Association of Low Baseline Levels of Erythrocyte Folate With Treatment Nonresponse at Three Months in Rheumatoid Arthritis Patients Receiving Methotrexate

Abstract

Objective. To investigate whether baseline concentrations of one-carbon metabolism biomarkers are associated with treatment nonresponse and adverse events in rheumatoid arthritis (RA) patients receiving methotrexate (MTX).Methods. A prospective derivation cohort (n ‫؍‬ 285) and validation cohort (n ‫؍‬ 102) of RA patients receiving MTX were studied. Concentrations of plasma homocysteine, serum vitamin B 12 , serum folate, erythrocyte vitamin B 6 , and erythrocyte folate were determined at baseline and after 3 months of treatment. Nonresponse after 3 months was assessed using the Disease Activity Score in 28 joints (DAS28) and the European League Against Rheumatism (EULAR) response criteria. Adverse events at 3 months were assessed using biochemical parameters and health status questionnaires. Analyses were corrected for baseline DAS28, age, sex, MTX dose, comedications, and presence of the methylenetetrahydrofolate reductase 677TT genotype.Results. In the derivation cohort, the mean DAS28 scores at baseline and 3 months were 4.94 and 3.12, respectively, and 78% of patients experienced adverse events. This was similar between the 2 cohorts, despite a lower MTX dose in the validation cohort. Patients with lower levels of erythrocyte folate at baseline had a higher DAS28 at 3 months in both the derivation cohort (␤ ‫؍‬ ؊0.15, P ‫؍‬ 0.037) and the validation cohort (␤ ‫؍‬ ؊0.20, P ‫؍‬ 0.048). In line with these results, lower baseline erythrocyte folate levels were linearly associated with a 3-month DAS28 of >3.2 in both cohorts (derivation cohort, P ‫؍‬ 0.049; validation cohort, P ‫؍‬ 0.021) and with nonresponse according to the EULAR criteria (derivation cohort, P ‫؍‬ 0.066; validation cohort, P ‫؍‬ 0.027). None of the other biomarkers (levels at baseline or changes over 3 months) were associated with the DAS28 or treatment nonresponse. Baseline levels of the biomarkers and changes in levels after 3 months were not associated with incidence of adverse events.Conclusion. A low baseline concentration of erythrocyte folate is associated with high disease activity and nonresponse at 3 months after the start of MTX treatment and could be used in prediction models for MTX outcome. None of the investigated one-carbon metabolism biomarkers were associated with incidence of adverse events at 3 months.

Folate Depletion and Increased Glutamation in Juvenile Idiopathic Arthritis Patients Treated With Methotrexate

“…Reductions in folates occurred despite supplementation with folic acid in 47% of patients receiving MTX. This finding is in contrast to studies that have found folic acid supplementation to prevent reductions in RBC and plasma folates that occur secondary to MTX therapy (19, 42). Although the reason for this apparent discrepancy is unclear, it is important to point out that this study differed in a number of ways from the previous studies, including: its cross-sectional design, patient population (i.e.…”

Novel insights in folate receptors and transporters: implications for disease and treatment of immune diseases and cancer

“…Beyond clinical parameters (body mass index, smoking) and baseline disease severity, genetic factors that were associated with unresponsiveness to MTX included SNPs in the efflux transporters ABCB1 (rs1045642 G > A) and ABCC3 (rs4793665 T > C), and methionine synthesis (MTRR, rs1801394 A > G) [90,91]. Furthermore, low baseline erythrocyte folate and erythrocyte MTX-polyglutamate levels after 3 months of treatment were predictive for a decreased MTX response [92]. None of these biomarkers was associated with adverse effects of MTX treatment.…”

Methotrexate in Rheumatoid Arthritis – 2015: New Facts and Ideas

“…Действительно, име-ются данные, что клинический эффект лечения МТ у боль-ных РА коррелирует с уровнем МТПГ в эритроцитах [56]. Важно, что низкий базальный уровень фолатов в эритро-цитах ассоциируется с высокой активностью РА и отсутст-вием эффекта на фоне лечения МТ в течение первых 3 мес терапии [57]. Также было показано, что прием ГК ассоци-ируется с более высоким накоплением МТПГ в эритроци-тах, что в свою очередь коррелирует со снижением актив-ности РА [58].…”