Inflammatory Bowel Disease

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[edit] Inflammatory Bowel Disease

Ciarán P. Kelly

Pierre F. Michetti

(Adapted from the work of Drs. Asher Kornbluth, David B. Sachar and Peter Salomon, originally published in Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 6th edition (1998), chapter 101, by Drs. Ciarán P. Kelly and Pierre F. Michetti.)

Inflammatory bowel disease (IBD) is characterized by idiopathic, chronic, or recurrent intestinal inflammation. Based on clinical, endoscopic, and histologic patterns, IBD is divided into two categories: ulcerative colitis and Crohn's disease.^[1] In ulcerative colitis, inflammation is confined to the mucosa and submucosa of the large intestine. In Crohn's disease, inflammation can affect any part of the intestinal tract and all layers of the intestinal wall, from mucosa to serosa.^[2][3][4][5]

IBD is more prevalent in North America and Northern Europe, where Caucasians have the highest incidence, estimated at 35 to 100 cases per 100,000 population for ulcerative colitis and 10 to 50 for Crohn's disease.^[1] IBD is reportedly fourfold higher among the Ashkenazi Jewish population of Europe and America. The prevalence of IBD among family members of IBD patients is 50 times higher than in the general population. Family members tend to be affected by the same form of IBD (ulcerative colitis or Crohn's disease), although not always. A study of monozygotic twins showed 6% concordance for ulcerative colitis and 44% concordance for Crohn's disease.^[1] These observations suggest a genetic predisposition to IBD, particularly Crohn's disease, and a requirement for unidentified environmental agents (e.g., bacterial, dietary) for disease expression.

Despite numerous studies, no specific dietary factor has been linked reproducibly with Crohn's disease or ulcerative colitis.^[6] The search for an infectious cause has also been unrewarding. Both mycobacterial and measles infection have been studied, but a firm causative link has not been established for either agent. In genetically modified mice, disruption of various immune response genes (e.g., interleukins 2 and 10) leads to intestinal inflammation that is similar to human IBD, and animals raised in a germ-free environment do not develop intestinal disease.^[7] Thus IBD may develop in genetically susceptible individuals because of a heightened or inappropriate immune response to commensal or pathogenic intestinal flora.^[8]

The peak age of onset of IBD is in early adult life (15 to 25 years). Symptoms may develop in childhood or in later life, however, and in some series a second peak of onset in men aged 55 to 65 years is reported. Cigarette smoking has a protective effect in ulcerative colitis but not in Crohn's disease. Prior appendectomy is also associated with a significant reduction in the risk of developing ulcerative colitis.

[edit] ULCERATIVE COLITIS

[edit] Clinical Presentation

The two main symptoms of ulcerative colitis are diarrhea and the passage of blood in the stool. Other common symptoms include cramping lower abdominal pain, abdominal tenderness, fever, and rectal symptoms. Patients with severe disease may develop weight loss and symptomatic anemia. Ulcerative colitis usually follows a chronic, intermittent course, with periods of disease activity interspersed with periods of spontaneous remission. However, as many as 18% of patients have only one episode of colitis, whereas 7% show chronic unremitting disease activity. For patients under age 50 the median time to relapse after a first episode is 2 years, with lower relapse rates in older patients.

Key elements in the evaluation of patients with ulcerative colitis are a determination of disease severity and disease extent, since these two factors will influence clinical presentation, management, and prognosis. Disease severity is determined mainly by clinical evaluation of the frequency of diarrhea, the amount of blood visible in the stool, abdominal tenderness or distention, and the presence or absence of systemic manifestations of disease (fever, tachycardia, postural hypotension, fatigue, anemia, hypoalbuminemia, electrolyte disorders, particularly hypokalemia) (Table 108-1).

Table 108-1 Severity of Ulcerative Colitis Based on Disease Manifestations

✢Passage of diarrhea may decrease in toxic megacolon.

†Heart rate may drop in fulminant colitis.

‡May require blood transfusion.

§May develop in prolonged, moderately active, extensive colitis.

Ulcerative colitis always involves the lower rectum; colonic mucosal inflammation extends proximally in a contiguous manner to a varying extent (Fig. 108-1). The extent of disease involvement is often described by the terms ulcerative proctitis (rectum only), distal or left-sided colitis (disease distal to the splenic flexure), and extensive colitis or pancolitis (disease proximal to the splenic flexure). In ulcerative proctitis, rectal symptoms predominate (fecal urgency, tenesmus, rectal pain, passage of bright-red bloodcoating the stool). With more extensive disease, diarrhea tends to increase, and blood becomes mixed into the stool. Only one quarter of patients with ulcerative colitis have extensive disease; this subgroup is at greater risk for severe disease requiring colectomy. The extent of disease involvement in individual patients usually remains constant, but about 10% of those who present initially with proctitis or distal colitis later develop more extensive disease. Neither disease severity nor disease extent influence the risk of relapse.

