Crohn's disease

Crohn's disease is a chronic, relapsing inflammatory disorder of the alimentary canal with involvement anywhere from the mouth to the anus. Manifestations of the disease cause considerable morbidity and social cost. This article will focus on the evaluation and management of Crohn's disease by the family physician.

Epidemiology, Etiology, and Pathophysiology

Crohn's disease affects approximately 380,000 to 480,000 persons in the United States. (1) Although it may occur at any age, the incidence is bimodal with a peak in the third decade of life and a smaller peak in the fifth decade. (2) The etiology of Crohn's disease is unknown, but suggested possibilities include genetic, environmental, immunologic, and infectious causes. Theories of a genetic basis for the disease are supported by family history and prevalence information, but no clear-cut pattern of inheritance has been established.

The incidence of Crohn's disease differs across racial and ethnic boundaries. It is more common in whites than in blacks, in women than in men, and in Jewish than in non-Jewish persons. (3) Environmental factors must play a role in the development of Crohn's disease, because while the disease is uncommon in African blacks, U.S. blacks have an incidence similar to that of whites. (2) Also, there is some association with diet, and the disease affects more smokers than expected. (2,3) While etiologic evidence suggests a complex interplay between many factors, pathophysiologically, Crohn's disease involves an immune system dysfunction. An imbalance in local mucosal production of pro-inflammatory cytokines over anti-inflammatory cytokines is theorized to cause the well-demarcated, discontinuous, transmural, ulcerative lesions characteristic of the disease. (4) Clinical features of Crohn's disease are listed in Table 1.5

Diagnosis

A diagnosis of Crohn's disease should be considered in any patient who presents with chronic or nocturnal diarrhea, abdominal pain, bowel obstruction, weight loss, fever, or night sweats. (5) However, symptoms of Crohn's disease are often insidious, and diagnosis can be difficult. Patients may have intermittent symptoms with varying periods of remission. Over time, symptomatic periods may increase in frequency and severity.

Crampy, intermittent pain is the most common symptom of Crohn's disease. The pain may evolve into a constant dull ache as the disease progresses. Diarrhea is present in 85 percent of patients; other symptoms include hematochezia, fever, weight loss, malaise, nausea, and arthralgias. The differential diagnosis depends on the presenting complaint, and includes acute appendicitis, small bowel obstruction, ulcerative colitis, irritable bowel syndrome, malabsorption syndromes, infectious or ischemic colitis, neoplasia, hemorrhoids, and diverticular disease. When joint manifestations or fatigue predominates, the differential is expanded further. (6)

Results from laboratory evaluation can be normal, but electrolyte abnormalities may occur secondary to diarrhea. Anemia also can be caused by malabsorption of vitamin B12, blood loss, or the effect of inflammation on the bone marrow. Patients may also have an elevated erythrocyte sedimentation rate. With the appropriate clinical presentation, the diagnosis can be suggested by radiography, but should be confirmed by endoscopy and biopsy when possible. When the colon is involved, endoscopy reveals the characteristic ulcers with normal surrounding mucosa. Radiographic studies of the small bowel may show luminal narrowing, nodular contour, linear ulcers, or fistulas. Computed tomography (CT) may help to identify abscesses and other complications. (2)

Management of Crohn's Disease

The medical management of Crohn's disease is based on the location and severity of disease and extra-intestinal complications (Table 2). (5) Therapy has two goals--to treat the acute disease flare-ups and to maintain remission. Because no "gold standard" exists to define disease severity, working definitions of disease activity have been established to help guide therapy. These definitions are listed and defined in Table 3,5 while the various treatment options for Crohn's disease are provided in Table 4. (5)

Because the natural history of Crohn's disease is characterized by a variable course with spontaneous flare-ups and remissions, it is difficult to prove therapeutic benefit from intervention. However, based on evidence from therapeutic trials, guidelines for the management of Crohn's disease have been developed. An algorithm for the medical management of Crohn's disease is provided in Figure 1. (4)

Mild to Moderate Disease

Mild to moderate Crohn's disease can be treated with a salicylate preparation, and in patients who are unresponsive, an antibiotic may help.5 Response to therapy should be evaluated after several weeks; patients who do not respond should be treated for moderate to severe disease or with alternative therapy.

