Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is an idiopathic disease caused by a dysregulated immune response to host intestinal microflora. The two major types of IBD are ulcerative colitis (UC), which is limited to the colon, and Crohn disease (CD), which can involve any segment of the gastrointestinal (GI) tract from the mouth to the anus, involves "skip lesions," and is transmural (see the images below). There is a genetic predisposition for IBD (see Etiology), and patients with this condition are more prone to the development of malignancy (see Prognosis).

Inflammatory bowel disease. Severe colitis noted during colonoscopy in a patient with inflammatory bowel disease. The mucosa is grossly denuded, with active bleeding noted. The patient had her colon resected very shortly after this view was obtained.

Inflammatory bowel disease. Stricture in the terminal ileum noted during colonoscopy in a patient with inflammatory bowel disease. This image depicts a narrowed segment visible upon intubation of the terminal ileum with the colonoscope. Relatively little active inflammation is present, indicating that this is a cicatrix stricture.

Ulcerative colitis and Crohn disease share many extraintestinal manifestations, although some of these tend to occur more commonly with either condition (see the image below). Eye-skin-mouth-joint extraintestinal manifestations (eg, oral aphthae, erythema nodosum, large-joint arthritis, and episcleritis) reflect active disease, whereas pyoderma gangrenosum, primary sclerosing cholangitis (PSC), ankylosing spondylitis, uveitis, kidney stones, and gallstones may occur in quiescent disease.[5]

Although both ulcerative colitis and Crohn disease have distinct pathologic findings, approximately 10%-15% of patients cannot be classified definitively into either type; in such patients, the disease is labeled as indeterminate colitis. Systemic symptoms are common in IBD and include fever, sweats, malaise, and arthralgias.

Inflammatory bowel disease. The table distinguishes features of Crohn disease (CD) and ulcerative colitis (UC).

The rectum is always involved in ulcerative colitis, and the disease primarily involves continuous lesions of the mucosa and the submucosa. Both ulcerative colitis and Crohn disease usually have waxing and waning intensity and severity. When the patient is symptomatic due to active inflammation, the disease is considered to be in an active stage (the patient is having a flare of the IBD). (See Presentation.)

In many cases, symptoms correspond well to the degree of inflammation present for either disease, although this is not universally true. In some patients, objective evidence linking active disease to ongoing inflammation should be sought before administering medications with significant adverse effects (see Medication), because patients with IBD can have other reasons for their gastrointestinal symptoms unrelated to their IBD, including coexisting irritable bowel syndrome (IBS), celiac disease, or other confounding diagnoses, such as nonsteroidal anti-inflammatory drug (NSAID) effects and ischemic or infectious colitis.

Although ulcerative colitis and Crohn disease have significant differences, many, but not all, of the treatments available for one condition are also effective for the other. Surgical intervention for ulcerative colitis is curative for colonic disease and potential colonic malignancy, but it is not curative for Crohn disease. (See Treatment.)

The common end pathway of ulcerative colitis is inflammation of the mucosa of the intestinal tract, causing ulceration, edema, bleeding, and fluid and electrolyte loss.[6] In several studies, genetic factors appeared to influence the risk of inflammatory bowel disease (IBD) by causing a disruption of epithelial barrier integrity, deficits in autophagy,[7] deficiencies in innate pattern recognition receptors, and problems with lymphocyte differentiation, especially in Crohn disease.[8]

Inflammatory mediators have been identified in IBD, and considerable evidence suggests that these mediators play an important role in the pathologic and clinical characteristics of these disorders. Cytokines, which are released by macrophages in response to various antigenic stimuli, bind to different receptors and produce autocrine, paracrine, and endocrine effects. Cytokines differentiate lymphocytes into different types of T cells. Helper T cells, type 1 (Th-1), are associated principally with Crohn disease, whereas Th-2 cells are associated principally with ulcerative colitis. The immune response disrupts the intestinal mucosa and leads to a chronic inflammatory process.[9]

In animal studies, 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 (IL-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 colitis very similar to ulcerative colitis when the animal is subjected to stress.

Ulcerative colitis

In ulcerative colitis, the inflammation begins in the rectum and extends proximally in an uninterrupted fashion to the proximal colon and could eventually involve the entire length of the large intestine. The rectum is always involved in ulcerative colitis; and unlike in Crohn disease, there are no "skip areas" (ie, normal areas of the bowel interspersed with diseased areas), unless pretreated with topical rectal therapy (ie, a steroid or 5-aminosalicylic acid [5-ASA] enema).

The disease remains confined to the rectum in approximately 25% of cases, and in the remainder of cases, ulcerative colitis spreads proximally and contiguously. Pancolitis occurs in 10% of patients. The distal terminal ileum may become inflamed in a superficial manner, referred to as backwash ileitis. Even with less than total colonic involvement, the disease is strikingly and uniformly continuous. As ulcerative colitis becomes chronic, the colon becomes a rigid foreshortened tube that lacks its usual haustral markings, leading to the lead-pipe appearance observed on barium enema. (See the images below.)

Inflammatory bowel disease. Inflamed colonic mucosa demonstrating pseudopolyps in a patient with ulcerative colitis.

Inflammatory bowel disease. Double-contrast barium enema study shows pseudopolyposis of the descending colon in a patient with ulcerative colitis.

Crohn disease

Crohn disease can affect any portion of the gastrointestinal tract, from the mouth to the anus, and causes three patterns of involvement: inflammatory disease, strictures, and fistulas. This disease consists of segmental involvement by a nonspecific granulomatous inflammatory process. The most important pathologic feature of Crohn disease is that it is transmural, involving all layers of the bowel, not just the mucosa and the submucosa, which is characteristic of ulcerative colitis. Furthermore, Crohn disease is discontinuous, with skip areas interspersed between two or more involved areas.

Late in the disease, the mucosa develops a cobblestone appearance, which results from deep, longitudinal ulcerations interlaced with intervening normal mucosa (see the images below). In 35% of cases, Crohn disease occurs in the ileum and colon; in 32%, solely in the colon; in 28%, in the small bowel; and in 5%, in the gastroduodenal region.[10] Diarrhea, cramping, and abdominal pain are common symptoms of Crohn disease in all of the above locations, except for the gastroduodenal region, in which anorexia, nausea, and vomiting are more common.[10]

Rectal sparing is a typical but not constant feature of Crohn disease. However, anorectal complications (eg, fistulas, abscesses) are common. Much less commonly, Crohn disease involves the more proximal parts of the GI tract, including the mouth, tongue, esophagus, stomach, and duodenum.

Inflammatory bowel disease. Cobblestone change of the mucosa of the terminal ileum in a patient with Crohn disease. Communicating fissures and crevices in the mucosa separate islands of more intact, edematous epithelium.

Inflammatory bowel disease. This computed tomography scan from a patient with terminal ileal Crohn disease shows an enteroenteral fistula (arrow) between loops of diseased small intestine.

Inflammatory bowel disease. Another example of a deep, fissuring ulcer in a patient with Crohn disease. Note the increase in submucosal inflammation and scattered lymphoid aggregates.

Cholelithiasis and nephrolithiasis

The incidence of gallstones and kidney stones is increased in Crohn disease because of malabsorption of fat and bile salts. Gallstones are formed because of increased cholesterol concentration in the bile, which is caused by a reduced bile salt pool.

Patients who have Crohn disease with ileal disease or ileal resection are also likely to form calcium oxalate kidney stones. With the fat malabsorption, unabsorbed long-chain fatty acids bind calcium in the lumen. Oxalate in the lumen is normally bound to calcium. Calcium oxalate is poorly soluble and poorly absorbed; however, if calcium is bound to malabsorbed fatty acids, oxalate combines with sodium to form sodium oxalate, which is soluble and is absorbed in the colon (enteric hyperoxaluria). The development of calcium oxalate stones in Crohn disease requires an intact colon to absorb oxalate. Patients with ileostomies generally do not develop calcium oxalate stones, but they may develop uric acid or mixed stones.[11]

Three characteristics define the etiology of inflammatory bowel disease (IBD): (1) genetic predisposition; (2) an altered, dysregulated immune response; and (3) an altered response to gut microorganisms. However, the triggering event for the activation of the immune response in IBD has yet to be identified. Possible factors related to this event include a pathogenic organism (as yet unidentified) or an inappropriate response (ie, failure to downgrade the inflammatory response to an antigen, such as an alteration in barrier function).

No mechanism has been implicated as the primary cause, but many are postulated. The lymphocyte population in persons with IBD is polyclonal, making the search for a single precipitating cause difficult. In any case, an inappropriate activation of the immune system leads to continued inflammation of the intestinal tract, with both an acute (neutrophilic) and chronic (lymphocytic, histiocytic) inflammatory response.

Several environmental risk factors have been proposed as contributing to the IBD pathogenesis, but the results are inconsistent, and the limitations of the studies preclude drawing firm conclusions. The most consistent association described has been smoking, which increases the risk of Crohn disease. However, current smoking protects against ulcerative colitis, whereas former smoking increases the risk of ulcerative colitis. Dietary factors have also been inconsistently described. In some studies, high fiber intake and high intake of fruits and vegetables appear protective against IBD.[12] The E3N prospective study found that high animal protein intake (meat or fish) carried a higher risk of IBD.[13]

Genetics

Persons with IBD have a genetic susceptibility for the disease,[14] and considerable research over the past decade has improved our understanding of the role of these genes. Note that these genes appear to be permissive (ie, allow IBD to occur), but they are 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, as compared with persons from unaffected families.[6, 8]  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. 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.

Crohn disease

An early discovery on chromosome 16 (IBD1 gene) led to the identification of 3 single nucleotide polymorphisms (2 missense, 1 frameshift) in the NOD2 gene (now called CARD15) as the first gene (CARD15) clearly associated with IBD (as a susceptibility gene for Crohn disease). CARD15 is a polymorphic gene involved in the innate immune system. The gene has more than 60 variations, of which 3 play a role in 27% of patients with Crohn disease, primarily in patients with ileal disease.

Subsequent studies have suggested that the CARD15 genotype is associated not only with the onset of the disease but also with its natural history. A study on a German and Norwegian cohort showed that patients with 1 of the 3 identified risk alleles for CARD15 were more likely to have either ileal or right colonic disease.[15, 16] These gene products appear to be involved in the intracellular innate immune pathways that recognize microbial products in the cytoplasm.

Another early genome-wide association study looked at Jewish and non-Jewish case-control cohorts and identified 2 single nucleotide polymorphisms in the IL23R gene, which encodes 1 subunit of the interleukin-23 receptor protein.[17] Interestingly, this study also described the promising nature of certain therapies that block the function of IL-23. Further research suggested that one particular polymorphism in the IL23R gene showed the strongest association in a German population.[18] However, another study found that the Arg381Gln substitution is associated with childhood onset of IBD in Scotland.[19] These gene products appear to be involved in regulating adaptive immunity.

Numerous other loci have been identified as conferring susceptibility to Crohn disease, including several large meta-analyses that found multiple novel susceptibility loci and confirmed earlier findings. In one meta-analysis of 3 genome-wide association scans, 526 single nucleotide polymorphisms from 74 distinct genomic loci were found.[20] In sorting out loci that have been previously discussed, there were 21 new loci that were associated with an increased risk of developing Crohn Disease and have functional implications, including the genes CCR6, IL12B, STAT3, JAK2, LRRK2, CDKAL1, and PTPN22.[20] Most of these genes are involved in signal transduction in the immune function.

The interlectin gene (ITLN1) is expressed in the small bowel and colon, and it is also involved in the recognition of certain microorganisms in the intestine. Other genome-wide association studies have found associations between susceptibility to Crohn disease and polymorphisms in genes that are associated with the intestinal milieu. One such study examined nearly 20,000 single nucleotide polymorphisms in 735 individuals with Crohn disease.[21] An association was found with the ATG16L1 gene, which encodes the autophagy-related 16-like protein, which is involved in the autophagosome pathway that processes intracellular bacteria.[21]

Single nucleotide polymorphisms in other autophagy genes have also shown association with susceptibility to Crohn disease, such as 2 polymorphisms that flanked the IRGM gene and may exert regulatory control for the gene.[22] Subsequently, there have been a number of other loci implicated in the autophagy pathway that have been associated with Crohn disease.[7]

There is strong support for IBD-susceptibility genes on chromosome 5p13.1, which is a gene desert but does modulate expression of the PTGER4 gene. A murine PTGER4 knockout model has significant susceptibility to severe colitis.[23] A large genomic study of multiple diseases confirmed many of the findings that were found in earlier studies, as well as several additional loci of interest for Crohn disease.[24]

Disruption of a homologous gene in a murine model resulted in defective development of the intestine.[25] It was hypothesized that changes in the expression of this gene could alter the migration of lymphocytes in the intestine and change its inflammatory response. The last locus discussed in this model is immediately upstream of the PTPN2 on chromosome 18p11 and encodes a T cell protein tyrosine phosphatase, which is a negative regulator of inflammation.[25]

Ulcerative colitis

The genetic predisposition for ulcerative colitis appears to be lesser in magnitude than Crohn disease but consists of a set of genetic susceptibilities that shows significant overlap with Crohn disease. One genome-wide association study found a previously unknown susceptibility locus at ECM1 and also showed several risk loci that were common to both ulcerative colitis and Crohn disease.[26] Genes that confer risk for both diseases appear to influence the immune milieu of the intestine, whereas the genes that influence only Crohn disease appear to be involved mainly in autophagy.[26, 27]

Additional susceptibility loci for ulcerative colitis have been found on 1p36 and 12q15. The 1p36 single nucleotide polymorphism is near the PLA2G2E gene, which is involved in releasing arachidonic acid from membrane phospholipids, leading to other proinflammatory lipids. The first 12q15 signal is located near the interferon (IFN)-gamma, interleukin (IL)-26, and IL-22 genes, whereas the second 12q15 signal is located in IL-26 gene. These genes play roles in the immune response to pathogens as well as the tissue inflammation processes.[28]

Data suggest that genetic influences increase the risk for one form of IBD while decreasing the risk for another. In a Japanese population, the HLA-Cw*1202-B*5201-DRB1*1502 haplotype increases the risk for ulcerative colitis but reduces the risk for Crohn disease.[29] This finding has not been replicated in other ethnic groups. However, as the authors noted, the human leukocyte antigen (HLA) type in question in this study is relatively common in the Japanese population but relatively rare in European populations. They suggest that the HLA type will favor a T-helper immune response, predisposing toward ulcerative colitis, as opposed to an IFN-predominant response, predisposing more toward Crohn disease.[29]

Smoking

The risk of developing ulcerative colitis is higher in nonsmokers and former smokers than in current smokers. The onset of ulcerative colitis occasionally appears to coincide with smoking cessation; however, this does not imply that smoking would improve the symptoms of ulcerative colitis. There has been limited success with the use of nicotine patches. Crohn disease patients have a higher incidence of smoking than the general population, and smoking appears to lessen the response to medical therapy.

United States statistics

Before 1960, the incidence of ulcerative colitis was several times higher than that of Crohn disease. More recent data suggest that the incidence of Crohn disease is approaching that of ulcerative colitis.

Annually, an estimated 700,000 physician visits and 100,000 hospitalizations are due to IBD.[30] Approximately 1-2 million people in the United States have ulcerative colitis or Crohn disease, with an incidence of 70-150 cases per 100,000 individuals.[31, 32] In persons of European descent in Olmstead County, Minnesota, the incidence of ulcerative colitis was 7.3 cases per 100,000 people per year, with a prevalence of 116 cases per 100,000 people; the incidence of Crohn disease was 5.8 cases per 100,000 people per year, with a prevalence of 133 cases per 100,000 people.[33, 34]

Racial, sexual, and age-related differences

The incidence and prevalence of inflammatory bowel disease (IBD) among Americans of African descent is estimated to be the same as the prevalence among Americans of European descent, with the highest rates in the Jewish populations of middle European extraction.[35] There is a higher prevalence along a north-south axis in the United States[36] and in Europe,[37] although trends show that the gap is narrowing.

The male-to-female ratio is approximately 1:1 for ulcerative colitis and Crohn disease, with females having a slightly greater incidence. Both diseases 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 the second decade of life, with the vast majority of new diagnoses made in people aged 15-40 years. A second, smaller peak in incidence occurs in patients aged 55-65 years and is increasing. Approximately 10% of IBD patients are younger than 18 years.

