AUTHOR INFORMATION

Section 1 of 12

Authored by William Shapiro, MD, Consulting Staff, Department of Urgent Care and Emergency Medicine, Scripps Clinic and Research Foundation

William Shapiro, MD, is a member of the following medical societies: Oakland County Medical Society

Edited by William K Chiang, MD, Associate Professor, Department of Emergency Medicine, New York University School of Medicine; Consulting Staff, Department of Emergency Medicine, Bellevue Hospital Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Eugene Hardin, MD, FACEP, FAAEM, Chair and Associate Professor, Department of Emergency Medicine, Charles R Drew University of Medicine and Science; Chair, Department of Emergency Medicine, Martin Luther King, Jr/Drew Medical Center; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Jonathan Adler, MD, Attending Physician, Department of Emergency Medicine, Massachusetts General Hospital; Division of Emergency Medicine, Harvard Medical School

Author's Email:	William Shapiro, MD
Editor's Email:	William K Chiang, MD

eMedicine Journal, July 13 2006, VOLUME 7, Number 7

INTRODUCTION

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Background: Inflammatory bowel disease (IBD) commonly refers to ulcerative colitis (UC) and Crohn disease (CD), which are chronic inflammatory diseases of the GI tract of unknown etiology. Crohn disease is also referred to as regional enteritis, terminal ileitis, or granulomatous ileocolitis.

Pathophysiology: Increasing evidence suggests that, at least in CD, there is a defect in the function of the intestinal immune system. As a consequence, there is a breakdown of the defense barrier of the gut, which, in turn, results in exposure of the mucosa to microorganisms or their products. The result is a chronic inflammatory process mediated by T cells. Hence, therapy should be directed at improving the intestinal immune system. It has been postulated that genetic factors may predispose certain individuals to developing a "leaky gut."

In UC, inflammation always begins in the rectum, extends proximally a certain distance, and then abruptly stops. A clear demarcation exists between involved and uninvolved mucosa. The rectum is always involved in UC, and no "skip areas" are present. UC primarily involves the mucosa and the submucosa, with formation of crypt abscesses and mucosal ulceration. The mucosa typically appears granular and friable. In more severe cases, pseudopolyps form, consisting of areas of hyperplastic growth with swollen mucosa surrounded by inflamed mucosa with shallow ulcers. In severe UC, inflammation and necrosis can extend below the lamina propria to involve the submucosa and the circular and longitudinal muscles, although this is unusual.

UC remains confined to the rectum in approximately 25% of cases. In the remainder of cases, UC spreads proximally and contiguously. Pancolitis occurs in 10% of patients. The small intestine is never involved, except when the distal terminal ileum is inflamed in a superficial manner, referred to as backwash ileitis. Even with less than total colonic involvement, the disease is strikingly and uniformly continuous. As the disease becomes chronic, the colon becomes a rigid foreshortened tube that lacks its usual haustral markings, leading to the lead pipe appearance observed on barium enema. The skip areas (ie, normal areas of the bowel interspersed with diseased areas) observed in CD of the colon do not occur in UC.

CD, on the other hand, consists of segmental involvement by a nonspecific granulomatous inflammatory process. The most important pathologic feature is involvement of all layers of the bowel, not just the mucosa and the submucosa, as is characteristic of UC.

Furthermore, CD is discontinuous, with skip areas interspersed between one or more involved areas. Late in the disease, the mucosa develops a cobblestone appearance, which results from deep longitudinal ulcerations interlaced with intervening normal mucosa. The 3 major patterns of involvement in CD are (1) disease in the ileum and cecum, occurring in 40% of patients; (2) disease confined to the small intestine, occurring in 30% of patients; and (3) disease confined to the colon, occurring in 25% of patients. Rectal sparing is a typical but not constant feature of CD. However, anorectal complications (eg, fistulas, abscesses) are common. Much less commonly, CD involves the more proximal parts of the GI tract, including the mouth, tongue, esophagus, stomach, and duodenum. CD causes 3 patterns of involvement: (1) inflammatory disease, (2) strictures, and (3) fistulas.

UC and CD are generally diagnosed using clinical, endoscopic, and histologic criteria. However, no single finding is absolutely diagnostic for one disease or the other. Furthermore, approximately 20% of patients have a clinical picture that falls between CD and UC; they are said to have indeterminate colitis.

The incidence of gallstones and kidney stones is increased in CD because of malabsorption of fat and bile salts. Gallstones are formed because of increased cholesterol concentration in the bile, caused by a reduced bile salt pool. Patients who have CD with ileal disease or resection also are likely to form calcium oxalate kidney stones. With the fat malabsorption, unabsorbed long-chain fatty acids bind calcium in the lumen. Oxalate in the lumen normally is bound to calcium. Calcium oxalate is poorly soluble and poorly absorbed; however, if calcium is bound to malabsorbed fatty acids, oxalate combines with sodium to form sodium oxalate, which is soluble and is absorbed in the colon (enteric hyperoxaluria). The development of calcium oxalate stones in CD requires an intact colon to absorb oxalate. Patients with ileostomies do not develop calcium oxalate stones.

Extraintestinal manifestations of IBD include iritis, episcleritis, arthritis, and skin involvement, as well as pericholangitis and sclerosing cholangitis.

Frequency:

• In the US: The incidence is 70-150 cases per 100,000 individuals.

Mortality/Morbidity: The quality of life generally is lower with CD than with UC, in part because of recurrences after surgery performed for CD.

• The most common causes of death in IBD are peritonitis with sepsis, malignancy, thromboembolic disease, and complications of surgery.

• Toxic megacolon, one of the most dreaded complications of UC, can lead to perforation, sepsis, and death.

