Chapter 3. Inflammatory Bowel Disease: Medical Considerations

• Crohn disease and ulcerative colitis are chronic inflammatory diseases with well-described epidemiologic and clinical features.
• Genetic factors, immune dysregulation, and microbial gut flora all influence disease susceptibility.
• No single symptom, physical finding, or test result can diagnose inflammatory bowel disease (IBD); the diagnosis is a clinical one based on consistent findings obtained from the history, physical examination, and laboratory, endoscopic, histologic, and radiologic studies.
• Multiple conditions can mimic IBD; infectious pathogens are a particular concern.
• Intestinal complications commonly occur in IBD, many of which are predictable on the basis of disease type, location, severity, or duration; extraintestinal complications also occur, typically in association with active disease.
• Patients with long-standing colitis are at increased risk of developing colorectal cancer (CRC) and should be evaluated for dysplastic changes predictive of subsequent or synchronous malignancy.
• 5-Aminosalicylates, steroids, antibiotics, and immunomodulators have been mainstays of therapy; the choice of appropriate medication is based on multiple variables, including disease type, location, and severity.
• Biologic medications offer multiple powerful therapeutic options; the optimal time to apply these medications remains to be clarified.

The inflammatory bowel diseases, Crohn disease and ulcerative colitis, are chronic inflammatory illnesses of the gastrointestinal tract. Although significant advancements have been made in our understanding of the pathogenesis of these conditions, their ultimate cause remains idiopathic. The immunologic basis of IBD is discussed in Chapter 2. This chapter addresses the diagnosis and medical treatment of IBD. Surgical considerations are discussed in detail in Chapter 4.

Epidemiology

Crohn disease and ulcerative colitis have low incidences of new diagnosis; however, as a chronic condition typically diagnosed in the young, IBD has a relatively high prevalence. Estimates of incidence and prevalence vary among studies, with significant geographic and socioeconomic variations. The incidence of ulcerative colitis in North America is estimated to be 8–15 per 100,000 persons, with a prevalence of 170–230 per 100,000. Crohn disease has an estimated incidence of 5–15 per 100,000 and prevalence of 140–200 per 100,000. An increased incidence and prevalence of both forms of IBD is found in developed nations, northern locale (at least within the northern hemisphere), and urban environments; among Caucasians; and among persons of Jewish ethnicity. In industrialized countries, the incidence of Crohn disease has risen significantly over the past half century, whereas that of ulcerative colitis has remained relatively steady. In developing countries, the incidence of both forms of IBD has dramatically risen.

IBD typically presents at a relatively young age, often in adolescence. The median age of diagnosis for Crohn disease and ulcerative colitis is the third and fourth decades of life, respectively. Studies have suggested a second, smaller peak in incidence of IBD in the sixth and seventh decades, although this association is clearer for ulcerative colitis than for Crohn disease.

Etiology

The cause of IBD remains elusive, although interplay of genetic, microbial, and immunologic factors clearly exists. Twin and familial studies demonstrate a component of genetic susceptibility. However, the concordance rates among monozygotic twins for ulcerative colitis (6–18%) and Crohn disease (~50%) indicate that genetics play a relatively minor role in disease manifestation. Presumably, specific mutations confer susceptibility to IBD but are not sufficient per se. Various susceptibility genes have been identified, including NOD2/CARD15 on chromosome 16 and IL23R on chromosome 1, in Crohn disease. Both play integral roles in immune regulation within the gut. At the same time, mutations in these genes are present in only a minority of Crohn disease cases. Clearly, other less well-described dysregulations in the gut immune defense systems exist. A more complete discussion of the immunopathology of IBD can be found in Chapter 2.

Animal studies have demonstrated that the presence of commensal gut bacteria is necessary for IBD to occur. In theory, the subsequent enteritis or colitis results from a dysregulated or inappropriate immune response to flora tolerated by healthy individuals. Other environmental factors appear important as well. Cigarette smoking increases the risk for Crohn disease but is protective for ulcerative colitis. Both oral contraceptive and nonsteroidal anti-inflammatory medications have been implicated as risk factors for IBD, although the association remains controversial. Various diets have been proposed as causes or remedies for IBD, but no rigorous scientific evidence supports their use.

Crohn Disease

The inflammation in Crohn disease is typically transmural. This frequently leads to complications from perforating disease or from progressive fibrosis and stricturing. Crohn disease can thus be thought of as fitting one of three phenotypes: inflammatory, stricturing, or perforating disease (the latter including abscesses and fistulae). Disease behavior is not necessarily constant in an individual patient. Indeed, inflammatory disease frequently progresses to penetrating disease, and then to fibrosis and stricturing.

Unlike ulcerative colitis, Crohn disease may affect any part of the alimentary canal, and may do so in a nonconfluent (so-called skip lesion) pattern. Nearly half of all patients with Crohn disease have inflammation localized to the terminal ileum and cecum (Table 3–1). Isolated small bowel or colonic involvement is also common. Crohn disease of the esophagus, stomach, or duodenum is rare, and virtually unheard of in the absence of small bowel or colonic disease. Perianal disease, including abscesses and fistulae, is commonly encountered, particularly in conjunction with terminal ileal disease.

Symptoms and Signs

The onset of symptoms in Crohn disease is typically insidious, and the subsequent clinical course highly variable. For the majority of patients, the clinical course is characterized by recurring episodes of symptomatic disease interspersed with periods of remission. Abdominal pain and diarrhea are the most typical symptoms. Unlike ulcerative colitis, the diarrhea in Crohn disease is often nonbloody. Fever and weight loss are common. As a general rule, the location and phenotype of disease (inflammatory, stricturing, or perforating), along with the severity of inflammation, dictate a patient's symptoms and signs.

