Crohn Disease 

Updated: Sep 11, 2018
Author: Leyla J Ghazi, MD; Chief Editor: Praveen K Roy, MD, AGAF 

Overview

Practice Essentials

Crohn disease is an idiopathic, chronic inflammatory process that can affect any part of the gastrointestinal tract from the mouth to the anus (see the image below). Individuals with this condition often experience periods of symptomatic relapse and remission.

Colonoscopic image of a large ulcer and inflammati Colonoscopic image of a large ulcer and inflammation of the descending colon in a 12-year-old boy with Crohn disease.

See Autoimmune Disorders: Making Sense of Nonspecific Symptoms, a Critical Images slideshow, to help identify several diseases that can cause a variety of nonspecific symptoms.

Signs and symptoms

The characteristic presentation in Crohn disease is abdominal pain and diarrhea, which may be complicated by intestinal fistulization or obstruction. Unpredictable flares and remissions characterize the long-term course.[1, 2, 3]

Other signs and symptoms of Crohn disease may include the following:

  • Rectal bleeding

  • Fever

  • Weight loss, anorexia

  • Nausea, vomiting

  • Malnutrition, vitamin deficiencies

  • Generalized fatigability

  • Bone loss

  • Psychosocial issues (eg, depression, anxiety, and coping difficulty); pediatric patients may also experience psychological issues regarding quality of life and body image[4, 5]

  • Growth failure in pediatric patients: May precede gastrointestinal symptoms by years

See Clinical Presentation for more detail.

Diagnosis

Examination for Crohn disease includes the following:

  • Vital signs: Normal, but possible presence of tachycardia in anemic or dehydrated patients; possible chronic intermittent fever

  • Gastrointestinal: May vary from normal to those of an acute abdomen; assess for rectal sphincter tone, gross rectal mucosal abnormalities, presence of hematochezia

  • Genitourinary: May include presence of skin tags, fistulae, ulcers, abscesses, and scarring in the perianal region; nephrolithiasis, hydronephrosis, and enterovesical fistulae

  • Musculoskeletal: Possible arthritis and arthralgia, particularly of the large joints[6]

  • Dermatologic: May show pallor or jaundice, mucocutaneous or aphthous ulcers, erythema nodosum, and pyoderma gangrenosum

  • Ophthalmologic: May reveal episcleritis; possible uveitis

  • Growth delay: Decreased growth velocity (eg, height), pubertal delay

  • Hematologic: Hypercoagulable state

Laboratory Tests

Although laboratory results for Crohn disease are nonspecific and are of value principally for facilitating disease management, they may also be used as surrogate markers for inflammation and nutritional status and to screen for deficiencies of vitamins and minerals.

Routine laboratory studies include the following:

  • CBC count

  • Chemistry panel

  • Liver function tests

  • Inflammatory markers

  • Stool studies

  • Serologic tests

Imaging studies

Imaging modalities used for Crohn disease include the following:

  • Plain abdominal radiography

  • Barium contrast studies (eg, small bowel follow-through, barium enema, enteroclysis)

  • CT scanning of the abdomen

  • CT enterography or magnetic resonance enterography: Replacing small bowel follow-through studies

  • MRI of the pelvis

  • Abdominal and/or endoscopic ultrasonography

  • Nuclear imaging (eg, technetium-99m hexamethyl propylene amine oxime, indium-111)

  • Fluorine-18-2-fluoro-2-deoxy-D-glucose scanning combined with positron emission tomography or CT scanning

Procedures

The following procedures may help in the evaluation of Crohn disease:

  • Endoscopic visualization and biopsy (eg, upper gastrointestinal endoscopy, esophagogastroduodenoscopy, endoscopic retrograde cholangiopancreatography)

  • Colonoscopy, ileocolonoscopy

  • Small bowel enteroscopy

  • Interventional radiology: For percutaneous drainages of abscesses

See Workup for more detail.

Management

Pharmacotherapy

Medications used in the treatment of Crohn disease include the following:

  • 5-Aminosalicylic acid derivative agents (eg, mesalamine rectal, mesalamine, sulfasalazine, balsalazide)

  • Corticosteroids (eg, prednisone, methylprednisolone, budesonide, hydrocortisone, prednisolone)

  • Immunosuppressive agents (eg, mercaptopurine, methotrexate, tacrolimus)

  • Monoclonal antibodies (eg, infliximab, adalimumab, certolizumab pegol, natalizumab, ustekinumab, vedolizumab)

  • Antibiotics (eg, metronidazole, ciprofloxacin)

  • Antidiarrheal agents (eg, loperamide, diphenoxylate-atropine)

  • Bile acid sequestrants (eg, cholestyramine, colestipol)

  • Anticholinergic agents (eg, dicyclomine, hyoscyamine, propantheline)

Surgery

Unlike ulcerative colitis, Crohn disease has no surgical cure. Most patients with Crohn disease require surgical intervention during their lifetime.

Surgical management of the terminal ileum, ileocolon, and/or upper gastrointestinal tract may include the following[7] :

  • Resection of the affected bowel

  • Ileocolostomy or proximal loop ileostomy

  • Drainage of any septic foci with later definitive resection

  • Strictureplasty

  • Bypass

  • Endoscopic dilatation of symptomatic, accessible strictures

Surgical management of the colon may include the following[7] :

  • Subtotal or total colectomy with end ileostomy (laparoscopic or open approach)

  • Segmental or total colectomy with or without primary anastomosis

  • Total proctocolectomy or proctectomy with stoma creation

See Treatment and Medication for more detail.

Background

Crohn disease is an idiopathic, chronic inflammatory process of the gastrointestinal (GI) tract that can affect any part of the tract from the mouth to the anus. Individuals with this condition often experience periods of symptomatic relapse and remission.

Crohn disease is believed to be the result of an imbalance between proinflammatory and anti-inflammatory mediators. Although genetic susceptibility, luminal antigenic drive, and environmental triggers are also important factors, animal models demonstrate that no single factor is sufficient to induce intestinal inflammation. (See Pathophysiology.)

Approximately 30% of Crohn disease cases involve the small bowel, particularly the terminal ileum, another 20% involve only the colon, and 45% involve both the small bowel and colon.[8] Once considered rare in the pediatric and black populations, Crohn disease is recognized with increasing frequency in children of all ages and in individuals of varying ethnicities. (See Epidemiology.)

The characteristic presentation is abdominal pain and diarrhea, which may be complicated by intestinal fistulization or obstruction. Unpredictable flares and remissions characterize the long-term course.[1, 2, 3] In addition, individuals can experience rectal bleeding, fever, weight loss, malnutrition, bone loss, and vitamin deficiencies. Psychosocial issues (eg, depression, anxiety, and coping difficulty) are common. Pediatric patients may also experience psychological issues regarding quality of life and body image.[4, 5] (See Presentation.)

Laboratory data for Crohn disease are nonspecific and are of value principally in assisting with management. However, various imaging modalities can aid in diagnosis and management; the choice among them depends upon the clinical question being asked. (See Workup.)

Plain radiography or computed tomography (CT) of the abdomen and pelvis can assess for bowel obstruction or pelvic intra-abdominal abscesses. Small bowel follow-through (SBFT) studies are being supplanted by CT enterography or magnetic resonance (MR) enterography, which is better able to distinguish inflammation from fibrosis. Magnetic resonance imaging (MRI) of the pelvis or endoscopic (transrectal) ultrasonography can identify perianal fistula anatomy and activity and determine the presence or absence of pelvic and perianal abscesses.

Endoscopic visualization and biopsy are essential in the diagnosis of Crohn disease. Colonoscopy is done to assess for colonic or terminal ileal disease. Upper GI endoscopy may be used to diagnose esophageal or gastroduodenal disease and is recommended for all children, regardless of the presence or absence of upper GI symptoms. (See Workup.)

The general goals of treatment are as follows:

  • To achieve the best possible clinical, laboratory, and histologic control of the inflammatory disease with the least adverse effects from medications

  • To permit the patient to function as normally as possible

  • In children, to promote growth with adequate nutrition; the unique problems encountered in the pediatric population necessitate a medical approach that promotes clinical improvement and reverses growth failure with minimal toxicity

Therapy is typically administered in a “step-up” approach, in which patients with mild disease are treated with 5-aminosalicylic acid (5-ASA), antibiotics, and nutritional therapy. If the patient does not respond to this approach or if the disease is more severe than was initially thought, corticosteroid and immunomodulatory therapy with 6-mercaptopurine (6-MP) or methotrexate is attempted. Finally, biologic and surgical therapies, at the tip of the treatment pyramid, are used.[9] (See Treatment.)

A subpopulation of patients with risk factors for complicated disease and rapid progression may benefit from a “top-down” approach. This approach involves early and aggressive use of tumor necrosis factor (TNF) antagonists, which may alter the natural history of the disease, improve treatment response, and decrease the need for steroid therapy. (See Treatment.)

Surgery plays an integral role in controlling medically refractory disease and treating complications of Crohn disease. Because of the high rate of disease recurrence after segmental bowel resection, the guiding principle of surgery is preservation of intestinal length and function.[1] (See Treatment.)

Pathophysiology

Chronic inflammation from T-cell activation leading to tissue injury is implicated in the pathogenesis of Crohn disease.

After activation by antigen presentation, unrestrained responses of type 1 T helper (Th1) cells predominate in Crohn disease as a consequence of defective regulation. Th1 cytokines such as interleukin (IL)-12 and TNF-α stimulate the inflammatory response. Inflammatory cells recruited by these cytokines release nonspecific inflammatory substances, including arachidonic acid metabolites, proteases, platelet activating factor, and free radicals, which result in direct injury to the intestine.

In a study from 2012, investigators suggested that genetic predispositions for inflammatory bowel disease (IBD) lead to abnormal epithelial barrier integrity and homeostasis, deficits in autophagy, deficiencies in innate pattern recognition receptors, and problems with lymphocyte differentiation, especially in Crohn disease.[10]

Microscopically, the initial lesion starts as a focal inflammatory infiltrate around the crypts, followed by ulceration of superficial mucosa. Later, inflammatory cells invade the deep mucosal layers and, in that process, begin to organize into noncaseating granulomas (see the image below). The granulomas extend through all layers of the intestinal wall and into the mesentery and the regional lymph nodes.

Colonic granuloma in patient with Crohn disease. H Colonic granuloma in patient with Crohn disease. Hematoxylin-eosin staining. Image courtesy of Dr E. Ruchelli.

Neutrophil infiltration into the crypts forms crypt abscesses, leading to destruction of the crypt and atrophy of the colon. Chronic damage may be seen in the form of villous blunting in the small intestine as well. Ulcerations are common and are often seen on a background of normal mucosa.

Although granuloma formation is pathognomonic of Crohn disease, its absence does not exclude the diagnosis.[11]

Macroscopically, the initial abnormality consists of hyperemia and edema of the involved mucosa. Later, discrete superficial ulcers form over lymphoid aggregates and are seen as red spots or mucosal depressions (see the image below). These can become deep, serpiginous ulcers located transversely and longitudinally over an inflamed mucosa, giving the mucosa a cobblestone appearance. The lesions are often segmental, being separated by healthy areas, and are referred to as skip lesions.[11]

Colonoscopic image of a large ulcer and inflammati Colonoscopic image of a large ulcer and inflammation of the descending colon in a 12-year-old boy with Crohn disease.

Transmural inflammation results in thickening of the bowel wall and narrowing of the lumen. As Crohn disease progresses, it is complicated by obstruction or deep ulceration leading to fistulization by way of the sinus tracts penetrating the serosa, microperforation, abscess formation, adhesions, and malabsorption.[1]

Bowel obstruction is caused initially by significant edema of the mucosa and associated spasm of the bowel. Obstruction is intermittent and can often be reversed by means of conservative measures and anti-inflammatory agents. With further disease progression, the obstruction becomes chronic because of fibrotic scarring, luminal narrowing, and stricture formation.[1]

Fistulae may be enteroenteral, enterovesical, enterovaginal, or enterocutaneous. The inflammation extending through the bowel wall may also involve the mesentery and surrounding lymph nodes. Creeping fat may be seen when the mesentery wraps around the bowel surface (see the following image).[1] Serosal inflammation causes adhesions; thus, free perforations are less common in Crohn disease than in other inflammatory bowel conditions.[1]

Laparoscopic view depicts creeping fat along the m Laparoscopic view depicts creeping fat along the mesentery of the terminal ileum.

Etiology

The exact cause of Crohn disease remains unknown. Genetic, microbial, immunologic, environmental, dietary, vascular, and psychosocial factors have been implicated, as have smoking and the use of oral contraceptives and nonsteroidal anti-inflammatory agents (NSAIDs).[12] Patients may inherit susceptibility for an aberrant immunologic response to 1 or more of these provoking factors.[11] Interaction between the predisposing genetic factors, environmental factors, host factors, and triggering event is likely necessary for the disease to develop.

Studies have found compelling evidence for an inheritable risk for the development of Crohn disease. However, classic mendelian inheritance is not seen. Most of the genes thought to be involved in the development of the disease play a role in mucosal immunity, and their products are found on the mucosal barrier epithelium.[11]

When the genetics of Crohn disease were first investigated, a strong association was found with chromosome 16 (IBD1 gene), which led to the identification of 3 single nucleotide polymorphisms (SNPs), 2 missense and 1 frameshift, in the NOD2 gene (now called CARD15), the first gene clearly identified as a susceptibility gene for Crohn disease.

NOD2/CARD15 is a polymorphic gene involved in the innate immune system. Of its more than 60 variations, 3 play a role in 27% of patients with Crohn disease, primarily in those with ileal disease. Subsequent studies suggest that CARD15 genotype is associated not only with the onset of disease but also with its natural history. A study in 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-colon disease.[13, 14]

Another early genome-wide association study (GWAS) looked at Jewish and non-Jewish case-control cohorts and identified 2 SNPs in the IL23R gene, which encodes 1 subunit of the IL-23 receptor protein.[15] 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.[16]

However, another study found that the Arg381Gln substitution is associated with childhood onset of IBD in Scotland.[17] Numerous other loci have been identified as conferring susceptibility to Crohn disease. Several large studies found multiple susceptibility loci and confirmed earlier findings.

In a meta-analysis of 3 GWASs, 526 SNPs from 74 distinct genomic loci were found.[18] In addition to loci that have been previously discussed, 21 new loci were found that were associated with an increased risk of developing Crohn disease. Among the new loci were some very interesting implications, including the genes CCR6, IL12B, STAT3, JAK2, LRRK2, CDKAL1, and PTPN22.[18] Most of these genes are involved in signal transduction in certain immune function, as well as genes involved more directly with immune function.

