Pediatric Annals

Inflammatory Bowel Diseases

Ari Silbermintz, MD; James Markowitz, MD

Abstract

The inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis (UC), are chronic disorders of the gastrointestinal tract affecting children and adults. Advances in genetics and basic immunology are providing new insights into the possible pathogenesis of these conditions. These insights are leading to improvements in the care of children and an explosion of investigational therapies. Developments in the diagnosis and management of Crohn's disease and ulcerative colitis in children are discussed in this article.

EPIDEMIOLOGY

The incidence of Crohn's disease in Western populations among all age groups, including pediatrics, has increased during the past few decades. The peak incidence of Crohn's disease occurs in late adolescence, with a second smaller peak noted in the sixth decade. On the other hand, the incidence of UC has remained fairly stable.

A recent population-based assessment from Wisconsin provides new epidemiological evidence drawn from a pediatric inception cohort. In contrast to earlier studies that suggested IBD typically affects Caucasians (especially Ashkenazi Jews) more than those of Asian or African descent, the Wisconsin study reveals an equal distribution of IBD among all racial and ethnic groups.1'2 This study also did not demonstrate a higher risk for developing IBD in urban populations, as had been suggested in earlier studies.

ETIOLOGY

Despite recent advances in understanding the immunology and genetics of IBD, the etiology of UC and Crohn's disease remains unclear. However, numerous animal models suggest that abnormalities in an array of different genes that control various aspects of immune function, coupled with exposure of the intestine to luminal bacteria or chemical insults, result in the development of chronic intestinal inflammation. It is therefore hypothesized that a triggering event, possibly a bacterial infection or another immune stimulus, in a genetically predisposed person results in human IBD. Research during the past few years has suggested that, in Crohn's disease, the chronic immune process is predominantly cellmediated and characterized by a T helper 1 (ThI) cytokine profile, while in UC the response is more humoral and mediated by T helper 2 (Th2) cells. However, more recent observations have identified significant overlap in the immune abnormalities of these two forms of IBD, suggesting that the above paradigm is too simplistic.

A gene on chromosome 16 (EBDl), now known to be the NOD2/CARD15 gene, was the first Crohn's disease susceptibility gene to be identified.3'4 A component of the innate immune system, the NOD2/CARD15 gene appears to serve as an intracellular receptor for muramyl dipeptide, a component of lipopolysaccharide (the cell wall substance of gram-negatives). As such, the gene is important in regulating the gut's response to luminal bacteria. The presence of two variant alleles increases the risk of developing Crohn's disease in Caucasian populations 20 to 40 times, while the risk in a heterozygote carrier is only 2 to 4 times greater than those with wild type alleles. However, only 15% to 40% of patients with Crohn's disease carry polymorphisms of NOD2/CARD15, and it is estimated that the penetrance of disease in homozygous carriers of variant alleles is less than 2%.5

The presence of NOD2/CARD15 polymorphisms does appear to predispose patients to the onset of disease early in life; 40% of pediatric patients with Crohn's disease in the United States carry one or more allelic variants.6'7 NOD2/ CARD 15 variants are consistently associated with ileal involvement. A pediatric study suggests that, in addition, certain variant alleles predispose to a stricturing phenotype and the early need for surgery.7 Other chromosomal linkages associated with Crohn's disease have now been identified, including regions on chromosome 5 (IBD5) and chromosome 6 (IBD3). Studies to determine the roles of these and other genes in the…

The inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis (UC), are chronic disorders of the gastrointestinal tract affecting children and adults. Advances in genetics and basic immunology are providing new insights into the possible pathogenesis of these conditions. These insights are leading to improvements in the care of children and an explosion of investigational therapies. Developments in the diagnosis and management of Crohn's disease and ulcerative colitis in children are discussed in this article.

EPIDEMIOLOGY

The incidence of Crohn's disease in Western populations among all age groups, including pediatrics, has increased during the past few decades. The peak incidence of Crohn's disease occurs in late adolescence, with a second smaller peak noted in the sixth decade. On the other hand, the incidence of UC has remained fairly stable.