The salicylates include mesalamine (Rowasa) and sulfasalazine (Azulfidine). In its various preparations, mesalamine can be released in the stomach, duodenum, ileum, and colon (Pentasa), or primarily in the terminal ileum and colon (Asacol). (7) Both mesalamine preparations are generally more effective than placebo in improving disease symptoms and inducing remission in patients with active Crohn's disease; however, greater benefit is seen in patients with ileitis versus colitis or ileocolitis. (8) The dosage of oral mesalamine is 3.2 to 4 g per day.

In a study (9) conducted in 1979, sulfasalazine demonstrated benefits over placebo, with approximately 50 percent of patients enrolled in large clinical trials achieving clinical remission. The suggested dosage of sulfasalazine is 3 to 6 g per day. Sulfasalazine does not have significant benefit in maintaining remission (9,10); mesalamine may maintain remission at higher dosages and in some subsets of patients.

In the treatment of mild to moderate active Crohn's disease, antibiotic therapy may be an acceptable alternative. Metronidazole (Flagyl) in a dosage of 10 to 20 mg per kg per day has demonstrated benefit in the treatment of ileocolitis and colitis, with most patients reporting clinical improvement and more than one half achieving remission. (11) [Evidence level A: randomized controlled trial (RCT)] In addition to a metallic taste, disulfiram-like effect, and gastrointestinal upset, long-term use of metronidazole is known to cause peripheral neuropathy, and patients should be monitored.

Ciprofloxacin (Cipro) in a dosage of 1 g per day has also decreased disease activity similar to that of mesalamine, 4 g per day. (12) [Evidence level B: lower quality RCT] In a study (130 of patients with active Crohn's disease, no difference was noted between patients treated with a combination of ciprofloxacin and metronidazole, and those treated with prednisone at 12 weeks. (13)

Moderate to Severe Disease

Patients with Crohn's disease that is classified as moderate to severe should be treated with steroids until symptoms resolve and weight loss is reversed. The immunomodulators azathioprine (Imuran) and mercaptopurine (Purinethol) may be used, but full response may not be achieved for several months. Infliximab (Remicade) may be an alternative if corticosteroids are ineffective or contraindicated.

Oral corticosteroids have been the mainstay for treating moderate to severe active Crohn's disease. Their effectiveness in inducing remission has long been known, and their onset of action is more rapid than that of salicylates. While studies have not revealed a generally accepted dosage schedule, 50 to 70 percent of patients receiving the equivalent of prednisone 40 mg daily over eight to 12 weeks have been shown to achieve a clinical response. (9)

After clinical response, dosage is tapered according to rapidity and completeness of response, often requiring months to discontinue. (14) Dosages can be tapered by 5 to 10 mg weekly until 20 mg, and by 2.5 to 5 mg weekly thereafter. (14) Steroids have no role in maintaining remission. In addition, concerns regarding the long-term side effects of steroid use, including diabetes mellitus, osteoporosis, and adrenal suppression, limit their long-term use. Prednisone enemas may be helpful in proctosigmoid disease but are not as effective as salicylate preparations.

