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<p>Monocytes and monocyte-derived macrophages play a key pathogenic role in inflammatory arthritis. Methotrexate (MTX) is the first-line disease-modifying antirheumatic drug (DMARD) for arthritis, yet the mechanisms and kinetics of its effects on monocyte/macrophages remain poorly understood. We have now investigated the temporal dynamics of the MTX's anti-inflammatory action by initially performing a phase I clinical trial (METOMAC) on healthy individuals following a single MTX dose, which revealed that MTX plasma levels peak at 1&#xa0;h after MTX treatment, with maximal suppression of LPS-induced IL-1β and IL-6 in whole blood 5&#xa0;days after MTX exposure. Building on these findings, we performed an observational clinical study (METOMAC-PAC) on 29 DMARD-naïve early arthritis patients receiving a weekly dose of MTX over a 3&#xa0;month period. The METOMAC-PAC study revealed that MTX polyglutamates (MTX-PG) accumulates in peripheral blood monocytes, where MTX-PG is detected as early as 5&#xa0;days post-treatment, and modulates the monocyte gene profile after 4 MTX doses, with specific enrichment of the aryl-hydrocarbon receptor (AhR)-molecular signature and genes coding for anti-inflammatory factors. Importantly, stratification of METOMAC-PAC patients according to their clinical response revealed that Good Responders exhibit increased expression of “non-classical monocyte”-specific genes (<i>MAF</i>, <i>FCGR3B</i>, <i>ICAM4</i>) both before and after MTX treatment, while Partial Responders patients showed a higher baseline expression of genes preferentially expressed by “classical monocytes”. Our results elucidate the kinetics of the anti-inflammatory action of MTX, demonstrate that MTX modulates the monocyte transcriptional signature <i>in vivo</i>, and identify “non-classical monocyte”-associated genes as predictors for an effective MTX clinical response.</p> Graphical abstract <p></p>

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Monocytes from inflammatory arthritis patients accumulate methotrexate and their transcriptome predicts methotrexate clinical response

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月17日

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  • Israel Ríos,
  • María Teresa Schiaffino,
  • Baltasar López-Navarro,
  • Ana Triguero-Martínez,
  • Marry Lin,
  • Mónica Torres-Torresano,
  • Eduard A. Struys,
  • Susana Álvarez,
  • Manuel Román,
  • Francisco Abad-Santos,
  • Santos Castañeda,
  • Noelia Garcia-Castañeda,
  • Robert de Jonge,
  • Gerrit Jansen,
  • Isabel Castrejón,
  • Isidoro González-Álvaro,
  • Amaya Puig-Kröger

摘要

Monocytes and monocyte-derived macrophages play a key pathogenic role in inflammatory arthritis. Methotrexate (MTX) is the first-line disease-modifying antirheumatic drug (DMARD) for arthritis, yet the mechanisms and kinetics of its effects on monocyte/macrophages remain poorly understood. We have now investigated the temporal dynamics of the MTX's anti-inflammatory action by initially performing a phase I clinical trial (METOMAC) on healthy individuals following a single MTX dose, which revealed that MTX plasma levels peak at 1 h after MTX treatment, with maximal suppression of LPS-induced IL-1β and IL-6 in whole blood 5 days after MTX exposure. Building on these findings, we performed an observational clinical study (METOMAC-PAC) on 29 DMARD-naïve early arthritis patients receiving a weekly dose of MTX over a 3 month period. The METOMAC-PAC study revealed that MTX polyglutamates (MTX-PG) accumulates in peripheral blood monocytes, where MTX-PG is detected as early as 5 days post-treatment, and modulates the monocyte gene profile after 4 MTX doses, with specific enrichment of the aryl-hydrocarbon receptor (AhR)-molecular signature and genes coding for anti-inflammatory factors. Importantly, stratification of METOMAC-PAC patients according to their clinical response revealed that Good Responders exhibit increased expression of “non-classical monocyte”-specific genes (MAF, FCGR3B, ICAM4) both before and after MTX treatment, while Partial Responders patients showed a higher baseline expression of genes preferentially expressed by “classical monocytes”. Our results elucidate the kinetics of the anti-inflammatory action of MTX, demonstrate that MTX modulates the monocyte transcriptional signature in vivo, and identify “non-classical monocyte”-associated genes as predictors for an effective MTX clinical response.

Graphical abstract