P602 Tofacitinib treatment prevents post-operative recurrence of Crohn’s Disease modeled by ileocecal resection in HLA-B27 transgenic rats.
Blondeaux, A.(1);Speca, S.(2);Valibouze, C.(3);Lambin, T.(1);Dubuquoy, C.(2);Titecat, M.(4);Genoscreen, L.(5);Neut, C.(6);Genin, M.(7);Zerbib, P.(3);Foligne, B.(6);Desreumaux, P.(1);
(1)Univ. Lille- Inserm- Infinite-U1286, CHU Lille- Service des maladies de l'appareil digestif, Lille, France;(2)Univ. Lille- Inserm- Infinite-U1286, CHU Lille, Lille, France;(3)Univ. Lille - Inserm - INFINITE - U1286, CHU Lille - Département de Chirurgie Digestive, Lille, France;(4)Univ. Lille- Inserm- Infinite-U1286, CHU Lille- Service de Bactériologie, Lille, France;(5)Genoscreen, Lille, Lille, France;(6)Univ. Lille- Inserm- Infinite-U1286, Faculté de Pharmacie, Lille, France;(7)Univ. Lille, Ulr 2694, Lille, France;
Background
Post-operative recurrence (POR) after ileocecal resection (ICR) affects most of Crohn's disease (CD) patients. Immunomodulatory treatments have not proven efficiency in preventing POR except for anti-TNFα biologic agents. We evaluate the efficacy of the JAK inhibitor Tofacitinib to prevent POR after ICR in HLA-B27 transgenic rat model (TgB27).
Methods
Thirty-three rats (strain F344, 29 TgB27, 4 control non Tg (nTg) rats) were operated on an ICR at the 12th week (W12) of life and were sacrificed at W18. Tofacitinib (15 mg/kg, n=17) or placebo (n=16) were daily administered by oral gavage at W10 until W18. Anastomotic recurrence were blindly analyzed using macroscopic (from 0 to 4) and histologic (from 0 to 6) scores. Luminal microbiome was analyzed by shotgun metagenomic sequencing (Hiseq Illumina) in 9/33 rats before (W9) and after Tofacitinib treatment or placebo (W12 and W18). STAT3 phosphorylation was quantified in ileal samples by western blotting. Data were expressed by median with IQR. Comparisons were performed using not parametric two tailed Mann-Whitney analysis for unmatched data and Wilcoxon matched-pairs test for matched data. Two tailed χ2 test was used for contingency analysis. Spearman rank correlation was used for microbiota analysis.
Results
8/14 TgB27 rats receiving placebo (57%) showed signs of POR (macroscopic score ≥ 2) which were significantly prevented in 2/15 TgB27 rats (13%) treated with Tofacitinib (p= 0.013). nTg animals did not show macroscopic signs of POR. Macroscopic lesions were located 2 cm around the anastomosis in the TgB27 placebo group and consisted in ulcerations with a score of 2 (1-2.25). 11/15 TgB27 rats (73%) treated with Tofacitinib did not show macroscopic lesions and their score were significantly improved (0 (0-1), p= 0,0006). Histologic scores were significantly higher in TgB27 placebo group vs TgB27 Tofacitinib-treated rats (3 (2-4) vs 2 (1-3), p=0.036). Tofacitinib did not impact on alpha diversity and the relative abundance of bacterial taxa either before and after surgery. In contrast, surgery led to a significant 47% decrease of alpha diversity (p=0.0008) and loss of specific taxa in both TgB27 and nTg animals. No correlation was found between individual lesion scores and alpha diversity indexes. Ileal pSTAT3/STAT3 ratios were decreased by 80% in TgB27 rats treated with Tofacitinib (n=4) compared to placebo group (n=4) (0.3 ± 0,16 vs 1.58 ± 0,3, p=0,028).
Conclusion
We develop a reliable model of ICR in TgB27 rats mimicking the POR of CD. Tofacitinib prevents the macroscopic and histologic POR after ICR, without major modifications of the microbioma.
Acknowledgments: Charity Foundation DigestScience and Pfizer SAS