A recent population-based assessment from Wisconsin provides new epidemiological evidence drawn from a pediatric inception cohort. In contrast to earlier studies that suggested IBD typically affects Caucasians (especially Ashkenazi Jews) more than those of Asian or African descent, the Wisconsin study reveals an equal distribution of IBD among all racial and ethnic groups.1'2 This study also did not demonstrate a higher risk for developing IBD in urban populations, as had been suggested in earlier studies.

ETIOLOGY

Despite recent advances in understanding the immunology and genetics of IBD, the etiology of UC and Crohn's disease remains unclear. However, numerous animal models suggest that abnormalities in an array of different genes that control various aspects of immune function, coupled with exposure of the intestine to luminal bacteria or chemical insults, result in the development of chronic intestinal inflammation. It is therefore hypothesized that a triggering event, possibly a bacterial infection or another immune stimulus, in a genetically predisposed person results in human IBD. Research during the past few years has suggested that, in Crohn's disease, the chronic immune process is predominantly cellmediated and characterized by a T helper 1 (ThI) cytokine profile, while in UC the response is more humoral and mediated by T helper 2 (Th2) cells. However, more recent observations have identified significant overlap in the immune abnormalities of these two forms of IBD, suggesting that the above paradigm is too simplistic.

A gene on chromosome 16 (EBDl), now known to be the NOD2/CARD15 gene, was the first Crohn's disease susceptibility gene to be identified.3'4 A component of the innate immune system, the NOD2/CARD15 gene appears to serve as an intracellular receptor for muramyl dipeptide, a component of lipopolysaccharide (the cell wall substance of gram-negatives). As such, the gene is important in regulating the gut's response to luminal bacteria. The presence of two variant alleles increases the risk of developing Crohn's disease in Caucasian populations 20 to 40 times, while the risk in a heterozygote carrier is only 2 to 4 times greater than those with wild type alleles. However, only 15% to 40% of patients with Crohn's disease carry polymorphisms of NOD2/CARD15, and it is estimated that the penetrance of disease in homozygous carriers of variant alleles is less than 2%.5

The presence of NOD2/CARD15 polymorphisms does appear to predispose patients to the onset of disease early in life; 40% of pediatric patients with Crohn's disease in the United States carry one or more allelic variants.6'7 NOD2/ CARD 15 variants are consistently associated with ileal involvement. A pediatric study suggests that, in addition, certain variant alleles predispose to a stricturing phenotype and the early need for surgery.7 Other chromosomal linkages associated with Crohn's disease have now been identified, including regions on chromosome 5 (IBD5) and chromosome 6 (IBD3). Studies to determine the roles of these and other genes in the susceptibility to and phenotypic expression of Crohn's disease are ongoing.8'9

The influence of genetics in UC appears to be smaller than in Crohn's disease. Several studies have shown that there is a lower rate of EBD in family members of patients with UC than in those with Crohn's disease. However, identification of defects in a number of genes involved in the control of the immune system support the idea that UC also can be caused by a defect in immune regulation. An association between UC and HLA alleles has been demonstrated, as has a polymorphism in the TNF-ot gene.10 In addition, a polymorphism in the multidrug resistance 1 gene (MDRl) has been associated with UC.11 The MDRl polymorphism has been associated with decreased production of P-glycoprotein (a barrier to microbial infection of the intestine), and a MDRl knockout mouse model spontaneously develops colitis.

Environmental factors also seem to play a role in the development of EBD. Breastfeeding decreases the risk of developing Crohn's disease, while infantile diarrhea seems to increase the risk.12"14 Cigarette smoking appears to be a risk factor for Crohn's disease. While it had been thought that cigarette smoking is protective against UC, this has been questioned recently.1215,16

PATHOLOGY

Crohn's disease can involve any area of the GI tract. Ileocolonic involvement is most frequent, followed by terminal ileum, colon only, and small bowel (jejunum or proximal ileum) involvement. In addition, endoscopic evidence of inflammation has been noted on upper endoscopy in as many as 40% of patients. In Crohn's disease, the transmural nature of the inflammatory process may lead to stricture formation, matting together of loops of bowel, fistulae, and intraabdominal abscess formation.

