Clinical Challenges: Managing Pediatric Crohn’s Disease

Pediatric Crohn’s disease (CD) is on the rise, with an estimated 40,000 U.S. children affected by this potentially growth-stunting condition.

This increase is not an artifact of better detection. “Rather, it appears that Western diets, antibiotic exposure early in life, and dietary emulsifiers may contribute to disease pathogenesis,” said Jeffrey Hyams, MD, of Connecticut Children’s Medical Center in Hartford.

According to Michael Kappelman, MD, MPH, of the University of North Carolina at Chapel Hill, childhood CD is especially challenging because it is more extensive and more severe than it is in adults. “That includes severity by symptom burden, laboratory biomarker abnormalities, and endoscopic findings,” he said. That can translate to a greater need for surgery in affected children, although definitive data are lacking.

Ileocolonic disease is more common in children, added Hyams, but the cause of the wider extent remains unclear. “One hypothesis is that earlier-in-life onset implies a greater genetic proclivity to developing disease rather than later in life, when it is perhaps more multifactorial and more environmental,” he said. “Adults smoke, eat bad things, drink, etc., and also have had more time for age-related changes.”

Growth, Development, and Mental Health

Managing CD in growing children is particularly challenging since treatment cannot be the only focus. “There are concerns about the impact of the inflammation and treatments on skeletal growth and the possibility of delayed puberty,” Kappelman said. Puberty may be delayed by 1 or 2 years, and some patients will not reach their full adult height.

Protecting psychosocial development is paramount. “It’s tough being a teen under the best of circumstances but having Crohn’s makes it really tough for adolescents,” Kappelman said. It complicates normal social life and reinforces the painful difference between patients and peers.

Psychological health is an underappreciated exacerbator in pediatric CD management, he added. “It’s a two-way street: the disease can worsen anxiety and depression, and anxiety and depression can make the symptoms harder to manage.”

Depression is common: a 2014 analysis identified clinically significant depressive symptoms in nearly 40% of pediatric CD patients.

With the majority diagnosed in the vulnerable preteens or early adolescence, proactive psychological care is essential. “These are critical times for developing independence, yet the disease often makes patients more dependent than ever on their parents,” said Hyams. “Missing school and bowel issues can cause children significant social anxiety.” And there is the added challenge of dealing with young patient’s parents.

The practical task is to treat while allowing youngsters to have as normal a childhood as possible with the least disruption of school and social life.

Treatment

With children presenting unique challenges owing to extensive disease and the effect of inflammation on growth, historical approaches with corticosteroids and immunomodulators are far less effective than early treatment with tumor necrosis factor (TNF) inhibitors.

“The early introduction of biologics, particularly anti-tumor necrosis factor agents, has changed the treatment paradigm,” Hyams said. “We can now realistically strive for intestinal healing rather than just symptom relief. We can now also monitor disease activity via colonoscopy and magnetic resonance enterography more frequently.”

As to safety, this must always be top of mind. “Our patients have a life horizon of 70 to 80 years, so getting disease under control without steroids is very important over the long term,” Hyams said. Fortunately, immunosuppression-related infections are quite rare.

Although children will be able to receive agents such as Janus kinase inhibitors or interleukin blockers following recent approvals in adults, “we often have to extrapolate the dose for children,” Hyams said. “That’s easy for teenagers, who get the same as the adult dose, but smaller kids are more problematic.”

And actually providing these agents off-label to children can be challenging since serious barriers prevent expediting advances in inflammatory bowel disease (IBD) treatment to children. “The pediatric community continues to be hampered by the inordinate delays in actually getting emerging therapies to children,” Hyams said. “Clinical trials often start only after approval in adults and are difficult to enroll because of limited off-label availability of these drugs.”

And getting insurance companies to cover these drugs for children can be challenging as well, said Hyams. “They declare the use ‘experimental.’ The pediatric IBD community has tried in vain for years to get FDA to mandate a faster track for pediatric approval.”

Research

The pediatric community has been successful in organizing prospective multicenter studies looking at IBD pathogenesis and response to therapies, Hyams noted. In particular, the RISK study predicting disease complications in CD, and the PROTECT study predicting therapeutic response in colitis, were highly informative. The newly launched NIH CAMEO study is examining factors involved in bowel healing following anti-TNF therapy in newly diagnosed children.

While new treatments await pediatric approval, established treatments continue to be refined and maximized. Kappelman’s group recently published a multicenter randomized trial in 297 CD patients on the impact of adding low-dose oral methotrexate to anti-TNF monotherapy with infliximab (Remicade) or adalimumab (Humira).

Among adalimumab — but not infliximab — initiators, patients concurrently treated with methotrexate experienced a twofold reduction in treatment failure compared with single-agent anti-TNF, the researchers found. The combination approach had a tolerable safety profile as well.

Therapeutic Future

Hyams said he foresees more options and more targeted treatments. “Today, anti-TNF agents are certainly the most effective and remain the choice for children with moderate to severe CD. Having said that, not everyone responds, and trivial-to-serious side effects can be seen.”

The challenge is to integrate newer agents into the early treatment plan, particularly those with favorable safety profiles, he said. “Remember, we need to get children to grow, and that only happens with disease control and good nutrition. So we can also strive to inform patients and families about healthy eating, which is likely to improve outcomes as well.”

While treatments approved only in adults will become more broadly available for children in the future, Kappelman said, “the challenge will be to find the right combination for the right patient.”