Genetic Signatures Can Help Predict Likelihood of Complications in Young Crohn’s Patients

Genetic Signatures Can Help Predict Likelihood of Complications in Young Crohn’s Patients

Specific biological markers in pediatric patients newly diagnosed with Crohn’s disease can help to predict those who will go on to develop disease-related complications, and those will best respond to treatment.

The study, “Prediction of complicated disease course for children newly diagnosed with Crohn’s disease: a multicentre inception cohort study,” was published in The Lancet journal.

While most children with Crohn’s disease present uncomplicated disease characteristics (phenotype), a “subgroup rapidly progress[es] to complicated disease behaviors, with stricturing and possible bowel obstruction or internal penetrating fistulas, or both, often resulting in intra-abdominal sepsis,” researchers wrote.

This means that a fraction of pediatric Crohn’s disease patients is more likely to develop the most severe and common complications, called stricturing and penetrating disease. These complications significantly contribute to morbidity in both pediatric and adult Crohn’s patients.

Stricturing (also known as fibrostenosis) is the narrowing of the intestine, resulting in difficult passage and caused by buildup of scar tissue within the intestine. Prolonged and sustained inflammation leads to a state of penetrating disease, where inflammation spreads beyond the intestinal wall into the surrounding tissue, often around the anus and rectum. These abnormal connections are called fistulas.

“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, and the study’s principal investigator and corresponding author, said in a press release.

The researchers’ aim was to develop a risk-stratification model that could help physicians identify and stratify patients more likely to progress and develop these complications.

“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,” Kugathasan said. “After analyzing millions of biological and clinical data points, RISK has generated a composite risk stratification model.”

These new findings are part of the Crohn’s & Colitis Foundation’s “RISK Stratification” study (NCT00790543), the largest prospective cohort study with pediatric patients with newly diagnosed Crohn’s disease.

Patients were recruited from 28 centers in the U.S. and Canada. Out of an initial cohort of 1,112 Crohn’s children, 913 were included in the final analysis.

Researchers identified a group of genes whose expression could correlate with an increased risk of developing strictures. This means that this genetic signature, together with other biological and clinical parameters, could be used to predict the risk for complications, as well as identify patients’ response to a certain therapy.

But within three months of diagnosis, those patients who received anti-TNF-alpha therapy were found to be less prone to develop penetrating complications. Those with stricturing complications, however, responded quite poorly to this type of treatment.

“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,” Greg Gibson, a professor in the Georgia Tech School of Biological Sciences and an author in the study, said. “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.”

These findings support the usefulness of risk stratification of pediatric patients with Crohn’s disease at diagnosis, identifying those that will benefit from anti- TNF-alpha therapy.

Moreover, it highlights the necessity of new therapies for children developing penetrating disease.

“These discoveries are great steps toward precision medicine in the treatment of pediatric Crohn’s disease,” said Andrés Hurtado-Lorenzo, PhD, director of Translational Research of the Foundation. “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.”