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We examined whether baseline clinical characteristics influence the effectiveness of ustekinumab and investigated molecular signatures associated with ustekinumab resistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u00a0months. Ustekinumab persistence was evaluated by Kaplan\u2013Meier analysis. Predictive factors of nonresponse at 6\u00a0months 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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\u201314.429). 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-1\u03b2 robustly induced matrix metalloproteinase 13 expression in intestinal fibroblasts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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-1\u03b2-driven inflammatory fibroblast program linked to diminished treatment responsiveness.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00535-026-02506-1","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T03:08:15Z","timestamp":1790564895000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prior vedolizumab exposure and fibroblast-derived MMP13 are associated with ustekinumab nonresponse in ulcerative colitis"],"prefix":"10.1007","author":[{"given":"Yuiko","family":"Tsuruta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoki","family":"Furuta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatoshi","family":"Nakashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shota","family":"Takano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Sakurai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Kitada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kana","family":"Omoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taichi","family":"Matsuyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinari","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suguru","family":"Chiyonaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotaro","family":"Fukubayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Shono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masakuni","family":"Tateyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotaro","family":"Waki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Munenori","family":"Honda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenshi","family":"Matsuno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Yamasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Miyamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryosuke","family":"Gushima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takehisa","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuya","family":"Nagaoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Naoe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Komohara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2473-6966","authenticated-orcid":false,"given":"Yasuhito","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"issue":"10080","key":"2506_CR1","doi-asserted-by":"publisher","first-page":"1756","DOI":"10.1016\/S0140-6736(16)32126-2","volume":"389","author":"R Ungaro","year":"2017","unstructured":"Ungaro R, Mehandru S, Allen PB, et al. 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Written informed consent was obtained from patients who provided endoscopic biopsy specimens. For patients whose data were obtained retrospectively from medical records only, informed consent was obtained through an opt-out process in accordance with local regulations. All patient data were anonymized prior to analysis to ensure confidentiality and privacy.","order":1,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"English-language editing and manuscript formatting assistance were provided by NAI, Inc. (Tokyo, Japan).","order":2,"name":"Ethics","label":"Writing assistance","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Dr. Furuta received lecture fees from Mochida Pharmaceutical Co., Ltd. Dr. Tanaka received scholarship donations and\/or research funding from Otsuka Pharmaceutical Co., Ltd., FUJIFILM Pharmaceutical Co., Ltd., FUJIREBIO Inc., Sysmex Corporation, GlaxoSmithKline plc, and Gilead Sciences, Inc.; lecture fees from AbbVie GK, Gilead Sciences, Inc., Chugai Pharmaceutical Co., Ltd., ASKA Pharmaceutical Holdings Co., Ltd., GlaxoSmithKline plc, and AstraZeneca; and served on an advisory board for GlaxoSmithKline plc. The other authors declare that they have no conflict of interest.","order":3,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}}]}}