Abstract

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

Inflamm Bowel Dis. 2020 Sep 23;izaa251. doi: 10.1093/ibd/izaa251. Online ahead of print.

Mark T Osterman 1, Kelli L VanDussen 2, Ilyssa O Gordon 3, Elisabeth M Davis 4, Katherine Li 5, Kate Simpson 6, Matthew Ciorba 7, Sarah C Glover 8, Bincy Abraham 9, Xueyan Guo 4, Eric U Yee 10, Felicia D Allard 10, Jacqueline G Perrigoue 5, Brian Claggett 11, Bo Shen 12, Thaddeus S Stappenbeck 6 13, Julia J Liu 4

 
     

Author information

  • 1Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • 2Divisions of Gastroenterology, Hepatology, and Nutrition and of Developmental Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
  • 3Department of Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA.
  • 4Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • 5Janssen Research and Development, Spring House, PA, USA.
  • 6Departments of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
  • 7Division of Gastroenterology and Hepatology, Washington University School of Medicine, St. Louis, MO, USA.
  • 8Division of Gastroenterology and Hepatology, University of Florida, Gainesville, FL, USA.
  • 9Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Houston, TX, USA.
  • 10Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • 11Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
  • 12Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic Foundation, Cleveland, OH, USA.
  • 13Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.

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.

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