The interlectin gene (ITLN1) is expressed in the small bowel and colon and is involved in recognition of certain microorganisms in the intestine. Other GWASs found associations between susceptibility to Crohn disease and polymorphisms in genes associated with the intestinal milieu. One study, involving nearly 20,000 SNPs in 735 individuals with Crohn disease, found an association in the ATG16L1 gene, which encodes the autophagy-related 16-like protein involved in the autophagosome pathway that processes intracellular bacteria.[19, 20]

SNPs in other autophagy genes have also been associated with susceptibility to Crohn disease, as in one study examining at 2 polymorphisms that flanked the IRGM gene and that may be in the regulatory material for the gene.[21] Subsequently, various other loci have been implicated in the autophagy pathway as being associated with Crohn disease, with mounting evidence that the autophagosome pathway is very important in the pathogenesis of the disease.

Studies have also provided 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 been studied and found to exhibit significant susceptibility to severe colitis.[22]

A large genomic study of multiple diseases confirmed many of the findings found in earlier studies and identified several additional loci of interest for Crohn disease.[23, 24] A locus at 3p21 is located within the BSN gene, which encodes a brain-specific scaffold protein involved in neurotransmitter release. However, the MST1 gene is located nearby and encodes a macrophage stimulation gene, and the authors felt that this represented a more plausible explanation for the association.[24]

A locus at 10q24.2 is located near the NKX2-3 gene, which is a homeodomain-containing transcription factor.

Disruption of the homologous gene in a murine model resulted in defective development of the intestine.[25] The investigators hypothesized that changes to 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]

Infectious agents such as Mycobacterium paratuberculosis, Pseudomonas species, and Listeria species have all been implicated in the pathogenesis of Crohn disease, suggesting that the inflammation seen with the disease is the result of a dysfunctional, but appropriate, response to an infectious source.[11]

Interleukins and TNF-α have also been implicated in the disease process. Crohn disease is characterized by a Th1 cellular immune response pattern that leads to production of IL-12, TNF-α, and interferon gamma. TNF-α has been shown to play a critical role in the inflammation in this disease. Increased production of TNF-α by macrophages in patients with Crohn disease results in increased concentrations of TNF-α in the stool, blood, and mucosa.[26]

Environmental influences such as tobacco use seem to have an effect on Crohn disease. Smoking has been shown to double the risk of Crohn disease, whereas the risk of developing ulcerative colitis is lower in people who smoke than in those who have never smoked or in those who stopped smoking before their diagnosis.[11, 27]

It has been suggested that a diet high in fatty foods may increase the risk of Crohn disease.[28] Concerns about the measles vaccine and the development of the disease have proved to be unfounded.[29] Although appendectomy has been suggested to be protective in ulcerative colitis, it is not a protective factor in Crohn disease.[30]

Epidemiology

United States statistics

In 1998, the prevalence of Crohn disease in the United States was estimated on the basis of data from Olmstead County, Minnesota, and was approximated at 8 cases per 100,000 population.[31] A subsequent analysis of a geographically diverse health insurance claims database estimated the prevalence of Crohn disease among US children and adults in 2003-2004 to be closer to 201 cases per 100,000 persons among adults and 43 per 100,000 among children.[32]

Urban areas may have a higher prevalence of IBD than rural areas do.[1, 2] Upper socioeconomic classes are thought to have a higher prevalence than lower socioeconomic classes, a difference that is likely influenced by increased access to health care, though genetic and environmental factors may also play a role.[1, 6]

International statistics

Within Europe and North America, a north-to-south gradient in the frequency of IBD in populations is present. This difference in incidence correlates with the highest frequency of IBD in temperate climates and more industrialized parts of the world, such as Western Europe and North America.[33] As new regions assume Western cultural practices, an increased prevalence of ulcerative colitis is usually found approximately 1 decade before the observed increase in Crohn disease.

The overall incidence of Crohn disease in Europe is about 5.6 per 100,000 inhabitants (7.0 per 100,000 person-years in northern centers vs 3.9 in southern centers).[34] In most Western European countries, the incidence has stabilized or slightly increased. Increases are reported from some high-incidence areas (eg, Denmark and Sweden). Earlier studies from the 1980s reported an incidence of 4.1 per 100,000 person-years, whereas data for 2003-2005 indicate an incidence of 8.6 per 100,000 person-years.[35]

Incidence figures in Asia range from 0.5 to 4.2 cases per 100,000 persons.[36]  In Japan, there are about 40,000 patients with Crohn disease (approximately 27 per 100,000 persons).[12] The lowest recorded rates of new cases appear to be in South Africa (0.3-2.6 cases per 100,000 persons) and Latin America (0-0.03 cases per 100,000 persons).[1, 2]

A systematic review revealed that the highest prevalence for Crohn disease in North America was 319 per 100,000 persons, compared with 322 per 100,000 persons in Europe.[37] The highest annual incidence figures were 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. In time-trend analyses, 75% of the epidemiologic studies showed statistically significant increases in the incidence of Crohn disease over time.[37]

Age-, sex-, and race-related demographics

The age of onset of Crohn disease has a bimodal distribution. The first peak occurs between the ages of 15 and 30 years (late adolescence and early adulthood), and the second occurs mainly in women between the ages of 60 and 70 years. However, most cases begin before age 30 years, and approximately 20-30% of all patients with Crohn disease are diagnosed before age 20 years. A greater proportion of colonic and distal Crohn disease has been diagnosed in older patients, whereas younger patients have predominantly ileal disease.[1]

In general, the frequency of IBD is similar in males and females, with some studies showing a very slight female predominance. The rate of Crohn disease is 1.1-1.8 times higher in women than in men.[38] This pattern is reversed with pediatric IBD, which has a higher incidence in boys than in girls (pediatric male-to-female ratio, ~1.6:1). In Japan, a male predominance exists.[12]

Crohn disease is reported to be more common in white patients than in black patients and rare in Asian and Hispanic children. Approximately 20% of all IBD patients are of black descent. Rates are higher in people of Jewish descent, particularly in Ashkenazi Jews and Jews of middle European origin as compared with Sephardic or eastern European Jews.[39]

Prognosis

Crohn disease is a chronic inflammatory condition with an indolent course. Appropriate medical and surgical therapy helps patients to have a reasonable quality of life, with an overall good prognosis and an extremely low risk of a fatal outcome.[1]

Several earlier studies estimated a slight decrease in life expectancy associated with certain prognostic indicators, such as female sex, long disease duration, and disease location. The increased mortality was related to pulmonary malignancies, genitourinary tract diseases, and GI, liver, and biliary diseases.

In contrast, other studies have reported normal survival in patients with Crohn disease. With the advent of new medical therapies, population-based studies have shown that overall survival for North American patients with IBD is similar to that expected in the US white population.[40] Individuals with Crohn disease were at increased risk of death from complications of GI disease, GI malignancy, and chronic obstructive pulmonary disease (COPD).[40]

In a Danish study that evaluated trends in mortality from 1982 to 2010, investigators observed a 50% higher mortality in patients with Crohn disease relative to the general population; this percentage did not change over time.[41]

Crohn disease is typically characterized by periods of remission and relapse. In the first year after diagnosis, the relapse rate approaches 50%, with 10% of patients having a chronic relapsing course.[1] Most patients develop complications that require surgery, and postoperative clinical relapse occurs in a significant proportion.[1] The risk of surgery at 5-year intervals after diagnosis is as follows[42] :

  • 5 years after diagnosis – The cumulative probability of having only 1 surgical procedure is 37%; 2 or more surgical procedures, 12%; and no surgical procedures, 51%

  • 10 years after diagnosis – The cumulative probability of having only 1 surgical procedure is 39%; 2 or more surgical procedures, 23%; and no surgical procedures, 39%

  • 15 years after diagnosis – The cumulative probability of having only 1 surgical procedure is 34%; 2 or more surgical procedures, 36%; and no surgical procedures, 30%

Patients with proximal small bowel disease have a higher risk of mortality than those who have ileal or ileocecal disease. The excess mortality may be ascribed to complications of Crohn disease.[1]

Acute Crohn disease of the terminal ileum is often discovered during laparotomy for suspected appendicitis and has an excellent prognosis. The acute episode is usually treated conservatively, and as many as two thirds of patients may show no subsequent evidence of regional enteritis.[1]

Discussion of the diagnosis, management, and surveillance of colorectal cancer in patients with IBD is beyond the scope of this article. Current data suggest that with the advent of improved therapies for patients with IBD, there is a trend toward decreasing risk of colorectal cancer. For more information, see the following 2 guidelines:

  • AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. 2010. Available at: http://www.gastrojournal.org/article/S0016-5085(09)02202-1/fulltext. Accessed September 11, 2012

  • Colonoscopic surveillance for prevention of colorectal cancer in people with ulcerative colitis, Crohn disease or adenomas. London, UK: National Institute for Health and Clinical Excellence (NICE); 2011. Available at: http://guideline.gov/content.aspx?id=34830. Accessed September 11, 2012

Genetic studies are yielding evidence associating particular variants of the CARD15 gene with the prognosis of Crohn disease.[10] Specific CARD15 mutations have been linked with the intestinal site of the disease (eg, ileal site), and certain variants have been found to be associated with the propensity for developing strictures and with an early onset of disease.[10] In the future, these variants may be helpful in predicting the course of the disease in affected individuals.

Patient Education

Education of patients and their families is encouraged and is extremely important in the treatment process. Useful education materials can be obtained from the following organization:

  • Crohn’s and Colitis Foundation of America, 386 Park Avenue South, 17th floor, New York, NY 10016; (800) 932-2423; http://www.ccfa.org; e-mail: info@ccfa.org

In addition, see the Digestive Disorders Center, as well as Inflammatory Bowel Disease, Crohn’s Disease, Crohn’s Disease FAQs, and Ulcerative Colitis.

 

Presentation

History

Patients with suspected Crohn disease should be evaluated initially by their primary care team, and symptoms should be elicited in detail. Obtain a complete medical, surgical, social, and family history, and perform a detailed review of systems. Preliminary laboratory data (eg, inflammatory and anemia markers) may be helpful. If Crohn disease is suspected, the patient should be promptly referred to a gastroenterologist for consultation.

In children, document growth parameters; growth failure may precede gastrointestinal (GI) symptoms by years. The etiology of growth failure is multifactorial, with nutritional, hormonal, and disease-related factors all contributing. Any child or adolescent with persistent alterations in growth or delayed puberty should undergo appropriate diagnostic evaluation for Crohn disease.

General manifestations

Low-grade fever, prolonged diarrhea with abdominal pain, weight loss, and generalized fatigability are usually reported. Crampy or steady right lower quadrant or periumbilical pain may develop; the pain precedes and may be partially relieved by defecation. Diarrhea is usually not grossly bloody and is often intermittent. If the colon is involved, patients may report diffuse abdominal pain accompanied by mucus, blood, and pus in the stool.[1, 2, 11, 43, 44]

It is important to note that colonic Crohn disease may be clinically indistinguishable from ulcerative colitis, with symptoms of bloody mucopurulent diarrhea, cramping abdominal pain, and urgency to defecate.

Crohn disease of the small intestine usually presents with evidence of malabsorption, including diarrhea, abdominal pain, weight loss, and anorexia. Initially, these symptoms may be quite subtle. Patients with gastroduodenal involvement more commonly have anorexia, nausea, and vomiting.[45] Those with perianal disease may have debilitating perirectal pain, malodorous discharge from the fistula, and disfiguring scars from active disease or previous surgery.

Patients may also present with complaints suggestive of intestinal obstruction. Initially, the obstruction is secondary to inflammatory edema and spasm of the bowel and manifests as postprandial bloating, cramping pains (lower right quadrant), and borborygmi. Once the bowel lumen becomes chronically narrowed from fibrosis, patients may complain of constipation and obstipation. These symptoms generally do not improve with anti-inflammatory agents. Complete obstruction may sometimes be caused by impaction of undigested foods.

Enterovesical fistulae may manifest as recurrent urinary tract infections and pneumaturia, enterovaginal fistulae as feculent vaginal discharge, and enterocutaneous fistulae as feculent soiling of the skin. Development of fistulae into the mesentery or luminal microperforation may result in intra-abdominal or retroperitoneal abscess formation.

Location and extent

The patient’s clinical presentation is primarily determined by the location and extent of the disease. Although any area of the GI system may be affected in patients with Crohn disease, the most common site of the chronic inflammatory process is the ileocecal region, followed by the colon (about 20%), the small intestine alone (about 30%), the stomach (rarely), and the mouth.[8] The esophagus is very rarely involved.[1]

The terminal ileum is involved in 50-70% of children. More than half of these patients also have inflammation in various segments of the colon, usually the ascending colon. Gastric inflammation, duodenal inflammation, or both may be observed in as many as 30-40% of children with Crohn disease. The primary pancreatic manifestation is pancreatitis.

About 45% of cases of Crohn disease occur in the ileum and colon, 20% solely in the colon, 33% in the small bowel, and 5% in the gastroduodenal region and perianal region alone (fistula, abscess, anal ulcer or stricture, or fissure).[45] Nearly 20-23% of patients with large bowel or small bowel disease have perianal complications, which may precede the development of intestinal symptoms and manifest as simple skin tags, anal fissures, perianal fistulae, or abscesses.[1] Symptoms may occur without involvement in any other area of the GI tract.

Physical Examination

The physical examination should focus on temperature, weight, nutritional status, the presence of abdominal tenderness or a mass, perianal and rectal examination findings, and extraintestinal manifestations (EIMs). Vital signs are usually normal in patients with Crohn disease, though tachycardia may be present in anemic or dehydrated patients. Chronic intermittent fever is a common presenting sign.

Abdominal findings may vary from normal to those of an acute abdomen. Diffuse abdominal tenderness or localized pain may be present.[12] Fullness or a discrete mass may be appreciated, typically in the right lower quadrant of the abdomen (which is usual with ileal involvement), or a mass may be felt secondary to thickened or matted loops of inflamed bowel.

The perineum should be inspected in all patients who present with signs and symptoms of Crohn disease because abnormalities detectable in this region substantially increase the clinical suspicion of inflammatory bowel disease (IBD). Inspection of the perianal region can reveal skin tags, fistulae, ulcers, abscesses, and scarring. A rectal examination can help to determine sphincter tone and aid in detecting gross abnormalities of the rectal mucosa or the presence of hematochezia.

