Ustekinumab enhances intestinal stenosis resolution by modulating fibrotic pathways in crohn's disease: a retrospective single-center study with translational analysis.

BACKGROUND AND AIM: Few studies have evaluated the impact of biologic therapy on endoscopic findings and stenoses of small intestinal lesions in Crohn's disease (CD). This study aimed to compare the endoscopic effectiveness and stenotic changes induced by anti-tumor necrosis factor inhibitors (anti-TNF) and ustekinumab (UST) in patients with CD, along with histological and molecular comparisons of stenosis between the groups.

METHODS

We retrospectively enrolled patients with CD who underwent balloon-assisted enteroscopy before and after initiating anti-TNF therapy or UST. For pathological and molecular evaluation of stenosis, we analyzed resected ileal specimens from patients with CD treated with anti-TNF, UST, or those who were biologic-naïve (bio-naïve).

RESULTS

The anti-TNF group (n = 18) showed a higher improvement rate in endoscopic activity scores compared to the UST group (n = 19). However, 27.8% of patients in the anti-TNF group experienced worsened stenosis, significantly higher than that in the UST group (0%). Histologically, the UST group showed a lower fibrosis score and reduced collagen III protein expression in the inactive ileum compared to both the anti-TNF and bio-naïve groups. Additionally, the UST group exhibited lower mRNA levels of IL22, TGFB1, and TNF in both active and inactive ilea. Immunostaining revealed fewer α-smooth muscle actin-positive cells in the UST group compared to the anti-TNF and bio-naïve groups in both active and inactive ileum.

CONCLUSION

This study suggests that inhibition of the IL-22/TGF-β pathway by anti-IL-23 treatment with UST may reduce myofibroblasts and improve small intestinal fibrous stenosis in patients with CD.