Inflammatory Bowel Disease in Children and Adolescents: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition

Abstract

I. SUMMARY OF THE PROBLEM Inflammatory bowel disease (IBD) encompasses two related but distinct disorders of as yet unknown cause. Ulcerative colitis (UC) is a chronic, idiopathic, diffuse inflammation of the rectum that frequently may extend continuously over variable lengths of more proximal colon. The inflammation is usually restricted to the mucosa and submucosa. Crohn's disease (CD) is a chronic, idiopathic, transmural inflammation that can affect one or several segments of the digestive tract. The predominant sites of disease are the terminal ileum, colon, and perianal region. The inflammation is often focal with involved areas adjacent to normal areas (skip lesions). In most cases, these two conditions can be distinguished after clinical, endoscopic, histopathologic, and radiologic examinations. The term indeterminate colitis is reserved for cases of colitis in which findings are not sufficient to allow differentiation between Crohn's colitis and UC. Whether these entities represent different disease processes with related phenotypic expressions or a single disease entity with variable phenotypic expression remains to be determined. The first description of UC dates from 1859. The landmark paper by Crohn et al describing a series of patients including a 17-year-old boy dates to 1932, but patients with chronic ileitis had been previously described. The symptoms of IBD are protean, but commonly include intestinal symptoms such as abdominal pain, bloody diarrhea, poor appetite, and weight loss, and at times a wide range of extraintestinal manifestations including fever, arthritis, skin rashes, renal calculi, and hepatobiliary disease, all of which are not significantly different from adults. There are, however, distinct differences in pediatric IBD compared with adult disease, particularly in its impact on growth and its potential to delay puberty. Current opinion regarding the cause of IBD favors the hypothesis that IBD results from an interaction between immunologic, genetic, and environmental factors. A natural model for UC has been described in the cotton top tamarin. Although no natural animal CD model exists, a large number of biologic (e.g., peptidoglycan polysaccharide), chemically induced (e.g., TNBS), and genetically derived (e.g., IL-I0 knockout mice) animal models of CD have been developed. These models offer insights into the immunologic basis of IBD, which in turn have led to advances in the study of human disease. It appears that it some cases CD and UC can be differentiated immunologically on the basis of serologic findings (e.g., pANCA in UC, ASCA in CD) and cytokine profiles. CD typically is characterized by a T lymphocyte helper 1 (Thl) cytokine pattern, in which ILl, IL2, TNFα and interferon-y are predominant. UC tends to be characterized by more of a T lymphocyte helper 2 (Th2) pattern. Although these models have advanced our understanding of the immunology of IBD, the cause of the human disease remains elusive. The role of pathogens as inducers of disease, such as mycobacteria or measles, remains controversial. Genetic factors play an important role, with about 15% of affected individuals having first-degree relatives with disease. However, IBD appears to be a complex, polygenic disorder that cannot be explained by a simple Mendelian model. Current therapeutic goals in children and adolescents seek to induce and maintain clinical and histologic remission and allow children to achieve their full potential for growth, social interaction, and educational attainment. Treatment modalities and clinical responses are similar to those seen in adult patients, although there are important differences in the treatment of pediatric patients. In particular, therapies for children must be designed to promote rather than interfere with growth, sexual development, and bone mineral accretion. These therapeutic requirements have resulted in a number of differences in the treatment of children and adolescents compared with adults, such as the increased use of nutritional interventions and the earlier use of immunomodulators. II. MAJOR ISSUES IN NEED OF INVESTIGATION OR IMPLEMENTATION Epidemiology The relatively few epidemiologic studies of IBD in the pediatric and adolescent age-groups have largely focused on the incidence, prevalence, and clinical features of IBD and how these features differ based on geographic location, demographic influences, ethnicity, and over time (1). The reported incidence of pediatric and adolescent IBD varies from 2.2 to 6.8 per 100,000, but there are significant differences between continents, within countries, and in particular areas over time (2,3). Although explanations for the variations in disease incidence have not been fully determined, a number of environmental factors such as hygiene, diet, breast feeding, smoking, the contraceptive pill, and infectious agents such as measles, mumps, Epstein-Barr virus, and Mycobacterium paratuberculosis have been explored (3,4). In adult patients, cigarette smoking is the factor most consistently demonstrated to be associated with the development of IBD. Smoking appears to predispose to CD and protect against the development of UC. By contrast, ex-smokers appear to have an enhanced risk of developing UC. The only pediatric study to examine the influence of passive smoking was a case control study, where passive smoking exposure at birth, and to a lesser extent at diagnosis, was associated with an increased risk of developing both forms of IBD (CD more than UC)(2). Interestingly, in contrast to the adult literature investigating personal smoking history, passive smoking was not protective against the development of UC. Other controversial data suggest that the early measles infection may be important in the development of a granulomatous vasculitis and CD. Epidemiologic studies require population-based data. Focusing studies on children potentially has great advantages compared with studying adults, as many confounding variables (such as smoking and the use of birth control pills) are much less prevalent in the pediatric population. The following represents the major epidemiologic issues that need to be addressed: Population-based databases from all parts of the world should be developed to determine and track IBD incidence and prevalence rates, disease behavior, and effect of therapy. Identifying areas of increased or rapidly changing incidence should allow more focused investigation of possible environmental and genetic factors. Prospective, standardized, and regularly updated databases should include health histories of first-degree and more distant relatives focusing specifically on whether any also have IBD. Complete descriptions of IBD phenotype in these relatives, as well as