ACP medicine, 3rd Edition

Gastroenterology

Inflammatory Bowel Diseases

Stephen B. Hanauer MD1

1Professor of Medicine and Clinical Pharmacology, University of Chicago Pritzker School of Medicine, Director, Section of Gastroenterology/Nutrition, University of Chicago Hospital

The author has received grant support from Centocor, Inc, The Procter & Gamble Company, and Prometheus Laboratories, Inc.; has been a consultant for Centocor, Inc., The Procter & Gamble Company, Prometheus Laboratories, Inc., Salix Pharmaceuticals, Inc., and Shire Pharmaceuticals Group; and has participated in speakers' bureaus for Centocor, Inc., The Procter & Gamble Company, and Salix Pharmaceuticals, Inc.

May 2005

Ulcerative colitis (UC) and Crohn disease (CD) constitute the two major idiopathic inflammatory bowel diseases (IBDs). Gastroenterologists recognize that there is a spectrum of IBDs, encompassing varying types and degrees of intestinal inflammation, and that these idiopathic disorders must be distinguished from inflammation caused by infections, drugs (particularly nonsteroidal anti-inflammatory drugs [NSAIDs]), ischemia, and radiation. UC and CD are the most common and best understood IBDs, with a well-defined epidemiology and pathogenesis; their etiologies, however, remain elusive.1

Epidemiology

UC and CD share most epidemiologic characteristics.2 These diseases are relatively common in developed nations and infrequent in countries with poor sanitation. In North America and Europe, the incidence is approximately five cases per 100,000 population for each disease, with a combined prevalence of approximately 100 per 100,000 population. The diseases can affect persons of any age, but onset most commonly occurs in the second and third decades of life. Much smaller, secondary peaks in incidence occur in the sixth and seventh decades. Males and females are affected equally. Risk of disease is higher in some ethnic groups than in others. Ashkenazi Jews have a higher risk of IBD than Africans, African Americans, and Asians; the incidence of IBD increases in these lower-risk groups, however, when they emigrate to developed nations or adopt Western culture and diet.

Etiology

The cause of IBD has yet to be established. IBD probably has multiple causes, involving an interplay between genetically mediated susceptibility, environmental factors, and aberrant immune function. These disorders may well prove to be a series of syndromes with overlapping features.1 As yet, no dietary factor has been identified, despite case-control studies suggesting a possible association with the ingestion of large amounts of refined sugar and, perhaps, fat (essentially, the Western diet).3 Extrapolation from animal models of IBD suggests that commensal (rather than pathogenic) flora can initiate inflammation in genetically susceptible individuals,1,4 but no specific infectious agent has been identified as causa tive of either UC or CD.

There are two major clues to the etiology of IBDs. The first is the familial association of IBD, which suggests a genetic predisposition.5 Both UC and CD are more common in families with an affected relative. Once a proband has been identified, the risk of the disease occurring in a second family member is approximately 20% (40% if the proband is a child). The risk is distributed throughout families, with an estimated risk for individuals of 3% to 5% spread among first-, second-, and third-degree relatives. If both parents have IBD, the risk of disease in an offspring is nearly 50%. There is a concordance for disease type (and subtype, in the case of CD) within families, although either UC or CD may be seen.5 Risk of disease is highest in identical twins, with a concordance of 20% for UC and 60% for CD. This degree of risk suggests a polygenic causation with higher penetrance in CD.6 Genetic loci for IBD have been found: for example, the NOD2/CARD15 gene on chromosome 16 (IBD1) increases susceptibility to CD; other potential loci are being investigated.5

The second etiologic clue is the relationship between cigarette smoking and UC and CD.7 Case-control studies from around the world have demonstrated that cigarette smokers are less likely to develop UC and more likely to develop CD. In contrast, ex-smokers are more likely to develop UC. Cigarette smoking also influences the course of IBD; for example, ex-smokers with UC are more likely to have refractory disease and to require surgery than are patients who have never smoked.8 Cigarette smoking also protects against the development of primary sclerosing cholangitis associated with UC.9 Conversely, current cigarette smokers with CD are more likely to have disease that is refractory to medical therapies and that recurs more rapidly after surgical resection; these effects can be reversed by smoking cessation.10It has not been established whether nicotine is the primary factor in the associations of cigarette smoking with UC and CD. Nicotine delivered by transdermal patch appears to have a modest therapeutic potential for UC,11 although not as much as resumption of smoking.

Pathogenesis

There are numerous animal models for IBD, including the cotton-top tamarin, a New World monkey that, in captivity, develops a so-called spontaneous colitis with many features that are similar to those of human UC. These shared features include the development of antiepithelial antibodies, response to anti-inflammatory medications, and the development of dysplasia and adenocarcinoma.

Other animal models more closely mimic CD. These include genetically engineered transgenic rats that overexpress human HLA-B27 and β2-microglobulin molecules and knock-out mice with targeted deletions of interleukin 2 (IL-2), IL-10, T cell receptor chains, and transforming growth factor-β. The transfer of enriched populations of functional T helper type 1 (Th1) lymphocytes into severe combined immunodeficient mice induces colitis and wasting that can be prevented by transfer of unfractionated CD4+ T cells.1

Regardless of species or immune status, animals raised in germ-free environments do not develop intestinal inflammation.12 The significantly higher rate of autoimmune diseases in developed versus developing countries suggests that infectious agents (bacterial, viral, and parasitic) act as antigenic triggers and that exposure to numerous microorganisms early in life may protect against autoimmunity later in life; this is the so-called hygiene hypothesis.13 The loss of immune tolerance to specific (bacterial) antigenic triggers has been demonstrated in patients with CD.14 Hypothetically, environmental factors interact with a genetically determined, defective innate immune response. The innate immune defects may involve dendritic cells15 and Toll-like receptors16 [see 6:II Innate Immunity]; in addition, bacterial invasion of the mucosa may be facilitated by impairment of the mucosal protection mediated by mucins, trefoil peptides, or defensins.17 Subsequently, the onset of IBD symptoms may be triggered by acute infections (e.g., traveler's diarrhea or acute gastroenteritis), antibiotic exposure, or other environmental factors in genetically susceptible hosts. Whether a trigger (specific or nonspecific) modifies the disease subtype cannot as yet be discerned.

Once intestinal inflammation begins, the primary difference between patients with IBD and unaffected persons is an impaired ability to downregulate mucosal inflammation.1 Chronic inflammatory cells are normal in the intestinal mucosa; they comprise the gut component of the mucosa-associated lymphoid tract. The number of lymphoid elements in the mucosa is proportional to enteric exposure to bacteria. Persons raised in a sanitary environment (as is typical of developed countries) have less chronic inflammation than those raised in countries with poor sanitation. An extreme example is that of tropical sprue, in which mucosal inflammation is extensive and is associated with atrophy and ulceration of the small bowel villi.

In IBD, most immune elements (including tissue macro phages and mucosal T cells) respond to an exaggerated degree when triggered by an antigen. Activated macrophages and T cells are prominent in the recruitment of nonspecific inflammatory cells—primarily neutrophils, which are the final mediators of tissue damage.1 The cytokine responses in UC and CD seem to differ, which may account for differences in disease phenotypes.18 Many studies have demonstrated increases in levels of IL-1, IL-6, and tumor necrosis factor-α (TNF-α) in the mucosa of patients with UC and CD, although it is becoming apparent that the balance of cytokines may be different in the two diseases. CD is marked by a higher Th1 cytokine profile (interferon gamma, IL-2, IL-12, and TNF-α), whereas in UC, the balance is more consistent with a Th2 profile, with increased proportions of mucosal B cells, plasma cells, and antibodies.1 In UC, increased production of both antineutrophil cytoplasmic antibodies and IgG antibodies reacting with a 40 kd tropomysin protein have been identified, although the pathogenic consequences of this interaction have not been defined.19 Conversely, patients with CD have a greater likelihood of developing antibodies to a common brewer's yeast (Saccharomyces cerevisiae).19

A final pathway of tissue destruction is through the recruitment and activation of macrophages and neutrophils.20 Activation of the arachidonic acid cascade leads to increased tissue levels of cyclooxygenase products (prostaglandins and thromboxanes), lipoxygenase products (primarily leukotriene B4), and platelet activating factor. These compounds and other nonspecific mediators (e.g., nitric oxide, neutrophil tissue proteases, and reactive oxygen species) contribute to tissue destruction and can be targeted for specific and nonspecific anti-inflammatory therapy.1,4

Ulcerative Colitis

CLASSIFICATION

UC is marked by diffuse, superficial inflammation of the colonic mucosa, beginning in the rectum and extending proximally to involve any contiguous length of colon. The small intestine is not involved, except in the setting of extensive colitis, in which the most distal terminal ileum may exhibit similar superficial inflammation, termed backwash ileitis. Because the extent of colitis usually remains constant from the onset, the length of involved colon defines the classification of UC: proctitis (limited to the rectum), proctosigmoiditis or left-sided colitis (extending up to the splenic flexure), or pancolitis (extending into the transverse colon). Proximal extension occurs in approximately one third of patients with distal disease, and regression from pancolitis is also possible.21,22 The extent of involvement does not necessarily imply severity but does pertain to prognosis (e.g., the risk of cancer) and to treatment selection. The symptoms and course of UC relate to both the extent and the severity of inflammation within the involved segment of colon.

DIAGNOSIS

The diagnosis of UC is made on the basis of clinical, endoscopic, and histologic findings. The presence of rectal bleeding or diarrhea should raise the suspicion of UC. Symptoms are often chronic, but they may also be intermittent or progressive. The easiest way to exclude UC is by direct examination of the rectosigmoid colon with a proctoscope or flexible sigmoidoscope. Radiography (barium enemas) has been almost completely replaced by more sensitive endoscopic examinations. Because UC always involves the rectum, inflammatory changes should be visible with a limited examination. In newly diagnosed patients, stool cultures are performed to rule out infectious diseases that may mimic or complicate UC, such as infection with Salmonella, Shigella, Campylobacter, hemorrhagic Escherichia coli, and Clostridium difficile.

Clinical Manifestations

The onset of UC typically is insidious rather than abrupt, although the disease occasionally presents acutely after infectious colitis or traveler's diarrhea.23 Rectal bleeding is the most consistent feature. Bleeding may be gross or may be noted with evacuation of mucopus. Associated rectal urgency and tenesmus are related to diminished compliance of the rectum. Diarrhea, distinguished from the passage of mucopus without stool, relates to the extent of colonic involvement. Patients with proctitis often present with constipated bowel movements with interim passage of blood or mucus. Abdominal cramps preceding bowel movements are common, although abdominal pain or tenderness (related to transmural inflammation) signifies progressive, severe disease. In severe or fulminant colitis, systemic symptoms of night sweats, fever, nausea and vomiting, and weight loss accompany diarrhea. Extraintestinal manifestations can include inflammation of the eyes, skin, joints, and liver.

Ulcerative proctitis

In the most common variant of UC, accounting for approximately 25% to 30% of cases and usually being the mildest, inflammation is limited to the distal 15 to 20 cm of rectum. Patients with ulcerative proctitis typically present with hematochezia, a sense of rectal urgency, and constipated bowel movements because of delayed transit of fecal material in the right colon. Systemic manifestations are uncommon, but skin or joint symptoms can occur.24 The disease usually remains confined to the rectum but may advance proximally in as many as 30% to 40% of patients.21

Proctosigmoiditis

Left-sided colitis is an intermediate syndrome of UC, accounting for about one third of cases. Patients present with either constipation or diarrhea accompanied by tenesmus, urgency, and rectal bleeding. Left lower quadrant cramping abdominal pain is more common than with proctitis, as are extraintestinal symptoms. The proximal disease margin usually remains fixed throughout the course but can spread more proximally or even retract distally.

Extensive colitis (pancolitis)

In pancolitis, inflammation extends into the transverse or right colon. Patients are more likely to present with diarrhea because of diminished absorptive capacity of the colon, accompanied by rectal bleeding and urgency. Abdominal cramps may be diffuse or localized, and patients are more likely to have weight loss, systemic or extraintestinal symptoms, and anemia.

Toxic megacolon

Toxic megacolon refers to the most severe manifestation of UC, which occurs when the inflammation extends from the superficial mucosa into the submucosa and muscular layers of the colon.25 Toxic megacolon occurs more commonly with extensive colitis but can also occur with severe distal colitis. The colonic wall becomes tissue-paper thin as the colon dilates and becomes hypomotile; perforation may occur. The patient often has fever, prostration, severe cramps, abdominal distention, and abdominal tenderness; the tenderness may be localized, diffuse, or rebound.

