Canada has one of the world's highest rates of childhood inflammatory bowel disease (IBD), with approximately 6,158 children currently affected and 600-650 new diagnoses annually in those under 16. This comprehensive review examines the latest advancements in pediatric IBD care, including rising incidence rates, genetic discoveries, dietary therapies like exclusive enteral nutrition, and new biological treatments that are transforming how doctors manage this complex condition in young patients.
Canada faces a significant challenge with childhood inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis. Recent data shows our country has one of the highest rates of childhood-onset IBD in the world. Currently, approximately 6,158 children and youth under 18 years are living with IBD, and doctors diagnose 600-650 new cases in children under 16 each year.
Concerningly, this number is expected to rise to 8,079 affected children by 2035. These new pediatric cases represent approximately 10-20% of all newly diagnosed IBD patients. The most significant increase has occurred in children under 5 years old, although adolescent-onset IBD remains more common.
Recent health administration data demonstrated the national incidence of IBD overall to be 29.9 per 100,000 people (95% confidence interval: 28.3, 31.5) in 2023. The incidence is increasing in pediatrics (average annual percent change: 1.27%; 95%CI: 0.82, 1.67) despite stable incidence in adults (AAPC: 0.26%; 95%CI: -0.42, 0.82). This increase in pediatric incidence is a worldwide phenomenon that researchers are actively studying.
Current IBD care in pediatrics is moving toward a precision medicine approach with unique and standardized approaches to genetics, risk stratification, disease phenotype identification, nutritional and advanced therapies, and specialized multidisciplinary clinics that understand the unique challenges pediatric patients and their families face with an IBD diagnosis.
Research has identified that genetic factors, microbial dysbiosis (imbalance in gut bacteria), and aberrant immune responses associated with environmental factors are the main influencing factors in IBD development. The contribution of these factors likely varies depending on the child's age at diagnosis.
With advances in next-generation DNA sequencing, doctors can now genetically diagnose children with IBD or IBD-like disease, labelled 'monogenic IBD'. These patients are typically rare, have severe disease, and are refractory to conventional therapies. A recent systematic review collected data on established monogenic IBD cases, finding the most commonly reported monogenic defect was interleukin (IL)-10-signalling colitis, followed by chronic granulomatous colitis (CGD), and X-linked inhibitor of apoptosis (XIAP) deficiency.
Notably, more than 10% of monogenic IBD cases were identified in adult age groups, showing that these genetic forms can present later in life. The research revealed that 76% of patients with monogenic IBD developed at least one extraintestinal issue during their disease course, with treatments including surgery (27.1%), hematopoietic stem cell transplantation (23.1%), and biological therapies (32.9%).
These data highlight the diverse nature of monogenic disease, and doctors should consider genetic testing in all patients who have an unusual disease presentation, significant extraintestinal disease, or who are refractory to standard therapies.
Diet has been implicated in both the development and relapsing/remitting nature of IBD, with extensive research into diet's role in this condition. Numerous nutritional epidemiology studies demonstrate harmful associations with Western diet patterns and protective benefits from a Mediterranean diet. Animal studies have implicated ultra-processed and industrialized foods in inflammation development.
The mainstay of nutritional therapy in pediatric IBD has been exclusive enteral nutrition (EEN) for Crohn's disease - a treatment where patients receive only liquid nutrition formula for several weeks. In Canada, rates of EEN use are similar to that of corticosteroids for induction therapy according to data from the Canadian Children IBD Network.
EEN has demonstrated efficacy across multiple studies to induce remission and mucosal healing, and for nutritional rehabilitation. It has also shown benefit in children with stricturing/penetrating disease or with inflammatory masses. Patient selection remains important for EEN success, and works best when supported by a dietitian in an IBD center with EEN experience.
Research shows that patients with predominantly distal ileal disease and mild-to-moderate disease severity are more likely to respond to EEN. Studies exploring microbiome signatures and genetic markers related to EEN success are ongoing, which may help identify which patients will benefit most from this therapy.
Multiple dietary therapies have been proposed as IBD 'treatment diets', with a recent literature review identifying more than 24 different diets used in IBD management. The most robustly assessed is the Crohn's Disease Exclusion Diet (CDED), which combines a restricted diet with partial enteral nutrition (PEN) across several phases of decreasing restriction.
Diet restrictions were based on animal data where food products impacted inflammation, dysbiosis, or intestinal permeability. This combination was similar to EEN in inducing remission at week 6 (75% in the CDED plus PEN group vs 59% in the EEN group), but has had limited success in patients with severe disease, or those who have lost response to biologic medications.
Across Canadian pediatric centres, significant variation remains in standard diet recommendations and uptake of diet therapies until more robust data on therapeutic diets emerge, which continues to be a source of frustration for patients and families seeking dietary approaches to manage IBD.
