Crohn's Disease: Managing a Complex and Chronic Condition

Crohn's disease, a type of inflammatory bowel disease, can be characterized by abdominal cramping, diarrhea, and greater complications over time. Rx treatment options can help manage these symptoms.

Crohn’s disease, a type of inflammatory bowel disease (IBD), is an idiopathic, chronic, transmural inflammatory process of the bowel, probably because of an imbalance between proinflammatory and anti-inflammatory mediators. Its incidence has increased progressively over the last 50 years. Today, approximately 7 of every 100,000 Americans have Crohn’s disease.¹

Most Crohn’s disease patients have small bowel involvement, particularly in the terminal ileum. Usually, they present with cramping abdominal pain and diarrhea in a pattern of unpredictable flares and remissions over time. Fistulas (abnormal passages connecting the bowel to other organs, most often the bladder, vagina, or skin), obstruction, or both can occur at any point in the gastrointestinal tract. Fistula formation can lead to abscesses. Patients with moderate-tosevere disease will also have rectal bleeding, fever, weight loss, arthritis, and often anemia.^1-3

This disease begins microscopically and proceeds to ulceration of the superficial mucosa. As inflammatory cells invade deep mucosal layers, granulomas form through all intestinal wall layers and into the mesentery and regional lymph nodes. Fistulas and intestinal wall thickening— sometimes to the point of intermittent or reversible obstruction—differentiate Crohn’s disease from ulcerative colitis, the other type of IBD.^1-3 Involved mucosa become bloody and edematous. Superficial ulcers are common.⁴ Allowed to progress, the disease can cause scarring, luminal narrowing, and strictures that create chronic obstruction.¹

Causes of Crohn’s disease may include genetics, microbial infection, immunology, environment (especially smoking), diet, vasculature, and psychosocial factors, but the exact cause is unclear. Patients may mount an aberrant immunologic response to one or more of the aforementioned provoking factors.⁴

Patients who have Crohn’s disease may develop protein-calorie malnutrition, dehydration, and nutrient deficiencies secondary to malabsorption. They are also more likely to suffer malabsorption of bile acids, leading to steatorrhea, fatsoluble vitamin deficiency, gallstones, and kidney stones.¹ The sidebar^1,5 presents other facts about Crohn’s disease.

Crohn’s Disease: Facts

• Crohn’s disease has a bimodal age distribution, peaking in the 20s and the 60s.

• Approximately 30% of patients with Crohn’s disease develop perianal fissures, fistulae, or abscesses.

• Any part of the gastrointestinal system may be affected, but the most common site is the ileocecal region.

• Extraintestinal manifestations may develop in the skin (ulcers, lesions), joints (arthritis), mouth (sores), eyes (episcleritis, recurrent iritis, uveitis), or liver (enzyme elevation, cholangitis, autoimmune chronic active hepatitis, and cirrhosis).

• Extraintestinal manifestations often parallel the course of bowel disease, waxing and waning with the disease.

• Relapse is common, approaching 80% in the first year after remission.

• Approximately 80% of patients will develop complications that require surgery, and surgeons try to preserve intestinal length and function.

• Crohn’s disease is more common in cold climates, in women, and in whites and Jewish whites specifically, compared with blacks or Asians.

Researchers have linked interleukins (ILs) and tumor necrosis factor (TNF)-alpha (which is strongly expressed in Crohn’s disease patients’ bowel walls and feces) to inflammation. Inhibiting TNF-alpha interferes with production of downstream inflammatory mediators (IL-1, prostaglandins, platelet activating factor, and nitric oxide). In Crohn’s disease, a T-helper type-1 cellular immune response pattern also increases production of IL-12, TNF, and interferon gamma.⁶

Nutritional Needs

Patients with Crohn’s disease need constant reminders that diet is critical. Highfiber diets or fiber supplementation that increases short-chain fatty acids in the gut may promote colonic mucosal healing. If obstruction seems to be developing, however, a low-roughage diet is preferred. Osteoporosis is a serious risk due to steroid use, malabsorption, and lactose intolerance in patients whose disease is concentrated in the small intestine. Additionally, cytokine release from inflammatory cells stimulates osteoclast activity, increasing bone breakdown. All these create a need for supplemental calcium.^7-9 If patients undergo extensive bowel resection or serious disease, dietary adjustments are needed. These may include consuming a low-fat diet, addition of medium-chain triglyceride preparations, enteral therapy, or short- or long-term total parenteral nutrition (TPN).^7-9

Medical Treatment

Crohn’s disease patients need an arsenal of medications to manage symptoms. As diarrhea is a ubiquitous symptom, loperamide, diphenoxylate with atropine, and tincture of opium can be used up to 4 times daily. They should be avoided in patients with active colitis because of the risk of toxic megacolon. Patients may also need bile acid sequestrants and a lowfat diet. Some patients find relief from abdominal cramps with propantheline, dicyclomine, or hyoscyamine, but only if they have no bowel obstruction.^2,10

Colon and small bowel inflammation generally require anti-inflammatory drugs or antibiotics, and patients who experience severe, resistant symptoms often need steroids. Short courses of 40 to 60 mg of prednisone, with dose tapering once remission occurs, are usually employed. Complications of steroid treatment—osteoporosis, cataracts, diabetes, and hypertension—are a serious concern. Steroids do not alter the disease course. Gastroenterologists always look for treatments that decrease exacerbations, are steroid-sparing, and alter the disease’s course.

