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

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.

Editorial: STAT3 phosphorylation for tofacitinib monitoring in ulcerative colitis—a step towards precision medicine?

“…6,7 Recently, Verstockt and colleagues have assessed the utility of monitoring of phosphorylation of Signal transducer and activator of transcription 3 (STAT3), a common downstream target of Janus kinase (JAK) signalling. 8 The authors focused on a real-world prospective cohort of 59 highly refractory UC patients with a median follow-up of 117.6 (IQR, 99.4-132.6) weeks. Tofacitinib induced and maintained endoscopic and histologic remission in up to one-quarter of patients, with a good safety profile and no major adverse cardiovascular events reported.…”

“…Recently, Verstockt and colleagues have assessed the utility of monitoring of phosphorylation of Signal transducer and activator of transcription 3 (STAT3), a common downstream target of Janus kinase (JAK) signalling 8 …”