Background Low-dose methotrexate (MTX) is gold standard in the treatment of rheumatoid arthritis (RA). Response to MTX is very variable and is related to the intracellular MTX-polyglutamate (MTX-PG) levels.1,2 Similar to response, the intracellular MTX-PG concentrations are very variable.3,4 There is little information on the effect of different MTX dosing schemes on the concentration, distribution and accumulationspeed of intracellular MTX-PGs.
Objectives The aim of this study was to measure the speed of erythrocyte MTX-PG accumulation as well as the concentration and distribution of MTX-PG species in RA patients on two different MTX dosing regimens.
Methods Erythrocyte MTX-PG concentrations were prospectively measured at 3, 6 and 9 months of treatment. Adult RA patients from two longitudinal cohorts were included. Patients in the MTX-R received 15 mg/week MTX, whereas patients from the tREACH received 25 mg/week MTX. Patients were included if they were treated with MTX during the whole observation period and had at least one MTX-PG measurement. A recently developed LC-MS/MS assay was used for the determination of the separate MTX-PG levels.5
Results The largest part of the accumulation of the MTX-PGs occurred during the first 3 months of treatment with only marginal increase in the months thereafter. Steady state levels for all MTX-PGs were reached after 6 months of treatment in both cohorts. Patients from the MTX-R needed a longer time to accumulate similar levels of MTX-PGs than patients from the tREACH and after 9 months of treatment the MTX-R still had lower levels of the long-chain MTX-PGs. Strikingly, during the early phase of treatment, patients from the MTX-R had higher levels of the short-chain MTX-PGs (p=0.02), but lower levels of long-chain MTX-PGs (p=0.006). In the MTX-R the distribution of MTX-PGs was biased towards short-chain MX-PGs whereas in the tREACH the distribution was biased towards long-chain MTX-PGs even though the total MTX-PG levels were not different.
Conclusions Higher treatment dose of MTX led to a faster accumulation and higher concentrations of long-chain MTX-PGs resulting in a selective distribution towards long-chain MTX-PGs. As the long-chain MTX-PGs are considered to be the more active MTX-species this study suggests that more intensive treatment may be more efficient. This is supported by a shift towards higher treatment doses and extended co-medication over time in the MTX-R, whereas in the tREACH medication stayed more or less stable. In contrast to previous findings, the main bulk of MTX-PG accumulation takes place during the first three months of treatment and steady states are reached at six months of treatment.
de Rotte MC, den Boer E, de Jong PH, et al., Ann Rheum Dis. Dec 5 2013.
Bulatovic Calasan M, den Boer E, de Rotte MC, et al., Ann Rheum Dis. Nov 28 2013.
den Boer E, de Rotte MCFJ, Pluijm SMF, Heil SG, Hazes JMW, de Jonge R. Determinants of erythrocyte methotrexate polyglutamate levels in rheumatoid arthritis. Submitted.
Stamp LK, O'Donnell JL, Chapman PT, et al., Arthritis Rheum. Aug 2009;60(8):2248-2256.
den Boer E, Meesters RJ, van Zelst BD, et al., Anal Bioanal Chem. Feb 2013;405(5):1673-1681.
Disclosure of Interest : None declared