Potential Complications of Crohn Disease

Crohn disease is characterized by periods of clinical remission alternating with periods of recurrence. Persistent inflammation can lead to complications that include strictures, fistulas, abscesses, and progressive bowel damage. Extensive or multiple jejunoileal strictures, intestinal obstruction, perforation of the small intestine, large intra-abdominal inflammatory masses, and deeply penetrating fistulas can occur.39,40

Hospitalizations occur in approximately 20% of patients and 50% of patients require surgery within 10 years of diagnosis.41,42 Extensive small bowel disease or multiple surgeries, or both, can result in intestinal failure and short bowel syndrome. Surgery is not curative; clinical recurrence is reported in 50% of patients.42 In addition to disease-specific complications, patients with CD also have an increased risk for intestinal and extraintestinal malignancies.39

Treatment of Crohn Disease

Two different treatment approaches are used in the management of CD. Traditional management involves using a step-up approach where less aggressive drugs are used initially before resorting to more aggressive medications. The second strategy is a top-down or step-down approach where the patient is initially treated aggressively and once remission is achieved the medication doses are decreased or discontinued. The choice of strategy depends on disease severity and response to previous treatment.31 Antibiotics may also be necessary for treating complications such as abscesses and fistulas.43


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The choice of treatment strategy often depends on patient comorbidities, such as diabetes mellitus, and genetic polymorphisms that alter metabolism of certain agents, which limits use of certain agents. For example, the NUDT15 polymorphism can alter hepatic enzyme activity that can inactivate thiopurine metabolites.44,45 Another treatment issue is immunogenicity, which can develop with use of biologic agents. Some patients can develop antibodies to biologic agents that can lead to treatment failure. Investigators have found that concomitant use of an immunomodulator (eg, thiopurine, azathioprine, mercaptopurine, or methotrexate) can mitigate the risk of this development.44,46,47

The most widely used drugs in CD are corticosteroids, immunomodulators (thiopurines [azathioprine and mercaptopurine] and methotrexate), and biologic agents such as anti-TNF-α agents (adalimumab, certolizumab pegol, infliximab), and antiadhesion molecules (vedolizumab or natalizumab).1,39

Corticosteroids

Systemic corticosteroids, budesonide or prednisone, are commonly used to induce remission in CD. However, data does not support their use in the maintenance of remission and they have numerous well-known side effects with long-term use.1,31 Corticosteroids are potent anti-inflammatory agents that broadly attack the immune system and cause immunosuppression. Oral budesonide is considered the preferred agent as it is effective and a relatively safe option for the treatment of mild to moderate CD.26 Budesonide has an extensive first-pass metabolism that results in lower systemic bioavailability and hence fewer systemic adverse effects when compared with prednisone.48

Immunomodulators

Thiopurines (azathioprine, 6-mercaptopurine) and methotrexate are the most commonly use immunomodulators in the management of CD. Immunomodulators are effective for the maintenance of remission but not for short-term induction of remission in patients with active disease because of their slow onset of action. Thiopurines interfere with DNA and RNA synthesis thereby inhibiting the proliferation of T and B lymphocytes.1 

Azathioprine and 6-mercaptopurine are effective steroid-sparing agents in CD and are recommended for use in patients with moderate to severe CD who are symptomatic despite current or prior treatment with corticosteroids and for maintenance of remission.1  

Thiopurines have potential adverse effects with approximately 10% of patients stopping therapy because of the side effects.26 Myelosuppression, pancreatitis, and hepatotoxicity are potential dose-dependent side effects that require discontinuation of thiopurines. More than 10% of patients experience nausea, vomiting, headache, fatigue, anorexia, weakness, rash, weight loss, stomatitis, alopecia, and arthralgia.49

Methotrexate is a folate antagonist that has been used for many years for the management of rheumatoid arthritis and IBD. It has potent anti-inflammatory effects when used weekly in low doses. Methotrexate is also an effective steroid-sparing agent in CD and should be considered for use in alleviating signs and symptoms in patients with steroid-dependent CD and for maintaining remission.1 The agent has similar side effects as thiopurines.1