Figure 108-1 Extent of disease involvement in ulcerative colitis.

[edit] Diagnosis

Colonoscopy with biopsy is the best diagnostic study for ulcerative colitis. At colonoscopy the severity of colonic inflammation and ulceration and the proximal extent of disease involvement can be evaluated by endoscopic appearance and by histologic examination of mucosal biopsies. In active disease, histologic examination reveals an acute colitis with neutrophil infiltration of the colonic glands, crypt abscess formation, and surface erosions. Architectural changes in the colonic glands reflect a chronic colitis and may be helpful in differentiating between an acute, self-limited infectious colitis and chronic IBD. Radiographic studies are useful in the diagnosis and management of Crohn's disease but play a lesser role in ulcerative colitis.

The most common diagnostic difficulty in ulcerative colitis is excluding infectious colitis (Box 108-1). This is particularly relevant in patients who present after a short duration of symptoms (less than 4 to 6 weeks) and in patients with risk factors for enteric infectious disease, such as recent travel to endemic areas, contact with cases, antibiotic use, receptive anal intercourse, and immunosuppression, including human immunodeficiency virus (HIV) infection. An infectious agent should be excluded by testing stool samples for relevant enteric pathogens, including Shigella, Yersinia, Campylobacter, Clostridium difficile, and Amoeba. In patients with a previous diagnosis of ulcerative colitis, enteric infection should also be considered as a possible cause of relapsing colitis.

Radiation colitis is suggested by the patient's history. Ischemic colitis should be considered in elderly patients and in those with risk factors for atherosclerotic, thromboembolic, or inflammatory vascular disease.

Clinical, endoscopic, radiographic, and histologic criteria are used to differentiate between ulcerative colitis and Crohn's disease of the colon (Box 108-2). In approximately 10% of patients it is not possible to differentiate with certainty between Crohn's disease and ulcerative colitis, and the term indeterminate colitis is used. Differentiation between ulcerative colitis and Crohn's disease becomes most important if surgery is being considered, since the surgical treatment of ulcerative colitis differs substantially from that of colonic Crohn's disease.

[edit] Treatment

[edit] Medical Therapy.

For many years, sulfasalazine (Azulfidine) was the mainstay of therapy for mild or moderately severe ulcerative colitis. It is inexpensive and effective in controlling active disease. Its efficacy is dose dependent, however, and side effects such as nausea and headache are frequent at higher doses. These effects may be reduced by taking the medication with food, using gradual dose escalations, or using an enteric-coated preparation. Other side effects include allergic reactions, hemolysis, folate deficiency, male infertility, and occasionally, life-threatening agranulocytosis or other severe drug reactions. Thus patients are monitored by periodic blood counts, including reticulocyte counts, and folic acid supplements are given to prevent folate deficiency.

Sulfasalazine comprises 5-aminosalicylic acid (5-ASA) linked by an azo bond to sulfapyridine. The sulfapyridine prevents 5-ASA absorption and degradation in the upper intestinal tract. The azo bond is cleaved by the action of colonic bacteria releasing the active 5-ASA moiety in the colon, where it is poorly absorbed. Most of the sulfasalazine's toxicity is attributed to the sulfapyridine moiety, which is well absorbed from the colon. A variety of 5-ASA preparations use different release systems to deliver 5-ASA to the inflamed intestinal mucosa while avoiding sulfa-related side effects (Table 108-2). These 5-ASA preparations are more expensive than sulfasalazine but have fewer side effects and avoid the need for routine hematologic monitoring and folate supplementation. As with sulfasalazine, they are effective in controlling active disease and in maintaining remission. Their efficacy is dose dependent, and high doses are usually well tolerated. Many patients with newly diagnosed ulcerative colitis are treated using a 5-ASA preparation. Patients who previously tolerated sulfasalazine well can continue to take it.

Table 108-2 Sulfasalazine and 5-Aminosalicylic Acid (5-ASA) Preparations✢

✢Only those currently approved for use in the United States are listed.

†Administered in two to four divided doses.

‡1 gm of sulfasalazine contains approximately 500 mg of 5-ASA.

*6.75 gm of balsalazide (9 capsules) contains 2.4 gm of 5-ASA 
 

§Each enema contains 4 gm of 5-ASA.

