PO76 - Methotrexate polyglutamates concentrations in patients with sarcoidosis treated with methotrexate monotherapy
Janssen Bonas, M (Netherlands)1; Sundaresan J. (Netherlands)2; Kahlmann V. (Netherlands)3; Wijsenbeek M.S. (Netherlands)3; Grutters, J.C. (Netherlands)1 4; de Rotte, M (Netherlands)2; Veltkamp, M (Netherlands)1 4;
1 - ILD Center of Excellence, member of European Reference Network-Lung, St Antonius Hospital, Nieuwegein, the Netherlands; 2 - Laboratory of Specialized Diagnostics and Research, Department of Laboratory Medicine, Amsterdam UMC, Amsterdam, the Netherlands; 3 - Center of Excellence for ILD and Sarcoidosis, Erasmus Medical Center, Rotterdam, The Netherlands; 4 - Division of Heart & Lungs, Utrecht University Medical Center, Utrecht, the Netherlands;
Keywords: Methotrexate; Treatment; Personalization;
Select the theme: Controversies in Sarcoidosis Treatment
Type: Original Papers
Presentation: Poster Presentation

Introduction: Methotrexate (MTX) is a folate antagonist widely used as an immunosuppressive agent in sarcoidosis. Following cellular uptake, MTX is converted into methotrexate polyglutamates (MTX-PGₙ) through the sequential addition of up to six glutamate residues resulting in pharmacologically active intracellular metabolites. As a result, therapeutic drug monitoring (TDM) based on serum MTX concentrations is currently not feasible.

Objectives: To investigate whether MTX-PGₙ concentrations in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) are associated with treatment response in patients with pulmonary sarcoidosis.

Materials and Methods: RBCs and PBMCs were isolated from patients receiving MTX during the PREDMETH trial at 4, 16, and 24 weeks after treatment initiation (n=68). MTX-PGₙ concentrations were quantified using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Treatment response was assessed by changes in forced vital capacity (FVC) and soluble interleukin-2 receptor (sIL-2R) levels over time. Associations between MTX-PGₙ concentrations and changes in FVC or sIL-2R were evaluated using Spearman’s rank correlation coefficients and linear regression analysis.

Results: In RBCs, MTX-PG₁ and MTX-PG₂ concentrations at week 16 were negatively correlated with change in FVC from baseline to week 24 (r = −0.551, p < 0.001 and r = −0.511, p = 0.001, respectively). In PBMCs, MTX-PG₁–₃ concentrations at week 24 were correlated with changes in sIL-2R levels from baseline to week 24 (r = −0.410, p = 0.008; r = −0.330, p = 0.031; and r = −0.325, p = 0.033, respectively).

Conclusions: MTX-PGₙ concentrations in RBCs at week 16 and in PBMCs at week 24 were associated with subsequent treatment response at week 24, as reflected by changes in FVC and sIL-2R. These findings could partly explain inter-individual variability in response to MTX and be a first step towards TDM for MTX in patients with pulmonary sarcoidosis.