Inflammatory Bowel Disease

Reviewed
January 19, 2005

Bret A.
Lashner, MD

Department of
Gastroenterology
and Hepatology

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* NOTE: This chapter discusses therapies that are not yet approved by the FDA for the use under discussion.

National Guidelines

American
College of Gastroenterology

DEFINITION

The two main categories of inflammatory bowel disease are ulcerative colitis and Crohn's disease.

Ulcerative colitis is characterized by recurring episodes of inflammation of the mucosal layer of the large bowel not related to an intestinal infection. The inflammation involves the rectum and may extend proximally in a continuous fashion. Ulcerative proctosigmoiditis refers to inflammation extending into the sigmoid colon. Left-sided colitis refers to inflammation extending up to, but not beyond, the splenic flexure. Pancolitis refers to disease that extends proximal to the splenic flexure.

Crohn's disease is characterized by recurring episodes of suppurative inflammation of any part of the bowel, from the mouth to the anus. This inflammation is transmural, and can result in strictures, microperforations, and fistulae. The inflammation is noncontiguous and thus can produce skip lesions throughout the bowel. Histologically, Crohn's disease can have either transmural lymphoid aggregates or non-necrotizing granulomas. Although granulomas are pathognomonic, they are seen in only 10% of patients with Crohn's disease.

INCIDENCE AND PREVALENCE

The annual incidence of ulcerative colitis and Crohn's disease ranges from 1 to 10 cases per 100,000 people annually depending on the region studied.^1-3 The peak age-specific incidence occurs near 20 years of age, and a second, smaller peak occurs near age 50. The prevalence of ulcerative colitis and Crohn's disease ranges from 10 to 70 per 100,000 people, but recent studies in Manitoba, Canada, and Rochester, MN, have shown prevalence as high as 200 per 100,000 people.^4,5 In the United States, males and females are equally affected, but both whites and Ashkenazi Jews are at much higher risk of developing inflammatory bowel disease than the rest of the population.

PATHOPHYSIOLOGY

The causes of ulcerative colitis and Crohn's disease are not known. However, a reasonable hypothesis for the pathogenesis of inflammatory bowel disease is as follows. As yet unidentified antigens, possibly a mycobacterium, paramyxovirus, or components of cigarette smoke, activate resting macrophages to release a wide variety of cytokines.⁶ "Cytokines" is a collective term for a group of low molecular-weight peptides that are active at very low concentrations and bind to specific receptors to produce autocrine, paracrine, and endocrine effects. The most abundant cytokine is interleukin-1 (IL-1), which not only produces diarrhea but also acts as a pyrogen. Other cytokines activated in the inflammatory process are IL-6, tumor necrosis factor-alpha (TNF-alpha), and IL-8. Cytokines cause differentiation of lymphocytes to different types of T cells. Helper T cells type-1 (T_H1) are associated principally with Crohn's disease, whereas T_H2 cells are associated principally with ulcerative colitis. These cytokines serve to stimulate the immune system and cause an inflammatory reaction, thus producing tissue damage in the intestinal mucosa.

SIGNS AND SYMPTOMS

Ulcerative colitis patients typically present with rectal bleeding, diarrhea, tenesmus (urgent desire to evacuate the bowels but with passage of little stool), and abdominal pain. The most commonly used criteria for assessment of mild, moderate, and severe disease were developed in 1955 by Truelove and Witts (Table 1).⁷ Patients with fulminant or toxic colitis usually have more than 10 bowel movements per day, continuous bleeding, abdominal distention and tenderness, and radiologic evidence of edema and possibly bowel dilation.

Table 1:

Criteria of Trulove and Witts for Assessing
Disease Activity in Ulcerative Colitis⁷

	Mild Activity	Severe Activity
Daily bowel movements (no.)	< or = to 5	> 5
Hematochezia	Small amounts	Large amounts
Temperature	< 37.5°C	> or = to 37.5°C
Pulse	< 90/min	> or = 90/min
Erythrocyte sedimentation rate	< 30 mm/h	> or = to 30 mm/h
Hemoglobin	> 10 g/dl	< or = to 10 g/dl

Patients with fewer than all 6 of the above criteria for severe activity have moderately active disease.

