As in adults around the world, inflammatory bowel disease (IBD) is on the rise in children in North America. “Anecdotally, all of us pediatric gastroenterologists have seen a dramatic rise in the number of U.S. children with IBD, at a mean age of 12 or 13,” Jeffrey S. Hyams, MD, head of the Division of Gastroenterology of Connecticut Children’s Medical Center in Hartford, told MedPage Today. “The landscape is very different now from what it was 15 years ago.”
Support for such anecdotal observations as well as for a decreasing age at diagnosis comes from a new study by Eric Benchimol, MD, of Children’s Hospital of Eastern Ontario Inflammatory Bowel Disease Centre, and colleagues, based on analysis of healthcare databases in five provinces representing almost 80% of the population of Canada, which has one of the world’s highest rates of IBD.
The findings revealed that the overall incidence per 100,000 children increased from 7.9 (95% CI 6.4-9.4) in 1999 to 10.6 (95% CI 8.5-12.6) in 2008. And while incidence has stabilized in the over-five age group, cases in younger children rose by 7.2% per year from 1999 to 2010, a situation unheard of 20 years earlier.
Prevalence, too, significantly increased during the study period at a rate of 4.56% per year (95% CI 3.71%-5.42%), reaching 38.25 per 100,000 (95% CI 35.78-40.73).
This increase is particularly alarming since the childhood-onset phenotype often has a more severe, possibly more genetically driven, clinical course. And despite ongoing research into genetic susceptibility, only about 15% of children with IBD have a first-degree relative with the disease, Hyams noted. Still, genetic predisposition may be a stronger factor in childhood IBD than IBD that manifests later when environmental factors have had time to come into play.
As in adults, the impetus behind the rise is doubtless a multifactorial interaction between several genes and environmental triggers: “IBD in kids is complex and not usually due to a single gene but in very early-onset IBD such as Crohn’s in infants, for example, increasingly that is thought to be due to a single gene,” Anne Griffiths, MD, head of the Division of Gastroenterology, Hepatology, and Nutrition, and director of the IBD Program at the Hospital for Sick Children in Toronto, said in an interview. This monogenic form is the subject of current genetic research at her hospital, which is also leading a large inception cohort study of early-onset IBD.
The end target of this causal complexity is thought to likely be the bacteria in the intestinal microbiome, whose normal development in children is somehow impaired. Potential causes of this compromise include lack of breastfeeding; early use of antibiotics; and overly sanitized environments with suboptimal exposure to immune-stimulating bacteria; low vitamin D stores in low-sunshine northern countries; and high-fat, high-sugar modern diets.
“We don’t really know the reasons,” Hyams said. “It’s likely multiple things combined with diet. For example, the foods we eat today contain stabilizers to increase shelf life, and these affect the barrier mucosal layer in the gut and make it more permeable to bacteria.” Add in early-life antibiotic exposure, which can alter the microbiome, and the result is a pro-inflammatory environment tailor-made for the development of IBD.
Currently, U.S. research in children is focusing on two areas of interest, Hyams noted: The first is assessing whether initiating biologic therapy, primarily tumor necrosis factor (TNF) inhibition, within 2 months of diagnosis can change the natural history of the disease. The second is risk prognostication to predict the severity of the course of disease in both Crohn’s disease and ulcerative colitis. “We want to develop the ability to see if a combination of clinical, serological, genetic, and microbiome data at diagnosis can be used to guide therapy in a precise way.”
Griffiths agreed: “A realistic goal of current research would be trying to identify better predictors of who is destined to have a mild clinical course and who is destined to have a severe course, so that therapy could be more personalized.”
Risk models for predicting complications such as penetrating and stricturing in pediatric Crohn’s disease were recently tested by Subra Kugathasa, MD, and colleagues in a study of 913 newly diagnosed children in the U.S. and Canada. Participants who received early anti-TNF therapy were less likely to have penetrating complications, for a hazard ratio (HR) of 0.30 (95% CI 0.10-0.89, P=0·0296), but were not less likely to have stricturing complications (HR 1.13, 95% CI 0.51-2.51, P=0.76).
As for possible bacterial factors, Ruminococcus was implicated in stricturing complications, and Veillonella, in penetrating complications. Genetically, ileal genes controlling extracellular matrix production were upregulated at diagnosis, a gene signature associated with stricturing (HR 1.70, 95% CI 1.12-2.57, P=0.0120).
As for the longer-term safety of anti-TNF in children with IBD, a large study led by Hyams recently reported that infliximab was not associated with any rise in the risk of malignancy or hemophagocytic lymphohistiocytosis. Thiopurine exposure, which has come under increasing suspicion of boosting the risk of cancers and lymphoproliferative conditions in children, was found to correlate with both.
Hyams is also a co-investigator in the PROTECT (Predicting Response to Standardized Pediatric Colitis Therapy) study, a National Institutes of Health-funded multicenter prospective investigation of how well newly diagnosed children do on usual drugs such as mesalamine or corticosteroids and whether some need more potent immunosuppressive aggressive therapy early on.
As for growth retardation in children, IBD is not usually a big factor, Griffiths said: “Ulcerative colitis is seldom associated with impaired growth, but Crohn’s can be associated with impaired linear growth. However, this is largely a direct effect of the inflammation and not a consequence of poor nutrient absorption. And children usually catch up if they are treated effectively while they still have linear growth potential.”
The only therapy that interferes with growth is the inappropriate use of corticosteroids, she explained. “But in the modern era, steroids have a much less important role as they provide only short-term relief. The emphasis is now on more effective treatments that can actually heal the bowel, and 60% to 79% of Crohn’s patients at our center are on biologics.”
And thanks to periodic intravenous infusions or injections, compliance is better with biologics than with multiple daily doses of pills. Ostomy is rarely necessary in Crohn’s patients under age 18, thanks to new therapies and surgical techniques, Griffiths added.
In many ways, pediatric IBD provides a better experimental model than its adult counterpart, since children usually don’t have as many confounding medical factors and are less likely to have engaged in behaviors such as smoking that may negatively impact IBD. Researchers studying this model are counting on the identification of phenotypic, genotypic, serologic, and bacterial characteristics to provide prognostics on individual response to therapy and disease — information that will be increasingly important as newer tailored therapies emerge.