Complications from fistulizing disease are common. Pain and drainage of purulent or fecal material are characteristic of perianal fistulae. Fistulae from the gut may cause a variety of symptoms, depending on the sites of origin and other organ(s) involved: gut—diarrhea, weight loss; skin—drainage; vagina— drainage; bladder—pneumaturia. Stricturing disease causes obstructive symptoms of pain, abdominal distention, nausea, and vomiting. Extraintestinal manifestations are frequently encountered with Crohn disease (as with ulcerative colitis) and are discussed in more detail below.

Signs of Crohn disease include abdominal tenderness, most classically in the right lower quadrant. An abdominal mass may be palpable. Temporal wasting and cachexia indicate significant malnutrition. Typical symptoms of small bowel obstruction (distention, tympany, high-pitched bowel sounds) may be present in stenosing disease. Perianal and cutaneous fistulae are readily identified on a careful perineal and skin examination.

Laboratory Findings

No single laboratory test is diagnostic or specific for Crohn disease. Patients are typically at least mildly anemic, often with iron deficiency. Leukocytosis and thrombocytosis are common and typically reflect systemic inflammation. Serum albumin may be low in the case of protein-losing enterocolitis or in malnutrition. Malabsorption due to inflammation, bacterial overgrowth, or surgical resection may lead to diminished levels of various minerals (serum calcium and magnesium) and vitamins (B12, D, and folate). C-reactive protein (CRP)—and, to a lesser extent, erythrocyte sedimentation rate (ESR)—are nonspecific markers of inflammation that are frequently elevated in Crohn disease.

Stool studies may reveal excess fat, indicative of malabsorption, or fecal leukocytes, indicative of gut inflammation. Stool studies should be negative for infectious pathogens, including standard bacterial pathogens, Clostridium difficile, and ova and parasites.

Various serologic markers have been linked with Crohn disease, including antibodies to the yeast Saccharomyces cerevisiae (ASCA), to bacterial proteins Omp-C and I2, and to clostridial flagellin, CBir-1. Several antibodies to bacterial carbohydrates, including ALCA, ACCA, and AMCA, have been studied but are not yet commercially available. Antineutrophil cytoplasmic antibodies (ANCA, P-subtype) are associated with both ulcerative colitis and Crohn colitis. As individual tests, these markers have limited diagnostic accuracy, but in select situations may be helpful in distinguishing Crohn disease from other inflammatory conditions.

New stool tests, fecal lactoferrin and calprotectin, are available that can help distinguish IBD from irritable bowel syndrome (IBS) (conditions that often have overlapping symptoms), potentially gauge disease activity, predict flare, and monitor and/or assess response to treatment. Lactoferrin is the major component of secondary granules in neutrophils and inhibits bacterial proliferation by iron binding. It is stable in the stool for 7 days. Calprotectin is present in neutrophils, monocytes, and macrophages. It comprises 60% of the cytosolic protein in neutrophils and is stable in the stool for 7 days. Both appear to be promising markers for monitoring therapy as well as surrogates for mucosal healing. Insurance coverage for these tests, unfortunately, remains a major barrier. Future drug trials are incorporating these markers and will hopefully lead to improved coverage.

Greater than 60 distinct susceptibility loci for IBD have been identified, and advances in the technology for analyzing genetic information have improved dramatically. These have allowed for the identification of over 40 genes associated with IBD including multiple genes that regulate the innate immune response. Five genes, including NOD2, have been identified as regulating innate immune function in the pathogenesis of Crohn disease. Nine genes involved in Crohn disease have been implicated in dysregulation of adaptive immunity. Thirteen genes have been associated with ulcerative colitis by gene array studies. The NOD2 (formerly CARD15) gene was the first to be well characterized, and its presence can predict the development of penetrating and fistulizing Crohn disease. IL-23R has been associated with both Crohn disease and ulcerative colitis and recently has been demonstrated to predict response to infliximab in ulcerative colitis patients. Recent studies have shown that using whole-blood gene array is a promising technology for distinguishing Crohn disease from ulcerative colitis and may have potential use in differentiating severity of disease and response to therapy.

Imaging Studies

Standard abdominal plain films are useful for detecting obstructive disease and megacolon, but otherwise have a limited role in imaging Crohn disease. Small bowel series are useful for imaging small bowel mucosal disease, including strictures, ulcerations, and fistulae. Enteroclysis, although more sensitive, is limited by patient discomfort, increased radiation exposure, and its technically demanding nature. Barium enema remains an option for imaging colonic disease, especially to help delineate obstructive or fistulizing disease.

Computed tomography (CT) of the abdomen and pelvis has revolutionized the imaging of Crohn disease by allowing imaging of the bowel wall itself, as well as extraluminal disease such as abscesses or inflammatory masses. Common abnormalities of the gut include thickening and excessive mesenteric fat proliferation (so-called creeping fat). CT enterography, which uses a special low-density oral contrast, combines the advantages of CT and small bowel series by allowing detailed pictures of the small bowel mucosa, while at the same time imaging the extraintestinal abdomen. Three-dimensional CT reconstruction allows imaging of complicated transmural disease (see Figure 9–10). CT colonography has developed as a technology, but its role in Crohn disease remains limited in comparison to colonoscopy.

Magnetic resonance enterography (MRE) has been increasingly used. Studies have shown MRE to have better detection of mild disease than CT enterography (CTE) and slightly improved detection of wall thickening and enhancement. No significant difference was seen for moderate to severe disease. Other significant advantages include lack of ionizing radiation and, importantly, comprehensive evaluation of the perianal region. Disadvantages include higher cost compared to CTE and additional time needed to perform the study. Although not yet widely available, positron emission tomography (PET)/CT enterography in which glucose transporters are overexpressed in inflamed segments may show improved detection of lesions, better severity stratification, and improved monitoring of therapy.

