AUTHOR AND EDITOR INFORMATION

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Inflammatory bowel disease (IBD) is an idiopathic disease, probably involving an immune reaction of the body to its own intestinal tract. The 2 major types of IBD are ulcerative colitis and Crohn disease. As the name suggests, ulcerative colitis is limited to the colon; Crohn disease can involve any segment of the gastrointestinal tract from the mouth to the anus.

Although ulcerative colitis and Crohn disease have significant differences, many (but not all) of the treatments available for one are also effective for the other. Likewise, both diseases share many extraintestinal manifestations, although some of these tend to occur more commonly with one disease or the other.

Both ulcerative colitis and Crohn disease usually have waxing and waning intensity and severity. When the patient is actively symptomatic, indicating significant inflammation, the disease is considered to be in an active stage; the patient is having a flare of the IBD.

When the degree of inflammation is less (or absent) and the patient is usually asymptomatic, then the patient's disease is considered to be in remission. In most cases, symptoms do correspond well with the degree of inflammation present for either disease, although this is not universally true. In some patients, objective evidence for disease activity should be sought before administering medications with significant adverse effects.

Pathophysiology

The pathophysiology of IBD is under active investigation. The common end pathway is inflammation of the mucosal lining of the intestinal tract, causing ulceration, edema, bleeding, and fluid and electrolyte loss.

Persons with IBD have a genetic predisposition (or perhaps susceptibility) for the disease. The triggering event for the activation of the immune response has yet to be identified. Possible factors related to this event include a pathogenic organism (as yet unidentified), an immune response to an intraluminal antigen (eg, protein from cow milk), or an autoimmune process whereby an appropriate immune response to an intraluminal antigen and an inappropriate response to a similar antigen is present on intestinal epithelial cells (ie, alteration in barrier function).

A great deal of research has been performed to discover potential genes linked to IBD. One of the early linkages discovered was on chromosome 16 (IBD1 gene), which led to the identification of the NOD2 gene (now called CARD15) as the first gene clearly associated with IBD (as a susceptibility gene for Crohn disease). Studies have also provided strong support for IBD susceptibility genes on chromosomes 5 (5q31) and 6 (6p21 and 19p). NOD2/CARD15 is a polymorphic gene involved in the innate immune system. The gene has more than 60 variations. Three of these variations play a role in 27% of patients with Crohn disease, primarily in patients with ileal disease. One important point to note with all of these potential genes is that they appear to be permissive (ie, allow IBD to occur) but not causative (ie, just because the gene is present does not necessarily mean the disease will develop).

First-degree relatives have a 5- to 20-fold increased risk of developing IBD compared to subjects from unaffected families. The child of a parent with IBD has a 5% risk of developing IBD. Twin studies show a concordance of approximately 70% in identical twins versus 5-10% in nonidentical twins. 

None of these mechanisms has been implicated as the primary cause, but they are postulated as potential causes. The lymphocyte population in persons with IBD is polyclonal, making the search for a single precipitating cause difficult. In any case, activation of the immune system leads to inflammation of the intestinal tract, both acute (neutrophilic) and chronic (lymphocytic, histiocytic).

For unclear reasons, research suggests that smoking increases the risk of Crohn disease but reduces the likelihood of ulcerative colitis.  

Appendectomy early in life also reduces the lifetime risk of developing ulcerative colitis.

Many of the mucosal changes seen in persons with IBD are nonspecific in nature; they are seen in any organ system in which active inflammation is occurring. Many inflammatory mediators have been identified; antibodies against these mediators or methods to block the production or receptors for these mediators hold great promise for potential therapy for IBD.

Frequency

United States

An estimated 1-2 million people in the United States have ulcerative colitis or Crohn disease. Before 1960, the incidence of ulcerative colitis was several times higher than that of Crohn disease. The latest data suggest that the current incidence of Crohn disease is approaching that of ulcerative colitis, although this change may reflect improved recognition and diagnosis of Crohn disease.

In the United States, the rates of IBD among persons of European descent have been measured in Olmstead County, Minn. In this population, the incidence of ulcerative colitis is 7.3 cases per 100,000 people per year and the prevalence is 116 cases per 100,000 people; the incidence of Crohn disease is 5.8 cases per 100,000 people per year and the prevalence is 133 cases per 100,000 people.

The prevalence of IBD among Americans of African descent is estimated to be the same as the prevalence among Americans of European descent. The prevalence is lower among Americans of Asian and Hispanic descent.

International

The incidence of IBD is assumed to be highest in developed countries and lowest in the developing regions of the world. A study in Italy showed the incidences of ulcerative colitis and Crohn disease to be similar to those found in the United States. Persons living in colder climates have a greater rate of IBD than persons living in warmer climates. Persons living in urban areas have a greater rate of IBD than persons living in rural areas.

Mortality/Morbidity

Multiple studies have been conducted from regions throughout the world on mortality in patients with IBD. The mortality from ulcerative colitis has decreased over the past 40-50 years.

• One study suggested decreased mortality for ulcerative colitis (standardized mortality ratio of 0.6 in Florence, Italy), but the vast majority of studies indicate a small but significant increase in mortality associated with IBD. The standardized mortality ratio for IBD generally ranges from approximately 1.4 times the general population (Sweden) to 5 times the general population (Spain). In general, the 95% confidence intervals suggest that the increase in relative risk is real. Ulcerative colitis and Crohn disease have approximately equal mortality rates.
• The most frequent cause of death in persons with IBD is the primary disease, followed by malignancy and thromboembolic disease.
• A generally accepted postulation is that the risk of colorectal cancer is not significantly higher in persons with ulcerative colitis compared with the general population until several years after diagnosis. Beyond 8-10 years after diagnosis, the risk of colorectal cancer increases by 0.5-1.0% per year. Data suggest that surveillance colonoscopies with random biopsies reduce mortality from colorectal cancer in patients with ulcerative colitis, primarily by allowing the detection of carcinoma at an earlier Duke stage. Data suggest that persons with Crohn colitis involving the entire colon have a risk of developing malignancy equal to that of persons with ulcerative colitis; however, the risk for most patients with Crohn disease is much smaller (albeit poorly quantified).

Race

The incidence of IBD has been reported to be highest in Jewish populations, followed by non–Jewish white populations. However, data suggest that incidences in non-Jewish, black, and Hispanic populations are increasing. The American Jewish population has one of the highest prevalences of IBD, 4-5 times that of the general population.

Sex

The male-to-female ratio is approximately equal for both ulcerative colitis and Crohn disease.

