Jeffrey S Hyams1, Michael Brimacombe1, Yael Haberman2,3, Thomas Walters4, Greg Gibson5, Angela Mo5, David Mack6, Anne Griffiths4, Brendan Boyle7, Neal LeLeiko8, James Markowitz9, Joel Rosh10, Ashish Patel11, Sapana Shah12, Robert Baldassano13, Marian Pfefferkorn14, Cary Sauer15, Joelynn Dailey1, Suresh Venkateswaran15, Subra Kugathasan15, Lee A Denson2. 1. Connecticut Children's Medical Center, Hartford, Connecticut, USA. 2. Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. 3. Sheba Medical Center, Tel-HaShomer, affiliated with Tel-Aviv University, Ramat Gan, Israel. 4. Hospital for Sick Children, Toronto, Ontario, Canada. 5. Georgia Tech University, Atlanta, Georgia, USA. 6. Children's Hospital of Eastern Ontario and Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada. 7. Nationwide Children's Hospital, Columbus, Ohio, USA. 8. Hasbro Children's Hospital, Providence, Rhode Island, USA. 9. Cohen Children's Medical Center, Queens, New York, USA. 10. Goryeb Children's Hospital, Morristown, New Jersey, USA. 11. Texas Children's Hospital, Houston, Texas, USA. 12. Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA. 13. Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 14. Riley Children's Hospital, Indianapolis, Indiana, USA. 15. Emory 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.
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.
Authors: Alex Krauthammer; Christos Tzivinikos; Amit Assa; Erasmo Miele; Caterina Strisciuglio; Darja Urlep; Elena Daniela Serban; Avantika Singh; Harland S Winter; Richard K Russell; Iva Hojsak; Mikkel Malham; Víctor Manuel Navas-López; Nicholas M Croft; Huey Miin Lee; Oren Ledder; Ibrahim Shamasneh; Seamus Hussey; Hien Q Huynh; Eytan Wine; Neil Shah; Margaret Sladek; Tim G de Meij; Claudio Romano; Valeria Dipasquale; Paolo Lionetti; Nadeem A Afzal; Marina Aloi; Kwangyang Lee; Javier Martín-de-Carpi; Anat Yerushalmy-Feler; Sreedhar Subramanian; Batia Weiss; Dror S Shouval Journal: J Crohns Colitis Date: 2019-12-10 Impact factor: 9.071
Authors: Michael J Rosen; Rebekah Karns; Jefferson E Vallance; Ramona Bezold; Amanda Waddell; Margaret H Collins; Yael Haberman; Phillip Minar; Robert N Baldassano; Jeffrey S Hyams; Susan S Baker; Richard Kellermayer; Joshua D Noe; Anne M Griffiths; Joel R Rosh; Wallace V Crandall; Melvin B Heyman; David R Mack; Michael D Kappelman; James Markowitz; Dedrick E Moulton; Neal S Leleiko; Thomas D Walters; Subra Kugathasan; Keith T Wilson; Simon P Hogan; Lee A Denson Journal: Gastroenterology Date: 2017-01-26 Impact factor: 22.682
Authors: I Arijs; K Li; G Toedter; R Quintens; L Van Lommel; K Van Steen; P Leemans; G De Hertogh; K Lemaire; M Ferrante; F Schnitzler; L Thorrez; K Ma; X-Y R Song; C Marano; G Van Assche; S Vermeire; K Geboes; F Schuit; F Baribaud; P Rutgeerts Journal: Gut Date: 2009-08-20 Impact factor: 23.059
Authors: Athos Bousvaros; Donald A Antonioli; Richard B Colletti; Marla C Dubinsky; Jonathan N Glickman; Benjamin D Gold; Anne M Griffiths; Gareth P Jevon; Leslie M Higuchi; Jeffrey S Hyams; Barbara S Kirschner; Subra Kugathasan; Robert N Baldassano; Pierre A Russo Journal: J Pediatr Gastroenterol Nutr Date: 2007-05 Impact factor: 2.839
Authors: Yael Haberman; Rebekah Karns; Phillip J Dexheimer; Melanie Schirmer; Judith Somekh; Ingrid Jurickova; Tzipi Braun; Elizabeth Novak; Laura Bauman; Margaret H Collins; Angela Mo; Michael J Rosen; Erin Bonkowski; Nathan Gotman; Alison Marquis; Mason Nistel; Paul A Rufo; Susan S Baker; Cary G Sauer; James Markowitz; Marian D Pfefferkorn; Joel R Rosh; Brendan M Boyle; David R Mack; Robert N Baldassano; Sapana Shah; Neal S Leleiko; Melvin B Heyman; Anne M Grifiths; Ashish S Patel; Joshua D Noe; Bruce J Aronow; Subra Kugathasan; Thomas D Walters; Greg Gibson; Sonia Davis Thomas; Kevin Mollen; Shai Shen-Orr; Curtis Huttenhower; Ramnik J Xavier; Jeffrey S Hyams; Lee A Denson Journal: Nat Commun Date: 2019-01-03 Impact factor: 14.919