P035 Serum markers predict outcome to ustekinumab in patients with refractory Crohn's disease and provide insides in the mechanism of action. (16th January 2018)

• Record Type: Journal Article
• Authors: Verstockt, B; Vermeire, S; Verstockt, S; Creyns, B; Ardeshir Davani, N; Breynaert, C; Van Assche, G; Van Assche, G; Ferrante, M
• Is Part Of: Journal of Crohn's and colitis. Volume 12:Number 1(2018:Jan.)Supplement 1
• Page Start: S110
• Page End: S110
• Publication Date: 2018-01-16
• Subjects: Inflammatory bowel diseases -- Periodicals; 616.344005
• DOI: 10.1093/ecco-jcc/jjx180.162
• Languages: English
• ISSNs: 1873-9946

Abstract

Abstract: Background: Ustekinumab (UST), targeting the IL-12/23 shared p40 subunit, was recently approved by FDA and EMA for treatment of moderate-to-severe Crohn's disease (CD). The aim of this study was to identify potential predictive immunological biomarkers for response, which may guide treatment strategies with ustekinumab. Methods: Serum samples of 36 CD patients (73% female, median disease duration 15.9 years), all refractory to anti-TNF therapy and vedolizumab and with baseline endoscopic active disease, were prospectively collected prior to UST initiation. Patients received UST 6 mg/kg IV at induction, with subcutaneous UST 90 mg q8w thereafter. Endoscopic response was assessed at week 24, and defined as ≥50% SES-CD decrease. Proteomic analysis (OLINK) was performed on baseline serum samples. Additionally, inflamed ileal ( n = 10) and colonic ( n = 17) biopsies, prior to UST therapy, were collected. Mucosal total RNA was isolated, and next-generation sequencing performed. Differentially gene expression was evaluated by DESeq R package. Results: Patients with ( n = 7) and without ( n = 29) endoscopic response at week 24 had a similar baseline inflammatory burden, reflected by similar median faecal calprotectin (1800 vs. 1721 µg/g, p = 0.22), C-reactive protein (20.3 vs. 9.4 mg/l, p = 0.36) and IL-6 ( p = 0.37, fold change (FC)=1.06) before start of UST. Baseline endoscopic activity was much higher in patients responding to UST, compared with non-responders (median SES-CD 21 vs. 13, p < 0.001). Several proteins significantly correlated with baseline SES-CD, but only one protein, CD40 ( r = 0.87, p = 0.05), also significantly differed between responders and non-responders before UST initiation ( p = 0.029 with corresponding FC 1.46). At baseline, CCL11 also varied between responders and non-responders ( p = 0.06, FC 1.45), but did not correlate with baseline SES-CD ( p = 0.97). ROC-statistics showed a significant area under the curve (81.5%, p = 0.011) for prediction of response based on the combination of both. On mucosal level, a non-significant increase in both CD40 and CD40L could be observed in colonic biopsies of responders at baseline (FC 1.6 and 1.5, respectively). Ileal biopsies also expressed increased CD40L in responders (FC 2.0). Conclusions: Two potential predictive biomarkers for response to UST were identified, which need validation in larger and independent cohorts. Because it has been shown that CD40/CD40L-triggering of dendritic cells induces expression of high levels of IL-23 and not IL-12, low CD40 levels in non-responders suggest another mechanism, apart from the IL-12/23 pathway, driving inflammation in these patients. These findings may aid in individualised selection of biological agents in Crohn's disease, and provide mechanisms of primary (non-)response to UST.