Jeffrey S Hyams1, Sonia Davis Thomas2, Nathan Gotman3, Yael Haberman4, Rebekah Karns5, Melanie Schirmer6, Angela Mo7, David R Mack8, Brendan Boyle9, Anne M Griffiths10, Neal S LeLeiko11, Cary G Sauer12, David J Keljo13, James Markowitz14, Susan S Baker15, Joel Rosh16, Robert N Baldassano17, Ashish Patel18, Marian Pfefferkorn19, Anthony Otley20, Melvin Heyman21, Joshua Noe22, Maria Oliva-Hemker23, Paul A Rufo24, Jennifer Strople25, David Ziring26, Stephen L Guthery27, Boris Sudel28, Keith Benkov29, Prateek Wali30, Dedrick Moulton31, Jonathan Evans32, Michael D Kappelman33, M Alison Marquis3, Francisco A Sylvester33, Margaret H Collins5, Suresh Venkateswaran12, Marla Dubinsky29, Vin Tangpricha12, Krista L Spada34, Bradley Saul3, Jessie Wang3, Jose Serrano35, Kevin Hommel5, Urko M Marigorta7, Greg Gibson7, Ramnik J Xavier36, Subra Kugathasan12, Thomas Walters10, Lee A Denson5. 1. Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT, USA. Electronic address: jhyams@connecticutchildrens.org. 2. Collaborative Studies Coordinating Center, University of North Carolina, Chapel Hill, NC, USA; Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA; RTI International, Research Triangle Park, NC, USA. 3. Collaborative Studies Coordinating Center, University of North Carolina, Chapel Hill, NC, USA. 4. Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA; Sheba Medical Center, affiliated with the Tel Aviv University, Tel Hashomer, Israel. 5. Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA. 6. The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biostatistics, Harvard T H Chan School of Public Health, Boston, MA, USA. 7. Georgia Institute of Technology, Atlanta, GA, USA. 8. School of Biological Sciences, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada. 9. Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children's Hospital, Columbus, OH, USA. 10. Divisioin of Pediatric Gastroenterology, Hospital For Sick Children, Toronto, ON, Canada. 11. IBD Centre, Department of Paediatrics, Hasbro Children's Hospital, Providence, RI, USA. 12. Divisioin of Pediatric Gastroenterology, Nutritiion, and Liver Disease, Emory University, Atlanta, GA, USA. 13. Division of Gastroenterology, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. 14. Division of Gastroenterology, Hepatology, and Nutrition, Cohen Children's Medical Center Of New York, New Hyde Park, NY, USA. 15. Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Women & Children's Hospital of Buffalo WCHOB, Buffalo, NY, USA. 16. Division of Gastroenterology, Hepatology, and Nutrition, Goryeb Children's Hospital, Atlantic Health, Morristown, NJ, USA. 17. Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. 18. Division of Gastroenterology, Hepatology, and Nutrition, UT Southwestern, Dallas, TX, USA. 19. Division of Gastroenterology, Hepatology, and Nutrition, Riley Children's Hospital Indiana, Indianapolis, IN, USA. 20. Division of Gastroenterology, Hepatology, and Nutrition, IWK Health Centre, Halifax, NS, Canada. 21. Division of Gastroenterology, Hepatology, and Nutrition, University of California at San Francisco, San Francisco, CA, USA. 22. Division of Gastroenterology, Hepatology, and Nutrition, Medical College of Wisconsin, Milwaukee, WI, USA. 23. Division of Gastroenterology, Hepatology, and Nutrition, Johns Hopkins Children's Center, Baltimore, MD, USA. 24. Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital Boston, Harvard Medical School Boston, MA, USA. 25. Division of Gastroenterology, Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA. 26. Division of Gastroenterology, Hepatology, and Nutrition, UCLA Medical Center, Los Angeles, CA, USA. 27. Division of Gastroenterology, Hepatology, and Nutrition, Primary Children's Hospital and the University of Utah, Salt Lake City, UT, USA. 28. Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota Medical Center, Minneapolis, MN, USA. 29. Division of Gastroenterology, Hepatology, and Nutrition, Mt Sinai Hospital, New York City, NY, USA. 30. Division of Gastroenterology, Hepatology, and Nutrition, State University of New York Upstate Medical University, Syracuse, NY, USA. 31. Division of Gastroenterology, Hepatology, and Nutrition, Monroe Carell Jr Children's Hospital of Vanderbilt, Nashville, TN, USA. 32. Division of Gastroenterology, Hepatology, and Nutrition, Nemours Children's Clinic, Jacksonville, FL, USA. 33. Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA. 34. Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT, USA. 35. National Institutes of Diabetes, Digestive and Kidney Diseases, Bethesda, MD, USA. 36. The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Computational and Integrative Biology, Gastrointestinal Unit, and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, USA.
