Management of Inflammatory Bowel Disease

Abdullah Assiri, PharmD, and Paul Dombrower, RPh
Published Online: Tuesday, July 15, 2014
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An Effective Treatment Plan Is Crucial for Patients with Crohn’s Disease and Ulcerative Colitis.
Background
Inflammatory bowel disease (IBD) is an idiopathic disease that comprises 2 major disorders: ulcerative colitis (UC) and Crohn’s disease (CD).1,2 IBD epidemiology has been evaluated by several studies in several geographic areas. The incidence and prevalence of both disorders are higher in North America than other areas such as Asia and the Middle East.3 The incidence and prevalence rate for UC was about 2.2 to 14.3 cases per 100,000 person-years, and 37 to 246 cases per 100,000 persons, respectively, and about 3.1 to 14.6 cases per 100,000 person-years, and 26 to 199 cases per 100,000 persons for CD.

IBD does not have any known etiology.1 It is thought to be a result of abnormal luminal flora activity that leads to inappropriate mucosal immune system activation, genetic predisposition that significantly contributes to the development of the disease, or environmental or antigenic factors.

Crohn’s Disease
Crohn’s disease generally affects any region of the gastrointestinal tract from the mouth to the anus, though it is more often involved in the small intestine.4 CD usually presents itself through fever, abdominal pain, weight loss, and bloody or non-bloody diarrhea. Around half of CD patients are diagnosed with extraintestinal manifestations such as arthritis, uveitis, and erythema. In CD, many proinflammatory cytokines are released in response to immune system dysregulation. These cytokines play an important role in the development of the disease.4,5 Most of the identifiable cytokines are derived from type-1 T-helper cells that include interferona and TNF-a IL-1, IL-6, and IL-12. These cytokines activate macrophages and increase the matrix metalloproteinase production in mucosal cells. The distribution of disease with CD is different than that of UC as the most affected area is the terminal ileum and colon; around 20% of patients have isolated colonic involvement. It is uncommon to see CD patients without small or large intestinal disease involvement.

The patient’s medical history and clinical examinations (including endoscopic, radiologic, serological, and histologic findings) are crucial to the diagnosis of CD.4,5 CD and UC are very similar in their symptoms, thus 10% to 15% of patients with IBD cannot be further diagnosed with CD or UC. However, it is very important for clinicians to diagnose the patient correctly with either CD or UC so that the right treatment plan can be chosen.

Ulcerative Colitis
Ulcerative colitis is another form of inflammatory bowel disease.2 Ulcerative colitis affects the intestinal mucosa, where inflammation starts in the rectum and can extend to the proximal colon and could possibly affect the entire large intestine. One important difference between CD and UC is that the rectum is always involved in UC. It is not enough to diagnose the patient with UC without defining the extent and severity of inflammation. Determining the severity of the disease helps the clinician select the appropriate treatment plan and allows for a more accurate prognosis.

Complications of IBD
Intestinal complications1:
  • Hemorrhage
  • Fistulas
  • Toxic megacolon
  • Perianal or pelvic abscesses
  • Malignancy

Extraintestinal complications6:
  • Osteoporosis
  • Gallstones
  • Anemia
  • Hypercoagulability resulting in venous thromboembolism
  • Primary sclerosing cholangitis
  • Iritis (uveitis) and episcleritis
  • Aphthous ulcers
  • Skin complications

Management
Treatment goal1:
  • Alleviate signs and symptoms
  • Suppress the inflammation during acute illness and induce remission
  • Maintain remission and prevent complications
  • Prevent treatment-associated adverse effects
  • Minimize surgical intervention and hospitalization

Pharmacological Therapy
The management of IBD has been focused on the relief of signs and symptoms while optimizing therapy until the desired response is achieved.1,7-9 This approach is called the conventional approach; therapy is intensified as the disease worsens. It is focused on inducing remission of the disease, followed by withdrawal therapy once a cure is achieved (Table 1). With the advent of biological treatments, the medical approach has been shifted from symptomatic care to mucosal healings. However, clinicians are still hesitant to start therapy with these agents due to their significant cost and safety profiles. Table 2 summarizes the medical approach for both CD and UC.1,7-11

