Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) refers to a group of chronic and relapsing inflammatory disorders of the gastrointestinal (GI) tract. The two major subtypes of IBD are ulcerative colitis (UC) and Crohn disease (CD). Although the clinical presentation of these two disorders can be similar, they can generally be distinguished based on disease location and histology.

• UC: The inflammation observed is limited to the mucosa, begins in the rectum, and extends, in a contiguous fashion, to involve some or all of the large intestine.

• CD: In contrast, the inflammation can occur in any portion of the GI tract, is often discontinuous, can extend to involve the full thickness of the bowel wall, and is frequently characterized by the presence of non-necrotizing granulomas in tissue biopsies.

For more information on how to distinguish UC and CD and colonic disease that is difficult to differentiate as UC or CD (termed inflammatory bowel disease-undefined or IBD-U), see a clinical report from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn’s and Colitis Foundation Working Group (NASPGHAN/CCF).

Pathogenesis

IBD appears to be polygenic in nature, and more than 200 disease-associated genetic loci have been identified. Although no individual or group of genetic loci have resulted in the development of a unifying mechanism to explain the pathogenesis of IBD, current hypotheses suggest that IBD is a common endpoint resulting from an aberrant interaction between the GI mucosa and luminal commensal bacteria or bacterial by-products. Nonetheless, data from recent studies have demonstrated direct implications of genetic variants in the pathogenesis of IBD. The NOD2 gene, a cytoplasmic toll-like receptor in the mucosa of patients with CD, demonstrates dysfunctional immune surveillance. Other examples include XIAP deficiency, IPEX-like; or interleukin-10 signaling defects.

IBD in children: IBD pathogenesis in patients presenting early in life is generally thought to have a prominent genetic component, whereas the pathogenesis in patients presenting later in life is more likely the result of environmental exposure exerting its influence in a patient with a genetic or epigenetic vulnerability. Read the NASPGHAN position paper on evaluation and management of very-early-onset IBD.

An estimated 20%−30% of patients with IBD are diagnosed before 20 years of age, and the incidence in children appears to be increasing. As such, recognition and consideration of these inflammatory disorders in the differential of patients presenting with compatible symptoms are becoming increasingly important for pediatric primary care clinicians. IBD in children and adolescents is often associated with more-extensive disease and more complications than IBD diagnosed in adulthood.

(Source: Inflammatory Bowel Disease. N Engl J Med 2009.)

Diagnosis

Presenting features of IBD (whether initial diagnosis or acute flare) include the following:

• abdominal pain

• diarrhea

• rectal bleeding

• weight loss, growth failure, and delayed progression through puberty (more common in patients with CD than UC)

• perianal involvement

Extraintestinal manifestations include the following:

• erythema nodosum

• pyoderma gangrenosum

• arthritis

• uveitis

• osteoporosis

• pancreatitis

• primary sclerosing cholangitis

• autoimmune hepatitis

• finger clubbing

• venous thromboembolism

• nephrolithiasis

See an interactive review of extraintestinal manifestations of IBD here.

Laboratory workup should assess for:

• anemia

• thrombocytosis

• hypoalbuminemia

• elevated serum inflammatory markers

• fecal markers of inflammation such as calprotectin and lactoferrin

Note: Normal laboratory results do not rule out the diagnosis of IBD; as many as 20% of patients with IBD have normal labs at diagnosis.

Endoscopy and histology include:

• esophagogastroduodenoscopy (EGD)

• ileocolonoscopy with biopsies

CD and UC have overlapping but distinctive endoscopic features that help in making a particular diagnosis. Click here to view endoscopic images of normal and inflamed gastrointestinal mucosa from pediatric patients with and without inflammatory bowel disease.

• UC: Macroscopic exam reveals continuous disease, beginning in the rectum and largely limited to the colon. Histology is typified by the presence of active neutrophilic inflammation.

• CD: CD can occur in any portion of the GI tract and present in a discontinuous fashion. Although the histology often demonstrates neutrophilic inflammation, mucosal biopsies may contain non-necrotizing granulomas, collections of activated histiocytes.

Imaging enables clinicians to assess for disease in the small bowel, in areas not typically accessible using standard endoscopic techniques. While upper GI and small-bowel fluoroscopy was the initial study of choice for assessing patients with IBD, MRI enterography is now used with increasing frequency, given the superior image quality and lack of ionizing radiation.