Clinical Severity

The severity of UC depends on both the length of colon involved and the severity of colonic inflammation. The set of criteria most commonly used to define the severity of disease was created by Truelove and Witts.26,27,28 Although the criteria were developed to assess improvement in clinical trials, they remain useful in classifying severity in clinical practice, and they have been modified to include fulminant colitis [see Table 1]. Severity criteria are as follows:

Table 1 Classification of Ulcerative Colitis

Feature

Mild Disease

Moderate Disease

Severe Disease

Fulminant Disease

History
   Stools

   Blood in stool

< 4/day (usually early in the day); minimal abdominal cramps and urgency

Intermittent

4–8/day; abdominal cramps and urgency

> 8/day; nocturnal bowel movements; severe urgency with or without incontinence

Frequent

> 10/day; nocturnal bowel movements; severe urgency; tenesmus, severe abdominal pain

Continuous

Physical examination
   Abdominal findings

Nontender abdomen; normal bowel sounds

Nontender or minimally tender over sigmoid

Tender abdomen; no rebound tenderness

Distended abdomen; decreased bowel sounds; rebound tenderness

   Temperature

Normal

Normal

> 37.5°C (99.5° F)

> 37.5° C

   Pulse

Normal

Normal

> 90

> 90

   Other physical findings

Normal

Pallor

Weakness, pallor, weight loss

Prostration, hypotension

Laboratory tests

 

 

 

 

   Hemoglobin

Normal

Mild anemia

< 75% of normal

Transfusion required

   Erythrocyte sedimentation rate

< 30 mm/hr

< 30 mm/hr

> 30 mm/hr

> 30 mm/hr

   Radiography

Normal gas pattern

Absent stool in involved segment

Edematous colon wall, thumbprinting

Dilated colon, mucosal edema, intramural air, free abdominal air

Mild

In mild UC, patients have less than four bowel movements daily, with minimal cramps and urgency. Usually, most of the bowel movements occur early in the day; and after the morning evacuations, the patient is able to proceed with activities of daily life.

Moderate

Patients with moderate UC have four to eight bowel movements daily, more frequent rectal urgency, and postprandial cramping and bowel movements. Blood is present in most stools, and nocturnal wakening for bowel movements is common. The disease can interfere with daily work or school activities and social life.

Severe

Patients with severe UC have more than eight bowel movements daily, nocturnal bowel movements, severe urgency with or without incontinence, and systemic signs that include low-grade fever, night sweats, weakness, and weight loss. Abdominal tenderness, tachycardia, anemia, leukocytosis, and hypoalbuminemia are common.

Fulminant

Patients with fulminant colitis have more than 10 bowel movements a day, nocturnal bowel movements, severe abdominal pain or relentless tenesmus, and rebound tenderness or distention with tympanic bowel sounds. They also have prostration, high fever, and hypotension. Radiographic studies show evidence of mucosal edema, intramural air (pneumatosis coli), colonic dilatation (toxic megacolon), or free abdominal air (perforation).

Physical Examination

In most patients with UC, the physical examination results are normal. There may be mild abdominal tenderness to deep palpation, particularly in the left colon, but significant abdominal findings are limited to patients with moderate to severe disease, in whom tenderness is more prominent. Surprisingly, despite the frequent diarrhea, perianal manifestations are absent. Any significant perianal findings (e.g., large hemorrhoids, skin tags, fissures, abscesses, or fistulas) suggest CD rather than UC.

Conjunctival pallor is common because of anemia. Patients may present with ocular inflammation, erythema nodosum, pyoderma gangrenosum, or arthritis of larger joints.29 Low back pain with diminished range of motion, or sacroiliac tenderness, is uncommon. Hepatomegaly, splenomegaly, or evidence of chronic liver disease is rare and limited to patients with end-stage primary sclerosing cholangitis.

Endoscopy

UC can almost always be diagnosed by endoscopic examination of the rectum and sigmoid colon.30 The disease presents as diffuse and continuous inflammation beginning in the rectum, with proximal extension that varies among individual patients. In most cases, it is advisable to determine the proximal margin of disease, from the standpoints of prognosis24 and therapy.26,27 The initial examination should be performed without enema preparation, to avoid confusion with trauma or inflammation from administration of the enema. Patients with active colitis rarely have any fecal material in the involved lumen.

Healthy colonic mucosa is smooth and glistening, reflects light back from the scope, and demonstrates a branching mucosal vascular pattern. With inflammation, the mucosa becomes erythematous and more granular, which breaks apart the light reflection, and the vascular pattern becomes obscured by edema [see Figures 1a, 1b, 1c and 1d]. The granularity of the mucosa may be fine or coarse. Coarse granularity represents microscopic or pinpoint ulcerations and is associated with friability (hemorrhage from the mucosa that may be spontaneous or induced by scope trauma). Exudates of mucopus are a common associated finding. Gross ulcerations represent more severe disease and, although usually shallow, can progress to a total denudation of the mucosa with exposure of the underlying circular musculature. These changes can be continuous up to a distinct margin where the mucosa appears normal, or they may extend diffusely to the cecum and, occasionally, into the distal ileum (backwash ileitis). In the setting of pancolitis, the ileocecal valve is usually wide open (patulous), allowing easy entry into the terminal ileum. Some patients with distal UC (involving the rectum or sigmoid) also may have limited inflammatory changes around the appendix in the cecum (cecal red patch).31

 

Figure 1a. Endoscopic Spectrum of Ulcerative Colitis: Mucosal Edema

The endoscopic spectrum of ulcerative colitis includes mucosal edema, erythema, and loss of vasculature.

 

Figure 1b. Endoscopic Spectrum of Ulcerative Colitis: Granular Mucosa

Granular mucosa with pinpoint ulceration and friability.

 

Figure 1c. Endoscopic Spectrum of Ulcerative Colitis: Healed Mucosa

Regenerated (i.e., healed) mucosa with distorted mucosal vasculature.

 

Figure 1d. Endoscopic Spectrum of Ulcerative Colitis: Postinflammatory Pseudopolyps

Regenerated mucosa with typical postinflammatory pseudopolyps.

As ulcerative colitis heals, the mucosal changes may become more focal.32 The colonic mucosa regenerates from ulceration to granularity, with gradual restitution of a distorted mucosal vascular pattern with less distinct branching or irregular, pruned-appearing vessels. In areas that had been more severely inflamed, granulation tissue may protrude and become reepithelialized as so-called pseudopolyps. These postinflammatory changes can arise in a variety of sizes and shapes and are more likely to become fingerlike projections, or even mucosal bridges, in areas that had severe, undermining ulcerations [see Figures 1a, 1b, and 1c]. Pseudopolyps have no neoplastic potential but can be difficult to differentiate from adenomatous polyps. When pseudopolyps are extensive, they can totally carpet the mucosa, making it impossible to discern distinct, potentially neoplastic polyps.

Histology

Samples for histologic analysis are typically taken during endoscopy. The histologic features of UC parallel the endoscopic appearance of diffuse, continuous mucosal inflammatory changes. The principal components are disruption of glandular architecture and an inflammatory infiltrate.33 A hallmark distinction between chronic IBDs such as UC and acute self-limited (infectious) colitis is architectural distortion [seeFigures 2a, 2b, and 2c]. In UC, the normal vertical (so-called test-tube) alignment of glands is distorted; the glands are separated by expanded lamina propria lymphocytes, plasma cells, and eosinophils, as well as by neutrophils, which normally are sparse. The glands themselves become irregular in shape and, often, branched. The neutrophil infiltrate is localized to the base of the glandular crypts and invades the crypts, producing crypt abscesses. In more severe disease, the epithelial lining is destroyed, leaving ulcerations over the lamina propria. The inflammatory changes are usually superficial, limited by the muscularis mucosae. Despite severe superficial changes, deeper inflammation is uncommon, except in the setting of fulminant colitis. In fulminant colitis, the muscular layers are breached by expanding inflammatory ulceration that can leave the bowel wall tissue-paper thin and protected only by the serosa.

 

Figure 2a. Pathologic Changes in Ulcerative Colitis: Acute Superficial Inflammation

Pathologic changes in ulcerative colitis include acute superficial inflammation with distortion of the normal crypt architecture.

 

Figure 2b. Pathologic Changes in Ulcerative Colitis: Crypt Abscesses

Crypt abscesses.

 

Figure 2c. Pathologic Changes in Ulcerative Colitis: Quiescent Colitis

Quiescent colitis without acute inflammation but with distortions of crypt architecture (abnormal branched crypts).

As the mucosa heals, the glands may become atrophied or shortened and irregularly shaped, with a thinned-out lamina propria. Inflammatory polyps are composed of vascular granulation tissue with a thin colonic epithelium. In quiescent colitis, the architectural distortion is present but acute inflammation (neutrophils and crypt abscesses) is absent [see Figures 2a, 2b, and 2c].

Both acute inflammation and regeneration of the colonic epithelium produce cellular atypia that must be distinguished from epithelial dysplasia.34 In regenerating mucosa, the glandular epithelium can become irregularly shaped and hyperchromatic, with depletion of normal apical mucus. Stratification of nuclei and loss of polarity are manifestations of neoplastic transformation (i.e., dysplasia).

Imaging Studies

Radiography

Radiographs have largely been supplanted by endoscopic examinations for the diagnosis of UC, but radiography remains a valuable adjunct to endoscopy in specified clinical situations. Plain abdominal radiographs are useful in the setting of severe colitis. These examinations outline the air-filled colon and can demonstrate the presence or absence of haustrations or dilatation of the colon (to rule out toxic megacolon) [see Figure 3]. Extraluminal gas under the diaphragm (free air) and evidence of an ileus pattern are additional features of severe colitis. Plain abdominal radiographs also provide a view of the sacroiliac joints and lumbosacral spine as a gross assessment of sacroiliitis or ankylosing spondylitis for patients presenting with low back pain.

 

Figure 3. Air-contrast Radiograph of Ulcerative Colitis

In this air-contrast radiograph of ulcerative colitis, the mucsosal pattern is granular with loss of normal haustrations in a diffuse, continuous pattern.

Contrast barium studies, once the primary diagnostic moda lity, are less commonly employed because endoscopic examinations provide higher diagnostic sensitivity and specificity and permit histologic sampling.26 Air-contrast barium enemas de monstrate the fine or coarse mucosal granularity of microscopic ulcerations or the diffuse, continuous, and symmetrical pattern of ulceration involving the rectum to the proximal extent of disease [see Figure 3]. Other features of UC that may be visible on barium enemas are the loss of haustration in inflamed segments, foreshortening of the colon, and an increase in the space between the sacrum and the rectum. Barium enema examinations are contraindicated in severely ill patients because of the potential for perforation or the induction of a toxic megacolon.

Scintigraphy

Scanning with indium-labeled or technetium-labeled leukocytes is occasionally indicated for severely ill adults or children when the extent of colitis is uncertain or when small bowel disease has not been excluded.35 These studies provide relatively rapid determination of the extent, severity, and continuity of intestinal inflammation. Scintigraphy is noninvasive, is sensitive and specific for intestinal inflammation, and is occasionally helpful in discriminating UC from CD.

Crohn Disease

CD is manifested by focal, asymmetrical, and transmural inflammation of the digestive tract, at times accompanied by granuloma formation. In contrast to the inflammation of UC, which is diffuse, continuous, superficial (mucosal), and typically limited to the colon, the inflammation of CD is more patchy, may be transmural, and can involve any segment of the gastrointestinal tract from mouth to anus. Because the inflammation may be transmural, CD can lead to intestinal complications of stenoses (strictures) and fistulas. Although a hallmark of CD is the histologic finding of noncaseating granulomas, these granulomas are identified in only about 30% of patients and are not necessary to make the diagnosis.

