Managing Crohn's Disease: An Integral Role for the Hospital Pharmacist

Introduction

Irritable bowel disease is a chronic inflammatory disease of the gastrointestinal (GI) tract which encompasses both Crohn’s disease (CD) and ulcerative colitis (UC). The inflammation in CD can spread through as much as the entire GI wall thickness and can extend anywhere along the GI tract from the mouth to the anus.¹ In UC, the inflammation is generally limited to the colon.

The incidence of CD in North America is about 0 to 20.2 per 100,000 people, with prevalence rates ranging from 16.7 to 318.5 per 100,000 annually.^2,3 Studies have shown that CD tends to be more prevalent in urban areas versus rural areas due to greater exposure to the following environmental risk factors: cigarette smoking, microbial exposure, sanitation, pollution, and lifestyle.^2-4 The highest incidences of CD are found in Westernized countries, and these incidences increase between the second and fourth decades of life.^2,3 Currently, there is no cure for CD. The increase in incidence presents an opportunity for pharmacists to understand how best to evaluate and manage this disease through pharmacologic and nonpharmacologic means.

Clinical Manifestations and Classification

CD is classified into 3 categories: mild to moderate, moderate to severe, and severe to life-threatening. Patients with CD may present with a variety of symptoms depending on their disease classification or severity.^3,4 Some may experience times of continuous symptomatic disease, while others may only experience a single incident and be asymptomatic for years.

The most common CD symptoms are abdominal pain and diarrhea.^3,4 Patients may also experience malaise and fever, frequent bowel movements, hematochezia, fistulas, weight loss/malnutrition, and arthritis. Upon further examination, an abdominal mass with tenderness, as well as perianal fissures or fistulas, may be seen.^3,4 In mild to moderate CD, patients usually have no signs of dehydration, weight loss, or abdominal tenderness. In moderate to severe CD, however, patients may present with a fever, weight loss, abdominal pain, vomiting, and significant anemia. Patients with severe to life-threatening CD present with persistent abdominal symptoms, intestinal obstruction, abscesses, and cachexia.^3,4

Patients with CD commonly present with extraintestinal manifestations affecting the muscles, bones, skin, liver, kidney, and pancreas.⁵ Most extraintestinal manifestations will resolve when the underlying CD is appropriately managed.⁵

Diagnosis

Imaging modalities can determine the severity and location of CD in the GI tract.⁶ These modalities include push enteroscopy, capsule endoscopy, computed tomography (CT) scanning, nuclear medicine imaging, and magnetic resonance imaging (MRI). Both push enteroscopy and CT scanning evaluate the whole colon, while MRI enterography can help identify fistulas and stenosis associated with CD. Although very useful in identifying disease progression and severity, these modalities also have associated risks and costs.⁶

Within the past several years, genetic and serologic markers have become useful tools in determining the severity of CD. Genetic factors are constant and present long before the onset of CD, making them valuable in verifying if a patient has the disease.⁷ Three common mutations of the innate immune gene NOD2 (found in the gastrointestinal tract), have been predictive of a more aggressive disease course. Patients with at least 1 of these mutations have a higher risk of having fibrostenosing CD.⁷

Patients with CD have been shown to be positive for the presence of anti— Saccharomyces cerevisiae antibodies.^4,6 Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are used to determine CD severity. The CRP and ESR values, however, are only useful in predicting short-term incidence of relapse.The Crohn’s Disease Activity Index (CDAI) has been used repeatedly in clinical practice to assess a patient’s well-being by quantifying symptoms.⁶ The CDAI includes number of liquid or soft stools each day, abdominal pain, general well-being, presence of complications, taking loperamide or opiates for diarrhea, presence of an abdominal mass, hematocrit of <0.47 in men and <0.42 in women, and percentage deviation from standard weight (in a 7-day period). Although a very subjective tool, the CDAI gives the physician a general idea of how well the patient is doing.⁶

Management

CD can be managed medically or surgically.^8,9 The goals of medical management in a patient with CD are to “approach, initiate, and maintain symptom control, improve quality of life, avoid hospitalizations and surgery, and minimize short- and long-term toxicity and complications.”⁸ Treatment choice depends on the severity, stage, and location of disease, and the extraintestinal complications.^8,9 Medications aid in the induction and maintenance of remission.

