Prior vedolizumab exposure and fibroblast-derived MMP13 are associated with ustekinumab nonresponse in ulcerative colitis

Abstract

Abstract Background As therapeutic options for ulcerative colitis increase, optimizing the sequencing of advanced therapies has become an important challenge. We examined whether baseline clinical characteristics influence the effectiveness of ustekinumab and investigated molecular signatures associated with ustekinumab resistance. Methods This multicenter, retrospective study enrolled 102 patients with ulcerative colitis who initiated ustekinumab at 11 institutions. Clinical response and remission were assessed at 2, 6, and 12 months. Ustekinumab persistence was evaluated by Kaplan–Meier analysis. Predictive factors of nonresponse at 6 months were analyzed by logistic regression. To explore the molecular determinants of ustekinumab nonresponse, colonic tissue analyses were performed to identify candidate genes and their cellular sources. Cytokine stimulation experiments using intestinal fibroblasts were conducted to investigate upstream regulatory pathways. Results The 6-month clinical response and remission rates were 69.6% and 42.2%, respectively, with a 1-year ustekinumab persistence rate of 72.5%. Prior vedolizumab exposure was independently associated with ustekinumab nonresponse (odds ratio = 3.956; 95% confidence interval = 1.085–14.429). Transcriptomic profiling demonstrated enrichment of extracellular matrix-related pathways in nonresponders, and quantitative polymerase chain reaction confirmed significantly elevated matrix metalloproteinase 13 expression. In vitro stimulation assays demonstrated that interleukin-1β robustly induced matrix metalloproteinase 13 expression in intestinal fibroblasts. Conclusions Prior vedolizumab exposure was associated with lower ustekinumab effectiveness, suggesting that treatment history may be important when determining therapeutic sequencing in ulcerative colitis. Fibroblast-derived matrix metalloproteinase 13 represents a promising molecular marker associated with nonresponse to ustekinumab and may reflect an interleukin-1β-driven inflammatory fibroblast program linked to diminished treatment responsiveness.