Using Methotrexate Metabolites to Make Clinical Decisions in JIA

Erythrocyte Folyl Polyglutamate Synthetase Activity Profiling as a Potential Tool for the Prediction of Methotrexate Efficacy and Toxicity in Rheumatoid Arthritis

“…After assay optimization, we tested our method on 42 clinical samples from our repository and observed the interpatient variability of FPGS activity among the patient samples. Interpatient variability has been consistently reported in previous works [25,[56][57][58][71][72][73][74][75]. The variation in FPGS enzyme activity observed among patients not only reflects differences in individual affinities for the formation of polyglutamate product, but also indicates genuine biological heterogeneity.…”

“…The efficacy of MTX is dependent on FPGS, which is responsible for the addition of glutamate residues on the drug [25,[57][58][59][60]. Previous studies suggest that a longer polyglutamate product is related to a more rapid anti-inflammatory response [5,24,25,61], but can also adversely affect the immune system, whereas the absence of polyglutamation can result in decreased drug effectiveness, potentially leading to inadequate treatment outcomes [18,59,62].…”

“…The efficacy of MTX is dependent on FPGS, which is responsible for the addition of glutamate residues on the drug [25,[57][58][59][60]. Previous studies suggest that a longer polyglutamate product is related to a more rapid anti-inflammatory response [5,24,25,61], but can also adversely affect the immune system, whereas the absence of polyglutamation can result in decreased drug effectiveness, potentially leading to inadequate treatment outcomes [18,59,62]. This will help clinicians to both adjust patients' MTX dosing regimens and select an alternative therapy for non-responders, effectively minimizing joint degradation due to a lack of therapeutic benefit from the insufficient polyglutamation of MTX.…”

“…These findings have suggested the monitoring of erythrocyte MTX + Glu n as a biomarker strategy to monitor MTX adherence and efficacy [16][17][18][19][20]. However, the slow accumulation of these metabolites in erythrocytes, requiring several months of therapy before reaching a steady state, precludes their use as pre-treatment or early treatment markers of MTX response in RA [20][21][22][23][24][25]. Recognizing that the enzyme responsible for the intracellular formation of MTX + Glu n is folyl polyglutamate synthetase (FPGS), this work seeks to develop an assay to measure erythrocyte FPGS activity in patients as a novel approach to predicting MTX response in RA.…”

Toward pharmacogenetic SLCO1B1‐guided dosing of methotrexate in arthritis using a murine Slco1b2 knockout model

“…Studies have shown that higher MTX polyglutamate concentrations are associated with improved therapeutic outcomes in patients with RA and JIA. 9 , 48 However, results remain conflicting, which highlights both the complexity of and variability in the folate pathway. Genes like SLC19A1 , encoding RFC1, which is responsible for folate homeostasis and intracellular folate transport, 5 , 15 and FPGS , which is responsible for the polyglutamation of folate analogs, have known polymorphisms that alter kinetic activity.…”