Background Methotrexate (MTX) is the gold standard in the management of rheumatoid arthritis (RA) and other arthritic diseases. Stable plasma MTX levels are not reached in RA but in the cell MTX polyglutamates (MTX-PGs) accumulate and can be measured. MTX-PGs occur with polyglutamate chains of up to five glutamate groups and longer chains correlate with clinical response. However, there is large inter-patient variability between intracellular MTX-PG concentrations and it is not yet known which factors influence this.
Objectives The aim of this study was to examine determinants for the red blood cell MTX-PG concentrations in patients treated with low-dose oral MTX.
Methods This study included data of RA patients treated with MTX from two combined longitudinal cohorts: 285 from the tREACH study and 102 from the MTX-R study. MTX-PG1-5 concentrations were separately measured at 3 months of treatment using an LC-MS/MS assay. MTX-PG1-2 are considered short chain, MTX-PG3 as medium chain and MTX-PG4-5 as long chain. The separate MTX-PGs and the sum of MTX-PG2-5(MTXPGtotal)were used as outcome measure. Various socio-demographic, clinical, biochemical determinants were assessed at baseline. Multiple regression analysis was used to examine the associations between these potential determinants and the different MTX-PG concentrations.
Results After 3 months of MTX treatment, median [IQR] MTX-PG concentrations were 17.8 [8.5-19.6], 9.4 [6.5-11.1], 18.6 [13.3-23.3], 7.9 [3.4-11.1] and 2.2 [0.-2.7] nmol/l for MTX-PG1-5 respectively, and 55.8 nmol/l [37.9-67.5] for total MTX-PG.
The MTX-PGtotal concentration, was associated with higher age (ß=0.28; p<0.001), male sex (ß=-0.12; p=0.021), higher MTX dose (ß=0.11; p=0.008), glucocorticoid use (ß=0.13; p=0.047), baseline CRP (ß=0.13; p=0.031) and baseline erythrocyte folate (ß=0.15; p=0.031).
Apart from age, no significant associations were found for MTX-PG1.
Higher age, male sex and MTX dose were the strongest determinants for the MTX-PG2 till MTX-PG5. Furthermore, the longer chain MTX-PG3 till MTX-PG5 were also associated with disease activity, glucocorticoid use, intracellular erythrocyte folate and creatinine, at start of treatment.
Conclusions This prospective study shows that age, sex and MTX dose are the most important determinants of MTX-PG concentrations. In addition, we showed that long chain MTX-PG concentrations are dependent on disease activity, glucocorticoid use and creatinine, at start of treatment. As response is thought to be mediated by the longer chain MTX-PGs, the identification of these determinants is a first step towards personalized treatment of RA.
Acknowledgements RDJ: Dutch Arthritis Association (06-02-402 and 09-1-402)
Disclosure of Interest None Declared
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