In addition to local complications, various EIMs may be associated with Crohn disease, usually involving the skin, joints, mouth, eyes, liver, or bile ducts.[46] The most common EIMs are arthritis and arthralgia. The large joints (eg, hips, knees, ankles) are typically involved.[6]

Examination of the skin and oral mucosa may show mucocutaneous or aphthous ulcers, erythema nodosum, and pyoderma gangrenosum. Skin examination may also reveal pallor in patients with anemia or jaundice in those with concomitant liver disease with cholestasis. Eye examination may reveal episcleritis. For the diagnosis of uveitis, a slit-lamp examination by an experienced physician is necessary.

Careful assessment of growth and development is an important part of evaluating pediatric patients. Growth abnormalities may be detected by evaluating the following parameters:

  • Height and weight

  • Height and weight percentiles for the patient’s age, as well as weight percentile for the patient’s height

  • Growth velocity

  • Body composition on anthropometry

  • Skeletal bone age

The most sensitive indicator of growth abnormalities in children is a decrease in growth velocity, which may be observed before the major percentile lines on standard growth curves are crossed. Decreased height velocity before the onset of intestinal symptoms can be observed in as many as 46% of patients with Tanner stage 1 or 2 development. Height at maturity is often compromised. Pubertal delay may precede the onset of intestinal symptoms, and accurate Tanner staging should be a part of routine physical examination.

Intestinal Manifestations

The major intestinal complications of Crohn disease are due to the transmural nature of the disease, which leads to the formation of abscesses, fistulae, sinus tracts (incomplete fistulae ending in a cul-de-sac), strictures, and adhesions. These features may also contribute to bowel obstruction.

Microperforation typically occurs into other segments of bowel, leading to fistulae, or into areas such as the retroperitoneum, resulting in abscess formation. Perianal and perirectal fistulae occur in approximately 20-23% of individuals. Other complications of fistulizing disease include enterovesical, enterocutaneous, and rectovaginal fistulae, as well as extension into muscle in severe progressive cases.

Frank perforation is more uncommon, but it is one of the most serious complications of Crohn disease if it occurs. The presenting features of frank perforation are those of classic peritonitis, although these features can sometimes be masked by high-dose corticosteroid or immunosuppressant therapy.

Colonic malignancy is a clinically significant complication of Crohn disease with colonic involvement. Chronic inflammation is the conjectured etiology for the development of dysplasia followed by cancer. Most cases of colorectal cancer develop from early histologic lesions referred to as low-grade dysplasia (LGD) or dysplasia-associated lesion or mass (DALM). Sporadic adenomas can also progress to colon cancer. These are premalignant or precancerous lesions that progress to cancer via a pathway of inflammation and genetic mutations.

A meta-analysis revealed that the cumulative risk of colon cancer in Crohn disease approaches 3% at 10 years and 8% at 30 years.[47] It is widely known that individuals diagnosed at a younger age have a long disease duration (> 8 years), and that those with concomitant primary sclerosing cholangitis are at an increased risk for colorectal cancer.

The association of IBD with increased risk of colon cancer has led to North American consensus statements that recommend regular surveillance with colonoscopy every 1-3 years for those with either ulcerative colitis or colonic Crohn disease who have a disease duration longer than 8 years.

However, subsequent studies yielded different findings regarding the risk for colorectal cancer in people with Crohn disease. A population-based study did not show any temporal trends in colorectal cancer for Crohn disease, nor did it find an increased risk of such cancer in patients with this condition as compared with the general population.[48] In contrast, a health maintenance organization (HMO) study from Northern California found a 60% increased relative risk of colorectal cancer, which did not change over a 12-year period.[49]

Overall, with the advent of new technology (eg, chromoendoscopy) and the accumulation of evidence for the use of chemoprophylactic agents (eg, 5-aminosalicylic acid [5-ASA] and low-dose ursodiol), it appears that there may be a reduction in the risk for colorectal cancer in Crohn disease. At present, surveillance colonoscopy every 1-3 years remains the standard of care.

There is also a significant association between small bowel cancer and Crohn disease. However, the absolute risk is low. Future research may be helpful in clarifying incidence rates, duration and extent of disease, medication use, and other disease-modifying factors (eg, smoking) that may alter the risk stratification for small bowel cancer and Crohn disease.

Extraintestinal Manifestations (EIM)

EIMs may carry prognostic importance in Crohn disease.

Musculoskeletal disease

Musculoskeletal pain is considered the most common EIM of adult IBD, occurring in 9-53% of affected patients.[50, 51, 52] The differential diagnosis of this condition is vast and includes IBD-associated arthritides such as arthralgia (5-20%), ankylosing spondylitis (1-26%), psoriatic arthritis, reactive arthritis, and sacroiliitis, as well as fibromyalgia and osteoporosis and osteoporosis-related fractures.

The most common EIM in children and adolescents is arthritis (7-25% of pediatric patients), which may occur years before any GI symptoms develop and may persist after surgical or medical remission of the disease. The arthritis is usually seronegative, transient, and nondeforming; has an asymmetric distribution; and involves the large joints of the lower extremities.

In adults, the arthritis occurs when the disease is active and can affect large and small joints. Type 1 peripheral arthritis is pauciarticular (< 5 joints), and is strongly associated with IBD activity and other EIMs. The joint most commonly involved is the knee. Type 2 peripheral arthritis is polyarticular and independent of disease activity. The metacarpophalangeal (MCP) joint is the most commonly involved site; less frequently, the knees, ankles, shoulders, proximal interphalangeal (PIP) joint, and metatarsophalangeal (MTP) joint may be involved.

Dermatologic disease

Dermatologic EIMs occur in 2-34% of Crohn patients, with erythema nodosum the most common manifestation. Erythema nodosum is more common in Crohn disease than in ulcerative colitis and usually follows the course of the disease. This condition affects 3% of pediatric patients with Crohn disease and is less frequent than in adults. Approximately 75% of patients with erythema nodosum ultimately develop arthritis.

The lesions of erythema nodosum are raised, red, tender nodules that appear primarily on the anterior surfaces of the lower leg. These ulcers can be either solitary or multiple and either unilateral or bilateral, and they can range in size from several centimeters to distribution along an entire limb.

Although pyoderma gangrenosum is uncommon in Crohn disease, it may occur, even when the disease is in remission: 50% of patients will develop the rash despite quiescent Crohn disease activity. Therefore, medical therapy for the underlying bowel disease is not always successful. Consultation with a dermatologist may be necessary.

Other dermatologic manifestations include the following:

  • Sweet syndrome

  • Orofacial granulomatosis

  • Angular and aphthous stomatitis

  • Acrodermatitis enteropathica

  • Alopecia

  • Metastatic Crohn disease

  • Crohn disease of the vulva and penis

  • Psoriasis

Oral lesions

Aphthous ulceration in the mouth is the most common oral manifestation of Crohn disease, and it is commonly associated with skin and joint lesions. Oral lesions appear to parallel intestinal disease in most cases, but they may also develop before any GI symptoms occur.

Ophthalmologic disease

Ophthalmologic manifestations of Crohn disease (primarily episcleritis and anterior uveitis) most frequently occur when the disease is active. The rate of such manifestations is 0.5-5% in the adult population but is lower in children and adolescents.

The most common ocular manifestation is episcleritis, or inflammation of the vascular-rich episclera. Episcleritis should be suspected in patients who present with acute redness in one or both eyes, irritation, and burning. Uveitis is usually symptomatic, causing pain or decreased visual acuity. Treatment for these ocular EIMs is geared toward controlling the underlying bowel disease.

Other manifestations may include increased intraocular pressure and cataracts in children who receive corticosteroid therapy. Conjunctivitis also occurs. All patients with Crohn disease require ophthalmologic examination at regular intervals.

Urologic disease

Urologic EIMs include nephrolithiasis, hydronephrosis, and enterovesical fistulae. The incidence of gallstones and kidney stones is increased in Crohn disease because of malabsorption of fat and bile salts. Nephrolithiasis occurs in fewer than 5% of children with Crohn disease, usually as a result of the fat malabsorption that occurs with small bowel Crohn disease. Dietary calcium binds to malabsorbed fatty acids in the colonic lumen; therefore, free oxalate is absorbed. The absorption of free oxalate results in hyperoxaluria and oxalate stones.

Gallstones are formed as a consequence of an increased cholesterol concentration in the bile, caused by a reduced bile salt pool. In patients with an ileostomy, increased fluid and electrolyte losses may lead to concentrated acidic urine and the formation of uric acid stones. External compression of the ureter by an inflammatory mass or abscess may lead to hydronephrosis. Enterovesical fistulae may present with recurrent urinary tract infections or pneumaturia.

Hepatobiliary disease

Hepatobiliary disease is among the most common EIMs of Crohn disease and its therapies. Abnormal serum aminotransferase levels are common during the course of Crohn disease in children. Most aminotransferase elevations are transient and appear to relate to medications or disease activity. Aminotransferase elevations that persist for longer than 6 months should be investigated because the likelihood of serious liver disease is increased.

Both intrahepatic and extrahepatic manifestations of liver disease occur in children with Crohn disease. Intrahepatic manifestations include chronic active hepatitis, granulomatous hepatitis, amyloidosis, fatty liver, and pericholangitis. Extrahepatic manifestations include cholelithiasis and obstruction.

Cholelithiasis is more frequent in patients with IBD than in the general population, probably because of bile salt pool alteration from malabsorption. Chronic active hepatitis and sclerosing cholangitis develop in fewer than 1% of children with Crohn disease. Sometimes, a hepatic abscess manifests as fever of unexplained origin.

Primary sclerosing cholangitis is a progressive chronic liver condition of unknown etiology that increases the risk for cholangiocarcinoma and colorectal cancer in patients with IBD. Patients can be asymptomatic with mild elevations of transaminase and alkaline phosphatase, or they may present with advanced findings of cholangitis and jaundice. Magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) typically reveals strictures of medium and large intrahepatic and extrahepatic bile ducts.

Primary sclerosing cholangitis has an established strong association with IBD, particularly ulcerative colitis. About 5-10% of patients with primary sclerosing cholangitis have Crohn disease, but only 2% of Crohn disease patients develop primary sclerosing cholangitis. There is a 2:1 male prevalence for the disorder.

The clinical course of primary sclerosing cholangitis does not parallel bowel disease, and this condition can develop in the years before or after the development of GI symptoms. Patients with this disease may require transplantation if cirrhosis develops or if severe recurrent cholangitis occurs.

Other pancreatic or hepatobiliary manifestations of Crohn disease include the following:

  • Cirrhosis related to long-standing primary sclerosing cholangitis

  • Portal vein thrombosis

  • Cholangiocarcinoma

  • Pancreatitis (idiopathic or drug-induced)

Thromboembolic disease

Thromboembolic disease is considered to be the result of a hypercoagulable state that parallels disease activity and is manifested by thrombocytosis, elevated plasma fibrinogen, factor V, factor VIII, and decreased plasma antithrombin III. This state may lead to deep vein thrombosis, pulmonary embolism, and neurovascular disease.

Compared with control subjects, patients with IBD have a 3-fold higher risk of thromboembolism. These patients have frequent exposure to classic thrombosis risk factors, including immobility, surgery, steroid therapy, and the presence of central venous catheters. Other factors that may play a role include smoking, antiphospholipid antibody syndrome, and hyperhomocystinemia.

Additional extraintestinal diseases

Bone metabolic disorders include osteopenia and osteoporosis. Hematologic manifestations include iron deficiency anemia, vitamin B-12 deficiency anemia, folate deficiency anemia, anemia of chronic disease, autoimmune hemolytic anemia, thrombocytosis, anemia due to GI bleeding, and thrombosis.

Genitourinary manifestations include nephrolithiasis, obstructive uropathy, glomerulonephritis, and amyloidosis. Pulmonary manifestations include granulomatous lung disease, fibrosing alveolitis, and pulmonary vasculitis. Cardiovascular manifestations include pericarditis, myocarditis, and vasculitis.

Malabsorption can occur as a result of loss of functional mucosal absorptive surface. This phenomenon can lead to protein-calorie malnutrition, dehydration, and multiple nutrient deficiencies. Involvement of the terminal ileum may result in malabsorption of bile acids, which leads to steatorrhea, fat-soluble vitamin deficiency, and gallstone formation.

Fat malabsorption, by trapping calcium, may result in increased oxalate excretion (normally complexed by calcium), causing kidney stone formation. Steatorrhea and fat-soluble vitamin deficiency may also lead to clotting abnormalities, calcium deficiency, and osteomalacia, which may progress to osteoporosis. Vitamin B-12 deficiency may also occur with ileal resection or long-standing ileal disease.[1]

Disease Classification and Activity Scoring Systems

A system to homogenize the classification of IBD on the basis of disease location and behavior was first established in 1998 in Vienna, Austria.[53] Further developments in the field were reviewed, and the Montreal revision of the Vienna classification was proposed (see below), with special attention to predominant parameters of age at diagnosis, location, and behavior of disease.[54]

Montreal classification system

The Montreal revision of the Vienna system is based on the following 3 variables:

  • Age at diagnosis

  • Disease distribution/location

  • Disease behavior

Age at diagnosis (A) has 3 categories, as follows[54] :

  • A1 – ≤ 16 years

  • A2 – 17-40 years

  • A3 – > 40 years

Disease distribution/location (L) has the following 4 categories, 1 of which is a modifier for upper GI involvement[54] :

  • L1 – Ileal

  • L2 – Colonic

  • L3 – Ileocolonic

  • L4 – Isolated upper GI disease; L4 is a modifier that can be added to L1-L3 when there is concomitant upper GI involvement

Disease behavior (B) has 1 interim category (B1) and 2 specified categories, with an additional modifier for perianal diseases (p), as follows[54] :

  • B1 – Nonstricturing, nonpenetrating; B1p: nonstricturing, nonpenetrating with perianal involvement

  • B2 – Stricturing; B2p: stricturing with perianal involvement

  • B3 – Penetrating; B3p: penetrating with perianal involvement

Crohn disease activity indices

Multiple scoring systems incorporating the patient’s history, physical examination findings, and laboratory data have been developed to assess disease activity in adults with Crohn disease. These scoring systems are used principally for assessing the efficacy of treatment and evaluating new therapies for research purposes.

One such index is the Crohn Disease Activity Index (CDAI), which was developed for use in adults. The Pediatric Crohn Disease Activity Index (PCDAI) was developed and validated in 1990; the results are correlated with the physician’s global assessment and with the Harvey-Bradshaw index (HBI), and they have significant interobserver reliability. The important difference between the PCDAI and the CDAI is the inclusion of growth parameters in the PCDAI score.