International statistics

The highest rates of IBD are assumed to be in developed countries, and the lowest are considered to be in developing regions; colder-climate regions and urban areas have a greater rate of IBD than those of warmer climates and rural areas. Internationally, the incidence of IBD is approximately 0.5-24.5 cases per 100,000 person-years for ulcerative colitis and 0.1-16 cases per 100,000 person-years for Crohn disease.[30] Overall, the prevalence for IBD is 396 cases per 100,000 persons annually.[30]

A review of IBD reported that the prevalence of Crohn disease in North America was 319 per 100,000 persons, whereas in Europe, it was 322 per 100,000 persons.[31] Prevalence rates for ulcerative colitis were 249 per 100,000 persons in North America and 505 per 100,000 persons in Europe. The annual incidence of Crohn disease was 20.2 per 100,000 person-years in North America, 12.7 per 100,000 person-years in Europe, and 5.0 per 100,000 person-years in Asia and the Middle East, whereas incidence rates of ulcerative colitis were 19.2 per 100,000 person-years in North America, 24.3 per 100,000 person-years in Europe, and 6.3 per 100,000 person-years in Asia and the Middle East. Time-trend analyses showed statistically significant increases in the incidence of IBD over time.[31]

The standardized mortality ratio for inflammatory bowel disease (IBD) ranges from approximately 1.4 times the general population (Sweden) to 5 times the general population (Spain). Most of this increase appears to be in the Crohn disease population; the ulcerative colitis population appears to have the same mortality rate as the general population.[38]

The majority of studies indicate a small but significant increase in mortality associated with IBD.[39] A frequent cause of death in persons with IBD is the primary disease[40] ; infections and COPD/respiratory illness are other major causes of death.[41] IBD is not a risk factor for cardiovascular mortality.[42]

Patients with IBD are more prone to the development of malignancy. Persons with Crohn disease have a higher rate of small bowel malignancy. Patients with pancolitis, particularly ulcerative colitis, are at a higher risk of developing colonic malignancy after 8-10 years of disease. The current standard of practice is to screen patients with colonoscopy at 1-2 year intervals once they have had the disease for greater than 10 years.

A comprehensive discussion regarding the diagnosis, management, and surveillance of colorectal cancer in patients with IBD is beyond the scope of this article. For more information, see the following two guidelines:

• AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. 2010.[43, 44]

• Colonoscopic surveillance for prevention of colorectal cancer in people with ulcerative colitis, Crohn's disease or adenomas. (National Institute for Health and Clinical Excellence (NICE), London).[45]

Morbidity

In addition to long-term, disease-related complications, patients can also experience morbidity from prolonged medical therapy, particularly as a consequence of steroid exposure.

There also appears to be an increased risk for IBD in patients with asthma or chronic obstructive pulmonary disease (COPD). In a population-based retrospective cohort study of 136,178 individuals with asthma and 143,904 individuals with COPD, Brassard and colleagues found a significantly increased incidence of IBD. The average incidences of CD and UC in asthma patients were 23.1 and 8.8/100,000 person-years, respectively. Corresponding figures in COPD patients were 26.2 CD and 17 UC cases/100,000 person-years, respectively.[46, 47]

Compared with the general population, the incidence of CD in asthma and COPD patients was 27% and 55% higher, and the incidence of UC was 30% higher among those with COPD. Among children up to 10 years old in the asthma group and adults aged 50 to 59 in the COPD group, the incidence of CD was more than twice that seen in the general population.[46, 47]

Psychologic morbidity affects patients with IBD, especially younger patients, and are typically associated with depression and anxiety symptoms but also exhibit externalizing behaviors.[48] Risk factors for psychologic morbidity appear to include increased disease severity, lower socioeconomic status, use of corticosteroids, parental stress, and older age at diagnosis.[48]  

Ulcerative colitis

The average patient with ulcerative colitis has a 50% probability of having another flare during the next 2 years; however, patients may have only one flare over 25 years, and others may have almost persistently active disease. A small percentage of patients with ulcerative colitis have a single attack and no recurrence. Typically, remissions and exacerbations are characteristic of this disease, with acute attacks lasting weeks to months.

Patients with ulcerative colitis limited to the rectum and sigmoid have a 50% chance of progressing to more extensive disease over 10 years[49] and a 7.5% rate of colectomy over 5 years.[50] Approximately 10% of patients presenting with proctitis will develop a pancolitis.[49, 50]

Surgical resection for ulcerative colitis is considered “curative” for this disease, although patients may experience symptoms related to the ileal pouch (J-pouch), including acute and chronic pouchitis. Pouchitis is far more common in patients who have had a colectomy for ulcerative colitis than in those who have had a colectomy for familial adenomatous polyposis.

Beyond 8-10 years after diagnosis, the risk of colorectal cancer increases by 0.5%-1.0% per year. Surveillance colonoscopies with random biopsies reduce mortality from colorectal cancer in patients with ulcerative colitis by allowing the detection of low- or high-grade dysplasia and early stage carcinoma.

Crohn disease

The clinical course of Crohn disease is much more variable than that of ulcerative colitis, and it is dependent on the anatomic location and extent of the disease. Periodic remissions and exacerbations are the rule in Crohn disease. The relapse rate over 10 years is 90%, and the cumulative probability of requiring surgery over 10 years is approximately 38%. Terminal ileum location, fistulizing, and structuring disease are all independent risk factors for subsequent surgery.[51]

A review of the literature indicates that approximately 80% of patients who are in remission for one year will remain in remission over subsequent years.[52] Patients with active disease in the past year have a 70% chance of having clinical disease activity in the following year. Approximately 20% of patients will have annual relapses, and 13% will have a course free of relapses. Less than 5% of patients with Crohn disease will have continually active disease.[52]

Surgery for Crohn disease is generally performed for complications (eg, stricture, stenosis, obstruction, fistula, bleeding, or abscess). Surgical intervention is an important treatment option for Crohn disease, but patients should be aware that it is not curative and that disease recurrence after surgery is high, mimicking the original disease pattern at the site of the surgical anastomosis.

Recurrence of perianal fistulas after medical or surgical treatment is common (59%-82%).[52] In one study, one year after surgery for Crohn disease, 20%-37% of patients had symptoms suggestive of clinical recurrence, and endoscopic evidence of recurrent inflammation was in the neoterminal ileum in 48%-93% of patients.[53]

Overall, the patient's quality of life with Crohn disease is generally lower than that of individuals with ulcerative colitis. Data suggest that in persons with Crohn colitis involving the entire colon, the risk of developing malignancy is equal to that in persons with ulcerative colitis; however, the risk is much smaller (albeit poorly quantified) in most patients with Crohn disease primarily involving the small bowel. Intestinal cancer may become a more important long-term complication in patients with Crohn disease because of longer survival.

Studies support evidence that specific CARD15 mutations are associated with the intestinal location of the disease, as well as course and prognosis,[8] and are correlated with the propensity for developing ileal strictures and with an early onset of disease.

Complications of IBD disease

Intestinal complications

IBD can be associated with several gastrointestinal complications, including risk of hemorrhage, perforation, strictures, and fistulas—as well as perianal disease and related complications, such as perianal or pelvic abscesses, toxic megacolon (complicating acute severe colitis), and malignancy (colorectal cancer, cholangiocarcinoma complicating primary sclerosing cholangitis).

Extraintestinal complications

Extraintestinal complications occur in approximately 20%-25% of patients with IBD.[1] In some cases, they may be more symptomatic than the bowel disease itself. These include osteoporosis (usually a consequence of prolonged corticosteroid use), hypercoagulability resulting in venous thromboembolism, anemia, gallstones, primary sclerosing cholangitis, aphthous ulcers, arthritis, iritis (uveitis) and episcleritis, and skin complications (pyoderma gangrenosum, erythema nodosum).

Table 1, below, summarizes the rates of the most common extraintestinal complications in patients with IBD the United States and Europe.

Table 1. Common Extraintestinal Complications of IBD in US and Europe ^[54] (Open Table in a new window)

The Swiss National IBD Cohort Study also demonstrated the risks of extraintestinal complications of IBD; their results are summarized in Table 2, below.[55] The risk factors of having complications included family history and active disease observed for Crohn disease only; no significant risk factors were noted in patients with ulcerative colitis.[55]

Table 2. Extraintestinal Complications of IBD in Swiss Patients ^[55] (Open Table in a new window)

Because inflammatory bowel disease (IBD) is a chronic, often lifelong disease that is frequently diagnosed in young adulthood, increasing patient knowledge improves medical compliance and assists in the management of symptoms.

Encourage the patient to join an IBD support group, such as the Crohn's & Colitis Foundation of America. This foundation can provide educational materials for patients and educational brochures for physicians.

Crohn's & Colitis Foundation of America

733 Third Avenue

Suite 510

New York, NY 10017

Phone: 800-932-2423

E-mail: info@ccfa.org

The manifestations of inflammatory bowel disease (IBD) generally depend on the area of the intestinal tract involved. The commonly experienced symptoms of Crohn disease include recurrent abdominal pain and diarrhea. Sometimes, the diagnosis may be delayed by several months to a few years, as these symptoms are not specific for IBD. Patients with IBD may have symptoms of irritable bowel syndrome (IBS), with cramping, irregular bowel habits, and passage of mucus without blood or pus.

Systemic symptoms are common in IBD and include weight loss, fever, sweats, malaise, and arthralgias. A low-grade fever may be the first warning sign of a flare. Patients are commonly fatigued, which is often related to the pain, inflammation, and anemia that accompany disease activity. Recurrences may occur with emotional stress, infections or other acute illnesses, pregnancy, dietary problems, use of cathartics or antibiotics, or nonadherence to therapy. Children may present with growth retardation and delayed or failed sexual maturation. In 10%-20% of cases, patients present with extraintestinal manifestations, including arthritis, uveitis, or liver disease (see Complications).

Grossly bloody stools, occasionally with tenesmus, although typical of ulcerative colitis, are less common in Crohn disease. Stools may be formed, but loose stools predominate if the colon or the terminal ileum is involved extensively. Fifty percent of patients with Crohn disease may present with perianal disease (eg, fistulas, abscesses). Occasionally, acute right lower quadrant pain and fever, mimicking appendicitis or intestinal obstruction, may be noted. Weight loss is observed more commonly in Crohn disease than in ulcerative colitis because of the malabsorption associated with small bowel disease, or small bowel disease may act as an appetite deterrent. In addition, patients may reduce their food intake in an effort to control their symptoms.

The World Gastroenterology Organization (WGO) indicates the following symptoms may be associated with inflammatory damage in the digestive tract[1] :

• Diarrhea: mucus or blood may be present in the stool; can occur at night; incontinence may occur

• Constipation: this may be the primary symptom in ulcerative colitis, when the disease is limited to the rectum; obstipation may occur and may proceed to bowel obstruction

• Bowel movement abnormalities: pain or rectal bleeding may be present, as well as severe urgency and tenesmus

• Abdominal cramping and pain: commonly present in the right lower quadrant in Crohn disease; occur periumbilically or in the left lower quadrant in moderate to severe ulcerative colitis

• Nausea and vomiting: occurs more often in Crohn disease than in ulcerative colitis

Other considerations include a family history of IBD, celiac disease, or colorectal cancer; the use of medications such as antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs); the presence of mood disorders; the use of tobacco; and recent travel.[1]

Fever, tachycardia, dehydration, and toxicity may occur in patients with inflammatory bowel disease (IBD). Pallor may also be noted, reflecting anemia. The prevalence of these factors is directly related to the severity of the attack.

Toxic megacolon is a medical emergency. Patients appear septic; have high fever, lethargy, chills, and tachycardia; and have increasing abdominal pain, tenderness, and distention.

Patients with Crohn disease may develop a mass in the right lower quadrant. Perianal complications (eg, perianal fissures or fistulas, abscesses, rectal prolapse) may be observed in up to 90% of patients with this disease.[2] Common presenting signs include occult blood loss and low-grade fever, weight loss, and anemia. The rectal examination often reveals bloody stool or a positive Hemoccult stool test.

Growth retardation may be the only presenting sign of IBD in young patients. The physical examination should also include a search for extraintestinal manifestations, such as iritis, episcleritis, arthritis, and dermatologic involvement. (see Complications.)

Several laboratory studies are of value in assisting with the management of inflammatory bowel disease (IBD) and provide supporting information. However, no laboratory test is specific enough to adequately and definitively establish the diagnosis of IBD. 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, but such studies are not recommended for routine diagnosis of Crohn disease or ulcerative colitis.

In individuals who are immunosuppressed, are from third world countries, or have a history of travel, intestinal tuberculosis (TB) may need to be excluded. In such cases, tuberculin purified protein derivative (PPD) or interferon-gamma assays (eg, QuantiFERON-TB, T-SPOT, TB test) may be indicated, as well as culture for amebiasis, giardiasis, Strongyloides infection, and studies for histoplasmosis and coccidioidomycosis.[1] Chest radiography may exclude pulmonary TB, but this imaging modality does not exclude extrapulmonary TB.[1]

Hematologic tests

Complete blood cell count

The components of the complete blood cell (CBC) count can be useful indicators of disease activity and iron or vitamin deficiency. An elevated white blood cell (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). Anemia may result from acute or chronic blood loss, malabsorption (iron, folate, and vitamin B12) or may reflect the chronic disease state. Note that the MCV can be elevated in patients taking azathioprine (Imuran) or 6-mercaptopurine (6-MP). Generally, the platelet count is normal, or it may be elevated in the setting of active inflammation.

Nutritional evaluation: Vitamin B12 evaluation, iron studies, RBC folate, nutritional markers

Vitamin B12 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 B12 is 1000 mg subcutaneously (SC) every month, because oral replacement is often insufficient.

Serum iron studies should be obtained at the time of diagnosis, because active IBD is a source for GI blood loss, making iron deficiency common. A microcytic hypochromic anemia suggests iron deficiency; if confirmed with serum iron/total iron-binding capacity (TIBC), iron should be replaced either enterally or parenterally. For parenteral replacement, intravenous (IV) iron sucrose can be used, and dosing is based on the table in the package insert, with a maximum of 30 mL (1500 mg) at once.

Although 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 of folate; thus, many practitioners commonly administer folate supplements in patients taking sulfasalazine. 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 mg/day or more (rather than the usual 1 mg/day) should be considered in those on sulfasalazine.

Nutritional status can be assessed by serum albumin, prealbumin, and transferrin levels. However, note that transferrin is an acute-phase reactant that can be falsely elevated in persons with active IBD. Hypoalbuminemia may reflect malnutrition because of poor oral intake or because of protein-losing enteropathy that can coexist with active IBD.

ESR and CRP levels

The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level are often used as serologic markers for inflammation, but they are not specific for IBD. However, measuring such inflammatory markers also aids in monitoring disease activity and response to treatment. A small but significant number of patients with Crohn disease or ulcerative colitis may not have elevated ESR or CRP levels even in the setting of significant active inflammation. In addition, inflammatory markers may be elevated in the setting of superimposed intestinal or extraintestinal infections.

Fecal calprotectin levels

Fecal calprotectin has been proposed as a noninvasive surrogate marker of intestinal inflammation in IBD.[57] As colorectal neoplasia and gastrointestinal infection also increase fecal calprotectin, this marker is not in widespread use. Note that relatives of patients with IBD may also have elevated levels of fecal calprotectin (with unknown degrees of inflammation).[57]

A study by Henderson et al indicated that fecal calprotectin has a high sensitivity and modest specificity for diagnosing IBD in children. The researchers conducted a systematic review and meta-analysis of 8 studies including 394 pediatric IBD cases and 321 non-IBD controls.[58, 59] The use of fecal calprotectin during the investigation of suspected pediatric IBD was associated with a pooled sensitivity of 97.8%, a pooled specificity of 68.2%, a positive likelihood ratio of 3.07, and a negative likelihood ratio of 0.03.

Metabolite/enzyme levels

Many experts routinely check levels of thiopurine methyltransferase (TPMT) prior to initiation of treatment with mercaptopurine and azathioprine. Individuals who have low enzyme activity or are homozygous deficient in the TPMT mutation are at risk of very severe leukopenia, with potential septic complications, and they may not be good candidates for therapy with these drugs.[60]

Biologic drug and biologic drug antibody levels

The measurement of biologic drug levels and antibodies to the biologic drugs are most useful in patients who are not responding as expected to these agents.