Colonoscopy remains a mainstay in the assessment of Crohn disease, as it allows direct visualization of the bowel mucosa and sampling of tissue. Hallmark findings include ulcerations, erythema, granularity, and strictures. Pseudopolyps may be present. Ileal ulceration and skip lesions help distinguish Crohn disease from ulcerative colitis. The rectum is often spared. Fistulae are often difficult to locate endoscopically, and are best seen by contrast studies or magnetic resonance imaging (MRI). Endoscopic ultrasound, as previously mentioned, is useful in delineating perianal disease. Enteroscopy occasionally allows visualization of proximal small bowel lesions.

Capsule ("pill") endoscopy has been revolutionary in terms of allowing direct visualization of the small bowel in Crohn disease. The most common finding is ulceration, ranging from shallow aphthous-type to deep "punched-out" lesions. Strictures may also be encountered, occasionally causing pill retention and subsequent obstruction.

Ulcerative Colitis

Unlike Crohn disease, inflammation in ulcerative colitis is limited to the mucosal layer of the colon. The rectum is virtually always involved, with inflammation extending proximally in a confluent fashion. The extent of proximal involvement is variable. A significant proportion of patients have disease confined to the rectum (ulcerative proctitis). Roughly one third of patients have proctosigmoiditis, and the majority of patients have gross colitis only distal to the splenic flexure. Approximately one third of patients have disease that extends proximal to the splenic flexure (extensive colitis), often involving the entire colon (pancolitis or universal colitis).

On occasion, a so-called cecal patch of periappendiceal inflammation is encountered. This does not represent a true skip lesion suggestive of Crohn disease. Similarly, limited ileal involvement (backwash ileitis) can be seen in patients with ulcerative colitis who have pancolonic disease. Deep ileal ulcers, long segments of ileal involvement, or stricturing disease are consistent with Crohn disease and not ulcerative colitis. Although confluent disease involving the rectum is the rule in ulcerative colitis, patients on medical therapy, particularly topical therapy, may have apparent skip lesions or rectal sparing. This should be recognized as a treatment effect and not a manifestation of Crohn disease.

Unlike Crohn disease, ulcerative colitis is frequently acute or subacute in onset. Like Crohn disease, the subsequent clinical course is one of recurring episodes of symptomatic disease interspersed with episodes of relative (or complete) quiescence.

Symptoms and Signs

As with Crohn disease, the symptoms of ulcerative colitis depend on the extent and severity of inflammation. Overt rectal bleeding and tenesmus are virtually universally present and may be the only symptoms in patients with proctitis alone. When the proximal colon is involved, diarrhea and abdominal pain are more frequent complaints. Nausea and weight loss portend more severe disease. Severe abdominal pain or fever suggests fulminant colitis or toxic megacolon.

Signs of ulcerative colitis include mild abdominal tenderness, often most localized in the hypogastrium or left lower quadrant. Digital rectal examination may disclose visible red blood. As with Crohn disease, signs of malnutrition may be evident. Severe tenderness, fever, or tachycardia heralds fulminant disease.

Laboratory Findings

Patients with active disease are generally anemic and often iron deficient. Hypoalbuminemia suggests extensive disease with subsequent colonic protein losses. Leukocytosis, thrombocytosis, ESR, and CRP are nonspecific markers of systemic inflammation. Elevations in ESR and CRP are less common in ulcerative colitis than in Crohn disease.

Stool studies should be sent and found negative for typical bacterial pathogens, C difficile, and ova and parasites. Common positive findings in ulcerative colitis include fecal leukocytes and fecal lactoferrin.

Serologic markers have also been studied for ulcerative colitis. P-ANCA is the most commonly associated marker. However, as previously mentioned, it is also present in Crohn colitis, which limits its ability to distinguish the two conditions. As with markers in Crohn disease, P-ANCA may be helpful in predicting disease activity. Studies have suggested that P-ANCA-associated ulcerative colitis is more likely to be medically refractory, require early surgery, and result in chronic pouchitis in patients who have undergone ileal pouch anal anastomosis (IPAA).

Imaging Studies

Plain films of the abdomen are useful predominantly in patients with symptoms of severe or fulminant colitis. So-called thumbprinting or thickening of the colon wall indicates severe colitis with bowel wall edema. With toxic megacolon, the bowel is dilated with loss of haustral markings. Intestinal pneumatosis is a late finding and signals bowel ischemia and infarction. Obstructive findings are less common in ulcerative colitis than in Crohn disease and usually suggest malignancy. Barium enema is less commonly used since the advent of flexible sigmoidoscopy and colonoscopy. Nonetheless, it can be useful for detecting active ulcerative disease, polyps, or masses. In ulcerative colitis, the colon typically appears granular and shortened, perhaps as a consequence of chronic inflammation or fibrosis. Pouchography (contrast study of the pouch) in patients who have undergone IPAA permits assessment of diseases related to this operation, including leaks, pouchitis, fistulae, or strictures.

CT of the abdomen typically reveals colonic wall thickening, as with other forms of colitis (see Figure 9–21). Small bowel disease is not present, other than perhaps mild ileal inflammatory changes. Once a diagnosis of ulcerative colitis has been made, CT has only a limited role as an imaging modality, because endoscopic examination is typically the preferred modality for disease assessment.

Colonoscopy allows assessment of the extent of disease and severity of involvement. Classic findings include confluent inflammation extending proximally from the anal verge, with mucosal erythema, edema, and granularity and loss of normal vasculature. With more severe disease, the mucosa becomes overtly hemorrhagic, with ulcerations and a purulent exudate. So-called backwash ileitis, characterized by mild terminal ileal erythema, is seen in patients who have pancolitis. Pseudopolyps are commonly encountered in patients with long-standing disease. These are polypoid nondysplastic colonic lesions of hypertrophied tissue, often with surrounding atrophic mucosa. They are thought to represent the sequelae of chronic recurrent inflammation and healing, and harbor no malignant potential. Dysplastic or frankly malignant polyps or mass lesions are also encountered at higher rates in patients with ulcerative colitis. These lesions are discussed in more detail under Complications, below. Both pseudopolyps and colitis-associated neoplastic lesions are also seen in patients with Crohn disease.

