Inflamm Bowel Dis. 2021 Apr 27;izab061. doi: 10.1093/ibd/izab061. Online ahead of print.

Jeffrey S Hyams ¹, Michael Brimacombe ¹, Yael Haberman ^2 3, Thomas Walters ⁴, Greg Gibson ⁵, Angela Mo ⁵, David Mack ⁶, Anne Griffiths ⁴, Brendan Boyle ⁷, Neal LeLeiko ⁸, James Markowitz ⁹, Joel Rosh ¹⁰, Ashish Patel ¹¹, Sapana Shah ¹², Robert Baldassano ¹³, Marian Pfefferkorn ¹⁴, Cary Sauer ¹⁵, Joelynn Dailey ¹, Suresh Venkateswaran ¹⁵, Subra Kugathasan ¹⁵, Lee A Denson ²

Author information

• ¹Connecticut Children's Medical Center, Hartford, Connecticut, USA.
• ²Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
• ³Sheba Medical Center, Tel-HaShomer, affiliated with Tel-Aviv University, Ramat Gan, Israel.
• ⁴Hospital for Sick Children, Toronto, Ontario, Canada.
• ⁵Georgia Tech University, Atlanta, Georgia, USA.
• ⁶Children's Hospital of Eastern Ontario and Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada.
• ⁷Nationwide Children's Hospital, Columbus, Ohio, USA.
• ⁸Hasbro Children's Hospital, Providence, Rhode Island, USA.
• ⁹Cohen Children's Medical Center, Queens, New York, USA.
• ¹⁰Goryeb Children's Hospital, Morristown, New Jersey, USA.
• ¹¹Texas Children's Hospital, Houston, Texas, USA.
• ¹²Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
• ¹³Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
• ¹⁴Riley Children's Hospital, Indianapolis, Indiana, USA.
• ¹⁵Emory University, Atlanta, Georgia, USA.

Abstract

Background: Develop a clinical and biological predictive model for colectomy risk in children newly diagnosed with ulcerative colitis (UC).

Methods: This was a multicenter inception cohort study of children (ages 4-17 years) newly diagnosed with UC treated with standardized initial regimens of mesalamine or corticosteroids (CS) depending upon initial disease severity. Therapy escalation to immunomodulators or infliximab was based on predetermined criteria. Patients were phenotyped by clinical activity per the Pediatric Ulcerative Colitis Activity Index (PUCAI), disease extent, endoscopic/histologic severity, and laboratory markers. In addition, RNA sequencing defined pretreatment rectal gene expression and high density DNA genotyping by the Affymetrix UK Biobank Axiom Array. Coprimary outcomes were colectomy over 3 years and time to colectomy. Generalized linear models, Cox proportional hazards multivariate regression modeling, and Kaplan-Meier plots were used.

Results: Four hundred twenty-eight patients (mean age 13 years) started initial theapy with mesalamine (n = 136), oral CS (n = 144), or intravenous CS (n = 148). Twenty-five (6%) underwent colectomy at ≤1 year, 33 (9%) at ≤2 years, and 35 (13%) at ≤3 years. Further, 32/35 patients who had colectomy failed infliximab. An initial PUCAI ≥ 65 was highly associated with colectomy (P = 0.0001). A logistic regression model predicting colectomy using the PUCAI, hemoglobin, and erythrocyte sedimentation rate had a receiver operating characteristic area under the curve of 0.78 (95% confidence interval [0.73, 0.84]). Addition of a pretreatment rectal gene expression panel reflecting activation of the innate immune system and response to external stimuli and bacteria to the clinical model improved the receiver operating characteristic area under the curve to 0.87 (95% confidence interval [0.82, 0.91]).

Conclusions: A small group of children newly diagnosed with severe UC still require colectomy despite current therapies. Our gene signature observations suggest additional targets for management of those patients not responding to current medical therapies.