{
  "abstract": "Background\n\nRheumatoid arthritis (RA) is a heterogeneous autoimmune disease for which selecting the most appropriate first targeted therapy remains challenging. We integrated ex vivo immune-cell functional assays, targeted proteomics, clinical outcomes, and a three-dimensional (3D) synovial model to identify treatment-associated molecular signatures and evaluate their relationship with subsequent response to Janus kinase inhibitors (JAKi) or tumour necrosis factor inhibitors (TNFi).Methods\n\nPeripheral blood mononuclear cells and neutrophils from 48 b/tsDMARDs-naïve RA patients were cultured with autologous serum and treated ex vivo with Baricitinib or Etanercept to assess proliferation, adhesion, NETosis, and 92 inflammation-related proteins. The resulting JAKi- and TNFi-modulated protein signatures were subsequently evaluated in pretreatment serum from four independent RA treatment cohorts (n = 223; naïve and non-naïve). Unsupervised clustering was used to identify molecular subgroups, which were related to longitudinal DAS28-CRP outcomes at 3, 6, and 12 months. Logistic regression, neural network, and random forest models were evaluated using repeated nested cross-validation in naïve patients to discriminate treatment-specific 6-month remission outcomes. In a subset of naïve remission achievers, paired baseline and 6-month sera were applied to a 3D synovial micromass model.Results\n\nEx vivo JAKi and TNFi comparably modulated immune cell functions but induced distinct protein signatures with limited overlap. When evaluated in pretreatment baseline serum, these signatures stratified b/tsDMARD-naïve patients into clusters with different baseline inflammatory profiles and treatment-specific ΔDAS28-CRP. High baseline expression of a drug-specific signature was associated with remission with the corresponding therapy and failure to achieve remission with the alternative treatment. Under repeated nested cross-validation, logistic regression showed the highest mean discrimination among the models, with an AUC of 0.70 (SD, 0.03; empirical 2.5th-97.5th percentile, 0.65-0.75) for distinguishing treatment-specific remission outcomes in b/tsDMARD-naïve RA. In remission achievers, 6-month sera from either therapy significantly reduced synovial lining thickness in 3D micromasses versus baseline.Conclusion\n\nEx vivo-derived JAKi- and TNFi-associated immune-related protein signatures, integrated within a machine-learning framework, showed moderate discriminatory ability for treatment-specific remission patterns in b/tsDMARD-naïve RA and, together with complementary evidence of reduced synovial lining thickness in remission achievers, support further investigation of biomarker-informed selection between JAKi and TNFi as first targeted therapies.",
  "abstract_shown": true,
  "affiliations": [
    "IMIBIC/Reina Sofia Hospital/University of Cordoba, Córdoba, Spain.",
    "Department of Cell Biology, Immunology and Physiology, Agrifood Campus of International Excellence, University of Córdoba, ceiA3, Córdoba, Spain.",
    "Cobiomic Bioscience, EBT IMIBIC/UCO, Córdoba, Spain.",
    "Rheumatology and Immuno-Mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain.",
    "Center for Genomics and Oncological Research (GENYO), Granada, Spain.",
    "Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.",
    "IMIBIC/Reina Sofia Hospital/University of Cordoba, Córdoba, Spain. rosario.lopez.exts@juntadeandalucia.es."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 22,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Sagrario Corrales"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Carlos Pérez-Sánchez"
    },
    {
      "affs": [
        0
      ],
      "name": "Tomas Cerdó"
    },
    {
      "affs": [
        0
      ],
      "name": "Christian Merlo"
    },
    {
      "affs": [
        3
      ],
      "name": "Beatriz Malvar-Fernández"
    },
    {
      "affs": [
        3
      ],
      "name": "Samuel García"
    },
    {
      "affs": [
        0
      ],
      "name": "Laura Muñoz-Barrera"
    },
    {
      "affs": [
        0
      ],
      "name": "Ismael Sanchez-Pareja"
    },
    {
      "affs": [
        0
      ],
      "name": "Lydia Formanti"
    },
    {
      "affs": [
        0
      ],
      "name": "Elena Moreno-Caño"
    },
    {
      "affs": [
        0
      ],
      "name": "Rafaela Ortega-Castro"
    },
    {
      "affs": [
        0
      ],
      "name": "Jerusalén Calvo"
    },
    {
      "affs": [
        0
      ],
      "name": "Concepción Aranda-Varela"
    },
    {
      "affs": [
        0
      ],
      "name": "Lourdes Ladehesa"
    },
    {
      "affs": [
        0
      ],
      "name": "Pilar Font"
    },
    {
      "affs": [
        0
      ],
      "name": "M Carmen Abalos-Aguilera"
    },
    {
      "affs": [
        0
      ],
      "name": "Desirée Ruiz-Vilchez"
    },
    {
      "affs": [
        0
      ],
      "name": "Mª Ángeles Aguirre"
    },
    {
      "affs": [
        0
      ],
      "name": "Nuria Barbarroja"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Marta E Alarcon-Riquelme"
    },
    {
      "affs": [
        0
      ],
      "name": "Alejandro Escudero-Contreras"
    },
    {
      "affs": [
        6
      ],
      "name": "Chary López-Pedrera"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cv72cnr41g4cm.bib",
  "cited_by": 0,
  "doi": "10.1186/s40364-026-01029-4",
  "fulltext_url": "https://europepmc.org/articles/PMC13689063",
  "id": "cv72cnr41g4cm",
  "issns": [
    "2050-7771"
  ],
  "landing_url": "https://europepmc.org/article/MED/42907925",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "RM1-950"
    ],
    [
      "openalex",
      "2745|Rheumatoid Arthritis Research and Therapies"
    ]
  ],
  "openalex": "W7223154847",
  "pdf_url": "https://europepmc.org/articles/PMC13689063?pdf=render",
  "pmcid": "PMC13689063",
  "pmid": "42907925",
  "published": "2026-10-22",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/cv72cnr41g4cm.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:53Z",
      "native_id": "MED:42907925",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42907925"
    },
    {
      "first_seen": "2026-10-30T13:46:11Z",
      "native_id": "9b95f10e193341e7a0c4821ef8f51719",
      "source": "doaj",
      "url": "https://doi.org/10.1186/s40364-026-01029-4"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "lcc:RM1-950",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Ex vivo JAK and TNF inhibitor-modulated immune signatures guide first-line therapy selection in rheumatoid arthritis.",
  "title_text": "Ex vivo JAK and TNF inhibitor-modulated immune signatures guide first-line therapy selection in rheumatoid arthritis.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:46:11Z",
  "url": "https://research.draconitic.com/paper/cv72cnr41g4cm",
  "venue": "Biomarker research",
  "versions": []
}