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Methotrexate Polyglutamate Concentrations as a Possible Predictive Marker for Effectiveness of Methotrexate Therapy in Patients with Sarcoidosis: A Pilot Study

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Abstract

Introduction

Methotrexate (MTX), a folate antagonist, is often used as second-line treatment in patients with sarcoidosis. Effectiveness of MTX has large inter-patient variability and at present therapeutic drug monitoring (TDM) of MTX is not possible. Upon administration, MTX is actively transported into cells and metabolized to its active forms by adding glutamate residues forming MTXPG(n=1–5) resulting in enhanced cellular retention. In this study we address the question whether different MTXPG(n) concentrations in red blood cells (RBC) of patients with sarcoidosis after 3 months of MTX therapy correlate with response to treatment.

Methods

We retrospectively included patients with sarcoidosis that had started on MTX therapy and from whom blood samples and FDG-PET/CT were available 3 and 6–12 months after MTX initiation, respectively. FDG-uptake was measured by SUVmax in the heart, lungs and thoracic lymph nodes. Changes in SUVmax was used to determine anti-inflammatory response after 6–12 months of MTX therapy. MTXPG(n) concentrations were measured from whole blood RBC using an LC–MS/MS method. Pearson correlation coefficients were calculated to evaluate the relationship between changes in the SUVmax and MTXPG(n) concentrations.

Results

We included 42 sarcoidosis patients treated with MTX (15 mg/week); 31 with cardiac sarcoidosis and 11 with pulmonary sarcoidosis. In MTXPG3 and MTXPG4 a significant negative relation between the absolute changes in SUVmax and MTXPG(n) was found r = − 0.312 (n = 42, p = 0.047) for MTXPG3 and r = − 0.336 (n = 42, p = 0.031 for MTXPG4). The other MTXPG(n) did not correlate to changes in SUVmax.

Conclusion

These results suggest a relation between MTXPG(n) concentrations and the anti-inflammatory effect in patients with sarcoidosis. Further prospective validation is warranted, but if measuring MTXPG concentrations could predict treatment effect of MTX this would be a step in the direction of personalized medicine.

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Funding

The authors declare that no funds, grants or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Pulmonology, ILD Center of Excellence, St. Antonius Hospital, Nieuwegein, The Netherlands

    Montse Janssen Bonás, Jan C. Grutters & Marcel Veltkamp

  2. Department of Clinical Chemistry, Amsterdam University Medical Center, Amsterdam, The Netherlands

    Janani Sundaresan, Eduard A. Struys & Maurits C. F. J. de Rotte

  3. Department of Nuclear Medicine, St. Antonius Hospital, Nieuwegein, Utrecht, The Netherlands

    Ruth G. M. Keijsers

  4. Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, Utrecht, The Netherlands

    Bas J. M. Peters

  5. Center of Excellence for ILD and Sarcoidosis, Erasmus Medical Center, Rotterdam, The Netherlands

    Vivienne Kahlmann & Marlies S. Wijsenbeek

  6. Division of Heart & Lungs, Utrecht University Medical Center, Utrecht, The Netherlands

    Jan C. Grutters & Marcel Veltkamp

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  1. Montse Janssen Bonás
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Contributions

Study conception and design was discussed by MJB, MV, BP and MR. All FDG-PET/CT SUVmax measurements were done by RK. Material preparation, data collection and analysis were performed by MJB and JS. The first draft of the manuscript was written by MJB and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Marcel Veltkamp.

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Janssen Bonás, M., Sundaresan, J., Keijsers, R.G.M. et al. Methotrexate Polyglutamate Concentrations as a Possible Predictive Marker for Effectiveness of Methotrexate Therapy in Patients with Sarcoidosis: A Pilot Study. Lung 201, 617–624 (2023). https://doi.org/10.1007/s00408-023-00656-0

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