SAT0238 Rapid elevation of erythrocyte methotrexate-polyglutamate3 (MTX-PG3) levels related to the efficacy of mtx in patients with rheumatoid arthritis (RA).

Background: MTX is transported into cells and retained long after polyglutamation. Recently, it has been described that the response to MTX treatment is related to the intracellular MTX-polyglutamate (MTX-PG) levels, but little is known about its details and determinants1). Objectives: To clarify the association of erythrocyte concentrations of MTX-PGs (PG1 to PG4) with the efficacy of MTX in 35 MTX naive patients with RA. Methods: We measured erythrocyte MTX-PGs at 4, 12, 24, and 48 weeks after administration of MTX using liquid chromatography (LC)-mass spectrometry (MS)/MS assay. The associations of MTX-PG concentrations with disease activity and the 9 SNPs including 5 SNPs reported for associations with MTX-efficacy were analyzed. Results: As shown in the figure, MTX-PG1 and PG2 elevated at week 4, and total MTX-PGs as well as MTX-PG3 and MTX-PG4 increased until week 12. The MTX-PG2 fraction (as percentage of total) was 26% to 29% and almost constant throughout the course. MTX-PG3 and MTX-PG4 fractions were gradually elevated over time, although MTX-PG1 fraction was decreased. A negative association of Disease Activity Score in 28 joints (DAS28) at week 4, 12 and 24 was observed with levels of MTX-PG2 (p=0.008), MTX-PG3 (p=0.0045), MTX-PG4 (p=0.0142) and total MTX-PG (p=0.023). On the other hand, ΔDAS28 (change in DAS28 scores from baseline) was positively correlated to fraction of MTX-PG3 (p=0.011) but negatively correlated to that of MTX-PG1 (p=0.0071). At week 12 and 24, MTX-PG2 fraction was higher (p=0.0783) in the patients who achieved the EULAR good response criteria than in those who did not. MTX-PG3 levels were associated with SLC19A1c.80G>A and FMO2_c.585A>G, and the fraction of MTX-PG2 in total MTX-PGs was associated with GGH c.452C>T and with FMO2_c.585A>G. Conclusions: This study suggests that rapid elevation of erythrocyte MTX-PG3 levels from MTX-PG1 through MTX-PG2 and higher distribution of MTX-PG3 is important to exert certain efficacy of MTX. We previously reported in retrospective study that MTX-PG concentration in RA patients keeping remission for long time was associated with several SNPs2), and some of the results were confirmed in this prospective study. References 1) de Rotte MCFJ, et al. Ann Rheum Dis, 2015;74:408–414. 2) Kumagai S, et al. Ann Rheum Dis76(Suppl2)282. doi:10.1136/annrheumdis-2017-eular.2585 Disclosure of Interest: None declared