Because CD may involve any segment of the gastrointestinal tract, the presentation is more heterogeneous than that of UC and is determined by the location, extent, severity of inflammation, and inflammatory pattern. The location and pattern tend to remain constant for each patient.36 CD produces a spectrum of inflammatory patterns: from superficial inflammation similar to that of UC, to formation of fibrostenosing strictures, to penetration of the bowel wall and fistula formation accompanied by a mesenteric inflammatory mass or perienteric abscess. An attempt to classify CD on the basis of inflammatory patterns37 has been compromised by the tendency of inflammatory patterns to progress to stenoses over time.38 In contrast to UC, CD is usually not curable by surgery; intestinal resection and anastomosis are almost inevitably followed by recurrence of the disease involving the anastomotic site and proximal intestine.39

In clinical trials, the instrument most commonly used to quantify disease activity has been the CD Activity Index (CDAI).40 However, because of its complex derivation and lack of discrimination between symptoms and inflammation, the CDAI is not used in clinical practice. Instead, patients require individualized assessments of the severity of disease according to inflammatory symptoms, obstruction, fistulization, abscess formation, systemic complications, and effect on the patient's quality of life.41

DIAGNOSIS

CD is diagnosed on the basis of clinical, radiographic, endoscopic, and histologic criteria. As with UC, there is no pathognomonic marker. The clinical presentation and key features of the history, physical examination, and laboratory studies determine the diagnostic workup and serve to differentiate CD from UC [see Table 2].

Table 2 Key Distinguishing Features of Ulcerative Colitis and Crohn Disease

Feature

Ulcerative Colitis

Crohn Disease

History

   Smoking status

Nonsmoker or ex-smoker

Smoker

Physical examination

   Symptoms

Rectal bleeding, cramps

Diarrhea, abdominal pain, weight loss, nausea, vomiting

   Signs

Normal perianal findings, no abdominal mass

Perianal skin tags, fistulas, abscesses; abdominal mass; clubbing of digits

Laboratory tests

   Endoscopy

Rectal involvement; continuous superficial inflammation with granular, friable mucosa; terminal ileum normal or showing backwash ileitis

Rectal sparing; local ulceration with normal intervening mucosa; aphthous, linear, or stellate ulcers; terminal ileum inflamed with aphthous or linear ulcers

   Radiology

Diffuse, continuous superficial ulceration; ahaustral (lead-pipe) colon; backwash ileitis

Focal, asymmetrical, transmural ulceration; strictures, inflammatory masses, fistulas; small bowel disease

   Histology

Diffuse, continuous, superficial inflammation; crypt architectural deformity

Focal inflammation, aphthous ulcers, lymphoid aggregates, transmural inflammation, granulomas (15%–30% of patients)

   Serology

Elevated p-ANCA (60%–80% of patients)

Elevated ASCA (~30% of patients)

p-ANCA—perinuclear antineutrophil cytoplasmic antibody   ASCA—anti-Saccharomyces cerevisiaeantibody

Clinical Manifestations

CD most commonly involves the terminal ileum and cecum. However, the pattern of CD can be quite varied [see Figure 4]. The presentation depends on the site, extent, severity, and complications of intestinal and extraintestinal disease.42,43 Patients usually present with chronic disease, but CD can be acute, with severe abdominal pain, intestinal blockage, or hemorrhage. Abdominal pain is a more common feature of CD than of UC because the transmural extension of CD results in stimulation of pain receptors in the serosa and peritoneum. Abdominal cramping and postprandial pain are common symptoms that often are accompanied by diarrhea, rectal bleeding, nocturnal bowel movements, fevers, night sweats, and weight loss. Nausea and vomiting occur in the presence of intestinal strictures that produce partial or complete bowel obstructions. Transmural disease commonly manifests in the perianal region as skin tags or perirectal abscesses or fistulas,44 but it also can present as an inflammatory mass in the right lower quadrant. In children and adolescents, the presentation often is more insidious, with weight loss, failure to grow or to develop secondary sex characteristics, arthritis, or fevers of undetermined origin. Skin lesions, primarily erythema nodosum, may precede intestinal symptoms.45,46

 

Figure 4. Crohn Disease Presentations

The spectrum of Crohn disease presentations includes (a) gastroduodenitis (7% of patients), (b, c) jejunoileitis and ileitis (33% of patients), (d) ileocolitis (45% of patients), and (e) colitis (15% of patients).

Crohn disease of the esophagus, stomach, and duodenum

Infrequently, primary manifestations of CD mimic gastroesophageal reflux or peptic ulcer disease.47,48 Heartburn, dysphagia, nausea, dyspepsia, epigastric pain, and early satiety or postprandial vomiting typically accompany other systemic inflammatory symptoms such as fever, night sweats, and rectal bleeding.

Jejunoileitis

Another relatively uncommon presentation of CD, jejunoileitis most often presents with vomiting and diarrhea, cramping abdominal pain, and weight loss.49 Patients describe borborygmi related to focal, segmental strictures compromising the passage of enteric contents. Diarrhea is multifactorial and can be secondary to malabsorption as a consequence of inflammation, protein-losing enteropathy, or stasis and small bowel bacterial overgrowth proximal to strictures.

Ileitis and ileocecal Crohn disease

CD most commonly presents as right lower quadrant abdominal pain and tenderness (often accompanied by an inflammatory mass), diarrhea with or without rectal bleeding, weight loss, fevers, chills, and night sweats. An acute presentation may mimic appendicitis; occasionally, Crohn ileitis will be diagnosed at exploratory laparotomy for presumed appendicitis.

Crohn colitis

Approximately 15% of CD cases are limited to the colon. Distinguishing these cases from UC can be difficult, because the clinical manifestations—diarrhea, rectal bleeding, and urgency—overlap with those of UC [see Table 2]. However, CD of the colon is more likely than UC to be accompanied by perianal manifestations (skin tags and perirectal abscess or fistulas), and the rectum often is spared, whereas UC always involves the rectum. In approximately 10% to 20% of patients presenting with colitis, the classification may be indeterminate in the setting of diffuse or severe inflammation or of questionable focal inflammation.50

Perianal Crohn disease

Perianal involvement in CD most often accompanies colonic disease and begins within the anal crypts.51 Small fistulas from the anorectal junction progress through or around the anal sphincter and present as perirectal abscesses or fistulas. Often, perianal tissue becomes hypertrophied, producing skin tags [see Figure 5]; these may be misdiagnosed as hemorrhoids. At times, perianal manifestations are the primary presentation, and in extreme situations, the anal sphincter and perineum can become grossly deformed.

 

Figure 5. Perianal Skin Tag of Crohn Disease

The typical perianal skin tag of Crohn disease differs from the typical hemorrhoid tag.

Physical Examination

Key findings on physical examination of patients with CD include both abdominal and general systematic abnormalities. The abdominal examination may be significant for distension and abnormal bowel sounds in the presence of intestinal strictures producing partial intestinal obstruction. Tenderness in the area of involvement and the presence of an inflammatory mass are common. It is important to examine the perianal region and rectum for evidence of abscess, fistula, skin tags, or anal stricture.

Patients with CD often are chronically ill and can present with weight loss and pallor. The eye exam may demonstrate episcleritis or uveitis. Aphthous ulcerations in the mouth are common, and in extreme cases, patients may exhibit evidence of nutritional deficiencies (e.g., cheilosis or tongue atrophy). Examination of the musculoskeletal system may demonstrate swelling or redness of large joints (e.g., knees, ankles, or wrists) or clubbing of the fingers. Skin examination can reveal erythema nodosum or, rarely, pyoderma gangrenosum.

Laboratory Studies

Anemia is common in CD. Anemia can result from deficiencies of iron, vitamin B12, or folic acid or may be the anemia of chronic disease. Serum ferritin levels correlate better than iron and iron-binding protein levels with bone marrow iron stores in IBD.52 Leukocytosis is common, depending on the severity of inflammation and the presence of suppurative complications. Thrombocytosis also is common and is related to inflammation or iron deficiency. Elevated erythrocyte sedimentation rates and C-reactive protein levels reflect nonspecific acute-phase reactions.53 Electrolyte disturbances depend on the severity of diarrhea and dehydration. Serum albumin levels often are reduced as a result of malnutrition and enteric protein losses. Patients with severe weight loss may have prolonged clotting times because of vitamin K deficiency. Urinalysis commonly demonstrates calcium oxalate crystals.

Quantitative stool examinations are useful in the setting of diarrhea to assess fecal leukocytes (confirming inflammatory diarrhea), stool volume, and fecal fat. Quantification of either fecal calprotectin54 or lactoferrin55 is a surrogate for the presence of fecal leukocytes. The presence of the serologic markers anti-Saccharomyces cerevisiae antibody and an antibody to the outer core membrane of E. coli (OmpC) have high specificity for CD.56

Imaging Studies

Radiography

Barium contrast studies are the most commonly used diagnostic tools to assess and confirm CD of the small intestine and are useful for assessing the upper digestive tract and colon. In colonic disease, barium studies can define intestinal complications (e.g., stricture formation or fistulas) that cannot be adequately assessed by endoscopy. Features of CD that are shown with barium examinations include mucosal edema, aphthous and linear ulcerations, asymmetrical narrowing or strictures, and separation of adjacent loops of bowel caused by mesenteric thickening. Abnormalities are focal and asymmetrical, with ulcerations most often involving the antimesenteric border. Cobblestoning of the mucosa represents networks of linear ulcerations outlining islands of residual normal mucosa. Pseudodiverticula formation or dilated loops of bowel are common proximal to strictures. There may be evidence of fistulas extending from any involved segment to an adjacent loop of bowel, the mesentery, or the urinary bladder or from the rectum to the vagina or perineum. CT scanning after direct injection of barium into the small bowel through a nasogastric tube (enteroclysis) provides excellent discrimination between intestinal and extra-intestinal disease.57

Other imaging studies

Ultrasound examinations or CT scans are useful to assess for abscess in patients who have an inflammatory abdominal mass or who have fever, leukocytosis, or abdominal tenderness. Ultrasound or CT scan is also warranted to assess for hydronephrosis in the setting of an inflammatory mass in the right lower quadrant, because these have the potential to obstruct the right ureter. Transrectal ultrasound, CT scan, and MRI also are useful to assess the extent of perianal and sphincter involvement in patients presenting with perianal or perirectal pain.51 Scintigraphy using leukocytes labeled with indium or technetium can be helpful to define locations of intestinal inflammation when barium studies are not possible or the results are indeterminate.35,58

Endoscopy

Colonoscopic examinations have become a primary means of diagnosing CD that involves the colon. Endoscopy in these patients typically reveals sparing of the rectum, with focal inflammatory changes in the more proximal colon and terminal ileum. Other typical features include the presence of aphthous, linear, or irregularly shaped ulcerations with normal intervening mucosa [see Figures 6a, 6b, 6c, and 6d]. Inflammatory strictures may preclude examination of proximal segments of bowel. Inflammatory pseudopolyps may be seen, as in UC. In some patients, polypoid or masslike inflammatory changes may be difficult to differentiate from neoplastic masses; biopsy and histologic analysis may be required. Similar endoscopic features may be present in the esophagus, stomach, or duodenum. An important aspect of endoscopic examinations is the ability to obtain samples for pathologic interpretation.

 

Figure 6a. Endoscopic Spectrum of Crohn Disease: Aphthous Ulcerations

Endoscopic spectrum of Crohn disease includes aphthous ulcerations amid normal colonic mucsosal vasculature.

 

Figure 6b. Endoscopic Spectrum of Crohn Disease: Punched-out Ulcers

Deeper, punched-out ulcers in ileal mucosa.

 

Figure 6c. Endoscopic Spectrum of Crohn Disease: Colonic Linear Ulcer

A single colonic linear ulcer.

 

Figure 6d. Endoscopic Spectrum of Crohn Disease: Deep Colonic Ulcerations

Deep colonic ulcerations forming a stricture.

Wireless capsule endoscopy is now being used to diagnose CD. This technique offers access to parts of the small bowel that cannot be reached by standard endoscopy and may be more sensitive than conventional radiographic studies for identifying subtle lesions.59

Histology

Pathologic findings in CD reflect the gross pattern of focal and asymmetrical intestinal involvement.32,33,50 The primary histologic lesion is an aphthous ulcer [see Figures 7a and 7b]. These begin as erosions overlying lymphoid aggregates. As the minute ulceration extends, in either a linear or a transmural pattern, the microscopic and macroscopic changes that develop include a mixed acute and chronic inflammatory cell infiltrate composed of lymphocytes, plasma cells, and neutrophils. Crypt abscesses are common, and the inflammatory infiltrates often are located adjacent to normal epithelium. Noncaseating granulomas, which may be identified in mucosal biopsies or in resected specimens, are characteristic of CD; however, they are not necessary for confirming the diagnosis.