Flexible sigmoidoscopy is a useful tool for disease assessment in the setting of flares of colitis. In this setting, a full colonoscopy is typically overly cumbersome for the patient and may carry an undue risk of perforation in patients with severe colitis. Flexible colonoscopy can assist with assessment of disease severity and help to exclude alternative diagnoses, such as infectious or ischemic colitis.

Diagnostic Considerations

No single symptom, physical finding, or test result can diagnose IBD. The diagnosis of both Crohn disease and ulcerative colitis is a clinical one, based on compatible patient history; physical examination; and laboratory, radiographic, endoscopic, and histologic findings. Diagnostic tools have been discussed at length in the preceding sections. A detailed discussion of the histologic findings of IBD is beyond the scope of this chapter. Noncaseating granulomas and transmural disease both are highly specific to Crohn disease. Colonic biopsies in both ulcerative colitis and Crohn colitis demonstrate evidence of acute inflammation, characterized by neutrophilic cryptitis, and chronic inflammation, such as crypt distortion and a plasmacytic infiltration of the lamina propria. A skilled pathologist is indispensable in helping to characterize the histologic findings and make the diagnosis of IBD.

For both the initial diagnosis and subsequent flares, other conditions that mimic IBD should be excluded (see next section). Of particular importance is the exclusion of infectious pathogens, as the treatment of active IBD frequently involves immunosuppressive medications. For patients who do not respond to medical therapy (or worsen despite it), the diagnosis of IBD should be rechallenged.

Many medical conditions can mimic IBD clinically, radiographically, or endoscopically. Infectious diseases of the gastrointestinal tract are of particular concern (Table 3–2). First, they are common; second, many of the immunosuppressive therapies directed toward IBD are potentially deleterious if given to a patient with an infectious illness. Common enteric bacterial pathogens, such as Campylobacter, Salmonella, Shigella, and Escherichia coli, can cause an infectious colitis characterized by abdominal pain, diarrhea, and hematochezia. The onset is usually acute with a self-limited course. Colitis, suggestive of ulcerative colitis or Crohn colitis, is often apparent by CT and colonoscopy. The E coli serotype O157:H7 is of particular note due to its propensity to produce a hemorrhagic colitis that may closely mimic fulminant ulcerative colitis. Campylobacter, Salmonella, Shigella, and Yersinia can cause an ileitis, which may mimic the radiographic appearance of Crohn disease. Yersinia is particularly notable for its predilection for the terminal ileum and cecum. Gram stains and cultures of stool are helpful for establishing the diagnosis of bacterial colitis. However, stool cultures have limited sensitivity, and a negative Gram stain and culture does not rule out a bacterial infection, particularly in the setting of a suggestive clinical history.

Clostridium difficile infection is common in IBD patients, even among those who have not been hospitalized or recently received antibiotics. The symptoms of C difficile infection may be the frequent, watery stools seen in non-IBD patients. Alternatively, infection may trigger an IBD flare, with a patient's typical symptoms of pain and bloody diarrhea. Thus, any patient presenting with symptoms suggestive of an IBD flare should be tested carefully for C difficile, and if ill, treated empirically for this until infection is satisfactorily excluded.

Mycobacterial infections of the gastrointestinal tract, including Mycobacterium tuberculosis, have a predilection for the terminal ileum and cecum, and thus may mimic Crohn disease. Active pulmonary disease may or may not be present. A patient's history usually includes travel to or immigration from endemic areas, exposure to infected patients, or immunosuppression. The diagnosis may be difficult to make, as histologic stains and cultures have limited sensitivity. Polymerase chain reaction amplification of biopsied tissue increases the yield and should be ordered when the clinical suspicion is high. A missed mycobacterial infection can have severe consequences, as the therapies frequently used for Crohn disease (ie, steroids, anti-tumor necrosis factor [anti-TNF] agents) suppress the immune response to mycobacterial infection.

Appendicitis and diverticulitis are commonly encountered abdominal infections, and are typically readily distinguished from IBD by their acute nature. However, occasionally they have subacute presentations, in which case they may closely resemble Crohn disease both clinically and radiographically.

Noninfectious colitides may also mimic ulcerative colitis or Crohn colitis. Ischemic colitis may cause pain and bloody diarrhea. However, it is typically acute in onset, self-limited, and localized to a specific segment of the colon. Biopsies readily identify acute ischemic injury. Radiation can cause proctitis, colitis, or enteritis. The injury can be chronic or acute, with symptoms similar to IBD. The diagnosis can usually be made on the basis of history, focal area of involvement, and characteristic biopsy findings. Diversion colitis is usually obvious by history, although distinguishing it from IBD can be a challenge when a patient with preexisting IBD (typically Crohn disease) undergoes a diversion. Segmental colitis is an idiopathic, recently appreciated entity characterized by focal colitis surrounding diverticula. Cardinal symptoms include rectal bleeding, abdominal pain, and diarrhea.

Gastrointestinal malignancies can manifest with symptoms similar to those of IBD. Adenocarcinoma of the colon or rectum may present with rectal bleeding, altered bowel habits, pain, and anemia. Lymphoma frequently involves the terminal ileum and cecum, creating a clinical picture similar to Crohn disease.

Irritable bowel syndrome is very common, and—like IBD—typically presents in younger patients. Hallmark symptoms include abdominal pain and diarrhea, which may make distinguishing irritable bowel syndrome from IBD challenging on a historical basis alone. Objective findings such as anemia, rectal bleeding, weight loss, or fever all point to IBD. A colonoscopy or small bowel study is helpful in documenting organic disease.