Age

Ulcerative colitis and Crohn disease are most commonly diagnosed in young adults (ie, late adolescence to the third decade of life). The age distribution of newly diagnosed IBD cases is bell-shaped; the peak incidence occurs in people in the early part of their second decade of life, with the vast majority of new diagnoses made in people aged 15-40 years. However, children younger than 5 years and elderly persons are occasionally diagnosed. Of patients with IBD, 10% are younger than 18 years.

CLINICAL

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History

The manifestations of IBD generally depend on the area of the intestinal tract involved. Patients with ulcerative colitis or Crohn colitis frequently have bloody diarrhea, occasionally with tenesmus. Patients with Crohn disease involving the small intestine frequently have abdominal pain and diarrhea, and occasionally they have symptoms of intestinal obstruction. A variety of intestinal and extraintestinal manifestations of IBD also may be observed in conjunction with either ulcerative colitis or Crohn disease.

• Ulcerative colitis 
• • The most typical manifestation of ulcerative colitis is bloody diarrhea. Pain is uncommon but may occur.
  • Patients are commonly fatigued, which is often related to the inflammation and anemia that accompany disease activity.
• Crohn disease 
• • The most typical manifestations of Crohn disease are abdominal pain and diarrhea. Not uncommonly, patients have been diagnosed with irritable bowel syndrome before being diagnosed with IBD.
  • Pain is particularly common, especially when some degree of obstruction is present. The pain may be almost anywhere within the abdominal cavity, although the classic location is the lower abdomen or right lower quadrant (appendicitislike).
  • Patients are commonly fatigued, which is often related to the pain, inflammation, and anemia that accompany disease activity.
• Intestinal complications  
• • Strictures and obstructions are not uncommon in persons with Crohn disease (see Media file 2 and Media file 4). These strictures are often inflamed and frequently resolve with medical treatment. Fixed (scarred or cicatrix) strictures may require endoscopic or surgical intervention to relieve obstructions. However, in persons with ulcerative colitis, colonic strictures are of significant concern and should be presumed to be malignant unless proven otherwise (usually by resection).
  • Fistulae and perianal disease are not uncommon in persons with Crohn disease and may be refractory to vigorous medical treatment, including antibiotic therapy (see Media file 3). Surgical intervention is often required for fistulae and perianal disease treatment, but both are associated with a high risk of recurrence.
  • Toxic megacolon is a life-threatening complication of ulcerative colitis and requires urgent surgical intervention.
  • Infectious colitis is in the differential diagnosis of ulcerative colitis and must be excluded before the diagnosis of ulcerative colitis can be made. However, in patients with well-established ulcerative colitis, superimposed infection can occur. Infection with Clostridium difficile is by far most common. Stools of patients hospitalized for a flare of ulcerative colitis should be tested for C difficile toxin. Treatment of C difficile (if present) infection generally helps put the flare into remission.
  • Malignancy is the most dreaded long-term intestinal complication of ulcerative colitis. The risk of colon cancer for persons with ulcerative colitis begins to rise significantly above that of the general population approximately 8-10 years after diagnosis. For cancer prevention, surveillance colonoscopy every 2 years after 8 years of disease is recommended, more frequently if areas of pathologic concern are evident. The risk of cancer in persons with Crohn disease may equal to that of persons with ulcerative colitis if the entire colon is involved, and screening may be beneficial for patients with pancolitis Crohn disease. The risk of small intestine malignancy is increased in persons with Crohn disease, but the malignancy is as likely to arise in a previously normal area as in an inflamed area. No screening protocol has ever been demonstrated to be effective for small bowel Crohn disease.

Physical

• Ulcerative colitis  
• • Presenting signs of ulcerative colitis include diarrhea with occult or frank blood loss (see Media file 1). Weight loss and anemia are also common. Persons with ulcerative colitis typically do not develop fistulae or perianal disease, although they may have perianal abscesses.
  • Diagnosis can be made endoscopically or radiologically, with contrast radiographs typically showing loss of the normal mucosal pattern and, with more advanced disease, loss of colonic haustrae.
  • Sigmoidoscopy or colonoscopy reveals that the rectum is almost always involved. The disease can be limited to the rectum (proctitis); to the rectum, sigmoid, and descending colon (left-sided colitis); or to the entire colon (pancolitis). Ulcerative colitis does not involve any other segment of the gastrointestinal tract. Colectomy is curative.
• Crohn disease  
• • Presenting signs of Crohn disease include occult blood loss and low-grade fever; weight loss and anemia are common. Growth retardation is seen in children and may be the only presenting sign in young patients. Fistulae and perianal disease are not uncommon.
  • Diagnosis can be made endoscopically or radiologically, with contrast radiographs typically showing a cobblestone pattern to the mucosa and areas of normal mucosa alternating with areas of inflamed mucosa (skip lesions).
  • Sigmoidoscopy or colonoscopy reveals that the rectum is frequently spared and right colonic predominance is common. Ninety percent of patients with Crohn disease have involvement of the terminal ileum and/or right colon. Pediatric patients are more likely (about 20%) to present with disease limited to the small intestine. Occasionally, gastric or duodenal Crohn disease manifests as seemingly refractory ulcer disease.
• Extraintestinal complications: Many complications associated with IBD can occur with either ulcerative colitis or Crohn disease. In addition, many of the medications used to treat IBD may cause significant adverse systemic effects.  
• • In addition to medication-induced arthropathies, the arthritides associated with the IBD are of 2 varieties, axial (or central) arthritis and peripheral arthritis.
  • • The axial arthritis associated with IBD consists of ankylosing spondylitis and sacroiliitis. Axial arthritis occurs in approximately 5% of patients with IBD (often Crohn disease) and typically is independent of disease activity. Axial arthritis is often associated with HLA-B27.
    • The peripheral arthritides vary with the activity of the underlying IBD. Peripheral arthritis occurs in approximately 10% of patients with IBD; it is a nondestructive arthritis, and patients have seronegative findings for rheumatoid factor. The peripheral arthritis typically is asymmetric, and it can be monoarticular or may involve different joints on different sides of the body. The classic peripheral arthritis affects large weight-bearing joints, although any joint may be involved.
  • Diseases of the eye associated with ulcerative colitis are episcleritis and iritis (uveitis). Treatment of these complications often requires high-dose systemic steroids or infliximab, and either condition can cause significant vision loss if left untreated.
  • The major skin diseases associated with IBD are erythema nodosum and pyoderma gangrenosum.
  • • Erythema nodosum is a painful, tender, raised, purplish lesion on the anterior surface of the tibia. Erythema nodosum tends to correlate well with the activity of the underlying bowel disease; with bowel disease treatment, the erythema nodosum usually dissipates.
    • Pyoderma gangrenosum, on the other hand, typically is not associated with disease activity (see Media files 6-7). This skin lesion starts as an inflamed patch of skin ranging from one to several centimeters in diameter that progresses until it ulcerates. Upon ulceration, the lesion may persist for many months before healing. Treatments that have been tried that may have some efficacy include dapsone, metronidazole (MetroGel), cyclosporine, and infliximab. Surgical removal of the diseased bowel (eg, colectomy) does not ameliorate pyoderma gangrenosum.
    • Infectious skin lesions related to immune suppression may also be seen (eg, herpetic lesions)
  • The urinary complications of IBD are more common in persons with Crohn disease. Calcium oxalate stones are the most common type of renal calculi associated with Crohn disease; treatment is to increase hydration and to use oral calcium citrate supplements, which bind the oxalate within the intestinal tract and prevent its excretion in the urinary tract. Because of its proximity to the ureters, inflammation of the small bowel may involve the ureters, causing obstruction and hydronephrosis. Fistulae occasionally occur between the bowel and bladder or ureters.
  • Sclerosing cholangitis is most commonly associated with ulcerative colitis. Sclerosing cholangitis is a disease of the biliary tree. Although sclerosing cholangitis typically manifests as fatigue and, perhaps, jaundice, it is far more commonly sought when abnormal LFT results in a cholestatic pattern are found in a patient with ulcerative colitis.
  • • Although ursodeoxycholic acid may help improve serum LFT results, this has not been translated into improved survival. If sclerosing cholangitis is diagnosed in the absence of a known history of ulcerative colitis, colonoscopy is indicated.
    • Ulcerative colitis may be expected to be clinically evident within 2 years of diagnosis of sclerosing cholangitis if the colitis is present and has not been diagnosed first. Sclerosing cholangitis may be indolent for many years but may progress to cirrhosis, for which hepatic transplantation may be necessary. The most dreaded complication of sclerosing cholangitis is the development of cholangiocarcinoma.
  • Gallstones are common in persons with Crohn disease, but these persons are usually asymptomatic; occasionally, cholecystectomy is necessary.
  • The anemia associated with IBD may be of 2 types: (1) iron deficiency anemia secondary to chronic blood loss, and (2) anemia of chronic disease. Because iron is absorbed in the duodenum, patients with Crohn disease involving the proximal small intestine may have difficulty absorbing oral iron; occasionally, parenteral iron replacement is necessary. IBD is a recognized cause of anemia of chronic disease.
  • A hypercoagulable state is associated with IBD. It is estimated to occur in as many as one third of patients with IBD, but it may go unrecognized until a thrombotic event occurs. Strokes, retinal thrombi, and pulmonary emboli are not uncommon in patients with IBD.

