Histological Outcomes And Jak-Stat Signalling In Ulcerative Colitis Patients Treated With Tofacitinib.

van Gennep, Sara; Fung, Ivan C N; de Jong, Djuna C; Ramkisoen, Rishand K; Clasquin, Esmé; de Jong, Jitteke; de Vries, Leonie C S; de Jonge, Wouter J; Gecse, Krisztina B; Löwenberg, Mark; Woolcott, John C; Mookhoek, Aart; D'Haens, Geert R (2024). Histological Outcomes And Jak-Stat Signalling In Ulcerative Colitis Patients Treated With Tofacitinib. (In Press). Journal of Crohn's & colitis Oxford University Press 10.1093/ecco-jcc/jjae031

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BACKGROUND AND AIMS

Histological outcomes and JAK-STAT signaling 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). Twenty-six of 40 (65%) patients had severe endoscopic disease (endoscopic Mayo score 3) and 31/40 (78%) failed prior 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 to 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 to responders (0.4%, IQR 0.1-2.1).

CONCLUSIONS

Tofacitinib treatment resulted in histological improvement in the majority of UC patients and a substantial decrease of STAT1, STAT3 and STAT5 expression. HEMI was associated with more profound suppression of STAT1.

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