 

Figure 7a. Pathologic Changes in Crohn Disease: Ileal Aphthous Ulceration

Pathologic changes in Crohn disease include ileal aphthous ulceration overlying a lymphoid aggregate.

 

Figure 7b. Pathologic Changes in Crohn Disease: Focal Colonic Ulcer

Focal colonic ulcer with noncaseating granuloma in lymphoid tissue.

Granulomas may be found in mucosal specimens that appear grossly normal. Specimens from resected intestine demonstrate transmural inflammatory changes extending from the mucosa into the serosa (which is hyperemic, with creeping mesenteric fat). At times, there may be paradoxical involvement of the deeper layers of the bowel wall, with lymphoid aggregates overlying normal-appearing epithelium. Submucosal fibrosis, deep fissuring ulcerations, and fistulizing ulcerations communicate between loops of bowel or into the adjacent mesentery.

Differential Diagnosis

IBD should be considered in any patient who presents with rectal bleeding or diarrhea. Identification of fecal leukocytes is the simplest means of discerning an inflammatory process of the intestine. Other causes of rectal bleeding are either traumatic or neoplastic. Diarrhea is nonspecific and has a large differential schema [see 4:III Diarrheal Diseases]. The primary chronic diarrheal illness that requires differentiation from UC or CD is irritable bowel syndrome (IBS). IBS is never associated with rectal bleeding, and nocturnal symptoms are uncommon. The presence of occult blood or fecal leukocytes excludes IBS.

Patients with gross or occult blood in the stool require endoscopic evaluation. Colonic neoplasia is a prominent consideration for patients older than 50 years, whereas hemorrhoids or anal fissures are common in younger patients. NSAID-induced colitis is common and may contribute to ischemic colitis in persons in older age groups.60 Ischemic colitis presents acutely in elderly patients after precipitating events such as dehydration or heart failure; in younger patients, the condition is associated with oral contraceptive use, vasculitis, and hypercoagulable states.61 Endoscopic examination demonstrates focal hemorrhagic or ulcerated mucosa in the so-called watershed segments of the sigmoid colon or splenic flexure. Diverticular hemorrhage is typically profuse and painless. Some patients, however—particularly elderly persons taking NSAIDs—may present with less vigorous rectal bleeding from diverticulosis involving a segment of the sigmoid colon.62

Inflammatory diarrhea can be infectious or noninfectious.63 The infectious colitides are caused by bacteria such as Salmonella, Shigella, Campylobacter, and hemorrhagic E. coli. Most of these diseases are acute and self-limited and need be considered only in patients who present with sudden onset of bloody diarrhea and fever. UC and CD develop insidiously, over weeks. C. difficile colitis can also mimic ulcerative colitis and may be more chronic, lasting weeks [see 7:V Anaerobic Infections]. In immunocompetent hosts, viral or parasitic infections rarely mimic UC. The exception is amebiasis, which may cause acute or subchronic symptoms. Amebiasis can often be distinguished from IBD by wet-mount examination of the stool for motile ameba and the more typical focal (so-called collar button) ulcerations in the colon [see 7:XXXIV Protozoan Infections]. Although most cases of infectious diarrhea are acute and self-limited, intercurrent infections and traveler's diarrhea can initiate flare-ups of IBD.64 Consequently, patients presenting with new-onset IBD or acute exacerbations of IBD should be evaluated for a complicating enteric infection.

Management

The treatment of UC or CD is based on the location, extent, and severity of disease, as well as the patient's response to past therapy.26,27Factors that contribute to exacerbations of activity or refractoriness to therapy should be addressed. Such factors may include concomitant medications (e.g., NSAIDs or antibiotics), intercurrent infections (e.g., with C. difficile), menstruation, and dietary or lifestyle changes.

Treatment follows a sequential approach: induction of remission and, then, maintenance of remission. Clinicians can now choose from a variety of medication classes for treatment of IBD, and both medication selection and dosage may vary according to whether the therapeutic intent is induction or maintenance. Surgical treatment is indicated in selected patients to treat severe disease activity or specific complications.

ANTI-INFLAMMATORY AGENTS

Aminosalicylates

Aminosalicylates are the primary therapies for mild or moderate UC and CD.26,27 These agents have a long history of clinical use and have been extensively studied in clinical trials for both UC and CD.65,66 Sulfasalazine, the prototype aminosalicylate [see Figure 8], was developed with the intention of providing both an antibacterial agent (sulfapyridine) and an anti-inflammatory agent (5-aminosalicylic acid [5-ASA], mesalamine, or mesalazine) into the connective tissues. It was subsequently recognized that sulfasalazine remains intact through the stomach and small intestine, with minimal enteric absorption. On reaching the colon, the azo bond between sulfapyridine and 5-ASA is cleaved by colonic bacteria. Released sulfapyridine is almost completely absorbed from the colon and undergoes hepatic acetylation and subsequent renal excretion. In contrast, the 5-ASA released into the colon is poorly absorbed and is primarily eliminated in the feces.67Therefore, sulfasalazine primarily serves as a carrier for 5-ASA to the colon. The 5-ASA moiety accounts for the primary therapeutic benefits, whereas sulfapyridine causes the majority of side effects attributed to sulfasalazine. These attributes have led to the development of a series of sulfa-free aminosalicylates (e.g., olsalazine, balsalazide, and formulations of mesalamine) that can be targeted to specific sites along the gastrointestinal tract. A basic premise regarding the aminosalicylates is that the effects of 5-ASA are topical (mucosal), rather than systemic, and that the active moiety needs to be delivered to the site of intestinal inflammation.

 

Figure 8. Structure of Sulfasalazine

Sulfasalazine is composed of sulfapyridine and 5-aminosalicylic acid (mesalamine), linked by an azo-bond.

Sulfasalazine and mesalamine have multiple anti-inflammatory effects, including inhibition of the arachidonic acid cascade along the cyclooxygenase, lipoxygenase, and platelet-activating factor pathways.65,66 In addition, the aminosalicylates inhibit oxygen radical production and scavenge free radicals.68 They inhibit lymphocyte and monocyte function and production of immunoglobulin by plasma cells. Sulfasalazine also has been shown to inhibit production of IL-1 and nuclear factor κB.69

Adverse effects of sulfasalazine are common and are primarily related to plasma sulfapyridine concentrations; these concentrations depend on the rate of hepatic acetylation of sulfapyridine, which is genetically determined.70 Intolerance side effects (i.e., nausea, vomiting, malaise, anorexia, dyspepsia, and headaches) are dose related. In contrast, hypersensitivity reactions (i.e., rash, fever, hemolytic anemia, agranulocytosis, hepatitis, hypersensitivity pneumonitis, pancreatitis, and worsening of colitis) are independent of dose. Reversible sperm abnormalities and folate malabsorption are unique complications related to sulfasalazine.

Mesalamine has relatively few side effects, and dose-related toxicities are unusual in patients taking up to 4.8 g/day of delayed-release formulations.70,71 Rare idiosyncratic reactions, including pancreatitis, interstitial nephritis, and worsening of colitis, have been reported. Eighty percent of patients who are unable to tolerate sulfasalazine can tolerate a nonsulfa aminosalicylate containing mesalamine. One unique complication of olsalazine is dose-related diarrhea.

Sulfasalazine and the oral aminosalicylates are equally effective for treatment of mild to moderate UC.26,27,72 Oral aminosalicylates are effective for both proximal and distal colitis. Mesalamine suppositories and enemas effectively treat distal colitis, provided the formulation reaches the proximal extent of disease.73 A dose-response relationship for the oral aminosalicylates is well defined for up to 4.8 g/day of mesalamine, with higher doses being more effective for moderately active disease.

Prevention of relapse and the prolongation of remission have been primary indications for all of the aminosalicylates in UC.26,27,74 All the nonsulfa formulations provide comparable efficacy to sulfasalazine for maintenance therapy.74 In ulcerative proctitis and distal colitis, topical mesalamine is also effective at preventing relapse and is more effective than oral treatment when continued on a long-term basis.73

The efficacy of aminosalicylates in CD is less definitive than that in UC and is more dependent on location of disease activity.27,66 In CD involving the colon, the efficacy of sulfasalazine is determined by the presence of the colonic bacteria needed to cleave the azo bond and liberate 5-ASA. Aminosalicylates are commonly used as maintenance therapy for patients with quiescent CD, despite differing interpretations of the clinical trials of this indication.27,65 The specific release characteristics [see Table 3] should correspond to the disease location.

Table 3 Aminosalicylate Preparations for Management of Ulcerative Colitis and Crohn Disease

Preparation

Formulation

Delivery

Dosing

Oral Agents

   Azo bond

   Sulfasalazine (Azulfidine, 500mg)

Sulfapyridine carrier

Colon

3–6 g/day (acute)
2–4 g/day (maintenance)

   Olsalazine (Dipentum, 250 mg)

5-Aminosalicylic acid dimer

Colon

1–3 g/day

   Balsalazide (Colazal, 750 mg)

Aminobenzoyl-alanine carrier

Colon

6.75 g/day

   Delayed Release

   Mesalamin (Asacol, 400 mg, 800 mg)

Eudragit S (pH, 7)

Distal ileum-colon

2.4–4.8 g/day (acute)
0.8–4.8 g/day (maintenance)

      (Claversal,* Mesasal,* Salofalk,*250 mg, 500 mg)

Eudragit L (pH, 6)

Ileum-colon

1.5–3.0 g/day (acute)
0.75–3.0 g/day (maintenance)

   Sustained Release

   Mesalamine
      (Pentasa, 250 mg, 500 mg, 1,000 mg*)

Ethylcellulose granules

Stomach-colon

2–4 g/day (acute)
1.5–4.0 g/day (maintenance)

Rectal Agents

   Mesalamine suppository
      (Canasa, 400 mg,* 500 mg, 1,000 mg*)

Rectum

1.0–1.5 g/day (acute)
500–1,000 mg/day (maintenance)

   Mesalamine enema
      (Rowasa, 1 g,* 4 g)

60 ml, 100 ml suspension

Rectum-splenic flexure

1–4 g/day (acute)
1 g q.d.–1 g t.i.w. (maintenance)

* Not available in the United States.

Corticosteroids

Corticosteroids are the primary therapy for moderate to severe and fulminant UC and moderate to severe active CD.27,75 They are ineffective at maintaining remissions of UC and CD, however.76 The mechanisms of action of corticosteroids in IBD are multifactorial and are similar to their mechanisms of action in other inflammatory diseases.77 Like aminosalicylates, corticosteroids can be targeted to specific sites within the digestive tract. Newer glucocorticoids (e.g., budesonide) both enhance potency and minimize systemic exposure.78

Ulcerative colitis

Oral corticosteroids are the primary treatment for outpatients with moderately severe UC.26,27,79 Prednisone, 20 to 60 mg daily, is administered once or in divided doses. In general, 40 mg is the optimal dose; the modest benefits of higher doses are offset by increasing side effects.80

Rectal (i.e., topical) administration of systemically absorbed glucocorticoids (e.g., hydrocortisone) and of rapidly metabolized glucocorticoids (e.g., budesonide) is effective therapy for active distal colitis and has been incorporated into the treatment of severe colitis as an adjunct to parenteral steroids.81

Parenteral corticosteroids are the mainstay of therapy for hospitalized patients with severe or fulminant UC. Although controlled trial data are limited, there is consensus supporting the use of intravenous hydrocortisone, methylprednisolone, or prednisolone in dosages equivalent to 40 to 60 mg/day of prednisone; these agents may be given either in a continuous infusion or in divided doses.26,27,79,80 There is no evidence supporting dosages higher than 60 mg of prednisone. Corticosteroids are not effective in preventing relapse of quiescent UC.26,27,79,80

Crohn disease

Corticosteroids are the primary therapy for moderate to severe CD.27,82 Both uncontrolled and controlled trials demonstrate a response rate of approximately 75%. Parenteral steroids have not been formally assessed in the setting of severe CD, but there is a consensus that they are as effective in severe CD as in severe UC. As a first-line therapy for mild to moderate CD, enteric-coated, delayed-release formulations of budesonide can deliver topically active steroids to targeted sites (ileum and proximal colon).78,83 However, as with corticosteroids in UC, neither conventional nor topically active steroids have proved effective for preventing relapse in CD.76,82

IMMUNOMODULATORY AGENTS

Immunomodulating therapies have had an expanding role in the treatment of IBD. These agents can be used either to induce or to maintain remission in UC and CD.