Crohn's disease patients typically present with diarrhea, abdominal pain, and weight loss. The abdominal pain usually is insidious, is in the right lower quadrant, occurs soon after eating, and may be associated with a tender, inflammatory mass. There may be hematochezia, but bleeding is much less common than in ulcerative colitis patients. Fever, weight loss, stomatitis, perianal fistulae and/or fissures, arthritis, and erythema nodosum are all commonly seen. The Crohn's Disease Activity Index (CDAI) is used in all clinical trials to measure disease activity.⁸ CDAI scores of less than 150 indicate a clinical remission, and scores over 450 indicate severely active disease.

There are many extraintestinal manifestations in inflammatory bowel disease. Approximately 2% of ulcerative colitis patients will develop primary sclerosing cholangitis, a cholestatic liver disease diagnosed by the appearance of extrahepatic and intrahepatic strictures on a cholangiogram. Primary sclerosing cholangitis is seen more often in ulcerative colitis than in Crohn's disease patients.⁹ Other hepatic manifestations of inflammatory bowel disease include fatty liver, chronic active hepatitis, amyloidosis, and drug-induced disease from medications used to treat inflammatory bowel disease (steroids, azathioprine, 6-mercaptopurine [6-MP], or sulfasalazine).

Erythema nodosum, seen in up to 3% of patients, is characterized by raised, tender, erythematous nodules appearing typically on the extremities. Pyoderma gangrenosum, a rare, ulcerating, and necrotic lesion, is seen in both Crohn's disease and ulcerative colitis. Arthritis usually is seronegative, mono- or pauciarticular, and asymmetric. The large joints are most often affected, and there is no synovial destruction. Ocular manifestations include blurred vision, eye pain, photophobia, and keratitic precipitates. Patients are susceptible to nephrolithiasis from calcium oxalate stones. Patients with uveitis often have HLA-B27, whereas patients with episcleritis and iritis usually do not. Cerebrovascular accidents and other thromboembolic events can result from hypercoagulability secondary to chronic inflammation or to other inherited syndromes such as the factor V Leiden mutation.

DIAGNOSIS

The diagnosis of ulcerative colitis or Crohn's disease is established by finding characteristic intestinal ulcerations and excluding alternative diagnoses, such as enteric infections or ischemia. Active disease in ulcerative colitis is characterized by the endoscopic appearance of superficial ulcerations, friability, a distorted mucosal vascular pattern, and exudate. Patients with severely active disease can have deep ulcers and friability that result in spontaneous bleeding. The typical distribution of disease is continuous from the rectum proximally. However, patients with partially treated ulcerative colitis may have discontinuous or patchy involvement.

The ulcerations of Crohn's disease may appear aphthoid, but could also be deep and serpiginous. Skip areas, a "cobblestone" appearance, pseudopolyps, and rectal sparing are characteristic findings. Air contrast barium enema, small-bowel series, or colonoscopy may demonstrate these typical lesions. On a small-bowel series, Crohn's disease often is manifested by separation of bowel loops and a narrowed-terminal ileal lumen, the so-called "string sign."

Histologic features of ulcerative colitis include disease limited to the mucosa and submucosa, mucin depletion, ulcerations, exudate, and crypt abscesses. In Crohn's disease, non-necrotizing granulomas, transmural lymphoid aggregates, and microscopic skip lesions can be seen. Typical lesions of Crohn's disease also may be seen in the upper gastrointestinal tract. The inflammation is localized in the ileocecal region in 50% of cases, the small bowel in 25% of cases, the colon in 20% of cases, and the upper gastrointestinal tract or perirectum in 5%.

The diagnosis of inflammatory bowel disease can be made only when other reasonable alternatives in the differential diagnosis are excluded (Table 2). The most common diagnoses that mimic ulcerative colitis are the infectious colitides. It is imperative to check stool for enteric pathogens including ova and parasites, Escherichia coli O157:H7, and Clostridium difficile. Infection with Yersinia enterocolitica or Mycobacterium tuberculosis can cause inflammation in the terminal ileum, resembling Crohn's disease. Other important diseases in the differential of Crohn's disease include intestinal lymphoma, celiac sprue, radiation enteropathy, and nonsteroidal anti-inflammatory drug-induced enteropathy.

Table 2:

Principal Alternatives in the Differential Diagnosis
of Inflammatory Bowel Disease

Ulcerative Colitis	Crohn's Disease
Infectious colitis Antibiotic-associated colitis Amyloidosis Solitary rectal ulcer syndrome Diarrhea of AIDS	Appendicitis Bacterial overgrowth Bowel tuberculosis Small-bowel cancer Nonsteroidal enteropathy Diverticulitis Celiac sprue Lymphoma Postsurgical adhesions Behcet's disease Ischemic colitis Radiation enteropathy

THERAPY

Therapy of Ulcerative Colitis
Management of ulcerative colitis is described in practice guidelines published in 2004.¹⁰ The severity of the ulcerative colitis flare is based on patient symptoms and on the extent of colitis, not on the histologic severity of inflammation.