Causes

The causes of IBD are currently unknown. See also Pathophysiology. 

• Genetics: IBD clearly has a familial tendency.  First-degree relatives have a 5- to 20-fold increased risk of developing IBD compared to subjects from unaffected families.  A parent with IBD has approximately a 5% chance of having a child develop IBD. Of patients with IBD, 10-25% are estimated to have a first-degree relative with the disease. Monozygous twin studies show a high concordance for Crohn disease but less so for ulcerative colitis; twin studies show a concordance of approximately 70% in identical twins versus 5-10% in nonidentical twins. 
• Animal models: Several animal models are used to study IBD. A local irritant (eg, acetic acid, trinitrobenzene sulfonic acid) can be inserted via an enema into the colon of rats or rabbits to induce a chemical colitis. An interleukin-10 knockout mouse has been genetically engineered to have some characteristics similar to those of a human with IBD. The cotton-top marmoset, a South American primate, develops a colitis very similar to ulcerative colitis when the animal is subjected to stress.

DIFFERENTIALS

Section 4 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

C1 esterase deficiency
Intestinal tuberculosis
Estrogens
Backwash ileitis

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Laboratory studies are of value in assisting with the management of IBD but are of minimal help in establishing the diagnosis. Laboratory values may be used as surrogate markers for inflammation and nutritional status and to look for deficiencies of necessary vitamins and minerals. Serologic studies have been proposed to help diagnose IBD and to differentiate Crohn disease from ulcerative colitis.
• • Stool studies: Perform a stool culture (and C difficile toxin assay) on patients before making a definitive diagnosis of idiopathic IBD. Any patient hospitalized with a flare of colitis should, at a minimum, have a C difficile toxin assay performed because, commonly, pseudomembranous colitis is superimposed on ulcerative colitis.
  • Complete blood cell count: The components of the CBC count can be useful indicators of disease activity and iron or vitamin deficiency. An elevated WBC count is common in patients with active inflammatory disease and does not necessarily indicate infection. Anemia is common and may be either an anemia of chronic disease (usually normal mean corpuscular volume [MCV]) or an iron deficiency anemia (MCV is often low). Generally, the platelet count is normal, or, it may be mildly to moderately elevated if active inflammation is occurring, particularly if gastrointestinal blood loss occurs. Note that the MCV can be elevated in patients taking azathioprine (Imuran) or 6-mercaptopurine (6-MP).
  • Erythrocyte sedimentation rate: The erythrocyte sedimentation rate (ESR) is used as a surrogate marker for inflammation; an elevation above normal generally indicates the presence of an inflammatory response. For most, but not all, patients, the ESR can be used to help determine whether active IBD is present. Persons with cicatrix strictures are not expected to have an elevated ESR.
  • Nutritional markers: Blood tests can also be used to help determine nutritional status. The most commonly used marker is serum albumin; prealbumin and transferrin can also be used, although the latter is an acute phase reactant and can be falsely elevated in persons with active IBD. Hypoalbuminemia may reflect malnutrition; it can also develop because of the protein-losing enteropathy that can occur with active IBD.
  • Serum vitamin B-12: Vitamin B-12 deficiency can occur in patients with Crohn disease who have significant terminal ileum disease or in patients who have had terminal ileum resection. The standard replacement dose of vitamin B-12 is 1000 mcg subcutaneously every month.
  • Serum iron studies: Because active IBD is a source for gastrointestinal blood loss, iron deficiency is common. A microcytic hypochromic anemia suggests iron deficiency; if confirmed with serum iron/total iron-binding capacity, iron can be replaced either enterally or parenterally. For parenteral replacement, intravenous iron dextran can be used and is dosed based on the table in the package insert, with a maximum of 30 mL (1500 mg) at once.
  • Red blood cell folate: While folate deficiency is not common in persons with IBD, several concerns have been raised regarding this vitamin. Sulfasalazine (Azulfidine) is a folate reductase inhibitor and may inhibit normal uptake. Although some practitioners administer folate supplements in patients taking sulfasalazine, few data demonstrate that this is universally necessary. Folate supplements are indicated in all women who are pregnant to help prevent neural tube defects; this is particularly true for patients with IBD, and supplementation with 2 or more mg/d (rather than the usual 1 mg/d) should be considered.

