Research agenda for pediatric gastroenterology, hepatology and nutrition: chronic inflammatory bowel disease. Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation.

Abstract

RATIONALE Both Crohn's disease (CD) and ulcerative colitis (UC) occur frequently in the pediatric age group, with a peak incidence in the second decade of life. Approximately 25% of all patients with these disorders are children. These two disorders, commonly grouped together as idiopathic inflammatory bowel disease (IBD), share many similarities in epidemiologic, immunologic, clinical and therapeutic characteristics. Despite intensive research efforts, the etiology of IBD remains unknown, although emerging data implicate genetic susceptibility as a major pathogenetic factor. Available evidence suggests that IBD results from a genetically conditioned susceptibility to immune-mediated bowel injury triggered by one or more environmental factors. Accordingly, basic research in early-onset IBD should focus on the predisposing factors, triggering events and potentiating mechanisms that lead to and sustain the disease. Studies have identified the presence of susceptibility loci for IBD on chromosomes 3, 5, 7, 12 and 16. Linkages on chromosomes 2 and 6 have been associated specifically with UC. Linkages with specific HLA haplotypes have also been reported. UC and CD clearly appear to be polygenic disorders with heterogeneous expression. Therefore, future research will require an understanding of genotype/phenotype relationships, modifier genes that influence onset, disease characteristics including extraintestinal manifestations, and response to therapy. Studies in animal models of IBD support a role for microbial flora in the initiation and propagation of the intestinal inflammatory response. For example, in the interleukin-10 (IL-10) knockout mouse, IBD does not develop in the germ-free state, which indicates that interaction with bacteria is necessary to sustain inflammation. Research is needed to determine whether these reactions, which have a genetic basis, are due to an overexuberant host response to normal flora, to altered flora or to, as yet unidentified, pathogens. Animal models have shed light on a variety of immunologic defects that can predispose to IBD, but it is clear that the complex factors involved require further elucidation. Interestingly, different immunologic defects can lead to similar pathologic findings. For example, genetic alterations in G proteins and E cadherin can lead to IBD, presumably through distinct immune pathways. Understanding the mechanisms by which these and other disparate pathways produce IBD is an important research goal. In this regard, pediatric-onset disease provides an important model. Elucidation of the immune responses predisposing to early-onset disease will enable the design of more specific therapy. Other immunologic events may involve activation of autoreactive T cells, leading to destruction of target intestinal epithelial cells. Accordingly, future research should focus on an enhanced understanding of the mechanisms of autoimmunity and immune tolerance, including the complex network of cytokines involved. Over the years, attempts have been made to implicate specific dietary components as triggers of IBD. Studies have also suggested that altered intestinal permeability is a contributing factor. Concerns about dietary and environmental influences arise from the increasing prevalence of IBD. Future research efforts should focus on possible associations with specific food-processing practices, additives, infant feeding practices and the introduction of genetically altered foods. Although a great deal is known about the characteristics and management of IBD in the pediatric population, important clinical questions remain unanswered. For a comprehensive understanding of pediatric IBD, it is critical to identify epidemiologic trends and correlations, define the economic impact, and better understand treatment outcomes. To accomplish this, an ongoing national data registry is mandatory. Initial support for such a database has been provided by the Crohn's and Colitis Foundation of America, Inc. (CCFA), but strategies for the long-term maintenance of the database need to be developed. Successful tracking of the impact of disease on the health status of children with IBD also depends on the development of validated quality-of-life indices. Management of pediatric IBD has largely been based on studies in adults. Only a few controlled clinical trials have been performed in children and adolescents with IBD. Accordingly, a major thrust of future research must be a comprehensive understanding of the pharmacology and pharmacogenomics of relevance to pediatric IBD. For example, basic pharmacokinetic and efficacy data in children are lacking even for the widely used aminosalicylates. Only limited information is available for other therapeutic modalities currently used to treat children and adolescents with IBD, including antibiotics, immunosuppressives, immunomodulators, probiotics and nutritional therapy. A unique aspect of pediatric IBD is the impact of disease activity on growth and nutritional status. Although uncontrolled disease activity appears to be the major pathogenetic factor for poor growth, the presence of modifier genes affecting stature may also be involved. Nutritional therapy has been associated with restored growth in children with CD, but in most studies, final adult height has not reached predicted levels. Another influence on growth may be the high prevalence of bone mineral abnormalities in children with IBD independent of exposure to corticosteroids. A well-planned and comprehensive research program addressing the basic and clinical questions described in this chapter will significantly improve the ability to diagnose and treat IBD in the pediatric population. At the same time, more extensive knowledge of early-onset IBD may provide important insights into the treatment of adults with IBD. AREAS OF EMPHASIS Elucidate the Genetic Basis of Pediatric IBD Research Goals An important goal is to identify the genes that confer susceptibility to early-onset IBD. In addition to known susceptibility loci, linkages to new genetic loci should be sought. Human homologues to genes known to be linked to IBD in animal models should be identified. For example, more