Predicting complications for pediatric Crohn's patients

RISK Stratification study identifies genetic signatures to predict if children with Crohn's disease will develop complications that will necessitate surgery

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NEW YORK—Crohn's disease, which consists of inflammation of the gastrointestinal tract (most often where the small and large intestines meet), affects roughly 780,000 individuals in the United States, according to the Crohn's & Colitis Foundation. Though Crohn's disease can develop at any age, it is more prevalent among adolescents and young adults, and a recent landmark study focused on the younger end of this disease population has uncovered biological signatures in pediatric Crohn's patients that can predict the likelihood of disease-related complications.
The discoveries are thanks to the Crohn’s & Colitis Foundation’s “RISK Stratification” study, the largest new-onset study completed on children with Crohn’s disease. The study consisted of 1,800 patients enrolled from 28 clinics, with a focus on 913 children with Crohn's disease who were enrolled at diagnosis and presented as complication-free more than 90 days after diagnosis. The three-year study collected data and samples on all patients every six months for the duration of the trial, and follow-up will continue for five years.
The goal for this work was to identify measurable indicators of stricturing and penetrating disease, the two most common complications in pediatric Crohn’s disease requiring surgery. Stricturing, or fibrostenosis, is a build-up of fibrotic scar tissue, which in turn causes the intestinal wall to thicken and intestinal passage to narrow. Penetrating disease occurs when sustained inflammation spreads beyond the intestinal wall and causes fistulas, abnormal connections between the intestine and other organs. This can also cause the formation of abscesses at the sites of fistulas.
“Twenty-five percent of patients with Crohn’s disease account for 80 percent of complications, hospitalizations, surgery and healthcare costs. The aim of RISK is to preemptively identify those 25 percent of patients at diagnosis,” Dr. Subra Kugathasan of Emory University, principal investigator and lead author of the paper, explained in a press release. “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.”
The research team focused on intestinal gene expression levels to try and identify risk factor genes whose levels are either increased or decreased at enrollment, and found biological gene expression signatures at baseline capable of determining children who would develop strictures from children who would develop fistulas or abscesses.
"Importantly, the functional nature of these genetic signatures is consistent with the clinical presentation of the complications," noted Dr. Ted Denson of Cincinnati Children's Hospital, co-principal investigator and lead author of the paper. "This means that while patients who develop fibrostenosis exhibit, at diagnosis, increased levels of several genes involved in the fibrosis process, patients who develop penetrating disease have increased levels of genes involved in the inflammatory response."
On the treatment side, this work revealed that patients who received early anti-TNFa biologic treatment, namely within three months of receiving a diagnosis, were less likely to develop penetrating complications, though patients with stricturing complications did not respond well to early intervention with biologics.
“We performed statistical and bioinformatic analyses of the genomic data which led to enhanced discrimination of which patients are likely to progress to complicated disease,” said Greg Gibson, a professor in the Georgia Tech School of Biological Sciences and one of the paper’s co-authors. “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.”
The study also saw Urko Marigorta, a postdoctoral researcher at Georgia Tech, analyze RNAseq gene expression data from biopsies provided by Cincinnati Children's Hospital. The analysis revealed dozens of pathways that are differentially expressed in complicated disease, as well as the fact that immune activity is more disrupted in penetrating disease while the extracellular matrix plays a greater role in stricturing disease. Adding those profiles to a statistical model with serological and classical markers resulted in a significant improvement in its predictive accuracy.
“These discoveries are great steps toward precision medicine in the treatment of pediatric Crohn's disease,” said Dr. Andrés Hurtado-Lorenzo, the Foundation's director of Translational Research. “In the coming years, we plan to translate these findings into a risk diagnostic tool that could use these biological signatures as biomarkers to predict risk of complications and to help clinicians make therapeutic decisions at diagnosis.”
The Crohn's & Colitis Foundation has put nearly a decade of study and more than $10 million investment into this work. Lead authorship is shared by Dr. Thomas Walters from the Hospital for Sick Kids, Canada in addition to Kugathasan and Denson. Dr. Jeffrey Hyams of Connecticut Children’s Medical Center, and Dr. Marla Dubinsky of Mount Sinai Hospital also share authorship.
The work was published in The Lancet in a paper titled “Prediction of complicated disease course for children newly diagnosed with Crohn’s disease: a multicentre inception cohort study.”
SOURCE: The Crohn's & Colitis Foundation

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