Lastly, Crohn disease and ulcerative colitis can have sufficient clinical overlap to make a definitive diagnosis difficult. The distinguishing features have already been discussed at length. Sometimes, however, a clear diagnosis of Crohn colitis versus ulcerative colitis cannot be made despite colonoscopy, biopsies, and other appropriate studies. In this circumstance, the term indeterminate colitis is used.

As previously discussed, Crohn disease frequently causes complications from penetrating and stenosing disease, including perforation, abscess, fistulae, and obstruction. Active small bowel disease or extensive small bowel resection may lead to complications from malabsorption, the severity of which depends on the location and extent of nonfunctioning (or surgically excised) bowel. Deficiencies in iron, folate, vitamin B12, and fat-soluble vitamins (A, D, E, and K) are common, with resulting complications including anemia and osteoporosis. Because Crohn disease has a predilection for the ileum, bile salt reabsorption is frequently compromised. Resection of 50–100 cm of ileum typically causes bile salts to spill into the colon, resulting in a bile-salt-induced diarrhea (responsive to bile-acid sequestrants). If more than 100 cm of ileum is resected or diseased, reabsorption of bile salts may be so impaired that the total pool is depleted, causing fat maldigestion and steatorrhea. Extensive small bowel disease or resection can also lead to short gut syndrome, with protein-calorie and micronutrient deficiency and dependence on parenteral nutrition. Small bowel bacterial overgrowth frequently complicates Crohn disease, particularly in the setting of stricturing disease or after resection of the ileocecal valve.

Malabsorption of fatty acids predisposes patients with Crohn disease to renal calculi. Calcium readily binds unabsorbed fatty acids, allowing oxalate to be taken up by the bowel in greater quantity. Subsequent renal excretion of this excess oxalate promotes the precipitation of calcium oxalate calculi.

The acute complications of ulcerative colitis (and Crohn colitis) are similar to that seen with other severe colitides. Severe, life-threatening hemorrhage occurs rarely. Toxic megacolon with subsequent infarction and perforation is also uncommon but requires a higher degree of clinical suspicion to diagnose. Colonic perforation bears a high mortality rate. Hence early diagnosis and treatment are critical.

Colorectal cancer (CRC) is the most feared long-term complication for ulcerative colitis. Risk factors include duration and extent of disease, severity of inflammation, family history of CRC, and concomitant primary sclerosing cholangitis (PSC). Early age of onset has been suggested to be a risk factor. The excess risk of CRC appears after 8–10 years of disease. Hence, a screening colonoscopy is recommended after 8 years for patients with extensive colitis, with surveillance examinations every 1–2 years. Unlike sporadic CRC, colitis-associated CRC does not typically arise from adenomatous polyps. Premalignant dysplastic epithelium may be flat and less readily recognized. For this reason, guidelines suggest random four-quadrant biopsies every 10 cm throughout the colon. Polyps should be resected and the flat mucosa at their base biopsied. Atypical polypoid lesions should also be biopsied. The presence of low-grade dysplasia in flat mucosa or any mass lesion other than a typical sporadic adenoma portends a high risk for synchronous or future CRC. In this situation, colectomy is advised, although in certain scenarios, intensive surveillance may be justified.

Although less well appreciated, Crohn colitis confers a risk of CRC comparable to that of ulcerative colitis. As with ulcerative colitis, the risk is proportional to the extent of colonic involvement. Surveillance guidelines are less well defined, but should roughly follow those for ulcerative colitis.

Other gastrointestinal malignancies occur with increased frequency in Crohn disease. Adenocarcinoma of the small bowel, although rare, is significantly more common among patients with small bowel Crohn disease than in the general population. Crohn patients also appear to have an excess risk of lymphoma, although the precise reason for this is unclear. Medications for treating Crohn disease have been implicated (see later discussion).

Pouchitis is a condition unique to patients who have undergone an IPAA. The etiology is unknown. Bacterial flora play a role, as evidenced by the effectiveness of antibiotic therapy. However, pouchitis is rare among non-IBD patients who have undergone IPAA, suggesting that other variables specific to IBD are at play. Typical symptoms include diarrhea, bleeding, urgency, incontinence, fever, and general malaise. Antibiotics (metronidazole and ciprofloxacin, among others), budesonide, and probiotics all have demonstrated efficacy.

Immunosuppressive therapy is a mainstay of treatment, and an increased risk of unique malignancies and infections has been documented. Thiopurine use has been proven to have a small increased risk of lymphoma, but it is concentrated in two populations: patients over the age of 65 and patients susceptible to mononucleosis infection. As a result, it is reasonable to check Ebstein-Barr virus (EBV) titers prior to instituting therapy in patients in their teens and twenties. Likewise, caution must be used in instituting therapy in the elderly. Initial reports linked the use of TNF-α agents with a rare type of lymphoma, hepatosplenic T-cell lymphoma (HSTCL). A review of cases shows numbers much smaller than initially reported and that most patients had received thiopurines either as monotherapy or in conjunction with TNF-α therapy. This issue may get more attention as further studies look at the use of combination therapy. Of note, most patients were men and less than 40 years old.

IBD may also cause extraintestinal complications (Table 3–3). PSC is linked to both ulcerative colitis and Crohn disease. The diagnosis of PSC may precede or follow that of IBD; symptoms and signs may arise years after colectomy. In addition to being at increased risk for CRC, these patients carry a high risk for cholangiocarcinoma. Of the dermatologic considerations, erythema nodosum is most common and typically responds to therapy directed toward active bowel disease. Pyoderma gangrenosum is rarer and more worrisome. It may occur even when IBD is quiescent and often does not respond to front-line IBD therapies. Dapsone, thalidomide, calcineurin inhibitors, mycophenolate, and high-dose corticosteroids have been used. Dermatologic referral is suggested. Uveitis is of special concern, as it can lead to blindness if untreated. Patients with eye pain, redness, and visual disturbance require urgent ophthalmologic evaluation.