A modified PCDAI (Mod PCDAI), consisting of the laboratory measures of the PCDAI plus the C-reactive protein (CRP) level, has been shown to correlate with the PCDAI, the physician’s assessment, and fecal calprotectin.[55] This modified index can be used as an alternative to the PCDAI, with the advantage of having additional objective laboratory values embedded in it.[55] Other authors have described a short PCDAI.[56]

Other activity indices and their parameters used for clinical and research purposes include the following:

  • HBI – General well-being, abdominal pain, number of liquid stools per day, presence of abdominal masses, and complications or EIMs

  • Seo index – General well-being, amount of blood in stool, number of bowel movements during the day and the night, urgency of defecation, and number of extracolonic manifestations

  • Perianal Crohn Disease Index (PDAI) – Perianal discharge, pain with restriction of daily activities, restriction of sexual activity, physician scoring of the type and number of perianal disease, and presence of induration

  • Fistula Drainage Assessment – Fistula healing, ranging from heavy drainage or abscess to complete closure

 

DDx

Diagnostic Considerations

Patients with Crohn disease frequently present with abdominal pain, nonbloody diarrhea, weight loss, fever, and, sometimes, obstructive symptoms such as nausea, early satiety, and vomiting. World Health Organization diagnostic criteria for Crohn disease include the following[57] :

  • Discontinuous or segmental lesions as well as a cobblestone appearance or longitudinal ulcer noted on radiologic studies, endoscopy, and resected specimens
  •  Transmural inflammation, as evidenced by clinical evaluation, radiologic studies, biopsy findings, and resected specimens
  • Noncaseating granulomas, as revealed on biopsy findings and resected specimens
  • Fissures and fistulas, as evidenced by clinical evaluation, radiologic studies, and resected specimens
  • Perianal disorders on clinical evaluation

A variety of intestinal manifestations and extraintestinal manifestations (EIMs) also may be observed in conjunction with either Crohn disease or ulcerative colitis. Features differentiating the two forms of inflammatory bowel disease (IBD) are summarized in Table 1, below.

Table 1. Characteristics Differentiating Crohn Disease and Ulcerative Colitis (Open Table in a new window)

Characteristic

 

Crohn Disease

Ulcerative Colitis

Distribution

Entire gastrointestinal tract

Colon only, though gastritis is recognized

Skip lesions

Continuous involvement proximally from rectum

Pathology

Full thickness

Mucosa only

Granulomas (15-30% in biopsy specimens; 40-60% in surgically resected bowel)

No granulomas

Radiology

Entire gastrointestinal tract

Colon only

Skip lesions

Continuous involvement proximally from rectum

Fistulae, abscesses, fibrotic strictures

Mucosal disease only

Cancer risk

Increased

Estimated to be 3% at 10 years, 8% at 30 years, and 18% at 30 years after diagnosis[47] ; risk is higher in patients with primary sclerosing cholangitis and long-standing colitis (> 8-10 y); may be lower in subsequent studies (see Intestinal Manifestations).

Presentation

 

Crohn Disease

Ulcerative Colitis

Bleeding

Occasional

Very common

Obstruction

Common

Uncommon

Fistulae

Common

None

Weight loss

Common

Uncommon

Perianal disease

Common

Rare

Other diagnostic considerations

Despite extensive workup, 15% of patients with isolated colitis have an undetermined type of IBD that shows features of both Crohn disease and ulcerative colitis. The distinction is often difficult to make, especially if the patient meets all diagnostic criteria for ulcerative colitis but is a smoker or has rectal sparing—features that suggest the possibility of Crohn disease or IBD of undetermined type.

In addition, there is a subpopulation of patients with Crohn colitis who will not develop small bowel disease in their lifetime. This group represents approximately 20% of the colitis patients.

Tuberculosis is also in the differential diagnosis of Crohn disease. Simple clinical findings (eg, fever, rectal bleeding, diarrhea, symptomatic duration) appear to be most accurate for differentiating Crohn disease from intestinal tuberculosis.[57] Anti–Saccharomyces cerevisiae antibodies (ASCA) do not help in differentiating small bowel tuberculosis from small bowel Crohn disease, but if both ASCA and interferon-gamma release assays are available and the ASCA result is positive, while the interferon gamma release assay result is negative, the specificity for Crohn disease is high, particularly in Asian populations.[57] Endoscopy in combination with radiologic and laboratory findings are also useful for differentiating between Crohn disease and intestinal tuberculosis.

In addition to excluding ulcerative colitis and intestinal tuberculosis, guidelines from the World Gastroenterology Organization recommend ruling out the following in the differential diagnoses of Crohn disease[58, 57] :

  • Behςet disease

  • Celiac disease

  • Irritable bowel syndrome (IBS) (if inflammatory changes are present, it is not IBS)

  • Nonsteroidal anti-inflammatory drug (NSAID) enteropathy

Differential Diagnoses

 

Workup

Approach Considerations

Crohn disease is initially diagnosed on the basis of a combination of clinical, laboratory, histologic, and radiologic findings. Laboratory study results are generally nonspecific but may be helpful in supporting the diagnosis and managing the disease. Serologic studies are sometimes used to facilitate differentiation of Crohn disease from ulcerative colitis or inflammatory bowel disease (IBD) of undetermined type.

Various imaging modalities are available to aid in the diagnosis and management of Crohn disease. Contrast radiologic studies are recommended to determine disease extent, disease severity and complications, and treatment strategy.[12] The choice of modality depends on the clinical question being asked, as follows:

  • Colonoscopy is the technique of choice to assess disease activity in patients with symptomatic colonic Crohn disease or ulcerative colitis;[59]  complementary cross-sectional imaging can be used to assess phenotype and as an alternative to evaluate disease activity[59]

  • Upper gastrointestinal (GI) endoscopy and/or colonoscopy and histologic examination are recommended in cases of suspected Crohn disease on the basis of clinical findings;[12] upper GI endoscopy is also recommended when lower GI endoscopy is unable to definitely diagnose Crohn disease or in the presence of upper GI symptoms, but not for asymptomatic newly diagnosed patients[59, 12]

  • Plain radiography or computed tomography (CT) scanning of the abdomen can be used to assess for bowel obstruction; these studies can also be used to assess the pelvis for the presence of any intra-abdominal abscesses

  • The use of CT enterography or magnetic resonance (MR) enterography is replacing small bowel follow-through (SBFT) studies; the enterographic images can better distinguish between inflammation and fibrosis

  • Magnetic resonance imaging (MRI) of the pelvis or endoscopic ultrasonography (ie, transrectal ultrasonography) can identify perianal fistulae anatomy and activity and detect the presence or absence of pelvic and perianal abscesses

Capsule endoscopy is sensitive for early mucosal inflammation, but it can only detect mucosal changes, whereas MRI and intestinal ultrasonography are able to reveal transmural inflammation, as well as identify complications.[59, 12] Furthermore, MRI detects fistulae, deep ulcerations, and a thickened bowel wall.[59] Ultrasonography is inexpensive and can be performed at the point of care by the treating gastroenterologist.

Ultrasonography, CT scanning, and MRI can determine pretreatment and posttreatment disease activity or identify disease complications.[12] Cross-sectional imaging should be used to detect strictures in the case of complications.[59] Because of radiation associated with CT scanning, the preferred methods are MRI and intestinal ultrasonography. Cross-sectional imaging is also recommended for the detection of abscesses. For the diagnosis of perianal Crohn disease, clinical and endoscopic rectal examination, as well as MRI, is recommended; ultrasonography in the absence of anal stenosis or transperineal ultrasonography is an alternative to MRI.[59]

A risk-stratification model based on levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), which are significantly associated with complications of Crohn disease, could reduce the use of computed tomography (CT) scans in patients reporting to the emergency department by 43%, while missing only 0.8% of emergencies, according to a retrospective analysis of 613 adult patients.[60] Researchers used logistic regression to model associations between these laboratory values and perforation, abscess, or other serious complications. Further validation studies of the models need to be performed.

Many centers favor judicious use of imaging and employ low-radiation protocols where possible, especially in younger individuals. Patients with complicated Crohn disease who undergo multiple radiologic examinations may be at risk for cumulative exposure to potentially excessive amounts of diagnostic radiation.[61, 62, 63, 64] Ultrasonography and MRI can be used as adjunct studies if radiation exposure is an issue in monitoring disease activity.

Interventional radiology is primarily used in the percutaneous drainages of abscesses that complicate Crohn disease, which may obviate the need for surgical resection.[65]

Endoscopic visualization and biopsy are essential in the diagnosis of Crohn disease. Colonoscopy with intubation of the terminal ileum is used to evaluate the extent of disease, to demonstrate strictures and fistulae, and to obtain biopsy samples to help differentiate the process from other inflammatory, infectious, or acute conditions. Given the increased risk of colorectal cancer in patients with IBD, colonoscopy may have a role in cancer surveillance, although the frequency of this practice remains controversial.

Upper gastrointestinal (GI) endoscopy may be used to diagnose gastroduodenal disease, if suspected. This study is recommended for all children, regardless of the presence or absence of upper GI symptoms.

For more information, see Imaging in Crohn Disease.

Routine Laboratory Studies

Laboratory results for Crohn disease are nonspecific and are of value principally for facilitating disease management. Laboratory values may also be used as surrogate markers for inflammation and nutritional status and to screen for deficiencies of vitamins and minerals.

Complete blood cell count

A complete blood cell (CBC) count  is useful in detecting anemia, which may be due to multiple causes, including chronic inflammation, iron malabsorption, chronic blood loss, and malabsorption of vitamin B-12 or folate. Leukocytosis may be due to chronic inflammation, abscess, or steroid treatment.

Chemistry panel

Electrolyte analysis can help determine the patient’s level of hydration and renal function. Hypoalbuminemia is a common laboratory finding in patients with suboptimally treated Crohn disease. Additional common abnormalities include deficiencies in iron and micronutrients (eg, folic acid, vitamin B-12, serum iron, total iron binding capacity, calcium, and magnesium). Liver function test results may be elevated, either transiently (because of inflammation) or chronically (because of sclerosing cholangitis).

Inflammatory markers

Acute inflammatory markers, such as C-reactive protein (CRP) level or erythrocyte sedimentation rate (ESR), may correlate with disease activity in some patients. If Crohn disease activity is suspected, however, a normal ESR or CRP level should not deter further evaluation.

Stool studies

Stool samples should be tested for the presence of white blood cells (WBCs), occult blood, routine pathogens, ova, parasites, and Clostridium difficile toxin. These studies should also be used to rule out infectious etiologies during relapses and before the initiation of immunosuppressive agents.[6]

Fecal calprotectin has been proposed as a noninvasive surrogate marker of intestinal inflammation in IBD.[66] The level of the inflammatory marker calprotectin in feces correlates significantly with endoscopic colonic inflammation in both ulcerative colitis and Crohn disease, and fecal lactoferrin is significantly correlated with histologic inflammation.[67] However, colorectal neoplasia and GI infection also increase fecal calprotectin; therefore, this study should be used with caution.

At present, fecal calprotectin is not in widespread use, except in research protocols. In the future, this marker may be made more available to clinicians for following patients’ disease activity.

Serologic Testing

There are 2 serologic tests that are currently used in efforts to differentiate ulcerative colitis from Crohn disease. Antibodies to the yeast Saccharomyces cerevisiae (ie, anti-S cerevisiae antibodies [ASCA]) are found more commonly in Crohn disease than in ulcerative colitis, whereas perinuclear antineutrophil cytoplasmic antibody (p-ANCA), a myeloperoxidase antigen, is found more commonly in ulcerative colitis than in Crohn disease.

The World Gastroenterology Organization (WGO) indicates that ulcerative colitis is more likely when the test results are positive for pANCA and negative for ASCA antigen;[57] however, the pANCA test may be positive in Crohn disease, and this may complicate obtaining a diagnosis in otherwise uncomplicated colitis.[58]

It should be noted that both tests are recommended only as an adjunct to the clinical diagnosis; the results are not specific and have been found to be positive in other bowel diseases. Patients with Crohn disease whose condition is ASCA-positive have a higher rate of surgery and require surgery earlier in the course of the disease, independent of the area of involvement.[1, 2, 6]

Additional serologic markers, such as Escherichia coli anti-ompC (outer membrane porin C), can be found in more than 50% of Crohn disease cases and in only a small percentage of ulcerative colitis cases. Pseudomonas fluorescens (anti-12) may be found in more than 50% of Crohn disease cases and in only 10% of ulcerative colitis cases. Flagellinlike antigen (anti-Cbir1) is associated independently with small bowel, intestinal penetrating, and fibrostenosing disease. These tests further increase sensitivity and diagnostic value.

Plain Abdominal Radiography

Abdominal radiography is a nonspecific test for evaluation of IBD; however, it can useful if there is concern about obstruction or perforation. If abdominal radiographs are obtained, findings may include mural thickening and dilatation, small bowel and colonic mucosal abnormalities, and abnormal fecal distribution with areas of colonic involvement without fecal material.[65]

In patients with known Crohn disease who present with acute exacerbation, symptoms, or suspected complications, radiographs can be obtained to evaluate for the presence of bowel obstruction, perforation (free air), or toxic colon distention.[65] These conditions necessitate rapid management.

For more information, see Imaging in Crohn’s Disease.

Barium Contrast Studies

Barium enema is noninvasive and usually well tolerated for evaluating features such as pseudodiverticula, fistulization, and the severity and length of colonic strictures. SBFT and enteroclysis may be valuable in demonstrating the distribution of small bowel disease in a patient presenting with suspected IBD. Mucosal fissures, bowel fistulae, strictures, and obstructions can be visualized. The terminal ileum may be narrowed and thickened, with a characteristic pipe appearance.

However, barium studies are contraindicated in patients with known perforation, and water-soluble agents should be used in place of barium. Barium can also cause peritonitis. Although in the past, barium contrast studies were the imaging modalities of choice for Crohn disease, these studies now are less commonly used, with the advent of new and more detailed CT, MRI, and capsule endoscopy techniques to assess for small bowel and pelvic Crohn disease.

For more information, see Imaging in Crohn Disease.

Small bowel follow-through

An upper GI SBFT and spot films of the terminal ileum can be used to assess the small bowel of patients with suspected Crohn disease. SBFT can also detect alteration of the small bowel wall indirectly (through findings such as enteroenteric and enterocolonic fistulization.

Radiographic findings in both the small and the large bowel parallel the clinical pattern. Edema and ulceration of the mucosa in the small bowel may appear as thickening and distortion of valvulae conniventes. Edema of the deep layers of the bowel wall results in separation of the barium-filled bowel loops. Tracking of deep ulcerations, both transversely and longitudinally, results in a cobblestone appearance (see the image below).

