Methotrexate Polyglutamation in a Myasthenia Gravis Clinical Trial.
Abstract
Introduction:Methotrexate (MTX) is an immunosuppressive and anti-inflammatory drug used to treat rheumatoid arthritis (RA) and other autoimmune conditions. MTX is transported into cells, where glutamate moieties are added and is retained as methotrexate polyglutamates (MTXPGs). In the RA literature, it has been reported that the degree of polyglutamation correlates with the anti-inflammatory effect of MTX in RA. There are no prior studies evaluating the relationship between MTXPGs and myasthenia gravis (MG) outcome measures. The objective of this study was to assess the correlation between methotrexate (MTX) polyglutamates (MTXPGs) with Myasthenia Gravis (MG) outcome measures. Methods:An analysis was done of blood drawn from patients enrolled in the 12-month randomized, placebo-controlled study of MTX in MG study. Red blood cell MTXPGs were measured via ultra-performance liquid chromatography and tandem mass spectrometry. MTXPG was correlated to MG outcome measures using Spearman Correlation Coefficient. A two-group t-test was used to determine the difference in MTXPG based on clinical outcome responder definitions. Results:Twenty-one polyglutamate samples were analyzed of subjects on MTX while eight samples were analyzed from subjects on placebo. Pentaglutamate had the strongest correlation with the MG-ADL (0.99), while tetraglutamate had the strongest correlation with the QMG (0.54). Triglutamate had the strongest correlation with MGC (0.76). Conclusion:There were variable correlations between MTXPG1-5 and MG outcomes (rho range: 0.08 to 0.99). There are strong correlations between MTXPG and the MG-ADL, QMG, and MGC. Long chain methotrexate polyglutamates correlate better with MG outcomes.
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Scholars@Duke
Mara Becker
Dr. Becker is currently a Professor of Pediatrics and the Vice Dean for Faculty at Duke University School of Medicine. Prior to arriving at Duke in 2019, she spent 13 years at Children’s Mercy, Kansas City where she completed additional fellowship training in pediatric clinical pharmacology and served as Division Director of Rheumatology and Associate Chair for the Department of Pediatrics. At Duke, Dr. Becker served as the Vice Chair for Faculty in Pediatrics, until she assumed the role of Vice Dean for Faculty in July, 2022.
Dr. Becker’s translational research interest is to identify factors that enhance response and minimize toxicity to drugs used for the treatment of diseases in children, focusing on an individualized therapeutic strategy. Her work focuses on methotrexate and its effect upon the folate pathway, utilizing cellular biomarkers and genetic differences to predict drug efficacy in patients with JIA. Her research has been funded by the Kansas City Area Life Sciences Institute, the PhRMA Foundation, the Rheumatology Research Foundation, and the National Institutes of Health. She has also served as a faculty leader at the Duke Clinical Research Institute where her work expanded to developing and supporting novel networks to carry out research and clinical trials, focusing on children with rare rheumatic and genetic conditions including the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry.
In her new role as Vice Dean, she has focused on fortifying and reimagining the Office for Faculty and the multiple programs and offices that support faculty in the School of Medicine. New efforts in this role will focus on identifying opportunities to create standardized and transparent processes within the office, prioritizing leadership development for current leaders in the School of Medicine, and developing a training and mentorship program in Restorative Justice to strengthen community and support a healthy and productive work climate. In addition to her administrative work at Duke, Dr. Becker has held multiple leadership roles in national committees and organizations in her field.
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