AB0263 THE LEVEL OF 7-HYDROXY METHOTREXATE IN BLOOD CELLS IN PATIENTS WITH RHEUMATOID ARTHRITIS DIRECTLY CORRELATES WITH THE LEVEL OF POLYGLUTAMATES OF METHOTREXATE
Authors: G. Gridneva, E. Samarkina, S. Glukhova, Y. Muraviev, A. Kudryavtseva, E. Aronova, N. Baymeeva, V. Sygyrta
Journal: Annals of the Rheumatic Diseases (2021)

Background: 7-hydroxy Methotrexate (7-hydroxy-MTX) is a phase I metabolite of MTX, which is converted by hepatic aldehyde oxidases. It is known that 7-hydroxy MTX can reduce the effectiveness of methotrexate, which is associated with increased excretion of methotrexate due to a decrease in polyglutamation and binding to enzymes [1]. Objectives: To analyze the level of 7-hydroxy-MTX in peripheral blood cells in order to study the correlation of the level of this metabolite with the level of polyglutamates of methotrexate (MTXPGs). Methods: The prospective study included 65 patients aged 53±11 years, 50 women, 13 men, diagnosed with RA, according to the ACR/EULAR 2020 criteria, methotrexate (MTX) naiive. The duration of the disease was 7,5[4;24] months. All patients were administrated MTX subcutaneously at a dose of 10-15 mg/m2. The visits were carried out at weeks 0, 4, 12, 24 and 36, at all visits samples were taken for the content of MTXPGs with 1,2,3 and 4 glutamate residues and 7-hydroxy MTX separately in red blood cells mass (RBC) and mononuclear cells (MO). The mononuclear fraction was isolated by layering on verografin-ficoll. All patients received folic acid at a standard dose of 5 mg 24 hours after parenteral MTX administration. Samples were collected no earlier than 36 hours after MTX administration. All patients had normal renal function. Disease activity was assessed using the DAS28 index calculated by C-reactive protein. Results: The average concentration of 7-hydroxy MTX is shown in Table 1. Table 1. Level of 7-hydroxy MTX in erythrocytes and mononuclear cells, nmol/L, Median [25; 75 quartiles] 7-hydroxy MTX level in: 4 weeks 12 weeks 24 weeks 36 weeks RBC 18,5[3,1;61,5] 10,2[3,6;50,8] 10,3[1,7;36,8] 7,2[0,1;25,3] MO 0,8[0,1;15,2] 4,0[0,1;42,2] 3,5[0,1;8,1] 0,4[0,1;8,9] The level of 7-hydroxy-MTX directly correlated with the level of MTXPGs 1-4, and summary MTXPG in both RBC and MO. Analysis of pairwise correlations according to Pearson showed that: after 4, 12 and 36 weeks, the level of 7-hydroxy-MTX did not correlate with the value of DAS28. After 24 weeks of therapy, the level of 7-hydroxy-MTX in RBC was inversely correlated with DAS28 of the disease (p=0.043). Conclusion: The preliminary results indicate a positive correlation between the level of 7-hydroxy-MTX and MTXPGs in RBC and MO. In this regard, the concentration of 7-hydroxy-MTX can be used as a prognostic marker for MTX therapy in the absence of opportunities in clinical centers to measure the entire line of MTXPGs in RBC and MO. Since the data obtained are somewhat at odds with the few literary sources, it is necessary to conduct further research on this fact. References: [1]Baggott JE, Morgan SL (2009) Methotrexate catabolism to 7-hydroxymethotrexate in rheumatoid arthritis alters drug efficacy and retention and is reduced by folic acid supplementation. Arthritis Rheum 60:2257–2261 Disclosure of Interests: None declared