• If a nonresponding patient has a low or undetectable drug level, then the presence of an antibody suggests that using a different biologic in the same class may be effective.
• If there is an undetectable or low drug level and no antibody, then increasing the dose of the same drug may be effective.
• If the drug level is normal or high and antibody is absent, then a primary nonresponse indicates that switching to a different class of biologics would be in order.

pANCA and ASCA tests

Perinuclear antineutrophil cytoplasmic antibodies (pANCA) have been identified in some patients with ulcerative colitis, and anti-Saccharomyces cerevisiae antibodies (ASCA) have been found in patients with Crohn disease. The combination of positive pANCA and negative ASCA has high specificity for ulcerative colitis, whereas the inverse pattern—positive ASCA, negative pANCA—is more specific for Crohn disease.[1] However, false-positive (and false-negative) results are not uncommon; therefore, at this time, serologic markers cannot be used to definitively rule in or exclude inflammatory bowel disease (IBD).

Note that a variant of Crohn disease particularly involving the colon may result in a positive pANCA test, which may complicate the diagnosis. Serum response to anti-CBir1, an antibody associated with the presence of IBD, has been shown to differentiate pANCA-positive results in ulcerative colitis versus ulcerative colitis–like Crohn disease.[61]

Patients with Crohn disease who have a greater number of positive ASCA may be at a greater risk for complications such as strictures and fistulas, and they may also be at a higher risk for surgery. However, serologic markers do not appear to predict response to medical therapy, and there is currently insufficient evidence to recommend the use of antibody testing to predict responses to medical treatment or surgery in patients with IBD.[61]

Before making a definitive diagnosis of idiopathic inflammatory bowel disease (IBD), perform a stool culture, ova and parasite studies, bacterial pathogens culture, and evaluation for Clostridium difficile infection.[3] At a minimum, a C difficile toxin assay should be performed on any patient hospitalized with a flare of colitis, or in any patient not responding to appropriate medical intervention, because pseudomembranous colitis is commonly superimposed on IBD colitis. Note that the level of the inflammatory marker calprotectin in feces correlates significantly with colonic inflammation in both ulcerative colitis and Crohn disease.[62]

Assessment for Cytomegalovirus colitis should be performed in cases refractory to steroids.[1] Amebiasis can be difficult to identify from the stool; therefore, consider serologic testing.

As many as 50%-80% of cases of acute terminal ileitis may be due to Yersinia enterocolitis infections. This produces a picture of pseudoappendicitis. As with IBD, yersiniosis has a high frequency of secondary manifestations, such as erythema nodosum and monoarticular arthritis. Thus, in the right clinical setting, a suspicion for Yersinia should be considered.

Upright chest and abdominal radiography

Abdominal radiography may allow for assessment of the kidneys, ureters, and bladder for nephrolithiasis and the vertebral bodies for osteopenia or osteoporosis and sacroileitis. If severe fulminant colitis is present, abdominal radiography may reveal an edematous, irregular colon with thumbprinting (see the first image below). Occasionally, pneumatosis coli (air in the colonic wall) may be present. Free air and evidence of toxic megacolon, which appears as a long continuous segment of air-filled colon greater than 6 cm in diameter, indicates a surgical emergency. (See the images below.)

Inflammatory bowel disease. Plain abdominal radiograph of a patient with known ulcerative colitis who presented with an acute exacerbation of his symptoms. This image shows thumbprinting in the region of the splenic flexure of the colon.

Inflammatory bowel disease. Plain abdominal radiograph in a 26-year-old with a 10-year history of ulcerative colitis shows a long stricture/spasm of the ascending colon/cecum (<i>arrow</i>). Note the pseudopolyposis in the descending colon.

Inflammatory bowel disease. Toxic megacolon. Courtesy of Dr. Pauline Chu.

Toxic megacolon is a life-threatening complication of ulcerative colitis and requires urgent surgical intervention. This condition occurs predominantly in the transverse colon, probably because air collects there in the supine position. The transverse colon is dilated, usually more than 8 cm (dilation more than 6 cm is considered abnormal). A colectomy is required if no improvement occurs within 24-48 hours. Repeat radiographs are required at 12- to 24-hour intervals to monitor the course of dilatation and to assess the need for emergency colectomy.

Barium enema double-contrast radiographic studies

The barium enema imaging technique was one of the first studies that allowed characterization of the typical findings associated with inflammatory bowel disease (IBD). Barium enemas may be useful in cases of limited or no access to endoscopy, in cases of incomplete colonoscopy, or to measure stricture length.[1]

Several terms have been used to describe abnormalities found after barium studies of the colon, including the following:

• A lead-pipe or stove-pipe appearance suggests chronic ulcerative colitis that has resulted in a loss of colonic haustra due to the colon becoming a rigid foreshortened tube (see the following image)

  Inflammatory bowel disease. Double-contrast barium enema study shows pseudopolyposis of the descending colon in a patient with ulcerative colitis.

• Rectal sparing suggests Crohn colitis in the presence of inflammatory changes in other portions of the colon (see the image below)

  Inflammatory bowel disease. Double-contrast barium enema study demonstrates marked ulceration, inflammatory changes, and narrowing of the right colon in a patient with Crohn colitis.

• Thumbprinting indicates mucosal inflammation (which can also be seen frequently on the abdominal flat plate) (see the following image)

  Inflammatory bowel disease. Plain abdominal radiograph of a patient with known ulcerative colitis who presented with an acute exacerbation of his symptoms. This image shows thumbprinting in the region of the splenic flexure of the colon.

• Skip lesions indicate areas of inflammation alternating with normal-appearing areas, again suggesting Crohn colitis

Barium can be refluxed into the terminal ileum in many cases (see the first image below), which can assist in the diagnosis of Crohn disease. The string sign (a narrow band of barium flowing through an inflamed or scarred area) in the terminal ileum is typical of one form of ileal Crohn disease observed on radiographs (see the first image below). Barium enema is contraindicated in patients with moderate to severe colitis, because it risks perforation or precipitation of a toxic megacolon (see the second image below).

Inflammatory bowel disease. Crohn disease involving the terminal ileum. Note the "string sign" in the right lower quadrant (viewer's left).

Inflammatory bowel disease. Toxic megacolon. Courtesy of Dr. Pauline Chu.

In Crohn disease, areas of segmental narrowing with loss of normal mucosa, fistula formation, and the string sign (a narrow band of barium flowing through an inflamed or scarred area) in the terminal ileum are typically observed on radiographs (see the images below). Some patients with ulcerative colitis also demonstrate inflammatory changes in the terminal ileum (ileitis), but these findings lack the skip pattern that is characteristic of Crohn disease.

Inflammatory bowel disease. Enteroenteric fistula noted on a small bowel series of x-ray films in a patient with inflammatory bowel disease. The narrow-appearing segments filled out relatively normally on subsequent films. Note that barium is just starting to enter the cecum in the right lower quadrant (viewer's left), but the barium has also started to enter the sigmoid colon toward the bottom of the picture, thus indicating the presence of a fistula from the small bowel to the sigmoid colon.

The small bowel series, or small bowel follow-through (see the image below), can reveal inflammation, can assist in the assessment of stricture length and severity, and can help determine the most appropriate surgical approach. Fistulas may be demonstrated on films from a small bowel series, even if they are not suggested on the basis of the clinical evaluation.

Inflammatory bowel disease. Cobblestoning in Crohn disease. Spot views of the terminal ileum from a small bowel follow-through study demonstrates linear longitudinal and transverse ulcerations that create a cobblestone appearance. Also, note the relatively greater involvement of the mesenteric side of the terminal ileum and the displacement of the involved loop away from the normal small bowel secondary to mesenteric inflammation and fibrofatty proliferation.

Although radiologists may remark on the 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 may make proper interpretation of colon findings difficult.

The small bowel series is usually sufficient for the evaluation of small intestine Crohn disease; however, in rare cases, it may not provide an adequate view of the terminal ileum, necessitating an enteroclysis.

Small bowel enteroclysis differs from a small bowel series in that a nasoenteric or oroenteric tube is placed and contrast material 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 owing to dilution of the contrast agent as it passes through the (usually dilated) small bowel. This has been supplanted for the most part by computed tomography (CT) enterography.

In fistulographic studies, 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.

Ultrasonography (US) is a non-invasive technique in diagnosing Crohn disease. Although this technique has a sensitivity of 84% and a specificity of 92%, it has less accuracy when disease is located proximal to the terminal ilium.[63] Ultrasonography, magnetic resonance imaging (MRI), and computed tomography (CT) scanning have similar accuracy for the entire bowel and are reliable in identifying fistulas, abscesses, and stenosis; however, US may lead to false positives for abscesses. US and MRI are often preferred over CT scanning because of the lack of radiation risk, especially in younger patients.[63]

Findings on computed tomography (CT) scanning of the abdomen and pelvis may be very suggestive of inflammatory bowel disease (IBD). Bowel 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 (eg, mesenteric fat stranding, wall enhancement, increased vascularity ["comb sign"]) 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. Fistulas may also be detected on CT scans. CT scanning is best for demonstrating intra-abdominal abscesses, mesenteric inflammation, and fistulas. (See the following images.)

Inflammatory bowel disease. This computed tomography scan from a patient with terminal ileal Crohn disease shows an enteroenteral fistula (arrow) between loops of diseased small intestine.

Inflammatory bowel disease. A teenage patient with Crohn disease underwent a contrast-enhanced upper gastrointestinal computed tomography study with small-bowel follow-through. Several loops of small bowel are in the pelvis. Note there is a loop of distal bowel with a thickened wall (solid arrow), which is contrasted with a less involved loop of bowel in which the intestinal wall is not thickened at all (dotted arrow).

Inflammatory bowel disease. Computed tomography scan depicting Crohn disease in the fundus of the stomach.

The use of magnetic resonance imaging (MRI) was validated in a prospective study that compared this imaging modality to the standard Crohn’s Disease Endoscopic Index of Severity (CDEIS).[64] MRI accurately assessed intestinal wall thickness, the presence and degree of edema, and ulcers in patients with Crohn disease. This study confirmed that through relative contrast enhancement (RCE), MRI can play an essential role in predicting disease activity and severity in Crohn disease.[64] In addition, pelvic MRI has a higher sensitivity for the diagnosis of perirectal complications of Crohn disease.

CT enterography

A newer CT technique (called CT enterography) is a contrast CT technique in which larger than normal amounts of oral contrast are ingested by the patient. This technique, which requires a skilled radiologist, allows for better visualization of the small bowel mucosa and is considered by some to be superior to the small bowel x-ray series because of its ability to identify extraintestinal lesions; for diagnosing intestinal disease, it compares favorably with capsule enterography, ileocolonoscopy, and small bowel follow-through x-ray. In situations where repeated studies are needed, MR enterography may be considered in order to avoid excess radiation exposure.[65, 66, 67]

Colonoscopy

Colonoscopy is one of the most valuable tools available to the physician for the diagnosis and treatment of inflammatory bowel disease (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, is nonulcerating, and may occur when a widely patent ileocecal valve is present. (See the following images.)

Inflammatory bowel disease. Severe colitis noted during colonoscopy in a patient with inflammatory bowel disease. The mucosa is grossly denuded, with active bleeding noted. The patient had her colon resected very shortly after this view was obtained.

Inflammatory bowel disease. Stricture in the terminal ileum noted during colonoscopy in a patient with inflammatory bowel disease. This image depicts a narrowed segment visible upon intubation of the terminal ileum with the colonoscope. Relatively little active inflammation is present, indicating that this is a cicatrix stricture.

Colonoscopy or sigmoidoscopy reveals that the rectum is almost always involved in ulcerative colitis, but it is frequently spared in Crohn disease. 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 GI tract. Colectomy is curative.

Colonoscopy with ileoscopy in the assessment of Crohn disease has a sensitivity of 74% and a specificity of 100%, leading to a positive predictive value of 100% as a diagnostic test.[68] When paired with small bowel follow-through, the sensitivity of this pair of diagnostic tests is increased to 78%, with a continued positive predictive value of 100%.[68]

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, but it is usually of transient value and has yet to be assessed in controlled trials.

Patients with IBD who are undergoing endoscopic procedures may have higher complication rates than the general population. The risks of colonoscopy apply (eg, reaction to medication, bleeding, perforation), and the risk of bleeding is increased in the presence of inflammation. The risk of perforation is also increased, particularly in patients taking high doses of steroids long term or who have severe colitis.

Colonoscopy also plays an important role in surveillance for colorectal cancer in patients with IBD. The utility of endoscopic surveillance can be further optimized by autofluorescence plus high-resolution endoscopy, chromoendoscopy-guided confocal laser microscopy, and confocal laser microscopy in combination with narrow-band imaging and high-resolution endoscopy, as well as chromoendoscopy with methylene-blue dye and spray-targeted biopsies.[69]

Flexible sigmoidoscopy

Flexible sigmoidoscopy 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. Rarely, Crohn colitis can be diagnosed based on flexible sigmoidoscopy findings. Note that sigmoid inflammation, particularly in older patients, may be confused with diverticulitis or ischemia.

Esophagogastroduodenoscopy (EGD) 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 may be made after gastric or duodenal ulcers fail to heal with acid suppression alone but is usually accompanied by ileal or ileocolonic Crohn disease.

Guidelines on the use of endoscopy in the diagnosis and management of IBD are available from the American Society for Gastrointestinal Endoscopy.[70]

Capsule enteroscopy

In capsule enteroscopy, the patient swallows an encapsulated video camera that transmits images to a receiver outside the patient. It is most commonly used for finding obscure sources of gastrointestinal (GI) blood loss, the images can find ulcerations associated with Crohn disease if upper endoscopy and colonoscopy are unrevealing. In one study, the detection rate of abnormalities was 70.5% for patients with suspected small bowel disease, and the diagnostic yield for patients with obscure GI bleeding was higher (85.7%) than that for patients with abdominal pain or diarrhea (53.3%).[71]

Capsule enteroscopy may also aid in the diagnosis of small bowel Crohn disease when the standard diagnostic workup with colonoscopy and upper endoscopy is negative.[1]

However, not all small intestinal ulcerations represent manifestations of Crohn disease. The major risk is the potential for the camera to become lodged at the point of a stricture, which may necessitate operative intervention for removal. The risk of the standard capsule can be avoided with a preliminary exam by using a patency capsule that disintegrates if a stricture is encountered or by performing an alternative small bowel imaging study to first exclude such strictures in patients with suspicious symptoms.

Double balloon enteroscopy

Double balloon enteroscopy, or deep small bowel enteroscopy, is a technique whereby a long enteroscope is passed into the intestine using an overtube. Both the endoscope and the overtube have balloons that can be inflated and deflated sequentially as the endoscope is advanced in an "inchworm" fashion. Successful evaluation of the entire small intestine with this technique is reported to be as high as 86% to as low as 23%.[72, 73, 74, 75] However, patients who have had previous surgery have a higher complication rate (perforation) with this technique relative to other small bowel imaging techniques.

Ulcerative colitis

Ulcerative colitis is a superficial inflammation of the bowel wall almost entirely limited to the large bowel (when the cecum is involved, there may be some inflammation in the distal-most ileum, the so-called "backwash ileitis"). Only in complicated cases such as evolution into toxic megacolon are the deeper layers of the bowel wall involved with the inflammatory process.

Ulcerative colitis primarily involves the mucosa and the submucosa, with the formation of crypt abscesses and mucosal ulceration. The mucosa typically appears granular and friable. In more severe cases, pseudopolyps form, consisting of areas of hyperplastic growth with swollen mucosa surrounded by inflamed mucosa with shallow ulcers. In severe ulcerative colitis, inflammation and necrosis can extend below the lamina propria to involve the submucosa and the circular and longitudinal muscles.

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

Inflammatory bowel disease. Chronic architectural changes in ulcerative colitis. Note the crypt branching and irregularity of size and shape, with an increase in chronic inflammatory cells in the lamina propria.

Inflammatory bowel disease. Low-power image of a colon biopsy specimen in a patient with ulcerative colitis illustrates changes limited to the mucosa. These changes include chronic alterations of the crypt architecture and an increase in chronic inflammatory cells in the lamina propria.

Inflammatory bowel disease. Chronic architectural changes in ulcerative colitis. Note the trifid crypt.

