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Clinical and Host Biological Factors Predict Colectomy Risk in Children Newly Diagnosed With Ulcerative Colitis
Jeffrey S Hyams1, Michael Brimacombe1, Yael Haberman2,3
1Connecticut Children's Medical Center, Hartford, Connecticut, USA.
Insights
A new predictive model combining clinical factors and gene expression can identify children with ulcerative colitis (UC) at high risk for colectomy. This approach aids in tailoring treatment for severe pediatric UC cases.
Area of Science:
- Pediatric Gastroenterology
- Inflammatory Bowel Disease Research
- Molecular Diagnostics
Background:
- Ulcerative colitis (UC) in children often requires colectomy, impacting quality of life.
- Predicting colectomy risk in newly diagnosed pediatric UC is crucial for optimal management.
- Current therapies are insufficient for a subset of severe pediatric UC cases.
Purpose of the Study:
- To develop a clinical and biological predictive model for colectomy risk in children with newly diagnosed UC.
- To identify key clinical and molecular markers associated with colectomy in pediatric UC.
- To improve risk stratification for guiding treatment decisions in severe pediatric UC.
Main Methods:
- Multicenter inception cohort study of 428 children (ages 4-17) with newly diagnosed UC.
- Standardized initial therapy with mesalamine or corticosteroids, with escalation based on criteria.
- Phenotyping included clinical activity (PUCAI), disease extent, severity, lab markers, rectal gene expression (RNA sequencing), and DNA genotyping.
Main Results:
- 35 patients (13%) underwent colectomy within 3 years; 32/35 failed infliximab.
- Initial Pediatric Ulcerative Colitis Activity Index (PUCAI) ≥ 65 strongly predicted colectomy (P=0.0001).
- A clinical model (PUCAI, hemoglobin, ESR) achieved an AUC of 0.78; adding a gene expression panel improved AUC to 0.87.
Conclusions:
- A significant proportion of children with severe UC require colectomy despite current treatments.
- Gene expression signatures indicate potential novel therapeutic targets for non-responsive pediatric UC.
- The developed model enhances prediction of colectomy risk, aiding personalized treatment strategies.
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.
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