Ulcerative colitis generally is considered a disease confined to the mucosal surface of the colon, although esophageal and gastroduodenal inflammation have been recognized endoscopically and histologically.17,18 As opposed to adult patients, in whom proctitis is the most common extent of disease, in children with UC, it has been estimated that 41% have pancolitis, 34% have leftsided disease, and 26% have proctitis or proctosigmoiditis.19 In a more recent study, 90% of pediatric patients had pancolitis at diagnosis.2

CLINICAL FEATURES

The symptoms of Crohn's disease can appear acutely or insidiously (Sidebar 1, see page 270). Typically, the most common symptoms are abdominal pain, diarrhea, decrease in appetite, and weight loss. In patients with disease involving the terminal ileum, the pain commonly is located in the right lower quadrant, often associated with tenderness and fullness in the region. In patients with Crohn's colitis, the pain may be located in the periumbilical area as well as the lower abdomen. Patients with left-sided colitis often present with bloody diarrhea and tenesmus, while patients with right-sided colitis can have nonbloody diarrhea. In cases of small bowel disease, diarrhea can be absent.

Perianal disease, including skin tags, fistulae, and abscesses, can accompany other symptoms or may be the sole presenting feature. Fever, anorexia, weight loss, growth delay, and delayed sexual development are seen commonly, and each may be the presenting symptom of Crohn's disease in the absence of GI complaints. Laboratory findings may include leukocytosis, anemia, thrombocytosis, hypoalbuminemia, and elevated acute phase reactants, including erythrocyte sedimentation rate and C-reactive protein.

Children with UC usually present with diarrhea, rectal bleeding, and abdominal pain, often associated with tenesmus and urgency (Sidebar 1). Loose stools can contain streaks of blood or clots. Mild disease activity, present in about 50% of children at disease onset, presents with fewer than four stools per day, intermittent hematochezia, and few or no systemic symptoms. These children often have normal physical examinations. Laboratory findings can be normal or may reveal mild anemia and elevated acute phase reactants.

Moderate disease activity, seen in about a third of pediatric patients, presents with more frequent stools accompanied by systemic symptoms and weight loss. Physical examination usually reveals more prominent abdominal tenderness, and laboratory findings often include a moderate leukocytosis with an associated mild anemia and elevated acute phase reactants. Severe disease, seen in 10% to 15% of patients, presents with fever, severe crampy abdominal pain, and frequent diarrheal stools that can be accompanied by large amounts of rectal bleeding. Physical examination reveals a diffusely tender distended abdomen often accompanied by tachycardia. Laboratory findings include leukocytosis often with a significant left shift, anemia, elevated acute phase reactants, and hypoalbuminemia. Toxic megacolon, rare in pediatrics, is the most dangerous form of severe colitis.

Extraintestinal manifestations of UC and Crohn's disease can accompany gastrointestinal disease or can present before the development of GI complaints. Arthralgia (common) and nondeforming arthritis (much less common) often are associated with periods of increased bowel disease activity. Erythema nodosum and pyoderma gangrenosum are also seen. Poor linear growth is present in up to 40% of children with Crohn's disease, but in only 10% of children with UC.20·21 The etiology for poor growth is multifactorial, due to a combination of decreased caloric intake, the chronic inflammatory process, and the use of corticosteroids. Other extraintestinal manifestations include uveitis, episcleritis, sclerosing cholangitis, autoimmune hepatitis, venous thrombosis, iron deficiency anemia, nephrolithiasis, and pneumonitis.

Patients with colitis (both UC and Crohn's) have an increased lifetime risk of developing colorectal cancer. The most significant risk factors include increasing extent and duration of disease, factors that put children with EBD at great lifetime risk. This risk is increased further in patients with associated primary sclerosing cholangitis. Because of the significant risk, surveillance colonoscopy, often beginning 7 years after diagnosis, is necessary.

DIAGNOSIS

Diagnosis begins with a thorough history directed at identifying the sometimes subtle signs and symptoms of IBD. The presence of abdominal pain, its location and quality, and the occurrence of nocturnal pain should be clarified. The consistency and frequency of bowel movements and the presence of blood in the stools need to be elicited. Review of growth charts to identify weight loss or poor linear growth is an integral part of the evaluation.