Imaging Studies

• Abdominal flat plate: For the patient with IBD, kidneys, ureter, and bladder radiography can provide a great deal of information. Evidence of obstruction can be seen. Evidence of inflammatory disease, especially involving the colon, can often be discerned, perforation can be detected, and toxic megacolon can be diagnosed. More subtle findings can include indications of osteopenia and nephrolithiasis.
• Barium enema: This was one of the first studies that allowed characterization of the typical findings associated with IBD. Normal barium enema findings virtually exclude active ulcerative colitis, whereas abnormal findings can be diagnostic. Several terms have been used to describe abnormalities found after barium studies of the colon. These include the following: (1) a "stove-pipe" appearance, which suggests chronic colitis that has resulted in a loss of colonic haustrae; (2) "rectal sparing," which suggests Crohn colitis in the presence of inflammatory changes in other portions of the colon; (3) "thumbprinting," which indicates mucosal inflammation (which can also be seen frequently on the abdominal flat plate); and (4) "skip lesions," which suggest areas of inflammation alternating with normal-appearing areas, again suggesting Crohn colitis. Barium can be refluxed into the terminal ileum in many cases, which can assist in the diagnosis of Crohn disease.
• Small bowel series/small bowel follow-through: The small bowel series, with or without an upper gastrointestinal tract series, provides invaluable information about Crohn disease. This study can reveal if inflammation is present, can assist in the assessment of stricture length and severity, and can help decide the most appropriate surgical approach. Fistulae are often demonstrated on films from a small bowel series, even if they are not suggested based on the clinical evaluation. The small bowel series is usually sufficient for the evaluation of small intestine Crohn disease; rarely, it affords an inadequate view of the terminal ileum and enteroclysis must be performed. Although radiologists may remark on abnormalities suggested in the cecum or ascending colon when the barium from a small bowel series enters the colon, independent confirmation must be sought because the presence of stool and dilution of the barium make proper interpretation of colon findings difficult.
• Small bowel enteroclysis: The enteroclysis differs from a small bowel series in that a nasoenteric or oroenteric tube is placed and contrast is instilled directly into the small intestine. This is usually performed when fine detail of the intestinal mucosa is required or the distal small intestine is not adequately seen on the small bowel series because the contrast is diluted as it passes through the (usually dilated) small bowel.
• Computed tomography scan of the abdomen and pelvis: CT scanning of the abdomen and pelvis has limited use in the diagnosis of IBD, but findings may be very suggestive of IBD. Wall thickening on CT scans is nonspecific and may occur from smooth muscle contraction alone, especially in the absence of other extraintestinal inflammatory changes; however, the presence of inflammatory changes significantly increases the predictive value of the CT scan. CT scanning is the ideal study to determine if the patient has abscesses, and it can be used to guide percutaneous drainage of these abscesses. Fistulae also may be detected on CT scans.
• Fistulogram: Contrast can also be inserted directly into an enterocutaneous fistula in order to help determine the course of the fistula in anticipation of surgical correction and to assist in guiding the surgical approach.

Procedures

• Colonoscopy
• • This is one of the most valuable tools available to the physician for the diagnosis and treatment of IBD, although its limitations must be recognized. Foremost, not all mucosal inflammation is idiopathic IBD. Infectious causes of inflammation must always be considered, as should diverticulitis and ischemia (which are far more common as new diagnoses in an elderly population than IBD, despite the similar colonoscopic and histologic appearance).
  • When used appropriately, colonoscopy can help determine the extent and severity of colitis, assist in guiding treatment, and provide tissue to assist in the diagnosis. In skilled hands, the colonoscope can frequently reach the terminal ileum and permit assessment of inflammation to assist in the diagnosis or exclusion of Crohn disease. Inflammation may occasionally occur in the terminal ileum in patients with ulcerative colitis; this is referred to as a backwash ileitis and is mild, nonulcerating, and may occur when a widely patent ileocecal valve is present.
  • Be cautious with colonoscopic intervention in patients with IBD. The usual risks of colonoscopy apply (eg, reaction to medication, bleeding, perforation); the risk of bleeding is increased in the presence of inflammation, and even mucosal biopsies may require cautery to limit bleeding. The risk of perforation is also increased, particularly in patients taking high doses of steroids long-term. Also, weigh the risks and benefits of continuing colonic intubation in a patient with IBD who has significant inflammation.
  • Colonoscopy can also be used for therapeutic intervention in patients with IBD. The most common therapeutic use is stricture dilation in persons with Crohn disease; colonic, anastomotic, and even small bowel strictures can often be dilated using pneumatic through-the-scope dilators. Intralesional injection of steroids (eg, triamcinolone at 5 mg in 4 quadrants) may help prevent reformation of the stricture, although this has yet to be demonstrated in controlled trials.
• Flexible sigmoidoscopy: This study is useful for a preliminary diagnosis in patients with chronic diarrhea or rectal bleeding; however, because of the limited length of the scope (60 cm), it can only help diagnose distal ulcerative colitis or proctitis, but not pancolitis. Rarely, Crohn colitis can be diagnosed based on flexible sigmoidoscopy findings; use caution interpreting sigmoid inflammation, particularly in older patients, because Crohn colitis may be confused with diverticulitis or ischemia.
• Upper endoscopy: Esophagogastroduodenoscopy is used for the evaluation of upper gastrointestinal tract symptoms, particularly in patients with Crohn disease. Aphthous ulceration occurs in the stomach and duodenum in 5-10% of patients with Crohn disease. The diagnosis of Crohn disease is occasionally made after gastric or duodenal ulcers fail to heal with acid suppression alone.
• Small bowel enteroscopy: This is of limited use in patients with Crohn disease and is of almost no value in those with ulcerative colitis. Although ulcerations and strictures in the upper half of the jejunum can be demonstrated with enteroscopy, the same information (and often more information) can be demonstrated on the small bowel follow-through x-ray film.
• Capsule enteroscopy: This technique is performed by having the patient swallow an encapsulated video camera that transmits images to a receiver outside the patient. Most commonly used for finding obscure sources of gastrointestinal blood loss, the images can find ulcerations associated with Crohn disease if upper endoscopy and colonoscopy are unrevealing. Its utility for the diagnosis of Crohn disease is currently under evaluation; the current generation of cameras do not allow for treatment. It must be borne in mind that not all small intestinal ulcerations represent manifestations of Crohn disease. The major risk in patients with Crohn disease is the potential for the camera to become lodged at the point of a stricture, which could require operative intervention for removal.

