Longitudinal transcriptomic analysis of mucosa in ulcerative colitis after anti-tumor necrosis factor withdrawal compared to continued treatment.

BACKGROUND AND AIMS: Monoclonal antibodies against tumor necrosis factor (anti-TNF) are effective agents in the treatment of moderate-to-severe ulcerative colitis (UC). It is unclear whether such treatment can safely be discontinued without relapse. This study aimed to identify biomarkers to predict which patients can successfully stop anti-TNF treatment, and to increase our understanding of the pathogenesis of relapse after withdrawal and flare on continued therapy. METHODS: We analyzed longitudinal bulk RNA-sequencing data derived from rectal mucosal biopsies from 163 patients in the BIOSTOP study collected at baseline, after 2 years (end of study), and at flares or relapse points. RESULTS: In this cohort, pre-withdrawal transcriptomic profiles did not distinguish patients who later relapsed from those who remained in long-term remission. Longitudinal analysis of patients who relapsed or flared were both characterized by inflammatory gene expression profiles (eg, CXCL9, CXCL10, OSMR, SELE) and changes in cell-type composition typical for active UC (eg, monocytes/macrophages and THY1+ FAP+ PDPN+ activated fibroblasts). Both groups showed enrichment of T-cell-associated transcriptional signatures, including CD8 T-cell-related genes and IL-17-associated pathways. Additionally, both patient groups showed increased expression of targets of alternative therapeutic agents, suggesting potential treatment options for specific patient subgroups. CONCLUSIONS: Our findings provide insights into the inflammatory mechanisms driving relapse after anti-TNF withdrawal and flare on continued treatment. The dataset offers a valuable resource for future research to improve personalized treatment strategies in UC.