Vaccinations

Vaccination guidelines in IBD have been published in both the United States and Europe. IBD patients should receive the same vaccinations as patients in the general population with the exception of live vaccines. It is imperative that vaccines be brought up to date immediately upon diagnosis of IBD, with the presumption that patients will be receiving immunosuppressive therapy. Immunosuppressive medications should be held, if possible, to allow vaccines ample time to take effect. The recent European guidelines recommended adding prophylaxis against Pneumocystis if three immunomodulators are used concurrently (Table 3–4).

The primary goal of medical therapy for IBD is directed toward the relief of clinical symptoms. For both Crohn disease and ulcerative colitis, medical therapy is generally considered as a two-step approach: (1) achieving remission from symptoms of active disease, and (2) maintaining remission. To a large extent, the clinical presentation dictates the choice of pharmaceutical agent. Patients with severe disease generally require more aggressive therapy, whereas patients with milder disease may do well with less potent medications or no therapy at all. All medical therapeutic options carry risks of toxicity, and this risk must be considered carefully against the potential benefit.

The secondary goal of preventing IBD-related complications has only recently become a serious consideration. Recent studies have suggested that medical therapy may help prevent postoperative recurrence of Crohn disease, or reduce the risk of CRC in ulcerative colitis. Preventing complications may also mean avoiding medical therapies. The goal of achieving steroid-free remission is now well recognized in IBD care.

Crohn Disease

5-Aminosalicylates

The pharmacology of 5-aminosalicylate (5-ASA) medications is discussed in detail under ulcerative colitis, for which their therapeutic benefit is better established. Studies have indicated a modest benefit of sulfasalazine for achieving remission in patients with colonic Crohn disease. Other 5-ASA drugs that lack the sulfa moiety of sulfasalazine have yielded more equivocal results, with some studies suggesting a modest clinical benefit. Neither sulfasalazine nor other 5-ASA agents have been shown to be effective in maintaining clinical remission in Crohn disease. Certain mesalamine preparations allow release of the drug in the small bowel, theoretically allowing therapy to be directed there rather than the colon. Unfortunately, evidence that such treatment alters disease course is lacking. Despite the limited evidence supporting their use, the favorable safety profile of 5-ASA medications has made them a popular choice for the treatment of patients with mild to moderate disease.

Antibiotics

Both ciprofloxacin (500 mg twice daily) and metronidazole (1–1.5 g/day) are widely used in the treatment of mild to moderate Crohn disease. As with 5-ASA agents, studies regarding the utility of antibiotics have shown conflicting results. Uncontrolled trials have suggested a clinical benefit for these two antibiotics in colonic and perianal Crohn disease, but convincing randomized placebo-controlled evidence is lacking.

Corticosteroids

Oral and intravenous corticosteroids are effective in inducing clinical remission in Crohn disease. Oral prednisone (40–60 mg/day) is a common option for patients with moderate disease. For patients with severe disease or in whom enteric absorption is a concern, intravenous methylprednisolone (40–60 mg/day) or hydrocortisone (200–300 mg/day) is an option. Larger dosages of steroids have a higher risk of side effects but offer no additional clinical benefit. It should be noted that even though 75–80% of patients respond to initial therapy with corticosteroids, only 25% of patients after 1 year are well without steroids. Seventy-five percent become either steroid refractory or steroid dependent. Steroids do not help to heal fistulae.

Although useful in achieving remission, steroids are not effective in maintaining it. Therefore, once a satisfactory clinical response has been achieved (usually within 2 weeks), steroids should be tapered gradually but steadily. A common approach is to reduce the daily dose of prednisone by 5 mg every week. The risks of chronic steroid exposure have been well described (Table 3–5).

Budesonide is an oral corticosteroid with significant first-pass hepatic metabolism. As such, it offers therapy to the gut (typical dose 9 mg/day) with reduced systemic effect. Its predominant region of effect is the ileum and right colon; it is generally not recommended for left-sided colonic disease. Its role is typically reserved for patients with mild to moderate ileocecal disease. As with other steroids, budesonide has not been shown to be useful as a maintenance medication. Furthermore, common corticosteroid side effects may occur (eg, osteopenia and osteoporosis) but significantly less frequently than with prednisone.

Thiopurines (Azathioprine and 6-Mercaptopurine)

Azathioprine and 6-mercaptopurine (6-MP) are purine analogs that function as immunosuppressive agents. Azathioprine is converted to 6-MP nonenzymatically. 6-MP is then converted via three distinct metabolic pathways to various metabolites, including the therapeutic metabolite, 6-thioguanine nucleotides. Both medications have been demonstrated to be effective for achieving and maintaining remission in Crohn disease. Moreover, they can help to heal fistulae and minimize steroid use. They are typically reserved for use in patients with moderate to severe disease due to their increased toxicity profile, which includes hepatitis, nausea, and pancreatitis. Perhaps the most serious common side effect is leukopenia, which can be life threatening. Several studies have suggested an increased risk of lymphoma, although the absolute risk appears to be well below 1%.

Standard therapeutic dosages for azathioprine and 6-MP are 2–2.5 mg/kg/day and 1–1.5 mg/kg/day, respectively. Over the past several years, studies have shown that 80% of patients will have an appropriate response to azathioprine/6-mercaptopurine (AZA/6-MP) if a serum level of the active metabolite (6-thioguanine, 6TGN) of the drug achieves a therapeutic range (235–450 pg/mL). Therefore, dosage adjustment is no longer based solely on weight. Because another metabolite of AZA/6-MP, 6-methylmercaptopurine (6-MMP), is associated with abnormal liver tests, it has become routine to check the metabolite levels of AZA/6-MP after 3–4 weeks to be sure the dose is appropriate in regard to a therapeutic level as well as risk for liver disease.