information is needed concerning the region on chromosome 5q31-33 that is associated with CD developing before the age of 16 years. Modifier genes that alter expression of genetic abnormalities warrant elucidation. Genotype-phenotype analysis should focus on the type, location, extent and severity of disease. Studies of sporadic cases should be compared with those of familial cases. Large numbers of sporadic cases should be useful in confirming loci identified from familial linkage studies. Genetic information should be sought that is linked to responses to various treatment approaches. Research Strategies A combination of techniques should be used, including trio analysis, haplotype analysis and single-nucleotide polymorphisms (SNPs). Microarrays and proteomic analyses should also be applied. Pharmacogenomics will be helpful in identifying drug responses in patients of differing genetic profiles, as well as in predicting toxicity. Projected Timetable and Funding Requirements These research questions are of high priority. While the National Institutes of Health (NIH) has instituted a U01 program for Genetics Research Centers for IBD, which includes six centers and a data-coordinating center, additional investigator-initiated research (R01) should be supported. Center grants (P50) and program project grants (P01) are also important, especially as they permit establishment of shared facilities, data and computer cores. Pharmacogenomics may be particularly appropriate for collaboration between NIH and industry. Evaluate the Role of Enteric Microbial Flora in the Pathogenesis of IBD Research Goals The most compelling evidence of a role for resident flora in the intestinal and systemic inflammatory response in IBD comes from studies in animal models. Intestinal inflammation and joint responses are absent in many models in the germ-free state. Goals for the future include identification of the organisms responsible for initiating and propagating the mucosal immune response. A number of classes of bacteria, fungi and viral agents may be involved. Cross-talk between flora and epithelial and immune cells needs to be characterized, and the potential for “molecular mimicry” to trigger autoimmune events should be studied. Studies are need to determine whether host responses in IBD are the result of over-responsiveness to normal flora or a reaction to altered intestinal flora, such as might result from chronic exposure to antibiotics. As yet unidentified pathogens might be involved in pathogenesis, a possibility that could yield novel therapeutic strategies. Studies should focus on: Analysis of normal resident flora Host response to luminal components (bacterial products, toxins, lipopolysaccharides) The types of immune activation triggered by luminal components Signaling by resident flora to the epithelial cell and immune system Research Strategies Important information will be acquired from studies in animal models, but techniques must be developed to search for comparable mechanisms in humans with IBD. Investigators studying these pathways need to work in collaboration with scientists interested in the genetics of IBD. Projected Timetable and Funding Requirements These research questions are particularly amenable to program projects and other collaborative efforts. Investigator-initiated research is appropriate for generating new ideas. Requests for applications (RFAs) to study the role of flora in initiating and propagating pediatric IBD would spur action in this field. Define the Role of the Immune System and the Mucosal Barrier in Early-Onset IBD Research Goals A careful analysis of early-onset IBD is needed to determine whether there are pathologic features distinctive from adult-onset disease. It is critical to further delineate cell-mediated and humoral-mediated immune events as well as the regulatory mechanisms governing epithelial injury. Both clinical trials and studies in animal models are needed to identify markers of autoimmunity and elucidate mechanisms of tolerance. A key research focus is the cytokine-driven intestinal and systemic response that leads to the establishment of pediatric IBD. Another focus is the immune response driven by resident luminal flora, dietary antigens and specific pathogens. Studies to date of intestinal permeability have been inconclusive regarding a primary or secondary role in pathogenesis; careful analysis in humans and in animal models should be initiated. Current research is focusing on: The intestinal response in animal models of mono- and complex bacterial reconstitution Alterations in response to flora in different genetic models The implications for pathogenesis using different background strains of mice Future research should focus on: The early intestinal immune response in animal models, coupled to similar analysis of the human response Identification of potential autoantigens and the associated immune responses Attempts to induce tolerance to reduced intestinal inflammation Research Strategies This is one of the largest areas of current research, involving a number of projects in animal models. Clinical studies must involve large numbers of study subjects, carefully stratified patients and a consistent methodology. Pediatric patients may be uniquely suited to such studies because of a lack of confounding factors, such as use of alcohol, comorbid conditions, long-standing subclinical disease and therapy for concomitant disorders. As specific pathways of immune response are confirmed, novel therapies can be defined based on these data. Projected Timetable and Funding Requirements This field has already generated interest in investigator-initiated research grants. Additional investigator-initiated projects as well as collaborative initiatives such as program projects are appropriate. Study the Role of Dietary, Nutritional and Environmental Factors in the Pathogenesis of Pediatric IBD Research Goals A major goal is the conduct of large population studies evaluating dietary influences on the prevalence and onset of IBD. Recognizing that large databases to date have focused on adults, the prospective acquisition of data may enable the identification of risk factors not previously identified. Such data could also answer specific questions, such as the impact on expression of IBD of food processing, genetically altered food, specific food substances, infant