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State-of-the-Art Pediatrics

February 2019

Novel Concepts in Pediatric Inflammatory Bowel Disease

Author: Alka Goyal, MD | Director, Inflammatory Disease Service, Division of Gastroenterology, Hepatology and Nutrition | Associate Professor of Pediatrics UMKC - School of Medicine

Column editor: Amita R. Amonker, MD | Pediatric Hospitalist | Assistant Professor of Pediatrics, UMKC School of Medicine
 

Inflammatory bowel disease (IBD) is a chronic, dysregulated bowel inflammation characterized by an imbalance of the gut bacteria (dysbiosis) resulting from a complex interplay between genetic predisposition, environmental factors, an incompetent gut barrier (intestinal epithelium and innate immune system) and inappropriate immune activation. The two main types of IBD are Crohn’s disease (CD) and ulcerative colitis (UC).  Crohn’s disease is a transmural inflammation involving both the small and large bowels characterized by skip lesions. Ulcerative colitis (UC) involves continuous inflammation of the colonic mucosa starting from the rectum ascending proximally. IBD is, however, a phenotypic manifestation of underlying chronic bowel inflammation, and these two entities can have overlapping features.  Symptoms include abdominal pain, diarrhea, hematochezia and weight loss. Children may present with isolated poor growth, delayed puberty, anemia or other extra-intestinal manifestations. IBD can be complicated by extra-intestinal manifestations including fevers, mouth ulcers, arthritis, uveitis, skin lesions, liver disease and malnutrition.1 

In the U.S., the annual incidence of pediatric IBD (defined as individuals diagnosed under 19 years of age) is 15.2/100,000-person years2 with a prevalence of 100-200 cases per 100,000 children.  Approximately 25% of incident cases occur before 18 years of age, of which 4% and 18% occur in children below 6 years (Very early onset IBD [VEOIBD]) and 10 years respectively.1 The disease distribution in VEOIBD is mostly colonic versus older children, with more ileo-colonic and small bowel disease.

So far, 230 risk loci have been described in IBD, yet it explains only 20-25% heritability of IBD.  The concordance rate for CD in monozygotic twins is only 50%, and together with an observed rise in incidence of IBD in children and newly industrialized countries, the role of environmental factors is further highlighted.  Children with very early onset IBD (VEOIBD) have a stronger genetic predisposition compared to adults. Some of the monogenic mutations may even be treatable by allogenic bone marrow transplantation, e.g., Il-10 receptor defects, X-linked inhibitor of apoptosis (XIAP) and chronic granulomatous disease.3 

The genetic risk loci for IBD seem to affect barrier function, epithelial restitution, cellular homeostasis or endoplasmic stress response and regulation of adaptive immune system.4  The gut microbiome links environmental factors to disease pathogenesis.  The IBD microbiome is characterized by decreased bacterial diversity and a disproportionate increase in pro-inflammatory bacteria versus protective bacteria.  Known environmental risk factors are smoking, diet (simple sugars, saturated fatty acids and processed foods) and drugs (antibiotics, non-steroidal anti-inflammatory agents and oral contraceptives).  Protective factors include a high-fiber diet, vaginal delivery, breastfeeding and childhood exposure to pets.  Gut permeability, microbial sensing receptors, anti-bacterial peptides (defensins), resident immune cells and autophagy are integral to innate immunity and help to create a tolerogenic environment.  Adaptive immune response involves differentiation of naïve CD4+ T-lymphocytes resulting in CD (Th1, Th17), UC (Th2) or tranquility (T-regulatory). The lymphocytes’ recruitment to the inflamed gut is mediated by adhesion molecules.4

Recent innovations in IBD include discovery of novel drugs and difference in overall approach toward management. Infliximab (Tumor necrosis factor-alpha [TNF-Image result for picture of alpha greek letter] antibody) was first approved in 1998, and subsequently several other anti TNF-Image result for picture of alpha greek letter agents and newer drugs with novel mechanisms of action have been approved. Examples include vedolizumab (leukocyte trafficking), Ustekinumab (Th17 pathway), and Tofacitinib (JAK 1,3 inhibitor).  Traditional drugs like steroids and azathioprine are being used more judiciously, though mesalamine maintains its status except for CD. 

The “top down approach” is being adopted due to which patients with high-risk phenotypes, like those with growth delay, deep ulcers, fistulae, strictures and perianal disease, are being treated initially with biological agents, rather than waiting after irreversible complications from traditional drugs. In patients with severe colitis, rescue medical and surgical strategies are implemented early rather than prolonging steroid therapy, which can result in greater short and long-term morbidity and complications.  Dietary therapies like enteral nutrition, CD partial elimination diet and specific carbohydrate diet are gaining popularity especially in pediatrics.  Currently, several newer drugs are in various stages of development.  Fecal microbiota transplantation (FMT) is being used for patients with recurrent Clostridium Difficile; however, its role in treatment of IBD is still being explored.

There has been a shift in the overall approach toward management of patients with IBD, with incorporation of quality of care measures, health maintenance, psychosocial health and development of care pathways for standardization of care across different centers.  Shared decision-making with parent partners has helped physicians in delivering tailored care for children. The care has evolved from reactionary treatment for “flares” and complications, to prevention with proactive drug monitoring, utilization of non-invasive biomarkers like calprotectin and lactoferrin, besides just routine clinical and laboratory assessment.  The endpoint of treatment is mucosal healing rather than symptom control, which is associated with decreased risk of cancer, medical and surgical complications.  The concept of “treat-to-target” is gaining momentum, to highlight the focus on follow-up assessment to ensure mucosal healing.  Magnetic resonance imaging and ultrasound are being preferentially utilized rather than traditional ionizing radiation-based assessment.5 

The future for IBD patients looks brighter with a comprehensive care model and personalized medicine using genetics and risk profile assessment to guide therapy at the time of diagnosis, before life-altering, irreversible damage has taken place.

 
 
References: 

  1. Inflammatory Bowel Disease in Children and Adolescents. Rosen MJ, Dhawan A, Saeed SA. JAMA Pediatr. 2015 Nov;169(11):1053-1060.

  2. Current Global Trends in the Incidence of Pediatric-Onset Inflammatory Bowel Disease. Sykora J, Pomahacova R, Kreslova M, et.al. World J Gastroenterol 2018 Jul 7;24(25):2741-2763.

  3. Inflammatory Bowel Disease: What Very Early Onset Disease Teaches Us. Crowley E, Muise A. Gastroenterol Clin North Am. 2018 Dec;47(4):755-772.

  4. Mechanisms of Disease: Inflammatory Bowel Disease. Ramos GP, Papadakis KA. Mayo Clin Proc. 2019 Jan;94(1):155-165.

  5. Improving Care in Pediatric Inflammatory Bowel Disease. Egberg MD, Kappelman MD, Gulati AS. Gastroenterol Clin North Am. 2018 Dec;47(4):909-919.