**Each suppository contains 500 mg of 5-ASA

Ulcerative proctitis and left-sided colitis can be treated effectively using enemas containing either 5-ASA or hydrocortisone. Enemas are usually administered once or twice daily for 7 to 14 days to control active disease. An hydrocortisone foam enema is available for patients who have difficulty retaining the liquid enema preparation. Some patients prefer 5-ASA suppositories.

Systemic corticosteroid therapy is used for patients with severe ulcerative colitis and extensive disease involvement and for patients with moderately severe disease who fail to respond to high-dose 5-ASA treatment. Depending on the severity of disease and the patient's response to previous steroid therapy, daily doses of 15 to 60 mg of prednisone are used. Therapy is tapered over 2 to 8 weeks as disease activity decreases. Since corticosteroid side effects are common and can be severe, the lowest effective dose should be used. Relapse may occur as the dose of prednisone is decreased, however, necessitating further dose escalation.

[edit] Severe Disease.

Severe ulcerative colitis, particularly if extensive, may be incapacitating and may require hospital admission for intravenous (IV) fluid and electrolyte repletion and high-dose IV corticosteroid therapy (hydrocortisone, 300 mg/day, or methylprednisone, 48 to 60 mg/day). If abdominal pain or cramps are exacerbated by oral intake, patients should fast until the colitis is under control; otherwise, "bowel rest" may be disadvantageous and feeding should be given as tolerated, since the colonic enterocytes require the short-chain fatty acid products of dietary intake for their metabolism and function. A nasogastric tube may be required for decompression if an ileus exists. Blood transfusion may also be needed for marked anemia or acute severe bleeding. If fasting is prolonged for more than 4 to 5 days, if the patient is already malnourished from the disease, or if urgent colectomy may be required, parenteral nutrition should be administered. Abdominal symptoms and signs should be monitored frequently for evidence of colonic distention or peritoneal inflammation indicating toxic megacolon or risk of perforation. If patients have not responded after 7 to 10 days of IV corticosteroid treatment, or are showing deterioration at any point, colectomy must be considered. IV cyclosporine has been used in these circumstances and may be effective in averting urgent colectomy in more than 50% of patients. Many subsequently relapse, however, and potential adverse effects of cyclosporine are a concern. IV infliximab has sometimes worked as "salvage" therapy, but if either cyclosporine or infliximab has failed, it is time for colectomy rather than continued attempts at medical therapy.

[edit] Refractory Disease.

Refractory disease occurs with incomplete response to systemic corticosteroid therapy or with relapse of symptoms as the steroid dose is reduced despite concurrent treatment with high-dose sulfasalazine or 5-ASA. Chronic treatment with corticosteroids should be avoided when possible, since these agents do not alter disease progression or relapse and are frequently associated with substantial drug-induced side effects. Alternatives include colectomy or immunosuppressive agents. Azathioprine or the closely related 6-mercaptopurine (6-MP) is effective in approximately two thirds of patients and allow reduced dosage or complete discontinuation of steroid therapy. Their onset of action is slow (3 to 6 months for maximal effect), and frequent monitoring is needed for neutropenia and other adverse effects. In patients who respond, maintenance treatment with azathioprine or 6-MP is usually given because discontinuation of therapy is often followed by disease relapse.

[edit] Surgical Treatment.

Fewer than 10% of patients undergo surgical treatment for ulcerative colitis. Surgery is required most often in patients with extensive colitis, for whom the colectomy rate is 20% to 25%. The most common indication for surgery is persistently active disease with an inadequate response to medical therapy or unacceptable medication-induced side effects. Colonic dysplasia or carcinoma is another common indication for elective colectomy. Urgent colectomy is occasionally required for fulminant colitis, toxic megacolon, or persistent severe colonic hemorrhage. Colonic perforation is an absolute indication for surgery in ulcerative colitis and is associated with a reported mortality rate of 40%.

Surgical treatment of ulcerative colitis consists of proctocolectomy. Partial or subtotal colectomy is not recommended because colitis frequently recurs in the remaining colon. The simplest procedure combines proctocolectomy with the formation of a Brooke's end ileostomy. This is associated with the lowest risk for perioperative complications and subsequent stoma dysfunction. Ileoanal anastomosis, with the formation of a pelvic pouch of small intestine, is technically more difficult and often requires more than one procedure. Fecal urgency, frequency, and incontinence are common after ileoanal anastomosis. Severe inflammation of the pouch (pouchitis), intractable diarrhea, or pelvic sepsis may require removal of the pouch and conversion to an end ileostomy. Despite these limitations, most patients undergoing colectomy for ulcerative colitis choose ileoanal anastomosis over a permanent end ileostomy. Surgical outcomes are excellent, with fewer than 5% of patients requiring conversion to an end ileostomy. Patients with Crohn's disease are poor candidates for an ileoanal anastomosis, which is an important consideration when patients with indeterminate colitis are evaluated for surgery.

