New taxonomy based on individual patient-reported response trajectories defines ulcerative colitis endotypes and reveals vascular inflammation as a mechanism for vedolizumab nonresponse.

ABSTRACT: A major barrier to precision medicine for ulcerative colitis (UC) is the inability to predict and mechanistically explain treatment responses. Using daily patient-reported outcomes from a phase 3b comparative trial of 768 participants, we identified four distinct patient response trajectory groups for vedolizumab (anti-integrin) and adalimumab (antitumor necrosis factor) in UC. Validation in a second phase 3 trial of 591 participants linked vedolizumab trajectories to long-term disease complications. Bulk, single-cell, and spatial, transcriptomics and proteomics, identified vascular inflammation to be associated with vedolizumab nonresponse via SPP1+ monocytes and the angiopoetin-2 pathway. In a real-world cohort of 3,187 patients with UC, concomitant use of renin-angiotensin system inhibitors (modulators of vascular inflammation and angiopoietin-2 signaling) was associated with reduced long-term complications for vedolizumab but not anti-cytokine therapies. These findings define a response trajectory-based taxonomy, and endotype-specific outcome prediction, implicating vascular inflammation as a drug-specific and targetable resistance pathway for vedolizumab in UC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE336853 | GEO | 2026/09/15

REPOSITORIES: GEO