For mild to moderate disease, the first-line agents are 5-aminosalicylates (5-ASAs), budesonide, and antibiotics. 9 5-ASA compounds consist of sulfasalazine or mesalamine, a delayedrelease 5-ASA. Mesalamine has an enteric coating, allowing slow release of the drug throughout the GI tract. Usual prescribed dosage range for oral mesalamine is 3.2 to 4 g daily and for oral sulfasalazine is 3 to 6 g per day. Although there has not been much clinical evidence to show the effectiveness of mesalamine over placebo, it is still often used in clinical practice.^8,9 Budesonide, however, at 9 mg daily has shown positive effects in studies compared with placebo and mesalamine.⁸ Controlled-release budesonide is the first-line agent for mild to moderate CD affecting the ileum and/or right colon. 8 Antibiotics have not shown efficacy or long-term benefit despite the hypothesis that bacteria may exacerbate CD.^8,9

In moderate to severe disease, patients are usually started on prednisone 40 to 60 mg a day for about 7 to 28 days until symptoms subside. Most patients using steroids long term become steroid dependent and may be prone to toxicities and side effects.⁸ The main role of corticosteroids for moderate to severe CD should be in the induction of remission. 8 Azathioprine 2 to 3 mg/ kg and 6-mercaptopurine (6-MP) 1.0 to 1.5 mg/ kg have shown benefit, when added to steroids, in maintaining a steroidinduced remission.^8,10

In refractory cases, anti-tumor necrosis factor (TNF) agents and methotrexate can be helpful.¹⁰ Infliximab, an anti-TNF agent, is the most commonly used biologic in CD. Studies with infliximab have demonstrated positive results with non-responders and as such its use in CD is reserved for patients who have failed or not responded to 5-ASAs, corticosteroids, 6-MP, or azathioprine.^8,10 Infliximab is given as a 5 mg/kg IV infusion at weeks 0, 2, and 6 to induce remission and every 8 weeks thereafter for maintenance therapy. Infliximab plus azathioprine was more likely to provide a steroid-free remission than infliximab alone.^11-13

Typically, 50% of these patients relapse after 1 year. Factors such as smoking, disease severity, and blood levels of coagulation factors may contribute.¹³ Adalimumab and cetolizumab pegol, other anti-TNF agents, have shown promising results in active disease.^8,14 Induction of remission and maintenance with 160 mg at week 0, 80 mg at week 2, and 40 mg subcutaneously every other week has been effective.¹⁵

Surgery is a safe and effective option in select patients with CD limited to the terminal ileum or anus.¹⁶ Surgery is often considered when patients fail medical treatment and/or demonstrate serious complications to pharmacologic therapy.^8,17 The goal of surgery is to relieve symptoms and improve quality of life.^8,17,18 The surgical modality employed could be laparoscopic or conventional. Laparoscopic bowel resection has demonstrated more favorable postoperative outcomes compared with a conventional approach.¹⁶ Unfortunately, surgery does not reduce the risk of CD recurrence.⁶ The timing of the surgery is patient-specific and dependent on several factors. Patients should be involved in this important decision process to maximize quality of life.^17,18

Tips for Hospital Pharmacists

Pharmacists can play an integral role in optimizing the management of a patient with CD. Obtaining a medication history and monitoring for signs of long-term side effects or toxicities with corticosteroids, infliximab, and methotrexate is essential. In the patient with a severe allergy, extreme caution is advised in the use of 5-ASA products.¹⁸ Risk factors for methotrexate hepatotoxicity include obesity, diabetes, history of alcohol abuse, elevated liver function tests, and a cumulative total dose of methotrexate of 1.5 g.⁶ If a patient’s transaminase levels exceed 2 to 3 times the upper limit of normal, exercise caution and reevaluate therapy. Infusion-related reactions can occur within 2 hours of infliximab treatment. Premedicating with corticosteroids, acetaminophen, and/or diphenhydramine is effective.⁹

If patients develop an acute infection in the face of biologic-induced immunosuppression, CD therapy must be stopped until the infection is treated. It is also recommended to screen patients for tuberculosis (TB) before initiation of infliximab to prevent activation of latent TB. The pharmacist can recommend stopping therapies when the risks outweigh the benefits or alert the physician of the patient’s response to prior regimens in the face of surgical consideration. 18 In the future, the pharmacist may be able to provide pharmacogenomics consultation as studies increase.⁷

Hana Kim, BS, is a student pharmacist at the University of Maryland Baltimore School of Pharmacy. Peter Kim, BA, is a student pharmacist at the University of Maryland Baltimore School of Pharmacy. Toyin Tofade, MS, PharmD, BCPS, CPCC, is associate director, Experiential Learning Program and associate professor in the Department of Pharmacy Practice and Science, University of Maryland Baltimore School of Pharmacy.

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