Budesonide (Entocort) is a potent corticosteroid with poor systemic absorption because of a 90 percent first-pass metabolism, apparently resulting in fewer side effects and less adrenal suppression than prednisone. (15,16) Budesonide is superior to mesalamine and placebo in patients with active Crohn's disease (17) and is comparable to oral prednisolone. (18)

The role of immunomodulators in Crohn's disease continues to be studied. Immunosuppressants, specifically azathioprine and 6-mercaptopurine, have demonstrated adjunctive benefits to use of steroids in adults, (19,20) but they may take up to four months to demonstrate benefit. (20) These medications should be considered in patients who are steroid dependent or resistant to other forms of treatment. (20) [Evidence level A: Systematic review of RCTs] Immunosuppressants have allowed reduction in steroid dosages with maintenance of remission after inductive therapy. Despite concerns, there is no suggestion of an increased risk for neoplasia; however, one patient developed a brain lymphoma generally seen in immunocompromised patients. (21)

Dose-response studies have yet to establish optimal dosages of azathioprine and mercaptopurine. Although often used at lower dosages, the benefits of azathioprine have been demonstrated at 2 to 2.5 mg per kg, (20) and at 1.5 mg per kg with 6-mercaptopurine. (22) Patients should have blood counts evaluated once a month to watch for leukopenia. In addition, patients are at risk of pancreatitis, which generally can occur at the induction of therapy.

A variety of other immunomodulatory agents have been studied in active, refractory Crohn's disease, including cyclosporine (Sandimmune), methotrexate (Rheumatrex), and tacrolimus (Prograf). Parenteral methotrexate in a dosage of 25 mg per week has shown effectiveness in steroid-dependent patients, allowing for steroid tapering. (23,24) Guidelines for using tacrolimus and cyclosporine have yet to be determined. (23,25)

Recently, the U.S. Food and Drug Administration approved infliximab, an antibody to human tumor necrosis factor alpha, to treat Crohn's disease. In persons unresponsive to salicylates, antibiotics, corticosteroids, or immunosuppressants, infliximab has proved successful in closure of fistulas, steroid-refractory disease, and in the improvement of moderate to severe disease. A study (26) using infliximab in patients with moderate to severe Crohn's disease showed improvement in 65 percent of patients, with complete remission in 33 percent. Single-dose infusions of 5 mg per kg, 10 mg per kg, and 20 mg per kg were used, with the best response seen at 5 mg per kg. Another study (27) showed improvement in four weeks in more than 80 percent of patients treated with 5 mg per kg, and more than 50 percent achieved remission. (27) Infliximab appears to be useful in maintaining remission, but retreatment is likely to be necessary on an ongoing basis. (27,28) Clinical improvement is accompanied by endoscopic and histologic improvements, which have not been demonstrated in many other therapies for Crohn's disease. (29,30) While antibody development and theoretic long-term sequelae are of concern, side effects such as serum sickness reactions are generally mild.

Severe Disease

Patients with severe Crohn's disease often require hospitalization. Indications for hospitalization include persistent symptoms despite use of steroids or infliximab, or if patients have fever, vomiting, intestinal obstruction, acute abdomen, cachexia, or evidence of abscess. In such cases, parenteral steroids should be administered. (5) Any abdominal mass requires ultrasonography or CT scanning for evaluation.

Surgical cure of Crohn's disease is not possible, but indications for surgical consultation include refractory disease, intestinal obstruction, formation of an abscess or fistula, perforation, hemorrhage, and perianal disease. Interestingly, some extra-intestinal manifestations of Crohn's disease, including arthritis, may subside after resection.

Co-morbidity

Crohn's disease may create a negative impact on self-image, employability, psychologic functioning, family relationships, and friendships. (31) Treatment of patients with Crohn's disease should not focus on disease activity alone, but also should include attention to these factors, and family physicians should use appropriate screening tools and treatment modalities.

Stress appears to play a role in the exacerbation of Crohn's disease. (32) While no adequate studies demonstrate the benefit of relaxation techniques for Crohn's disease, studies have been done assessing psychotherapy as treatment. One study (33) showed improvement in patients' coping ability and psychologic well-being. Low-impact exercise programs also have been shown to improve patients' quality of life and bone density, an important consideration with chronic steroid use. (34,35) Generally, patient education, relaxation techniques, simple exercise programs, and involvement in support groups may help improve quality of life for patients with Crohn's disease.

