Session Type: Abstract Submissions (ACR)
Background/Purpose: Despite widespread use, there are no predictors of methotrexate (MTX) response or toxicity. The objective of this study is to test the hypothesis that the variability in response to MTX is a function of inter-individual differences in folate homeostasis.
Methods: This is a single center prospective cohort study at a tertiary care children’s hospital evaluating newly treated JIA patients on standardized doses and routes of MTX (15mg/m2 PO) and folic acid (1mg/day). After obtaining informed consent, samples are collected prior to, and after 3 and 6 months of MTX. Concentrations of tetrahydrofolate (THF), 5-methylTHF (5-MTHF), 5,10-methenylTHF (5,10-METHF), folic acid (FA), and MTX polyglutamates (MTXGlun) are determined in plasma, whole blood and erythrocytes by UPLC-tandem mass spectrometry. Clinical data are recorded from chart review and forms provided to the treating physician and patient/parent (CHAQ, MD VAS, PT VAS). Clinical outcomes at 3 months were measured via ACR pediatric 30, 50, 70 criteria and the JADAS71. We report preliminary 3 month data on the first 20 patients recruited to the study.
The study consisted of 12 females and 8 males with JIA. The mean (± SD) age at study entry was 135.2 (± 49.5) months. After 3 months on standardized MTX therapy, paired t-test revealed an overall statistically significant decline in MD VAS (p < 0.0001), PT VAS (p < 0.001), active joint count (p = 0.002), JADAS71 (p < 0.001), and 5-MTHF concentrations (p= 0.004). There were no statistically significant differences in CHAQ, ESR, CRP, or 5,10-METHF from 0-3 months on therapy. These results were confirmed with additional nonparametric testing. At 3 months, 8 (40%) subjects failed to reach ACR Ped 30 (“non-responders”), while 10 (50%) subjects reached ACR Ped 30 or 50, and 2 (10%) reached ACR Ped 70 (“responders”).
The mean decline from baseline of 5-MTHF concentrations at 3 months was found to be significantly greater in boys (-420.8 nmol/L), compared to girls (-122.9 nmol/L) (p=0.03), and negatively correlated with age (ρ=-0.7, p=0.0006). A trend towards greater changes in 5-MTHF concentrations from baseline were observed in responders (-333.3 nmol/L) compared to non-responders (-105.1 nmol/L) (p=0.07). No statistically significant differences were seen in absolute 5-MTHF concentrations at 0 or 3 months and ACR outcomes, although responders had comparatively higher 5-MTHF concentrations (885.3 nmol/L vs. 666.2 nmol/L, p NS) at baseline. Multivariate testing supported an association between change in 5-MTHF and response (p=0.05) controlling for gender and age. Two patients had exceptionally high 5,10-METHF concentrations (>4x IQR). Omitting the outliers revealed a pronounced change in 5-MTHF in responders (p=0.04). No association between long chain MTXGlu and outcomes or change in folate concentrations has been observed to date.
Conclusion: These preliminary data suggest that an initial decline in 5-MTHF concentrations may be correlated to MTX response, and might provide clinicians with a more effective biomarker than intra-cellular concentrations of the drug itself in JIA. Future work will investigate factors that contribute to 5-MTHF depletion.
L. van Haandel,
R. S. Funk,
M. F. Ibarra,
M. F. Hoeltzel,
J. S. Leeder,
M. L. Becker,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/degree-of-initial-intracellular-folate-depletion-may-predict-methotrexate-response-in-juvenile-idiopathic-arthritis/