Baseline serum and stool microbiome biomarkers predict clinical efficacy and tissue molecular response after ritlecitinib induction therapy in ulcerative colitis.
Academic Article
Overview
abstract
BACKGROUND AND AIMS: Ritlecitinib, an oral JAK3/TEC family kinase inhibitor, was well- tolerated and efficacious in the phase 2b VIBRATO study in participants with moderate-to-severe ulcerative colitis (UC). The aim of this study was to identify baseline serum and microbiome markers that predict subsequent clinical efficacy and to develop noninvasive serum signatures as potential real-time noninvasive surrogates of clinical efficacy after ritlecitinib. METHODS: Tissue and peripheral blood proteomics, transcriptomics, and fecal metagenomics were performed on samples before and after 8-week oral ritlecitinib induction therapy (20 mg, 70 mg, 200 mg, or placebo once daily, N=39, 41, 33, and 18, respectively). Linear mixed models were used to identify baseline and longitudinal protein markers associated with efficacy. The combined predictivity of these proteins was evaluated using a logistic model with permuted efficacy data. Differential expression of fecal metagenomic was used to differentiate responders and nonresponders. RESULTS: Peripheral blood serum proteomics identified 4 baseline serum markers (LTA, CCL21, HLA-E, MEGF10) predictive of modified clinical remission (MR), endoscopic improvement (EI), histologic remission (HR), and integrative score of tissue molecular improvement. In responders, 37 serum proteins significantly changed at Week 8 compared with baseline (FDR<0.05); of these, changes in 4 (IL4R, TNFRSF4, SPINK4, and LAIR-1) predicted concurrent EI and HR responses. Fecal metagenomics analysis revealed baseline and treatment response signatures that correlated with EI, MR, and tissue molecular improvement. CONCLUSIONS: Blood and microbiome biomarkers stratify endoscopic, histologic, and tissue molecular response to ritlecitinib, which may help guide future precision medicine approaches to UC treatment.
