Histological Outcomes and JAK-STAT Signalling in Ulcerative Colitis Patients Treated with Tofacitinib

Abstract Background and aims Histological outcomes and JAK-STAT signalling were assessed in a prospective ulcerative colitis UC patient cohort after 8 weeks treatment with tofacitinib, an oral Janus kinase JAK inhibitor. Methods Forty UC patients received tofacitinib 10 mg twice daily for 8 weeks. Treatment response was defined as histo-endoscopic mucosal improvement HEMI. Histological remission was defined as a Robarts Histopathology Index RHI ≤3 points and histological response as 50% decrease in RHI. Mucosal expression of JAK1-3, tyrosine kinase 2 TYK2, and total signal transducer and activator of transcription STAT 1-6 were assessed using immunohistochemistry IHC. Results At baseline, the median RHI was 14 (interquartile range IQR 10–19). Of 40 65% patients, 26 had severe endoscopic disease endoscopic Mayo score 3 and 31/40 78% failed prior anti-tumour necrosis factor anti-TNF treatment. At Week 8, 15 patients 38% had HEMI, 23 patients 58% histological remission, and 34 85% histological response. RHI decreased by a median of 14 points IQR 9-21 in responders p 0.001 and by 6 points IQR 0-13 in non-responders p = 0.002. STAT1, STAT3, and STAT5 expression levels decreased significantly in the whole cohort. Responders had lower Week 8 STAT1 expression levels compared with non-responders 0.2%, IQR 0.1-2.8 vs 4.3%, IQR 1.2-11.9, p = 0.001, suggesting more profound STAT1 blockade. A trend of higher baseline JAK2 expression was observed in tofacitinib non-responders 2.7%, IQR 0.1-7.7 compared with responders 0.4%, IQR 0.1-2.1. Conclusions Tofacitinib treatment resulted in histological improvement in the majority of UC patients and in a substantial decrease of STAT1, STAT3, and STAT5 expression. HEMI was associated with more profound suppression of STAT1.