Researchers have successfully identified biological signatures in pediatric patients with newly diagnosed Crohn’s disease (CD) capable of predicting whether a child will develop disease–related complications requiring major surgery within three to five years. The results of this research, “Prediction of complicated disease course for children newly diagnosed with Crohn’s disease: a multicentre inception cohort study,” was published in The Lancet journal.

This groundbreaking work is a multicenter research initiative that consists of 25 U.S. institutions and three from Canada and a cohort of 1,112 CD children enrolled at diagnosis, of which 913 were included in the published study. Of the 28 research sites, four are located in Atlanta – Emory University, Georgia Institute of Technology, Children’s Healthcare of Atlanta, and the Children’s Center for Digestive Health Care. The goal of this research was to identify measurable indicators of the two most common complications in pediatric Crohn’s disease that require surgery – stricturing and penetrating disease.

“Twenty five percent of patients with Crohn’s disease account for 80 percent of complications, hospitalizations, surgery and health care costs. The aim of RISK is to preemptively identify those 25 percent of patients at diagnosis,” Subra Kugathasan, MD, Emory University, principal investigator and lead author of the paper. “Through the study of baseline gene expression, immune reactivity, and intestinal bacteria, we have identified distinct biological signatures capable of predicting stricturing and penetrating disease, at diagnosis. After analyzing millions of biological and clinical data points, RISK has generated a composite risk stratification model.”

RISK study researchers looked at intestinal gene expression levels to identify risk factor genes whose levels are altered at enrollment, and identified distinct biological gene expression signatures at baseline that could distinguish children who will develop strictures form those who develop fistulas or abscesses, without the confounding effects of treatment on gene expression. Therefore, these genetic signatures together with other biological and clinical variables they evaluated could be used as predictors of complications and treatment outcomes at diagnosis.

In addition to providing predictive biological signatures for development of complications, the RISK study also found that patients who receive early anti–TNFa biologic treatment, within three months of diagnosis, were less likely to develop penetrating complications. However, patients with stricturing complications were poorly responsive to early intervention with biologics. These data support the utility of risk stratification of pediatric Crohn’s disease patients at diagnosis, and may guide early tailored use of anti–TNFa therapy.

As part of the study, Georgia Tech postdoctoral researcher Urko Marigorta analyzed RNAseq gene expression data from biopsies provided by Cincinnati Children's Hospital. The work identified dozens of pathways that are differentially expressed in complicated disease, and showed that immune activity is more disrupted in penetrating disease while extracellular matrix is more involved in stricturing disease.

“The involvement of TNF–alpha signaling in progression to stricturing disease is consistent with the overall finding that these are the patients who respond to TNF–alpha therapy,” said Greg Gibson, a professor in the Georgia Tech School of Biological Sciences and one of the paper’s co–authors.