Intraintestinal Heterogeneity of Drug Target Expression in Inflammatory Bowel Disease.

Abstract

Objective: There has been no significant improvement in remission rate in inflammatory bowel disease (IBD) despite several new drugs being introduced in the past two decades. Post-treatment biopsies sometimes show histologic healing in some areas of the intestine while other areas within the same intestine continue to show active inflammation. The aim of this short descriptive study was to determine whether heterogeneous treatment response in IBD may be caused by heterogeneous expression of treatment targets within the same intestine.

Methods: Six cases of Crohn's disease and five cases of ulcerative colitis in which moderate to severe active inflammation was present in at least two biopsies from the same intestine obtained during the same endoscopy procedure were entered in the study. Sections were stained for TNFα and phospho-JAK1 (p-JAK1) using immunohistochemistry. Expression of TNFα and p-JAK1 was recorded as high when the staining intensity was moderate or high, or low when there was no or week staining. The number of eosinophils per high power field was counted in the area of peak density.

Results: Different sites within the same intestine from IBD patients with moderate to severe active inflammation may express different levels of TNFα and p-JAK1. For example, in one patient with Crohn's disease with histologically moderate to severe activity in biopsies from the ileum (site 1) and cecum (site 2), there was high expression of p-JAK1 and low TNFα in the ileum biopsy with the exact opposite in the cecum biopsy (low p-JAK1 and high TNFα expression). In this example neither small molecule drug targeting JAK1 nor anti-TNFα biologic given as single agent therapy would be expected to induce histologic remission in both actively inflamed sites in this patient.

Conclusions: The heterogeneous expression of treatment targets within the same intestine may explain why some patients with IBD may not have complete remission on single drug. Studies are needed to determine whether assay for target expression in mucosal biopsies from IBD patients can help to optimize treatment selection.