The typical histologic findings of ulcerative colitis include expansion of chronic inflammation in the mucosa and, in active cases, the presence of acute inflammation. In mildly active cases, there is an acute cryptitis that progresses to crypt abscesses in moderately active cases. In severe cases, mucosal ulcers develop as a result of the ongoing acute inflammatory process. Areas of relatively preserved mucosa between ulcerated areas may have a polypoid appearance grossly and are referred to as "pseudopolyps." In cases of many years’ duration, dysplasia of the large bowel mucosa may develop and signifies an increased risk for the development of colorectal adenocarcinoma. (See the images below.)

Inflammatory bowel disease. High-power view of a crypt abscess in ulcerative colitis shows the crypt to be dilated and filled with neutrophils and debris.

Inflammatory bowel disease. This is an example of low-grade glandular dysplasia in a patient with longstanding ulcerative colitis. Note the loss of mucin, nuclear hyperchromasia, and nuclear pseudostratification. See the next image.

Inflammatory bowel disease. High-grade dysplasia in the same patient as the previous image. There is significant cytologic atypia, with rounding of the nuclei and a greater degree of pseudostratification.

Inflammatory bowel disease. Histologic section from another location in the same patient as described in the previous image. This field shows glands that are suspicious for invasive carcinoma.

Crohn disease

The entire intestinal wall is involved with inflammation in Crohn disease. Biopsy specimens may demonstrate granulomas (approximately 50% of the time). The presence of granulomas is often helpful in making the diagnosis but is not necessary.

Because biopsy specimens obtained at colonoscopy are generally superficial mucosal samples, the pathologist may have difficulty making a definitive diagnosis of ulcerative colitis or Crohn disease based on histologic findings alone. However, histology also helps rule out other causes of inflammation, including infectious colitis and ischemic colitis. The characteristic pattern of inflammation in Crohn disease is a transmural involvement of the bowel wall by lymphoid infiltrates that contains sarcoidlike granulomas in about half of the cases (most commonly in the submucosa). Also characteristic are proliferative changes in the muscularis mucosa and in the nerves scattered in the bowel wall and myenteric plexus. In the involved foci of the small and large bowel, Paneth cell hyperplasia is frequent and areas of pyloric metaplasia may be seen. In full-blown cases, long and deep fissurelike ulcers form. (See the following images.)

Inflammatory bowel disease. A deep knifelike, fissuring, transmural ulcer in Crohn disease is shown in this histologic image.

Inflammatory bowel disease. Granuloma in the mucosa in a Crohn disease patient.

Inflammatory bowel disease. Colonic granuloma in a patient with Crohn disease (arrow). Hematoxylin-eosin staining. Courtesy of Dr E. Ruchelli.

Inflammatory bowel disease. A crypt abscess demonstrating active, neutrophilic inflammation in Crohn disease.

The two goals of therapy are the achievement of remission (induction) and the prevention of disease flares (maintenance). Note that a top-down approach, with earlier introduction of biologics and immunomodulators, is frequently advocated to forestall complications.[76]

The care of a patient with inflammatory bowel disease (IBD) can be either medical or surgical in nature or, in many patients, a combination of both. The management algorithm is also dependent on whether the diagnosis is Crohn disease or ulcerative colitis. The medical approach for patients with IBD is both symptomatic care (ie, relief of symptoms) and mucosal healing. Mild disease can follow a stepwise approach to medication, with escalation of the medical regimen until a response is achieved. More moderate to severe disease, however, warrants more aggressive initial treatment for the prevention of intestinal complications.

The concept of deep mucosal healing, particularly in Crohn disease, is becoming routine care. There are several studies, primarily involving anti-TNF agents (and occasionally immune modifiers); that have shown that the elimination of inflammation (as demonstrated by endoscopic and histologic criteria) results in a decrease in the rate of surgery, the use of corticosteroids, and the rate of hospitalization.[77, 78, 79, 80, 81, 82, 83] This supports the use of immune-modifying agents (mercaptopurine or azathioprine) or one of the anti-TNF agents earlier in the course of IBD.[77, 78, 79, 80, 81, 82, 83]

Symptomatic therapy

In addition to treatment of the underlying inflammation, patients with inflammatory bowel disease (IBD) may require symptomatic therapy, particularly when their symptoms are not related to active inflammation. Treatment with antidiarrheal agents such as loperamide or diphenoxylate/atropine should generally be avoided in patients with active inflammation, as these drugs can precipitate toxic megacolon in individuals with significant colonic inflammation. Similarly, other agents that may have anticholinergic effects should be avoided, although antispasmodic medications may sometimes be useful for symptomatic relief. In patients with Crohn disease who have significant ileal disease or who have had an ileal resection, diarrhea may sometimes be due to bile salt malabsorption. In such patients, treatment with bile-binding resins, such as cholestyramine, may be helpful in managing the diarrhea.

Supportive care

IBD flares in patients with mild to moderate disease are usually managed in an outpatient setting. However, an important and sometimes overlooked concern in the management of IBD is the dosing and duration of the use of corticosteroid therapy. For a flare of moderate severity, a dose of prednisone of 20-40 mg/day or equivalent is often sufficient to treat the flares. Once symptoms are controlled, a dedicated tapering of the steroid dose follows.

Patients are candidates for immunomodulators (azathioprine, 6-mercaptopurine, methotrexate) or anti-TNF agents (infliximab, adalimumab, certolizumab pegol) and biologic agents if flares are frequent (>1-2 times), if the duration of steroid use is prolonged (more than a few weeks per year), if reduction of the steroid dose causes recurrence of symptoms (steroid dependent), or if steroids do not appear to be working (steroid refractory).

A subset of patients (pediatric patients with Crohn disease [not ulcerative colitis]) has been shown to benefit from the use of exclusive enteral nutrition (EEN); in many parts of the world this is used prior to other forms of treatment. EEN can produce remission rates as high as 60%-80% in this population, although significant mucosal healing and significant longevity of remission have not been demonstrated. EEN uses elemental or polymeric feeding formulae that can be consumed by mouth but is often administered by nasoenteric feeding tube, generally at night. It has not been well studied in adult populations; the taste of the formulae, the large quantity required to meet nutritional needs, and the adverse impact on quality of life are all inhibitors to its use in the adult population.[84]

A health maintenance issue of particular importance to patients with IBD is a reduction in bone density because of decreased calcium absorption (due to the underlying disease process) or corticosteroid use. Osteoporosis is a very serious complication, involving 40% of patients with IBD, and increases the risk for fractures. All patients who have been using steroids for longer than 3 months, as well as postmenopausal women, should undergo testing with bone-density studies; treatment with bisphosphonates and calcium supplements can be initiated in patients with significantly low bone density.

A stepwise approach (now generally referred to as the step-up approach), such as outlined in the following sections, may be taken in mild inflammatory bowel disease (IBD). More moderate to severe IBD should be treated more aggressively up front to prevent permanent damage.

The first step in medication therapy for mild IBD is usually aminosalicylates. There are several different aminosalicylates, but none have been consistently demonstrated to be superior to the others for all patients. These agents appear to have greater efficacy for the treatment of ulcerative colitis than for Crohn disease, for which efficacy data are limited. For Crohn disease, metronidazole or ciprofloxacin is occasionally used, particularly for perianal disease or an inflammatory mass.

If the patient's condition fails to respond to an adequate dose of aminosalicylates, the second step is often corticosteroids, which tend to provide rapid relief of symptoms and a significant decrease in inflammation.[85] The most common range for moderate flares of IBD is oral prednisone at 10-40 mg/day; for more severe flares, the higher end of the range is used (occasionally doses up to 60 mg/day). Once a clinical response is seen, the dose is tapered. Most patients who use oral corticosteroids can tolerate a relatively rapid taper after a response is achieved; occasionally, a very prolonged steroid taper is necessary to prevent relapse in patients who have had prolonged exposure to steroids in the past. Inability to taper down the steroids without recurrence of symptoms should trigger discussion regarding the use of alternative drugs (immunomodulators or anti-TNF therapy). The advantage of steroids is that they work quickly and are effective for acute flares; they are not effective for maintenance of remission, however.

The immune-modifying agents are used if corticosteroids fail or are required for prolonged periods for milder disease; they can be used up front for moderate and severe disease. Anti-TNF monoclonal antibody therapies are also effective in both Crohn disease and ulcerative colitis; some studies have demonstrated that they have a greater efficacy than azathioprine. Historically, anti-TNF agents have been administered when Crohn disease has been unresponsive to steroids and immunosuppressants; however, the early introduction of these agents in conjunction with immunosuppressants in those with an increased risk of a complicated, severe, or possibly aggressive IBD has the potential to modify the disease course and is commonly pursued.[76]

Drugs from different therapeutic classes may be used additively. In patients with moderate to severe or high-risk disease, a step-down approach with early introduction of stronger agents such as the anti-TNF agents has been advocated to prevent complications and improve patient outcomes. There are many situations, especially in patients with more severe disease, where early use of anti-TNF agents or other biologics is clearly in the patient’s best interest.

In general, one major goal is to wean the patient off steroids as soon as possible to prevent long-term adverse effects from these agents. Ardizzone et al suggest that a lack of mucosal healing after corticosteroid therapy is the only factor associated with negative outcomes at 5 years.[86]

The five oral aminosalicylate preparations available for use in the United States are sulfasalazine (Azulfidine), mesalamine (Asacol, Asacol HD, Pentasa, Lialda, Apriso), 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 and site of delivery. Some of these agents also have unique adverse effects lacking in other agents of this class.

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 than any of the others for the treatment of ulcerative colitis. As a class, these agents appear to be more effective in persons with ulcerative colitis than in persons with Crohn disease; in persons with mild Crohn disease, the primary utility is for colonic disease (as is the case with sulfasalazine[1] ; administer folic acid if sulfasalazine is used). Aminosalicylates have only a weak effect in preventing recurrence after surgery in patients with Crohn disease.[87]

For patients in remission from distal ulcerative colitis, oral or rectal 5-ASA can be used to manage this disease, as well as a combination regimen of oral and topical 5-ASA.[1] In treating rectal disease, rectal 5-ASA is preferred over rectal steroids.[1] A dose response has been described regarding the use of these agents for ulcerative colitis. For moderate disease, a dose of 4.8 g/day of mesalamine has been shown to be more efficacious than 2.4 g/day.[88]

Probiotic agents

Supplementation of the high-potency probiotic mixtures (eg, VSL#3[24, 89, 90] ) have been shown in some reports to reduce ulcerative colitis disease activity index scores in patients with mild to moderate relapsing ulcerative colitis who are being treated with 5-ASA. Studies in patients with Crohn disease have been much less promising.

The antibiotics metronidazole and ciprofloxacin are the most commonly used antibiotics in persons with inflammatory bowel disease (IBD). According to a systemic review, antituberculosis therapy, macrolides, fluoroquinolones, 5-nitroimidazoles, and rifaximin (alone or in combination) have not consistently been shown to induce remission in selective active Crohn disease and have rarely been shown to induce remission in ulcerative colitis.[91]

Antibiotics are used only sparingly in persons with ulcerative colitis because of limited treatment efficacy and because of an increased risk of developing antibiotic-associated pseudomembranous colitis. In persons with Crohn disease, antibiotics are used for various indications, most commonly for perianal disease, fistulas, and intra-abdominal inflammatory masses.

Antibiotics have potential adverse effects, including nausea, anorexia, diarrhea, and monilial (candidal) infections. Peripheral neuropathy can be observed in association with metronidazole and, when present, requires discontinuation of therapy with that drug. Finally, antibiotics can also increase the risk of Clostridium difficile colitis.

Corticosteroids are rapid-acting anti-inflammatory agents used in the treatment of inflammatory bowel disease (IBD). These drugs are indicated for acute flares of disease only and have no role in the maintenance of remission.

Corticosteroids may be administered by various 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).Corticosteroids are limited by their adverse effects, particularly with prolonged use.

The potential complications of corticosteroid use include fluid and electrolyte abnormalities, osteoporosis, avascular bone necrosis, peptic ulcers, cataracts, glaucoma, neurologic and endocrine dysfunctions, infectious complications, and occasional psychiatric disorders (including psychosis).

The consensus regarding treatment with these agents is that they should be tapered once remission has been induced. (see Surgical Intervention for information on Tapering corticosteroids in the postoperative setting). Corticosteroids do not have a role in maintaining remission.

Patients who are concerned about immunosuppressive therapies, including immunomodulators or anti–tumor necrosis factor (TNF) agents, should be educated about the potential greater incidence of complications occurring with long-term steroid use and with undertreated disease. Patients with prolonged use of steroids may also require ophthalmologic examination because of the risk of development of glaucoma and cataracts.

Periodic assessment of bone mineral density is recommended for patients taking steroids for more than 3 months.[60] Agents used for osteoporosis prevention and treatment (eg, the bisphosphonates) are useful for preventing the bone loss associated with corticosteroid use.

Intravenous corticosteroids

Intravenous corticosteroids are often used in patients who are severely ill and hospitalized; few data have been published on the optimum dosage of IV or oral corticosteroids. The upper end of dosing generally includes IV methylprednisolone at 20 mg every 8 hours or IV hydrocortisone at 100 mg every 8 hours. Typically, once a clinical response is observed (usually within 3-5 days), the dose of the IV corticosteroid can be tapered. Before hospital discharge, conversion to an oral corticosteroid is made with dosage tapering in an outpatient setting.

Oral corticosteroids

When oral corticosteroids are used, dosing is 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/day. For more severe flares, doses up to 60 mg/day may be used, but there are no supportive data. Once a clinical response is seen, the dose is tapered. Most patients who use oral corticosteroids can occasionally tolerate a relatively rapid taper after a response is achieved; a prolonged steroid taper is rarely necessary to prevent relapse. When the latter situation occurs, consider escalation of therapy with the use of alternative drugs (immune modifiers or anti-TNF therapy).

Budesonide (Entocort EC), a synthetic corticosteroid, is available for Crohn disease with ileal or ileocecal involvement.[71] Budesonide has extensive first-pass metabolism, which limits systemic adverse effects.[60] However, some absorption occurs over a prolonged period of exposure. Budesonide is also less effective than other standard glucocorticosteroids for the treatment of ileal Crohn disease and has not demonstrated efficacy in maintaining therapy beyond 12 months.[91]

According to the American Gastroenterological Association (AGA) guidelines, ileal-release preparations of budesonide are indicated for the treatment of patients with mild to moderate ileal and right-sided colonic Crohn disease.[60] A newer preparation of budensonide, budesonide MMX 9 mg once daily, has demonstrated efficacy in inducing remission in mild to moderate ulcerative colitis.[92]  

Topical corticosteroids

Topical corticosteroids are used in persons with distal colonic disease in a manner similar to that of 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. According to AGA guidelines, topical therapy with either hydrocortisone (grade A recommendation) or budesonide (grade B recommendation) is effective for distal colonic inflammation in patients with mild to moderate IBD.[60]

Patients with ulcerative colitis with predominantly distal disease may be treated with topical budesonide, a synthetic steroid which has local anti-inflammatory effects and limited systemic effects.[93] Although topical budesonide is effective, novel oral controlled-release formulations have been developed to enable treatment of the entire colon.[93]

Rectal corticosteroids

Cortenema, Cortifoam, and Anusol-HC suppositories, as well as Uceris (budesonide) foam are useful in treating distal disease (proctitis and proctosigmoiditis).

Immune modifiers have a slower onset of action (typically, a 2- to 3-month lag) and, consequently, are not used for induction of remission. However, these agents have shown effectiveness for their steroid-sparing action in persons with refractory disease; they are also used as primary treatment for fistulas and maintenance of remission in patients intolerant of or not responsive to aminosalicylates.

