Tool helps predict complications in kids with newly diagnosed Crohn's

Last Updated: 2017-03-10

By Megan Brooks

NEW YORK (Reuters Health) - Researchers have developed and validated a risk-stratification model that can help predict whether a child with newly diagnosed Crohn's disease (CD) will develop disease-related complications requiring major surgery within three years.

The goal of the study - called RISK, for Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease - was to identify measurable indicators of the two most common complications in pediatric CD 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," principal investigator Dr. Subra Kugathasan of Emory University in Atlanta, Georgia, said in a statement from the Crohn's and Colitis Foundation, which helped fund the study.

"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,” said Dr. Kugathasan.

The researchers derived and validated their model based on clinical and serological factors defined at diagnosis in 913 children with CD from 28 centers in the U.S. and Canada, 78 (9%) of whom experienced CD complications over 36 months follow up.

According to the March 1 report in The Lancet, older age at diagnosis, African American race, ileal disease location, and ASCA and CBir1 seropositivity were associated with increased risk of CD complications. These patients could be prioritized for early treatment with a TNF inhibitor, the researchers say.

Their “validated competing-risk model” had a sensitivity of 66%, a specificity of 63% and a negative predictive value of 95%. The high negative predictive value of the model “could be used to classify patients at low risk for complications with a high degree of confidence,” the researchers say.

The team also found that ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was significantly associated with stricturing in the risk model (HR, 1.70). When this gene signature was included, the model’s specificity improved to 71%.

Based on their risk model, the researchers say more than half of children (57%) who received early treatment with a TNF inhibitor were projected to be at low risk and would have been deprioritized for this approach if the treatment had been based on the risk model. For these children, treatment decisions might be guided by other considerations such as corticosteroid-dependent or refractory inflammatory disease behavior, or growth failure.

The researchers also tested the effect of anti-TNF therapy within 90 days of diagnosis on risk of complications. They found patients who received early treatment with a TNF inhibitor were less apt to develop penetrating complications (hazard ratio, 0.30), but not stricturing complications (HR, 1.13), relative to those who did not receive early treatment with a TNF inhibitor.

This finding supports the value of risk stratification of pediatric CD patients at diagnosis, and may guide early tailored use of TNF inhibitor therapy, the researchers say.

In an email to Reuters Health, Dr. Kugathasan noted that pediatric-onset Crohn’s is “the fastest-growing incident age group and exhibits a more aggressive course than adult-onset disease. Most of the children present with a just inflammatory which is non-penetrating and non-stricturing disease. However, a subgroup of patients rapidly progress to complicated disease behaviors with stricturing and possible bowel obstruction and/or internal penetrating fistulas often resulting in intra-abdominal sepsis.”

“Collectively these results advance understanding of the pathogenesis of disease complications, and advise more tailored tactics for treating children newly diagnosed with Crohn’s disease,” Dr. Kugathasan said. “Our findings will definitely assist clinicians in making appropriate treatment choices (early anti-TNFa treatment to prevent penetrating complications). However, the risk model is not yet ready to be used in the clinic as the ileal gene signatures discovered to be associated with the stricturing disease in our study would be explored and validated further.”

This year, the RISK team will be completing five years’ follow-up on the entire cohort. “Using that 5-years follow-up data we plan to further refine/validate our risk prediction model. Another main future goal would be to test the results of novel anti-fibrotic approaches in high risk patients through clinic trials,” Dr. Kugathasan said.

The co-authors of a Lancet Comment say the findings “suggest that in the future, a more rational and personalized approach to disease management” in newly-diagnosed children with Crohn's will be possible.

“The clinical application of this model, however, still needs to be proven in prospective trials. Nevertheless, this study holds promise that a paradigm shift in disease management will be possible in the future,” write Ingrid Arijs and Isabelle Cleynen of KU Leuven, Belgium.

The authors have disclosed no relevant financial relationships.

SOURCE: http://bit.ly/2lIsIJv and http://bit.ly/2mLT2Cl

Lancet 2017.