Aminosalicylates
Aminosalicylate derivatives are commonly used for inducing and maintaining remission of inflammatory bowel disease.1,9 They are most effective in treating mild to moderate UC while their efficacy in CD is still not proven. They are available in different several formulations (eg, Azulfidine, Asacol, Delzicol, Asacol HD, Pentasa, Dipentum, Colazal, Apriso, Lialda) that target various gastrointestinal tract areas (Online Table 3). The side effect profile for aminosalicylates varies between the agents. Common drug-related adverse effects include nausea, vomiting, dyspepsia, and fatigue.

Table 3: Aminosalicylates for Inflammatory Bowel Disease Management
Drug Formulation Site of Action Side Effects12 Monitoring Parameter12
sulfasalazine
(2 to 6 g per day)
Immediate-release tablet
Enteric coated tablet
Colon Abdominal pain, loss of appetite, nausea, vomiting, oligozoospermia
 
Stool frequency, complete blood count, urinalysis, and renal function test
mesalamine
(2 to 4 g per day)
Capsule Colon Abdominal pain, diarrhea, nausea, vomiting
 
 
Enema Left colon and rectum
Rectal suppository Rectum
olsalazine
(1 to 3 g per day)
Delayed-release capsule Colon Abdominal pain, diarrhea, nausea
balsalazine
(2 to 6.75 g per day)
Delayed-release capsule Colon Abdominal pain, diarrhea, nausea
 

Systemic Corticosteroids and Budesonide
Corticosteroids are very potent antiinflammatory agents. They rapidly suppress the inflammation process that is involved in IBD.1,4 Thus, they are the treatment of choice for an acute IBD attack. Corticosteroids can be administered intravenously in severe cases. They should not be used for long-term maintenance due to the associated adverse effects and the lack of efficacy data. Topical corticosteroids can be used as a first-line therapy or as an alternative to aminosalicylate. Budesonide is the most potent corticosteroid that can be administered orally while acting locally due to its poor absorption. Budesonide is the first-line therapy in patients with mild to moderately active CD; however, it is not recommended for use in maintenance of remission. Systemic side effects are much fewer with budesonide than with conventional glucocorticoids. Thus, it is used as an alternative to the other oral corticosteroids when a patient is at high risk of complications from steroids.

Antibiotics
Antibiotics are commonly used to treat IBD, although the benefits to this form of treatment of the primary disease are not well established.13 The use of antibiotics in treating IBD is based on the possible involvement of luminal bacteria and fungi in the pathogenesis of the disease. Strong trial results suggest that the intestinal inflammation in IBD is primarily due to the interaction between the mucosal immune compartments and the gut microbiota. Several antibiotics have been evaluated regarding IBD treatment, but the outcomes have been inconsistent.14 Many studies did show clinical improvement with use of antibiotics, but it is not clear if the benefit is due to treatment of an undetected pathogen or the potential existence of another actionable target. The most common antibiotics that can be used in the treatment of IBD are listed in Table 4.

 
Table 4: Antibiotics for Inflammatory Bowel Disease Management
Drug Dose
metronidazole 500 mg orally 3 times a day for 10 to 14 days12
ciprofloxacin 500 mg twice daily for 6 months15
rifaximin 800 mg twice daily for 12 days16
 

Immunosuppressant Agents
Immunosuppressant agents are also used in treatment of refractory IBD or in cases where a patient is unable to tolerate either steroids or aminosalicylates. 1,4 They are very useful agents since they target the excessive immune response in IBD. However, clinicians tend not to use them due to their side effect profile. They are also used as steroid- sparing agents to reduce long-term steroid therapy exposure. Their use in active disease treatment is very limited as they have slow onset of action (which could extend to 6 months). The agents that been evaluated in this form of IBD treatment are azathioprine and its metabolite, 6-mercaptopurine, which inhibit purine synthesis in the T cell; this plays an important role in IBD-associated inflammation (Table 5). Other agents evaluated in IBD treatment are methotrexate and cyclosporine, used mostly in remission of CD. Given these agents’ serious adverse effects, their use is limited to very particular situations.