For patients with mild to moderate distal and left-sided colitis, therapy includes oral and/or topical agents. Mesalamine (5-aminosalicylic acid or 5-ASA) enemas (Rowasa) are frequently used topical agents, dosed at 4g daily. They are efficacious for both active colitis and for maintaining a patient in remission, and are superior to rectal corticosteroids for distal disease.¹¹ Steroid enemas are effective in active disease, but are not useful in maintaining a remission. A rectal steroid foam preparation (Cortifoam) is particularly useful for helping patients retain their enemas when rectal disease is so severe that the sphincter's ability to retain the enema is compromised. Mesalamine suppositories (Canasa) are also useful in this situation. Mesalamine therapy has not failed until a patient has either been moved to maximal doses of the drug or has experienced intolerable side effects. Asacol is dosed at 2.4g/day for maintenance and up to 4.8g/day for active disease. Sulfasalazine is dosed at 2g for maintenance and up to 8g/day for active disease. Pentasa is dosed at 2g/day for maintenance and up to 4g/day for active disease (Table 3). The combination of oral and topical mesalamine is more effective than either alone for active disease. While sulfasalazine is less expensive than the other 5-ASA agents, it has a high frequency of side effects, such as nausea, vomiting, anorexia, dyspepsia, malaise, and headaches. Some rare idiosyncratic reactions include fever, rash, hepatitis, pancreatitis, pneumonitis, and agranulocytosis. Folate supplementation is recommended because sulfasalazine can inhibit folate absorption. The other 5-ASA agents, can be more expensive but generally are better tolerated.

For patients with mild to moderate pancolitis, first-line therapy involves oral 5-ASA agents. If this therapy is ineffective, oral steroids can be used for active disease, with the usual starting prednisone dose of 40 mg/day. For patients with mild to moderate disease who do not completely respond to, or are dependent on, oral steroids, immunosuppressives such as 6-mercaptopurine or azathioprine can be used. These purine analogues act by causing chromosome breaks, and blunt the proliferation of rapidly dividing cells such as lymphocytes. These agents are effective in both active disease and in maintaining remission. Metabolite levels of 6-MP can be measured to better determine optimal therapeutic dose.¹² Measurement of metabolite levels are best done on patients who are not responding, but are on adequate doses. Metabolite levels can be used to distinguish between those who are non-responders, those who are not adherent to medication, and those in whom the dose can be safely increased. One shortcoming, however, is that 6-MP azathioprine usually require 3 to 6 months to become maximally effective. In addition, they have the rare side effects of allergy (abdominal pain, fever, or rash), pancreatitis, and bone marrow suppression.

For ulcerative colitis patients with severe colitis refractory to maximal oral therapy, admission to the hospital and intravenous steroids are required. The usual dose of steroids is 0.5 to 0.75 mg/kg/day of prednisone equivalence. Usual regimens include intravenous hydrocortisone 100 mg every 8 hours or intravenous methylprednisolone 40 mg daily. It is important to rule out toxic megacolon by checking a radiograph of the abdomen. A colorectal surgery consultation should be obtained, as a significant number of these patients may require surgery during their hospitalization. The indications for a colectomy during a colitis flare include massive hemorrhage, perforation, toxic megacolon, or active disease unresponsive to conventional therapy. Surgery is also indicated in patients with persistent moderate disease that is medically refractory or in those with intolerable steroid side effects. Cyclosporine has been shown to be useful in the treatment of severely active ulcerative colitis as an alternative to colectomy.¹³ However, since cyclosporine has many side effects and has not been shown to be effective in maintaining remission long term, this medication is not widely used in the treatment of severe ulcerative colitis.

Therapy of Crohn's Disease
The therapy of Crohn's disease is discussed in practice guidelines published in 1997.¹⁴ These guidelines set up a definition for the severity of a Crohn's disease flare. Mild to moderate disease is indicated when patients are able to tolerate oral intake without dehydration, high fevers, abdominal pain, abdominal mass, or obstruction. Moderate to severe disease describes the disorder in patients who have failed to respond to therapy for mild/moderate disease, or to those with fevers, weight loss, abdominal pain, anemia, or nausea/vomiting without frank obstruction.