Other Considerations

Commonly, patients with Crohn's disease need vitamin and mineral supplementation. Supplementation with vitamin B12, folic acid, fat soluable vitamins, and calcium should be considered, and periodic checks may be necessary. Osteopenia and osteoporosis are potential complications of Crohn's disease, often aggravated by chronic steroid use, and patients should be monitored appropriately.

Despite expanding evidence of the carcinogenic potential of longstanding Crohn's disease, surveillance guidelines have yet to be determined. (5) Frequent colonoscopic monitoring 10 years after the onset of disease is recommended, the frequency of which depends on the extent of colonic disease. Research suggests that supplemental folate may have a protective effect against colon cancer. (36)

TABLE 1

Clinical Features of Crohn's Disease

Common complaints

Abdominal pain

Diarrhea

Fever

Fatigue

Rectal bleeding

Weight loss

Anorexia

Nausea

Common physical examination findings

Abdominal tenderness

Palpable mass

Guaiac-positive stool

Common laboratory and radiographic findings

Mild anemia

Mild leukocytosis

Elevated erythrocyte sedimentation rate

Small bowel involvement

Fistulas

Strictures

Information from Hanauer SB, Sanborn W. The management of Crohn's disease in adults. Am J Gastroenterol 2001;96:635-43.

TABLE 2

Extra-intestinal Manifestations of Crohn's Disease

Joint manifestations (25 percent)

Arthralgia

Arthritis

Skin manifestations (15 percent)

Erythema nodosum

Pyoderma gangrenosum

Aphthous ulcers of the mouth

Ocular manifestations (5 percent)

Episcleritis

Uveitis

Recurrent iritis

Information from Hanauer SB, Sanborn W. The management of Crohn's disease in adults. Am J Gastroenterol 2001;96:635-43.

TABLE 3

Working Definitions of Crohn's Disease Activity

Mild to moderate disease

The patient is ambulatory and able to take oral alimentation. There is no dehydration, high fever, abdominal tenderness, painful mass, obstruction, or weight loss of more than 10 percent.

Moderate to severe disease

Either the patient has failed treatment for mild to moderate disease OR has more pronounced symptoms including fever, significant weight loss, abdominal pain or tenderness, intermittent nausea and vomiting, or significant anemia.

Severe fulminant disease

Either the patient has persistent symptoms despite outpatient steroid therapy OR has high fever, persistent vomiting, evidence of intestinal obstruction, rebound tenderness, cachexia, or evidence of an abscess.

Remission

The patient is asymptomatic OR without inflammatory sequelae, including patients responding to acute medical intervention.

Information from Hanauer SB, Sanborn W. The management of Crohn's disease in adults. Am J Gastroenterol 2001;96:635-43.

The authors indicate that they do not have any conflicts of interest. Sources of funding: none reported.

REFERENCES

(1.) Calkins BM, Mendeloff AI. Epidemiology of inflammatory bowel disease. Epidemiol Rev 1986;8:60-91.

(2.) Evers BM, Townsend CM Jr, Thompson JC. Small intestine. In: Schwartz SI, et al., eds. Principles of surgery. 7th ed. New York: McGraw-Hill, 1999: 1229-34.

(3.) Inflammatory bowel disease. In: Yamada T, Alpers DH, et al., eds. Textbook of gastroenterology. 3d ed. Philadelphia: Lippincott Williams & Wilkins, 1999:1776-8.

(4.) Wall GC, Heyneman C, Pfanner TP. Medical options for treating Crohn's disease in adults: focus on antitumor necrosis factor-alpha chimeric monoclonal antibody. Pharmacotherapy 1999;19:1138-52.

(5.) Hanauer SB, Sandborn W. Management of Crohn's disease in adults. Am J Gastroenterol 2001;96: 635-43.

(6.) Glickman RM. Inflammatory bowel disease: ulcerative colitis and Crohn's disease. In: Fauci AS, et al., eds. Harrison's Textbook of internal medicine. 14th ed. New York: McGraw-Hill, 1998:1633-45.