[edit] Maintenance Therapy.

Strong evidence supports the use of oral sulfasalazine or 5-ASA as maintenance therapy in ulcerative colitis. In one study, 73% of patients with ulcerative colitis in remission treated by placebo relapsed within 1 year, whereas only 21% of patients treated with sulfasalazine (2 gm/day) had a relapse.^[9] Similar results have been obtained using 5-ASA preparations. The duration of maintenance therapy varies depending on disease severity. A patient with a single episode of mild colitis may discontinue therapy after 1 year, whereas a patient with previous repeated episodes of severe colitis may choose to continue therapy indefinitely. The efficacy of sulfasalazine or 5-ASA in preventing disease relapse is dose dependent.

5-ASA enemas, used daily or every second day, help to maintain remission in patients with proctitis or limited colitis. 6-MP prevents relapse in patients whose active colitis responded to this agent. Corticosteroids have no role in maintenance therapy because they do not prevent disease relapse.

[edit] CROHN'S DISEASE

Crohn's disease is manifest by chronic or recurrent transmural inflammation that may involve any part of the digestive tract, from mouth to anus. Its distribution is characteristically focal or segmental rather than uniform and diffuse. The most frequent symptoms are abdominal pain and diarrhea. Intestinal fistula formation and bowel obstruction are common complications. Disease recurrence is highly likely, even after surgical resection. The term Crohn's disease has replaced other designations, such as granulomatous enteritis and regional or terminal ileitis, because granulomas are not always present and ileal involvement is common but not universal (Table 108-3). The three main patterns of involvement are isolated small bowel disease, ileocolitis, and isolated Crohn's colitis. In all locations, transmural inflammation results in thickening of the bowel secondary to edema and inflammatory cell infiltration, as well as narrowing of the lumen secondary to fibrosis.

Table 108-3 Sites of Involvement in Crohn's Disease

✢The terminal ileum is involved in 80% of patients.

Early lesions consist of hyperemia, edema, and discrete superficial ulceration, or aphthous ulcers. As the disease progresses, these mucosal lesions coalesce into deep transverse and longitudinal serpiginous ulcers accompanied by swelling of the intervening mucosa, providing the characteristic “cobblestone” appearance of the mucosa. Over time the bowel wall thickens and becomes fibrotic and stenotic, setting the stage for chronic, recurrent bowel obstruction. The mesentery participates in the chronic inflammatory process and is greatly thickened and edematous, generating fingerlike projections encasing the bowel called “creeping fat.” Microscopically the inflammatory infiltrate is composed of neutrophils, plasma cells, lymphocytes, and macrophages; crypt abscesses are evident. Macrophages aggregate in noncaseating granulomas that may be recognized in all layers of the bowel wall. Microscopic focality is also a characteristic feature of Crohn's disease.

[edit] Clinical Presentation

Signs and symptoms of Crohn's disease are secondary to chronic transmural inflammation of the bowel. The onset of symptoms is usually insidious but occasionally is abrupt. In active ileal disease, pain is usually colicky and located in the right lower quadrant or suprapubic region. Because it is often associated with the passage of intestinal contents through the congested and narrowed segments of inflamed bowel, pain precedes evacuation of liquid stools. When cramping pain follows food intake along with nausea and abdominal distention, more proximal disease (gastroduodenitis or jejunitis) or chronic partial obstruction caused by fibrotic cicatrization must be suspected.

Intestinal inflammation is associated with increased fluid secretion and impaired absorption, resulting in diarrhea. Distal colitis and proctitis are associated with fecal urgency, tenesmus, and passage of mucus, pus, and blood. Bacterial overgrowth, fistula formation, impaired bile acid absorption, and generalized malabsorption can contribute to diarrhea in Crohn's disease. Low-grade fever, chills, and nocturnal sweats can result from chronic inflammation. High-grade fever suggests a suppurative complication. In contrast, fibrostenotic disease and remission are marked by a normal temperature. A 10% to 20% loss of body weight often results from anorexia and diarrhea. In the absence of intestinalresection, enterocolonic fistula formation, or bacterial overgrowth, malabsorption rarely plays a major role. In longstanding disease without signs of activity, weight loss should suggest a small bowel or colonic adenocarcinoma.

