Introduction Ulcerative colitis is a chronic inflammatory disorder driven by dysregulated immune pathways, with the interleukin-23 (IL-23)/Th17 axis playing a central pathogenic role. Modern treatment strategies have shifted toward achieving deep remission, including histological and endoscopic healing, rather than symptom control alone.
Introduction
Ulcerative colitis is a chronic inflammatory disorder driven by dysregulated immune pathways, with the interleukin-23 (IL-23)/Th17 axis playing a central pathogenic role. Modern treatment strategies have shifted toward achieving deep remission, including histological and endoscopic healing, rather than symptom control alone. Guselkumab, a selective IL-23p19 inhibitor, has demonstrated clinical efficacy in moderate-to-severe disease. However, the molecular and cellular mechanisms underlying its therapeutic benefit remain incompletely understood, particularly in relation to mucosal healing and tissue-level remission.
Problem Statement
While clinical trials have confirmed the efficacy of IL-23 inhibition, there is a critical gap in understanding how these therapies translate into molecular remission. Specifically, the absence of integrated multiomic data limits the ability to define biomarkers of response, predict outcomes, and refine precision medicine approaches in ulcerative colitis.
Summary
This Phase IIb QUASAR multiomic analysis demonstrates that guselkumab induces early and sustained suppression of systemic and mucosal inflammatory pathways. Treatment reduced pro-inflammatory cytokine signatures and downregulated IL-23/Th17-driven transcriptional activity, while simultaneously promoting epithelial repair mechanisms.
Single-cell and transcriptomic analyses revealed a decrease in inflammatory monocytes, fibroblasts, and plasma cells, alongside an increase in epithelial and reparative cell populations in responders achieving histo-endoscopic mucosal improvement at 12 weeks.
These findings establish a biological basis for deep remission, linking IL-23 blockade to both immune suppression and mucosal restoration. Importantly, this study lays the groundwork for molecular definitions of remission and predictive biomarkers, advancing precision therapy in ulcerative colitis.
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