(7.) Tromm A, Griga T, May B. Oral mesalazine for the treatment of Crohn's disease: clinical efficacy with respect to pharmacokinetic properties. Hepatogastroenterology 1999;46:3124-35.

(8.) Prantera C, Cottone M, Pallone F, Annese V, Franze A, Cerutti R, et al. Mesalamine in the treatment of mild to moderate active Crohn's ileitis: results of a randomized, multicenter trial. Gastroenterology 1999;116:521-6.

(9.) Summers RW, Switz DM, Sessions JT Jr, Becktel JM, Best WR, Kern F Jr, et al. National Cooperative Crohn's Disease Study: results of drug treatment. Gastroenterology 1979;77(4 Pt 2):847-69.

(10.) Camma C, Giunta M, Rosselli M, Cottone M. Mesalamine in the maintenance treatment of Crohn's disease: a meta-analysis adjusted for confounding variables. Gastroenterology 1997;113: 1465-73.

(11.) Sutherland L, Singleton J, Sessions J, Hanauer S, Krawitt E, Rankin G, et al. Double blind, placebo controlled trial of metronidazole in Crohn's disease. Gut 1991;32:1071-5.

(12.) Colombel JF, Lemann M, Cassagnou M, Bouhnik Y, Duclos B, Dupas JL, et al. A controlled trial comparing ciprofloxacin with mesalazine for the treatment of active Crohn's disease. Groupe d'Etudes Therapeutiques des Affections Inflammatoires Digestives (GETAID). Am J Gastroenterol 1999;94: 674-8.

(13.) Prantera C, Zannoni F, Scribano ML, Berto E, Andreoli A, Kohn A, et al. An antibiotic regimen for the treatment of active Crohn's disease: a randomized, controlled clinical trial of metronidazole plus ciprofloxacin. Am J Gastroenterol 1996;91:328-32.

(14.) Hanauer SB. Inflammatory bowel disease. N Engl J Med 1996;334:841-8.

(15.) Campieri M, Ferguson A, Doe W, Persson T, Nilsson LG. Oral budesonide is as effective as oral prednisolone in active Crohn's disease. The Global Budesonide Study Group. Gut 1997;41:209-14.

(16.) Rutgeerts P, Lofberg R, Malchow H, Lamers C, Olaison G, Jewell D, et al. A comparison of budesonide with prednisolone for active Crohn's disease. N Engl J Med 1994;331:842-5.

(17.) Thomsen OO, Cortot A, Jewell D, Wright JP, Winter T, Veloso FT, et al. A comparison of budesonide and mesalamine for active Crohn's disease. International Budesonide-Mesalamine Study Group. N Engl J Med 1998;339:370-4.

(18.) Entocort EC package insert. Accessed May 9, 2003, at www.entocort.com.

(19.) Bouhnik Y, Lemann M, Mary JY, Scemama G, Tai R, Matuchansky C, et al. Long-term follow-up of patients with Crohn's disease treated with azathioprine or 6-mercaptopurine. Lancet 1996;347:215-9.

(20.) Sandborn W, Sutherland L, Pearson D, May G, Modigliani R, Prantera C. Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease. Cochrane Database Syst Rev 2002;(4): CD000545.

(21.) Korelitz BI, Mirsky FJ, Fleisher MR, Warman JI, Wisch N, Gleim GW. Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine. Am J Gastroenterol 1999; 94:3248-53.

(22.) Kim PS, Zlatanic J, Korelitz BI, Gleim GW. Optimum duration of treatment with 6-mercaptopurine for Crohn's disease. Am J Gastroenterol 1999;94: 3254-7.

(23.) Korelitz BI, Present DH. Methotrexate for Crohn's disease. N Engl J Med 1995;333:600-1.