• Malnutrition and chronic anemia are observed in long-standing CD.

• Children with CD or UC can exhibit growth retardation.

Race:

• Incidence among whites is approximately 4 times that of other races.

• IBD is observed most commonly in Northern Europe and North America. It is a disease of industrialized nations.

• Incidence is higher in Ashkenazi Jews (ie, those who have immigrated from Northern Europe) than in other groups.

Sex: Incidence is slightly greater in females than in males.

Age:

• Incidence peaks in the second and third decades of life.

• A second smaller peak occurs in patients aged 55-65 years.

• CD and UC can occur in childhood, although the incidence is much lower in children younger than 15 years.

CLINICAL

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History:

• Patients with ulcerative colitis (UC) most commonly present with bloody diarrhea, whereas patients with Crohn disease (CD) usually present with nonbloody diarrhea.

• Abdominal pain and cramping, fever, and weight loss occur in more severe cases.

• The greater the extent of colon involvement, the more likely the patient is to have diarrhea.

• Rectal urgency or tenesmus reflects reduced compliance of the inflamed rectum.

• Patients might have formed stools if their disease is confined to the rectum.

• As the degree of inflammation increases, systemic symptoms develop, including low-grade fever, malaise, nausea, vomiting, sweats, and arthralgias.

• Fever, dehydration, and abdominal tenderness develop in severe UC, reflecting progressive inflammation into deeper layers of the colon.

• The presentation of CD is generally more insidious than that of UC, with ongoing abdominal pain, anorexia, diarrhea, weight loss, and fatigue.

• Grossly bloody stools, while typical of UC, are less common in CD.

• Stools may be formed, but loose stools predominate if the colon or the terminal ileum is involved extensively.

• One half of patients with CD present with perianal disease (eg, fistulas, abscesses).

• Occasionally, acute right lower quadrant pain and fever may be noted, mimicking appendicitis.

• Commonly, the diagnosis is established only after several years of recurrent abdominal pain, fever, and diarrhea.

• CD with gastroduodenal involvement may mimic peptic ulcer disease and can progress to gastric outlet obstruction.

• Many patients with inflammatory bowel disease (IBD) have irritable bowel syndrome, which can produce occasional cramping, irregular bowel habits, and passage of mucus without blood or pus.

• Weight loss is observed more commonly in CD than in UC because of the malabsorption associated with small bowel disease. Patients may reduce their food intake in an effort to control their symptoms.

• Systemic symptoms are common and include fever, sweats, malaise, and arthralgias. A low-grade fever may be first warning sign of a flare.

• Recurrences may occur with emotional stress, infections or other acute illnesses, pregnancy, dietary indiscretions, use of cathartics or antibiotics, or withdrawal of anti-inflammatory or steroid medications.

• Children may present with growth retardation and delayed or failed sexual maturation.

• In 10-20% of cases, patients present with extraintestinal manifestations, including arthritis, uveitis, or liver disease.

Physical:

• Fever, tachycardia, dehydration, and toxicity may occur. Pallor may be noted, reflecting anemia. The magnitude of these factors is related directly to the severity of the attack.

• Evaluate for signs of localized peritonitis, although abdominal tenderness is common. Patients with toxic megacolon appear septic. They have high fever; lethargy; chills; tachycardia; and increasing abdominal pain, tenderness, and distention.

• Patients with CD may develop a mass in the right lower quadrant.

• The rectal examination often reveals bloody stool on gross or Hemoccult examination.

• Complications (eg, perianal fissures or fistulas, abscesses, rectal prolapse) may be observed in up to 90% of patients with CD.

• Include in the examination a search for extraintestinal manifestations, such as iritis, episcleritis, arthritis, and dermatologic involvement.

  Distinguishing Features of CD Versus UC

  Features	Crohn Disease	Ulcerative Colitis
  Skip areas	Common	Never
  Cobblestone mucosa	Common	Rare
  Transmural involvement	Common	Occasional
  Rectal sparing	Common	Never
  Perianal involvement	Common	Never
  Fistulas	Common	Never
  Strictures	Common	Occasional
  Granulomas	Common	Occasional

Causes: The etiology of IBD is unknown. Environmental, infectious, genetic, autoimmune, and host factors have been suspected. Interactions among these factors may be more important.

The risk of developing UC is higher in nonsmokers and former smokers than in current smokers. The onset of UC occasionally appears to coincide with smoking cessation. This does not imply that smoking would improve the symptoms of UC. Interestingly, some success in the use of nicotine patches has been reported. On the contrary, patients with CD have a higher incidence of smoking than the general population, and those patients with CD who continue to smoke appear to be less likely to respond to medical therapy.

• Inflammatory mediators

• Interleukin-1

• Tumor necrosis factor–alpha (TNF-alpha)

• Aggravation by bacterial infection and inflammatory cascade

• Positive family history: The most important risk factor for developing IBD is a positive family history.

DIFFERENTIALS

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Appendicitis, Acute
Diverticular Disease
Endometriosis
Pelvic Inflammatory Disease

Other Problems to be Considered:

AIDS (The chronic diarrhea and diffuse colonic involvement of Kaposi sarcoma may mimic chronic UC.)
Antibiotic-associated colitis
Arteriovenous malformations
Collagenous colitis
Colon cancer
Fever of unknown origin
Infectious colitis (if confined to the rectum, rule out "gay bowel syndrome")
Intestinal lymphoma
Irritable bowel syndrome (can be present along with IBD): In IBS, diarrhea often alternates with constipation. In contrast to IBD, IBS is not associated with blood in the stool, nocturnal diarrhea, weight loss, or other inflammatory sequelae (eg, fever, arthritis, skin or eye lesions, perianal disease). Fecal WBCs are not observed in IBS.
Ischemic colitis
Pseudomembranous colitis
Radiation-induced colitis

WORKUP

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Lab Studies:

• CBC with differential

• Anemia may result from acute or chronic blood loss or malabsorption (iron, folate, vitamin B-12) or may reflect the chronic disease state.