Azathioprine and 6-Mercaptopurine

Although azathioprine (AZA) and 6-mercaptopurine (6-MP) have been used to treat IBD for over 30 years, their mechanisms of action and optimal use remain incompletely known. AZA is rapidly absorbed and converted to 6-MP, which is metabolized to thioinosinic acid, an inhibitor of purine ribonucleotide synthesis and cell proliferation.84 Although AZA is considered a purine antimetabolite, its exact mechanism of action has not been defined. Presumably, AZA inhibits some function of long-lived lymphocytes, which accounts for the 3- to 6-month delay in onset of action. There is increasing evidence that these agents promote apoptosis of T cells.85 In addition, a genetic polymorphism has been recognized in the enzyme thiopurine methyltransferase, which metabolizes the purine analogues into 6-thioguanine.84,86 One in 300 persons lacks this enzyme, and an additional 11% of the population has depressed levels of it. Homozygotes are susceptible to increased accumulation of 6-thioguanine nucleotides and bone marrow suppression.

AZA and 6-MP usually are well tolerated.80 Pancreatitis occurs in 3% to 15% of patients, usually within the first few weeks of therapy, and resolves completely upon withdrawal of the drug. Other potential side effects include nausea, fever, rash, and hepatitis. Bone marrow suppression, particularly leukopenia, is dose related and may be delayed, necessitating long-term monitoring of blood counts. IBD patients treated with purine analogues may experience a slight increase in relative risk of neoplasia, but the absolute risk remains extremely small.80,87 There is a growing consensus that these agents are effective and safe for use through pregnancy and lactation.88

Ulcerative colitis

Both controlled trials with AZA and uncontrolled series with 6-MP have supported the role of purine analogues for the long-term (maintenance) treatment of UC.26,27,79 There have not been adequate comparative studies between AZA and 6-MP or dose-ranging trials for these agents, and to date, there are no standard guidelines for their use in UC.26 Most authorities agree that if patients are to be started on full-dose therapy (i.e., 2.5 mg/kg/day of AZA or 1.5 mg/kg/day of 6-MP), activity of the enzyme thiopurine methyltransferase should be measured before therapy is initiated.80,89 However, many clinicians start therapy at lower doses and monitor the white blood cell count. Alternatively, in the event of therapeutic unresponsiveness, elevated liver enzymes, or potential noncompliance, these clinicians measure levels of the thiopurine metabolites 6-methylmercaptopurine and 6-thioguanine.

Crohn disease

AZA and 6-MP can induce remission in active CD, but prolonged therapy is necessary: 56% of patients with active CD respond after 4 months of treatment with either AZA (2.0 to 2.5 mg/kg/day) or 6-MP (1.0 to 1.5 mg/kg/day).82,90 Because of their delayed onset of action, AZA and 6-MP are most often used to maintain remission or as steroid-sparing agents.91 They can also be used to treat CD fistulas and perianal disease.51

Cyclosporine

Cyclosporine is a potent inhibitor of T cells, primarily via inhibition of IL-2 production by helper T cells, and inhibits recruitment of cytotoxic T cells and production of IL-3, IL-4, interferon gamma, and TNF-α. Treatment with cyclosporine can provide dramatic results in severe IBD, particularly in UC.79,92 Cyclosporine has a much more rapid onset of action than AZA or 6-MP; its effects are usually evident within the first week. There is controversy regarding the long-term benefits of cyclosporine, however. Cyclosporine is metabolized by a cytochrome P-450 enzyme, and interactions with a number of drugs can increase or decrease cyclosporine levels.80

UC trials have used intravenous cyclosporine as a continuous infusion of 2 to 4 mg/kg/day.93 However, a dosage of 2 mg/kg/day appears to be as effective as higher doses and may reduce toxicity.94 Correlations between response and blood levels have not been defined; similarly, the correlation between blood levels and toxicity is poor.80

The narrow therapeutic margin and significant potential toxicity of cyclosporine remain obstacles for its use outside of centers with transplantation expertise. Major toxicities include nephrotoxicity and opportunistic infections. Nephrotoxicity can manifest as hypertension or elevations in blood urea nitrogen and creatinine levels. Because of the increased risk of opportunistic infections, including Pneumocystispneumonia, prophylaxis with trimethoprim-sulfamethoxazole has been recommended for patients receiving cyclosporine in conjunction with high-dose steroids.

The primary use of cyclosporine for IBD is in hospitalized patients with severe UC in whom therapy with oral or intravenous steroids has failed26,27; 50% to 80% of such patients respond to short-term treatment with intravenous cyclosporine.79 Duration of use is limited to 3 to 6 months. The long-term prognosis after cyclosporine therapy is controversial, but approximately 40% to 50% of responders to cyclosporine may avoid eventual surgical colectomy.93 This response improves to greater than 60% when patients are transitioned to long-term therapy with AZA or 6-MP.95

Cyclosporine also has been successfully used for steroid-refractory and fistulizing CD.96 Beneficial results are primarily achieved with intravenous cyclosporine. Oral cyclosporine has not been found to be effective for maintaining remission in CD, possibly because of poor and variable absorption.

Methotrexate

Only limited evidence supports the use of methotrexate in UC. Despite early optimism from uncontrolled clinical experience, methotrexate has not been effective therapy for UC in a small number of clinical trials.97

In studies of steroid-dependent CD patients, approximately 40% of patients were able to achieve clinical remission while tapering steroids during a 16-week trial of methotrexate, given parenterally (intramuscularly or subcutaneously) in a weekly dose of 25 mg.82,98 In a subsequent study, approximately two thirds of patients who achieved remission and remained on parenteral methotrexate, at a dosage of 15 mg/wk, continued in remission for 40 weeks.99

Methotrexate is well tolerated in IBD patients. Toxicity, which includes bone marrow suppression and hepatic fibrosis, is uncommon provided that blood counts and liver enzyme levels are monitored.97 Hypersensitivity pneumonitis is a rare but potentially irreversible complication. Methotrexate is a known teratogen and abortifacient, precluding its use in women anticipating pregnancy.

Other Immunomodulatory Agents

Tacrolimus has been used as therapy for refractory fistulas in CD100 and as an oral therapy for refractory UC.101 The indications for tacrolimus are very limited, however, now that infliximab has become available for CD [see Biologic Therapies, below].

ANTIBIOTICS

Antibiotic therapy has been used selectively in both UC and CD.102 Although a specific therapeutic role for antibiotics in UC remains unproved, most centers continue to advocate broad-spectrum antibiotics as a component of the intensive intravenous therapy used in patients with fulminant colitis and toxic megacolon.26,27 Antibiotics are also effective in the treatment of pouchitis after ileoanal anastomoses in patients with UC.103

In CD, the role for antibiotic therapy as a first-line agent for mild to moderate disease continues to be debated.104,105,106 In mild to moderate CD, metronidazole has proved to be comparable to sulfasalazine and superior to placebo at doses of 20 mg/kg/day.107Metronidazole is also effective for the treatment of perianal CD51 and can reduce the likelihood of relapse after intestinal resection.108Ciprofloxacin is comparable to mesalamine for mild to moderate CD and has been used successfully in combination with metronidazole for ileal disease and perianal CD.109,110,111 Combinations of antimycobacterial therapies for CD have not had consistent results in the treatment of active CD or as maintenance therapies.112

BIOLOGIC THERAPIES

The introduction of biologic agents has opened a new era in the treatment of IBD. Current biologic agents target cellular messengers, including cytokines, chemokines, and adhesion molecules.

The first biologic agent approved by the Food and Drug Administration for CD was infliximab, a chimeric monoclonal antibody of the IgG1 subclass that targets TNF-α. In clinical trials, infliximab has been shown to induce and maintain clinical remissions in patients with moderate to severe active luminal or fistulizing CD refractory to therapy with aminosalicylates, corticosteroids, and immunomodulators.113,114,115Infliximab is administered intravenously in a dose of 5 mg/kg. After the initial dose, repeat doses are given 2 weeks and 6 weeks later and, then, every 8 weeks on average. Infliximab is similarly effective in UC. Two large trials that enrolled patients with moderately active UC that was refractory to aminosalicylates, corticosteroids, and immunomodulators also demonstrated positive results.116

Infliximab is generally well tolerated. The primary risk with infliximab therapy is infection with intracellular organisms (e.g., tuberculosis, histoplasmosis, or cryptococcosis) in exposed or endemic populations.117 Pretreatment skin testing with purified protein derivative and chest x-rays is recommended, but false negative results are possible because many patients with CD are anergic.118 For that reason, clinicians must exercise clinical judgment regarding potential tuberculosis exposure. Infliximab is contraindicated in patients with active infections.

Unique adverse events with infliximab include the development of antibodies to the drug that reduce the effectiveness of the agent and are associated with infusion reactions (e.g., acute infusion reactions and serum sickness-like reactions).119 Additionally, antinuclear antibodies and anti-DNA antibodies develop in approximately 10% of patients with CD who are receiving infliximab therapy. Drug-induced lupus reactions have been reported but are uncommon. Delayed hypersensitivity (i.e., serum sickness-like reactions) has been observed in patients retreated after a long hiatus between doses (3 months to 4 years) but not in patients who have received continuous retreatment at 8-week intervals. A small increase in the risk of lymphomas has been observed with anti-TNF therapy in IBD,120 but it is not clear whether the increase reflects a small underlying risk in patients with CD or is the result of immune suppression.121 Other biologic therapies under development to treat IBD include inhibitors of so-called selective adhesion molecules122; anti-IL-12, anti-IL-2, and anti-CD3 monoclonal antibodies123,124; epidermal growth factor125; and granulocyte-macrophage colony-stimulating factor.126

MISCELLANEOUS THERAPIES

The recognition that cigarette smoking can protect against the development of UC has led to trials utilizing nicotine as adjunctive therapy. Although trials have demonstrated a role for nicotine in the symptomatic management of UC, nicotine therapy has not been shown to be effective at inducing remissions.127 Currently, nicotine is not a proven therapy for UC, but it may be a useful adjunctive measure in patients with UC that develops after smoking cessation.

Omega-3 fatty acids inhibit synthesis of leukotriene B4 and, at high doses, have shown a modest benefit in the treatment of active UC or as maintenance therapy.128,129 An enteric-coated fish oil preparation has proved to be effective in reducing relapse rates in CD130 and may eventually offer an alternative therapeutic option in IBD. However, current treatment guidelines do not include these agents.

Other novel therapeutic approaches to IBD that are currently under investigation include phosphodiesterase inhibitors,131 small molecules targeting mitogen-activated protein kinases,132 probiotics,133 apheresis,134 and targeting of costimulatory molecules.135

NUTRITIONAL THERAPIES

Hypotheses regarding dietary intraluminal antigens as important stimuli of the mucosal immune response have led to the investigation of nutritional therapies for IBD.3,136 Dietary manipulations have not been effective in treating UC, but patients with active CD have responded to several nutritional approaches.136,137 Bowel rest and total parenteral nutrition (TPN) are as effective as corticosteroids at inducing short-term remissions in active CD. In contrast, enteral nutrition in the form of elemental or liquid polymeric preparations has been shown to be less effective than corticosteroids.138 It has been suggested that elemental diets may provide the small intestine with nutrients vital to cell growth (e.g., glutamine) while avoiding complications related to TPN. However, despite their efficacy in active CD, neither enteral nor parenteral nutrition is effective at maintaining remissions.136

Patients with IBD are susceptible to nutritional deficits as a consequence of blood loss, protein-losing enteropathy, small bowel bacterial overgrowth, surgical resections (in CD), or inanition. IBD does not increase the risk of lactose intolerance, but ingestion of lactose can contribute to diarrhea in IBD patients with an inflamed small bowel or impaired colonic absorptive capacity. Similarly, consumption of nonabsorbable carbohydrates (e.g., sorbitol) or fats (e.g., olestra) can lead to excess flatus, bloating, or diarrhea. Occasionally, patients with proctitis present with constipation that improves with additional dietary fiber.

SUPPORTIVE THERAPIES

Many symptoms of IBD are not related to active inflammation and can therefore be treated separately from the inflammation. The management of these symptoms, which include pain and diarrhea, is as important to the patient's well-being as the treatment of mucosal inflammation. Treatment should be individualized according to symptoms and clinical disease state.