The immunomodulators 6-mercaptopurine (6-MP) and azathioprine (AZA) are used in patients with inflammatory bowel disease (IBD) in whom remission is difficult to maintain with the aminosalicylates alone, or they can be started in patients with more moderate to severe disease whereas steroids are used to induce remission. Calcineurin inhibitors such as cyclosporin A (CSA) and tacrolimus, as well as methotrexate (MTX), are also immune-modifying agents[1] ; CSA is almost exclusively limited to acute severe colitis, whereas tacrolimus has been used in both perianal Crohn disease and ulcerative colitis.[1]

Data on MTX support the use of intramuscular MTX in Crohn disease, but such data are lacking in ulcerative colitis. Methotrexate has been shown to be ineffective to treat ulcerative colitis.[94] Two clinical trials showed that AZA continuation in patients with ulcerative colitis prevented relapse, as compared to those who discontinued the medication. However, other trials have shown trends but no statistically significant benefit of AZA in ulcerative colitis.[95]

Thiopurine agents

The American Gastroenterological Association (AGA), in accordance with the US Food and Drug Administration (FDA), recommends that patients undergo assessment of the thiopurine methyltransferase (TPMT) genotype or phenotype before starting therapy with AZA or 6-MP.[60] Individuals who have low enzyme activity or are homozygous deficient in the TPMT mutation are at risk of very severe leukopenia, with potential septic complications, and may not be good candidates for therapy with these drugs.[60]

About 11% of individuals with heterozygous TPMT activity respond well to therapy but are prone to myelotoxicity, although this can be minimized with the use of lower doses. These patients, as well as those with wild-type TPMT activity, require monitoring for complications.[60]

Adverse effects and monitoring

Use of immune modifiers mandates monitoring of blood parameters; they can cause significant neutropenia or pancytopenia that warrants a dose reduction or discontinuation. Routine complete blood cell (CBC) counts with differentials and platelet counts are checked monthly, and liver function tests (LFTs) can be performed intermittently. After a year of stable dosing with no difficulties with blood counts (except the expected lymphopenia), the interval between blood count monitoring can be increased.

The cytopenic effect is typically dose dependent, although some patients are more sensitive than others. The typical AZA dose is 2-2.5 mg/kg/day, whereas the dose of 6-MP is 1-1.5 mg/kg/day. In some studies, blood levels of 6-thioguanine has been shown to guide dosing, but such tests offer little advantage, at a much greater cost for routine monitoring and dose adjustment, over CBC counts and liver function tests. In independent studies, metabolite levels have not shown any correlation with clinical efficacy, but they may help in monitoring compliance.

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 6-MP and azathioprine. These agents have been associated with a 2- to 4-fold greater incidence of lymphoma and an increase in nonmelanoma skin cancers, but curiously, there is a 3.5-fold decrease in colorectal carcinoma. A higher risk is present based on age.[96]

Janus kinase (JAK) inhibitor

The oral JAK inhibitor tofacitinib (Xeljanz) has been approved for the treatment of moderate to severe ulcerative colitis. Unpublished studies in the package insert show an induction of remission in 15% to 20% of patients within 8 weeks; at 1 year, maintenance of remission was demonstrated in approximately 35% of patients. The side-effect profile of tofacitinib is very similar to that of mercaptopurine and azathioprine, with the additional concern for elevations of cholesterol. Like the above immune modulators, tofacitinib is associated with an increase in malignancies. Strong inhibitors of CYP3A4 (eg, clarithromycin) can increase serum concentrations of tofacitinib, while inducers of CYP3A4 (eg, rifampin) can decrease serum concentrations of tofacitinib. Tofacitinib should not be used with other biologic agents or with immunosuppressant drugs such as azathioprine or mercaptopurine. Live vaccines should be avoided.

Anti-TNF-alpha monoclonal antibodies

Infliximab

Infliximab (Remicade) is an anti-TNF-alpha monoclonal antibody that is administered by infusion for the treatment of Crohn disease. Infliximab is FDA approved for both ulcerative colitis and Crohn disease; it appears to have a higher efficacy rate in Crohn disease. Infliximab is generally administered as 3 separate infusions of 5 mg/kg for the induction of remission of moderate to severe IBD at weeks 0, 2, and 6, followed by infusions every 8 weeks for maintenance of remission. Vande Casteele et al found that targeting the trough concentrations of infliximab to levels of 3-7 μg/mL results in a more efficient use of this agent in patients with IBD.[97]

A systemic review of the efficacy of biologic therapies in IBD confirmed that anti-TNF-alpha agents and natalizumab were effective in inducing remission of active Crohn disease.[98] For Crohn disease, the response rate may be as high as 80% (the usual response rate to natalizumab is about 60%), and the induction of remission rate is 30%-50% after a single dose; with multiple dosing, higher rates of remission are attained. For ulcerative colitis, the response rates may be as high as 50%-70%.

Patients with moderate to severe Crohn disease who have documented active inflammation, dependence on corticosteroids and an inability to taper these agents, or disease refractory to steroids are most likely to benefit from anti-TNF therapy.[99] Before anti-TNF agents are administered, screening should be done for coexistent infection with perianal and abdominal abscess (including Mycobacterium tuberculosis), and caution is advised if a patient is a carrier for the hepatitis B virus.[99]

Cessation of infliximab therapy, even in patients who are in prolonged remission, is associated with high rates of disease flare. In a study of 115 patients with Crohn disease who were treated for a minimum of 1 year with infliximab and an antimetabolite, who had at least 6 months of corticosteroid-free remission, and who subsequently stopped infliximab therapy, 45% (52/115) had a relapse at a median of 28 months’ follow-up, with a 1-year relapse rate of 43.9%.[100] Risk factors for relapse included male sex, leukocyte count greater than 6.0 × 109/L, C-reactive protein level of 5.0 mg/L or greater, and a fecal calprotectin level of 300 µg/g or more. Re-treatment with infliximab was successful in 88% of patients who had a relapse.[100]

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% may develop an abscess. The response can be maintained by continuing regular dosing (ie, every 8 weeks) after the induction dose.

Adverse effects of infliximab

The adverse effects of infliximab are uncommon but can include hypersensitivity and flulike symptoms; the latter can often be avoided by pretreatment with acetaminophen and diphenhydramine. There have been rare reports of lupus-like reactions and lymphoproliferative malignancies, although whether the malignancies are related to the drug or to the underlying disease process remains uncertain; they are more likely to be due to the concomitant use of immunomodulators.

Adalimumab, certolizumab,golimumab

Other anti-TNF agents include adalimumab (Humira), which is given by subcutaneous (SC) injection every 2 weeks after a loading dose of 6 injections over 4 weeks[101] ; certolizumab pegol (Cimzia), which is given by SC injection every 4 weeks (only approved for Crohn diesase); and golimumab (Simponi), which is given by subcutaneous (SC) injection every 4 weeks after two loading doses (only approved for ulcerative colitis).

Natalizumab

Natalizumab (Tysabri), an agent aimed at preventing the accumulation of lymphocytes in the diseased bowel by blocking the effects of both α4β7 integrin (gut specific) and α4β1 integrin (CNS specific), has been approved by the FDA, but it is only available through a restricted distribution program. Natalizumab is an intravenous medication that has shown efficacy in Crohn disease, but there have been three reports of progressive multifocal leukoencephalopathy, a potentially fatal opportunistic viral infection. Risk is typically apparent in those with prior immunosuppressant exposure or with a duration of infusion for longer than 2 years.[102] Patients in whom this agent is used should first be tested for John Cunningham (JC) virus, and they should be periodically tested for this during treatment.

Vedolizumab

Vedolizumab (Entyvio), another integrin antagonist, is approved for Crohn disease and ulcerative colitis.[103] It is specific for α4β7 integrin. Approval was based on several phase 3 clinical trials that simultaneously evaluated vedolizumab for both ulcerative colitis and Crohn disease and involved patients in nearly 40 countries. Among patients with Crohn disease who had a response to induction therapy with vedolizumab, 39.0% of those assigned to vedolizumab every 8 weeks were in clinical remission at week 52, compared with 21.6% assigned to placebo.

In patients with ulcerative colitis who had a response to vedolizumab induction, 41.8% continued to be in clinical remission at 52 weeks compared with 15.9% of patient taking placebo.

Ustekinemab

Ustekinemab (Stelara) is an antibody that blocks IL-12 and IL-23. It is used in patients with moderate to severe Crohn disease after failure with treatment using other agents. In clinical trials ustekinemab induced a clinical response of 34% by week 6 and remission in 21% by week 8 in patients with previously failed anti-TNF treatment. Results were better in patients who had treatment failure with immunosuppressants and corticosteroids, with response of 56% and remission and 40% at the same time periods.[104] Remission was achieved in 53% of patients at 44 weeks. Adverse effects include the common infectious agents seen with other immune inhibitors, as well as occasional cases of a noninfectious interstitial or eosinophilic pneumonia.[104] Use of ustekinemab has been demonstrated to decrease hospitalization and requirements for surgery.[105]

Clinical trial agents tend to be disease-specific (ie, an agent works for Crohn disease but not for ulcerative colitis, or vice versa). These include anti-adhesion molecules and anticytokine therapies.[1] In Crohn disease, additional agents include T-cell marker therapies and mesenchymal stem cells; in ulcerative colitis, anti-inflammatory proteins have also been studied.[1]

Patients should be admitted to the hospital if surgical intervention is anticipated or if their condition does not respond to outpatient treatment, if they are dehydrated, or if they have uncontrolled pain or diarrhea. Start IV hydration. If indicated, obtain an abdominal flat-plate image to exclude obstruction or megacolon. If the patient is nauseous or vomiting or has evidence of obstruction or megacolon, nasogastric intubation may be helpful. Consider early consultation with a surgeon in the setting of severe colitis or bowel obstruction.

If the patient has active colitis, send a stool sample for Clostridium difficile toxin assay and routine microbiologic culture. Laboratory studies to be considered include a complete blood cell (CBC) count with differential; erythrocyte sedimentation rate; levels of albumin, glucose, calcium, magnesium, phosphate, and BUN/creatinine; electrolyte status; and a pregnancy test in females of childbearing age.

Patients with acute severe colitis are treated with IV corticosteroids. Antibiotics are not routinely used but may be indicated in select patients. Electrolyte correction and, potentially, blood transfusion can be administered if indicated on the basis of laboratory findings. The IBD Sydney Organisation and the Australian Inflammatory Bowel Diseases Consensus Group recommendations include the following for patients with acute severe ulcerative colitis[106] :

• Hospitalization
• Unprepared flexible sigmoidoscopy to assess severity and exclude cytomegalovirus colitis
• Intravenous thromboembolism prophylaxis
• IV hydrocortisone 100 mg tid/qid and close monitoring
• If insufficient response by day 3, initiate rescue therapy with infliximab or cyclosporine
• If no response by day 7 of rescue therapy or if clinical deterioration occurs, consider colectomy

Author information

Patients with suspected bowel obstruction should be given nothing by mouth (NPO), except for medications. Most patients with ulcerative colitis may maintain a regular (or low-fiber) diet, unless megacolon is present or surgery is being contemplated.

Although a colonoscopic evaluation may also be contemplated, consider the increased risk of perforation in persons with acute colitis. Assess and correct the posthydration CBC count and electrolyte levels, as indicated. Depending on the response to the initial interventions, advancement of the diet may be considered.

By the second or third hospital day, most patients should be showing clear evidence of clinical improvement with IV steroids. Assess the electrolyte status if IV fluids are still being administered. Consider advancement of the diet. The corticosteroid dose can be tapered. If the patient is not improving, consider other treatment options; these may include hyperalimentation, other medical therapies, surgical intervention, or transfer to a tertiary care facility.

Continue to advance the diet, as tolerated, on hospital day 4. Continue the switch to oral medications. Many patients with a flare of Crohn disease or ulcerative colitis may be discharged by this time (occasionally even sooner); some may require another day of IV therapy.

If no progress has been made in the patient's condition since admission, additional treatments are necessary, including surgery (see Surgical Intervention, below) or more aggressive medical treatments. Again, consider transfer to a tertiary care facility. If the patient has been unable to tolerate an oral diet, initiate hyperalimentation and/or reconsider surgical intervention.

Most patients should be able to be discharged on or before the fifth hospital day. A regular diet should be tolerated, with some restrictions if strictures are present. An ESR level may be obtained to assist in future disease assessment, but its result is unlikely to alter current management.

Discharge the patient on oral medications, with appropriate follow-up as an outpatient, typically within a few weeks.

Aggressive therapy should be considered early in the management of patients with difficult or refractory inflammatory bowel disease (IBD). This approach uses immune modifiers and/or anti-tumor necrosis factor (TNF) agents earlier in the treatment of the IBD patient (see Overview of Stepwise Therapy).

Immune modifiers

If it is difficult to reduce the dose of corticosteroids, if the disease is refractory to corticosteroid therapy, or if patients are corticosteroid dependent, the use of immune modifiers 6-MP or azathioprine should be used. The typical dosing of 6-MP or azathioprine is 1-2 mg/kg/day. At higher doses, closer monitoring is warranted, including measurement of the thiopurine methyltransferase (TPMT) enzyme; obtaining 6-TG and 6-MMP levels; doing a CBC; and determining liver, kidney, pancreatic functions.

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 immune modifiers may be dose dependent; monitoring of blood counts is required to protect the patient from the hematologic toxicity associated with these agents.

Monoclonal antibodies

An alternative agent is infliximab, a monoclonal antibody against TNF-alpha. The FDA approved infliximab for the treatment of Crohn disease in July 2005 and for the treatment of ulcerative colitis in August 2005. To be effective for maintaining remission, this medication is generally administered in 3 doses of 5 mg/kg over 6 weeks (at weeks 0, 2, and 6), with maintenance doses every 8 weeks.

A randomized, controlled trial demonstrated that adalimumab can induce remission in patients with Crohn disease that is refractory to treatment with infliximab.[107] This therapy led to mucosal healing and a reduction in hospitalization and surgical intervention. The rate of serious infection was 2%-4%, which was no greater than the rate in patients receiving placebo.[107]

Note that in September 2011, the US Food and Drug Administration (FDA) issued a notification regarding updates to the Black Box Warning for the entire class of tumor necrosis factor (TNF)-alpha blockers.[108] The advisory included the risk of Legionella and Listeria infections, as well as consistency of the information in the Boxed Warning and the Warnings and Precautions sections regarding the risk of serious infections and the associated disease-causing organisms.[108]

Smoking cessation

A lifestyle change that may benefit patients with Crohn disease is smoking cessation. Tobacco use has been linked to increases in the number and severity of flares of Crohn disease, and smoking cessation alone is occasionally sufficient to achieve remission of refractory Crohn disease.

The top-down approach (ie, earlier use of immunomodulators and biologics) includes the need for steroid-enhanced mucosal healing and achieves an earlier and more complete remission than step-up therapy. A general rule of thumb is that once remission is achieved, the medications used to achieve remission should be continued, except steroids, which should be tapered off, because they have no role in maintaining remission[109] and their use may lead to debilitating illness, particularly after long-term use. Home infusion of IV hyperalimentation is becoming increasingly available for those rare patients with Crohn disease in whom prolonged bowel rest is necessary (eg, cases of severe fistulizing disease). Patients with a short bowel may require prolonged hyperalimentation.

Diseases of the lung (primarily chronic obstructive pulmonary disease [COPD]) in Crohn disease are common comorbidities, primarily because of smoking; however, cardiovascular disease, although common in the older patient, does not have any direct link with IBD. IBD may also be a factor in the treatment of prostate cancer (to avoid rectal injury), but is generally not a factor in breast cancer.

Most of the concerns regarding the interaction of other disease processes and IBD revolve around the medications used to treat various conditions; therefore, the physician treating the older patient must continually be aware of the potential for medication interactions. Although the advent of electronic medical records makes it easier to check for such interactions, it remains up to the physician to determine which interactions are clinically significant.

Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used for cardiovascular and rheumatologic disorders; these agents and cyclooxygenase type 2 (COX-2) inhibitors are known to cause flares in IBD (not universally, but often enough to be clinically important).[110]

Most aminosalicylates do not have substantial interactions with non-IBD agents. The side effects of corticosteroids may be exacerbated in the older population, particularly in those with diabetes, accelerated bone loss, and cataract formation. The anti-TNF agents are generally contraindicated in patients with congestive heart failure (CHF) but can be used once the CHF is controlled. The immune-modifying agents have a clinically important interaction with allopurinol, as allopurinol tremendously increases the serum levels of mercaptopurine and azathioprine to the point where these agents can quickly manifest toxicity.

Ulcerative colitis is a surgically curable disease. However, Crohn disease can involve any segment of the gastrointestinal tract from the mouth to the anus; surgical resection is not curative, as recurrence is the norm. In addition, repeated need for surgery and bowel resection may result in short gut syndrome and dependence on parenteral nutrition.