• Leukocytosis, anemia, and thrombocytosis are common. A modestly elevated WBC is observed in active disease, but a marked elevation suggests the presence of an abscess or other suppurative complication.

• Erythrocyte sedimentation rate: The sedimentation rate is typically elevated and has been used to monitor disease activity.

• Serum chemistry

• Hypokalemia reflects the severity of the diarrhea.

• Abnormal liver function test results may represent pericholangitis or sclerosing cholangitis.

• Hypoalbuminemia, resulting from protein-losing enteropathy, suggests extensive colitis.

• Decreased serum calcium may reflect reduced serum albumin.

• Type and cross-match: Consider obtaining a type and cross-match.

• Stool examination: Send stool for fecal leukocytes, ova and parasite studies, bacterial pathogens culture, and Clostridium difficile titer.

• Amebiasis can be difficult to identify from the stool. Consider serologic testing in this regard.

• As many as 50-80% of cases of acute terminal ileitis are due to Yersinia enterocolitis infections. This produces a picture of pseudoappendicitis. Yersiniosis also has a high frequency of secondary manifestations, such as erythema nodosum and monarticular arthritis, similar to IBD.

• Blood culture: Cultures may be positive if peritonitis or fulminant colitis is present.

• New serologic tests: Recently, new serologic tests have become available to aid in the diagnosis of IBD and differentiate between CD and UC. Perinuclear antineutrophil cytoplasmic antibodies (pANCA) have been identified in some patients with UC, and anti-Saccharomyces cerevisiae antibodies (ASCA) have been found in patients with CD. Furthermore, those patients with IBD who are seronegative appear to have a lower incidence of resistant disease. Currently, these markers are not sensitive enough to be used as screening tests for IBD.

Imaging Studies:

• Upright chest radiography and abdominal series

• Evaluate for an edematous irregular colon with “thumb printing.” Occasionally, there may be pneumatosis coli (air in the colonic wall).

• Look for free air and especially for evidence of toxic megacolon, which appears as a long continuous segment of air-filled colon greater than 6 cm in diameter (see Image 2).

• In the supine position, dilatation is predominantly noted in the transverse colon secondary to air collection.

• Repeat radiographs at 12- to 24-hour intervals to monitor the course of dilatation and to assess the need for emergency colectomy.

• Associated findings include nephrolithiasis, cholelithiasis, or arthritis of the spine or the sacroiliac joints.

• Barium enema

• In UC, a barium enema (BE) may reveal a shortened colon, with loss of haustrations and destruction of the mucosal pattern (ie, lead pipe colon).

• Skip areas and rectal sparing are noted in CD.

• BE is contraindicated in patients with moderate-to-severe colitis because it risks perforation or precipitation of a toxic megacolon.

• Upper GI with small bowel follow-through

• In CD, areas of segmental narrowing with loss of normal mucosa, fistula formation, and the string sign (a narrow band of barium flowing through an inflamed or scarred area) in the terminal ileum are typically observed.

• Some patients with UC also demonstrate inflammatory changes in the terminal ileum (ileitis), but they lack the skip pattern characteristic of CD.

• CT scanning and ultrasonography: CT scanning and ultrasonography are best for demonstrating intra-abdominal abscesses, mesenteric inflammation, and fistulas.

• More recently, wireless capsule endoscopy, used most often to investigate the source of GI bleeding, has been found useful in diagnosing mucosal lesions in CD.

Procedures:

• Findings on sigmoidoscopy may be diagnostic in UC because the rectum is always involved.

• The mucosal surface becomes irregular and friable, bleeds easily when touched, and may have pseudopolyps.

• Because of the degree of sensitivity, a colonoscopy is recommended for making the diagnosis and for evaluating the extent and severity of disease.

• Avoid procedures in acutely ill patients.

TREATMENT

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Emergency Department Care:

• Initiate supportive care with bowel rest, nasogastric suction, and intravenous (IV) fluids containing electrolytes.

• Admit for toxicity, obstruction, hemorrhage, or localized peritonitis.

• Monitor severe cases for fat malabsorption.

• Treat perirectal disease.

• Sitz baths

• Soap and water after stooling

• Surgical drainage of perirectal abscesses

• Surgical treatment of recurrent fistulas if medical management fails

• Administer folate supplementation as needed.

Consultations:

• Consult a surgeon for complicating obstruction, hemorrhage, perforation, abscess or fistula formation, toxic megacolon, or perianal disease.

• Consider surgical intervention for patients in whom medical therapy fails. The 2 most common choices today (for UC) are proctocolectomy with ileostomy and total colectomy with ileoanal anastomosis. Elective surgery can sometimes be performed laparoscopically. For fulminant colitis, the surgical procedure of choice consists of a subtotal colectomy with end ileostomy and creation of a Hartman pouch.

• In CD, surgically resect only as much bowel as necessary to correct the problem because the recurrence rate after surgery approaches 100%.

• Patients with toxic megacolon initially require nasogastric suction and IV steroids. Failure to improve within 48 hours is an indication for total colectomy.

• Extracolonic manifestations (ie, uveitis, arthritis, dermatitis, sclerosing cholangitis) are best managed with the aid of specialty consultation.