Physical examination findings can vary based on the location and severity of disease. The general physical and nutritional status of the patient should be assessed. The examination should look for the presence of abdominal tenderness, distention, fullness, or mass. The mouth, skin, and joints should be inspected for findings associated with EBD. The perianal area should be inspected for tags, fissures, fistulae, or abscesses, as identification of these lesions greatly increases the likelihood of identifying Crohn's disease. Finally, assessment of pubertal status to identify possible delayed sexual development must be included in the examination.

Laboratory findings can include anemia, leukocytosis, thrombocytosis, hypoalbuminemia, and an elevated erythrocyte sedimentation rate. Elevated liver-associated tests may indicate the presence of primary sclerosing cholangitis or autoimmune hepatitis. Stool studies for enteric bacterial pathogens, Clostridium difficile toxins, and parasites such as giardia should be obtained to rule out an infectious etiology. Serologic tests such as perinuclear antineutrophü cytoplasmic antibody (pANCA), anti-Saccharomyces cerevisiae antibody (ASCA), and antiouter membrane porin of Escherichia coli (ompC) are at times helpful in differentiating a child with IBD from one with functional complaints. A positive pANCA is found in about 60% of children with UC and much less commonly (approximately 10%) in Crohn's disease. ASCA or ompC are found in up to 60% of children with Crohn's disease. These serologic assays therefore have poor sensitivities but good specificities and positive predictive values.22

An upper GI series with small bowel follow through assists in assessing the existence, location, and extent of disease in patients with Crohn's disease. Computed tomography and ultrasound also may be used to identify bowel wall inflammation or intra-abdominal abscesses.

Upper endoscopy and colonoscopy with biopsies are an integral part of the evaluation of IBD. Colonoscopy can define the extent of the colitis, the existence of skip lesions, and the existence of terminal ileal disease. At colonoscopy, UC shows continuous involvement, usually from the rectum extending proximally, with no involvement of the terminal ileum except for mild backwash ileitis in cases of pancolitis. The mucosal findings include the loss of vascular markings, diffuse erythema, and mucosal granularity. In Crohn's disease, rectal sparing, skip areas, aphthous ulcers, and terminal ileal inflammation can be noted, although at times the endoscopic findings in severe Crohn's colitis can mimic those of UC. In both conditions, biopsies demonstrate evidence of chronic inflammation - diffuse in UC, patchy in Crohn's. In addition, noncaseating granulomas can be found in up to 30% of cases of Crohn's disease. Wireless capsule endoscopy is a relatively new technology that allows for the visualization, but not biopsy, of the mucosal lining of the entire small bowel. In selected cases, capsule endoscopy has been used successfully in the evaluation of EBD in children and can identify subtle lesions not apparent on more traditional diagnostic modalities.23 Indications for the use of capsule endoscopy in the evaluation of IBD are evolving.

TREATMENT

The goal of any treatment regimen is first to induce remission of acute symptoms and then to maintain remission over time (Sidebar 2). When determining the appropriate treatment for a patient, one takes into account the extent, location, and severity of disease, as well as the potential side effects of any medication.

5-Aminosalicylates (5-ASAs)

5-ASAs are effective in the induction and maintenance of remission in mild to moderate UC. The first agent of this class that was used in IBD, sulfasalazine, is associated with a relatively high rate of side effects. Therefore, other agents of this class, such as mesalamine, olsalazine and balsalazide, are preferred. Suppository and enema preparations of mesalamine are efficacious in the treatment of left sided colitis. 5-ASAs can be used to induce remission in mild Crohn's disease, but they are not effective in moderate to severe disease. 5-ASAs are no longer considered effective in maintaining remission in Crohn's disease.

Corticosteroids

Corticosteroids are indicated as induction therapy in patients with moderate to severe UC and Crohn's disease. In patients with severe disease or in those who do not respond to oral therapy, intravenous therapy is used.