Histologic Findings

In ulcerative colitis, the inflammation is limited to the mucosa. Inflammation almost always involves the rectum and is contiguous, virtually regardless of the extent of the colon involved. The exception to this rule is that the initial inflammation may appear patchy during colonoscopy performed very early in the ulcerative colitis process, although biopsy specimens of intervening normal-appearing mucosa often do reveal inflammation. The intestinal inflammation of ulcerative colitis only involves the colon; the remainder of the gastrointestinal tract is not inflamed. Biopsy specimens demonstrate neutrophilic infiltrate along with crypt abscesses and crypt distortion. Granulomas do not occur in ulcerative colitis.

The entire intestinal wall is involved with inflammation in Crohn disease, not just the mucosa, as in ulcerative colitis. Biopsy specimens frequently demonstrate granulomas (approximately 50% of the time). The presence of granulomas is often helpful for making the diagnosis but is not necessary.

Because biopsy specimens obtained at colonoscopy are generally superficial mucosal tissue samples, the pathologist often has difficulty making a definitive diagnosis of ulcerative colitis or Crohn disease based on histologic findings alone. However, other causes of inflammation may be suggested based on pathology findings (eg, infectious colitis).

TREATMENT

Section 6 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

The care of a patient with IBD can be either medical or surgical in nature, or commonly a combination of both. The medical approach for patients with IBD is symptomatic (flaring) care and generally follows a step-wise approach to medication therapy, with progression of the medical regimen until a response is achieved. Whether patients whose disease is in remission benefit from continuing to take aminosalicylate is controversial. In persons with Crohn disease, earlier data suggested that postoperative recurrences are decreased in frequency and severity, although later data suggest that this preventive effect may not apply to flares of this IBD.

• The first step in medication therapy is usually aminosalicylates; no advantage has been demonstrated for any particular agent for either ulcerative colitis or Crohn disease. For Crohn disease, metronidazole or ciprofloxacin is occasionally used, particularly for perianal disease or an inflammatory mass.
• If the IBD fails to respond to aminosalicylates, the second step is corticosteroids. Corticosteroids tend to provide rapid relief of symptoms and a significant decrease in inflammation, but they are limited by their adverse effects, particularly for prolonged use. The consensus regarding treatment with corticosteroids is that they should be tapered as rapidly as possible. Corticosteroids do not have a role in maintaining remission.
• If patients have difficulty reducing the dose of corticosteroids, have IBD that is refractory to corticosteroid therapy, or have frequent flares that require corticosteroid therapy, the third step for medication is one of the immunomodulatory agents, either 6-MP or azathioprine. These agents are not used for acute flares because the time from the initiation of treatment to the onset of significant action may be as long as 2-3 months. Response to these agents may be dose dependent; monitoring of blood counts is required to protect the patient from the hematological toxicity associated with these agents. Some authors suggest earlier use of these agents.
• An alternative third step is available for persons with IBD. This alternative is infliximab, a monoclonal antibody against tumor necrosis factor (TNF)–alpha. Administer this agent by intravenous infusion. This medication is generally administered in 3 doses over 6 weeks (at weeks 0, 2, and 6) followed by a maintenance regimen. Administering the drug every 8 weeks has been demonstrated to be effective for maintaining remission.
• • The practitioner is advised to have the patient seek insurance approval for the administration of this medication because it is extremely expensive (typically, several thousand dollars per dose). Infliximab has an excellent response rate for Crohn disease (>80%); its response rate for ulcerative colitis is clearly less (approximately 50%).
  • The US Food and Drug Administration (FDA) approved prednisone, budesonide, and infliximab for the treatment of Crohn disease in July 2005. The FDA approved infliximab for the treatment of ulcerative colitis in August 2005.
• The final step for the treatment of IBD involves agents that have less well-demonstrated levels of efficacy but have been shown to be useful in some subsets of patients. For Crohn disease, methotrexate at 12.5-25 mg/wk may fall into this category. For ulcerative colitis, cyclosporine A (usually started intravenously for overwhelming disease) and nicotine patches fall into this category. Finally, a number of clinical trials of biological agents and diets are being conducted and may demonstrate efficacy in persons with IBD.

Surgical Care

The approach to surgical treatment of IBD varies depending on the disease. Most important, ulcerative colitis is a surgically curable disease because the disease is limited to the colon. However, Crohn disease can involve any segment of the gastrointestinal tract from the mouth to the anus; thus, surgical resection is not curative. On the contrary, excessive surgical intervention can leave the patient with a crippling short bowel syndrome. Situations arise in Crohn disease in which surgical intervention without resection can be used to defunctionalize the colon in order to possibly allow healing of distal disease.

• Surgery for ulcerative colitis
• • Surgical intervention for ulcerative colitis is curative for colonic disease and potential colonic malignancy. The indications for colectomy are (1) inflammation that is difficult to control, (2) early changes found during surveillance (high-grade dysplasia, low-grade dysplasia in some instances), (3) strictures, (4) significant adverse medication effects, and/or (5) an unacceptable quality of life referable to the ulcerative colitis.
  • The surgical options for ulcerative colitis vary. While segmental resection is rarely performed, total proctocolectomy is common. Total proctocolectomy with ileostomy creation is the simplest procedure with the lowest overall complication rate. A variation on this is the continent ileostomy or Koch pouch. This procedure creates an ileal reservoir that can be emptied with catheterization several times per day. However, incontinence from the pouch may necessitate use of an ileostomy bag. A colectomy may be performed, leaving a few centimeters of rectum intact; this ensures anal continence, but continued malignancy surveillance is needed for any colonic mucosa that remains and the remaining diseased rectal mucosa can continue to be problematic from a symptomatic standpoint.
  • The most technically demanding option is ileal pouch/anal anastomosis (IPAA). In this multistage procedure, a diverting ileostomy is performed and an ileal pouch is created and anastomosed directly to the anus, with complete removal of the rectal mucosa. After the ileoanal anastomosis is healed, the ileostomy is taken down and flow through the anus is reestablished. The major complications of this procedure are anal incontinence and impotence. Occasionally, postoperative pouchitis is a problem. If the diagnosis is incorrect and this procedure is performed on a patient with colonic Crohn disease, the likelihood of disease recurrence at the ileoanal anastomosis is high, which requires takedown, ileostomy creation, and loss of additional small bowel. When performed by a surgeon skilled in this technique, it offers an excellent option for younger patients with ulcerative colitis and concerns about body image.
• Surgery for Crohn disease
• • Surgery in Crohn disease is most commonly performed for complications of the disease (ie, strictures, fistulae, bleeding) rather than for the disease itself.
  • The most straightforward surgery for Crohn disease is the segmental resection, in which a segment of intestine with active Crohn disease or a stricture is resected and the remaining bowel is reanastomosed. This surgery requires margins of resection; in general, as little bowel as possible is resected because the risk of disease recurrence is significant.
  • In patients with a very short cicatrix (scar tissue) stricture, a bowel-sparing stricturoplasty can be performed. In this procedure, a longitudinal incision is made across the stricture and then the incision is repaired with a vertical suture. All mucosa is spared, and the obstruction is relieved. As many as 6-8 stricturoplasties can be performed in a single operative session. Stricturoplasty is associated with a 6-8% septic complication rate (2-3% of patients require reoperation); this can generally be prevented with optimal preoperative management to control the inflammatory component of the stricture before surgical intervention.
  • Ileorectal or ileocolonic anastomosis is an option available to some patients who have distal ileal or proximal colonic disease. This is a variation on the simple segmental resection.
  • In patients with severe perianal fistulae, a diverting ileostomy or colostomy is a surgical option. In this procedure, the distal colon is defunctionalized and a temporary ileostomy or colostomy is created. The defunctionalized rectum is allowed to heal, and the ileostomy or colostomy is then taken down 6 months or a year later. Many patients who pursue this option choose to forego reanastomosis after experiencing a stoma and a consequent improvement in quality of life. Approximately 50% of patients who have the reanastomosis performed have recurrences of perianal disease.
  • Symptomatic enteroenteric fistulae are generally resected, although recurrence is common. Postoperative medical therapy is often used to prevent recurrence, although data are lacking on efficacy.

