGlu3-5, the percentage of short and long chains(MTXGlu1+2*100/MTXGluTOT and MTXGlu1+2*100/MTXGluTOT), and the ratio of the long/short chain concentrations (MTXGlu3-5/MTXGlu1+2).
Results: We recruited 280 JIA patients in this cohort, 68.8% of participants were female, and 31.2% were male. The majority of patients were White (79.2%), followed by Hispanic (5%), Asian (3.8%), and Black (3.5%). We observed a wide range in the concentration of different MTX metabolites in JIA patients treated with MTX, ranging from 0-230 nmol/L. The median concentrations for MTXPG1, MTXPG2, MTXPG3, MTXPG4, MTXPG5, were 16.1, 26.5, 54.5, 39.8, and 16.3 nmol/L, respectively. The median concentrations for MTXGluTOT, MTXGlu1-2, and MTXGlu3-5 were 155.9, 42.2, and 108.7 nmol/L, respectively. The percentage of short chain MTXGlu had a median of 28.3% with values ranging from 3.7% and 100. The median percentage of long chain MTXGlu was 71.7% with a range of 0-96.3% The ratio of long/short chain concentrations ranged from 0.05 to 26, with a median of 2.54.
Conclusions: We established a cohort of 280 JIA patients treated with methotrexate and measured the levels of MTX metabolites present in red blood cells using a less invasive sampling method (MMS). Our findings reveal a wide variation in MTX metabolite concentrations within this cohort of JIA patients. Moving forward, we aim to correlate the levels of polyglutamation with clinical outcomes and genetic variations for each patient. This comprehensive analysis intends to provide valuable insights into personalized treatment strategies and improve the efficacy of methotrexate therapy for JIA patients.
Variability in Methotrexate Metabolites in a Cohort of JIA Patients
Background: Methotrexate (MTX) is the cornerstone disease-modifying anti-rheumatic drug for the treatment of Juvenile Idiopathic Arthritis (JIA). While most patients receiving MTX have a favorable outcome, approximately 30% do not respond, and several experience toxic events, suggesting interindividual difference. Furthermore, evaluation of MTX response takes several months, with the risk of missing the early “window of opportunity” for treatment. Predicting MTX response prior to administration would greatly benefit these patients and their treating physicians by saving valuable time during the early stages of the disease onset. MTX is a folate antagonist and, similar to folate, it undergoes polyglutamation inside the cell (MTXGlu(n)). Long chain MTXGlu3-5 have been shown to correlate with clinical response in JIA and RA patients. Therefore, levels of MTXGlu(n) could be used as a biomarker for MTX response prediction.
Objectives/Goal: The goal of this study is to elucidate the pharmacogenomic predictors of methotrexate pharmacokinetics and pharmacodynamics, aiming to optimize personalized treatment strategies for JIA patients.
Methods/Design: We recruited JIA patients from three participating clinical sites in two countries (Kansas City, Cincinnati, and Italy) and from the CARRA Registry. JIA patients were diagnosed with polyarticular JIA by a trained rheumatologist and treated with MTX. Blood samples were collected after 6 months of treatment using the mitra microsampling (MMS) method. MTXGlu(n) was measured using an established a published LC/MS/MS method. Red blood cell (RBC) MTXGlu(n) levels were reported as individual glutamate concentrations, total (summed) MTXGluTOT concentration, "short chain" MTXGlu1+2, "long chain" MTXGlu3-5, the percentage of short and long chains(MTXGlu1+2*100/MTXGluTOT and MTXGlu1+2*100/MTXGluTOT), and the ratio of the long/short chain concentrations (MTXGlu3-5/MTXGlu1+2).
Results: We recruited 280 JIA patients in this cohort, 68.8% of participants were female, and 31.2% were male. The majority of patients were White (79.2%), followed by Hispanic (5%), Asian (3.8%), and Black (3.5%). We observed a wide range in the concentration of different MTX metabolites in JIA patients treated with MTX, ranging from 0-230 nmol/L. The median concentrations for MTXPG1, MTXPG2, MTXPG3, MTXPG4, MTXPG5, were 16.1, 26.5, 54.5, 39.8, and 16.3 nmol/L, respectively. The median concentrations for MTXGluTOT, MTXGlu1-2, and MTXGlu3-5 were 155.9, 42.2, and 108.7 nmol/L, respectively. The percentage of short chain MTXGlu had a median of 28.3% with values ranging from 3.7% and 100. The median percentage of long chain MTXGlu was 71.7% with a range of 0-96.3% The ratio of long/short chain concentrations ranged from 0.05 to 26, with a median of 2.54.
Conclusions: We established a cohort of 280 JIA patients treated with methotrexate and measured the levels of MTX metabolites present in red blood cells using a less invasive sampling method (MMS). Our findings reveal a wide variation in MTX metabolite concentrations within this cohort of JIA patients. Moving forward, we aim to correlate the levels of polyglutamation with clinical outcomes and genetic variations for each patient. This comprehensive analysis intends to provide valuable insights into personalized treatment strategies and improve the efficacy of methotrexate therapy for JIA patients.