The use of steroids must be weighed against the potential side effects. Budesonide, a synthetic corticosteroid, is designed for controlled release in the ileum and is therefore indicated for ileal and right-sided colonic disease. It has fewer steroid-associated side effects than the older agents such as prednisone because of rapid first-pass metabolism. Rectal steroid therapy, delivered as enemas and foam-based preparations, are used for both induction and maintenance therapy in left-sided colitis.

In general, however, corticosteroids are not good maintenance therapies. Their toxicities and the frequent development of corticosteroid dependence preclude their long-term use.

Immunomodulators

Immunomodulators, such as 6-mercaptopurine (6-MP) and azathioprine, are used increasingly in children with IBD. These medications have been shown in double-blind, placebo-controlled trials in both adults and children to be efficacious in inducing and maintaining remission in IBD patients who are steroid resistant or dependent and in treating chronic draining fistulae.24·25 Methotrexate also has been shown to be useful in inducing and maintaining remission in patients with Crohn's disease unresponsive to standard therapies.26 Methotrexate's efficacy in UC has not been as well demonstrated as in Crohn's disease.

Cyclosporine and tacrolimus have both been shown to be effective in treating severe steroid-resistant attacks of UC.27'28 However, the response has been shown to be transient without the addition of 6-MP or azathioprine, and toxicity associated with these treatments often limits the usefulness of these agents.29

Biological Therapy

Infliximab is a chimeric human-murine monoclonal antibody to TNF-alpha that is administered intravenously. In Crohn's disease, infliximab is approved for inducing and maintaining remission in adult patients with moderate to severe disease that have not responded sufficiently to conventional therapy.30'31 Numerous open-label pediatric clinical experiences and a recently completed multicenter pediatric trial (the REACH trial, presented at the 2005 annual meeting of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition) document that children respond in a similar fashion to adults. In addition, infliximab is approved for the treatment of fistulae in patients with Crohn's disease. Certain systemic manifestations of IBD, such as ankylosing spondylitis, pyoderma gangrenosum, and chronic uveitis, also are responsive to infliximab.

Recent adult trials have demonstrated the efficacy of infliximab in UC that was unresponsive to steroids, and the Food and Drug Administration recently granted a new indication for the use of infliximab for the treatment of UC.32 Many patients receiving infliximab relapse if not retreated, and therefore long-term maintenance therapy with infliximab every 8 weeks may be required. Patients generally require concurrent treatment with immunomodulators such as 6-MP or methotrexate to avoid the development of antibodies to infliximab, which often is associated with infusion reactions and subsequent loss of efficacy.

Newer biologic agents are under development. These include a variety of novel technologies including monoclonal antibodies, receptor antagonists, and antisense molecules. Targets for therapy include TNF and other inflammatory cytokines, adhesion molecules, and a variety of intracellular mediators.

Antibiotics

Antibiotics such as metronidazole and ciprofloxacin have been used successfully in the treatment of perianal disease and mild to moderate Crohn's colitis.33,34 However, antibiotics have not demonstrated significant efficacy in the treatment of UC and therefore play little role in its treatment.

Surgery

UC is curable surgically with a total mucosal proctocolectomy. The ileal pouch-anal anastomosis is the most commonly performed restorative surgery. Indications for surgery in UC include failure of medical therapy, persistent hemorrhage requiring transfusions, dysplasia, and carcinoma. Pouchitis, an inflammation of the surgically created pouch, is the most common late complication of this procedure and has been reported in up to 50% of cases.35'36 Metronidazole and ciprofloxacin are effective in treating pouchitis. Other therapies used include 5 -ASA and steroids. VSL3, a probiotic, has been shown to be effective in the prevention of pouchitis.37

Surgery often is required in the treatment of Crohn's disease for indications such as failure of medical therapy, obstruction, intra-abdominal abscess, and fistulae. However, unlike in UC, surgery in Crohn's disease is not curative, and eventual relapse is common.

SUMMARY

The inflammatory bowel diseases remain at the forefront of clinical investigation. Immunologic and genetic advances are fueling an explosion of novel diagnostic and therapeutic modalities. With further breakthroughs, there is hope that in the near future, these illnesses will no longer be considered either idiopathic or chronic.

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10.3928/0090-4481-20060401-11

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