Consultations

In addition to possible studies performed by an endoscopist or radiologist, patients with IBD who are admitted to a medical facility typically require consultation with a surgeon.

• Colorectal surgeon (where available) or general surgeon: Early consultation with a surgeon is particularly useful in patients with stricturing or fistulizing disease and in patients with ulcerative colitis who experience frequent flares, have significant adverse effects from medications, or have an unacceptable quality of life.
• Radiologist: An interventional radiologist may be consulted when percutaneous drainage of an abscess is desired.

Diet

No known dietary substances cause activation of IBD. Diet may influence intestinal inflammation in persons with Crohn disease, but it does not play a role in influencing inflammation in those with ulcerative colitis.

• Lactose intolerance is common in persons with Crohn disease or ulcerative colitis and some patients with other types of IBD.
• Diet has been well demonstrated to have little or no influence on inflammatory activity in persons with ulcerative colitis. However, diet may influence symptoms. For this reason, patients are often advised to make a variety of diet modifications, especially the adaptation of a low-residue diet. Evidence does not support a low-residue diet as beneficial in the treatment of ulcerative colitis, although it might decrease the frequency of bowel movements.
• Unlike in persons with ulcerative colitis, diet can influence inflammatory activity in persons with Crohn disease. Nothing by mouth (status NPO) can hasten the reduction of inflammation, as might the use of a liquid or predigested formula for enteral feeding. Although a meta-analysis in 1993 demonstrated that steroids were superior to liquid diet alone for Crohn disease, a liquid diet seemed superior to a regular diet for reducing inflammation. The problem with using enteral liquid diets, especially the predigested formulations, is that palatability limits the intake of adequate energy (calories) to meet patient requirements. Parenteral alimentation may be needed.

Activity

Generally, patients do not need to limit activity when IBD is quiescent. Even during flares of disease activity, activity is limited only by the extent of fatigue and the abdominal pain or diarrhea the patient is experiencing.

• Abdominal pain may limit the ability of the patient to work productively during flares of disease. When abdominal pain persists beyond medical therapy–induced resolution of the active inflammation, other causes of pain must be considered, including nephrolithiasis, abscess, stricture, irritable bowel syndrome, and psychiatric disease.
• In most instances, diarrhea limits activity primarily because of the lack of immediate access to toilet facilities in many locations and/or occupations. This can often be resolved with employers. Occasionally, dehydration may be an issue, requiring intravenous hydration or the use of oral rehydration solutions.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

While several drugs have been used successfully for the treatment of IBD for many years, medical treatment has advanced rapidly. The medications used are broken down into several classes based on the chemical similarities of the individual agents and similarities in the mechanisms of action. A step-wise approach may be taken. With this approach, the most benign (or temporary) drugs are used first. As they fail to provide relief, drugs from a higher step are used.

The aminosalicylates and symptomatic agents are step I drugs under this scheme; the antibiotics are a step IA, given the limited situations in which they are used. The corticosteroids constitute the step II drugs to be used if the step I drugs fail to adequately control the IBD. The immune-modifying agents are step III drugs and are used if corticosteroids fail or are required for prolonged periods. Infliximab is also a step III drug that can be used in some situations in patients with Crohn disease and ulcerative colitis. The experimental agents are step IV drugs and are used only after the previous steps fail and, then, are administered only by physicians familiar with their use.

Note that drugs from all steps may be used additively; in general, the goal is to wean the patient off steroids as soon as possible to prevent long-term adverse effects from these agents. Opinions differ regarding the use of certain agents in this step-wise approach.

Step I (aminosalicylates)

The 5 oral aminosalicylate preparations available for use in the United States are sulfasalazine (Azulfidine), mesalamine (Asacol, Pentasa), balsalazide (Colazal), and olsalazine (Dipentum). Enema and suppository formulations are also available. All of these are derivatives of 5-aminosalicylic acid (5-ASA); the major differences are in the mechanism of delivery. Some of these also have unique adverse effects that other agents of this class lack. All of the aminosalicylates are useful for treating flares of IBD and for maintaining remission. None of the aminosalicylates has been proven to have greater efficacy for the treatment of ulcerative colitis or Crohn disease over any of the others. All of them are clearly more effective in persons with ulcerative colitis than in persons with Crohn disease; in persons with Crohn disease, the primarily utility is for colonic disease.

Step IA (antibiotics)

The antibiotics metronidazole and ciprofloxacin are the most commonly used antibiotics in persons with IBD. Antibiotics are used only sparingly in persons with ulcerative colitis because ulcerative colitis increases the risk of developing antibiotic-associated pseudomembranous colitis. When used in persons with ulcerative colitis, antibiotics are most commonly administered in the perioperative setting. However, in persons with Crohn disease, antibiotics are used for a variety of indications, most commonly for perianal disease. They are also used for fistulae and inflammatory masses in the abdomen, and they may have some efficacy in treating ileitis. The antibiotics have potential adverse effects, including nausea, anorexia, diarrhea, and monilial (candidal) infections; peripheral neuropathy can be observed in association with metronidazole use and, when present, requires discontinuation of therapy with that drug.

Step II (corticosteroids)

Corticosteroids are rapid-acting anti-inflammatory agents used in the treatment of IBD. Indications are for acute flares of disease only; corticosteroids have no role in the maintenance of remission. Corticosteroids may be administered by a variety of routes depending on the location and severity of disease; they may be administered intravenously (ie, methylprednisolone, hydrocortisone), orally (ie, prednisone, prednisolone, budesonide, dexamethasone), or topically (ie, enema, suppository, or foam preparations).

