Providing a brighter future in pediatric Crohn’s disease

On November 17-18, 2020, the Crohn’s & Colitis Foundation hosted its third annual IBD Innovate: Product Development for Crohn’s & Colitis™ conference. This meeting brings together researchers, start-up companies, industry companies, accelerator organizations and more who are committed to accelerating the discovery and development of novel products with the potential to address the unmet needs of patients with IBD. This is the first blog post of three recapping the presentations from the 2020 IBD Innovate.

The Crohn’s & Colitis Foundation’s research priorities are geared toward addressing unmet needs of patients affected by Crohn’s disease and ulcerative colitis. These unmet needs, which are identified every few years through the Challenges in IBD Research manuscript, fall into several categories, including preclinical human mechanisms, environmental triggers, novel technologies, precision medicine, and pragmatic clinical research.

During IBD Innovate, we heard presentations from leading experts who are working on developing different novel products that are being researched to help improve the lives of patients. As a patient myself, I have watched the landscape of IBD treatments advance over the years since I was a pediatric patient and had few options available. This research, which will help find kids who might have more severe disease and identify the right treatment for them, is both exciting and hopeful for kids with IBD and their parents.

Addressing the unmet needs of pediatric IBD patients

Diagnosing and treating Crohn's disease in pediatric patients is a challenge for healthcare providers. How Crohn's disease will progress in any one particular patient is an unknown. This leaves clinicians with concerns about either under- or over-treating their young patients. Children with IBD have different potential complications than adults do, such as problems with their growth. Some patients have severe disease, while others will have a less serious course. For providers who treat children diagnosed with Crohn's, knowing a patient's risk of severe disease will help guide treatment and prevent complications and loss of quality of life.

Dr. Andres Hurtado-Lorenzo, the Foundation’s Vice President, Translational Research, and Ciaran Fulton, Associate Director, Head of Diagnostics at LifeArc, addressed two significant unmet needs in the pediatric IBD community – developing an understanding of which patients may go on to have severe disease and which treatment is likely to be effective for which patients.

Dr. Hurtado-Lorenzo gave a sobering picture of pediatric Crohn's disease during his presentation. For pediatric patients, about 20% will experience severe complications that often require surgery. Even after surgery, recurrence of Crohn's disease in these patients is common. Biologic medications have been shown to be most effective for treating severe disease. However, anywhere between 40% and 50% of patients have disease that doesn't respond to treatment with biologics. What's more, 30% of patients have disease that stops responding to a biologic therapy over time. 

Those pediatric patients who may be at greater risk for future complications may benefit from using more aggressive treatment options earlier. Patients who are at a lower risk for complications from Crohn's disease may choose to pursue different treatment options. The key, and a stumbling block in treating pediatric Crohn's disease, is in knowing which patients are at the greatest risk for relapses and ongoing disease in order to choose the most effective treatment for them. 

As Dr. Hurtado-Lorenzo noted in his presentation, "There is a big challenge in the clinical management of Crohn's disease because it is a very heterogeneous illness. This means that the course of the disease is highly variable, with some patients having more aggressive disease than others."

Using gene analysis to understand risk of disease complications in pediatric patients

We already know that IBD is connected to certain genes. What's not yet well understood is how these genes relate to the onset of IBD or the seriousness of the disease course. Simply put, you can have one of the genes associated with IBD and never develop the disease, or you can develop it without having any of the genes. Further, it's not clear how to use genetic markers along with other factors, such as age of diagnosis and the location of inflammation in the small intestine, to predict who will have mild disease and who will not.

The Crohn’s & Colitis Foundation’s Pediatric RISK Stratification Study is the largest to involve children newly diagnosed with Crohn's disease at 28 clinics in the United States and Canada. Over the course of 10 years, researchers studied 1,800 newly-diagnosed pediatric patients, with the focus placed on 913 children with Crohn’s who were complication-free 90 days after diagnosis. Biopsies taken from the small intestine of the patients were analyzed along with their clinical and demographic information. 

Through the initial study, researchers identified biological signatures capable of predicting if a child newly diagnosed with Crohn’s will develop disease-related complications that will require major surgery within three to five years after diagnosis.

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Pediatric RISK Stratification Study

Dr. Hurtado-Lorenzo discussed how the Foundation’s next goal is to take the findings of this research and turn them into a practical test to predict Crohn's disease complications in pediatric patients. Scientists started by re-sequencing the biopsies that were taken during the RISK Stratification Study and, by doing this, they were able to identify a panel of 13 genes that are important in differentiating between the different types of Crohn's disease.

The gene analysis was shown, with some degree of certainty, to help predict which patients were more likely to develop the complicated types of Crohn's disease. This includes the forms of the disease which are associated with the development of a stricture, a fistula, or a combination of the two. The performance of this 13 gene panel in predicting severe disease was found to be an improvement on the original model.

Furthermore, scientists were also able to determine which patients would see the most benefit from use of anti-tumor necrosis factor (TNF) biologic medications. Dr Hurtado-Lorenzo pointed out that this research is important because it may help physicians "deliver the right drug at the right time to the right patient, which is the core of precision medicine."

Developing a prognostic test to identify risk and prevent complications

The next step for this research is to translate the results into a test that can be done for pediatric patients diagnosed with Crohn's disease. It was originally thought that there might need to be as many as three tests in order to get the right information. The goal now, however, is to use this data to develop a single test. This test could then ideally be used in a clinical setting and will give physicians and patients more information that can be used in treatment decisions. 

Having a test like this would be groundbreaking for pediatric patients. Essentially, doctors would be able to tell the patients and their caregivers, at the time of diagnosis, their risk of developing complications down the road. By knowing this early on after diagnosis, healthcare providers could make more strategic decisions about treatment to help avoid some life-altering complications, such as strictures and fistulae. Additionally, by learning which patients might respond best to an anti-TNF drug, those patients can be started on that medication sooner after diagnosis in order to avoid future complications and surgeries.

To develop this test, the Foundation has partnered with LifeArc, a UK-based charity that focuses on translational science activities. Ciaran Fulton from LifeArc explained that these tests are currently in the feasibility stage where LifeArc is "kicking the tires." The target now is to continue moving forward through the development, manufacturing, and clinical evaluation stages to provide a test that can be used by clinicians to help evaluate their pediatric patients newly diagnosed with Crohn's disease.

“In summary, we have identified a single optimized 13 gene panel to predict a diagnosis that a child might develop fistula or fibrosis or a combination of both,” said Dr. Hurtado-Lorenzo. “And this is very exciting because these means that with a single biopsy sample, and with a single test, we could [predict] three possible complications...In addition, we also discovered and optimized a 13 gene panel to predict whether anti-TNF-alpha treatment can induce or not corticosteroid-free remission in children with IBD." 

This is great news for IBD pediatric patients. Complications from IBD can be devastating to patients, especially children and teens. The applications of this research will mean that newly diagnosed kids with IBD have not only a better chance at reaching remission sooner but also in avoiding potential complications. That way, kids with IBD can live a life closer to that of their healthy peers, leaving behind the days of hospitalizations, missing school and social functions, and medication side effects that my generation experienced. 

Amber Tresca is a writer for the Crohn's & Colitis Foundation. She is the IBD expert for VeryWell and hosts the About IBD podcast.