Cobblestoning in Crohn disease. Spot view of the t Cobblestoning in Crohn disease. Spot view 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.

Ileitis can also manifest as a string sign on barium studies secondary to spasm or, rarely, because of fibrotic stricture (see the following images).

Crohn disease of terminal ileum. Small bowel follo Crohn disease of terminal ileum. Small bowel follow-through study demonstrates the string sign in terminal ileum. Also, note pseudodiverticula of the antimesenteric wall of terminal ileum, secondary to greater distensibility of this less-involved wall segment.
Spot view of the terminal ileum from a small bowel Spot view of the terminal ileum from a small bowel follow-through study in a patient with Crohn disease demonstrates the string sign, consistent with narrowing and stricturing. Also, note a sinus tract originating from the medial wall of the terminal ileum and the involvement of the medial wall of the cecum.

Enteroclysis

Overall, enteroclysis is reserved for complicated cases. This imaging modality is roughly as accurate as SBFT and has a shorter examination time; however, the peroral SBFT examination uses less total room time, radiologist time, and radiation, and it has greater patient tolerability.[65]

A useful adjunct study to the initial SBFT or enteroclysis is the peroral pneumocolon evaluation, in which air is instilled per rectum after the opacification of the terminal ileum.[65] This double-contrast examination allows assessment of the distal small bowel or ascending colon or both and often yields improved mucosal detail and greater distention of the terminal ileum.[65]

Barium enema

If the patient can tolerate a barium enema, this study may help in the evaluation of colonic lesions (see the following images).

Aphthous ulcers. Double-contrast barium enema exam Aphthous ulcers. Double-contrast barium enema examination in Crohn colitis demonstrates numerous aphthous ulcers.
Double-contrast barium enema study demonstrates ma Double-contrast barium enema study demonstrates marked ulceration, inflammatory changes, and narrowing of right colon in patient with Crohn colitis.

Fistulae can also be detected by barium studies of the digestive tract or through injection into the opening of the suspected fistulae (see the image below).[68, 69, 70]

Enterocolic fistula in patient with Crohn disease. Enterocolic fistula in patient with Crohn disease. Double-contrast barium enema study demonstrates multiple fistulous tracts between terminal ileum and right colon adjacent to the ileocecal valve (so-called double-tracking of ileocecal valve).

Computed Tomography Scanning

Computed tomography (CT) scanning is helpful in—and considered the imaging technique of choice for—the assessment of extramural complications as well as hepatobiliary and renal complications in adults and children.[65, 68, 69, 70]  It may show bowel wall thickening, bowel obstruction, mesenteric edema, abscesses, or fistulae (see the image below).

Active small bowel inflammation in a patient with Active small bowel inflammation in a patient with Crohn disease. This CT scan demonstrates small bowel wall thickening, mesenteric inflammatory stranding, and mesenteric adenopathy.

CT enterography can be helpful in the assessment of subtle and obvious mucosal damage. VoLumen oral contrast (Bracco Diagnostics, Princeton, NJ) is used as a negative agent to enhance small bowel wall changes, if present. Active disease is demonstrated by bowel wall thickening and mural hyperenhancement that occurs in a stratified enhancement pattern and a hyperemic vasa recta.[65] In the presence of severe inflammation, perienteric inflammatory changes can be seen.

CT enterography is also useful in deciphering whether a stricture is fibrostenotic rather than inflammatory or mixed. The degree and length of narrowing are important in planning for endoscopic examination (eg, by determining whether dilation is possible) and in preoperative staging.

The American College of Radiology (ACR) indicates that CT may be more sensitive than barium studies in detecting Crohn disease, owing to its ability to visualize pelvic small bowel loops,[71, 72] which are often obscured by overlapping bowel in barium studies. This and other evidence partially explain why CT has become the procedure of choice not only for helping diagnose Crohn disease but also for managing abscesses. Moreover, a growing body of literature shows that CT-guided percutaneous abscess drainage may obviate surgery.

For more information, see Imaging in Crohn Disease.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) has been shown to yield a higher sensitivity and specificity than ileocolonoscopy (the criterion standard) both for diagnosing Crohn disease and for determining its severity.[73, 74] It is especially useful for evaluating pelvic and perianal disease when one is investigating for evidence of perianal fistulae and abscesses (see the image below). Typical changes depicting active disease include thickening of the bowel wall, high T2 signal of the walls with hyperenhancement and stratification, and hyperemic vasa recta.[65]

MRI demonstrates inflamed terminal ileum in 10-yea MRI demonstrates inflamed terminal ileum in 10-year-old girl with Crohn disease.

In a prospective study comparing the use of MRI to the standard Crohn Disease Endoscopic Index of Severity (CDEIS), MRI was validated as a modality that accurately assesses intestinal wall thickness, the presence and degree of edema, and ulcers in patients with Crohn disease.[75] This study confirmed that through relative contrast enhancement (RCE), MRI plays an essential role in predicting disease activity and severity in Crohn disease.[75]

MRI is the study of choice for evaluation and management of perianal Crohn disease. It can be superior to CT in demonstrating pelvic lesions. In addition, MRI can be used when ionizing radiation is contraindicated and in children and pregnant women (if done without gadolinium).[65] Compared with CT, MRI of the pelvis can more accurately detect pelvic and perianal abscesses, as well as better categorize fistula anatomy and activity.

MR enterography and CT enterography are increasingly being used for evaluation of the small bowel. Compared with SBFT, both of these studies are as sensitive and specific, and possibly more accurate, in detecting extraenteric complications, including fistulae and abscesses.[76] Because of the lack of radiation exposure, MR enterography is a particularly attractive option.

Owing to the differential water content, MRI can differentiate active inflammation from fibrosis as well as distinguish between inflammatory and (fixed) fibrostenotic lesions in Crohn disease.[68, 69, 70]

Studies have shown that MR enterography may be superior to CT enterography in the depiction of disease activity (eg, mural thickening and enhancement)[77] and in the detection of stricture presence.[78] In particular, the positive impact on medical or surgical management has been noted in evaluation of small bowel Crohn disease[79] ; these conclusions have been gathered by comparing findings on MR enterography to endoscopic evaluations and surgical pathology reports.

For more information, see Imaging in Crohn Disease.

Ultrasonography

Ultrasonography is a quick, inexpensive, and noninvasive screening method used for the diagnosis of IBD or for repeated evaluation for complications.[68, 69, 70] Abdominal ultrasonography can rule out gallbladder and kidney stones as well as detect enlarged lymph nodes and abscesses. However, it has a steep learning curve that yields a range of sensitivity that is operator-dependent. Because of their lack of radiation exposure, ultrasonography and MRI are often preferred to CT, especially in younger patients.[65]

Rectal endoscopic ultrasonography has been used as an alternative to MRI in the assessment of perianal disease. This technique allows differentiation of simple fistulae from complex ones, as well as assessment of fistula tracts in relation to the sphincter muscle.[68, 69, 70] Ultrasonography has been shown to improve the outcomes of fistula healing when used in conjunction with surgical seton (silk string) placement and anti-tumor necrosis factor (TNF) therapy.[80, 81, 82]

For more information, see Imaging in Crohn’s Disease.

Endoscopy and Colonoscopy

Colonoscopy

Ileocolonoscopy is a highly sensitive and specific tool in the diagnosis and management of patients with suspected or already established IBD. This procedure is useful in obtaining biopsy tissue, which helps in the differentiation of other diseases, in the evaluation of mass lesions, and in the performance of cancer surveillance.

Colonoscopy also enables dilation of fibrotic strictures in patients with long-standing disease and has been used in the assessment of mucosal healing. In addition, it may be used in the postoperative period to evaluate surgical anastomoses as a means of predicting the likelihood of clinical relapse as well as the response to postoperative therapy.[1]

Ileocolonoscopy has a sensitivity of 74% and a specificity of 100% in the assessment of Crohn disease, leading to a positive predictive value of 100% as a diagnostic test.[45] When paired with small bowel imaging, the sensitivity of this pair of diagnostic tests is increased to 78%, with a continued positive predictive value of 100%.[45]

For patients with Crohn disease of the colon, magnifying endoscopy allows a more detailed view of the mucosal surface than conventional endoscopy does. In combination with chromoendoscopy (methylene blue), it is possible to analyze the surface staining pattern further to help identify neoplastic changes in situ and take targeted biopsies.[6, 25, 68, 69, 70]

For more information, see Colonoscopy.

Upper GI endoscopy

Upper GI endoscopy (or esophagogastroduodenoscopy [EGD]) with biopsy is helpful in differentiating Crohn disease from peptic ulcer disease induced by nonsteroidal anti-inflammatory drugs (NSAIDs) or Helicobacter pylori or from fungal and viral gastroenteritis in patients with upper GI tract symptoms. A history of ileocolic Crohn disease in a patient with unexplainable upper GI symptoms warrants an EGD.

Endoscopic retrograde cholangiopancreatography

Endoscopic retrograde cholangiopancreatography (ERCP) is helpful as a diagnostic procedure and a therapeutic tool in patients with sclerosing cholangitis and biliary stricture formation. Magnetic resonance cholangiopancreatography (MRCP) may provide equally valuable information without invasive complications. A dominant biliary stricture may benefit from balloon dilation, stent placement, or both, though the latter is controversial in the management of primary sclerosing cholangitis.

Small bowel enteroscopy and capsule endoscopy

Single- and double-balloon enteroscopy allows complete evaluation of the small bowel and makes distal ileal biopsies feasible. Enteroscopy can also be helpful in the detection of complications of Crohn disease, such as stricture and active disease.

Wireless capsule endoscopy helps to identify involvement of the upper GI tract and may be especially useful in cases of jejunal or proximal ileal anastomotic surveillance. Drawbacks of this technique include the inability to take biopsies and the risk of acute obstruction. If an obstruction is suspected, small bowel imaging should be done before capsule endoscopy.

Guidelines on the use of enteroscopy and endoscopy in the diagnosis and management of IBD are available from the American Society for Gastrointestinal Endoscopy.[83]

Nuclear Imaging

Radionucleotide scanning may be helpful in assessing the severity and extent of the disease in patients who are too ill to undergo colonoscopy or barium studies.[68, 69, 70] However, nuclear imaging studies are not the tests of choice: MRI, CT, and endoscopic examination of the mucosa for active disease are preferred.

Leukocytes labeled with either technetium-99m (99m Tc )-HMPAO (hexamethyl propylene amine oxime) or indium-111 (111 In) can be used to assess for active bowel inflammation in IBD. The99m Tc-labeled leukocytes may be able to obtain an exact image of the inflammatory disease distribution and intensity at a moment in time—in a single examination.[65]

Compared with the111 In label, the99m Tc-HMPAO label has better imaging characteristics and can be imaged much sooner after injection. However, imaging must typically be performed within 1 hour after the injection of99m Tc- HMPAO–labeled leukocytes because there is normal excretion into the bowel after this time; in contrast,111 In-labeled leukocytes have no normal bowel excretion.

Fluorine-18-2-fluoro-2-deoxy-D-glucose (FDG) combined with positron emission tomography (PET) or CT helps improve localization of the tracer in areas of active inflammation, but false-positive results can occur with inadequate distention of the bowel.[65] Studies are being conducted to evaluate combining PET/CT with CT enterography/enteroclysis techniques with the aim of further improving localization while reducing the rate of false-positive findings.[65]

For more information, see Imaging in Crohn’s Disease.

Histology

The characteristic pattern of inflammation in Crohn disease is transmural involvement of the bowel wall by lymphoid infiltrates that contain noncaseating granulomas in about 15-30% of cases of biopsy samples and 40-60% of surgical specimens. A granuloma is defined as a collection of monocyte/macrophage cells and other inflammatory cells, with or without giant cells (see the image below).

Granuloma in mucosa of a patient with Crohn diseas Granuloma in mucosa of a patient with Crohn disease.

Other characteristics include 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 severe cases, long and deep fissurelike ulcers form.

Upper GI tract Crohn disease may be more challenging to diagnose. The histologic picture of gastric Crohn disease is typically described as focally enhancing gastritis in the setting of negative H pylori or other infections. Esophageal or duodenal biopsies in Crohn disease may reveal villous architectural changes with moderate inflammation. Granulomas generally are not identified, but when they are present, they provide substantial corroborative evidence for the diagnosis.

 

Treatment

Approach Considerations

Treatment of Crohn disease is made on the basis of the disease site, pattern, activity, and severity.[12]  The general goals of treatment for Crohn disease are as follows:

  • To achieve the best possible clinical, laboratory, and histologic control of the inflammatory disease with the least adverse effects from medication

  • To permit the patient to function as normally as possible

  • In children, to promote growth with adequate nutrition

Treatment of Crohn disease has changed over the past few years, reflecting new therapies that can target specific locations in the gastrointestinal (GI) tract and specific cytokines. The development of biologic anti–tumor necrosis factor (anti-TNF) agents (eg, infliximab, adalimumab, certolizumab pegol, and natalizumab) has significantly advanced the treatment of Crohn disease and improved the induction and maintenance of clinical remission in patients with moderate to severe disease, especially in those who are corticosteroid dependent.[84]  Anti-TNF agents are effective for induction and maintenance of remission in patients with Crohn disease and active inflammation.[12]

Antibiotics can decrease anal fistula discharge and may induce remission in Crohn disease.[12]

If medical therapy for active Crohn disease fails, surgical resection of the inflamed bowel, with restoration of continuity, is indicated. Urgent surgery may be required in rare cases of sustained or recurrent hemorrhage, perforation, abscess, and toxic megacolon. Partial small bowel obstruction or intra-abdominal abscess may sometimes be treated conservatively with intravenous (IV) hydration, nasogastric suction, and parenteral nutrition if there is no evidence of ischemia.[2, 85]

If pharmacotherapy or nutritional therapy is ineffective or unadaptable for those with active colonic disease, the combination with granulocyte monocyte apheresis may be considered.[12]

The first randomized controlled trial of stem cell transplantation in treatment-resistant Crohn disease was performed in 2013, in 45 patients with moderately to severely active disease. All patients underwent stem cell mobilization with cyclophosphamide and filgrastim and were then randomly assigned to immediate stem cell transplantation (at 1 month) or delayed transplantation (at 13 months; control group). At 1-year follow-up, objective endoscopic findings were substantially better in the treatment group; on the Simple Endoscopic Score for Crohn's Disease (SES-CD), the mean lower gastrointestinal score fell from 13 to 4 in the treatment group but remained unchanged in the control group. The treatment group also showed a greater decrease than the control group in median Crohn's Disease Activity Index score (approximately 165 vs 50 points). Two thirds of the treatment group were able to discontinue immunosuppressive drugs and steroids at 1 year, compared with 15% of the control group.[86]

About 7% of large bowel strictures in patients with long-standing Crohn disease are malignant; these should be surveyed with multiple biopsies and cytologic brushing for neoplastic transformation.[7] Resection is generally performed when strictures cannot be appropriately surveyed, if neoplastic changes are observed, or obstruction is persistent.[7]

Outpatient vs inpatient management

Many patients with an exacerbation of Crohn disease can be treated on an outpatient basis. However, if a serious complication of Crohn disease (eg, obstruction, perforation, abscess, or hemorrhage) is a concern or if outpatient treatment fails, IV therapy (eg, corticosteroids, antibiotics, or total parenteral nutrition [TPN]) may be required, and hospitalization is warranted.