A minority of patients carry one or more mutant alleles in one of the genes that regulate thiopurine metabolism—thiopurine methyltransferase (TPMT). Patients carrying this mutation are highly susceptible to leukopenia, even with lower doses of drug. Therefore, it is common practice to test for this mutation prior to starting therapy with these medications. Patients homozygous for TPMT mutations (1%) should not be treated with azathioprine or 6-MP. Regular laboratory testing for leukopenia (every 1–2 weeks for first 3 months, then every 2–3 months indefinitely) is important for all patients (including those homozygous wild-type for TPMT), as leukopenia can occur late in the course of medical therapy.

Methotrexate

Methotrexate is a folate antimetabolite that has been shown to be effective for achieving remission when delivered intramuscularly or subcutaneously (25 mg/week). The drug is also effective at maintaining remission at lower doses (15 mg/week). Oral therapy has not been shown to be effective, possibly due to decreased absorption. Common toxicities include nausea, pancytopenia, pneumonitis, hepatitis, and hepatic fibrosis. Methotrexate is an abortifacient, and should be used only with extreme caution in women of childbearing age.

Anti-TNF Agents (Infliximab, Adalimumab, Certolizumab Pegol)

The introduction of infliximab, a chimeric immunoglobulin G monoclonal antibody directed against TNF, revolutionized the medical therapy of moderate to severe Crohn disease. The importance of TNF as a proinflammatory cytokine in IBD has long been appreciated (see Chapter 2). Administered intravenously (starting dose 5 mg/kg) at weeks 0, 2, and 6, it is effective for achieving and maintaining remission in Crohn disease, including disease refractory to the standard medications discussed previously. Like 6-MP, it is steroid sparing and effective in healing fistulae. Infliximab also can maintain remission in Crohn disease (dosed every 8 weeks). However, despite an initial response rate of 80%, by the end of 1 year, only 25% of patients remain in a complete clinical remission. For patients who are losing response to infliximab, the dose may be increased to 10 mg/kg with no change in the infusion interval or, alternately, the interval to next infusion may be shortened to every 6 weeks. A recent trial comparing steroid-free remission in immunomodulator-naïve patients treated with combination of azathioprine and infliximab therapy showed statistically significant improvement in combination therapy over infliximab or azathioprine monotherapy up to 26 weeks (Table 3–6). Previous studies have not shown clinical benefit for patients who failed azathioprine and then started infliximab.

More recently, other anti-TNF biologic agents have been introduced (adalimumab, certolizumab pegol). All share the same putative mechanism of action and appear comparably effective. Both adalimumab (induction dose of 160 mg subcutaneously [SQ], followed by 80 mg SQ at week 2, then 40 mg SQ every 2 weeks) and certolizumab pegol (400 mg SQ at weeks 0, 2, and 4, followed by 400 mg SQ every 4 weeks) provide a similar response and remission rates as infliximab. Recent multicenter trials have demonstrated that both adalimumab (Table 3–7) and certolizumab pegol (Table 3–8) are effective in maintaining a clinical response in 50–60% of patients at either 6 months or 1 year and remission in 40–50% of patients. Additionally, among patients who have lost their response to infliximab, approximately 35% of patients will regain response with adalimumab or certolizumab therapy over 12 weeks. Patients who failed infliximab, including primary nonresponders, have been shown to have a clinical remission rate of approximately 45% after 2 years of adalimumab therapy. Adalimumab can heal fistulae in 40% of patients, and this outcome is maintained in 90% of patients over 2 years. As foreign proteins, these agents can generate an immune response in terms of antibody formation against the drug itself, particularly if administered intermittently. For this reason, continuous therapy is the current standard of care. Loss of response to one medication does not necessarily mean a loss of response to the class.

Infection is the most serious complication with anti-TNF biologic agents. Patients are particularly vulnerable to tuberculosis and should be screened carefully for this prior to initial administration. Patients with latent hepatitis B are vulnerable to reactivation. Anti-TNF therapy should be held in the setting of pyogenic infections. Concern has been raised about possible increased risk of lymphoma, although this remains controversial. Less serious adverse effects include infusion or injection reactions, lupus-like reaction, and serum sickness.

Other Agents

The calcineurin inhibitor tacrolimus has demonstrated efficacy in fistulizing disease but is rarely used in adults due to its long-term risk of renal disease and opportunistic infections. Thalidomide appears effective, in part through anti-TNF effects, but is similarly limited by its known toxicities. Natalizumab is an antibody directed against α4 integrin, designed to inhibit trafficking of leukocytes. Although effective for Crohn disease, initial enthusiasm for natalizumab has been tempered by an apparent associated risk for developing progressive multifocal leukoencephalopathy. The drug is available in a strictly monitored setting for select patients. MLN-02, directed against α4β7 integrin, has shown early promise. Antibodies against interleukin (IL)-12, IL-23, and IL-17, implicated in the pathogenesis or Crohn disease, are currently being studied as potential therapeutic agents.

Surgery

Surgery in Crohn disease is frequently required to address complications of stricturing, penetrating, or fistulizing disease. Because recurrence at anastomotic sites is common, surgery is not recommended as a primary treatment strategy. Refer to Chapter 4 for detailed discussion of surgical considerations in the treatment of Crohn disease.