MEDICATION

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Therapy for CD generally is less effective than that for UC. In addition to the therapies outlined herein, IV cyclosporine is helpful in refractory UC. Zileuton, a 5-lipoxygenase inhibitor, has shown some efficacy in treating CD.

Hyperbaric oxygen therapy may be helpful in the treatment of IBD that is unresponsive to other therapies. Its therapeutic efficacy appears to result from decreased generation of prostaglandin E2. Previous work has linked mucosal prostaglandin E2 to the intestinal damage associated with IBD.

Agents for symptomatic treatment include loperamide and the combination of diphenoxylate and atropine, which are useful in mild disease to reduce the number of bowel movements and to relieve rectal urgency. Cholestyramine, a resin that binds bile salts, is useful for reducing diarrhea in patients with CD who have had ileal resections. The anticholinergic agent dicyclomine may help relieve intestinal spasms. Antidiarrheal and anticholinergic medications must be avoided in acute severe disease because they may precipitate toxic megacolon. Avoid the long-term use of narcotics for pain. An iron supplement should be added when significant rectal bleeding is present.

Drug Category: Antidiarrheal agents -- These agents inhibit peristalsis in the GI tract.

Drug Name	Loperamide (Imodium) -- Acts in intestinal muscles to inhibit peristalsis and to slow intestinal motility. Prolongs movement of electrolytes and fluid through bowel; increases viscosity and loss of fluids and electrolytes.
Adult Dose	Initial dose: 4 mg PO Maintenance: 2 mg PO after each loose stool; not to exceed 16 mg/d
Pediatric Dose	2-6 years: 1 mg PO tid initially; followed by 0.1 mg/kg PO after each loose stool; not to exceed 1 mg tid 6-8 years: 2 mg PO bid initially; followed by 0.1 mg/kg PO after each loose stool; not to exceed 2 mg bid 8-12 years: 2 mg PO tid initially; followed by 0.1 mg/kg PO after each loose stool; not to exceed 2 mg tid >12 years: Administer as in adults Chronic diarrhea: 0.08-0.24 mg/kg/d PO divided bid/tid; not to exceed 2 mg/dose
Contraindications	Documented hypersensitivity; diarrhea resulting from infection; pseudomembranous colitis
Interactions	Phenothiazines, tricyclic antidepressants, and CNS depressants may increase toxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Discontinue use if no clinical improvement is noted in 48 h; because metabolized primarily in liver, monitor for CNS toxicity in patients with hepatic insufficiency; do not use if high fever or blood in stool coincides with diarrhea

Drug Name	Diphenoxylate and Atropine (Lomotil) -- Drug combination that consists of diphenoxylate, a constipating meperidine congener, and subtherapeutic amount of atropine to discourage abuse. Inhibits excessive GI propulsion and motility.
Adult Dose	15-20 mg/d PO tid/qid; followed by 5-15 mg/d
Pediatric Dose	<2 years: Not recommended >2 years: 0.3-0.4 mg/kg/d PO divided qid 2-5 years: 2 mg PO tid 5-8 years: 2 mg PO qid 8-12 years: 2 mg PO 5 times/d >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; narrow-angle glaucoma; hepatic insufficiency
Interactions	May delay metabolism of drugs by liver; CNS depressants, MAOIs, and antimuscarinic agents may increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Dehydration may influence variability of response in young children, predisposing them to delayed diphenoxylate intoxication; caution in patients with UC; decrease in intestinal motility may be detrimental to patients with diarrhea resulting from Shigella and Salmonella species and toxigenic strains of Escherichia coli

Drug Name	Cholestyramine (Questran) -- Useful in treating diarrhea associated with pseudomembranous colitis. Inhibits enterohepatic reuptake of intestinal bile salts by forming nonabsorbable complex with bile acids in intestine.
Adult Dose	4 g PO qd/bid; not to exceed 24 g/d or 6 doses/d
Pediatric Dose	240 mg/kg/d PO divided tid
Contraindications	Documented hypersensitivity
Interactions	Inhibits absorption of numerous drugs, including warfarin, thyroid hormone, amiodarone, NSAIDs, methotrexate, digitalis glycosides, glipizide, phenytoin, imipramine, niacin, methyldopa, tetracyclines, clofibrate, hydrocortisone, and penicillin G
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in constipation and phenylketonuria

Drug Category: Antispasmodic agents -- These agents are used to treat functional disturbances of GI motility.

Drug Name	Dicyclomine (Bentyl) -- Useful in treating GI motility disturbances; blocks action of acetylcholine at parasympathetic sites in secretory glands, smooth muscle, and CNS.
Adult Dose	80 mg/d PO divided qid initially, then increase to 160 mg/d
Pediatric Dose	10 mg/dose PO tid/qid
Contraindications	Documented hypersensitivity; myasthenia gravis; narrow-angle glaucoma
Interactions	Effects are weakened when administered with anti-Parkinson drugs, haloperidol, and phenothiazines; toxicity increases when administered concurrently with amantadine, antihistamines, type I antiarrhythmics, phenothiazines, TCAs, or narcotic analgesics
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution when administering to patients with hepatic or renal insufficiency, cardiovascular disease, urinary tract obstruction, UC, GI obstruction, hyperthyroidism, or hypertension

Drug Category: Aminosalicylates -- These agents are effective for treating acute UC and for maintaining its remission; they are also beneficial in mildly to moderately active CD when the colon is involved. Sulfasalazine has not been clearly shown to maintain remission in CD. Furthermore, there is some question as to its effectiveness versus small bowel disease.