IBS is as common in IBD patients as it is in the general population.139 A dietary history is important to identify potentially aggravating components contributing to digestive symptoms. Although the stress of day-to-day living does not impact on the inflammatory activity of IBD, many patients identify stressful aspects in life as being associated with worsening of symptoms. IBS often responds to antispasmodics, antidiarrheals, fiber supplementation, or low doses of tricyclic antidepressants [see 4:XIV Gastrointestinal Motility Disorders]. Antispasmodics, primarily anticholinergic agents (e.g., dicyclomine, clidinium bromide, hyoscyamine, propantheline, or belladonna alkaloids), can treat cramping abdominal discomfort or symptoms of IBS that accompany UC and CD. Similarly, antidiarrheal preparations (e.g., diphenoxylate, loperamide, or codeine) can be utilized in patients with mild or moderate IBD to reduce the frequency of bowel movements and rectal urgency. Antimotility agents should be avoided in patients with severe or fulminant IBD because of the risk of inducing toxic megacolon.

In women with IBD, flares of disease activity are often related to the menstrual cycle, occurring more often during the premenstrual and menstrual phases.140 If menstrual cycles impact greatly on symptoms, ablation of the menstrual cycle with progesterone or leuprolide may be warranted. Pregnancy is associated with both exacerbations and remissions of IBD.141

There is no predisposing psychiatric personality profile in IBD, and there is no routine role for sedative, anxiolytic, antidepressant, or antipsychotic therapy. Psychopharmacologic therapies are reserved for individual patients as needed, usually after consultation with a psychiatrist.

Treatment of IBD patients with narcotic analgesia is rarely indicated. Pain in UC is related either to visceral hyperalgesia and muscle spasm or to transmural inflammation. The former condition is treated with antispasmodics and the latter with specific anti-inflammatory therapy. In CD, abdominal pain may be related to transmural inflammation or stenosis, but given the chronic nature of the disease, addictive analgesics should be avoided because of the risk of tolerance. Attempts should be made to reduce the inflammatory component of symptoms and to treat irritability with antispasmodics or nonaddictive analgesics.

NSAIDs (both nonspecific agents and cyclooxygenase-2 inhibitors) may exacerbate disease activity in IBD and can contribute to refractory disease.139,142,143,144 Minor pain, fever, menstrual symptoms, or arthralgias should be treated with alternatives to NSAIDs. If these agents are used, it should be with great caution and continued observation for their potential to exacerbate IBD.

Approximately half of patients with IBD use complementary therapies.145 Consequently, the history should include a careful review of nonprescription vitamins, health foods, homeopathic agents, or herbs, which may identify factors contributing to changes in bowel habits.

Patients with CD who have undergone bowel resection often have increased diarrhea, related to the length of bowel removed. Bile salt malabsorption may complicate resections of less than 100 cm; the diarrhea in these patients often responds to cholestyramine or alternative bile-salt sequestrants. Longer resections result in steatorrhea, which is managed with a low-fat diet.

MEDICAL TREATMENT OF ULCERATIVE COLITIS

Ulcerative Proctitis

Induction therapies

Topical aminosalicylates are the most effective treatments for distal UC.73 A daily dose of 1,000 to 4,000 mg is administered nightly as an enema or in divided doses as a suppository or foam. Topical corticosteroids (given via suppository, enema, or foam) are acceptable alternatives to mesalamine.26,27 Foam preparations are easier to retain and are better tolerated, allowing maintenance of daily activities despite twice-daily administration.

Oral aminosalicylates can be used to treat mild to moderate symptoms of proctitis but are less effective than topical therapies.146Sulfasalazine, 2 to 6 g/day in divided doses, is the most cost-effective aminosalicylate, but sulfa intolerance, toxic reactions, or allergy can compromise therapy. Mesalamine, olsalazine, or balsalazide formulations are preferable for patients with a history of sulfa allergy or for patients who develop sulfa-related side effects.

Inductive therapy is continued until the patient is asymptomatic. Although improvement should begin within a week, a complete response may require 4 to 12 weeks. Clinicians should recognize that patients with treated UC are capable of, as well as expected to, achieve a clinical remission, which is defined by the resolution of all inflammatory symptoms and a regeneration of the colonic mucosa.

Maintenance therapies

Maintenance therapy is indicated for the majority of patients with UC. In patients with proctitis, however, the limited nature of the disease permits treatment of any recurrent attacks on an as-needed basis.

Once remission has been achieved, the daily dose of mesalamine can be tapered according to the initial response; nevertheless, continuation of the inductive therapy, excluding steroids, is most effective for maintenance treatment. Mesalamine suppositories (or enemas) administered nightly, with gradual tapering to every other night and then every third night, will maintain remission in most patients. An oral aminosalicylate is added if patients continue to experience flares despite attempts to wean them from topical therapy; it may also be added after induction and then tapering of topical steroids.133

Left-Sided Colitis

Induction therapies

Mesalamine enemas are the most effective therapy for left-sided colitis, with steroid enemas being an alternative.73 Oral aminosalicylates also are effective, with improvement generally noted by 2 to 4 weeks.147 The oral amnosalicylates are generally equivalent in their efficacy for distal colitis.67,148

Patients with moderate to severe disease and those in whom therapy with topical and oral aminosalicylates has failed are treated as outpatients with oral steroids to induce remission, in a manner similar to that for patients with extensive colitis (see below). As with extensive colitis (see below), severe left-sided colitis requires hospitalization and treatment with systemic steroids.

Maintenance therapies

Inductive therapy is continued until the patient achieves clinical remission (normal bowel movements without bleeding, urgency, tenesmus, or inability to evacuate flatus). The transition to a maintenance regimen is then begun. Neither oral steroids nor topical steroids are effective at maintaining remissions. Patients who have responded to rectal mesalamine can continue with this therapy or switch to oral treatment.26,148 The combination of oral and topical mesalamine has advantages over either therapy alone for maintenance therapy for left-sided UC.149

If patients who are taking an oral aminosalicylate experience relapse, the dose should be increased to up to 4.8 g of mesalamine. Maintenance of remission in such patients may require topical mesalamine. After inductive treatment with steroid enemas, patients should be transitioned to an oral aminosalicylate, with gradual tapering of the topical therapy. Those requiring systemic steroids should be maintained on an oral aminosalicylate, with or without topical mesalamine.

Extensive Colitis

Induction therapies

Oral aminosalicylates are the primary therapy for outpatients with mild to moderate extensive colitis, but these agents may be supplemented with topical mesalamine or steroids.26,27,108 The dose of the oral aminosalicylate is more important than the specific formulation.67,72 Response rates of up to 80% can be anticipated with 4 to 6 g of sulfasalazine or 2 to 4.8 g of a mesalamine formulation given over 6 to 8 weeks. Therapy is continued as long as the patient is improving, to the point of clinical remission (i.e., normal bowel movements without blood or urgency). In the absence of a complete response, the dose of the aminosalicylate should be increased to a maximum of 4.8 g of mesalamine. An antispasmodic or antidiarrheal preparation may be added to treat abdominal cramping or mild diarrhea.

In patients who fail to improve or whose condition worsens, steroid therapy should be added in the form of prednisone, 40 to 60 mg/day.75Once the patient has achieved a clinical remission, which generally takes 2 to 4 weeks, steroids are tapered according to the time course to improvement. Prednisone can be tapered by approximately 5 mg every week down to 20 mg daily. Below 20 mg of prednisone, the daily dosage is reduced 2.5 to 5 mg every 1 to 2 weeks. Aminosalicylate therapy is continued as steroids are reduced.

Patients who respond to steroids but who are unable to completely taper without relapse despite optimal doses of an aminosalicylate should be started on AZA or 6-MP, which typically permits steroid withdrawal.26,27 Achieving the therapeutic benefits of these agents requires 3 to 6 months, during which time steroids are maintained at the lowest dose needed to prevent recurrence of symptoms. Calcium and vitamin D supplementation is indicated during steroid therapy to prevent metabolic bone disease. Reduced bone density is an indication for additional therapy with a bisphosphonate, estrogen replacement in postmenopausal women, or calcitonin.150

Hospitalization is indicated for patients who have significant weight loss, fever, disabling extraintestinal manifestations, frequent nocturnal bowel movements, severe anemia, or progressive symptoms despite outpatient therapy with corticosteroids.26,27 A low-residue diet is prescribed, to minimize abdominal cramps and bowel movements; the diet should contain sufficient protein and calories to counter the catabolic influence of active inflammation and steroids. Antispasmodics or antidiarrheals should be used with caution, and patients should be monitored for worsening symptoms.

Intravenous steroids are indicated for severely ill patients with fever, orthostasis, evidence of dehydration, more than 10 to 12 stools daily, rectal bleeding necessitating transfusion, protein depletion, or abdominal tenderness or distention. Prompt correction of fluid and electrolyte imbalances is critical. In patients with active bleeding, transfusions of packed red blood cells should be given to maintain the hematocrit above 30%. Anticholinergics, antidiarrheals, and narcotic analgesics are contraindicated because they can worsen colonic dilatation and mask peritoneal signs in debilitated, steroid-treated patients.

The intensive intravenous steroid regimen consists of prednisolone (40 to 60 mg/day), methylprednisolone (32 to 48 mg/day), or hydrocortisone (300 to 400 mg/day) administered in divided doses or as a continuous infusion. Steroid enemas (e.g., with 100 mg of hydrocortisone) can be used as adjunctive treatment to reduce rectal urgency or tenesmus. Oral aminosalicylates are discontinued because their anti-inflammatory effects are minor compared with those of high-dose steroids, as well as because of the potential for intolerance and the rare instances in which 5-ASA can worsen colitis.

When vital signs normalize, the hematocrit stabilizes, and the patient is able to tolerate a full (low-residue) diet with formed bowel movements without blood or urgency, treatment can be transitioned to an oral regimen. Full-dose therapy with an aminosalicylate is resumed and intravenous steroids are replaced with oral steroids.

If the patient is not improving after 5 to 7 days of intensive intravenous steroid therapy, the likelihood of improvement is small and the patient should be considered a candidate for cyclosporine therapy or surgery. Intravenous cyclosporine has been an important advance in the therapy of severe UC, but its use should be limited to clinicians experienced in the monitoring of immune suppression. A response is anticipated within 4 to 5 days, but if there is no significant improvement within 1 week, the patient should be referred for surgery. When clinical remission is achieved with intravenous cyclosporine, the regimen is replaced with both oral cyclosporine and prednisone. The daily dose of cyclosporine is doubled and administered in two divided doses (e.g., if the patient was receiving 200 mg daily, the oral dosing is 200 mg twice daily). Because of the high relapse rate after intravenous cyclosporine therapy, AZA or 6-MP is usually added to the oral regimen.26,151 In addition, trimethoprim-sulfamethoxazole is given three times weekly as prophylaxis against Pneumocystis pneumonia.26

Outpatient monitoring of cyclosporine levels and other laboratory measures are repeated weekly for the first month and then less often. Steroids are tapered (see above), generally over 8 to 12 weeks; cyclosporine is gradually discontinued; and maintenance therapy is begun.

Maintenance therapy

Maintenance therapy for extensive UC is determined by the intensity of therapy needed to induce remission. If aminosalicylate therapy has been sufficient to induce remission, continuation of the same dosage is optimal for maintenance. Patients treated with steroids require a more individualized approach, with the rate of steroid tapering determined by the rapidity of response as maximum doses of aminosalicylate are continued. Patients receiving AZA or 6-MP also are continued on maximum aminosalicylate therapy. The optimum doses of immunomodulators, as well as the doses that will cause leukopenia, have not been clarified.26,89 Complete blood counts should be obtained on at least a quarterly basis to detect delayed bone marrow suppression.152

Fulminant Colitis and Toxic Megacolon

Fulminant colitis, with or without colonic dilatation (toxic megacolon), is a medical emergency that is best managed by an experienced team of gastroenterology specialists and surgeons. Management is similar to that for severe colitis but with several modifications. Patients take nothing by mouth until they show clinical improvement. In the presence of small bowel ileus, a nasogastric tube should be inserted and maneuvers undertaken to reduce colonic distention and to allow passage of colonic gas by rectum (i.e., by rolling the patient from side to side, inserting a rectal tube, or placing the patient in the knee-elbow position).26 Intravenous steroids are continued and broad-spectrum antibiotic coverage is added for presumed transmural extension of disease, risk of microperforation, and systemic bacteremia. Cyclosporine in this setting is controversial but has been used in selected cases.