Visible blood is evident in the stool in about 50% of patients with Crohn's colitis and in less than 25% of those with ileal disease. Bleeding occurs less often in Crohn's disease than in ulcerative colitis (see Box 108-2). Massive bleeding is a rare but dangerous and sometimes recurrent complication of Crohn's disease. Perianal disease is present in 30% of patients. Fissures, fistulas, and abscesses can be a presenting or predominant feature of Crohn's disease. These lesions develop after occlusion of circumanal glands, creating abscesses that dissect into the intersphincteric plane.

It is of paramount importance to remember that pediatric patients may present with few or no GI symptoms relative to such systemic manifestations as fever or anemia of undetermined origin, joint inflammation mimicking juvenile rheumatoid arthritis, and especially failure of growth and development.

[edit] Intestinal Complications.

The inflammatory process of Crohn's disease tends to evolve into two distinct patterns, fibrostenotic (obstructing) or penetrating (fistulous), with different implications for therapy and prognosis. Chronic partial intestinal obstruction with acute episodes of transient complete obstruction is common in Crohn's disease (Figure 108-2). In the early stages, obstruction results from edema and spasm. Diarrhea and inflammatory signs are present, and conservative therapy is almost always effective; urgent surgery is rarely if ever required. On the other hand, chronic obstructive symptoms often result from fibrosis, and constipation typically replaces diarrhea. Surgery is often required at this stage because the obstruction will not be reversed by antiinflammatory agents.

Figure 108-2 Terminal ileal stricture in 39-year-old woman with 8-year history of Crohn's disease who reported postprandial cramping abdominal pain and distention. Small bowel follow-through demonstrated fixed narrowing of terminal ileum with some dilation of ileum proximal to stricture. No other areas of intestinal disease were identified.

Transmural inflammation results in the formation of sinus tracts that may either end blindly, creating abscesses, or break into adjacent organs, creating fistulas. Mesenteric abscesses are most common, but retroperitoneal and psoas abscesses also occur, usually on the right side. Symptoms include abdominal pain, spiking fevers, and pain referred to the hip, thigh, or knee. A palpable tender mass and psoas sign may be evident on examination.

Enteroenteric fistulas, usually ileoileal, ileocecal, or ileosigmoid, are the most common fistulas. They are often relatively asymptomatic and found during barium studies or surgery. In contrast, the rare cologastric or coloduodenal fistulas, always originating from Crohn's colitis, result in foul-smelling eructation, feculent vomiting, and malabsorption from a combination of “short circuiting” and small intestinal bacterial overgrowth. Enterovesical fistulas typically present with dysuria and recurrent bladder infections and less often with pneumaturia and fecaluria. An intraabdominal abscess is present in about 50% of cases. Enterovaginal fistulas present with dyspareunia or feculent, foul-smelling vaginal discharge. They can arise from the ileum in women with prior hysterectomy but are much more frequently rectovaginal, secondary to extension of penetrating perianal and rectal disease. Enterocutaneous fistulas follow the planes of least resistance, typically through prior surgical scars, to the periumbilical area along a persistent urachal segment or along the psoas muscle to the groin. These fistulas may also develop after drainage of an intraabdominal abscess, indicating persistent underlying disease. Periileostomy fistulas complicate 2% of ileostomies and manifest recurrent proximal disease. Enterocutaneous fistulas rarely heal spontaneously.

Free perforation is uncommon (1% to 2% of patients) because transmural inflammation promotes extensive adhesions that generate pathways for abscess or fistula formation rather than free perforation. Perforations arise from the ileum or jejunum or secondary to toxic megacolon. Generalized peritonitis may also result from rupture of an intraabdominal abscess.

[edit] Diagnosis

In patients with a brief history of right lower quadrant pain, the first step in the differential diagnosis of Crohn's disease is to exclude acute appendicitis (Box 108-3). A prior history of GI symptoms like abdominal pain and diarrhea or the presence of palpable mass should raise suspicion of Crohn's disease and evaluation by abdominal computed tomography (CT) scan. Stool cultures and examination for ova and parasites are done to rule out infection. Because enteric infection may trigger a recurrence, these stool studies should also be considered in patients with established Crohn's disease. The presence of peritoneal signs should prompt the search for extramural complications.