Newer aminosalicylate preparations without sulfapyridine (eg, 5-aminosalicylic acid [5-ASA]) were developed because tolerance of sulfasalazine has been limited by the sulfa-containing moiety. Because free 5-ASA is absorbed rapidly from the proximal GI tract, it has been modified in the newer formulations. Olsalazine consists of two 5-ASA molecules linked together by an azo bond. Intestinal bacteria cleave the bond, which enables olsalazine to work, primarily in the colon.

Additional formulations of 5-ASA (mesalamine) are Asacol, Pentasa, Rowasa, and Balsalazide. Asacol is composed of 5-ASA coated in a pH-dependent acrylic resin, which allows delayed release of 5-ASA in the distal ileum and the right colon. Pentasa consists of 5-ASA encapsulated into microgranules of ethylcellulose and released continuously throughout the GI tract. Therefore, it is useful in patients with CD involvement of the small bowel and the colon. Rowasa contains 5-ASA in suppository or enema formulations, which are useful for treating and maintaining remissions in ulcerative proctitis and proctosigmoiditis. Balsalazide is mesalamine linked to an inert carrier molecule. In the colon, bacteria cleave the bond and release free mesalamine.

Because oral aminosalicylates interfere with folate absorption, folic acid supplementation (1 mg/d) should be given.

Drug Name	Sulfasalazine (Azulfidine) -- Combination of 5-ASA or mesalamine and sulfapyridine. Taken PO, remains intact until it reaches terminal ileum and colon, where it is split by bacteria into its 2 moieties. Active portion appears to be 5-ASA, which inhibits prostaglandin synthesis; sulfa portion is absorbed and causes most adverse reactions. Abdominal discomfort common. Folate deficiency may result from competition between folate and sulfasalazine for absorption.
Adult Dose	3-4 g PO qd in divided doses
Pediatric Dose	<2 years: Not established >2 years: 30 mg/kg PO divided qid
Contraindications	Documented hypersensitivity; GI or GU obstruction
Interactions	Decreases effects of iron, digoxin, and folic acid; increases effects of PO anticoagulants, PO hypoglycemic agents, and methotrexate
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Pregnancy category D in last trimester of pregnancy; caution in patients with renal or hepatic impairment, blood dyscrasias, or urinary obstruction

Drug Name	Olsalazine (Dipentum) -- Alternate treatment for patients who do not tolerate sulfasalazine. Useful in maintaining remission in UC; exerts anti-inflammatory activity in UC.
Adult Dose	500 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Relatively high incidence of diarrhea may be dose related (unclear whether other underlying causes may contribute)

Drug Name	Mesalamine (Asacol, Pentasa, Rowasa, Canasa) -- Treats mildly to moderately active UC. Usual course of therapy in adults is 3-6 wk. Some patients may need concurrent PR and PO therapy.
Adult Dose	Cap: 1 g PO qid Tab: 800 mg PO tid Rectal supp: Insert 1 PR bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Decreases effects of iron, digoxin, and folic acid; mesalamine increases effect of PO anticoagulants, methotrexate, and PO hypoglycemic agents
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Elderly patients may have difficulty administering and retaining rectal suppositories; caution in renal or hepatic impairment

Drug Category: Corticosteroids -- These agents are the treatments of choice for an acute IBD attack; administer IV in severe disease. Give increased or stress doses to patients already on steroids. Do not use steroids for maintaining remission because of their lack of efficacy and potential complications, including avascular necrosis, osteoporosis, cataracts, emotional lability, hypertension, diabetes mellitus, cushingoid features, acne, and facial hair. Cortenema, Cortifoam, and Anusol-HC suppositories are useful in treating distal disease (proctitis and proctosigmoiditis).

Recently, budesonide (Entocort EC), a synthetic corticosteroid, has been released for CD with ileal or ileocecal involvement. It is indicated for PO treatment to induce remissions of attacks of mild-to-moderate severity involving the ileum and/or ascending colon. The drug contains budesonide granules in an ethylcellulose matrix coated with a methacrylic acid polymer. The coating, which requires a pH more than 5.5 to dissolve, prevents release of the drug in the stomach. The ethylcellulose matrix delays release further until the drug reaches the ileum and ascending colon. A potential advantage is that fewer adverse effects occur than with the use of systemic corticosteroids. However, some absorption occurs and may slow growth in adolescents.

Drug Name	Prednisone (Deltasone, Sterapred, Orasone) -- Used as immunosuppressant in treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.
Adult Dose	5-60 mg/d PO qd or divided bid/qid
Pediatric Dose	4-5 mg/m2/d PO; alternatively, 1-2 mg/kg PO qd; not to exceed 60 mg/d; taper over 2 wk as symptoms resolve
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular skin infections
Interactions	Estrogens may decrease clearance; concurrent digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur

Drug Name	Methylprednisolone (Adlone, Medrol, Solu-Medrol) -- Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and increasing permeability or capillaries.
Adult Dose	125-250 mg IV loading dose, followed by maintenance dose of 0.5-1 mg/kg/dose IV q6h for up to 5 d
Pediatric Dose	2 mg/kg IV loading dose, followed by maintenance dose of 0.5-1 mg/kg/dose IV q6h for up to 5 d
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular skin infections
Interactions	Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels; phenobarbital, phenytoin, and rifampin may decrease levels (adjust dose); monitor patients for hypokalemia when taking concurrently with diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications

Drug Name	Hydrocortisone (Anusol-HC, Anuprep HC) -- Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.
Adult Dose	10-100 mg PR qd/bid for 2-3 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular skin infections
Interactions	Clearance may decrease with estrogens; may increase digitalis toxicity secondary to hypokalemia
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hyperthyroidism, osteoporosis, peptic ulcer, cirrhosis, nonspecific UC, diabetes mellitus, and myasthenia gravis

Drug Category: Immunosuppressants -- These agents are useful as steroid-sparing agents, in healing fistulas, or when the patient has serious contraindications to surgery. They are used in patients refractory to or unable to tolerate steroids. Some agents, including azathioprine and its metabolite, 6-mercaptopurine, have been useful in CD complicated by recurrent rectal fistulas or perianal disease; response can take up to 6 months. Methotrexate has also been tried.