The number of approved drug therapies for IBD in adult patients has increased rapidly in recent years. However, the unavailability of these drugs for children has been an increasing problem for pediatric IBD practitioners. There is a significant lag time before pediatric randomized controlled trials are completed and regulatory approval is granted, leading to prolonged off-label use of new therapies in children.
Traditional induction therapies like corticosteroids and EEN continue to be used, but the use of immunomodulators as maintenance monotherapy, especially in Crohn's disease, has decreased significantly as doctors move to a focus on 'early effective therapies' as part of a treat-to-target approach. This is especially important as most pediatric patients present with moderate-to-severe and extensive disease.
In ulcerative colitis, the PROTECT study demonstrated a reasonable proportion of steroid-responsive children respond to standard 5-ASA therapies, but at 52 weeks, only 40% of patients were able to maintain 5-ASA therapy without requiring treatment escalation.
Anti-tumour necrosis factor (TNF) therapies continue to be the most utilized maintenance therapies in pediatrics given their prolonged availability and effectiveness, with infliximab and adalimumab being the only licensed biologics for children. However, approximately one-third of IBD patients are non-responders to anti-TNF therapy, and another 20-30% will develop secondary loss of response, with or without development of anti-drug antibodies.
The use of body surface area (BSA)-based dosing for young children and proactive therapeutic drug monitoring has shown some benefit in children compared to adults, potentially related to differences in drug clearance and body composition. The youngest and lightest children require the most drug per kilogram to achieve comparable drug exposure to older children and adults.
In 2014, vedolizumab became the first anti-integrin medication designed specifically for gastrointestinal disease in adults, targeting α4β7. It has been used off-label in pediatrics, initially in anti-TNF refractory patients, but more recently in treatment-naïve patients, especially in ulcerative colitis.
Multiple pediatric observational studies demonstrate its safety and efficacy, the largest being the VEDOKIDS study which showed 42% steroid-free remission rates at Week 14 in ulcerative colitis and 32% in Crohn's disease. Some benefit was seen in treatment-naïve patients. Safety data to date are excellent, making this drug an attractive therapy for pediatric patients.
Ustekinumab, a monoclonal antibody that binds to the p40 sub-unit of IL-12 and IL-23, is approved in adults and has been used off-label in Canada since 2016 in children. Canadian data showed 44% steroid-free remission at Week 52 in ulcerative colitis patients who had failed anti-TNF therapy. In Crohn's disease, Canadian data demonstrated 38.6% of patients achieving clinical remission at Week 52. Both studies reported good safety profiles.
JAK-STAT inhibitors, which interrupt intracellular STAT pathway phosphorylation, were the first family of targeted small molecules used in IBD. Published series demonstrate efficacy and early safety data in children, with up to 41.2% of patients achieving clinical response and steroid-free remission at 52 weeks. A second small study showed improvements in colectomy rates in hospitalized patients who were steroid and anti-TNF refractory.
Newer molecules targeting p19 found only on IL-23, including risankizumab, mirikizumab and guselkumab, are undergoing clinical trials in adult patients with encouraging data. Pediatric clinical trials are ongoing. Sphingosine-1-phosphate (S1P) receptor modulators are another new class of drugs undergoing clinical trials in IBD, with ozanimod currently being studied in pediatric Crohn's disease.
With multiple new drugs and pathways available, pediatric IBD specialists will have more treatments for patients. Data regarding treatment sequencing and positioning will become increasingly important. Research is also emerging on 'multi-modal' therapy combining dual biologics or biologics and small molecules for refractory pediatric patients, expanding treatment options for those with difficult-to-control disease.
The goals of care in pediatric IBD are initially similar to those of adults: achieving long-term, steroid-free clinical remission and mucosal healing to prevent long-term disease-related complications. However, children have unique additional goals that require special attention from healthcare teams.
These additional priorities include optimizing physical, pubertal and psychological growth, maintaining nutrition and quality of life through school and adolescence, and careful consideration of potential treatment toxicities given the extended periods of time children will be on medications. This is especially important as our patient population at disease onset continues to get younger and treatments more complicated.
Given these complex needs, it is increasingly recognized that children with IBD should be treated in specialized, multidisciplinary centres with access to physicians, specialized nurses, dietitians, and mental health professionals with expertise in IBD. This team approach helps ensure children and families can access the highest quality care for their IBD throughout childhood and adolescence.
Original Article Title: Updates in the Management of Pediatric Inflammatory Bowel Disease
Author: Nicholas Carman, MBBS, FRACP
Author Affiliations: SickKids Inflammatory Bowel Disease Centre, Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children (SickKids), Toronto, Ontario; University of Toronto
Publication: Volume 2, Issue 1, Spring 2024
This patient-friendly article is based on peer-reviewed research and maintains all significant findings, statistics, and clinical information from the original scientific publication.