A small bowel follow-through study is used for diagnosis and to delineate the extent of disease (see Figure 108-2). Because the anatomic location of Crohn's disease rarely changes (except after surgery), repeat examinations are performed only if symptoms change or a major change in medical therapy or surgery is contemplated. Barium enema is complementary to colonoscopy and is especially useful before surgery and in evaluating fistulas and narrow strictures. Colonoscopy is the examination of choice to evaluate possible segmental colonic involvement and allows biopsy of inflamed and adjacent normal mucosa, strictures, and mass lesions. Routine colonoscopy, however, is not used to follow response to therapy. Histology may be useful in differentiating Crohn's colitis from ulcerative colitis. Intubation of the ileocecal valve allows examination and biopsy of the terminal ileum. Upper intestinal endoscopy with biopsy is more sensitive than barium studies for diagnosis of gastroduodenal Crohn's disease. The presence of noncaseating granulomas is considered almost pathognomonic of Crohn's disease, but granulomas are found only in 30% of biopsies and 50% of surgical specimens. Multiple biopsies can confirm the focality of disease involvement.

CT plays an important role in patient evaluation. It can demonstrate transmural intestinal thickening and is the modality of choice to evaluate extramural complications (e.g., fistulas, phlegmons, abscesses). In some centers, CT enterography is becoming preferred to routine small bowel series as a diagnostic procedure for small bowel Crohn's disease. Magnetic resonance imaging (MRI) is inferior to CT in demonstrating intraperitoneal lesions but is essential to evaluate pelvic lesions (e.g., ischiorectal abscesses, perirectal fistulas). Ultrasonography is useful in the initial evaluation of right lower quadrant pain to rule out tuboovarian pathology and extrauterine pregnancy.

[edit] Treatment

[edit] Medical Therapy

[edit] Gastroduodenal Crohn's Disease.

Omeprazole, sucralfate, or histamine receptor antagonists (H₂RAs) may induce partial or even complete remission of symptoms. Slow-release mesalamine in methylcellulose granules (Pentasa) is partly released in the proximal small intestine and may be useful in duodenal Crohn's disease, but its benefit has not been tested in clinical trials. Patients who do not respond to these therapies are treated with prednisone. Azathioprine or 6-MP is indicated for patients who remain symptomatic despite steroid therapy or who are steroid dependent. Duodenal strictures associated with Crohn's disease have been treated by balloon dilation with good long-term results.

[edit] Ileitis, Ileocolitis, and Colitis.

When systemic symptoms are absent or minimal, treatment can be initiated with an oral 5-ASA agent. Sulfasalazine has limited efficacy in ileitis, probably related to its need for bacterial degradation for activation. Mesalamine (Pentasa, 4 gm/day) has some efficacy in ileitis. 5-ASA therapy is started at a low dose to evaluate the patient's tolerance, then increased to a higher dosage (see Table 108-2). Both sulfasalazine and mesalamine can induce remission in ileocolitis or colitis. Improvement should be noted in 2 to 4 weeks. Treatment with antibiotics can be tried in patients with ileitis who do not respond to 5-ASA. Metronidazole is the preferred antibiotic in Crohn's ileocolitis or colitis, starting at 10 mg and increasing to 20 mg/kg/day if tolerated. A clinical response is expected within 3 to 4 weeks; prolonged treatment with metronidazole can cause peripheral neuropathy. Ciprofloxacin and clarithromycin can be used as alternatives.

Corticosteroid therapy should be considered for patients with marked systemic symptoms and those who fail to respond to 5-ASA compounds and antibiotics. Prednisone, 30 to 60 mg daily by mouth, is the usual starting dose depending on the patient's clinical state. An aggressive approach is favored, using 60 mg for 10 days before initiating a slowly tapering schedule. Steroids with reduced systemic penetration have a role in these patients. In two well-controlled and randomized studies a controlled-release form of budesonide induced remission in about 50% of patients. This steroid is more potent than prednisone and is largely degraded during first hepatic passage, leading to minimal systemic delivery of the drug. The overall efficacy of budesonide in Crohn's disease may be reduced compared with systemic steroids, however, and this agent is not yet approved for this use in the United States.

Severely ill patients with ileocolitis or colitis may require immediate hospitalization for bowel rest, rehydration, parenteral steroids, and possibly antibiotic therapy. These patients should be monitored for anemia, severe intestinal bleeding, or toxic megacolon.

[edit] Localized Peritonitis.

Patients with localized peritoneal signs should be evaluated for extramural complications, and treatment with broad-spectrum antibiotics should be started. The combination of metronidazole with a broad-spectrum cephalosporin or with ampicillin plus gentamicin provides appropriate coverage. The use of steroids is controversial because they may mask and facilitate progressive sepsis and peritonitis.

[edit] Chronic Small Bowel Obstruction.

