Ethan den Boer1, Maurits C J F de Rotte1, Saskia M F Pluijm1, Sandra G Heil1, Johanna M Hazes1, Robert de Jonge2. 1. From the Department of Clinical Chemistry; Department of Rheumatology; Department of Pediatric Hemato-Oncology; Erasmus University Medical Center, Rotterdam, the Netherlands.E. den Boer, MSc; M.C.J.F. de Rotte, PharmD; S.G. Heil, PhD; R. de Jonge, PhD, Department of Clinical Chemistry; J.M. Hazes, MD, PhD, Department of Rheumatology; S.M.F. Pluijm, PhD, Department of Pediatric Hemato-Oncology, Erasmus University Medical Center. 2. From the Department of Clinical Chemistry; Department of Rheumatology; Department of Pediatric Hemato-Oncology; Erasmus University Medical Center, Rotterdam, the Netherlands.E. den Boer, MSc; M.C.J.F. de Rotte, PharmD; S.G. Heil, PhD; R. de Jonge, PhD, Department of Clinical Chemistry; J.M. Hazes, MD, PhD, Department of Rheumatology; S.M.F. Pluijm, PhD, Department of Pediatric Hemato-Oncology, Erasmus University Medical Center. r.dejonge@erasmusmc.nl.
Abstract
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.
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 FPGSrs4451422 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.
Authors: Willy Albert Flegel; Kshitij Srivastava; Tristan Michael Sissung; Barry Ronald Goldspiel; William Douglas Figg Journal: Vox Sang Date: 2020-09-30 Impact factor: 2.996
Authors: Jason J Lee; Vivian P Bykerk; George K Dresser; Gilles Boire; Boulos Haraoui; Carol Hitchon; Carter Thorne; Diane Tin; Shahin Jamal; Edward C Keystone; Janet E Pope Journal: Clin Med Insights Arthritis Musculoskelet Disord Date: 2016-04-04
Authors: N Oosterom; M Fiocco; R Q H Kloos; I M van der Sluis; R Pieters; B D van Zelst; D E C Smith; M M van den Heuvel-Eibrink; R de Jonge; S G Heil Journal: BMC Cancer Date: 2020-09-30 Impact factor: 4.430