Table 5: Immunosuppressant Therapies for Inflammatory Bowel Disease Management
Drug Dose Route Side Effects Monitoring Parameter
azathioprine 1.5 to 2.5 mg/kg/day Orally Nausea, vomiting, leukopenia, myelosuppression, pancytopenia, thrombocytopenia CBC, platelet counts, and total bilirubin
6-mercaptopurine 1.5 to 2.5 mg/kg/day Orally Diarrhea, loss of appetite, nausea, vomiting, myelosuppression, drug fever CBC, platelet counts, and uric acid
methotrexate 15 to 25 mg/kg/day IM/SC/orally Diarrhea, nausea, vomiting, thromboembolic disorder, renal failure CBC, platelet count, creatinine clearance, and liver function tests
cyclosporine 2 mg/kg/day IV Hypertension, tremor, headache, hyperkalemia, hypomagnesemia hepatotoxicity Serum electrolytes, renal function, lever function, vitals
CBC = complete blood count; IM = intramuscular; IV = intravenous; SC = subcutaneous.

Biologic Agents
As mentioned, several inflammatory mediators play an important role in the pathological and clinical characteristics of IBD.2,17 These mediators are released by macrophages and produce various effects in different areas of the body. Drugs that target cytokines interrupt the work of the mediators and thus alleviate the symptoms, stop the inflammatory process, and promote intestinal mucosal healing. The approved agents in this class for both CD and UC are infliximab, adalimumab, and vedolizumab (Table 6). The other 2 agents, certolizumab and golimumab, are approved for CD and UC, respectively. Infliximab was the first agent in this class to be used for IBD. The potential for developing antibodies to infliximab results in lower efficacy in its use over time. This phenomenon has encouraged scientists to develop a new, humanized agent with a lower potential for antibody development.

Table 6: Biologic Agents for Inflammatory Bowel Disease Management
Drug Dose Route Side Effects12 Contraindication
infliximab Induction: 5 to 10 mg/kg
Maintenance: 5 mg/kg
IV Abdominal pain, nausea, headache, hypersensitivity reaction, infusion reaction Hypersensitivity to the used agent (infliximab, adalimumab, or certolizumab), severe infection, and moderate to severe heart failure
adalimumab Induction: 160 mg
Maintenance: 40 mg
SC
certolizumab Induction: 400 mg
Maintenance: 400 mg
SC
vedolizumab Induction: 300 mg
Maintenance: 300 mg
IV
natalizumab Induction: 300 mg
Maintenance: 300 mg
IV Abdominal pain, nausea, headache, depression, hypersensitivity reaction, infusion reaction Hypersensitivity to natalizumab current or history of progressive multifocal leukoencephalopathy (PML)
 
IV = intravenous; SC = subcutaneous.

Summary
In conclusion, IBD is a chronic disease that is most frequently seen in young patients. Diagnosing the disease at the right time and selecting an appropriate treatment plan are crucial to achieving remission in a timely manner. With the advent of new agents, the pharmacist’s role in treating the disease is more important than ever. Pharmacists play an active part in education as well as in monitoring drug levels and drug-related adverse effects. Ensuring that patients understand their disease and why it is important for them to take their medications regularly, as prescribed, may help prevent symptoms from progressing, while improving the final outcome for the patient.


Abdullah Assiri, PharmD, is an adjunct instructor in the department of pharmacy at UNC Eshelman School of Pharmacy.

Paul Dombrower, RPh, is a clinical assistant professor at UNC Eshelman School of Pharmacy.


References
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  14. Khan KJ, Ullman TA, Ford AC, et al. Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol. 2011;106(4):661-673.
  15. Arnold GL, Beaves MR, Pryjdun VO, Mook WJ. Preliminary study of ciprofloxacin in active Crohn's disease. Inflamm Bowel Dis. 2002;8(1):10-15.
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