Longitudinal monitoring of STAT3 phosphorylation and histologic outcome of tofacitinib therapy in patients with ulcerative colitis

Aliment Pharmacol Ther. 2022 Jul;56(2):282-291. doi: 10.1111/apt.16955. Epub 2022 Apr 28.

Abstract

Background: Tofacitinib is the first in class, pan-JAK inhibitor approved for ulcerative colitis (UC). Clinical efficacy has been shown, but long-term real-life endoscopic and histologic data are lacking.

Aim: To investigate the effects of tofacitinib in patients with refractory UC focussing on endoscopic, histologic and molecular outcomes, including STAT3 phosphorylation (pSTAT3) detection in the spatial context of mucosal inflammation METHODS: We prospectively monitored 59 highly refractory patients (96.7% anti-TNF exposure, 91.7% vedolizumab exposure) initiating tofacitinib at two IBD referral centres and assessed outcome at the end of induction and after 48 weeks of therapy. Endoscopic improvement was defined as a Mayo endoscopic subscore ≤1, endoscopic and histologic remission as Mayo endoscopic subscore 0 and Nancy histologic score 0. Multiplex immunohistochemistry with multispectral imaging was used to assess pSTAT3.

Results: Endoscopic improvement was achieved by 24.4% and 30.5% of patients at weeks 8 and 48, respectively. Endoscopic and histologic remission rates were 11.1%, 23.7 and 16.7%, 21.4%, respectively. Endoscopic improvement at week 8 was significantly associated with treatment continuation in the long-term (72.7% vs 20.6%, p = 0.003). Although we observed a gradual decrease of mucosal pSTAT3 levels in both remitters and non-remitters (p < 0.05), no association with treatment outcome could be demonstrated. However, lamina propria pSTAT3 was significantly associated with the Nancy Histologic index (p = 0.004).

Conclusion: Tofacitinib can induce and maintain endoscopic and histologic remission in up to one-quarter of highly refractory UC patients. Longitudinal monitoring of nuclear pSTAT3 in mucosal tissue compartments reflects distinctive on-target effects, independently of long-term treatment outcomes.

MeSH terms

  • Colitis, Ulcerative* / diagnosis
  • Colitis, Ulcerative* / drug therapy
  • Humans
  • Janus Kinase Inhibitors* / therapeutic use
  • Phosphorylation
  • Piperidines* / therapeutic use
  • Pyrimidines* / therapeutic use
  • Remission Induction
  • STAT3 Transcription Factor* / metabolism
  • Treatment Outcome

Substances

  • Janus Kinase Inhibitors
  • Piperidines
  • Pyrimidines
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • tofacitinib