The potential side effect of nausea can be reduced by use of ondansetron and daily folic acid. The risk for hepatic fibrosis increases if high cumulative doses of methotrexate are used and if the patient has other risk factors such as history of alcohol abuse and nonalcoholic fatty liver disease.50 Methotrexate is teratogenic and an abortifacient; therefore, patients should be educated and counseled about contraception before starting the medication. Concomitant use of NSAIDs has been shown to increase serum methotrexate concentration and associated toxicity.39

Biological Medications

Tumor necrosis factor inhibitors have revolutionized the medical management of IBD.  Adalimumab, certolizumab pegol, and infliximab are TNF inhibitors recommended by the American College of Gastroenterology (ACG) for induction of remission and maintenance therapy in patients with moderately severe CD; to treat corticosteroid-resistant CD; and in patients who are refractory to thiopurines or methotrexate.1 Infliximab used in combination with thiopurines is more effective than either treatment alone in patients who are naive to those agents, according to the ACG guidelines.1 Anti-TNF agents also can be considered to treat severely active CD.

Tumor necrosis factor inhibitors counteract disease activity and lead to mucosal healing. Adalimumab and infliximab are monoclonal antibodies that bind to and inactivate TNF. Certolizumab pegol is a pegylated antigen-binding fragment (Fab) anti-TNF monoclonal antibody.31 Pegylation is the addition of polyethylene glycol (PEG) to prolong the half-life of the medication.51 Tuberculosis testing and evaluation of the patient for infection is necessary prior to the initiation of a TNF inhibitor or any biologic agent.

Except for infliximab, which is administered intravenously, TNF inhibitors can be administered as subcutaneous injections. Tumor necrosis factor inhibitors are effective at inducing and maintaining remission in CD.26

Long-term combination immunosuppressive therapy (corticosteroids, thiopurines, and anti-TNF agents) increases the risk for opportunistic infections and potentially hepatosplenic T-cell lymphoma. Meticulous follow-up of patients for opportunistic infection because of immunosuppression is necessary.26

The monoclonal antibody ustekimumab is recommended for patients with moderate to severe CD who failed previous treatment with corticosteroids, thiopurines, methotrexate, or anti-TNF inhibitors or with no prior exposure to anti-TNF inhibitors.1  

The anti-integrin natalizumab should be considered for use in induction of symptomatic response and remission in patients with active CD. Natalizumab also may be used for maintenance of natalizumab-induced remission in patients with negative serum antibody testing for John Cunningham virus (JCV) because of a risk for progressive multifocal leukoencephalopathy (PML) related to John Cunningham virus (JCV) reactivation.1 Testing for JCV should be repeated every 6 months.1

The anti-integrin vedolizumab should be considered for use with or without immunomodulatory therapy for induction of symptomatic remission in patients with moderately to severely active CD and for maintenance of vedolizumab-induced remission in CD.1  

Guidelines on treating patients with severe/fulminant and perianal/fistulizing CD are provided in the ACG and American Gastroenterological Association guidelines.1,43

Surgery

Surgical interventions for CD include bowel resection, stricturoplasty, and drainage of abscess. One of these interventions is required in up to two-thirds of patients with CD during their lifetime.31 The most common indications for surgical resection include medically refractory disease, bowel perforation, persisting or recurrent obstruction, abdominal abscess not amenable to percutaneous drainage, intractable hemorrhage, dysplasia, and cancer.31

Conclusion

Crohn disease is a chronic IBD that can affect any region of the upper or lower GI tract. Incidence of CD is increasing in the US, Europe, and Asia for unclear reasons. Early anti-inflammatory and immunologic treatment are important for effective management. Monoclonal antibodies are newer biological agents that target specific inflammatory mediators such as TNF-α and integrins. Patients with CD need close monitoring and follow-up as the disease can interfere with many aspects of their life. Primary care providers play key roles in identifying patients with CD, managing this condition, and monitoring patients for potential opportunistic infection, nutritional deficiencies, anemias, and cancer screening in this population.

Theresa Capriotti, DO, MSN, CRNP, RN, is clinical professor at Villanova University M. Louise Fitzpatrick College of Nursing in Villanova, Pennsylvania. Brianna DeVincenzo and Keeva Fay are BSN Honor Students at Villanova University M. Louise Fitzpatrick College of Nursing.

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