{
  "abstract": "Around 20% of patients with rheumatoid arthritis (RA) have disease that remains refractory to multiple targeted treatments, highlighting a major clinical challenge. We determine single-nucleus transcriptional and chromatin landscapes (10x Genomics Epi Multiome) on 14,625 primary CD4+ T-cells isolated from treatment-naive early and refractory (defined as per the EULAR definition of difficult-to-treat) patients with RA. We systematically analyze circulating regulatory profiles to reveal potential mechanisms and therapeutic targets that may contribute to the difficult-to-treat phenotype. We highlight disease-stage-specific alterations in naive and Th1-like memory CD4+ T-cells. In particular, refractory naive cells show signatures of heightened activation, upregulation of pathways aligning with T cell anergy, diminished regulation at regulatory loci (e.g., FOXP1, ICOS) and blunted stimulation responses; consistent with a more desensitized or exhausted state. Genes such as LGALS3, ZBTB7B and FOXO4 emerge as potential candidate regulators of the difficult-to-treat state. Finally, through RA GWAS integration, we prioritize putative causal variants in cis-regulatory elements.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "Article",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "name": "Samantha L. Smith",
      "orcid": "0000-0002-4108-8497"
    },
    {
      "name": "Stefano Rossi"
    },
    {
      "name": "Rudresh Shukla"
    },
    {
      "name": "Chuan Fu Yap"
    },
    {
      "name": "Nisha Nair"
    },
    {
      "name": "Jake Butler"
    },
    {
      "name": "Yvonne Tan"
    },
    {
      "name": "Amirah Binti Mohammad Ariff"
    },
    {
      "name": "Ilinca Lazar"
    },
    {
      "name": "Khadijah Patel"
    },
    {
      "name": "Stephen Eyre"
    },
    {
      "name": "Maya H. Buch"
    },
    {
      "name": "Paul Martin"
    },
    {
      "name": "Gisela Orozco"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4v0yvk5553se5.bib",
  "cited_by": 0,
  "doi": "10.1016/j.isci.2026.117949",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13734958/",
  "id": "4v0yvk5553se5",
  "issns": [
    "2589-0042"
  ],
  "landing_url": "https://www.cell.com/iscience/fulltext/S2589-0042(26)03332-8",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "http://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "heading",
      "Immunology"
    ],
    [
      "heading",
      "Transcriptomics"
    ],
    [
      "openalex",
      "2745|Rheumatoid Arthritis Research and Therapies"
    ]
  ],
  "openalex": "W7223696491",
  "pdf_url": "https://www.cell.com/iscience/pdf/S2589-0042(26)03332-8.pdf",
  "pmcid": "PMC13734958",
  "pmid": "42990950",
  "published": "2026-10-26",
  "publisher": "Elsevier BV",
  "ris": "https://research.draconitic.com/paper/4v0yvk5553se5.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:16Z",
      "native_id": "10.1016/j.isci.2026.117949",
      "source": "feed-cell",
      "url": "https://www.cell.com/iscience/fulltext/S2589-0042(26)03332-8"
    },
    {
      "first_seen": "2026-10-30T12:17:49Z",
      "native_id": "10.1016/j.isci.2026.117949",
      "source": "crossref",
      "url": "https://linkinghub.elsevier.com/retrieve/pii/S2589004226033328"
    },
    {
      "first_seen": "2026-11-09T12:20:45Z",
      "native_id": "PMC13734958",
      "source": "pmc",
      "url": "https://doi.org/10.1016/j.isci.2026.117949"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "heading:Immunology",
      "subfield": "immunology"
    }
  ],
  "title": "Exploratory single-cell multiomics suggests naive CD4+ T cell dysregulation in treatment refractory rheumatoid arthritis",
  "title_text": "Exploratory single-cell multiomics suggests naive CD4+ T cell dysregulation in treatment refractory rheumatoid arthritis",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:20:45Z",
  "url": "https://research.draconitic.com/paper/4v0yvk5553se5",
  "venue": "iScience",
  "versions": []
}