Obstruction can result from a stricture, intestinal adhesion, or rarely an enterolith. Obstructive episodes are often precipitated by inflammation or spasm of the narrowed segment, and patients usually respond to medical therapy. Nasogastric suction, IV fluids, and steroids often lead to prompt improvement. Patients who fail to improve or who depend on high-dose steroids should undergo surgery.

[edit] Refractory and Steroid-dependent Disease.

Controlled trials and a meta-analysis indicate that azathioprine and 6-MP are effective in both refractory and steroid-dependent Crohn's disease.^[10] Treatment is initiated at 50 mg/day with either of these purine analogs. If no improvement is obtained after 4 weeks, the dose is increased by 25-mg increments every month, to a maximum of 2.5 mg/kg/day of azathioprine or 1.5 mg/kg/day of 6-MP. The prolonged time to peak response (3 to 6 months) suggests that a reduction in steroid dosage should be delayed. Clinical remission occurs in 60% to 70% of patients with resistant small or large bowel Crohn's disease. Intramuscular or oral methotrexate is effective in patients who do not respond or are intolerant to purine analogs. A liver biopsy is recommended for patients who receive a cumulative dose of 1 to 1.5 gm of methotrexate. Folic acid supplements are given to patients taking methotrexate to decrease side effects.

Parenteral infusion of monoclonal chimeric anti–tumor necrosis factor (TNF)-α antibodies is now approved for severe Crohn's disease. In one study, 65% of patients with moderate to severe Crohn's disease showed improvement and 33% entered remission, compared with 17% and 4% in the placebo group, respectively.^[11] Caution should be used in administering this new drug until its safety profile is better defined.^[12] The development of anti-DNA antibodies and some cases of lymphoma have been reported in patients receiving this compound. Other agents currently under evaluation for use in Crohn's disease include anti-CD4 antibodies, recombinant interleukin-10, and intercellular adhesion molecule 1 (ICAM-1) antisense oligonucleotides.

[edit] Perianal Disease.

Metronidazole, 10 to 20 mg/kg/day, is the drug of choice for perianal disease. Because high dosages may need to be maintained for a prolonged period, patients should be made aware of potential side effects, particularly the occurrence of paresthesias, that may persist for long periods after discontinuation of the drug. A 50% relapse rate follows cessation of metronidazole. Abscesses require surgical drainage. Patients who do not improve with metronidazole and local surgical management are candidates for 6-MP therapy.

[edit] Fistulas.

Attempts should be made to manage fistulas medically because of the high rate of recurrence after surgery. Metronidazole is initiated at 10 mg/kg/day and increased to 20 mg/kg/day if needed and tolerated. 6-MP is the second-line agent. Patients with jejunocolic fistulas may have bacterial overgrowth responsive to antibiotics. In one study, anti-TNF-α antibodies induced closure of 46% of fistula vs. 13% in the placebo group.^[11] Treatment of enterovesical fistulas should include antibiotics to control the urinary tract infection as well as therapy for the underlying active Crohn's disease. 6-MP is the agent of choice for enterovesical fistulas, but most patients will require surgery because of progression of the underlying bowel disease.

[edit] Dietary Management.

No compelling evidence exists to recommend a specific diet for all patients with Crohn's disease. Those with active disease or chronic strictures often benefit from a low-residue diet. Severely ill patients should be treated by bowel rest. Enteral feeding with an elemental diet or total parenteral nutrition may be used in patients with steroid-refractory or steroid-resistant Crohn's disease. Both these nutritional approaches seem to be equally effective in inducing remission.

[edit] Maintenance of Remission.

Although less successful in Crohn's disease than in ulcerative colitis, 5-ASA agents are indicated for maintaining remission (see Table 108-2). The role of steroids as maintenance agents in Crohn's disease is still unclear, but their systemic toxicity make them less than ideal. Both azathioprine and 6-MP are used to maintain remission, especially for patients who entered remission while taking these agents.

[edit] Surgical Treatment.

Approximately 70% of patients with Crohn's disease require surgery at some point in their disease course. Because recurrence after surgery is the rule rather than the exception, surgery should always be as conservative as possible. Abscesses should be drained under CT guidance when feasible, but the frequent occurrence of secondary enterocutaneous fistulas is an indication for surgical resection. Symptomatic ileal strictures may require surgical correction by stricturoplasty or resection. Gastroduodenal strictures are managed by gastrojejunal anastomosis. If proctocolectomy is indicated, a permanent ileostomy is necessary because patients with Crohn's disease are not good candidates for an ileoanal anastomosis with pouch. A surgeon should be involved in the management of patients with perianal Crohn's disease.

