This article is more than 5 years old. Information may no longer be current.
RISK study finds predictors of complications in children with Crohn's disease
Click Here to Manage Email Alerts
A competing-risk model including genetic, biological and clinical variables was predictive of complications and treatment outcomes in children newly diagnosed with Crohn’s disease, according to results from the Crohn’s & Colitis Foundation’s RISK Stratification study.
Further, study investigators found that early treatment with anti-TNFs was preventive of internal penetrating but not stricturing complications.
“Twenty five percent of patients with Crohn’s disease account for 80% of complications, hospitalizations, surgery, and health care costs. The aim of RISK is to preemptively identify those 25% of patients at diagnosis,” Subra Kugathasan, MD, of the division of pediatric gastroenterology at Emory University School of Medicine in Atlanta, said 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.”
Subra Kugathasan
Because validated models for predicting the risk for complications are not currently available, Kugathasan and colleagues prospectively evaluated 913 children newly diagnosed with Crohn’s disease at 28 sites throughout the U.S. and Canada from November 2008 through June 2012 (median age at diagnosis, 12.4 years; 62% boys; 75% white; 13% black or mixed race; 9% experienced complications). They aimed to develop a risk-stratification model based on genetic, clinical, biological and microbial factors at diagnosis, and treatments including anti-TNFs, that would predict the risk for developing complications within 3 to 5 years.
The resulting risk model included age, race, disease location and antimicrobial serologies, and predicted the development of complications with 66% sensitivity, 63% specificity, a 14% positive predictive value and a 95% negative predictive value.
Further, the investigators found that treatment with anti-TNFs within the first 3 months of diagnosis was not associated with a lower risk for stricturing complications, but was associated with a lower risk for penetrating complications (HR = 0.3; 95% CI, 0.1-0.89).
Microbial analysis also showed that Ruminococcus was involved in structuring complications, while Veillonella was involved in penetrating complications.
Finally, the researchers identified significant differences in gene expression between patients, and found that a novel ileal extracellular matrix gene signature was associated with stricturing in the risk model (HR = 1.7; 95% CI, 1.12-2.57), and after inclusion it increased the risk model’s specificity to 71%.
“Importantly, the functional nature of these genetic signatures is consistent with the clinical presentation of the complications,” Lee A. Denson, MD, medical director of the Inflammatory Bowel Disease Center at Cincinnati Children’s Hospital Medical Center, said in the press release. “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.”
“While promising, the model’s clinical application needs to be confirmed in clinical trials,” Ingrid Arijs, PhD, of Hasselt University and Jessa Hospital in Belgium, and Isabelle Cleynen, PhD, of the University of Leuven in Belgium, wrote in a related editorial.
The model’s ability to classify patients at low risk for complications “would be very useful for clinical practice,” and “the identification of an ileal profibrotic gene signature detectable at diagnosis in the stricturing subgroup holds promise for future antifibrotic therapies,” they wrote. However, their concerns included the lack of microbial findings incorporated into the model, and the model’s inability to “distinguish high-risk patients who will develop strictures from patients developing penetrating disease.”
Nonetheless, these findings show promise for the future of precision medicine in pediatric Crohn’s disease, according to Andrés Hurtado-Lorenzo, PhD, the Crohn’s & Colitis 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,” he said in the press release.
While the RISK study has been the “flagship” project within the foundation’s PRO-KIIDs network for pediatric IBD research, Michael Osso, the foundation’s president and CEO, said that additional projects are expected.
“Pediatric patients are the fastest growing group of the IBD population,” he said in the press release. “Under the auspices of the PRO-KIIDS network, every major pediatric IBD center in the country is touched by our work or funding. Through the network, and the results of the RISK study, we are furthering research that will significantly lower the treatment burden on kids, and help minimize side effects on the quality of life surrounding the most vulnerable of patients.” – by Adam Leitenberger
Disclosures: The researchers and editorial authors report no relevant financial disclosures.
Click Here to Manage Email Alerts