Intravenous corticosteroids are often used for patients who are severely ill and hospitalized; few data have been published on the optimum dosage of intravenous (or oral form) corticosteroids. The generally used upper ends of dosing are methylprednisolone at 40 mg intravenously every 6 hours or hydrocortisone at 100 mg intravenously every 8 hours. Some situations mandate a higher initial intravenous dose, but many practitioners start hospitalized patients at lower intravenous doses.

In general, once a clinical response is observed (typically within a 1-2 d, occasionally longer), the dose of the intravenous corticosteroid can be tapered. Before hospital discharge, conversion to an oral corticosteroid is made; further dosage tapering can be accomplished in an outpatient setting. When oral corticosteroids are used, dosing is highly variable and few data have been published to guide optimal dosing. The most common range for moderate flares of IBD is prednisone at 10-40 mg/d; for more severe flares, the higher end of the range is used (occasionally even higher doses are used). Again, once a clinical response is seen, the dose is tapered. Most patients who use oral corticosteroids can only occasionally tolerate a relatively rapid taper after a response is achieved; occasionally, a very prolonged steroid taper is necessary to prevent relapse. When the latter situation occurs, consider the use of alternative drugs (immune modifiers or anti-TNF therapy).

Topical corticosteroids are used in persons with distal colonic disease in a manner similar to topical mesalamine; the major difference is that even though topical mesalamine may be used to help maintain remission, topical corticosteroids are used for active disease and have only a small role in the maintenance of remission. The potential complications of corticosteroid use are multiple and include fluid and electrolyte abnormalities, osteoporosis, aseptic necrosis, peptic ulcers, cataracts, neurologic and endocrine dysfunctions, infectious complications, and occasional psychiatric disorders (including psychosis). Patients who are taking corticosteroids, especially for longer than a few weeks, must be warned about the associated complications; this discussion should be documented in the medical record. Some data assert that some agents used for osteoporosis prevention and treatment (eg, the bisphosphonates) are useful for preventing the bone loss associated with corticosteroid use.

Step III (immune modifiers)

The immune modifiers 6-MP and azathioprine are used in patients with IBD in whom remission is difficult to maintain with the aminosalicylates alone. Immune modifiers work by causing a reduction in the lymphocyte count, and because of that mechanism of action, their onset of action is relatively slow (typically 2-3 mo). They are used most commonly for their steroid-sparing action in persons with refractory disease; they are also used as primary treatment for fistulae and the maintenance of remission in patients intolerant of aminosalicylates. Use of these agents mandates monitoring of blood parameters; they can cause significant neutropenia or pancytopenia that would warrant a dose reduction or discontinuation. Routine CBC counts with differentials and platelet counts are checked monthly, and LFTs can be performed intermittently. After a year of stable dosing with no difficulties with blood counts (except the expected lymphopenia), the intervals between blood count monitoring can be increased.

The cytopenic effect is typically dose dependent, although some patients are more sensitive than others. Typical dosing of the immune modifiers (either 6-MP or azathioprine) is 1-2 mg/kg/d. If needed, the dose can be increased to the point when cytopenia occurs; obviously, at higher doses, closer monitoring is warranted. Blood tests are available to measure metabolite levels, but the results have not been shown in independent studies to have any correlation with clinical efficacy. These blood tests for monitoring toxicity offer little advantage (but much greater expense) over monitoring CBC counts and LFT results.

Other adverse effects of the immune modifiers include fever, rash, infectious complications, hepatitis, pancreatitis, and bone marrow depression. The most common reason for discontinuing the immune modifiers within the first few weeks is the development of abdominal pain; occasionally, a biochemically demonstrable pancreatitis occurs.

Concerns have been raised about the development of malignancy in patients taking azathioprine and 6-MP. Because the population that requires these medications is already at higher risk for the development of malignancy, the author believes that the available data on the use of azathioprine or 6-MP are insufficient and do not demonstrate a significant increase in the risk of malignancy.

Additional step III agents work by a different mechanism. Infliximab (Remicade) is an anti–TNF-alpha monoclonal antibody administered by infusion for the treatment of Crohn disease. Infliximab is FDA approved for both ulcerative colitis and Crohn disease, although it does appear to have a higher efficacy rate in the latter. Infliximab is generally administered as infusions of 5 mg/kg for the treatment of moderate-to-severe IBD. It is administered as 3 separate infusions of 5 mg/kg at weeks 0, 2, and 6, often followed by doses every 8 weeks for maintenance of remission. For Crohn disease, the response rate is 80% and the induction of remission rate is 50% after a single dose; with multiple dosing, higher rates of remission are attained. For ulcerative colitis, the response rates are 50-70%.

Infliximab is also indicated for the treatment of fistulizing Crohn disease; for this indication, the fistula responds (closes) in 68% of patients treated with infliximab, although 12% develop an abscess. The response can be maintained by continuing regular dosing (ie, every 8 wk) after the induction dose.

The adverse effects of infliximab commonly include hypersensitivity and flulike symptoms; the latter can often be avoided by pretreatment with acetaminophen and diphenhydramine. Rare reports of lupuslike reactions and lymphoproliferative malignancies have been reported, although whether the malignancies are related to the drug or to the underlying disease process remains uncertain.

Other newer anti-TNF agents include adalimumab (Humira), which is given by subcutaneous injection every 2 weeks after a loading dose of 6 injections, and certolizumab pegol (Cimzia), which is given by subcutaneous injection every 4 weeks.

Natalizumab (Tysabri; formerly called Antegrin), an agent aimed at preventing the accumulation of lymphocytes in the diseased bowel by blocking the effects of integrin, has been approved but is only available through a restricted distribution program.  Natalizumab is an intravenous medication that has shown efficacy in Crohn disease but is not as effective as anti-TNF agents.  Natalizumab has been linked to reports of progressive multifocal leukoencephalopathy (a potentially fatal opportunistic viral infection) in 3 patients.

Step IV (experimental treatments)

Generally, use these agents as part of an experimental protocol or in a setting in which the toxicities of the agents can be rapidly recognized and managed. Examples of some agents are provided, but a review of the literature is warranted before using them. In most cases, some subsets of patients respond; in general, large placebo-controlled trials have not yet established efficacy for these agents for the treatment of IBD.