Drug Name	Azathioprine (Imuran) -- Inhibits mitosis and cellular metabolism by antagonizing purine metabolism and inhibiting synthesis of DNA, RNA, and proteins; these effects may decrease proliferation of immune cells and result in lower autoimmune activity.
Adult Dose	1 mg/kg/d PO for 6-8 wk; increase by 0.5 mg/kg PO q4wk until response noted; not to exceed 2.5 mg/kg/d
Pediatric Dose	Initial dose: 2-5 mg/kg/d PO/IV Maintenance dose: 1-2 mg/kg/d PO
Contraindications	Documented hypersensitivity
Interactions	Allopurinol increases toxicity; ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxic effects may occur; check TPMT level before therapy and monitor liver, renal, and hematologic functions; pancreatitis is rarely associated

Drug Category: Antibiotics -- Institute parenteral antibiotics active against coliforms and anaerobes for fulminant disease, including toxic megacolon. Agents may include metronidazole or ampicillin or a cephalosporin and an aminoglycoside.

Drug Name	Metronidazole (Flagyl) -- Useful in treating fulminant disease; used successfully in CD complicated by perianal ulcers and perirectal abscesses and fistulas; unclear whether drug is active because of its antibacterial properties or through some other mechanism.
Adult Dose	20 mg/kg/d PO in divided doses
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May increase toxicity of anticoagulants, lithium, and phenytoin; cimetidine may increase toxicity; disulfiram reaction may occur with orally ingested ethanol
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adverse reactions include peripheral neuropathy, possible carcinogenesis, and mutagenesis; adjust dose in patients with severe hepatic disease (may metabolize metronidazole slowly); monitor patients for seizures and development of peripheral neuropathy

Drug Category: Tumor necrosis inhibitors -- Infliximab (Remicade), given intravenously, consists of monoclonal antibodies to TNF-alpha. It has recently been approved by the FDA for use in IBD. Infliximab is somewhat more effective against CD than UC. The drug appears to promote mucosal healing, which not even prednisone does. Furthermore, it heals perianal and enterocutaneous fistulae and has been shown to reduce signs and symptoms, achieve clinical remission and mucosal healing, and eliminate corticosteroid use. Infliximab is indicated for patients who have experienced inadequate response to conventional therapy.

Etanercept (Enbrel) is a tumor necrosis factor (TNF) receptor fusion protein that binds to TNF-alpha and TNF-beta, blocking their interaction with TNF receptors. Although it is approved for the treatment of moderate-to-severe rheumatoid arthritis, it has also been used investigationally for CD, although such use is not yet approved. Etanercept can cause an increased risk of infections, which can be serious and life threatening.

Drug Name	Infliximab (Remicade) -- Neutralizes cytokine TNF-alpha and inhibits binding to TNF-alpha receptor.
Adult Dose	5 mg/kg IV as single infusion When long-term administration is needed, an induction dose of 5 mg/kg IV infusion at 0, 2, and 6 wk is administered, then 5 mg/kg q8wk for maintenance IV infusion must be administered over at least 2 h; must use infusion set with in-line, sterile, nonpyrogenic, low-protein-binding filter (pore size <1.2 mm)
Pediatric Dose	Induction: 5 mg/kg IV infusion; repeat for a total of 3 doses at 2, and 6 wk Maintenance: 5 mg/kg IV infusion q6wk
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	TNF-alpha modulates cellular immune responses; anti-TNF therapies, such as infliximab, may adversely affect normal immune responses and allow development of superinfections; chest pain or rash may occur during infusion; more cases of lymphoma were observed in TNF alpha-blockers compared to controlled groups; may increase risk of reactivation of tuberculosis in patients with particular granulomatous infections

FOLLOW-UP

Section 8 of 12

Further Outpatient Care:

• Nutritional support in CD includes supplementation with trace metals, fat-soluble vitamins, and medium-chain triglycerides.

• A low-oxalate diet with citrate supplementation helps reduce the risk of nephrolithiasis.

• Oral calcium or cholestyramine may serve as an intestinal oxalate binder.

• Encourage the patient to join an IBD support group, such as the Crohn’s and Colitis Foundation of America (386 Park Avenue South, 17th Floor; New York, NY 10016; 1-800-932-2423).

Complications:

• Perforation and toxic megacolon are the most dreaded complications of UC. Perforation can occur in the presence of fulminating disease, even in the absence of toxic megacolon.

• The mortality rate is 50% if perforation occurs.

• Suspect toxic megacolon in a patient with fulminant UC, especially if the number of daily stools has declined sharply without a corresponding improvement in symptoms. The abdomen is typically distended, tender, and tympanitic. Toxic megacolon can be precipitated by antidiarrheal agents, hypokalemia, narcotics, cathartics, and enemas, including barium enemas. The best method of diagnosing toxic megacolon is through the use of plain radiography. Toxic megacolon occurs predominantly in the transverse colon, probably because air collects there in the supine position. The transverse colon is dilated, usually more than 8 cm. Dilation more than 6 cm is considered to be abnormal. A colectomy is required if no improvement occurs within 24-48 hours.

• Strictures usually are benign but can lead to obstruction.

• Fistulas and abscesses are much more common in CD, but they are observed in about 20% of patients with UC.