Sulfasalazine has been used for years for colonic (as opposed to small bowel) disease, because bacterial degradation in the large bowel releases its active compound, 5-aminosalicylic acid. It does not seem to maintain remission and is not considered steroid-sparing. Patients who have small bowel disease are more likely to respond to long-term treatment with mesalamine, delaying relapse, because it releases 5-aminosalicylic acid there due to pH.^2,10

When patients experience exacerbations during steroid tapering, clinicians can try azathioprine (2 mg/kg/d) or its active metabolite, 6-mercaptopurine. Response may take 3 to 6 months, and bone marrow suppression is a serious concern requiring monitoring.^2,10

Patients who develop uncomplicated partial small bowel obstruction may need intravenous hydration, nasogastric suction, and parenteral nutrition. If adhesion, strangulation, recurrent hemorrhage, obstruction, or toxic megacolon occur, surgery may be indicated.^2,10

Fistulae may or may not create serious problems depending on their location. They become a surgical emergency if obstruction, abscess, or significant bowel bypass occur and result in health-compromising diarrhea and malabsorption. Oral metronidazole (1 g/d) for 30 to 60 days can relieve and decrease symptoms, and adding ciprofloxacin may help patients unresponsive to metronidazole alone. Antimetabolites, TPN, and bowel rest may reduce drainage and promote fistulae healing.^2,10

Disease-Modifying Agents

Identification and approval of diseasemodifying agents has improved life for many patients who have Crohn’s disease (Table^2,6,11-15). Many of these new agents are TNF-alpha blockers. Across this category of drugs, pharmacists need to remember:

• Serious infections (eg, invasive fungal infections and other opportunistic infections) and fatalities have been reported, especially with concomitant immunosuppressant use.

• Tuberculosis, reactivation or newonset, may occur.

• Autoantibody formation, including lupus-like syndrome, has occurred.

• Central nervous system demyelinat-ing disorders, new-onset, or worsening of preexisting conditions may occur.

• Concomitant use with anakinra or live vaccines is not recommended.

• Congestive heart failure, new-onset or worsening, has been reported.

• Hepatitis B reactivation in chronic carriers is possible.

• Patients may be at increased risk of malignancy.

Pharmacists should work with the health care team and monitor for adverse events, discontinuing the agent if the event is serious.

Table

Disease-Modifying Agents Used in Crohn’s Disease

Agent

Mechanism of Action

Infliximab, a chimeric mouse-human anti-TNF mAb

Blocks TNF in the serum and at the cell surface, leading to the lysis of TNF-producing macrophages and T cells

Adalimumab, a recombinant human immunoglobulin G1 mAb

Binds to human soluble TNF-alpha with high affinity and specificity, but not to lymphotoxin (TNF-beta)

Natalizumab, an anti-alpha4 integrin subunit mAb

Inhibits leukocyte adhesion and migration to areas of inflammation

Certolizumab pegol, a humanized Fab' antibody fragment conjugated to polyethylene glycol

Binds and selectively neutralizes TNF-alpha

Fab' = fragment, antigen binding; mAb = monoclonal antibody.

Other agents, although not FDA-approved, have been used in Crohn’s disease. These include tacrolimus, mycophenolate mofetil, and tocilizumab.

Adapted from references 2, 6, and 11-15.

Ms. Wick is a senior clinical research pharmacist at the National Cancer Institute, National Institutes of Health, Bethesda, Maryland. The views expressed are those of the author and not those of any government agency.

References

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2. Panes J, Gomollon F, Taxonera C, et al. Crohn’s disease: a review of current treatment with a focus on biologics. Drugs. 2007;67:2511-2537.

3. Tierney LM. Crohn’s disease. In: Tierney LM, McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis and Treatment. 40th ed. New York, NY: McGraw-Hill Professional Publishing; 2001:638-642.

4. Thoreson R, Cullen JJ. Pathophysiology of inflammatory bowel disease: an overview. Surg Clin North Am. 2007;87:575-585.

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6. Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut. 2007;56:1232-1239.

7. Harpavat M, Keljo DJ, Regueiro MD. Metabolic bone disease in inflammatory bowel disease. J Clin Gastroenterol. 2004;38:218-224.

8. Heuschkel R. Enteral nutrition in Crohn’s disease: more than just calories. J Pediatr Gastroenterol Nutr. 2004;38:239-241.

9. Razack R, Seidner DL. Nutrition in inflammatory bowel disease. Curr Opin Gastroenterol. 2007;23:400-405.

10. Robinson M. Optimizing therapy for inflammatory bowel disease. Am J Gastroenterol. 1997;92(12 suppl):12S-17S.

11. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N EnglJ Med. 1999;340:1398-1405.

12. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N EnglJ Med. 1997;337:1029-1035.

13. Peyrin-Biroulet L, Laclotte C, Bigard MA. Adalimumab maintenance therapy for Crohn’s disease with intolerance or lost response to infliximab: an open-label study. Aliment Pharmacol Ther. 2007;25:675-680.

14. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn’s disease previously treated with infliximab: a randomized trial. Ann Intern Med. 2007;146:829-838.