Ulcerative colitis

Consider surgical intervention for patients in whom medical therapy fails, as it is curative for colonic disease, and for those with colonic dysplasia or malignancy.[3] Approximately 25%-30% of patients may require operative management.[1] The indications for colectomy are the following:

• Intractable inflammation

• Precancerous changes (high-grade dysplasia or proven multicentric, low-grade dysplasia confirmed by 2 expert pathologists)

• Intolerance to medical therapy

• Toxic megacolon

• Perforation

The surgical options for ulcerative colitis vary. Currently, the two  most common choices are proctocolectomy with ileostomy and total proctocolectomy with ileal pouch/anal anastomosis (IPAA).

The most common operation performed to treat ulcerative colitis 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 complication of this procedure is postoperative development of acute or chronic pouchitis. Very rarely, particularly in those with a preoperative diagnosis of indeterminate colitis, Crohn disease of the pouch may develop. IPAA offers an excellent option for younger patients with ulcerative colitis and those with concerns with body image. However, IPAA is also associated with a substantial rate of infertility (due to pelvic dissection).

Elective surgery can sometimes be performed laparoscopically. For fulminant colitis, the surgical procedure of choice consists of a subtotal colectomy with end ileostomy and creation of a Hartmann pouch.

A population-based study by de Silva et al showed that the primary predictors of severe postoperative complications are age and multiple comorbidities. Furthermore, the worst outcomes occurred when surgery was performed 14 or more days after hospital admission under emergency conditions in patients who had no response to medical treatment.[111]

For patients who plan to become pregnant, a subtotal colectomy is preferred to avoid the 48% decrease in fecundity with the IPAA procedure.

Crohn disease

Surgery for Crohn disease is most commonly performed in patients with complications of the disease (ie, strictures, fistulas). Approximately 70% of patients with ileocolonic Crohn disease require surgical intervention.[1]  In general, conservative resection is advocated (including potential stricturoplasty, as opposed to resective surgery) to preserve bowel length in case additional surgery is needed in the future.[4]

Although surgery is an important treatment option for Crohn disease, patients should be aware that it is not curative and that disease recurrence after surgery is the rule. Disease recurrence generally mimics the original disease pattern at the surgical anastomosis. Endoscopic evidence of recurrent inflammation is present in 93% of patients 1 year after surgery.

In segmental resection, a segment of intestine with active Crohn disease or a stricture is resected, and the remaining bowel is reanastomosed. In general, as little bowel as possible is resected, because the risk of disease recurrence is significant.[112]

In patients with a very short cicatrix 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 horizontal 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% rate of septic complications (2%-3% of patients require reoperation); this may 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. In patients with severe perianal fistulas, a diverting ileostomy or colostomy is an option. In this procedure, the distal colon is defunctionalized and a temporary ileostomy or colostomy is created. The ileostomy or colostomy is then taken down after 6 months or longer. Many patients who pursue this option choose to forego reanastomosis after placement of 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 fistulas are generally resected, although recurrence is common. Postoperative medical therapy often prevents recurrence, although data are lacking regarding efficacy. A meta-analysis of nine randomized trials suggested that 5-ASA preparations provide a very modest benefit for maintenance.[87] The preferred program of prevention varies between immunomodulators and biologic therapy.

Contraception in the perioperative setting

Before undergoing major elective surgery, women with IBD should stop using combined oral contraception for a minimum of 4 weeks before the surgery, and alternative methods of contraception should be used.[113] Advise each patient when oral contraception can be restarted.

If a woman with IBD is considering sterilization, counsel her and her partner regarding alternative contraceptive methods (eg, long-acting reversible contraception, vasectomy). Note that in women with a history of pelvic or abdominal surgery, laparoscopic sterilization may not be considered an appropriate contraceptive method.[113]

Tapering corticosteroids in the postoperative setting

If possible, the use of corticosteroids should be minimized before surgery. Poor postoperative outcomes have been associated with prednisone doses greater than 30 mg/day.[1]

The World Gastroenterology Organization (WGO) recommendations for tapering corticosteroids depend on the duration of corticosteroid use, as follows[1] :

• Less than 1 month: abrupt cessation postoperatively is allowed

• 1-3 months, with a dose of 20 mg/day or greater: taper by 5 mg/day per week after surgery

• 3-6 months: taper by 2.5 mg/day per week

• More than 6 months: taper slowly, at 1 mg/wk or less once the dose is 10 mg/day

No known dietary or lifestyle changes prevent inflammatory bowel disease (IBD), and no known dietary substances have been consistently shown to cause activation of IBD. Tobacco use has been linked to increases in the number and severity of flares of Crohn disease, and smoking cessation can help achieve remission in patients with Crohn disease. Lactose intolerance is common in persons with Crohn disease or ulcerative colitis and can mimic symptoms of IBD.

Diet

Although diet has been well demonstrated to have little or no influence on inflammatory activity in persons with ulcerative colitis, it may influence symptoms. For this reason, patients are often advised to make a variety of dietary modifications, especially adaptation of a low-residue diet, although the evidence does not support a low-residue diet as beneficial in the treatment of ulcerative colitis. Such a diet, however, might decrease the frequency of bowel movements.

Unlike in patients with ulcerative colitis, diet can influence inflammatory activity in persons with Crohn disease. Nothing by mouth (NPO) can hasten the reduction of inflammation, as may the use of a liquid or predigested formula for enteral feeding. Although a meta-analysis in 1995 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.

In a prospective study of 56 patients with quiescent Crohn disease on maintenance infliximab therapy (5 mg/kg, q 8 wk), Yamamoto et al found that concomitant enteral nutrition did not significantly improve the maintenance rate of clinical remission in patients with Crohn disease.[114] In the study, 32 patients received concomitant enteral nutrition (elemental diet infusion at night; a low-fat diet during the day), and 24 patients did not receive enteral nutrition and had no dietary restrictions.[114]

Multivitamin supplementation is recommended in patients with IBD.[1] For patients with vitamins B12 or vitamin D deficiency, supplementation of these vitamins should be given. The results of 2 studies suggest that the link between vitamin D and IBD may be of particular importance.[115, 116, 117]

In one of the studies, 3217 patients with Crohn disease or ulcerative colitis and low vitamin D levels had an increased risk of surgery and hospitalization.[116] Crohn disease patients with 25-hydroxyvitamin D levels lower than 20 ng/ml had an increased risk of surgery and IBD-related hospitalization than those with levels higher than 30 ng/ml. Similar estimates were seen for ulcerative colitis. In the other study, Crohn disease patients who took 2000 IU of vitamin D daily for 3 months gained muscle strength and improved quality of life.[117]

Patients receiving steroid therapy should receive vitamin D and calcium supplementation. Parenteral iron (IM weekly or IV) may be used in patients with chronic iron-deficiency anemia who are unable to tolerate the oral formulation.[1]

Activity

Generally, patients do not need to limit activity when IBD is quiescent. During disease flares, physical activity is limited only by the extent of fatigue and the abdominal pain or diarrhea the patient is experiencing. When abdominal pain persists beyond medical therapy­-induced resolution of the active inflammation, other causes of pain must be considered, including abscess, stricture, nephrolithiasis, IBS, 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. Dehydration may be an issue, often requiring IV hydration or the use of oral rehydration solutions.

Moderate to vigorous physical activity for as long as 12 weeks has been shown to improve symptom scores and many specific quality-of-life dimensions, including energy, sleep, emotion, and physical functioning.[118] This degree of activity was defined as 20-60 minutes of intense exercise 3-5 days per week. The improvements occur despite lack of change in body weight, oral-anal transit time, bowel movements per week, or stool consistency. This study also highlights that symptomatic deterioration is more likely in physically inactive individuals.

Clinicians are advised to review the prescribing information for medications in women who are attempting to conceive, are pregnant, or are breastfeeding.[113] All of the aminosalicylates (sulfasalazine, mesalamine, olsalazine, balsalazide) and corticosteroids appear to be safe in women in all phases of fertility, pregnancy, and lactation. Men should avoid sulfasalazine during periods when they and their mates are attempting to become pregnant.

Reproduction

In women with IBD, fertility is normal or only minimally impaired. The majority of case reports and small series show no adverse outcomes of pregnancies in patients with IBD who are taking immune modifiers. Birth defects have not been reported at a rate higher than that of the general population. If a patient is taking an immune modifier and becomes pregnant, current data support the consensus that continuing the immune modifier throughout the pregnancy is the safest course of action for both the mother and the fetus.[119]

The only agent that is contraindicated in women considering pregnancy is methotrexate (MTX), which has demonstrated teratogenic effects. MTX should be discontinued 3 months prior to planned conception.

For men with IBD, sulfasalazine can decrease sperm counts and sperm motility, causing a functional azoospermia; the other aminosalicylates do not have this effect. The sperm effects are reversible by discontinuing the sulfasalazine. No firm evidence indicates that the use of immune modifiers in the father leads to increased birth defects, although this has been suggested in one Spanish study.

Pregnancy

Most infants born to parents with IBD are healthy. The prevalence of prematurity, stillbirth, and birth defects is similar to that in the general population. The prevalence of spontaneous abortion is slightly higher in patients with IBD (12.2%) than in the general population (9.9%). Previous proctocolectomy or ileostomy is not an impediment to successful pregnancy; however, controversy exists regarding the type of delivery (cesarean or vaginal) that is most appropriate when a woman has had ileal pouch/anal anastomosis surgery.[113] Women who have undergone such a procedure should consult with their obstetricians and gastroenterologists.[113]

The aminosalicylates, including sulfasalazine, are safe during pregnancy. Folate supplements should be taken. Corticosteroids are also safe, but if high doses are needed near the end of the pregnancy, monitor the infant for signs of adrenal suppression. Continuation of immune modifiers (ie, 6-MP, azathioprine) appears to be safe in pregnancy,[110, 120] as well as metronidazole (Flagyl) and ciprofloxacin (Cipro).

It is considered safe to continue TNF-alpha inhibitors during pregnancy (FDA category B), but concerns have been raised about high levels of maternally administered anti-TNF agents being found in the fetal circulation.[121, 122, 123, 124] There is no documentation of any fetal harm with the use of any of the anti-TNF agents during pregnancy. Certolizumab does not cross the placenta.[121, 122, 123, 124]

In a retrospective, multicenter study, treatment of IBD with thiopurines and anti-TNF-alpha drugs did not increase the risk of complications during pregnancy or neonatal complications.[125] The rate of unfavorable Global Pregnancy Outcome and the rate of neonatal complications were lower in pregnant women treated with thiopurines alone than in those exposed to anti-TNF-alpha drugs or those not exposed to either group of agents.

Effective contraception must be used with certain drug therapy.[113] Both male and female partners receiving methotrexate should use effective contraception for a minimum of 3 months following treatment with this agent.

Other concerns that have been raised include the potential reduction of fertility with total abdominal colectomy with ileal pouch/anal anastomosis (IPAA) surgery (primarily because of adhesions).[126, 127] This possibility can likely be reduced by using a laparoscopic approach.[128]

According to the Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit in the United Kingdom, women with IBD should plan for conception when their disease is stable and well controlled.[113] Male and female patients require prepregnancy counseling to help them with the best management of their condition before conception occurs.[113]

Contraception precautions

Advise women who have Crohn disease with small bowel disease and malabsorption that oral contraception may have reduced effectiveness.[113] Additional contraception is recommended for women on combined hormonal contraception who are also receiving antibiotic regimens for less than 3 weeks, as well as for 7 weeks following cessation of the antibiotic. Note that certain medications prescribed for rectal or genital use may adversely affect the efficacy of condoms.[113] In addition, consider whether contraceptive agents may have an effect on diseases associated with IBD (eg, osteoporosis, venous thromboembolism, primary sclerosing cholangitis).

In women with IBD who will undergo major elective surgery, combined oral contraception should be discontinued for a minimum of 4 weeks before the procedure.[113] These women should use alternative contraception.

Breastfeeding

Sulfasalazine metabolites can be detected in the breast milk. Low concentrations of mesalamine and higher concentrations of its metabolites can also be detected in breast milk, but the significance of this is unknown. In addition, corticosteroids can also be detected in breast milk.

Immune modifiers are excreted in breast milk and should be considered only on a case-by-case basis; either the immune modifier should be discontinued or the infant should be bottle fed.

Antibiotics (metronidazole [Flagyl], ciprofloxacin [Cipro]) should generally be avoided during lactation, because they are excreted in breast milk; either breastfeeding or the drugs should be discontinued. These agents are probably safe for fertility and during pregnancy.

Anti-TNF agents (ie, infliximab, adalimumab) traverse the placenta, whereas certolizumab does not, because of the absence of the Fc fragment. They are found in the cord blood but not in breast milk.

Although small amounts of the topical agents are absorbed and thus may be excreted in breast milk, the concentrations are much lower than those with the oral forms of the same medications. These medications are probably reasonably safe in breastfeeding.

In patients with severe inflammatory bowel disease (IBD), with complications such as strictures or fistulas, and with flares requiring hospitalization, consultation with a surgeon is often required. Early consultation with a surgeon is particularly important in patients with severe disease or extraluminal complications, because delayed surgery can be associated with poorer outcomes.

An interventional radiologist may be consulted when percutaneous drainage of an abscess is desired. Specialty consultation is best for managing extracolonic manifestations (ie, uveitis, arthritis, dermatitis, sclerosing cholangitis). Also consider arranging consultations for patients with a registered dietitian and a stoma nurse, if indicated.

 In September 2019, the British Society of Gastroenterology released consensus guidelines on the management of inflammatory bowel disease.[129]  In November 2019, the European Crohn's and Colitis Organisation (ECCO) published separate guidelines on the medical and surgical management of Crohn disease.[130, 131]

In January 2020, the American Gastroenterological Association (AGA) released their recommendations on the medical management of adult outpatients with moderate to severe ulcerative colitis (UC) and hospitalized adult patients with acute severe UC (ASUC).[132]  These guidelines are summarized below.

Consensus guidelines on the management of inflammatory bowel disease in adults were released in September 2019 by the British Society of Gastroenterology.[129]

Ulcerative Colitis

In circumstances in which ulcerative colitis is diagnosed by sigmoidoscopy, the recommended procedure is a full ileocolonoscopy to delineate the extent of disease and the severity of inflammation, as well as to exclude Crohn disease.

The target of medical therapy for ulcerative colitis is symptomatic remission combined with mucosal healing.

For the initial treatment of active mild-to-moderate ulcerative colitis with 5-aminosalicylic acid (5-ASA), oral 5-ASA at 2-3 g/day is recommended; 5-ASA enemas are also recommended, rather than oral treatment alone. All patients treated with 5-ASA should undergo monitoring for nephrotoxicity, with baseline renal function testing repeated after 2-3 months, and then annually thereafter.

For corticosteroid treatment in mild-to-moderate ulcerative colitis in patients in whom 5-ASA therapy has failed or is not tolerated, oral prednisolone is recommended. Also recommended is topically acting oral corticosteroids (eg, budesonide MMX).

For corticosteroid treatment in moderate-to-severe ulcerative colitis, oral corticosteroids (eg, prednisolone at 40 mg/d with weaning over 6-8 wk) is recommended.

5-ASA is recommended as standard maintenance medical therapy. Considerations for the choice of formulation include patient preference, likelihood of adherence, and cost. Once-daily dosing is considered effective and may help improve adherence.

In cases of 5-ASA treatment failure, options to consider include thiopurine, anti–tumor necrosis factor therapy, vedolizumab, or tofacitinib. Considerations for choice of drug include clinical factors, patient choice, cost, likelihood of adherence, and local infusion capacity.

Regarding surgical management for ulcerative colitis, it is generally suggested that surgical resection of the colon and rectum should be offered to those patients with chronic active symptoms that are refractory to optimal medical therapy.

Proctitis in ulcerative colitis

The recommended treatment for mild or moderately active ulcerative proctitis is a 1-g 5-ASA suppository.

If patients do not respond to or are intolerant of 5-ASA suppositories and oral 5-ASA, they can be switched to corticosteroid suppositories.

In refractory proctitis, it is suggested that patients may require treatment with corticosteroids, immunomodulators, and/or biological therapy.

Acute severe ulcerative colitis

The recommended treatment for acute severe ulcerative colitis is high-dose intravenous corticosteroids (eg, methylprednisolone at 60 mg/day or hydrocortisone at 100 mg q6h), along with prophylactic low-molecular-weight heparin. Do not delay corticosteroid treatment for patients with suspected acute severe ulcerative colitis pending results of stool cultures and Clostridium difficile assay.