Patients should be examined on a regular basis, with the frequency of examination depending on the severity and activity of their disease. Follow-up laboratory workup and diagnostic testing should be performed regularly as needed to monitor the safety and success of therapy. Clinical and biochemical responses to treatment should be determined in the 12-week period after the initiation of therapy, and endoscopy or transmural responses to therapy should be evaluated in the 6 months after the start of therapy.[59]

Step-up vs top-down approach

Therapy for mild Crohn disease is typically administered in a sequential “step-up” approach, in which less aggressive and less toxic treatments are initiated first, followed by more potent medications or procedures if the initial therapy fails. Patients are treated with preparations of 5-aminosalicylic acid (5-ASA), antibiotics, and nutritional therapy. However, the use of 5-ASA for the treatment of Crohn disease is controversial; only a small subset of patients may benefit from this agent. Although 5-ASA is effective for reducing disease activity in active Crohn disease, it typically has a lower efficacy for Crohn disease than for ulcerative colitis, and its efficacy for maintenance of remission remains unproven.[12]

If no response occurs or if the disease is more severe than initially thought, corticosteroids and inhibitors of DNA synthesis (ie, immunomodulators) with 6-mercaptopurine (6-MP)/azathioprine or methotrexate are administered. Finally, biologic agents (infliximab, adalimumab, certolizumab pegol, and natalizumab) and surgical therapies can be useful.

For the treatment of moderate to severe Crohn disease, current recommendations include the “top-down” approach, which differs from the conventional step-up approach in that more potent agents are administered initially. Top-down therapies include biologic agents and steroids as needed versus combination therapy with both biologic drugs and immunomodulator agents.

Randomized trials have shown that the combination of azathioprine or 6-MP with a biologic agent is more effective in the induction of remission, steroid-free remission, and mucosal healing than either azathioprine/6-MP alone or a biologic agent alone.[87] However, it is unclear whether these findings hold true in clinical practice; thus, physicians must consider the risks and benefits of therapy to avoid overtreatment.

Azathioprine or 6-MP is effective for maintenance of remission in Crohn disease; each is effective for avoiding surgery and for preventing postoperative and endoscopic relapse.[12] Both agents can be used in combination with infliximab.

At present, it is clear that a subset of patients with Crohn disease is at a higher risk for complications of the disease; these individuals should be considered for top-down therapy. Poor prognostic indicators include young age at diagnosis, perianal disease, upper GI tract involvement, multiple extraintestinal manifestations (EIMs), active tobacco use, and perforating (ie, fistulizing) disease.

Pharmacologic Therapy for Diarrhea

Diarrhea may develop as a result of active disease. Other possible causes include acute infection (ie, C difficile), bacterial overgrowth, loss of ileocecal valve, short bowel syndrome, lactase deficiency, concomitant celiac disease, and functional bowel syndrome. Chronic diarrhea in Crohn disease responds well to antidiarrheal agents such as loperamide, bile acid binders (for bile acid diarrhea), diphenoxylate with atropine, and tincture of opium. Such agents should be considered with care in active colitis because of the risk of toxic megacolon.

Patients with terminal ileal disease or previous terminal ileal resection may not absorb bile acids normally, and this abnormality can lead to secretory diarrhea in the colon. These patients may benefit from bile acid sequestrants (eg, cholestyramine or colestipol). Those who have extensive ileal disease or have undergone resection of more than 100 cm of the ileum have defective bile salt absorption and develop steatorrhea; they benefit from a low-fat diet and medium-chain triglyceride preparations. Bile sequestrants exacerbate this type of diarrhea.

Abdominal cramps may be reduced with antispasm agents such as propantheline, dicyclomine, or hyoscyamine. However, these drugs should not be used if there is the possibility of bowel obstruction.[2, 85]

Anti-inflammatory and Immunosuppressant Therapy for Active Crohn Disease

For colon and small bowel inflammation in Crohn disease, anti-inflammatory drugs or antibiotics are helpful. Sulfasalazine is useful mainly in colonic disease; the active compound 5-ASA is released in the large bowel by bacterial degradation of the parent compound. Sulfasalazine does not alleviate small bowel disease and has no additive effect or steroid-sparing effect when used together with corticosteroids. In addition, in contrast to its action in ulcerative colitis, sulfasalazine seems not to maintain remission in Crohn disease.[88]

Products such as mesalamine, which release 5-ASA in the distal small bowel when triggered by pH changes, are more useful in patients with small bowel Crohn disease. Long-term maintenance with mesalamine may delay clinical relapse. Controlled release of mesalamine is thought to begin at the pylorus and to continue at a constant rate throughout the small bowel and colon; consequently, this drug is sometimes used when proximal intestinal and gastric Crohn disease is found.

5-ASA provides only modest benefit in preventing relapse of Crohn disease in remission after surgery. It can be considered for mild Crohn disease when immunosuppressive therapy is either not warranted or contraindicated.

A short course of corticosteroid therapy is indicated in patients with severe systemic symptoms (eg, fever, nausea, or weight loss) and in those whose condition does not respond to anti-inflammatory agents. Prednisone is generally helpful in acute inflammation without signs of obvious infection. In patients with a tender, palpable mass, the possibility of an underlying abscess should be excluded before steroids are started. Adding antibiotics such as ciprofloxacin or metronidazole is always beneficial if coexisting infection exists.

Steroids are not indicated for maintenance, because of serious complications (eg, aseptic necrosis of the hip, osteoporosis, cataract, diabetes, and hypertension). Accordingly, once remission is achieved, the agent is slowly tapered. It should be noted that steroids do not modify disease or induce sustained mucosal healing.

Enteric-coated ileal-release preparations with decreased systemic effects (eg, budesonide) have been developed to treat ileal and cecal Crohn disease. Budesonide induces remission in active Crohn disease but is less effective than other standard glucocorticosteroids and is of no benefit in preventing relapse.[89] For relapse after steroid withdrawal, other treatment options are required.

If steroid withdrawal proves difficult, immunosuppressants such as azathioprine or its active metabolite 6-MP may be considered. Treatment response is usually observed within 3-6 months. Because of the risk of bone marrow suppression, careful supervision is needed.

Before the initiation of therapy, thiopurine methyltransferase (TPMT) activity should be measured to identify patients predisposed to altered drug metabolism, which increases the risk of early leukopenia. Measurement of 6-thioguanine nucleotide (6-TG) metabolites is helpful in assessing compliance and adjusting dosing.

Methotrexate is effective in inducing and maintaining remission in Crohn disease in adults; it has also been shown to be effective and well tolerated for maintenance of remission in children.[90] The onset of action is shorter for methotrexate than for 6-MP, and the once-weekly dosing is sometimes preferred. Whether oral therapy is as effective as parenteral therapy is unclear.

A systemic review of the efficacy of biologic therapies in IBD (see below) confirmed that placebo is inferior to anti−TNF-α antibodies and natalizumab in inducing remission of active Crohn disease.[91]

Biologic Therapy

Tumor necrosis factor (TNF), a key inflammatory cytokine and mediator of intestinal inflammation, is expressed prominently in inflammatory bowel disease (IBD). Patients likely to benefit from anti-TNF therapy include the following[84] :

  • Patients who have moderate to severe debilitating symptoms of Crohn disease, who have documented active inflammation, or who are dependent on corticosteroids and unable to taper these agents without return of symptoms

  • Patients who do not show evidence of active bowel infection as a cause of GI symptoms

Before administering anti-TNF agents, clinicians should screen patients for Mycobacterium tuberculosis. In addition, caution is advised if a patient is a hepatitis B virus carrier.[84]

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 TNF-α blockers.[92] The advisory addressed the risk of Legionella and Listeria infections, as well as the consistency of the information in the Boxed Warning and Warnings and Precautions sections regarding the risk of serious infections and the associated disease-causing organisms.[92]

Another area of concern with the use of these anti−TNF-α medications is that several patients have been reported to develop a rare hepatosplenic T-cell lymphoma when treated with dual therapy of 6-MP or azathioprine as well as a TNF-α inhibitor. Although this has been a rare complication, all reported cases have been in adolescents and young adults.

A meta-analysis that evaluated the efficacy of anti-TNF treatment with or without immunomodulator (IM) therapy in patients with Crohn disease following ileal pouch anal anastomosis (IPAA) for ulcerative colitis showed no difference in clinical outcomes (both complete and partial clinical response rates) with anti-TNF monotherapy relative to anti-TNF therapy administered concurrently with IM.[93]  However, use of anti-TNF monotherapy showed a trend toward a higher risk of major and minor adverse events compared with anti-TNF with IM.

Infliximab

Infliximab is a chimeric mouse-human monoclonal antibody against TNF-α that has shown promise in Crohn disease treatment; it blocks TNF-α in the serum and at the cell surface, leading to the lysis of TNF-producing macrophages and T cells. Infliximab has also been approved for the treatment of pediatric Crohn disease.

According to the American Gastroenterological Association (AGA), infliximab is indicated for the following:

  • Treatment of patients with Crohn disease who do not achieve adequate clinical response despite treatment with conventional therapy (ie, a corticosteroid or an immunosuppressive agent)

  • Treatment of fistulizing Crohn disease that is refractory to conventional therapy (ie, antibiotics, surgical drainage with examination under anesthesia, immunosuppressive therapy, or combinations thereof)[94]

Patients who respond to induction therapy with infliximab should receive maintenance therapy.[94]

In one study, nearly 65% of refractory cases of Crohn disease responded well to treatment with infliximab (5 mg/kg), and one third went into complete remission.[95] Patients who relapsed after the initial response responded again to further infusions.

Infliximab is also effective in patients who have refractory perianal and enterocutaneous fistulae. Current clinical practice is to give 5 mg/kg IV at 0 weeks, 2 weeks, and 6 weeks, followed by maintenance IV infusions every 8 weeks. On average, the effect lasts for 12 weeks.

Important adverse effects include the development of a lupus like syndrome, multiple sclerosis, psoriasiform rash, and opportunistic or fungal infections (eg, Pneumocystis jiroveci pneumonia or histoplasmosis). Anti–double-stranded DNA is not always associated with clinical lupus. An added benefit of infliximab treatment is the potential ability to taper steroids, which will decrease further adverse effects.[96, 97]

In a study of 115 patients with Crohn disease who were treated for 1 year with infliximab and an antimetabolite, with at least 6 months of corticosteroid-free remission, and then followed up at 1 year (median, 28 months), nearly half (52/115; 45.2%) experienced a relapse.[98] The 1-year relapse rate was 43.9%.

In this study, risk factors for relapse included male sex, leukocyte count higher than 6.0 × 109/L, C-reactive protein (CRP) level of 5.0 mg/L or higher, and fecal calprotectin level of 300 µg/g or higher.[98] However, retreatment with infliximab was effective in 88% of patients with a relapse and was well tolerated.

Unfortunately, infliximab is immunogenic, and long holidays between infusions may result in the development of antibodies to infliximab that lead to infusion reactions, loss of efficacy, and delayed hypersensitivity reactions.[99]

Adalimumab and certolizumab pegol

Two other anti−TNF-α agents, adalimumab and certolizumab pegol, may be less immunogenic than infliximab and have shown efficacy in the treatment of Crohn disease that is refractory to the standard medical treatment of corticosteroids and inhibitors of DNA synthesis.[99]

Adalimumab is a recombinant human immunoglobulin (Ig) G1 monoclonal antibody that binds with a high affinity and specificity to human soluble TNF-α but not to lymphotoxin (TNF-β). Study results have shown that the immunogenicity of adalimumab is low compared with that of the chimeric agent infliximab.[99]

Two placebo-controlled trials, CLASSIC I and II (CLinical assessment of Adalimumab Safety and efficacy Studied as Induction therapy in Crohn’s disease), showed that adalimumab was effective for both induction and maintenance of remission in patients who were previously naive to anti-TNF therapy.[26, 100]

The CHARM (Crohn’s trial of the fully Human antibody Adalimumab for Remission Maintenance) trial demonstrated the same effect in a mixed population of patients who were either naive to infliximab therapy or who had previously been on infliximab therapy.[101] In patients who had lost response to or become intolerant of infliximab, the GAIN (Gauging Adalimumab efficacy in Infliximab Nonresponders) trial results showed a benefit from adalimumab therapy induction with remission at 4 weeks.[102]

Furthermore, an open-label study conducted in France that assessed the long-term efficacy and safety of adalimumab maintenance therapy in this population showed that it was well tolerated and effective in maintaining clinical remission in patients who had Crohn disease with a lost response to or intolerance of infliximab.[26, 103, 104]

A review of randomized clinical trials using adalimumab in the treatment of Crohn disease recommended initiating adalimumab as a loading dose of 160/80 mg subcutaneously at week 0/week 2, followed by 40 mg every other week as a maintenance dose in order to determine whether there is a response.[84]

In the PRECISE (Pegylated Antibody Fragment Evaluation in Crohn’s Disease: Safety and Efficacy) trials, certolizumab pegol, a humanized Fab’ antibody fragment conjugated to polyethylene glycol, demonstrated efficacy in maintaining remission in patients with moderately to severely active Crohn disease.

In PRECISE 1, certolizumab yielded greater clinical response (37%) in patients with high CRP levels (≥ 10 mg/L) at week 6 than placebo (26%), as well as greater persistence of response at 6 months (22% vs 12%, respectively).[105] Remission rates did not differ between treatment and placebo groups. In PRECISE 2, when week 6 responders were randomized to drug or placebo, certolizumab yielded clinical remission in 36% and clinical response in 63%.[106] In PRECISE 3, 41% of patients achieved remission at 12 months and 36% at 18 months.[107]

Natalizumab

Natalizumab is a humanized monoclonal antibody that prevents the accumulation of lymphocytes in the diseased bowel by binding α4β7 integrin (gut specific). It also binds to α4β1 integrin (CNS specific). Clinical data indicate that this drug is effective in inducing clinical response and remission of active moderate to severe Crohn disease. It is administered in a single 300-mg dose every 4 weeks up to 12 weeks, at which time it may be stopped if it is not effective.