• Fistula types include enterovesical (leading to recurrent urinary tract infections and pneumaturia), enteroenteric, enteromesenteric, enterocutaneous, rectovaginal, and perianal.

• Additional problems include stenosis and obstruction.

• Perianal complications occur in 90% of patients with CD.

• In CD, obstructive hydronephrosis may result from a right lower quadrant inflammatory mass, leading to external compression of the right ureter.

• Massive hemorrhage occurs in fewer than 1% of patients.

• Cancer concerns are as follows:

• UC carries a 10- to 30-fold increase in development of carcinoma of the colon.

• Risk increases with extent and duration of the disease.

• Cumulative risks of cancer after 15, 20, and 25 years are 8%, 12%, and 25%, respectively.

• Perform periodic colonoscopies with biopsies, especially in patients with pancolitis. Most authors recommend beginning surveillance approximately 10 years after onset of disease and repeating surveillance at 1- to 2-year intervals. Evidence currently does not support the need for cancer surveillance in CD.

  The risk of cancer in CD may be equal to that of UC if the entire colon is involved. Hence, screening may be beneficial for patients with CD who have pancolitis. The risk of small intestinal malignancy in CD is increased. However, the malignancy is as likely to arise in a normal as in an inflamed area, and no screening protocol has ever been demonstrated to be effective against small bowel CD.

• Extraintestinal complications occur in approximately 20% of patients with IBD. In some cases, they may be more problematic than the bowel disease itself.

• Arthritic
  • Peripheral arthritis, usually migratory and monoarticular, tends to parallel disease activity but may antedate it.

  • Ankylosing spondylitis is associated with human leukocyte antigen-B27 (HLA-B27).

• Ocular
  • Episcleritis manifests with burning eyes and scleral injection (see Image 3) and is observed in 3-4% of IBD cases. Episcleritis parallels the course of the disease and resolves with treatment of the IBD. Topical steroids may be administered.

  • Iritis, which manifests as an acute painful red eye with photophobia and conjunctival injection, often runs a course independent of intestinal disease. It can progress to blindness. Treatment is with topical or systemic steroids.

  • Cataracts are associated with long-term steroid use. Patients taking long-term steroids should have an annual slit-lamp examination.

• Dermatologic
  • Erythema nodosum is characterized by painful, tender, raised red or violaceous subcutaneous nodules, usually found over the extensor aspects of the arms and the legs, especially the anterior tibia. Activity usually follows that of the intestinal disease and often heralds onset of increased bowel activity.

  • Pyoderma gangrenosum is characterized by ulcerating relatively painless lesions that correlate with bowel activity in about 50% of patients (see Image 4). Although ulcers may exhibit purulent drainage, culture to the present time, the treatment of pyoderma gangrenosum has involved the use of corticosteroids and cyclosporine. Reports have indicated that, not only does the condition respond to infliximab, but this drug should probably be considered the drug of choice against pyoderma gangrenosum.

  • Aphthous ulcers are more common in patients with IBD than in the general population.

• Other
  • Additional extraintestinal manifestations include pericholangitis, chronic active hepatitis, cirrhosis, primary sclerosing cholangitis, and bile duct carcinoma. Pericholangitis is the most common hepatic complication of IBD and is usually asymptomatic. Look for elevations of the alkaline phosphatase, less often bilirubin. Primary sclerosing cholangitis can progress to cirrhosis, in which case liver transplantation is the treatment of choice. However, it can recur in the transplanted liver.

  • Gallstones occur in about one third of patients with CD, resulting from increased lithogenicity of the bile due to impaired ileal absorption of bile acids.

  • A hypercoagulable state can occur, leading to deep venous thromboses, pulmonary embolism, and arterial thromboses. Additionally, portal or hepatic vein thrombosis, stokes, retinal venous thrombosis, gonadal vein thrombosis, and mesenteric venous thrombosis have been reported. The incidence of thrombotic complications may be as high as 39%. The hypercoagulable state correlates with the activity of the disease. Its cause is unclear, but it may be related to increased levels of plasminogen activator inhibitor, factors V and VIII and fibrinogen or to decreased levels of factor V Leiden, antithrombin III, and proteins C and S.

Prognosis:

• UC

• A small percentage of patients have a single attack and no recurrence. Typically, however, remissions and exacerbations are characteristic of UC, with acute attacks lasting weeks to months.

• Twenty percent of patients require colectomy, which is curative.

• Long-term morbidity primarily results from complications of medical therapy, especially long-term steroids.

• CD

• Prognosis depends on the site and extent of disease.

• Periodic remissions and exacerbations are the rule.

• Approximately 50% of patients require surgical intervention; 50% of patients undergoing surgery require a second operation; of these patients, 50% have a third operation.

• Rate of recurrence is 25-50% within 1 year for patients who have responded to medical management. This rate is higher for patients who require surgery.

• Overall, the quality of life with CD generally is lower than with UC. Death usually occurs as a consequence of surgery, pulmonary embolus, or sepsis.

• Intestinal cancer may become a more important long-term complication in patients with CD because of longer survival.

Patient Education:

• For excellent patient education resources, visit eMedicine's Crohn Disease Center and Esophagus, Stomach, and Intestine Center. Also, see eMedicine's patient education articles, Inflammatory Bowel Disease, Crohn Disease, Crohn Disease FAQs, and Irritable Bowel Syndrome.

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Failure to obtain early surgical consultation for suspected obstruction, peritonitis, or fulminant disease

• Failure to consider diagnosis of IBD, especially CD, in patients presenting with perianal disease: Look for fistulous openings, induration, redness, or tenderness near the anus.