Severe to fulminant disease describe patients with persisting symptoms despite the introduction of steroids on an outpatient basis or for those presenting with high fever, persistent vomiting, obstruction, rebound tenderness, cachexia, or an abscess. In addition, it is important to distinguish between differing behavior of disease: inflammatory, fistulizing, or fibrostenotic.

For Crohn's disease patients with mild to moderate disease, the oral mesalamine is only modestly effective and is not approved for use in Crohn's disease. While sulfasalazine has some potential benefit in the treatment of colonic disease, it is not useful for isolated small-bowel disease.

Two mesalamine formulations, Asacol and Pentasa, are packaged in forms that are released in the small bowel. Asacol is designed to release 5-ASA in the distal ileum whereas Pentasa is designed to release 5-ASA as proximal as the jejunum. Mesalamine can be used for both active disease and for maintaining remission. Budesonide is a topically-active corticosteroid that, when given orally, is effective in treating mucosal inflammation and is then inactivated through first-pass metabolism. The side-effect profile of budesonide is much lower than oral corticosteroids. In patients with mildly to moderately active Crohn's disease, budesonide 9mg daily was significantly better in inducing remision than 4 grams daily of a mesalamine preparation.¹⁵ Gastroduodenal Crohn's disease has been shown to improve with oral proton pump inhibitors.

For moderate to severe Crohn's disease, oral steroids are considered first-line therapy. Prednisone is dosed as in ulcerative colitis patients, at 40 mg/day. It is important to rule out any concomitant infection or abscess before initiating steroid therapy. For patients who are either steroid-resistant or who become steroid-dependent, 6-MP, azathioprine, or methotrexate can be used. These agents have been shown to be safe and effective in Crohn's disease, enabling patients to avoid long-term use of corticosteroids.¹⁶ Infliximab, a chimeric mouse-human monoclonal antibody to TNF, has been shown to be effective for the acute management of both inflammatory and fistulous Crohn's disease.^17,18 Infliximab also is effective for maintenance therapy of both inflammatory and fistulous Crohn's disease.

For Crohn's disease patients with severe or fulminant disease, hospitalization is advisable. An abdominal CT should be obtained if an abscess is clinically suspected. Stool studies should be done to rule out infection. Once this has been excluded, intravenous steroids should be instituted in the same doses as used in ulcerative colitis. Surgical intervention is indicated with perforation, obstruction, or fulminant disease unresponsive to medical therapy.

OUTCOMES

Colorectal Cancer
Patients with either ulcerative colitis or Crohn's disease have an increased risk of colonic epithelial dysplasia and carcinoma. Ulcerative colitis patients have colon cancer risks that are at least 3 times higher than in the general population. This risk of colon cancer is greater with both increasing duration and extent of disease as well as with primary sclerosing cholangitis.^21,22 Crohn's disease patients with at least 30% of the colon involved with disease may have an increased risk of colorectal dysplasia and cancer.²³

Entering a patient into a cancer surveillance program is important in both of these groups. However, the exact method and timing of surveillance is still a matter of much debate. Most guidelines recommend beginning screening colonoscopies after 8 years of disease. Multiple biopsies should be taken at regular intervals throughout the colon and include polypoid lesions. All specimens with any grade of dysplasia should be reviewed by an expert gastrointestinal pathologist to confirm the findings.

It is generally agreed that high-grade dysplasia is an absolute indication for a colectomy, as these patients have a 42% risk for concurrent cancer.²⁴ Low-grade dysplasia in flat mucosa also is an indication for colectomy since progression to more advanced neoplasia often occurs.²⁵

The frequency with which colonoscopic screenings should be performed varies according to the extent of colitis, duration of disease, and history of primary sclerosing cholangitis. Since the risk of cancer is low through the first decade after the diagnosis of ulcerative colitis, surveillance need not be performed more frequently than every 3 years. As the cancer risk increases, the testing interval should shorten. One reasonable approach calls for tests every 3 years for 12 years, then every 2 years for 10 years, then annually thereafter.²⁶ Since patients with primary sclerosing cholangitis have an increased risk of colorectal cancer, endoscopic surveillance examinations should be performed annually.

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REFERENCES

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Van Assche G, D'Haens G, Noman M, et al. Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis. Gastroenterology. 2003;25:1025-31.

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