{
  "abstract": "Objective Selective inhibition of interleukin (IL)-23 through antagonism of the IL-23p19 subunit has demonstrated clinical efficacy in inflammatory bowel disease, but the molecular changes underlying the efficacy outcomes have not yet been described. Here, we provide a detailed evaluation of the cellular and molecular changes associated with guselkumab treatment in patients with moderately to severely active ulcerative colitis (UC) from the QUASAR Phase IIb induction study.Methods In this double-blind, placebo-controlled, dose-ranging induction study, patients (n=313) were randomised (1:1:1) to receive intravenous guselkumab 200 or 400 mg or placebo at weeks 0, 4, and 8. Colon biopsy samples were collected at weeks 0 and 12, enabling molecular profiling by bulk RNA sequencing (RNA-seq, n=257), single-cell RNA sequencing (n=52), and flow cytometry (n=30). Serum proteomic profiling was also performed at weeks 0, 4, and 12 (n=302).Results Guselkumab treatment significantly reduced pro-inflammatory serum proteins by week 4 with continued decline through week 12, compared with placebo. Unsupervised analysis of tissue gene modules revealed significant changes in transcriptional states related to pro-inflammatory and epithelial repair pathways, which were most pronounced in patients who achieved histological-endoscopic mucosal improvement (HEMI) at week 12, an important tissue-based end point. Single-cell analyses supported a decrease in the cellular abundance of pro-inflammatory and an increase in mucosal cell types in tissue following treatment.Conclusion This analysis of guselkumab in UC demonstrated changes in key pathways and cell types that are associated with achieving important clinical end points including HEMI at week 12.Trial registration number NCT04033445.",
  "authors": [
    {
      "affiliations": [
        "Immunology Translational Sciences & Medicine, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Amy Hart"
    },
    {
      "affiliations": [
        "Immunology Translational Sciences & Medicine, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Sunandini Sridhar"
    },
    {
      "affiliations": [
        "Immunology Translational Sciences & Medicine, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Swati Venkat"
    },
    {
      "affiliations": [
        "Immunology Translational Sciences & Medicine, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Tae Lee"
    },
    {
      "affiliations": [
        "Immunology Translational Sciences & Medicine, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Joshua J Rusbuldt"
    },
    {
      "affiliations": [
        "Immunology Translational Sciences & Medicine, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Dylan Richards"
    },
    {
      "affiliations": [
        "Immunology Translational Sciences & Medicine, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Christopher Sisk"
    },
    {
      "affiliations": [
        "Immunology Translational Sciences & Medicine, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Dan Horowitz"
    },
    {
      "affiliations": [
        "Immunology Translational Sciences & Medicine, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Lynn Tomsho"
    },
    {
      "affiliations": [
        "Immunology Translational Sciences & Medicine, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Arun K Kannan"
    },
    {
      "affiliations": [
        "Immunology Translational Sciences & Medicine, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Darren Ruane"
    },
    {
      "affiliations": [
        "Statistics and Decision Sciences, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Koen Van den Berge"
    },
    {
      "affiliations": [
        "Medicine Inflammatory Bowel Disease Center, University of Chicago, Chicago, Illinois, USA"
      ],
      "name": "David T Rubin"
    },
    {
      "affiliations": [
        "Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA"
      ],
      "name": "Bruce E Sands"
    },
    {
      "affiliations": [
        "Laboratory of Pathology, University Hospitals Leuven, Leuven, Belgium",
        "Department of Imaging & Pathology, Laboratory of Translational Cell & Tissue Research, KU Leuven, Leuven, Belgium"
      ],
      "name": "Gert De Hertogh"
    },
    {
      "affiliations": [
        "Immunology Clinical Development, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Kuan-Hsiang G Huang"
    },
    {
      "affiliations": [
        "Immunology Clinical Development, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Matthew Germinaro"
    },
    {
      "affiliations": [
        "Immunology Clinical Development, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Dan Cua"
    },
    {
      "affiliations": [
        "Immunology Translational Sciences & Medicine, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Dawn Waterworth"
    },
    {
      "affiliations": [
        "Immunology Translational Sciences & Medicine, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Tom C Freeman"
    },
    {
      "affiliations": [
        "Immunology Clinical Development, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Marion L Vetter"
    },
    {
      "affiliations": [
        "Immunology Translational Sciences & Medicine, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Bradford McRae"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium",
        "Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium"
      ],
      "name": "Bram Verstockt"
    },
    {
      "affiliations": [
        "Immunology Translational Sciences & Medicine, Johnson and Johnson Limited, New Brunswick, New Jersey, USA"
      ],
      "name": "Patrick Branigan"
    }
  ],
  "title": "Multiomic characterisation of the clinical efficacy of guselkumab induction therapy in ulcerative colitis",
  "uid": "553051ab-ff59-558f-a703-16c833ad3226"
}