• MRI enterography is not associated with any radiation burden and can assess for mucosal disease through contrast enhancement, wall thickening, and abnormal peristalsis. MRI is particularly useful in the assessment of perirectal disease including fistulae.

• CT enterography is useful when immediate information is needed concerning the presence or absence of a complication of IBD, including perforation, abscess, and stricture or obstruction.

• Video capsule endoscopy can also be used to assess for suspicion of CD. It allows visualization of the small bowel, which is difficult to view in a scope, and can show inflammation or ulcerations.

Management

The goals of therapy in the treatment of children and adolescents with IBD are to:

• eliminate symptoms and complications of IBD

• mucosal healing

• improve quality of life

• restore normal growth

Treatment of IBD includes interventions that aim for both the induction of remission of active disease and the maintenance of remission after induction is achieved. Some treatments are used for both of these goals, while others are more appropriate for use in either induction or maintenance.

Therapies used in the treatment of IBD:

• Exclusive enteral nutrition (EEN)

  • EEN is defined as the receipt of 90%-100% of caloric intake from liquid formula.

  • Used for inducing remission in patients with CD, it is not typically as effective in patients with UC.

  • EEN is as effective at inducing clinical remission and better at achieving mucosal healing then oral glucocorticoid therapy.

  • For more information on the use of EEN in pediatrics, see the NASPGHAN guideline.

• Glucocorticoids

  • Glucocorticoids are used for induction of remission in patients with UC or CD.

  • They are not an effective maintenance therapy, and long-term use should be avoided due to acute (i.e., mood changes and weight gain) and chronic (i.e., decreased bone mineralization) adverse effects.

  • If required for more than 6 to 8 weeks, additional treatments should be considered.

• Antibiotics

  • Antibiotics are used for induction of remission (particularly in CD with perianal disease and fistulizing disease).

  • Examples include ciprofloxacin, metronidazole, or rifaximin.

• 5-aminosalicylates

  • 5-aminosalicylates are used for both induction and maintenance therapy for UC.

  • They exert a topical anti-inflammatory effect on the intestinal mucosa and can be administered orally or rectally (as an enema or suppository).

  • Treatment is most effective in patients with mild-to-moderate UC and less effective in patients with CD and severe UC.

• Biologics

  • Biologics can be used for both induction of remission and maintenance therapy.

  • Examples include the tumor necrosis factor-alpha­-inhibitor drugs infliximab and adalimumab, as well as newer biologics, such as certolizumab, vedolizumab, ustekinumab, golimumab, and risankizumab.

  • Read a clinical review of biologics in pediatric IBD.

• Small Molecule Kinase Inhibitors

  • JAK1 and JAK3 inhibitors (e.g., tofacitinib or upadacitinib) are newer medications that are taken orally.

  • They have the advantage of quick onset of action

• Immunomodulators

  • Immunomodulators are used primarily for maintenance therapy. The long onset of action (up to 3 months) makes them less effective for induction therapy.

  • They include thiopurines (azathioprine and its active metabolite 6-mercaptopurine) and methotrexate.

  • Combination therapy refers to the use of a biologic agent in combination with an immunomodulator. Studies have indicated that this approach is more effective than single-drug therapy. For a review of combination therapy in children, see the NASPGHAN guideline on combination therapy in pediatric IBD.

• Surgery

  • In patients with UC, proctocolectomy is curative. However, patients require follow-up and may require treatment for recurrent or chronic pouchitis.

  • In patients with CD, surgical resection is an option for both medically refractory localized disease or to address surgical complications (e.g., perforations or strictures). Although surgery was once only considered appropriate for patients failing therapy, it is now considered as an adjunct to medication for moderate-to-severe CD. However, surgery is not curative in CD, and patients will continue to require biologic or immunomodulator therapy in the postoperative period to prevent disease recurrence, particularly at the site of any surgical anastomosis.

Response to therapy can be evaluated using the Pediatric Ulcerative Colitis Activity Index (PUCAI) or Pediatric Crohn Disease Activity Index (PCDAI).

Complications

Children and adolescents with under-recognized, undertreated, or medically refractory IBD can experience a number of long-term sequelae, including:

• micronutrient deficiencies

  • iron

  • folate

  • vitamin B₁₂

  • vitamin D

• growth failure

• delayed puberty

• osteopenia

• psychosocial dysfunction (see the NASPGHAN guideline on psychosocial issues in pediatric IBD)

• colon cancer