Various experimental agents tend to be more disease-specific, ie, an agent works for Crohn disease but not ulcerative colitis, or vice versa. Experimental agents used in persons with Crohn disease include methotrexate (12.5-25 mg/wk orally or intramuscularly), thalidomide (50-300 mg/d orally), and interleukin 11 (1 mg/wk subcutaneously). Experimental agents used in persons with ulcerative colitis include cyclosporine A at a dose of 2-4 mg/kg/d intravenously (measure level; convert to oral dosing at 2-3 times the intravenous dose), nicotine patch (14-21 mg/d via topical patch), butyrate enema (100 mL per rectum twice daily), and heparin (10,000 U subcutaneously twice daily). Multiple contraindications, interactions, and precautions are associated with these drugs.

Symptomatic treatments

Because patients report symptoms (eg, diarrhea, spasm/pain, epigastric discomfort) and not inflammation per se, symptomatic relief is appropriate when indicated. This includes therapy with antidiarrheal agents, bile acid–binding agents, antispasmodics, and acid suppressants, as needed. These medications are not without complications, and caution is necessary.

Drug Category: Aminosalicylates (step I)

Effective in reducing inflammatory reactions.

Drug Name	Mesalamine (Asacol, Pentasa, Canasa, Rowasa, Lialda)
Description	A 5-ASA acts systemically and also has activity as a topical anti-inflammatory. The currently approved oral mesalamine products in the United States differ only in the mechanism of drug delivery. Asacol has mesalamine within a Eudragit-S coating that dissolves and releases the mesalamine at pH 7, which typically occurs in the terminal ileum. Pentasa is 5-ASA in ethylcellulose and has a time-release coating. Release of mesalamine from Pentasa begins at the pylorus; because of this, the drug is often used when proximal intestinal Crohn disease is suggested. Despite its proximal release, no convincing data indicate the site of release translates into clinical superiority. Lialda is indicated to induce remission in active ulcerative colitis. It has a proprietary release mechanism that is referred to as MMX technology. This is actually a combination of the release mechanisms of Asacol (with a pH dependent coating) and Pentasa (a water-soluble matrix). Available as a 1.2 g tab. Rectal dosage forms deliver high concentrations of mesalamine to the left colon as high as the splenic flexure (enema with 30 min retention) or to the rectum for use in proctitis (suppository). Although effective, associated with relatively high relapse rate upon discontinuation. Widespread use of topical agents is limited by patient acceptance in many cases; often, patients with active rectal disease have difficulty holding in enema.
Adult Dose	Asacol: 400 mg PO bid to 1200 mg PO qid, usual 800 mg PO tid Pentasa: 500 mg PO bid to 1000 mg PO qid (usual dose) Usual maximum dose is 4.8 g/d, but even higher doses have been used Lialda: 1.2-4.8 g (ie, 1-4 tabs) PO qd pc Canasa: Insert 1 supp PR bid Rowasa, rectal: 1 enema (4 g/60-mL) PR qd/bid; alternatively, 1 supp (500-mg) PR qd/bid
Pediatric Dose	PO: 30-50 mg/kg/d divided bid/qid, not to exceed 3.2 g/d PR: Administer as in adult
Contraindications	Documented hypersensitivity
Interactions	Decreases effects of iron, digoxin, and folic acid; increases effects of oral anticoagulants, methotrexate, and oral hypoglycemic agents
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Most common adverse effects are rash, occasional fever, and flulike syndrome; rare reports of interstitial nephritis at high doses; also rare reports of pancreatitis and pericarditis; diarrhea may occur; caution in patients with renal or hepatic impairment; elderly patients may have difficulty administering and retaining rectal suppository

Drug Name	Balsalazide (Colazal)
Description	Prodrug 5-ASA connected to a 4-aminobenzoyl-(beta)-alanine carrier by an azo bond; colonic bacteria break the azo bond, releasing the active 5-ASA. Metabolites of drug may decrease inflammation by blocking production of arachidonic acid metabolites in colon mucosa. Considered best for colonic disease. Used for acute disease and for maintenance of remission; some studies suggest better at maintaining remission than sulfasalazine.
Adult Dose	3 cap (2.25 g) PO tid for 8-12 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity to 5-ASA or any component; GI or GU obstruction
Interactions	None known, but oral antibiotics may interfere with 5-ASA release in colon
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in renal impairment; gastric retention may be prolonged in pyloric stenosis; safety and efficacy of long-term use (>12 wk) not established; headache, abdominal pain, and nausea may occur, but not more than with placebo; rare hepatitis reported

Drug Name	Olsalazine (Dipentum)
Description	Aminosalicylate is useful for active disease and maintenance of remission in ulcerative colitis. Dipentum is 5-ASA connected to a 5-ASA by an azo bond; colonic bacteria break the azo bond, releasing the active 5-ASA.
Adult Dose	500-1000 mg PO bid
Pediatric Dose	30 mg/kg/d PO divided bid
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Major common adverse effect is diarrhea; other adverse effects are similar to those of mesalamine; occasional exacerbation of disease

Drug Category: Antibiotics (step IA)

Antimicrobial therapy must cover all likely pathogens in the context of the clinical setting.

Drug Name	Ciprofloxacin (Cipro)
Description	Fluoroquinolone antibiotic commonly used for treatment of urinary, skin, and respiratory tract infections.
Adult Dose	500 mg PO bid
Pediatric Dose	<18 years: Not recommended >18 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy

Drug Name	Rifaximin (Xifaxan)
Description	Nonabsorbed (<0.4%), broad-spectrum antibiotic specific for enteric pathogens of the gastrointestinal tract (ie, gram-positive, gram-negative, aerobic, anaerobic). Rifampin structural analog. Binds to beta-subunit of bacterial DNA-dependent RNA polymerase, thereby inhibiting RNA synthesis.
Adult Dose	200 mg PO tid
Pediatric Dose	<12 years: Not established >12 years: Administer as in adults
Contraindications	Documented hypersensitivity to rifaximin or rifamycin antimicrobial agents (eg, rifampin)
Interactions	Induces CYP450 3A4 in vitro; limited data exist; no significant interactions shown in single dose studies with midazolam and oral contraceptives
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	May promote intestinal bacterial overgrowth and cause superinfection; discontinue if diarrhea persists more than 24-48 h or worsens; seek immediate medical care if fever and/or bloody stools emerge (tablets not effective); not effective for travelers' diarrhea due to suspected pathogens other than E coli; postmarketing reports include allergic dermatitis, rash, angioneurotic edema, urticaria, and pruritus

Drug Category: Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects. Modify the body's immune response to diverse stimuli.

Drug Name	Prednisone (Deltasone, Orasone, Sterapred)
Description	Acts as potent inhibitor of inflammation. May cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body. Alternative corticosteroids may be used in equivalent dosage. PO corticosteroids are generally tapered over days to weeks, depending on duration and dose of administration to control disease.
Adult Dose	40-60 mg PO qd
Pediatric Dose	1-2 mg/kg/d PO in single or divided doses, taper after response