DOP89 Pre-treatment mucosal inflammatory and wound healing gene programmes reveal mechanisms associated with future stricturing behaviour during 5-year follow-up in paediatric Crohn’s disease

Abstract

S127 what aspect of body mass determine these outcomes. We hy-pothesise that a large visceral fat area is associated with a lower anti-TNFα level and a higher rate of SLOR. Our aim was to determine the impact of fat and muscle compartment areas on these outcomes. Methods: Crohn's disease (CD) patients who were prescribed standard doses of an anti-TNFα agent [5 mg/kg, 8 weekly infliximab (IFX) or 40 mg EOW of adalimumab (ADA)] from 1 February 2015 to 30 June 2018 were examined retrospectively. Primary responders with a minimum therapy duration of 12 weeks, at least 12 months of follow-up and a trough level within 6 months of a CT or MRI, were eligible for inclusion. The primary outcome was the trough level and the secondary outcome was time to SLOR, defined as a need to dose escalate, change out of class, requiring ≥3 courses of corticosteroids in a 12-month period, or surgery. Patients were followed until they met a SLOR or the census date of 30 June 2019. Visceral fat area (VFA), subcutaneous fat area (SFA) and skeletal muscle area (SMA) were measured on the CT/MRI at the L3 vertebral level in cm 2 by a radiologist blinded to the clinical outcome and corrected for patient height (cm 2 /m 2). Results: Of 813 patients prescribed an anti-TNFα agent in the study period, data from 69 eligible CD patients were included for analysis. The median age was 43.5 ± 16.2 years, and 42 (60.9%) were males. Forty-four (63.8%) and 25 (36.2%) patients were treated with IFX and ADA respectively. The mean BMI was 26.9 ± 5.2. Univariate analysis of infliximab trough levels found that total fat area, VFA, visceral fat index [VFI (VFA/height in m 2)] and VFA/SMA ratio were inversely correlated with anti-TNFα trough level (p < 0.05). No association was found between ADA trough level and muscle/fat areas. After multivariate adjustment for CRP, albumin, presence of antibodies, concurrent immunomodulator use and gender, IFX levels were inversely associated with VFA [-0.021 (−0.038, −0.003) p = 0.025], VFI [−0.066 (−0.119, −0.013) p = 0.016] and VFA/SMA [−3.805 (−7.132, −0.477) p = 0.026] but not BMI [−0.232 (−0.520, 0.055) p = 0.11). No association was found for ADA trough levels. Kaplan-Meir analyses showed a trend towards a shorter time to SLOR with an increasing tertile of VFI in both IFX and ADA treated patients. Conclusion: Visceral fat area corrected for height (VFI) is a better determinant of anti-TNFα trough levels and SLOR than BMI. Background: Stricturing complications account for substantial morbidity in Crohn's disease (CD). We aimed to define ileal gene programmes present at diagnosis in paediatric CD associated with future stricturing behaviour (B2), and to identify potential small molecules to reverse these gene signatures. Methods: Antimicrobial serologies and ileal gene expression (RNASeq) were assessed at diagnosis in 249 CD patients enrolled in a 5-year inception cohort study. These data were used to define genes associated with stricturing behaviour and for model testing to predict stricturing. Sirius Red immuno-histochemistry was utilised to determine the extent of col-lagen infiltration into the sub-cryptal space. A bioinformatics approach defined small molecules which may reverse the stric-turing gene signature. Results: Of 249 (8%) patients, 19 developed B2 behaviour during the 5-year follow-up, while 218 remained B1 inflammatory. We defined 518 genes that were differentially expressed in the ileum at diagnosis (FC≥1.5, FDR<0.05) in B1 patients who later developed B2 stricturing complications vs. those who remained B1 throughout. These were notable for baseline up-regulation of OSM implicated in anti-TNF non-response, NCF2 and CSF3R implicated in myeloid cell activation, TGFBI implicated in tissue fibrosis, and a panel of 17 collagen genes in patients who progressed to stricturing. Sirius red staining confirmed an increase in sub-cryptal type I/III collagen in B1 patients at diagnosis who progressed to B2 behaviour. Of these 518 genes, we highlighted an inflammatory OSM co-expression signature that was tightly associated with an extracellular matrix COL1A2 co-expression signature (Pearson r = 0.88, p < 0.0001). Network annotation analyses of those co-expression signatures showed that response to wounding, myeloid dendritic cells, and gp38+ stromal cells signatures are linked to both. Extracellular matrix (ECM) annotation , collagen binding, fibroblasts, and angiogenesis were more specific to the COL1A2 signature, and granulocytes and response to other organisms were more specific to the OSM co-expression signature. We further define small molecules targeting macrophage and fibroblast activation, and angiogenesis, which may reverse the stricturing gene signature including ephrin inhibitors, eicosa-tetraynoic acid (cyclooxygenase/lipoxygenase inhibitor), orantinib (PDGFR inhibitor), and PT-630 (fibroblast activation inhibitor). Our previous model containing serologies and a refined ECM gene set was significantly associated with stricturing development by year 5 (AUC:0.82) Conclusion: An ileal gene program for macrophage and fibroblast activation is linked to future stricturing complications in treatment naïve paediatric CD, and may inform small-molecule therapeutic approaches.