Hyams JS¹, Davis Thomas S², Gotman N³, Haberman Y⁴, Karns R⁵, Schirmer M⁶, Mo A⁷, Mack DR⁸, Boyle B⁹, Griffiths AM¹⁰, LeLeiko NS¹¹, Sauer CG¹², Keljo DJ¹³, Markowitz J¹⁴, Baker SS¹⁵, Rosh J¹⁶, Baldassano RN¹⁷, Patel A¹⁸, Pfefferkorn M¹⁹, Otley A²⁰, Heyman M²¹, Noe J²², Oliva-Hemker M²³, Rufo PA²⁴, Strople J²⁵, Ziring D²⁶, Guthery SL²⁷, Sudel B²⁸, Benkov K²⁹, Wali P³⁰, Moulton D³¹, Evans J³², Kappelman MD³³, Marquis MA³, Sylvester FA³³, Collins MH⁵, Venkateswaran S¹², Dubinsky M²⁹, Tangpricha V¹², Spada KL³⁴, Saul B³, Wang J³, Serrano J³⁵, Hommel K⁵, Marigorta UM⁷, Gibson G⁷, Xavier RJ³⁶, Kugathasan S¹², Walters T¹⁰, Denson LA⁵. Lancet. 2019 Mar 29. pii: S0140-6736(18)32592-3. doi: 10.1016/S0140-6736(18)32592-3. [Epub ahead of print]

Author information

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