If patients do not respond by day 3, rescue therapy with intravenous infliximab or cyclosporine should be offered for patients in whom previous thiopurine therapy has failed. If patients treated with infliximab have not responded sufficiently to a 5-mg/kg dose 3-5 days after the first infusion, offer an accelerated induction regimen after a colorectal surgical consult to determine if an emergency colectomy is required.

In patients with acute severe ulcerative colitis who do not respond to rescue therapy with infliximab or cyclosporine within 7 days, or in those who deteriorate or experience complications (including severe hemorrhage, perforation, or toxic megacolon) before 7 days, subtotal colectomy and ileostomy, with preservation of the rectum, are required. Note that a delay in surgery increases the risk of surgical complications; therefore, early referral and direct involvement with specialist colorectal surgical and stoma care teams is required.

Pouches and pouchitis

The recommend first-line treatment for acute pouchitis is a 2-week course of ciprofloxacin or metronidazole. Ciprofloxacin may be better tolerated and more effective than metronidazole.

The suggested treatment for chronic pouchitis is combination antibiotic therapy (ciprofloxacin, metronidazole, tinidazole, rifaximin), oral budesonide, or oral beclomethasone.

In chronic refractory pouchitis that does not respond to antibiotics or locally acting corticosteroids, reassess the patient and consider other factors. If other factors can be excluded, the suggested next step is to offer patients biologics.

Crohn Disease

Diagnosis

Diagnostic procedures for suspected Crohn disease include ileocolonoscopy with segmental colonic and ileal biopsies, to investigate for microscopic disease, and imaging to assess the location and extent of small bowel disease.

Conventional barium fluoroscopic and nuclear medicine techniques have largely been replaced by cross-sectional imaging (ie, MRI, CT, and ultrasonography). The latter techniques have the advantage of evaluating both luminal and extraluminal disease. To avoid exposing the patient to ionizing radiation, an emphasis should be placed on magnetic resonance enterography and ultrasonography.

Capsule endoscopy may provide better sensitivity for mucosal small bowel Crohn disease compared with radiological imaging techniques, and, generally, capsule endoscopy can be performed in situations in which inflammatory small bowel disease is still suspected despite normal or equivocal cross-sectional imaging findings.

Treatment

For remission-induction treatment for mild-to-moderate ileocecal Crohn disease, the recommended therapy is ileal-release budesonide at 9 mg once daily for 8 weeks.

For remission-induction treatment for mild-to-moderate Crohn colitis, the recommended therapy is an 8-week course of systemic corticosteroids.

The suggested surgical treatment for localized ileocecal Crohn disease in patients (1) in whom initial medical therapy failed, (2) who relapsed after initial medical therapy, or (3) who prefer surgery over continued medical treatment is laparoscopic resection.

For moderate-to-severe uncomplicated luminal ileocolonic Crohn disease, the recommended treatment is systemic corticosteroids initially, but if patients have extensive disease or other poor prognostic features, consideration should be given to early introduction of biological therapy.

Avoid systemic or locally acting corticosteroids for maintenance treatment in ileocolonic Crohn disease, owing to toxicity and lack of efficacy.

For moderate-to-severe Crohn disease that is responsive to prednisolone, consider early introduction of maintenance therapy with thiopurines or methotrexate in order to minimize the risk of disease flare when prednisolone is withdrawn.

Mesalazine is not recommended for induction or maintenance of remission in Crohn disease.

Biologic therapy is recommended in patients with disease refractory to immunomodulator therapy despite dose optimization. Considerations in the drug choice (ie, anti–tumor necrosis factor therapy, ustekinumab, vedolizumab) include patient preference, cost, likelihood of adherence, safety data, and response speed to the drug.

Leucocyte apheresis should not be used for active Crohn disease, owing to lack of efficacy.

Perianal Crohn disease

The recommend procedure for assessment of perianal disease is pelvic MRI; it is an important adjunct to the clinical assessment and examination under anesthesia for evaluating the possibility of fistulizing perianal Crohn disease. Endoanal ultrasonography may also be used depending on local availability and expertise.

Setons should be placed in order to prevent reaccumulation of perianal sepsis in fistulizing Crohn disease.

Post surgery, the recommended first-line biological treatment for complex perianal fistulas is infliximab; this should be started immediately upon achieving adequate drainage of sepsis.

Owing to poor long-term results, particularly for patients with complex disease and/or ongoing disease activity, surgical options for perianal Crohn disease fistulas (eg, advancement flap, ligation of intersphincteric fistula tract, infill procedures) should only be offered to selected patients after counseling.

Postsurgical management of Crohn disease

If patients have recurrent symptoms after surgical resection for Crohn disease but no evidence of active inflammation, consider alternate diagnoses, including bacterial overgrowth, adhesions, bile salt malabsorption, functional bowel disorders, or fibrostenotic or anastomotic strictures.

Actively encourage all patients to quit smoking after intestinal resection for Crohn disease.

Mesalazine is not recommended to prevent recurrence after ileocolonic Crohn disease resection.

In November 2019, the European Crohn's and Colitis Organisation (ECCO) published its guidelines on the medical management of Crohn disease (CD).[130]

Induction of Remission

Mild-to-moderate disease

Budesonide is recommended for the induction of clinical remission in patients with active mild-to-moderate CD limited to the ileum and/or ascending colon (strong recommendation).

ECCO suggests against using 5-aminosalicylic acid (5-ASA) for induction of remission of CD (weak recommendation).

Moderate-to-severe disease

In patients with active, moderate-to-severe CD, ECCO suggests using systemic corticosteroids for the induction of clinical response and remission (weak recommendation).

The use of tumor necrosis factor (TNF) inhibitors [infliximab, adalimumab, and certolizumab pegol] is recommended to induce remission in patients with moderate-to-severe CD refractory to conventional therapy (strong recommendation).

ECCO suggests against the use of thiopurines as monotherapy for the induction of remission of moderate-to-severe luminal (weak recommendation). ECCO also suggests against the combination of adalimumab and thiopurines over adalimumab alone to achieve clinical remission and response (weak recommendation).

Combination therapy with a thiopurine is recommended when starting infliximab to induce remission in patients with moderate-to-severe CD, who have had an inadequate response to conventional therapy (strong recommendation).

Ustekinumab is recommended for induction of remission in patients with moderate-to-severe CD with inadequate response to conventional therapy and/or to anti-TNF therapy (strong recommendation).

Vedolizumab is recommended for induction of response and remission in patients with moderate-to-severe CD with inadequate response to conventional therapy and/or to anti-TNF therapy (strong recommendation).

ECCO equally suggests the use of either ustekinumab or vedolizumab for the treatment of moderate-to-severe active luminal CD in patients with previously failed anti-TNF therapy (weak recommendation).

Maintenance of Remission

ECCO recommends against the use of oral 5-ASA for maintenance of medically induced remission in patients with CD (strong recommendation).

Thiopurines are recommended for the maintenance of remission in patients with steroid-dependent CD (strong recommendation).

The early introduction of thiopurine therapy is not recommended in patients with newly diagnosed CD for maintaining remission (weak recommendation).

Parenteral methotrexate is recommended for the maintenance of remission in patients with steroid-dependent CD (weak recommendation).

Patients with CD who achieved remission with anti-TNF agents should use the same treatment for maintenance therapy (strong recommendation).

Vedolizumab is recommended for maintaining clinical remission in patients with moderate-to-severe CD who achieved remission with vedolizumab (strong recommendation).

Ustekinumab is recommended to maintain clinical remission in patients with CD who achieved remission with ustekinumab (strong recommendation).

Maintenance strategies

For CD patients in clinical remission under anti-TNF treatment, there is currently insufficient evidence to recommend for or against the use of proactive therapeutic drug monitoring to improve clinical outcomes as compared to routine care (weak recommendation).

For CD patients who have lost response to an anti-TNF agent, there is currently insufficient evidence to recommend for or against the use of reactive therapeutic drug monitoring to improve clinical outcomes (weak recommendation).

Continuation of thiopurines is suggested in CD patients in long-term remission on thiopurine maintenance therapy, as the risk of relapse is higher when the treatment is discontinued (weak recommendation).

For patients with CD who have achieved long-term remission with the combination of infliximab and immunosuppressants, ECCO suggests monotherapy with infliximab (weak recommendation).

For patients with CD who have achieved long-term remission with the combination of adalimumab and immunosuppressants, ECCO suggests monotherapy with adalimumab (weak recommendation).

There is insufficient evidence to recommend either continuation or withdrawal of anti-TNF therapy in CD patients after achieving long-term remission. Therefore, individualize the decision to continue anti-TNF therapy and always discuss potential consequences (risks/benefits) with the patient.

Perianal Fistulizing Disease

Therapeutic management of complex perianal fistulizing disease

Infliximab is recommended for the induction and maintenance of remission in complex perianal fistulae in CD (strong recommendation).

It is suggested that adalimumab may be used for induction and maintenance of remission in complex perianal fistulae in CD (weak recommendation).

In CD with complex perianal fistula, there is insufficient evidence regarding the effect of adding immunomodulators to anti-TNF on fistula healing (weak recommendation).

In CD with complex perianal fistula, there is insufficient evidence to recommend the use of either ustekinumab or vedolizumab for fistula healing (weak recommendations).

Antibiotic therapy alone is not suggested for fistula closure in patients with CD and complex perianal fistulae (weak recommendation).

Thiopurine monotherapy (azathioprine, mercaptopurine) is not suggested for fistula closure in patients with CD with complex perianal fistulae (weak recommendation).

In November 2019, the European Crohn's and Colitis Organisation (ECCO) published its guidelines on the surgical management of Crohn disease (CD).[131]

Complex Perianal Fistula

Medical therapy and surgical drainage

No prospective study directly compares medical or surgical treatment of complex perianal CD fistulae either in isolation or in combination with both modalities. Observational studies support a combined medical/surgical approach to control sepsis and luminal activity.

Surgical techniques

For patients with CD and complex perianal fistulae:

• Advancement flaps are a therapeutic option.

• Ligation of the intersphincteric fistula tract is an option.

• Fibrin glue may be a potential treatment with limited efficacy.

Do not routinely consider anal fistula plugs for closure of anoperineal fistulas in CD, as seton removal alone is equally effective.

Ano- and rectogenital fistulae related to CD are very complex and rare; thus, treatment should involve an experienced multidisciplinary team.

Stem cell therapy

Allogeneic adipose-derived stem cell (ASC) therapy could be an effective and safe treatment for complex perianal fistulae in patients with CD.

Autologous ASCs may have a positive effect for patients with CD and complex perianal fistulae, with good tolerability and safety.

Refractory Pelvic Sepsis

Pelvic sepsis and symptoms from complex perineal CD refractory to medical or surgical interventions can be controlled by a diverting stoma, but with limited rates of fistula healing and stoma closure.

Surgical Management of Abdominal CD

Approach to intra-abdominal abscess

The recommended primary approach is percutaneous image-guided drainage of well-defined accessible intra-abdominal abscesses.

Following successful image-guided drainage of an intra-abdominal abscess, medical management without surgery may be considered. A low threshold for surgery is recommended if medical management is not successful.

Preoperative Optimization

Perform preoperative nutritional assessment for all patients with CD who need surgery. Preoperative nutritional optimization with enteral or parenteral nutrition is recommended for patients with nutritional deficiencies.

Preoperative corticosteroid use is associated with an increased risk of postoperative complications. Preoperative reduction of corticosteroid doses may reduce postoperative complications but should be monitored carefully to avoid increasing the disease burden.

Current evidence suggests that preoperative treatment with anti-tumor necrosis factor (TNF) therapy, vedolizumab, or ustekinumab does not raise the risk of postoperative complications in patients with CD having abdominal surgery. Preoperative cessation of these medications is not mandatory.

Preoperative control of sepsis is recommended prior to abdominal surgery for CD.

Small-Bowel Obstruction

Deferred surgery is the preferred option in adult patients with CD who present with acute small-bowel obstruction without bowel ischemia or peritonitis.

Endoscopic balloon dilatation or surgery are both suitable treatment options for patients with short (< 5 cm) strictures of the terminal ileum in CD. Local expertise and patient preference guide the treatment selection.

Strictureplasty is a safe option to treat small bowel strictures related to CD. Strictureplasty may be preferable to resection of long segments of bowel, with a potential reduction in surgical recurrence rates.

Surgical Techniques for Abdominal CD

Laparoscopic surgery should be offered as the first-line approach in surgery for CD, depending on the presence or availability of appropriate expertise.

Consider a temporary stoma if steroids cannot be withdrawn or significantly reduced prior to surgery.

Primary anastomosis may safely be performed in the presence of anti-TNF therapy, vedolizumab, and ustekinumab, as long as other risk factors have been taken into account.

A reasonable alternative to infliximab therapy is laparoscopic resection in patients with limited, nonstricturing, ileocecal CD (diseased terminal ileum < 40 cm).

Stapled small-bowel or ileocolic side-to-side anastomoses are associated with lower rates of postoperative complications than end-to-end anastomoses in CD.

Segmental colectomy is appropriate for patients with a single involved colonic segment in CD.

A defunctioning stoma for non-acute refractory Crohn colitis may delay or avoid the need for colectomy.

Restorative proctocolectomy with ileal pouch-anal anastomosis can be considered in selected patients with refractory pancolonic CD without a history of perianal disease, taking into account the high risk of pouch failure.

In January 2020, the American Gastroenterological Association (AGA) released their recommendations on the medical management of adult outpatients with moderate to severe ulcerative colitis (UC) and hospitalized adult patients with acute severe UC (ASUC).[132] The focus of the guidelines is on immunomodulators, biologic agents, and small molecules for induction and maintenance of remission (for moderate to severe UC) and reducing the risk of colectomy (for ASUC).

Adult Outpatients With Moderate-Severe UC

The AGA makes a strong recommendation for using infliximab, adalimumab, golimumab, vedolizumab, tofacitinib, or ustekinumab over no treatment.

For patients who are naïve to biologic agents, the AGA recommends that tofacitinib only be used in the setting of a clinical or registry study (no recommendation). (Updated FDA recommendations [07/26/2019] on indications for use of tofacitinib in UC recommends its use only after failure of, or intolerance to, tumor necrosis factor-alpha [TNFα] antagonists.)

Conditional recommendations

For adult outpatients with moderate-severe UC who are naïve to biologic agents, the AGA suggests using infliximab or vedolizumab, rather than adalimumab, for induction of remission.

In adult outpatients with moderate-severe UC with previous exposure to infliximab, particularly those with primary nonresponse, the AGA suggests using ustekinumab or tofacitinib, rather than vedolizumab or adalimumab, for induction of remission.

In adult outpatients with active moderate-severe UC, the AGA suggests against using thiopurine monotherapy for INDUCTION of remission. However, in adult outpatients with moderate-severe UC in remission, the AGA suggests using thiopurine monotherapy, rather than no treatment, for MAINTENANCE of remission.

In adult outpatients with moderate-severe UC, the AGA suggests against using methotrexate monotherapy, for induction or maintenance of remission.

In adult outpatients with active moderate-severe UC, the AGA conditionally suggests using biologic monotherapy (TNFα antagonists, vedolizumab, ustekinumab) rather than thiopurine monotherapy for INDUCTION of remission, whereas in those with moderate-severe UC in remission, the AGA makes no recommendation in favor of, or against, using biologic monotherapy (TNFα antagonists, vedolizumab or ustekinumab), rather than thiopurine monotherapy for MAINTENANCE of remission.

In adult outpatients with moderate-severe UC, the AGA suggests combining TNFα antagonists, vedolizumab, or ustekinumab with thiopurines or methotrexate, rather than biologic monotherapy or thiopurine monotherapy.

In adult outpatients with moderate-severe UC, the AGA suggests early use of biologic agents with or without immunomodulator therapy, rather than gradual step-up after failure of 5-aminosalicylates.

In adult outpatients with moderate-severe UC who have achieved remission with biologic agents and/or immunomodulators, or tofacitinib, the AGA suggests against continuing 5-aminosalicylates for induction and maintenance of remission.

Hospitalized Patients With ASUC

In hospitalized adult patients with ASUC refractory to intravenous (IV) corticosteroids that is being treated with infliximab, the AGA makes no recommendation on routine use of intensive versus standard infliximab dosing.