Slow-release mesalamine (Pentasa), metronidazole, and 6-MP have shown efficacy in preventing postoperative relapse after ileal resection and anastomosis. The effect of metronidazole does not appear to exceed 1 year, and its toxicity may not be compatible with long-term use.

[edit] COLON CANCER SURVEILLANCE

Patients with ulcerative colitis are at increased risk for colon cancer. Cancer risk increases with duration of disease and disease extent. Disease activity is not closely associated with cancer risk. Patients with extensive colitis have a 5% risk of colon cancer after 20 years of colitis, 12% after 25 years, and 25% after 35 years. Colon cancer surveillance is usually recommended for patients with extensive colitis for 8 to 10 years or left-sided colitis for 12 to 15 years. Colonoscopy is performed initially every 2 years and annually after 15 years of colitis. Serial biopsies are done to look for histologic evidence of dysplasia. Colon cancer in ulcerative colitis is frequently a flat, broad-based lesion rather than an exophytic mass, so even small, sessile, mucosal lesions should be biopsied. Indications for colectomy include carcinoma, confirmed high-grade dysplasia, or dysplasia in a mucosal plaque or nodule (dysplasia-associated lesion or mass). Patients with low-grade dysplasia should undergo repeat surveillance within 6 months. Recommendations for colon cancer screening in ulcerative colitis have not been tested by controlled clinical trials, and the cost-effectiveness is questionable.

Patients with Crohn's disease are at increased risk for small bowel adenocarcinoma and probably also for colon cancer. Colonoscopic screening may be appropriate for patients with longstanding, extensive Crohn's colitis, but no established screening protocols exist for intestinal carcinoma in Crohn's disease.

[edit] EXTRAINTESTINAL MANIFESTATIONS

The most common symptomatic extraintestinal manifestation of IBD is an asymmetric, nondeforming, pauciarticular, migratory arthralgia affecting the knees, hips, ankles, or elbows (Box 108-4). It is most common in Crohn's colitis, less common in ulcerative colitis, and rarely complicates Crohn's disease isolated to the small intestine. This arthritis follows the activity of the colitis and responds to effective treatment of the colonic disease. Arthralgia may occur in combination with other extraintestinal manifestations of IBD that mirror disease activity, such as erythema nodosum and uveitis. Erythema nodosum is more common in Crohn's disease, usually occurs during a disease flare, and seldom recurs. Pyoderma gangrenosum is characterized by large skin ulcers, typically on the lower limbs. It usually develops in patients with extensive and active ulcerative colitis and usually resolves when the colitis remits.

Patients with ulcerative colitis have a 30-fold increased risk for developing the rare condition of sacroiliitis with ankylosing spondylitis. The majority of affected IBD patients are HLA-B27 positive. The progress of ankylosing spondylitis does not reflect the severity of intestinal disease and is not altered by medical management of IBD or by colectomy. Sacroileitis alone is more common than sacroileitis with ankylosing spondylitis and is often asymptomatic and nonprogressive.

Sclerosing cholangitis is characterized by inflammation and fibrosis of the intrahepatic and extrahepatic biliary-tree leading to cholestasis. Most patients with sclerosing cholangitis have ulcerative colitis. Their colitis is frequently mild or even asymptomatic, however, and the course of the liver disease does not parallel that of their colonic disease. Sclerosing cholangitis frequently progresses to severe cholestatic liver disease and liver failure requiring transplantation. Cholangiocarcinoma develops in approximately 15% of patients with chronic sclerosing cholangitis and ulcerative colitis.

Patients with Crohn's disease of the terminal ileum and ileal resection are at increased risk for developing cholesterol gallstones due to interruption of the enterohepatic circulation of bile salts. Calcium oxalate renal stones are also more common in Crohn's disease as a result of fatty acid malabsorption. The fatty acids sequester calcium, thereby reducing the luminal formation of poorly absorbed calcium oxalate. Instead, sodium oxalate forms and is readily absorbed in the colon, leading to increased urinary oxalate secretion. Urinary tract complications may also occur in Crohn's disease when intestinal inflammation involves the ureter or fistula formation involves the urinary bladder.

[edit] SPECIALIST REFERRAL

The majority of patients with IBD are managed in consultation with a gastroenterologist. After initial diagnosis, patients with mild, limited ulcerative colitis that responds well to 5-ASA or sulfasalazine therapy may not require regular specialist consultation and management. Patients with severe, extensive ulcerative colitis and most patients with Crohn's disease should have regular consultation with a physician experienced in the treatment of IBD.

[edit] REFERENCES