Abstract
BACKGROUND: Lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children who are newly diagnosed with ulcerative colitis. We hypothesised that pretreatment clinical, transcriptomic, and microbial factors predict disease course. METHODS: In this inception cohort study, we recruited paediatric patients aged 4-17 years with newly diagnosed ulcerative colitis from 29 centres in the USA and Canada. Patients initially received standardised mesalazine or corticosteroids, with pre-established criteria for escalation to immunomodulators (ie, thiopurines) or anti-tumor necrosis factor-α (TNFα) therapy. We used RNA sequencing to define rectal gene expression before treatment, and 16S sequencing to characterise rectal and faecal microbiota. The primary outcome was week 52 corticosteroid-free remission with no therapy beyond mesalazine. We assessed factors associated with the primary outcome using logistic regression models of the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01536535. FINDINGS: Between July 10, 2012, and April 21, 2015, of 467 patients recruited, 428 started medical therapy, of whom 400 (93%) were evaluable at 52 weeks and 386 (90%) completed the study period with no protocol violations. 150 (38%) of 400 participants achieved week 52 corticosteroid-free remission, of whom 147 (98%) were taking mesalazine and three (2%) were taking no medication. 74 (19%) of 400 were escalated to immunomodulators alone, 123 (31%) anti-TNFα therapy, and 25 (6%) colectomy. Low baseline clinical severity, high baseline haemoglobin, and week 4 clinical remission were associated with achieving week 52 corticosteroid-free remission (n=386, logistic model area under the curve [AUC] 0·70, 95% CI 0·65-0·75; specificity 77%, 95% CI 71-82). Baseline severity and remission by week 4 were validated in an independent cohort of 274 paediatric patients with newly diagnosed ulcerative colitis. After adjusting for clinical predictors, an antimicrobial peptide gene signature (odds ratio [OR] 0·57, 95% CI 0·39-0·81; p=0·002) and abundance of Ruminococcaceae (OR 1·43, 1·02-2·00; p=0·04), and Sutterella (OR 0·81, 0·65-1·00; p=0·05) were independently associated with week 52 corticosteroid-free remission. INTERPRETATION: Our findings support the utility of initial clinical activity and treatment response by 4 weeks to predict week 52 corticosteroid-free remission with mesalazine alone in children who are newly diagnosed with ulcerative colitis. The development of personalised clinical and biological signatures holds the promise of informing ulcerative colitis therapeutic decisions. FUNDING: US National Institutes of Health.
BACKGROUND: Lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children who are newly diagnosed with ulcerative colitis. We hypothesised that pretreatment clinical, transcriptomic, and microbial factors predict disease course. METHODS: In this inception cohort study, we recruited paediatric patients aged 4-17 years with newly diagnosed ulcerative colitis from 29 centres in the USA and Canada. Patients initially received standardised mesalazine or corticosteroids, with pre-established criteria for escalation to immunomodulators (ie, thiopurines) or anti-tumor necrosis factor-α (TNFα) therapy. We used RNA sequencing to define rectal gene expression before treatment, and 16S sequencing to characterise rectal and faecal microbiota. The primary outcome was week 52 corticosteroid-free remission with no therapy beyond mesalazine. We assessed factors associated with the primary outcome using logistic regression models of the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01536535. FINDINGS: Between July 10, 2012, and April 21, 2015, of 467 patients recruited, 428 started medical therapy, of whom 400 (93%) were evaluable at 52 weeks and 386 (90%) completed the study period with no protocol violations. 150 (38%) of 400 participants achieved week 52 corticosteroid-free remission, of whom 147 (98%) were taking mesalazine and three (2%) were taking no medication. 74 (19%) of 400 were escalated to immunomodulators alone, 123 (31%) anti-TNFα therapy, and 25 (6%) colectomy. Low baseline clinical severity, high baseline haemoglobin, and week 4 clinical remission were associated with achieving week 52 corticosteroid-free remission (n=386, logistic model area under the curve [AUC] 0·70, 95% CI 0·65-0·75; specificity 77%, 95% CI 71-82). Baseline severity and remission by week 4 were validated in an independent cohort of 274 paediatric patients with newly diagnosed ulcerative colitis. After adjusting for clinical predictors, an antimicrobial peptide gene signature (odds ratio [OR] 0·57, 95% CI 0·39-0·81; p=0·002) and abundance of Ruminococcaceae (OR 1·43, 1·02-2·00; p=0·04), and Sutterella (OR 0·81, 0·65-1·00; p=0·05) were independently associated with week 52 corticosteroid-free remission. INTERPRETATION: Our findings support the utility of initial clinical activity and treatment response by 4 weeks to predict week 52 corticosteroid-free remission with mesalazine alone in children who are newly diagnosed with ulcerative colitis. The development of personalised clinical and biological signatures holds the promise of informing ulcerative colitis therapeutic decisions. FUNDING: US National Institutes of Health.
Authors: Talin Haritunians; Kent D Taylor; Stephan R Targan; Marla Dubinsky; Andrew Ippoliti; Soonil Kwon; Xiuqing Guo; Gil Y Melmed; Dror Berel; Emebet Mengesha; Bruce M Psaty; Nicole L Glazer; Eric A Vasiliauskas; Jerome I Rotter; Phillip R Fleshner; Dermot P B McGovern Journal: Inflamm Bowel Dis Date: 2010-11 Impact factor: 5.325
Authors: Dan Turner; David Mack; Neal Leleiko; Thomas D Walters; Krista Uusoue; Steven T Leach; Andrew S Day; Wallace Crandall; Mark S Silverberg; James Markowitz; Anthony R Otley; David Keljo; Petar Mamula; Subra Kugathasan; Jeffrey Hyams; Anne M Griffiths Journal: Gastroenterology Date: 2010-02-26 Impact factor: 22.682
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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
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Authors: Tanima De; Honghong Zhang; Cristina Alarcon; Bianca Lec; Juan Avitia; Erin Smithberger; Chuyu Chen; Minnie Horvath; Sara Kwan; Mary Young; Sarbani Adhikari; John Kwon; Jennifer Pacheco; Gail Jarvik; Wei-Qi Wei; Frank Mentch; Hakon Hakonarson; Patrick Sleiman; Adam Gordon; John Harley; Jim Linneman; Scott Hebbring; Loukia Parisiadou; Minoli A Perera Journal: Pharmacogenet Genomics Date: 2022-01-01 Impact factor: 2.089
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