Ulcerative Colitis

5-Aminosalicytes

5-ASA medications are the mainstay of therapy for mild to moderate ulcerative colitis. Sulfasalazine, the original drug in this class, consists of sulfapyridine attached to the 5-ASA moiety. The sulfa component causes the majority of side effects from sulfasalazine (nausea, vomiting, dyspepsia, headache, malaise). Hence, formulations consisting solely of the therapeutic 5-ASA compound have been developed, including both orally and rectally administered preparations. These formulations have used different mechanisms to control the site of drug delivery (Table 3–9). Medications that release 5-ASA at more than pH 7 selectively target the terminal ileum and colon. Those that require cleavage of an azo-bond by bacteria release 5-ASA only in the colon.

5-ASA medications have demonstrated efficacy in both the induction and maintenance of remission for ulcerative colitis. In the majority of patients, they are well tolerated. Interstitial nephritis, pulmonitis, pericarditis, rash, pancreatitis, or worsening of colitis occurs rarely. Patient adherence is a concern, as many formulations require three- to four-times-daily dosage. Rectally administered topical therapy is highly effective for distal ulcerative colitis but has similar problems with patient adherence.

Recent evidence has suggested that 5-ASA medications may decrease the risk for CRC. The mechanism is unclear but may involve decreased colonic inflammation. This apparent protective effect suggests that chronic 5-ASA therapy may be warranted not just as a maintenance drug, but as a chemopreventative agent.

Corticosteroids

Much as with Crohn disease, corticosteroids are useful for the acute treatment of moderate to severe ulcerative colitis. Typical starting doses of prednisone are 40–60 mg, with methylprednisolone (40–60 mg/day) or hydrocortisone (200–300 mg/day) reserved for hospitalized patients. Approximately one third of patients with ulcerative colitis require steroids. Only about 50% of patients will achieve a remission and about 30% will have a response. However, after 1 year, about 20% of patients are steroid dependent and about 30% require surgery. As with Crohn disease, steroids are ineffective as maintenance medications. Therefore, they should be tapered off once a satisfactory maintenance medication has been started. Rectally administered steroid enemas offer the benefits of steroid therapy for flares of distal ulcerative colitis, and some may have less systemic side effects.

Thiopurines

The efficacy of 6-MP and azathioprine for ulcerative colitis has not been extensively studied. They are effective medications for the maintenance of remission in ulcerative colitis, although anecdotal experience suggests that they are less so than when used in Crohn disease. Due to their slow onset of action, they are not appropriate as solo induction agents for patients with severe disease, especially in light of other available medical or surgical options. Dosing and adverse effects are as discussed earlier for Crohn disease.

Infliximab

Several years after infliximab had been in wide use for Crohn disease, it was demonstrated to be effective both for the induction and maintenance of remission in ulcerative colitis. It offers a valuable and less toxic alternative to cyclosporine for patients with severe disease who otherwise would be facing surgery. The appropriate time to initiate infliximab vis-a-vis steroid and thiopurine therapy remains controversial. However, infliximab may be considered in patients who are steroid refractory or steroid dependent and definitely for patients who are failing AZA/6-MP. Dosing and toxicity have previously been discussed. A recent study has identified several surrogate markers that predict a strong response to infliximab, including a high colitis activity index (CAI), ANCA seronegativity, and a genetic polymorphism called the IL-23R variant.

Cyclosporine

Cyclosporine is a calcineurin inhibitor used as last-line medical therapy to treat hospitalized patients with severe ulcerative colitis. Given as a continuous infusion (2–4 mg/kg/day), cyclosporine can induce a short-term response in 50–80% of patients. It is best begun in a hospitalized patient who has failed intravenous corticosteroids in hospital within 7 days. Toxicities limit its long-term use. Nephrotoxicity and opportunistic infections are prime concerns. Seizures are also possible; for this reason, cyclosporine should be avoided in patients with low cholesterol (<100 mg/dL) or hypomagnesemia. Moreover, long-term data suggest that half of patients treated with cyclosporine ultimately require colectomy within 1 year. Therefore, the risks of toxicity must be weighed carefully against the limited long-term benefit of even short-term cyclosporine use. Cyclosporine is not appropriate as a long-term maintenance medication.

Probiotics

Several recent studies have looked at the use of probiotics, specifically VSL #3, in both inducing and maintaining remission in mild to moderate ulcerative colitis as monotherapy or as an adjunct to 5-ASA and/or immunomodulator therapy. Limitations to the data include, varying dosages used in different studies and the fact that most probiotics are not currently covered by insurance and are costly.

Surgery

Unlike with Crohn disease, surgery offers a therapeutic option in ulcerative colitis. Total proctocolectomy removes the diseased tissue and eliminates the need for further medical therapy directed toward colitis. It is indicated in fulminant disease, severe disease refractory to maximal medical therapy, and when colitis-associated dysplasia or malignancy is detected. As discussed previously, colectomy does not preclude other complications, such as PSC or pouchitis. IPAA is the current surgery of choice in the elective setting. Total proctocolectomy with end ileostomy is also a reasonable choice, and may be more appropriate given the clinical setting. Surgical considerations in the treatment of ulcerative colitis are discussed in detail in Chapter 4.

Ulcerative colitis and Crohn diseases are chronic, relapsing illnesses that can be managed for the most part with medical therapy. However, 75% of patients with Crohn disease can expect to have surgery over the course of the illness; this figure may be somewhat less with the introduction of biologic therapies. The majority of patients with ulcerative colitis can be managed using medical therapy with the prospect of surgery reaching 25%. It is important to remember that patients with ulcerative colitis and extensive Crohn colitis are at increased risk for CRC when the disease has been present for more than 8–10 years, and patients must be screened by colonoscopy every 1–2 years, depending on the extent of disease.

This chapter is a revised version of the chapter by Dr. Robert Burakoff and Dr. Scott Hande that was in the previous edition of Current Diagnosis & Treatment: Gastroenterology, Hepatology, & Endoscopy.