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New Model Predicts Crohn's Disease Complications

NEW YORK (GenomeWeb) – Researchers from the US and Canada have developed a model to predict whether newly diagnosed pediatric Crohn's disease patients will develop disease-related complications.

About a quarter of Crohn's disease patients have complications within a few years of diagnosis. Often, they have to deal with stricturing, which is the buildup of fibrotic scar tissue in in the intestines that narrows the intestinal passage, or penetrating disease, which is sustained inflammation that can lead to the development of fistulas and abscesses. These complications can require surgery and be costly.

As they reported yesterday in the Lancet, researchers from the multicenter Crohn's and Colitis Foundation's RISK Stratification study developed a model to predict such complications based on clinical, serological, and gene expression factors. They also reported that early treatment with anti-TNF alpha agents was associated with a decreased incidence of penetrating complications, suggesting that the risk model could be used to tailor treatment choices.

"Twenty-five percent of patients with Crohn's disease account for 80 percent of complications, hospitalizations, surgery, and healthcare costs," lead author Subra Kugathasan from Emory University said in a statement. "The aim of RISK is to preemptively identify those 25 percent of patients at diagnosis."

Kugathasan and his colleagues enrolled 913 patients into their study, collecting clinical data such as age at diagnosis, laboratory data such as C-reactive protein levels, and other data such as ileal gene expression and bacteria content of stool samples from a portion of patients. Some 54 patients developed stricturing and 24 developed penetrating complications.

Stricturing complications were associated with anti-Saccharomyces cerevisiae antibodies (ASCA), CBir1, and granulocyte-macrophage colony-stimulating factor seropositivity, while penetrating disease was associated with older age at diagnosis and being African American, as well as with ASCA and CBir1 seropositivity, the researchers reported. They incorporated these clinical and serological findings into a competing risk-based model that could predict disease complications with a sensitivity of 66 percent, specificity of 63 percent, and a negative predictive value of 95 percent.

The researchers also examined the ileal gene expression patterns in about 25 percent of the patients, and found differences between them. For instance, they noted that genes regulating extracellular matrix accumulation were induced at diagnosis in patients who later developed strictures, and that genes regulating the acute inflammatory response were induced in patients who developed penetrating disease.

When the researchers folded this data into their predictive model, its sensitivity increased to 69 percent while its specificity increased to 71 percent.

Kugathasan and his colleagues also reported that patients who were treated with anti-TNF alpha therapies within three months of diagnosis were less likely to develop penetrating complications. Treatment, however, did not affect their likelihood of developing stricturing complications.

Still, the researchers said that their findings support stratifying patients based upon their risk for complications to receive such early treatment.

"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," Andrés Hurtado-Lorenzo from the Crohn's and Colitis Foundation said in a statement.

In a related commentary in the Lancet, Ingrid Arijs from Hasselt University and Isabelle Cleynen at KU Leuven, both in Belgium, wrote that while the study is "noteworthy," they also had concerns about its limitations. In particular, they pointed out that the genotyping, microbial profiling, and gene expression analysis were performed in different subsets of the patient cohort.

Because of this, even though Kugathasan and his colleagues reported that Rothia and Ruminococcus were linked to stricture development and that there were increased levels of Collinsella in patients who developed penetrating disease, they were unable to incorporate that into their model.

At the same time, Arijs and Cleynen said, the model cannot distinguish high-risk patients who will develop strictures from those who will develop penetrating disease. "This distinction could be important, because the authors found that early anti-TNF alpha therapy was associated with a reduction in penetrating, but not stricturing, complications," they wrote.

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