Aggressive medical management is successful in 40% to 50% of patients with fulminant colitis or toxic megacolon. Unfortunately, many patients are destined to develop complications or resistant disease, including recurrent toxic megacolon.25 Persisting peritoneal signs, any deterioration, or failure to improve within 24 to 72 hours is an indication for immediate colectomy.

SURGICAL TREATMENT OF ULCERATIVE COLITIS

UC is cured by proctocolectomy, and the quality of life after such surgery is generally excellent. The advantages of surgery include the elimination of the drawbacks of medical treatment, which include continued morbidity, adverse reactions to therapy, and the risk of neoplasia.26

Indications for Surgery

Indications for colectomy in UC are emergent, urgent, or elective. Emergent indications include exsanguinating hemorrhage, perforation, and unresponsive fulminant colitis or toxic megacolon. Urgent indications are chronic refractory colitis and significant complications of the disease or medical therapy (e.g., hemolytic anemia, pyoderma gangrenosum, and steroid-induced psychosis).

Surgical indications are often less acute and allow preparation and education of the patient and family to optimize timing and minimize physical and emotional consequences. Patients with quiescent colitis but with dysplasia diagnosed during colonoscopic surveillance are often feeling well and must adjust to the need for a major operation.

The most common indications for surgery are medically intractable disease, poor quality of life, or chronic complications from colitis or medical therapy. Given the availability of a surgical cure, it is not acceptable for patients to suffer physical debility, psychosocial dysfunction, or intolerable side effects.

Surgical Procedures

Proctocolectomy

Removal of the colon with an end ileostomy cures UC. This is the standard procedure with which all other treatments must be compared. Proctocolectomy and ileostomy are usually performed in a single procedure, even in the most urgent of settings. This approach has the least likelihood of complications. The primary drawback is the need for a permanent stoma. Quality of life after proctocolectomy is usually good, although many patients have difficulty adjusting to the cosmetic and functional aspects of the ileostomy. An unanticipated complication of proctocolectomy has been reduced fecundity in women.153

Sphincter-saving procedures

Because UC is essentially limited to the colonic mucosa, alternative procedures have been developed that involve removing the proximal colon, stripping the rectal mucosa off the distal rectal musculature, and sparing the anal sphincter.154 These so-called sphincter-saving procedures afford the opportunity of curing colitis and reestablishing continuity between the ileum and anus via an ileoanal anastomosis. Although a direct communication is technically feasible, it would result in intolerable postoperative diarrhea. Thus, these procedures include the provision of an ileal pouch to provide reservoir function. These J-, S-, or W-shaped pouches are created by folding the distal ileum and anastomosing the outlet to the anal canal.

Additional surgical modifications include the actual surgical stripping of the distal rectal mucosa or the stapling of the distal ileum to a short strip of residual rectal mucosa. In experienced surgical centers, the outcomes of stripping and stapling procedures are comparable.

Most often, sphincter-saving procedures are performed in stages: first, the surgeon removes the colon and performs an ileostomy, leaving the distal rectum as a Hartmann pouch; then, the surgeon creates the ileoanal anastomosis with a diverting ileostomy; and finally, the surgeon closes the ileostomy, which allows continuity of enteric flow through the pouch. Depending on surgeon preference and patient status, these procedures can be performed in one, two, or three stages.

Quality of life after an ileoanal anastomosis is excellent. Most patients describe full continence, with an average of six unformed (but not urgent) bowel movements daily.155 Approximately 10% of patients develop small bowel obstructions, either between stages or after completion of the procedure. The most common complication after colectomy and ileoanal anastomosis is the development of so-called pouchitis, a superficial inflammation within the pouch that is similar to the inflammation of UC.156 Pouchitis presents as increased urgency and evacuations that may be associated with bleeding and extraintestinal manifestations such as arthralgias, fever, and malaise. Most episodes of pouchitis respond to a course of an antibiotic, such as metronidazole or ciprofloxacin.103 Approximately 15% of patients who develop pouchitis will have a more chronic course requiring long-term antibiotics or oral budesonide.156 There is also evidence that high doses of the probiotic agent VSL#3 can prevent the onset of pouchitis or maintain remission of pouchitis after antibiotic therapy for recurrent or refractory pouchitis.157,158,159 As with proctocolectomy, ileoanal anastomoses have been associated with reduced fecundity in women.153

TREATMENT OF CROHN DISEASE

Gastroduodenal Crohn Disease

Dyspepsia, epigastric burning, or nausea in CD patients with gastroduodenal involvement usually responds to acid reduction therapy with an H2 receptor antagonist or a proton pump inhibitor.160,161 More profound nausea or vomiting responds to corticosteroids, followed by an immunomodulator for steroid-sparing effects. Gastric outlet obstruction that does not respond to steroids or immunomodulators, or both, is an indication for surgical decompression with a gastrojejunostomy.

Jejunoileitis

In patients with isolated proximal small bowel CD, diarrhea should be evaluated from a mechanistic standpoint. Malabsorption from short bowel syndrome or resection is treated with a low-fat diet, whereas small bowel bacterial overgrowth is managed with antibiotics. Patients presenting with prominent pain or small bowel obstruction are treated with short-term corticosteroids and then usually with AZA or 6-MP. Bowel obstructions that do not respond to short-term steroid therapy require surgical resection or, more commonly, stricturoplasty.

Ileitis, Ileocolitis, and Colitis

In patients with limited ileal or ileocolonic CD, therapy should be staged to alleviate presenting symptoms, then to maintain long-term well-being, while minimizing chronic complications related to the disease or therapy.

Mild to moderate disease

Outpatient therapy with anti-inflammatory agents, symptom-specific medications, and diet is utilized in patients who have abdominal pain and tenderness, diarrhea, low-grade fevers, weight loss without obstruction, painful mass, or severe malnutrition. Aminosalicylates, including sulfasalazine and mesalamine, have been effective at relatively higher doses than those that are used in UC. Sulfasalazine is effective in dosages of 3 to 6 g/day for ileocolonic and colonic CD but has not had significant benefits in limited small bowel disease.27 In contrast, mesalamine, 4 g/day, provides modest benefits for small bowel and colonic involvement if the formulation releases the mesalamine at involved segments.162 Benefits of sulfasalazine and mesalamine are modestly better than those achieved with placebo and less than those achieved with corticosteroids.163 Enteric-coated, delayed-release budesonide, 9 mg daily, is an alternative first-line therapy for mild to moderate CD affecting the ileum, right colon, or both; it is more effective than mesalamine therapy.163 Despite the limited potency of aminosalicylates, however, their potential long-term efficacy and absence of side effects make them first-line agents. As long as the patient continues to respond, the medication should be continued at the same dose used for induction. For patients with ileal or right colon disease who fail to respond within a short time (i.e., 2 to 4 weeks), budesonide therapy is a logical alternative.

Antibiotic therapy with metronidazole or ciprofloxacin, alone or in combination, is an alternative to aminosalicylates for ileocolonic and colonic CD.27,102 Although there are no long-term data regarding antibiotic therapy for ileal or ileocolonic CD, clinical observations have suggested that maintenance therapy is likely to be necessary. Patients receiving long-term metronidazole therapy should be monitored for peripheral neuropathy.

Dietary and nutritional therapy should focus on reduction of symptoms, prevention or correction of nutritional deficits, and avoidance of long-term complications. Elemental diets have short-term efficacy but are not practical for the majority of adult patients.27,138 The disease location, complications, and surgical history will direct attention to potential nutritional deficiencies. Calorie and protein requisites are the primary concern. Secondary considerations include maintenance of iron stores and levels of water-soluble vitamins in the setting of proximal small bowel disease, as well as levels of vitamins B12, A, D, and E with ileal disease or resection. Adequate calcium and vitamin D intake are of particular importance to avoid metabolic bone disease.

Moderate to severe disease

A different therapeutic approach is required in patients who fail to respond to aminosalicylates or steroids or who present with fever, greater than 10% weight loss, and abdominal pain accompanied by tenderness (without obstruction) but who are able to maintain oral intake. Corticosteroids are required to induce a clinical remission; however, clinicians must exclude perforating complications (i.e., abscesses) before starting corticosteroids. Oral treatment with prednisone, 0.5 to 1 mg/kg, reduces symptoms in most patients.27,75 However, the clinical response usually does not persist after steroid tapering; approximately 70% of patients will have a relapse or become steroid dependent within 1 year.164

Prednisone is continued at the initial dose until the patient responds completely (i.e., resolution of inflammatory symptoms). The dose is then decreased according to the time course to response. Tapering can usually proceed by 5 to 10 mg/wk, until a daily dose of 20 mg is reached, and then by 2.5 to 5 mg/wk. Calcium and vitamin D supplements reduce the risk of accelerated osteoporosis; in patients with reduced bone density, bisphosphonate or calcitonin should also be considered.150 Clinical monitoring is continued, with attention paid to relapse of inflammatory symptoms. Persisting noninflammatory symptoms (e.g., nonbloody diarrhea or abdominal cramps) can be treated with dietary modifications, antispasmodics, and antidiarrheals without intensifying anti-inflammatory therapy.

Severe disease

Infliximab may be beneficial in CD patients whose symptoms persist despite use of oral corticosteroids.119 A single infusion of 5 mg/kg provides significant improvement and clinical remission for patients who have not responded to aminosalicylates, antibiotics, steroids, or immune suppressants. However, a three-dose induction regimen followed by maintenance infusions given every 8 weeks affords a more optimal long-term approach. Concomitant treatment with an immune suppressant minimizes the risk of developing antibodies to infliximab that are associated with loss of response and infusion reactions.119 Before receiving infliximab, patients should be interviewed regarding exposure to tuberculosis and should undergo skin testing and chest x-rays.

Patients presenting with dehydration, high fever, cachexia, GI bleeding, obstructive symptoms, rebound tenderness, or an abscess require hospitalization and resuscitation with intravenous fluids, electrolytes, or transfusion. Acute obstructive symptoms, in the absence of chronic symptoms, mandate assessment for a mechanical cause (i.e., adhesions) rather than an inflammatory narrowing. Parenteral nutritional support is indicated as a supplement for patients unable to tolerate sufficient caloric intake and is mandatory for patients with profound malnutrition and an inability to eat.

Intravenous corticosteroids are indicated for severe manifestations of CD, once an abscess has been ruled out.27 Prednisolone (40 to 60 mg), hydrocortisone (200 to 300 mg), or methylprednisolone (32 to 48 mg) is given in an intermittent or continuous infusion and continued until the patient is free of pain and is passing flatus and stool or until the patient no longer has diarrhea. Oral steroids are then substituted at an equivalent dose. Failure to improve with intravenous steroids should cause consideration of surgical intervention, prolonged total parenteral nutrition and bowel rest, use of intravenous cyclosporine, or use of infliximab. Broad-spectrum antibiotics are added for febrile patients and those with abdominal tenderness or an inflammatory mass. These agents are continued until defervescence unless a specific pathogen has been identified and a narrow-spectrum agent can be substituted.

Maintenance Therapy

Maintenance therapy for CD was once discounted because of poor results from early studies that evaluated low-dose sulfasalazine and corticosteroids. However, it is now apparent that other forms of maintenance therapy can reduce the possibility of clinical relapse in certain patients.165 As with UC, steroids are not effective and should not be routinely used as maintenance agents for CD.

The aminosalicylates are useful maintenance agents when continued after inductive therapy, but they have limited value after steroid-induced remissions.27,66 In contrast, immunomodulators have been shown to have steroid-sparing and maintenance benefits. AZA and 6-MP are effective steroid-sparing agents for patients who cannot be weaned from steroids. Initial therapy is AZA, 2 to 2.5 mg/kg, or 6-MP, 1 to 1.5 mg/kg. The dosage is adjusted at 2-week intervals according to the leukocyte count, which must be maintained above leukopenic levels. The efficacy of these agents may not be evident until after 3 to 6 months of treatment, but benefits have been demonstrated to last for at least 4 years. To avoid unanticipated bone marrow suppression, monitoring of blood counts on a quarterly basis must continue once the patient is off steroids.

