Abstract
ABSTRACT
B
ackground &
O
bjective
Tofacitinib, a Janus kinase (JAK) inhibitor, is approved for ulcerative colitis (UC). We investigated baseline and longitudinal transcriptomics and proteomics in intestinal biopsies, peripheral blood, and serum from UC patients starting tofacitinib to characterize treatment-associated effects and identify which molecular compartment harbors the most predictive response-associated biomarkers.
M
ethods
In this prospective, open-label study, patients with moderately to severely active UC started tofacitinib 10 mg BID for eight weeks. Clinical, biochemical, endoscopic, and histological data were collected at baseline and week 8. The primary outcome, histo-endoscopic mucosal improvement (HEMI), was defined as endoscopic Mayo subscore ≤1 with histologic remission (Robarts Histopathology Index ≤3, no mucosal neutrophils). Mucosal biopsies and peripheral blood were collected at baseline and week 8 for bulk RNA-sequencing (RNA-seq); biopsies and serum underwent proteomic profiling using Olink Explore 384 (Cardiometabolic, Inflammation, Neurology, Oncology panels).
R
esults
In total, 127 paired multi-omic samples were collected longitudinally from 40 UC patients: 15 (38%) achieved HEMI at week 8 (responders), 13 (32.5%) were late responders, and 12 (30%) were non-responders. Pretreatment mucosal biopsies from future responders showed elevated interferon, IL-6-family, IL-2/common-γ-chain, and T-cell-receptor signaling gene expression, which declined on treatment only in responders. A responder-specific JAK-STAT-dependent mechanism spanned interferon, cytokine-receptor, T-cell-receptor, and NF-κB signaling, with concordant gene- and protein-level reductions. Compared with a public infliximab dataset, JAK-STAT/interferon downregulation was shared and response-independent, while non-canonical NF-κB downregulation was tofacitinib-specific. In blood, shared pathway labels reflected distinct genes from mucosal effectors.
C
onclusion
Response to tofacitinib depends on a JAK-tractable mucosal pathway absent in non-responders, suggesting a pretreatment biomarker for predicting treatment response.
What is already known on this topic
Prior studies have individually interrogated transcriptomic and/or epigenomic signatures of tofacitinib response as a single modality.
What this study adds
Our study provides simultaneous profiling of both the transcriptome and proteome across paired mucosal and systemic compartments in patients, comparing responders with non-responders at baseline and over time. Our data support a model where tofacitinib response in UC depends on a JAK-dependent pro-inflammatory phenotype that the drug can dismantle, in contrast to non-responders representing distinct, JAK-independent pathways.
How this study might affect research, practice or policy
This study provides a foundation for treatment response studies in UC towards the development and validation of predictive biomarkers in colonic mucosa and blood, which could ultimately result in more personalized treatment strategies.