title: Nicotinamide Phosphoribosyltransferase Attenuates Methotrexate Response in Juvenile Idiopathic Arthritis and In Vitro.
abstract: Variability in response to methotrexate (MTX) in the treatment of juvenile idiopathic arthritis (JIA) remains unpredictable and poorly understood. Based on previous studies implicating an interaction between nicotinamide phosphoribosyltransferase (NAMPT) expression and MTX therapy in inflammatory arthritis, we hypothesized that increased NAMPT expression would be associated with reduced therapeutic response to MTX in patients with JIA. A significant association was found between increased plasma concentrations of NAMPT and reduced therapeutic response in patients with JIA treated with MTX. Inhibition of NAMPT in cell culture by either siRNA-based gene silencing or pharmacological inhibition with FK-866 was found to result in a fourfold increase in the pharmacological activity of MTX. Collectively, these findings provide evidence that NAMPT inhibits the pharmacological activity of MTX and may represent a predictive biomarker of response, as well as a therapeutic target, in the treatment of JIA with MTX.
authors.affiliation: Department of Pharmacy Practice, University of Kansas Medical Center, Kansas City, Kansas, USA.|Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri, USA.|Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Funk
authors.affiliation: Department of Pharmacy Practice, University of Kansas Medical Center, Kansas City, Kansas, USA.|Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: R
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Pharmacy Practice, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: L
authors.initials: L
authors.lastname: Pramann
authors.affiliation: Division of Immunology Research, Children's Mercy Kansas City, Kansas City, Missouri, USA.
authors.forename: N
authors.initials: N
authors.lastname: Gigliotti
authors.affiliation: Division of Experimental and Translational Genetics, Children's Mercy Kansas City, Kansas City, Missouri, USA.
authors.forename: S
authors.initials: S
authors.lastname: Islam
authors.affiliation: Division of Experimental and Translational Genetics, Children's Mercy Kansas City, Kansas City, Missouri, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: Heruth
authors.affiliation: Division of Experimental and Translational Genetics, Children's Mercy Kansas City, Kansas City, Missouri, USA.|Department of Biomedical and Health Informatics, University of Missouri Kansas City School of Medicine, Kansas City, Missouri, USA.
authors.forename: S Q
authors.initials: SQ
authors.lastname: Ye
authors.affiliation: Division of Immunology Research, Children's Mercy Kansas City, Kansas City, Missouri, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Chan
authors.affiliation: Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri, USA.|Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Leeder
authors.affiliation: Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri, USA.|Division of Rheumatology, Children's Mercy Kansas City, Kansas City, Missouri, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Becker
mesh_terms: D000072283:A549 Cells; D000293:Adolescent; D001171:Arthritis, Juvenile / Q000188:drug therapy* / Q000201:enzymology*; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D003710:Demography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; D008727:Methotrexate