This drug was initially taken off of the market in 2005 as a result of reported cases of progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis[2] ; it was then reintroduced into the market with restrictions for the indication of refractory multiple sclerosis in 2006 and Crohn disease in 2008.

PML is an opportunistic infection caused by the JC virus that typically only occurs in patients who are immunocompromised. As of August 1, 2012, there were 271 confirmed cases of PML worldwide; in individuals treated with natalizumab, one was a patient with Crohn disease who was receiving 35 infusions of natalizumab.[108] Individuals at risk include those with the following[109] :

  • JC virus antibody positivity

  • Previous exposure to immunosuppressant therapy

  • More than 2 years of treatment with natalizumab

The risk of developing PML is less than 1 in 1000 users, but it increases to 11 per 1000 users if all 3 risk factors are present.[109]

Natalizumab therapy is currently reserved for individuals with moderate to severe Crohn disease who are intolerant of or have lost response to other biologic or immunosuppressant therapies. The ENACT (Evaluation of Natalizumab As Continuous Therapy)[110] and ENCORE (Efficacy of Natalizumab in Crohn’s Disease Response and Remission)[111] trials evaluated the efficacy of natalizumab in the induction of response (ENACT 1 and ENCORE) and maintenance of response (ENACT 2) in patients with active Crohn disease.

In ENACT 1, natalizumab induced clinical response at week 10 in patients with an elevated C-RP level.[110] ENCORE found a 48% clinical response rate and 26% clinical remission rate at week 8.[111] In ENACT 2, of patients from ENACT 1 who had had a clinical response to natalizumab and who were rerandomized to maintenance therapy with natalizumab 300 mg or placebo every 4 weeks for 1 year, 61% of patients in the natalizumab group maintained response, and 44% achieved remission through weeks 36 and 60.[110]

Vedolizumab

Vedolizumab, another integrin antagonist, is approved for Crohn disease and ulcerative colitis. It is specific for α4β7 integrin. Approval was based on a large phase 3 clinical trial conducted to simultaneously evaluate vedolizumab for both UC and CD that included several clinical studies involving 2,700 patients in nearly 40 countries.

Among patients with CD 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 (P< 0.001).[112]

Ustekinumab

Ustekinumab inhibits interleukin (IL)-12 and IL-23 cytokines, which play a key role in inflammatory and immune responses. In September 2016, the FDA approved ustekinumab for adults with moderately to severely active Crohn disease who have[113, 114] :

  • Failed or were intolerant to immunomodulators or corticosteroids, but never failed treatment with a TNF blocker, OR
  • Failed or were intolerant to treatment with 1 or more TNF blockers

FDA approval was based on three phase 3 studies (UNITI-1, UNITI-2, IM UNITI) in more than 1300 patients.[113, 114] Of patients who were either new to, experienced with, or failed biologic therapy (TNF blockers), between 34% (UNITI-1 study) and 56% (UNITI-2 study) of patients experienced relief of symptoms within 6 weeks after receiving ustekinumab as a one-time IV infusion. Noticeable improvement was observed as early as 3 weeks. A majority of those who responded to induction dosing and continued treatment with subcutaneous (SC) maintenance doses every 8 weeks were in remission at the end of 44 weeks (52 weeks from the initiation of the induction dose).[115, 116, 117]

Other agents

Tacrolimus may be effective in treating Crohn disease. A systematic review of the role of tacrolimus found remission rates of 44.3% for patients with luminal Crohn disease and 28.6% for patients with perianal disease when this agent was used systemically.[118] The review noted that in studies of topical use of tacrolimus, 35.7% of patients achieved remission and 28.6% a partial response.[118]

Side effects included tremor, paresthesia, and headache; recurrent nephrotoxicity occurred in 16% of patients.[118] Although this review appears to support the use of tacrolimus, the investigators noted that randomized controlled trials are needed.

Mycophenolate mofetil has been used in the short- and long-term treatment of difficult IBD. This agent inhibits a de novo pathway of purine synthesis in lymphocytes, leading to intracellular depletion of guanosine monophosphate and resulting in the suppression of cytotoxic T cells and the formation of antibodies by activated B cells. A dose of 500 mg twice daily in 2 divided doses is well tolerated by patients and can be used to reduce the steroid dose.[2, 85]

Early studies have suggested the use of the helminth Trichuris suis for the treatment of Crohn disease. This suggestion is based on the observation that the disease is common in highly industrialized Western countries, where helminths are rare, but uncommon in less developed areas of the world, where most people carry the worms. It is believed that helminths diminish immune responsiveness in naturally colonized humans and reduce inflammation in experimental colitis. Studies evaluating the use of T suis eggs for this purpose are under way.

Evidence supporting the efficacy of low-dose oral naltrexone for the treatment of Crohn disease is limited; the 2 main studies had small patient cohorts and short duration of follow-up. Thus, at present, there is no clear indication for the use of low-dose oral naltrexone for Crohn disease. However, a small subpopulation may benefit from treatment. Further, larger studies may be warranted.

Management of Fistulae

Fistulae between bowel loops (ileoileal, ileocecal, ileosigmoid, enterovesicular, enterocutaneous, cologastric, and coloduodenal) can occur in patients with progressive Crohn disease. Surgical intervention may be required; left untreated, fistulae can cause complications such as unexplained diarrhea, abdominal pain, or abscess formation. Occasionally, medical management with oral metronidazole or ciprofloxacin can be used to treat underlying infections and symptoms until more definitive medical or surgical planning can be established.

In general, localized and systemic sepsis do not occur in fistulae that originate in diseased bowel and involve other intra-abdominal organs or the skin.[7] However, the presence of sepsis necessitates the initiation of broad-spectrum antibiotic agents. Radiologic studies should be performed to rule out concomitant abscesses, which should be drained when present. In cases of persistent sepsis, the diseased bowel is generally excised, whether an abscess is present or not (see Surgical Intervention).

Perianal fistulae can be a debilitating complication of Crohn disease. A multidisciplinary and top-down approach may be required to induce remission of more complex fistulae. A small study demonstrated that the combination of ciprofloxacin and metronidazole in 14 patients with perianal fistulae healed the fistulae in 3 patients and improved the condition of 85% of the patients.[119]

There is good evidence that the combination of antibiotics, current medical therapy (anti­­–TNF-α agents with or without azathioprine/6-MP) and surgical drainage of abscesses followed by seton placement is of greatest efficacy in improving the outcome of perianal fistulizing disease.[82]

In addition, the use of endoscopic ultrasonography (EUS), magnetic resonance imaging (MRI), or both to identify the anatomy and monitor fistula activity in conjunction with the above-mentioned management approach has been shown to help in the maintenance of fistula closure.[82]

Nutritional Therapy and Diet Modification

Nutritional therapy is another important modality for the treatment of disease, malnutrition, and growth failure in Crohn disease. Although ineffective as a primary therapy, nutritional manipulations that facilitate bowel rest can be effective adjuncts in the treatment of active Crohn disease. A dramatic reversal of malnutrition and a change in growth velocity can be expected in all children treated with adequate nutrition in conjunction with medical therapy to control symptoms of Crohn disease.

Both parenteral and enteral nutrition are effective. Additionally, exclusive enteral nutrition (EEN) has been shown to be as effective as corticosteroids for the induction of remission and might promote better gastrointestinal (GI) tract mucosal healing.[120]  An elemental diet is effective for maintaining remission.[12] Consumption of at least 1200 kcal/day has been associated with lower rates of disease relapse, but patients frequently relapse after initiation of a normal diet.[121, 122, 123]

Because most patients have appetite suppression, overnight nasogastric feeds are often used in children. Nighttime supplemental enteral nutrition without daytime dietary restrictions has been shown to be beneficial in maintaining disease remission. Although the exact mechanism of action is unknown, beneficial effects could be due to an altered intestinal flora, a reduced antigen load, and decreased inflammatory cytokine levels.

Patients with Crohn disease require a balanced diet. Fiber supplementation is said to be beneficial for patients with colonic disease, in that dietary fiber can be converted to short-chain fatty acids, which provide fuel for colonic mucosal healing; a low-roughage diet is usually indicated for patients with obstructive symptoms.

Because patients with Crohn disease of the small intestine are often lactose-intolerant, avoidance of dairy products may be indicated. However, calcium supplementation may be required. Osteoporosis is a common nutritional complication, resulting not only from decreased calcium absorption in those with active small bowel disease but also from the release of cytokines from inflammatory cells, which stimulate osteoclast activity and lead to increased bone breakdown. Corticosteroid use is another risk factor for osteoporosis.[121, 122, 123]

An international survey of enteral nutrition formula protocols for children with Crohn disease found that the most common duration of EEN administration was 6-8 weeks and that 90% of centers used polymeric formulas with a variety of flavorings added.[124] The most common recommendation for the reintroduction of food after EEN was gradually introducing food as the use of formula was decreased (52%) or beginning a low-fiber diet (26%).[124]

Patients who undergo extensive resection of the terminal portion of the ileum may benefit from a low-fat diet with the addition of medium-chain triglyceride preparations.

Selected patients may require TPN. Short-term use of TPN (given preoperatively) is appropriate for patients with active inflammation, abscesses, fistulae, and severe malnutrition. Long-term TPN is suitable for patients who have undergone extensive intestinal resection, resulting in short bowel syndrome.[85]

Surgical Intervention

Indications

Surgery plays an integral role in controlling the symptoms and treating the complications of Crohn disease, but operative resection is not curative. Because of the high rate of disease recurrence after segmental bowel resection, the guiding principle of surgical management of Crohn disease is preservation of intestinal length and function.[1] Recommended indications for surgical intervention include the following[1] :

  • Persistent symptoms despite high-dose corticosteroid therapy

  • Treatment-related complications, including intra-abdominal abscesses

  • Medically intractable fistulae

  • Fibrotic strictures with obstructive symptoms

  • Toxic megacolon

  • Intractable hemorrhage

  • Perforation

  • Cancer

In 2007, the Standards Practice Task Force of the American Society of Colon and Rectal Surgeons (ASCRS) published recommendations for surgery in patients with Crohn disease (see Table 2, below).[7]

Table 2. ASCRS Indications for Surgical Management of Crohn Disease (Open Table in a new window)

Operative Indication

Factors for Considering Surgery

Failed medical therapy

  • Presence of disease-related symptoms not responsive to medical management; condition demonstrates an inadequate response

  • When first- and second-line therapies do not induce remission safely in severe disease

  • Before escalating medical therapy in severe or steroid-dependent disease with limited extent (eg, disease with stricturing behavior, patients who have contraindications or risk factors for further medical therapy)

Perforation

  • Presence of symptoms or signs of free perforation

  • Immediate resection of perforated segment (has a relatively high mortality)

  • After small bowel resection or perforation, other procedures can be performed, as needed (eg, end stoma, diverted or nondiverted anastomosis)

  • When large anteroparietal, interloop, intramesenteric, or retroperitoneal abscesses cannot be or are unsuccessfully managed with antibiotics and percutaneous drainage

  • Perform surgical drainage in such cases, with or without resection

  • Persistent enteric fistulae and symptoms or signs of localized or systemic sepsis despite appropriate medical management

  • Persistent sepsis warrants excision of the diseased bowel, whether or not an abscess is present

For target or “innocent bystander” organs, diseased bowel is typically resected, noninflamed bowel primarily closed, and other internal organs primarily closed or allowed to heal by secondary intention

Note: Operative intervention may be avoided for asymptomatic internal fistulae

Obstruction

  • Presence of symptomatic strictures in regions not amenable or responsive to medical therapy

  • Presence of asymptomatic colonic strictures that cannot be adequately surveyed by biopsy or cytology brushing

Inflammation

  • Presence of acute colitis and symptoms or signs of impending or actual perforation (eg, transverse colon distention > 6 cm on abdominal x-ray or persistent gaseous colonic distention indicate toxic megacolon, pneumatosis coli, evolving local peritonitis, multiple organ failure)

  • Presence of severe or fulminant colitis

  • Worsening acute colitis or failure to significantly improve despite 48-96 hours of appropriate medical therapy

Hemorrhage

  • Presence of massive hemorrhaging of any origin that (1) cannot be or fails to be managed with interventional or endoscopic techniques and (2) occurs in hemodynamically unstable patients

Mesenteric angiography with embolization may be attempted when adequate endoscopic visualization is not possible or when the bleeding source cannot be identified; if this technique is not successful or the patient is hemodynamically unstable, laparotomy with or without intraoperative endoscopy and resection of the responsible bowel segment may be required

Neoplasia

  • Presence of chronic Crohn disease of the ileocolon or colon (endoscopic surveillance)

  • Presence of adenomatous-appearing polyps (excision)

  • Presence of carcinoma, DALM, high-grade dysplasia, multifocal colonic or rectal low-grade dysplasia (resection)

  • Presence of chronic Crohn disease of the terminal ileum, ileocolon, or upper GI region

Growth retardation and EIMs

  • Presence of significant growth retardation in prepubertal patients despite appropriate medical therapy

  • Presence of symptomatic dermatologic, oral, ophthalmologic, or joint disorders refractory to medical therapy (resection of diseased intestine)

ASCRS = American Society of Colon and Rectal Surgeons; DALM = dysplasia-associated lesion or mass; EIM = extraintestinal manifestation; GI = gastrointestinal.