(24.) Feagan BG, Rochon J, Fedorak RN, Irvine EJ, Wild G, Sutherland L, et al. Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study Group Investigations. N Engl J Med 1995;332:292-7.

(25.) Fellermann K, Ludwig D, Stahl M, David-Walek T, Stange EF. Steroid-unresponsive acute attacks of inflammatory bowel disease: immunomodulation by tacrolimus (FK506). Am J Gastroenterol 1998; 93:1860-6.

(26.) Targan SR, Hanauer SB, Van Deventer SJ, Mayer L, Present DH, Braakman T, 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 Engl J Med 1997;337:1029-35.

(27.) Rutgeerts P, D'Haens G, Targan S, Vasiliauskas E, Hanauer SB, Present DH, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease. Gastroenterology 1999;117:761-9.

(28.) Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002;359:1541-9.

(29.) D'Haens G, Van Deventer S, Van Hogezand R, Chalmers D, Kothe C, Baert F, et al. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: a European multicenter trial. Gastroenterology 1999; 116:1029-34.

(30.) Baert FJ, D'Haens GR, Peeters M, Hiele MI, Schaible TF, Shealy D, et al. Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn's ileocolitis. Gastroenterology 1999;116:22-8.

(31.) Ferry GD. Quality of life in inflammatory bowel disease: background and definitions. J Pediatr Gastroenterol Nutr 1999;28:S15-8.

(32.) Greene BR, Blanchard EB, Wan CK. Long-term monitoring of psychosocial stress and symptomatology in inflammatory bowel disease. Behav Res Ther 1994;32:217-26.

(33.) Jantschek G, Zeitz M, Pritsch M, Wirsching M, Klor HU, Studt HH, et al. Effect of psychotherapy on the course of Crohn's disease. Results of the German prospective multicenter psychotherapy treatment study on Crohn's disease. German Study Group on Psychosocial Intervention in Crohn's Disease. Scand J Gastroenterol 1998;33:1289-96.

(34.) Loudon CP, Corroll V, Butcher J, Rawsthorne P, Bernstein CN. The effects of physical exercise on patients with Crohn's disease. Am J Gastroenterol 1999;94:697-703.

(35.) Robinson RJ, Krzywicki T, Almond L, al-Azzawi F, Abrams K, Iqbal SJ, et al. Effect of a low-impact exercise program on bone mineral density in Crohn's disease: a randomized controlled trial. Gastroenterology 1998;115:36-41.

(36.) Nensey YM, Arlow FL, Majumdar AP. Aging. Increased responsiveness of colorectal mucosa to carcinogen stimulation and protective role of folic acid. Dig Dis Sci 1995;40:396-401.

Members of various medical faculties develop articles for "Practical Therapeutics." This article is one in a series coordinated by the Department of Family Medicine at Ohio State University College of Medicine and Public Health, Columbus. Guest editor of the series is Doug Knutson, M.D.

DOUG KNUTSON, M.D., is an assistant professor in the Department of Family Medicine at the Ohio State University College of Medicine and Public Health, Columbus, where he also serves as associate residency director. Dr. Knutson received his medical degree from Ohio State University and completed a residency at Riverside Methodist Hospital in Columbus, Ohio.

GREG GREENBERG, M.D., is a family medicine resident at Grant Hospital in Columbus, Ohio. He received his medical degree from the Ohio State University College of Medicine and Public Health.

HOLLY CRONAU, M.D., is the predoctoral director for the Department of Family Medicine and ambulatory care clerkship director for the Ohio State University College of Medicine and Public Health. She received her medical degree from Ohio State University, and served a residency in family practice at the Mount Carmel Medical Center, Columbus, Ohio.

Address correspondence to Doug Knutson, M.D., Department of Family Medicine, Ohio State University College of Medicine and Public Health, 2231 N. High St., Columbus, OH 43201. Reprints are not available from the authors.

COPYRIGHT 2003 American Academy of Family Physicians
COPYRIGHT 2003 Gale Group