data on associated illnesses such as autoimmune disease and malignancy, should be compiled. Databases should be designed to identify potential risk factors for developing IBD and its complications. They should also seek to identify which factors influence the course of IBD. The data collected could be used to develop large case-controlled studies. Early immunologic influences such as infectious history, tonsillectomy, appendectomy, antibiotic usage, vaccination, diet, and atopy need to be examined further. As infectious agent(s) may be directly pathogenic, or may trigger an immunologically mediated and perpetuated response, there is a need for population-based studies to determine the role of suspected microorganisms in the pathogenesis of IBD. The organism(s) may be ubiquitous or even a part of the normal flora. Studies evaluating differences in the bowel flora between IBD and controls are needed. Similarly, evaluation of the functional aspects of the bowel flora, within IBD patient groups and clinical subgroups, should be undertaken. Such studies should include examination of the epidemiology of Mycobacterium paratuberculosis and measles and its association with CD. Genetics The importance of genetic susceptibility to IBD is evident from twin and family studies (5,6). Among 80 Swedish twin pairs, the concordance rate for CD was 58.3% in monozygotic twin pairs but only 6.3% for UC. In dizygotic twin pairs, most were discordant for IBD (96% for CD and 100% for UC). The increase in IBD prevalence among siblings is 10- to 15-fold compared with the general population. This sibling risk is much higher than is seen in other complex genetic illnesses such as diabetes mellitus, schizophrenia, and asthma. The lifetime risk for developing IBD for first-degree relatives of IBD patients is estimated at 7.8% in patients of Jewish ancestry and 5.25% in non-Jews. For CD, the risk is 16.8% for siblings of CD patients in Jewish families. Particularly high risks of susceptibility occur in children when both parents have IBD. It is increasingly evident that IBD represents one or more complex genetic diseases. This has led to an increasingly sophisticated search for the genes responsible for the development and evolution of both CD and UC. Genetic Anticipation The question of whether true genetic anticipation is present in IBD needs to be more clearly elucidated, as current studies are often in conflict. In one study of two-generation pedigrees with CD, affected individuals from the second generation were often younger at diagnosis than were their parents. However, once it is recognized that IBD is “in the family,” children in the next generation may be rapidly brought for consultation with the express desire to “rule out IBD.” This “first ascertainment bias” can influence the age at which CD is diagnosed, resulting in the appearance of genetic anticipation when there is none. Recent European studies provide evidence that this may be the case (7). Gene Linkage Studies Initially, investigations involving genes and IBD focused on the major histocompatibility complex (MHC) because of its role in immune function. In California, associations were found between HLA-DR2 and UC and the combination ofDR1 and Dqw5 and CD. However, the association of HLA-DR2 and UC was not confirmed in Pittsburgh. In England, linkage was found between DRB 1 (but not DR2) and UC but no association with CD was evident. By contrast, in Japan, an HLA-linked Crohn's disease susceptibility gene was associated primarily with DQB 1 *04. These studies illustrate the important ethnic differences that can influence genetic studies. Subsequently, gene associations have been sought through linkage studies and genome-wide searches. This method led to the identification of the CD susceptibility locus, IBD 1, on chromosome 16 and to a second putative locus, IBD2, associated with both CD and UC on chromosome 12 (8,9). However, the association with chromosome 12 was not confirmed in the United States (using genome-wide screening) or in Canada (using selected microsatellite markers). Additional loci have been suggested on chromosomes 1, 3, 4, and 7 as well as a link between the X chromosome and UC. However, these associations are not universally confirmed when new populations are studied, demonstrating the polygenic nature of IBD and the importance of ethnic differences. These studies provide evidence that non-MHC genes are important susceptibility genes for IBD that need to be identified and their gene products and functions characterized. Candidate Gene Studies In contrast to genome-wide searches, directed studies of non-HLA genes important in the function of the immune system have been initiated. In particular, cytokine gene polymorphisms are being investigated. A TNFα has been associated with and appears to represent a risk factor for CD. have the role of different of an of the gene and the 1 gene Other genes important in the development and function of the immune system such as the 3, and the all of which are on chromosome 16 of the putative susceptibility may be important The study of genes represents a for The interaction between these genetic and potential environmental may one our patients are to developing IBD. Studies and studies the of affected pedigrees for gene linkage studies to potential IBD susceptibility patients with and may provide an enhanced for gene linkage associations are higher in pedigrees when an affected is in the of different genetic between and within ethnic groups within a must also be investigated. that ethnic groups (such as have a particularly high prevalence of IBD the importance of of patients. IBD susceptibility genes different of association on genes on chromosome and are associated with IBD in linkage on and 16 is more commonly with These particular associations have however, been evident in other studies. of the among studies may be explained by ethnic in for to of in Jewish and populations but in patients in and in for of studies are to concordance and between and ethnic groups within one studies concordance within for and (e.g., or of CD. with more than two affected enhanced concordance for disease and compared with those with only two genes in affected should a particularly method of These studies require clinical of patients. should be compared with large populations of patients with disease. of These have also been with genetic For the association of and UC is among patients with extraintestinal manifestations such as arthritis, and studies are to determine which susceptibility or or in are responsible for the manifestations of CD and UC. of with and to associations are the influence of genetic differences on to can be Linkage between the and UC has been Although this not with the need for it was suggested that genes may influence the course of UC. 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