Epithelial Cell Biomarkers Are Predictive of Response to Biologic Agents in Crohn's Disease

Abstract

Background: Therapeutic efficacy of biologics has remained at about 50% for 2 decades. In Crohn's disease (CD) patients, we examined the predictive value of an epithelial cell biomarker, ileal microvillar length (MVL), for clinical response to ustekinumab (UST) and vedolizumab (VDZ) and its relationship to another biomarker, intestinal epithelial cell (IEC) pyroptosis, with respect to response to VDZ.

Method: Ileal biopsies from the UNITI-2 randomized controlled trial were analyzed for MVL as a predictor of clinical response to UST. In a 5-center academic retrospective cohort of CD patients, ileal MVL was analyzed to determine its predictive value for response to VDZ. Correlation between ileal MVL and IEC pyroptosis was determined, and the discriminant ability of the combination of 2 biomarkers to VDZ was examined.

Results: Clinical response in UST was significantly higher than placebo (65% vs 39%; P = 0.03), with patients with normal MVL (>1.7 µm) having the greatest therapeutic effect: 85% vs 20% (P = 0.02). For VDZ, clinical response with MVL of 1.35 to 1.55 µm was 82% vs 44% (<1.35 µm) and 40% (>1.55 µm; P = 0.038). There was no correlation between ileal MVL and IEC pyroptosis. The combination criteria of ileal pyroptosis <14 positive cells/1000 IECs or MVL of 1.35 to 1.55 µm could identify 84% of responders and 67% of nonresponders (P = 0.001).

Conclusion: Ileal MVL was predictive of response to UST and VDZ in prospective and retrospective CD cohorts. It was independent of ileal IEC pyroptosis, and combination of the 2 biomarkers enhanced the discriminate ability of responders from nonresponders to VDZ.

Keywords: biomarker; clinical remission; clinical response; endoscopic improvement; epithelial cells.

FIGURE 1.

Ileal MVL is predictive of therapeutic response to ustekinumab in CD patients from UNITI-2. (A) Ileal MVL is an effect modifier of clinical response to ustekinumab (N = 95). (C) Clinical remission to ustekinumab stratified by pretreatment ileal MVL (N = 95). (D) Endoscopic response to ustekinumab stratified by pretreatment ileal MVL (N = 71).

FIGURE 2.

Correlation between ileal MVL length and baseline disease activity indices. (A) Clinical disease activity by CDAI (N = 95). (B) Endoscopic disease activity by SES-CD total score (N = 95). (C) Endoscopic ileal disease activity by SES-CD ileal subscore (N = 67). (D) Histologic disease activity by global histology activity score (N = 95).

FIGURE 3.

Ileal MVL is predictive of response to vedolizumab in CD patients from the multicenter retrospective cohort. (A) Clinical response as a function of ileal MVL (N = 64). (B) Correlation between ileal MVL and baseline clinical disease activity by HBI (N = 64). (C) Correlation between ileal MV length and baseline endoscopic disease activity by SES-CD (N = 58).

FIGURE 4.

Ileal MVL and ileal IEC pyroptosis are independent and synergistic biomarkers for prediction of response to vedolizumab in CD. (A) Correlation between ileal MVL and ileal IEC pyroptosis on pretreatment biopsy samples (N = 64). (B) Improved discriminant ability for responders from nonresponders to vedolizumab (N = 64).