Maintenance therapy to delay postsurgical relapse has been evaluated according to different end-point criteria (e.g., endoscopic evidence of relapse, clinical symptoms, or repeat surgery).39 There is evidence that mesalamine, 3 to 4 g/day, can prevent postoperative recurrence, particularly when therapy is initiated shortly after surgery27; conversely, postponing therapy for more than 3 months circumvents any benefits. In addition to mesalamine, metronidazole is effective for reducing postoperative recurrence when administered at high doses (20 mg/kg) for 3 months after resection. There are no data regarding lower doses of metronidazole, prolongation of therapy beyond 3 months, or the use of other antibiotics.27,102 Finally, 6-MP at doses of 50 mg/day may reduce postoperative relapse for at least 2 years after resection.166 In view of the negative impact of cigarette smoking on the postoperative course of CD, however, all patients who smoke should be advised to stop.27

Surgical Therapy

Unlike UC, CD is not cured by surgery, except in the case of CD confined to the colon, for which proctocolectomy and ileostomy provide similar likelihoods of cure; sphincter-saving procedures are not advocated because of the high likelihood of recurrence after anastomoses. With CD in other locations, disease recurrence at the anastomotic site is virtually inevitable. Therefore, surgery is undertaken to treat refractory disease or complications, rather than to cure the disease. Nevertheless, in view of the excellent quality of life after limited surgery and the evolving capability to reduce or delay recurrence, it is imperative that surgery not be deferred because of fear of recurrence.

Purulent complications (e.g., abscesses) require percutaneous or surgical drainage. Surgery in CD patients is also indicated for intractable hemorrhage, perforation, persisting or recurrent obstruction, or toxic megacolon. The most common indications for surgery are intractable disease, failure of medical therapy, or complications related to treatment (e.g., steroid dependence). Many of these indications are subjective, requiring experienced clinical judgment and cooperative consultation between medical and surgical specialists. Surgical resections should be limited to macroscopic disease, and in general, primary anastomoses should not be performed in the setting of uncontained purulent complications.27

IBD AND PREGNANCY

Fertility is usually normal in both men and women with IBD, although an increase in disease activity correlates with a decrease in libido and with menstrual irregularities.167 Risk of early miscarriage is increased in women with active disease. When disease activity is controlled, the course and outcome of pregnancy do not differ substantially from those in the general population. Therefore, the best means of ensuring normal fetal outcome is to time conception when disease is under control, aggressively treat disease activity during pregnancy, and maintain the health of the mother.27 Aminosalicylates, steroids, and immunomodulators are safe during pregnancy and lactation, but they should be added only when necessary to maintain maternal well-being.88,168,169 Conversely, because of the risk of maternal worsening, neither acute nor maintenance therapy should be withdrawn during or after pregnancy. Attention to the mother's nutritional status is essential throughout pregnancy and during lactation. Neonates born to women on high doses of steroids should be monitored for adrenal suppression.

Complications

INTESTINAL COMPLICATIONS

The intestinal complications of IBD include hemorrhage, stricture, fistulas, toxic megacolon, and neoplasia. Chronic blood loss, with subsequent iron deficiency anemia, is common in both UC and CD. Profuse bleeding, however, is uncommon, particularly in UC, because the inflammation is superficial. Occasionally, patients with CD experience severe lower gastrointestinal bleeding when deep ulcerations erode into large vessels.

Strictures are more common in CD than in UC and result from transmural inflammation and fibrosis. These strictures remain fixed and lead to progressive bowel obstruction. In UC, narrowing of the lumen can occur from smooth muscle hypertrophy; the narrowing is related to disease activity and is reversible with treatment of acute inflammation. Fixed strictures in UC are almost always dysplastic or malignant. Toxic megacolon, although more common in UC, is not unique to UC and can occur in infectious colitis or CD.170

EXTRAINTESTINAL COMPLICATIONS

The extraintestinal complications of IBD can result from inflammation or from an HLA-related autoimmune process that un derlies the intestinal disease.171 Complications may also occur as a metabolic consequence of intestinal disease or its treatment.29

Mucocutaneous complications include eye changes of episcleritis or scleritis. These complications most commonly parallel colonic disease activity. Involvement of the anterior or posterior chambers with iritis or uveitis is related to HLA-B27 and follows a course that is independent of disease activity in the bowel.172 Skin lesions of erythema nodosum and pyoderma gangrenosum usually accompany or herald the onset of colitis and respond to treatment of bowel inflammation.

Musculoskeletal lesions can either be independent of or correlate with intestinal disease activity. Peripheral arthralgias and arthritis commonly involve larger joints (e.g., the hips, knees, ankles, elbows, and wrists) in an asymmetrical pattern. The inflammation usually accompanies intestinal disease activity and is almost never deforming, progressive, or associated with rheumatoid nodules. In contrast, arthritis of the central spine, ankylosing spondylitis, and sacroiliitis are associated with HLA-B27 and progress independently of intestinal disease. Metabolic bone disease is most often a consequence of long-term steroid use and, in CD, can be accelerated by malabsorption or inadequate dietary supplementation with vitamin D or calcium.150

A spectrum of hepatobiliary involvement occurs in both UC and colonic CD.173 Inflammation of the intrahepatic and extrahepatic bile ducts may take the form of a mild, periportal inflammatory infiltrate (pericholangitis or small-duct sclerosing cholangitis) that is asymptomatic, nonprogressive, and manifested only as mild elevations of γ-glutamyltransferase (GGT), alkaline phosphatase, and transaminases. At the other extreme, such inflammation may lead to full-blown sclerosing cholangitis with progressive secondary biliary cirrhosis. Of interest, cigarette smoking, which protects against UC, also protects against primary sclerosing cholangitis.9 Hepatic steatosis commonly manifests as a mild elevation of biliary enzymes in the presence of malnutrition or steroid therapy. Patients with CD who have ileal involvement or have had ileal resections are at increased risk for gallstones because of reduced enterohepatic circulation of bile salts, which increases biliary cholesterol saturation.

Urinary tract complications are more common in CD than UC.174 Kidney stones may reflect dehydration from diarrhea or an ileostomy.175 In the setting of ileitis or after ileal resections, the mechanism of nephrolithiasis is hyperoxaluria caused by steatorrhea. Normally, oxalate in the diet binds to free calcium in the colonic lumen and is excreted in the feces as calcium oxalate crystals. In patients with steatorrhea, free luminal calcium preferentially binds to fatty acids, creating soaps that are similarly excreted in the feces. Lacking calcium to bind it, the free oxalate is instead absorbed by the colon and excreted by the kidneys in abnormally high amounts. In the urine, oxalate complexes with urinary calcium to form calcium oxalate crystals. Patients with CD are also more susceptible to nephrolithiasis because their kidneys excrete low amounts of citrate, which acts as a nonspecific solubilizer in the urine. Calcium oxalate stones may result from either hyperoxaluria or idiopathic hypercalciuria; the two conditions can be differentiated by measuring calcium and oxalate levels in a 24-hour urine sample. If hyperoxaluria is identified, the treatment is to reduce fat intake (to reduce steatorrhea) and increase calcium supplementation.

Hematologic complications of IBD include anemia and clotting abnormalities. Anemia is most often caused by iron loss from bleeding or, in CD, from impaired iron absorption because of proximal small bowel disease.176 Folic acid deficiency is most often related to concurrent use of sulfasalazine, but occasionally, it is related to inadequate dietary consumption of folic acid or extensive jejunal disease. Vitamin B12deficiency from extensive ileal disease or resection can lead to macrocytic anemia. Hypercoagulability is a nonspecific complication of active IBD that results from increased production of acute-phase reactants and that increases the risk of venous thrombosis.177 Rarely, enteric losses of anticoagulant factors are a consequence of protein-losing enteropathy. In contrast, hypocoagulability may be a complication of vitamin K malabsorption or prolonged antibiotic administration.

Management of Extraintestinal Complications

Treatment of extraintestinal complications of IBD varies according to whether the manifestations are dependent or independent of intestinal (usually colonic) inflammation.29,171 Peripheral arthritis, erythema nodosum, pyoderma gangrenosum, and episcleritis occur in the presence of active disease and require intensification of anti-inflammatory therapy.

In some patients, complications can be treated independently, along with therapy for intestinal inflammation. For example, inflamed joints can be drained or injected with steroids, and pyoderma gangrenosum can be approached with a combination of topical and systemic approaches. Infliximab therapy has been very effective for the treatment of pyoderma gangrenosum associated with CD.178 Ocular complications should be evaluated by an ophthalmologist to prevent irreversible damage. Erythema nodosum usually responds to more aggressive therapy for colitis and should not be treated with NSAIDs. Peripheral articular manifestations of colitis can be treated with acetaminophen and increased doses of sulfasalazine; again, NSAIDs should be avoided.

Ankylosing spondylitis, sacroiliitis, and iritis (uveitis) are HLA-B27-associated manifestations that follow a course independent from colitis. The same is true of primary sclerosing cholangitis. Physical therapy is critical for patients with ankylosing spondylitis and sacroiliitis. Concurrent immunomodulatory therapy with methotrexate, hydroxychloroquine, or infliximab is indicated for inflammatory arthropathies.

NEOPLASIA

Adenocarcinoma of the intestines is a potential long-term complication of IBD, with features that are distinct from those of spontaneous adenocarcinomas in the general population.179 The risks of colonic neoplasia are similar in UC and CD and historically have been related to the extent and duration of disease, age at onset, and stricture formation, with primary sclerosing cholangitis indicating an increased risk for cholangiocarcinoma. In addition, evidence now suggests that in UC, severity of inflammation is also a risk factor for development of neoplasia.180 In contrast to colorectal cancer in the general population, which develops from adenomatous polyps, dysplasia is the precursor to cancer in IBD patients.34 Dysplasia is a neoplasia and has been defined on a pathologic basis and categorized as indefinite, low grade, or high grade (carcinoma in situ).34 Patients with dysplasia have an increased risk of cancer elsewhere in the colon if they have high-grade lesions (up to 50% of these patients have other colonic cancers) or low-grade lesions that are multifocal or in a raised plaque (dysplasia-associated lesion or mass).181

The ability to identify histologic dysplasia in UC makes it possible to perform surveillance colonoscopic examinations. Despite the absence of prospective data regarding colonoscopic surveillance for dysplasia in UC, most North American centers recommend that, after 8 to 10 years of UC, patients who are at increased risk for adenocarcinoma be entered into a colonoscopic surveillance program.26,181,182 Surveillance colonoscopies are recommended every 2 to 3 years for patients with 10 to 20 years of disease and every 1 to 2 years for patients with over 20 years of disease. The confirmation of low-grade dysplasia on surveillance colonoscopy strongly predicts progression to advanced neoplasia and warrants a recommendation for colectomy.183 Patients with indefinite dysplasia are treated aggressively to control inflammation and should undergo repeat colonoscopy after 3 to 6 months.

The risk of cancer in CD is also related to the location and chronicity of inflammation and, thus, includes a risk for small bowel adenocarcinoma in long-standing small bowel disease.184 However, because of the varied locations and segmental involvement in CD, there are no standardized guidelines for surveillance. Although there is no means of screening for small bowel dysplasia or cancer in CD, patients with colonic CD can be followed with colonoscopic surveillance in a manner similar to that used in patients with UC. Unfortunately, stricture formation in these patients often prevents visualization of the entire colon.

In addition to being associated with adenocarcinomas, IBD is associated with a small increase in the relative risk of lymphomas.185 This increase may be associated with immunosuppressive therapy.186,187,188 However, it is difficult to tease out any small increase in the relative risk from immunomodulatory therapy from the underlying risk associated with the chronic inflammatory disease and a potential association with Epstein-Barr virus infection.189,190

Prognosis and Conclusion

The diagnosis and treatment of IBD challenge the physician to guide patients through chronic illness. It is important to recognize the perceptions and concerns of the patient and family members confronted with a chronic, medically incurable, socially embarrassing, and potentially disfiguring condition.27 Despite the absence of known causes, medical therapy is usually effective, and surgical techniques have improved to the point that both longevity and quality of life can be preserved. The life expectancy of patients without fulminant disease is the same as that of the general population. Patience, optimism, and empathy are required to balance the concerns and misinformation that surround the disease, as well as the guilt associated with misconceptions that IBD is a so-called neurotic, psychosomatic, or self-induced disorder.

Patient information and support groups constitute a valuable part of management in IBD. Resources for high-quality patient information and support are available through national organizations such as the Crohn's and Colitis Foundation of America (http://www.ccfa.org).

Acknowledgment

Figure 4 Tom Moore.

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Editors: Dale, David C.; Federman, Daniel D.