Conditional recommendations

In hospitalized adults with ASUC, the AGA suggests using an IV methylprednisolone dose equivalent of 40 to 60 mg/d rather than higher dose IV corticosteroids.

In hospitalized adults with ASUC without infections, the AGA suggests against adjunctive antibiotics.

In hospitalized adults with ASUC refractory to IV corticosteroids, the AGA suggests using infliximab or cyclosporine.

For more information, go to Crohn Disease and Ulcerative Colitis.

For more Clinical Practice Guidelines, go to Guidelines.

Many inflammatory mediators have been identified in inflammatory bowel disease (IBD); antibodies against these mediators and methods to block the production or receptors for these mediators hold great promise as potential therapy for IBD.

Although mild inflammatory disease can be treated with aminosalicylates, moderate to severe disease should be aggressively treated early in the disease course to prevent inflammatory and structuring complications of the intestinal disease. Although the standard immune modulators mercaptopurine and azathioprine are very effective, the delay in onset of therapeutic effect is suboptimal. Early use of biologic agents can promote mucosal healing and maintain remission while preventing complications. Early use of biologic agents should be considered in any patient with severe IBD, although it may require aggressive dealing with pharmacy benefits managers to get coverage for these agents without having failed some of the less aggressive medications.

The stepwise approach for mild disease is as follows:

1. Aminosalicylates and symptomatic agents are early step; antibiotics are step IA drugs, given the limited situations in which they are used.

2. Corticosteroids are used in more symptomatic disease; they should be used if the earlier step drugs fail to adequately control the IBD. These agents can also be used in more severe disease to attempt to induce remission.

3. Immune-modifying agents are used if corticosteroids fail or are required for prolonged periods, but they have the disadvantage of delay before efficacy; infliximab, adalimumab, and vedolizumab are drugs that should be used early in moderate to severe inflammatory disease.

4. Step IV drugs are experimental agents, are used only after the previous steps fail, and 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 stepwise approach.

Class Summary

The 5-aminosalicylic acid (ASA) derivatives are effective in reducing inflammatory reactions. All of the aminosalicylates are useful for treating flares of mild to moderate ulcerative colitis and occasionally Crohn colitis and for maintaining remission.

Sulfasalazine (Azulfidine, Azulfidine EN-tabs, Sulfazine, Sulfazine EC)

Sulfasalazine is considered best for colonic disease, although it is also considered first-line therapy for Crohn disease. This agent is used for acute disease and for maintenance of remission.

Mesalamine (Asacol HD, Pentasa, Canasa, Rowasa, Lialda, Apriso, Delzicol)

Mesalamine is a 5-ASA that acts systemically and also has activity as a topical anti-inflammatory.

Balsalazide (Colazal, Giazo)

Balsalazide is a 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 the drug may decrease inflammation by blocking the production of arachidonic acid metabolites in colonic mucosa.

Olsalazine (Dipentum)

Olsalazine is useful for active disease and maintenance of remission in ulcerative colitis. Dipentum is a 5-ASA connected to a 5-ASA by an azo bond; colonic bacteria break the azo bond, releasing the active 5-ASA. Note that an adverse event of high ileal secretion of chloride creates a different type of diarrhea, which lessens its acceptability.

Class Summary

Metronidazole (Flagyl) and ciprofloxacin (Cipro) are the most commonly used antibiotics in persons with inflammatory bowel disease (IBD). Antibiotics are less effective in persons with ulcerative colitis, except in fulminant toxic megacolon or pouchitis. Rifaximin (Xifaxan) is an FDA-approved broad-spectrum antibiotic that may also help treat patients with IBD.

Metronidazole (Flagyl, Flagyl ER, Metro)

Metronidazole is a widely available, inexpensive antibiotic and antiprotozoal agent. This agent inhibits protein synthesis and causes cell death in susceptible organisms by diffusing into the organism and causing a loss of helical DNA structure and strand breakage. Metronidazole's adverse-event profile includes headache, dysgeusia, and neuropathy.

Ciprofloxacin (Cipro, Cipro XR)

Ciprofloxacin is a fluoroquinolone antibiotic commonly used for the treatment of urinary, skin, and respiratory tract infections. This agent inhibits bacterial DNA synthesis and, consequently, growth by inhibiting DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Caution is advised with the use of ciprofloxacin regarding tendon rupture.

Rifaximin (Xifaxan)

Rifaximin is a nonabsorbed (<0.4%), broad-spectrum antibiotic specific for enteric pathogens of the gastrointestinal tract (ie, gram-positive, gram-negative, aerobic, anaerobic). It is a rifampin structural analog and it binds to the beta-subunit of bacterial DNA-dependent RNA polymerase, thereby inhibiting RNA synthesis.

Class Summary

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

Hydrocortisone (Solu-Cortef, Cortef, A-Hydrocort )

Adrenocortical steroids act as potent inhibitors of inflammation. They 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 adrenocortical steroids may be used in equivalent dosage.

Prednisone (Rayos)

Prednisone acts as a potent inhibitor of inflammation. It 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.

Methylprednisolone (Medrol, Solu-Medrol, Depo-Medrol, A-Methapred)

Adrenocortical steroids act as potent inhibitors of inflammation and may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to modification of the immune response. Alternative adrenocortical steroids may be used in equivalent dosage. Methylprednisolone has a greater salt- and water-retention side effect.

Prednisolone (Orapred, Pediapred, Millipred, Veripred 20, Flo-Pred)

Corticosteroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to modification of the immune response. Alternative corticosteroids may be used in equivalent dosage.

Budesonide (Entocort EC, Uceris, Uceris Foam)

Budesonide alters the level of inflammation in tissues by inhibiting multiple types of inflammatory cells and decreasing the production of cytokines and other mediators involved in inflammatory reactions. Only 10% is bioavailable because of first-pass metabolism.

Dexamethasone (Baycadron, DoubleDex)

Dexamethasone has many pharmacologic benefits, but there are also significant adverse effects. It stabilizes cell and lysosomal membranes, increases surfactant synthesis, increases serum vitamin A concentrations, and inhibits prostaglandin and proinflammatory cytokines.

Class Summary

Immunosuppressant agents are useful as steroid-sparing agents, in healing fistulas, and in patients with serious contraindications to surgery.[109] These drugs are used in patients who are refractory to or unable to tolerate steroids and in patients in whom remission is difficult to maintain with the aminosalicylates alone. Azathioprine and its metabolite, 6-mercaptopurine (MP), are useful in Crohn disease complicated by recurrent rectal fistulas or perianal disease; however, the clinical response can take up to 6 months. Methotrexate has also been tried.

Azathioprine (Imuran, Azasan)

Azathioprine inhibits mitosis and cellular metabolism by antagonizing purine metabolism and inhibiting synthesis of DNA, RNA, and proteins; these effects may decrease the proliferation of immune cells and result in lower autoimmune activity.

6-Mercaptopurine (Purinethol, Purixan)

6-Mercaptopurine is a purine analog that inhibits DNA and RNA synthesis, causing arrest of cell proliferation.

Methotrexate (Rheumatrex, Trexall, Otrexup, Rasuvo)

Methotrexate impairs DNA synthesis and induces the apoptosis and reduction in interleukin (IL)-1 production. It is indicated for moderate to severe disease and maintenance of remission. The onset of action is delayed.

Cyclosporine (Sandimmune, Neoral, Gengraf)

According to the American Gastroenterological Association (AGA) guidelines, intravenous cyclosporine is effective for avoiding surgery in patients with ulcerative colitis who have failed to respond to 7-10 days of high-dose oral or parenteral corticosteroids. Concomitant administration of IV corticosteroids is recommended in these cases.

Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions, such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-versus-host disease.

For children and adults, dosing is based on ideal body weight.

Class Summary

Monoclonal antibodies targeted against tumor necrosis factor alpha (TNFα) interrupt endogenous TNF. Increased TNFα levels have been observed in Crohn disease and ulcerative colitis and are thought to be part of the pathogenesis of IBD. TNFα induces proinflammatory cytokines (eg, interleukins), enhances leukocyte migration, activates neutrophils and eosinophils, and induces enzymatic degradation.

This class includes adalimumab, certolizumab, golimumab, and infliximab. Infliximab and adalimumab are FDA approved for both Crohn disease and ulcerative colitis, whereas certolizumab is FDA approved only for Crohn disease and golimumab only for ulcerative colitis.

Infliximab was the first of this class for use in inflammatory bowel disease.[70] Infliximab is more effective against Crohn disease than ulcerative colitis. This drug promotes mucosal healing; heals perianal and enterocutaneous fistulas; and has been shown to reduce signs and symptoms, achieve clinical remission and mucosal healing, and eliminate corticosteroid use.[133] Infliximab is indicated for patients who have experienced inadequate response to conventional therapy.[109]

Infliximab (Remicade)

Infliximab neutralizes cytokine TNF-alpha and inhibits its binding to the TNF-alpha receptor. It is mixed in 250 mL of normal saline and infused IV over 2 hours. It is indicated for both ulcerative colitis and Crohn disease.

Adalimumab (Humira)

Adalimumab is a TNF blocking agent that has been FDA approved for both Crohn disease and ulcerative colitis. It is administered by subcutaneous injection.

Adalimumab is recombinant human immunoglobulin (Ig) G1 monoclonal antibody specific for human TNF. It binds specifically to TNF-alpha and blocks the interaction with p55 and p75 cell-surface TNF receptors.

Certolizumab pegol (Cimzia)

Certolizumab is a TNF blocking agent that has been FDA approved for the treatment of Crohn disease but not for ulcerative colitis. It is administered by subcutaneous injection.

Certolizumab pegol is a pegylated antitumor necrosis factor (TNF)–alpha blocker, which results in disruption of the inflammatory process. It is indicated for moderate to severe Crohn disease in individuals whose condition has not responded to conventional therapies.

Golimumab (Simponi, Simponi Aria)

Human anti-TNF-alpha monoclonal antibody. Indicated for ulcerative colitis but not Crohn disease. It is administered by SC injection.

Class Summary

Integrin inhibitors are emerging as options for moderate-to-severe IBD in patients who have had an inadequate response with, lost response to, or were intolerant to a TNF blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids.

Natalizumab (Tysabri)

Natalizumab is a recombinant humanized IgG4-1C monoclonal antibody produced in murine myeloma cells. It binds to alpha-4 subunits of α4β1 and α4β7 integrins expressed on the leukocyte surface, which inhibit α4-mediated leukocyte adhesion to their receptors. In Crohn disease, the interaction of the α4β7 integrin with the endothelial receptor MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of the disease.

Vedolizumab (Entyvio)

Vedolizumab is a recombinant humanized monoclonal antibody that binds specifically to α4β7 integrin. It blocks the interaction of α4β7 integrin with a gut-associated addressin cell adhesion molecule-1 (MAdCAM-1) and inhibits the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. It is indicated for both ulcerative colitis and Crohn disease.

Class Summary

H2-receptor antagonists are reversible competitive blockers of histamines at the H2 receptors, particularly those in the gastric parietal cells, where they inhibit acid secretion. The H2 antagonists are highly selective, do not affect the H1 receptors, and are not anticholinergic agents.

Cimetidine (Tagamet)

Cimetidine inhibits histamine at H2 receptors of gastric parietal cells, which results in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.

Ranitidine (Zantac, Deprizine FusePaq)

Ranitidine inhibits histamine stimulation of the H2 receptor in gastric parietal cells, which, in turn, reduces gastric acid secretion, gastric volume, and hydrogen ion concentrations.

Famotidine (Pepcid)

Famotidine competitively inhibits histamine at H2 receptor of gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen ion concentrations.

Nizatidine (Axid)

Nizatidine competitively inhibits histamine at the H2 receptor of the gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.

Class Summary

Proton pump inhibitors (PPIs) reduce gastric acid secretion by inhibition of the H+ -K+ -ATPase enzyme system in the gastric parietal cells. These agents are used in patients with severe esophagitis and in patients whose disease is not responsive to H2-antagonist therapy.

Omeprazole (Prilosec)

Omeprazole decreases gastric acid secretion by inhibiting the parietal cell H+/K+-ATPase pump.

Lansoprazole (Prevacid)

Lansoprazole suppresses gastric acid secretion by specific inhibition of the H+/K+-ATPase enzyme system (ie, proton pump) at the secretory surface of the gastric parietal cell. It blocks the final step of acid production. The effect is dose-related and inhibits both basal and stimulated gastric acid secretion, thus increasing the gastric pH.

Esomeprazole magnesium (Nexium)

Esomeprazole magnesium is an S-isomer of omeprazole. It inhibits gastric acid secretion by inhibiting the H+/K+-ATPase enzyme system at the secretory surface of gastric parietal cells. Esomeprazole is used in severe cases and in patients not responding to H2-antagonist therapy. This agent is used for up to 4 weeks to treat and relieve symptoms of active duodenal ulcers; however, it may be used for up to 8 weeks to treat all grades of erosive esophagitis.

Rabeprazole sodium (Aciphex)

Rabeprazole sodium decreases gastric acid secretion by inhibiting the parietal cell H+/K+-ATPase pump.

Pantoprazole (Protonix)

Pantoprazole suppresses gastric acid secretion by specifically inhibiting the H+/K+-ATPase enzyme system at the secretory surface of gastric parietal cells.

Class Summary

These agents provide symptomatic relief when patients report symptoms of diarrhea.

Diphenoxylate and atropine (Lomotil)

Diphenoxylate and atropine is a drug combination that acts as an antidiarrheal agent chemically related to the narcotic analgesic meperidine. This agent acts on intestinal muscles to inhibit peristalsis and slow intestinal motility, prolonging the movement of electrolytes and fluid through the bowel, and increasing the viscosity. A subtherapeutic dose of anticholinergic atropine sulfate is added to discourage overdosage, in which case diphenoxylate may clinically mimic the effects of codeine.

Loperamide (Imodium A-D, Diamode)

Loperamide acts on intestinal muscles to inhibit peristalsis and slow intestinal motility. It prolongs the movement of electrolytes and fluid through the bowel and increases viscosity.

Class Summary

Anticholinergic antispasmodic agents are used to treat spastic disorders of the gastrointestinal tract.

Dicyclomine (Bentyl)

Dicyclomine is used to treat gastrointestinal motility disturbances. It blocks the action of acetylcholine at parasympathetic sites in secretory glands, smooth muscle, and the central nervous system (CNS).

Hyoscyamine (Levbid, Levsin, Levsin-SL, HyoMax SL, Symax-SL, Symax-SR, NuLev, Oscimin)

Hyoscyamine blocks the action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the CNS, which, in turn, has antispasmodic effects. The sublingual (SL) tablets may be administered orally, sublingually, or chewed.

Ustekinumab (Stelara)

Ustekinumab (Stelara) is an antibody that blocks IL-12 and IL-23. It interferes with the triggering of the body's inflammatory response through the suppression of cytokines (interleukins IL-12 and IL-23) which help activate certain T-cells. Ustekinumab binds to the p-40 subunit of both IL-12 and IL-23 so that they subsequently cannot bind to their receptors.

Budesonide rectal (Uceris Rectal Foam)

Budesonide rectal foam is a glucocorticosteroid indicated for the induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge.

Tofacitinib (Xeljanz, Xeljanz XR)

Tofacitinib is an inhibitor of the enzyme janus kinase 1 (JAK1) and janus kinase 3 (JAK 3). It interferes with the JAK-STAT signaling pathway, which transmits extracellular information into the cell nucleus, influencing DNA transcription.

Cholestyramine (Questran, Prevalite)

Cholestyramine may be used to treat diarrhea associated with excess bile acids. It binds bile acids, thus reducing the damage to the intestinal mucosa. Cholestyramine also reduces the induction of colonic fluid secretion and forms a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits enterohepatic reuptake of intestinal bile salts.

Colestipol (Colestid)

Colestipol forms a soluble complex after binding to bile acid, increasing fecal loss of bile acid-bound low-density lipoprotein cholesterol.

Colesevelam (WelChol)

Colesevelam forms complex with bile acids that is not absorbed through intestine; inhibits enterohepatic reuptake of intestinal bile salts. It can be used for symptomatic chronic diarrhea due to bile salt malabsorption (bile acid diarrhea) secondary to Crohn's disease.