feeding practices and use of antibiotics in childhood. Research Strategies Retrospective reviews of large databases (e.g., the Nurses' Health Study, Physicians' Health Study and Kaiser databases) should be performed for information relating to dietary and nutritional risk factors for IBD. If possible, National Health and Nutrition Examination Survey (NHANES) data should be reviewed for pertinent data. As the large surveys are updated, new questions should be added which will be valuable for identifying factors associated with IBD. The short-term analysis of specific risk factors may be better accomplished by prospective case-control studies. Projected Timetable and Funding Requirements These studies may be funded by individual R01 grants, but collaboration between the principal investigators and managers of the large databases will be required. Supplemental support from organizations such as the Children's Digestive Health and Nutrition Foundation (CDHNF), the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and American Gastroenterological Association (AGA), in the form of seed grants, might be useful in establishing new investigators in this important field. Seed grants from CCFA also might be helpful. Establish A North American Database of Pediatric Patients With IBD Research Goals A pediatric IBD database needs to be established that can be utilized to prospectively characterize disease. The database would contain information on family history, disease expression on presentation, disease characteristics recorded annually, potential predisposing factors, extraintestinal manifestations, treatment course, history of surgery, and outcome. The database can also serve as a reference for investigators studying genetics, drug therapy, health outcomes and the socioeconomic impact of IBD. Research Strategies The Pediatric IBD Consortium, which was established under CCFA pilot support, should be expanded beyond the original centers in Boston, Philadelphia, Atlanta, Chicago, Houston and San Francisco. A mechanism for NIH support should be developed to expand the database to include all 50 states. An important advance will be the involvement of Canadian physicians and pediatric IBD centers in Canada. A focused effort should be made to establish a validated self-reported health status instrument for use in children across the developmental spectrum. In addition, appropriate quality-of-life indices can be developed for children with IBD. Projected Timetable and Funding Requirements Initial funding for a pediatric database has been provided by CCFA, but NIH support is needed to sustain and expand the database. The success of the Cystic Fibrosis Registry and existing cancer registries attests to the value of such investments. Evaluate Therapies and Management Approaches for Pediatric IBD Research Goals Are novel approaches needed for the management of pediatric patients with IBD? The traditional paradigm has been to treat mild disease with “mild” drugs and to intensify therapy as the disease intensifies. This paradigm also assumed that the first drug used (e.g., aminosalicylates) could also serve as maintenance therapy. Alternative treatment paradigms do need to be evaluated, such as suppression of early, mild disease by a potent agent, which is quickly replaced by an effective maintenance treatment. For example, initial therapy with budesonide could be followed by early institution of 6-mercaptopurine. Or short-term use of a potent biologic to “turn off” the active immune response could be accompanied by an equally potent maintenance drug suitable for long-term oral administration. Thus, smoldering disease could be eliminated and outcomes in young adulthood altered. Once the role of enteric flora is better understood, a targeted antibiotic could be used as initial treatment, to be followed by a probiotic. Growth failure persists as a common complication of IBD, particularly CD, and optimal therapy has not yet been defined. Studies are needed to determine the role of nutritional support and the potential of growth hormone, insulin-like growth factor 1 (IGF 1) and pharmacotherapy other than corticosteroids. The concept of control of disease activity at the appropriate time requires further study. Bone mineral status also requires further study. Bone mineral depletion has been reported in pediatric patients with IBD who never received corticosteroids. Optimal approaches for the management of all patients with osteopenia/osteoporosis are needed. Studies evaluating specific therapies are also needed, including the use of 6-mercaptopurine early in the course of treatment; anti-tumor necrosis factor alpha (TNFα) therapy; nutritional therapy (e.g., prebiotics, eicosapentanoic acid/docosahexanoic acid [EPA/DHA]) both for induction and for maintenance; combination therapies; and both preventive and therapeutic interventions for steroid-induced bone mineral loss. Research Strategies The first priority is to understand the pharmacokinetic, pharmacodynamic and pharmacogenomic characteristics in children of commonly used anti-IBD drugs, which were originally evaluated in adult patients. Another priority is the establishment of collaborative controlled clinical trials. These will be facilitated by the large pediatric database described above. Projected Timetable and Funding Requirements Support from a broad range of resources can be explored. Investigator-initiated proposals are appropriate for the study of the pharmacology and pharmacogenomics of specific agents. Support also can come from collaboration between industry and independent investigators. HEALTH AND ECONOMIC OUTCOMES At present, the health care costs associated with pediatric IBD include not only the direct costs of treatment, but also the economic impact on families of expenses not covered by insurance and days missed from work. There is a further impact on society as a whole, as the productivity of entire families can be impaired by these chronic diseases. In addition, pediatric-onset disease may alter the capacity of the child to become a successful and productive adult. Advances in therapeutics for pediatric IBD should therefore yield a significant reduction in both individual and societal costs. The successful accomplishment of these research goals will enable us to better quantify the current and future impact of these diseases.