Determinants of Erythrocyte Methotrexate Polyglutamate Levels in Rheumatoid Arthritis
| Autor: | Maurits C J F de Rotte, Robert de Jonge, Saskia M F Pluijm, Ethan den Boer, Sandra G. Heil, Johanna M. W. Hazes |
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| Přispěvatelé: | Clinical Chemistry, Pediatrics, Rheumatology |
| Rok vydání: | 2014 |
| Předmět: |
Male
Erythrocytes Time Factors Arthritis Pharmacology Gastroenterology Severity of Illness Index Arthritis Rheumatoid Cohort Studies immune system diseases Immunology and Allergy heterocyclic compounds Longitudinal Studies Prospective Studies Prospective cohort study skin and connective tissue diseases Netherlands Age Factors Middle Aged Treatment Outcome Polyglutamic Acid Rheumatoid arthritis Cohort Female Cohort study medicine.drug Adult musculoskeletal diseases medicine.medical_specialty Immunology Single-nucleotide polymorphism Risk Assessment Drug Administration Schedule Statistics Nonparametric Rheumatology Internal medicine medicine Humans Aged Dose-Response Relationship Drug business.industry Folylpolyglutamate synthase Reproducibility of Results medicine.disease Methotrexate Multivariate Analysis Linear Models business Follow-Up Studies |
| Zdroj: | Journal of Rheumatology, 41(11), 2167-2178. Journal of Rheumatology |
| ISSN: | 0315-162X |
| Popis: | Objective.Low-dose methotrexate (MTX) is the anchor drug in the treatment for rheumatoid arthritis (RA). Response to MTX is related to the intracellular MTX-polyglutamate (MTX-PG) levels and little is known about its determinants. We aimed to define the determinants of erythrocyte MTX-PG concentrations in 2 prospective cohorts of patients with RA.Methods.Patients with RA treated with MTX from 2 longitudinal cohorts were included: 93 from the MTX-R study (Rotterdam, the Netherlands derivation cohort), and 247 from the treatment in Rotterdam Early Arthritis Cohort study (validation cohort). MTX-PG concentrations were measured at 3 months of treatment using liquid chromatography/mass spectrometry. The MTX-PG were used as outcome measure. Various sociodemographic, clinical, biochemical, and genetic factors were assessed at baseline. Associations with MTX-PG levels were analyzed using multivariate regression analysis.Results.Age was positively associated with MTX-PG1 (stβ 0.23, p = 0.033) and total MTX-PG (stβ 0.23, p = 0.018) in the derivation cohort, and with all MTX-PG in the validation cohort (MTX-PG1: stβ 0.13, p = 0.04; MTX-PG2: stβ 0.21, p = 0.001; MTX-PG3: stβ 0.22, p < 0.001; MTX-PG4+5: stβ 0.25, p < 0.001; and total MTX-PG: stβ 0.32, p < 0.001). Erythrocyte folate levels were positively associated with MTX-PG3 (stβ 0.3, p = 0.021) and total MTX-PG levels (stβ 0.32, p = 0.022) in the derivation cohort, which was replicated for MTX-PG3 (stβ 0.15, p = 0.04) in the validation cohort. Patients with the folylpolyglutamate synthase (FPGS) rs4451422 wild-type genotype had higher concentrations of MTX-PG3 (p < 0.05), MTX-PG4+5 (p < 0.05), and total MTX-PG (p < 0.05) in both cohorts. In the combined cohort, MTX dose was positively associated with levels of MTX-PG3 (stβ 0.23, p < 0.001), MTX-PG4+5 (stβ 0.30, p < 0.001), and total MTX-PG (stβ 0.20, p = 0.002), but negatively associated with MTX-PG2 levels (stβ −0.22, p < 0.001).Conclusion.Our prospective study shows that higher age, higher MTX dose, higher erythrocyte folate status, and the FPGS rs4451422 wild-type genotype are associated with higher MTX-PG concentrations. While only up to 21% of interpatient variability can be explained by these determinants, this knowledge may aid in the development of personalized treatment in RA. |
| Databáze: | OpenAIRE |
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