• Failure to recognize unusual presentations, such as sciatica resulting from a terminal ileal abscess with right iliopsoas extension

• Failure to recognize that steroids may mask the clinical severity of illness: The febrile patient on steroids may be harboring a serious bacterial infection or abscess.

• Failure to consider concomitant enteric infection (eg, C difficile) as the cause of an exacerbation

• Use of antidiarrheals, anticholinergics, and narcotics in fulminant disease, which should be avoided

• Overzealous use of steroids in the presence of an undrained abscess or when symptoms are due to a stricture or fibrotic process, rather than active inflammation

• Failure to perform endoscopic examination: Remember that all patients with new-onset rectal bleeding should undergo an endoscopic evaluation of the colon, unless an infectious etiology seems likely. For a young patient with apparent distal rectal bleeding (red blood on toilet paper and coating the stool), a flexible sigmoidoscopy may suffice.

• Prescribing NSAIDs: Beware of prescribing NSAIDs because they can lead to disruption of GI mucosal integrity and cause a flare of IBD.

• Failure to consider the diagnosis of Crohn disease in a patient with seemingly refractory gastric or duodenal ulcer disease.

Special Concerns:

• Children

• Approximately 15-30% of patients with IBD are younger than 20 years.

• Presentation can include growth failure from malnutrition and delayed sexual maturation. Many of these children also have depression.

• Sulfasalazine may be used as in adults, but administer steroids on an alternate day regimen, if possible, to diminish adverse effects.

• Although immunosuppressives have been used in children, concern for adverse reactions is high; the possibility of malignancy exists in view of potential for longer exposure.

• Pregnancy

• Outlook generally is favorable; however, IBD is associated with an increased frequency of adverse pregnancy outcomes, especially if the disease is active at the time of conception.

• Fertility in women with IBD is normal or only minimally impaired. The incidence of prematurity, stillbirth, and developmental defects in IBD are similar to those of the general population.

• If the IBD is inactive at time of conception, it is likely to remain inactive during pregnancy. If IBD is active at the time of conception, UC tends to worsen. In two thirds of patients who have active CD at the time of conception, the degree of activity remains the same; in the other third, some have improvement and others have deterioration.

• Sulfasalazine and steroids may be administered during pregnancy. Sulfasalazine can be taken throughout pregnancy; however, it interferes with folate absorption, and pregnant women have an increased requirement for folic acid. Hence, women taking sulfasalazine should also take 1 mg of folate twice a day. The use of steroids during pregnancy has not been associated with an increased rate of activity; thus, the risks of treatment with sulfasalazine or corticosteroids in pregnant women with IBD are less significant than the risks of allowing disease activity to go untreated.

TEST QUESTIONS

Section 10 of 12

CME Question 1: Which of the following is not typical of Crohn disease?

A: Rectal sparing
B: Cobblestoning
C: Skip areas
D: Backwash ileitis
E: Transmural involvement

The correct answer is D: Backwash ileitis is observed in ulcerative colitis and refers to occasional occurrence of superficial inflammation in the terminal ileum associated with contiguous proximal colonic involvement.

CME Question 2: Which of the following is not an extraintestinal manifestation of inflammatory bowel disease?

A: Arthritis
B: Uveitis
C: Coronary artery aneurysms
D: Erythema nodosum
E: Pericholangitis

The correct answer is C: Although cases of myocarditis associated with inflammatory bowel disease have been reported, coronary artery aneurysms have not been described.

Pearl Question 1 (T/F): Ulcerative colitis (UC) involves the colon in a continuous fashion, but it is usually limited to the mucosa and the submucosa. In Crohn disease (CD), the entire GI tract can be involved, accompanied by transmural inflammation with skip areas.

The correct answer is True: Even with less than total colonic involvement, UC is strikingly and uniformly continuous. CD is discontinuous, with skip areas interspersed between one or more involved areas. CD consists of segmental involvement by a nonspecific granulomatous inflammatory process. The most important pathologic feature of CD is involvement of all layers of the bowel, not just the mucosa and the submucosa.

Pearl Question 2 (T/F): The precipitants of an acute flare-up of inflammatory bowel disease are unknown.

The correct answer is False: Emotional stress, infections or other acute illnesses, pregnancy, dietary indiscretions, use of cathartics or antibiotics, or withdrawal of anti-inflammatory or steroid medications can precipitate flare-ups of inflammatory bowel disease.

Pearl Question 3 (T/F): Plain abdominal radiography is not helpful in evaluation of patients with inflammatory bowel disease.

The correct answer is False: Plain abdominal radiography may reveal the presence of free air, which is indicative of a perforation. Additional findings might include the presence of toxic megacolon (dilatation > 6 cm in diameter), nephrolithiasis, cholelithiasis, or arthritis of the spine or the sacroiliac joints.

Pearl Question 4 (T/F): A sigmoidoscopy should be obtained when an acute exacerbation of inflammatory bowel disease is suspected.

The correct answer is False: Barium enema, sigmoidoscopy, and colonoscopy may cause perforation or precipitate toxic megacolon under such circumstances.

PICTURES

Section 11 of 12

Caption: Picture 1. Inflammatory bowel disease. Distinguishing features of Crohn disease (CD) and ulcerative colitis (UC).
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Caption: Picture 2. Inflammatory bowel disease. Toxic megacolon. Courtesy of Dr Pauline Chu.
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Caption: Picture 3. Inflammatory bowel disease. Episcleritis. Courtesy of Dr David Sevel.
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Caption: Picture 4. Inflammatory bowel disease. Pyoderma gangrenosum. Courtesy of Dr Gene Izuno.
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Section 12 of 12

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