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. 2025 Feb;39(1):e13050.
doi: 10.1111/fcp.13050.

Long-term evaluation of rheumatoid arthritis activity with erythrocyte methotrexate-polyglutamate 3

Jean Escal  1 , Marion Poudret  2 , Sophie Hodin  3 , Tiphany Neel  2 , Irina Coman  2 , Hervé Locrelle  2 , Adamah Amouzougan  2 , Thierry Thomas  4 , Xavier Delavenne  1 , Hubert Marotte  4
Affiliations

Long-term evaluation of rheumatoid arthritis activity with erythrocyte methotrexate-polyglutamate 3

Jean Escal et al. Fundam Clin Pharmacol. 2025 Feb.

Abstract

Background: Methotrexate (MTX) is the first-line treatment for Rheumatoid Arthritis (RA), yet 30%-50% of RA patients develop resistance to MTX, which can manifest several years after treatment initiation.

Objective: This study investigates the relationship between erythrocyte methotrexate polyglutamates (MTX-PGs) subtype concentrations and clinical disease activity in RA patients undergoing long-term MTX treatment.

Methods: In this cross-sectional study, patients on a stable dose of subcutaneous MTX for several years were included. The study protocol was registered in the European Medicines Agency's clinical trials register (n°2017-004348-39). Patients were classified as either in clinical remission (DAS28 <2.6) or having active disease (DAS28 >3.2). Erythrocyte MTX-PGs concentrations were measured using liquid chromatography coupled with mass spectrometry. Multivariate logistic regression analysis assessed the probability of remission status based on MTX-PG3 concentrations.

Results: The study included 34 patients with active RA and 25 in remission. The remission group had a median MTX treatment duration of 6.4 years compared to 2.6 years for the active group (p = 0.001). Patients in remission had a longer median disease duration (p = 0.02) and a lower Body Mass Index (BMI) (p = 0.03) than those with active RA. A positive correlation was found between remission status and high MTX-PG3 concentrations in patients with a BMI <25 kg/m2.

Conclusion: Erythrocyte MTX-PG3 concentrations may serve as a marker for RA activity after prolonged treatment. However, BMI could limit their utility as a biomarker.

Keywords: biomarker; liquid chromatography‐mass spectrometry; methotrexate resistance; methotrexate‐polyglutamate; rheumatoid arthritis.

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Conflict of interest statement

Pr. Hubert Marotte reports personal fees or nonfinancial support or grants outside the submitted work from Nordic Pharma. The other authors have disclosed no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Association between erythrocyte methotrexate polyglutamate (MTX‐PG) concentrations and RA activity.
FIGURE 2
FIGURE 2
Probabilities for rheumatoid arthritis patients treated by MTX to be in remission, depending on the MTX‐PG3 concentrations and their body mass index.
See this image and copyright information in PMC

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