Evolution of Pediatric Inflammatory Bowel Disease Unclassified (IBD-U): Incorporated With Serological and Gene Expression Profiles

Chandradevan R1, Hofmekler T1,2, Mondal K1, Harun N3, Venkateswaran S1, Somineni HK1, Ballengee CR1,2, Kim MO3, Griffiths A4, Noe JD5, Crandall WV6, Snapper S7, Rabizadeh S8, Rosh JR9, Walters TD4, Bertha M1, Dubinsky MC10, Denson LA11, Sauer CG1,2, Markowitz JF12, LeLeiko NS13, Hyams JS14, Kugathasan S1,2. Inflamm Bowel Dis. 2018 May 30. doi: 10.1093/ibd/izy136. [Epub ahead of print]

Author information

1 Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, Georgia, USA.

2 Children's Healthcare of Atlanta, Atlanta, Georgia, USA.

3 Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA.

4 Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

5 Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

6 Department of Pediatric Gastroenterology, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, Ohio, USA.

7 Department of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA.

8 Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA.

9 Department of Pediatrics, Goryeb Children's Hospital, Morristown, New Jersey, USA.

10 Department of Pediatrics, Mount Sinai Hospital, New York, New York, USA.

11 Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

12 Department of Pediatrics, Northwell Health, New York, New York, USA.

13 Division of Pediatric Gastroenterology, Nutrition and Liver Disease, Hasbro Children Hospital, Brown Medical School, Providence, Rhode Island, USA.

14 Division of Digestive Diseases, Hepatology, and Nutrition Connecticut Children's Medical Center, Hartford, Connecticut, USA.


BACKGROUND: Inflammatory bowel disease (IBD) mainly consists of Crohn's disease (CD) and ulcerative colitis (UC). About 10%-15% of patients with IBD cannot be firmly diagnosed with CD or UC; hence, they are initially diagnosed as inflammatory boweldisease unclassified (IBD-U). Having a firm diagnosis is clearly preferred to guide treatment choices, and better understanding of the nature of IBD-U is required.

METHODS: We performed an analysis of a subset of pediatric subjects from an inception IBD cohort of patients initially enrolled in a prospective multicenter study (the RISK study). Initial diagnosis and 2-year follow-up data from the subjects diagnosed with IBD-U were analyzed. An expert panel verified final diagnosis using predefined criteria as a guide. Serological and disease-relevant ileal and rectal tissue gene expression profiles were investigated. The use and the time to initiate anti-TNFα treatment was analyzed among the outcome groups.

RESULTS: A total of 1411 subjects were enrolled with initial diagnosis of IBD, and among them, 136 subjects were initially diagnosed as IBD-U at enrollment. And 26% were reclassified as UC and 14% as CD within 2 years of diagnosis, while 60% remained as IBD-U. Of those who were reclassified, there was a 2:1 ratio, UC (n = 35) to CD (n = 19). The molecular and serological features of IBD-U at the end of follow-up were very similar to UC and very different from CD. There was less likelihood of receiving anti-TNFα agents if the diagnosis was IBD-U compared with CD (P < 0.0001).

CONCLUSIONS : In our cohort, 60% of the IBD-U subjects remained as unclassified at 2 years; of those subsequently classified, a higher percentage followed a course more similar to UC. Most of the IBD-U subjects at diagnosis had serological and molecular signatures that are very similar to UC. Although the atypical presentations made the clinician to make an interim diagnosis of IBD-U, results of the molecular and serological factors performed at the time of diagnosis suggests that they were very similar to UC. However, long-term studies are needed to better understand the natural history and molecular characterization of pediatric onset IBD-U.

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