Ileal Gene Expression Data from Crohn's Disease Small Bowel Resections Indicate Distinct Clinical Sub-Groups.

BACKGROUND AND AIMS: Heterogeneity in Crohn's disease (CD) provides a challenge for development of effective therapies. Our goal was to define a unique molecular signature for severe, refractory CD to enable precision therapy approaches to disease treatment and facilitate earlier intervention in complicated disease.

METHODS: We analyzed clinical meta-data, genetics and transcriptomics from uninvolved ileal tissue from CD patients that underwent a single SB resection. We determined transcriptional risk scores, cellular signatures and mechanistic pathways that define patient subsets in refractory CD.

RESULTS: Within refractory CD, we found three CD patient sub-groups (CD1, CD2 and CD3). Compared to CD1, CD3 was enriched for subjects with increased disease recurrence after first surgery (OR= 6.78, P=0.04); enhanced occurrence of second surgery (OR=5.07, P=0.016); and presence of perianal CD (OR=3.61, P=0.036). The proportion of recurrence-free survival was less in CD3 than CD1 (p=0.02, median survival time (months), CD1=10 and CD3=6). Overlaying differential gene expression between CD1 and CD3 with CD subgroup-associated genetic polymorphisms, identified 174 genes representing both genetic and biological differences between the CD subgroups. Pathway analyses using this unique gene signature indicated EIF2 and cAMP signaling as dominant pathways associated with CD3. Furthermore, the severe, refractory subset, CD3, was associated with higher transcriptional risk score and enriched with eosinophil and NKT cell gene signatures.

CONCLUSION: We characterize a subset of severe, refractory CD patients that may need more aggressive treatment after first resection and likely to benefit from targeted therapy based on their genotype and tissue gene expression signature.