Source: Strong SA, Koltun WA, Hyman NH, Buie WD, for the Standards Practice Task Force of The American Society of Colon and Rectal Surgeons. Practice parameters for the surgical management of Crohn’s disease. Dis Colon Rectum. 2007;50(11):1735-46.[7]

Recommended procedures

Unlike ulcerative colitis, Crohn disease has no surgical cure. Most patients with Crohn disease require surgical intervention during their lifetime. Within 15 years of diagnosis, 70% of patients with Crohn disease have required 1 or more surgical procedures, and many require multiple procedures.[42]

Approximately 85-90% of patients develop disease recurrence within the first postoperative year. Therefore, every attempt at conserving the small bowel should be made in the surgical approach to Crohn disease. However, repeated intestinal resection for Crohn disease is a major cause of short bowel syndrome. Several agents have been shown to decrease the likelihood of disease recurrence in individuals who have had ileocolic resections, including antibiotics, azathioprine/6-MP, and biologic agents.[125, 126, 127, 128, 129]

The ASCRS has identified recommended surgical procedures for site-specific Crohn disease (see Table 3, below).[7]

Table 3. ASCRS Recommendations for Site-Specific Operative Management of Crohn Disease (Open Table in a new window)

Site

Surgical Intervention

Terminal ileum, ileocolon, upper GI tract

  • Resection of the affected bowel for jejunal, proximal ileal, terminal ileal, or ileocolic disease in the absence of existing or impending short bowel syndrome

  • Ileocolostomy or proximal loop ileostomy in cases where there is concern about damage to nondiseased bowel, superior mesenteric vessels, retroperitoneal structures

  • Drainage of any septic foci with later definitive resection (after several months’ delay)

  • Strictureplasty for nonphlegmonous jejunal, ileal, or ileocolic strictures in the absence of existing or impending short bowel syndrome

  • Strictureplasty when multiple jejunal or proximal/terminal ileum strictures are present

  • Bypass or strictureplasty for symptomatic gastric or duodenal disease

  • Endoscopic dilatation of symptomatic, accessible strictures of the intestinal tract

Note: Surgical services should be available in case of perforation

Colon

  • Subtotal or total colectomy with end ileostomy for colonic disease requiring emergency or urgent surgery (via laparoscopic or open approach)

  • Segmental or total colectomy with or without primary anastomosis for colonic disease requiring elective surgery

  • Total proctocolectomy or proctectomy with stoma creation for rectal disease requiring surgery

ASCRS = American Society of Colon and Rectal Surgeons; GI = gastrointestinal.

Source: Strong SA, Koltun WA, Hyman NH, Buie WD, for the Standards Practice Task Force of The American Society of Colon and Rectal Surgeons. Practice parameters for the surgical management of Crohn’s disease. Dis Colon Rectum. 2007;50(11):1735-46.[7]

The most common complication of Crohn disease, occurring in 30-50% of patients, is small bowel obstruction. Typically, it is due to intestinal strictures from repeated bouts of inflammation and subsequent fibrosis. For a partial or complete obstruction refractory to nonsurgical management, surgical intervention is required. Surgical options include resection of the strictured bowel and strictureplasty. For long (> 12 cm) strictures or multiple strictures in close proximity, surgical resection with primary anastomosis is often required.

Strictureplasty for multiple shorter strictures has the benefit of conserving the bowel. A Foley catheter (inflated to 25 mm) can be passed through the lumen to detect additional distal strictures. The strictured bowel is incised longitudinally to a point 1-2 cm beyond the narrowing and then closed transversely without resection.

For long or multiple confluent strictures, a stricturoplasty that resembles a Finney side-to-side pyloroplasty (“essentially a side-to-side gastroduodenostomy”[130] or a “side-to-side anastomosis of antrum and duodenum that … does not exclude the pyloric area”[131] ) can be used to conserve bowel length.

Hydrostatic balloon dilatation of ileocolic strictures has been performed, but its effects may not be long lasting. Bypass procedures are usually reserved for duodenal obstructions.[132, 133]

Other complications of Crohn disease that may require operative intervention include free perforation, abscesses, fistulae, toxic megacolon, and massive hemorrhage. More than 10% of patients with Crohn disease have an intra-abdominal or pelvic abscess during their lifetime. Unfortunately, many patients at risk for perforation or abscess will be on corticosteroids, which are known to suppress peritoneal signs and fever and mask the presenting signs of infection. Computed tomography (CT) helps confirm the diagnosis.

Abscesses must be drained, either surgically or percutaneously, and treated with broad-spectrum antibiotics. Although surgical drainage is more often successful, attempting percutaneous drainage first may spare some patients an operation.[134]

Enteroenteric, enterocutaneous, enterovesical, and rectovaginal fistulae are often treated initially according to the principles of fistula healing and medical therapy. If medical therapy is unsuccessful, resection of the involved bowel is required in symptomatic patients.

Toxic megacolon and massive hemorrhage are much less common complications but may require urgent bowel resection when present. Total abdominal colectomy with a Hartmann pouch has been advocated for fulminant toxic megacolon; this allows future restoration of bowel continuity with a sphincter-preserving ileorectal anastomosis. However, a permanent ileostomy may ultimately be required to treat recurrent rectal disease.[135]

In a study comprising a strictly defined cohort of patients, Kiran et al were not able to identify segmental bowel resection as an independent risk factor for recurrence or stoma formation; additionally, they found no reduction in quality of life scores to suggest an adverse effect of recurrence.[136] Nevertheless, segmental colectomy provides good function, and the data support practice of a conservative approach with anastomosis in anatomically linked Crohn disease.

Perianal Crohn disease presents a particularly difficult management challenge. Fissures, fistulae, and abscess may be multiple and recurrent, and repeat operations may lead to sphincter damage and incontinence.

True abscess requires drainage. When a fistula tract can be identified, a seton can be used to prevent premature skin closure and recurrent abscesses. These indwelling setons should be left in place for an extended period (up to 6-12 months) to allow complete epithelialization of the tract as visualized by MRI or EUS. This approach leads to a chronically draining fistula tract. In cases where severe perianal disease has destroyed the sphincter, proctectomy with permanent ileostomy may be necessary.[80, 137, 138, 139]

Laparoscopic versus open resection

The laparoscopic approach to Crohn disease has been shown to be feasible as well as safe.[140, 141] Complications of Crohn disease such as abscesses, phlegmons, and recurrent disease have been safely treated laparoscopically and are not contraindications to laparoscopy in these patients.

Although open resection is still performed by many surgeons and should be considered the criterion standard, the laparoscopic approach is being employed with increasing frequency. In children, laparoscopic intestinal resections have been used for proctectomy and pull-through procedures in Hirschsprung disease for more than a decade.[142] Segmental intestinal resections in Crohn disease can easily be accomplished as well.

No difference in recurrence rates has been found in adults undergoing laparoscopic as opposed to open ileocolic resection, and the laparoscopic approach has been found to shorten the duration of postoperative ileus significantly.[143, 144] Adult patients who undergo laparoscopic ileocecectomy tend to experience a better quality of life than those who undergo the equivalent open procedure. In addition, patients undergoing laparoscopic resection report that they are more satisfied with the physical appearance of their surgical scar.[145]

A study comparing laparoscopic ileocolic resection with infliximab in the treatment of distal ileitis is in progress in the Netherlands. The primary outcomes of the study are quality of life and costs, with recurrence being a secondary outcome.[146] To date, no data have been published on recurrence rates in children undergoing open versus laparoscopic resection.

Preparation for resection

Preoperatively, a recent evaluation of the extent of intestinal disease with appropriate radiologic and endoscopic studies is essential. Steroids are tapered as much as is tolerable, and the patient’s nutritional status is optimized.

In cases where stomas may be required, preoperative counseling better prepares the patients and their families for this possibility. A stomal therapist or nurse should be involved with patient care before the surgical procedure. Patients should also be counseled about the expectations of surgery, because future recurrences are likely.

Most patients will have received corticosteroids recently. Therefore, perioperative steroid dosing will likely be required.

Perianal, rectal, and sigmoidoscopic examinations are often performed while the patient is under anesthesia to determine the presence and extent of perianal disease.

The goal of surgical resection is to remove the grossly involved bowel; microscopic disease at resection margins is acceptable. Primary anastomosis of bowel can usually be achieved. Occasionally, a proximal functioning stoma or Brooke ileostomy is required in patients in whom an anastomosis would be unsafe.

Operative steps: laparoscopic resection

After the patient is placed under general endotracheal anesthesia and a urinary catheter is introduced, the abdomen is prepared and draped widely. A 12-mm incision is made in the umbilicus, through which a 12-mm cannula is introduced for future insertion of the endoscopic stapling device. Two 5-mm incisions are made, one in the left mid abdomen and the other in the left suprapubic region; through these, grasping forceps are inserted for retraction.

The final port (if necessary) is initially 5 or 10 mm in length and is placed in the right lower abdomen in a location similar to an open appendectomy incision. This incision is subsequently enlarged to approximately 2 cm, and the specimen is extracted from the abdominal cavity through this incision (see the image below). In addition, the 2 ends of the intestine to be anastomosed are exteriorized through this incision, and a 2-layer extracorporeal anastomosis is created.

This postoperative photograph depicts incisions us This postoperative photograph depicts incisions used for laparoscopic ileocolectomy in a 14-year-old male adolescent with obstruction of terminal ileum. Note 2-cm incision in right lower abdomen, through which the specimen was extracted and extracorporeal anastomosis performed. 12-mm umbilical incision is nicely hidden in the depths of the umbilicus. 5-mm incision is visible in left lower abdomen, and another is in left suprapubic region just above the top of the pants.

The first step in the operation is ligation and division of the proximal ileum with the endoscopic stapler. Next, with either an UltraCision Harmonic Scalpel (Ethicon Endosurgery, Cincinnati, OH) or a LigaSure device (Valley Lab, Boulder, CO), the mesentery of the proximal right colon is coagulated and transected (see the image below). Then, the right lower abdominal incision is enlarged to 2 cm and the specimen is exteriorized.

On this laparoscopic photograph, the mesentery of On this laparoscopic photograph, the mesentery of the terminal ileum is being coagulated with a sealing device (LigaSure; Valley Lab, Boulder, Colo). Note that the ligation of the mesentery proceeds near the border of the ileum rather than at the base of the mesentery.

Alternatively, the umbilical incision may be enlarged to allow exteriorization of the specimen. With this technique, the distal margin of resection is more precisely determined, and the distal resection margin can be divided with the surgical stapler. This procedure may also be performed intracorporeally with an endoscopic stapler.

Once the resected specimen is removed, the proximal small intestine is delivered through the right lower abdominal incision (or the enlarged umbilical incision), and a 2-layer extracorporeal anastomosis is created between the proximal and distal margins. The bowel is then returned to the abdominal cavity, and all incisions are closed.

Postoperative management

Postoperatively, steroids are tapered appropriately. Patients who were receiving low-dose or short-term steroids preoperatively may be treated with a more rapid taper. Often, patients who have received long-term steroid therapy will be given so-called stress-dose steroids intraoperatively to prevent adrenal insufficiency during a time when the body is under high stress (as is the case in surgery). This stress dose is tapered rapidly. Parenteral nutrition is often continued until bowel function returns.

Complications of surgery

The most common complication of surgical treatment of Crohn disease is the development of intraperitoneal adhesions. Patients with Crohn disease undergoing abdominal surgery are also at increased risk for the development of enterocutaneous fistulae as a result of their surgery. Those who are being treated with steroids or immunosuppressive agents may be at increased risk of wound or intra-abdominal infections.

Consultations

Crohn disease is a chronic disease that requires treatment by a team of experts consisting of primary care providers, gastroenterologists, psychologists, nutritionists, social workers, and nurses. A multidisciplinary approach involving the participation of specialists such as surgeons, dermatologists, rheumatologists, endocrinologists, and obstetricians is often necessary to manage complications of the disease, as well as potential side effects of therapy, if these occur unexpectedly.

A critical factor in the successful management of Crohn disease is the willingness of the patient to participate and cooperate with the team. Adherence to therapy and the management plan is essential in improving outcomes. Patients and parents must be educated and receive support to treat this disorder effectively.

Preventive Care

The American College of Gastroenterology released their guideline on preventive care in inflammatory bowel disease (IBD) in 2017.[147] Their preventive health maintenance recommendations are outlined below.

Strong recommendations

These include the following:

  • Patients with IBD (both ulcerative colitis and Crohn disease) should undergo screening for melanoma independent of the use of biologic therapy. IBD patients on immunomodulators (6-mercaptopurine or azathioprine) should undergo screening for nonmelanoma skin cancer (NMSC) while using these agents, particularly those older than 50 years. 
  • Patients with conventional risk factors for abnormal bone mineral density with ulcerative colitis and Crohn disease should undergo screening for osteoporosis with bone mineral density testing at the time of diagnosis and periodically after diagnosis.
  • Adults with IBD older than 50 years should consider vaccination against herpes zoster, including certain subgroups of immunosuppressed patients.

Conditional recommendations

These include the following:

  • Patients with conventional risk factors for abnormal bone mineral density with ulcerative colitis and CD should undergo screening for osteoporosis with bone mineral density testing at the time of diagnosis and periodically after diagnosis.
  • Adults with IBD should receive age-appropriate vaccinations before initiation of immune suppression when possible.
  • Household members of immunosuppressed patients can receive live vaccines with certain precautions.
  • All adult patients with IBD should undergo annual vaccination against influenza. Those on immunosuppressive therapies and their household contacts should receive the non-live trivalent inactivated influenza vaccine, but not the live inhaled influenza vaccine.
  • Adult patients with IBD receiving immunosuppressive therapy should receive pneumococcal vaccination with both the PCV13 and PPSV23 vaccines, in accordance with national guidelines.
  • Adults with IBD should be assessed for prior exposure to varicella and vaccinated if naive before initiation of immunosuppressive therapy when possible.
  • Patients with IBD who are immunosuppressed and traveling to areas that are endemic for yellow fever should consult with a travel medicine or infectious disease specialist prior to travel
  • Adolescents with IBD should receive meningococcal vaccination in accordance with routine vaccination recommendations.
  • Vaccination against tetanus, diphtheria, and pertussis (Tdap); hepatitis A and B (HAV, HBV, respectively); and human papillomavirus (HPV) should be administered as per Advisory Committee on Immunization Practice (ACIP) guidelines.
  • Women with IBD on immunosuppressive therapy should undergo annual cervical cancer screening.
  • Screening for depression and anxiety is recommended in patients with IBD.
 

Guidelines

Guidelines Summary

American College of Gastroenterology

In 2018, the American College of Gastroenterology published the following guidelines on the management of Crohn disease in adults[148] :

  • Fecal calprotectin is a helpful test that should be considered to help differentiate the presence of inflammatory bowel disease (IBD) from irritable bowel syndrome (IBS).
  • In patients at particularly high risk for colorectal neoplasia (eg, personal history of dysplasia, primary sclerosing cholangitis), chromoendoscopy should be used during colonoscopy, as it may increase the diagnostic yield for detection of colorectal dysplasia, especially compared with standard-definition white light endoscopy.
  • For patients undergoing surveillance colonoscopy, there is insufficient evidence to recommend universal chromoendoscopy for IBD colorectal neoplasia surveillance if the endoscopist has access to high-definition white light endoscopy.
  • Narrow-band imaging should not be used during colorectal neoplasia surveillance examinations for Crohn disease.
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) may exacerbate disease activity and should be avoided when possible in patients with Crohn disease.
  • Cigarette smoking exacerbates disease activity and accelerates disease recurrence and should be avoided.
  • Use of antibiotics should not be restricted in Crohn disease patients in order to prevent disease flares.
  • Perceived stress, depression, and anxiety, which are common in IBD, are factors that lead to decreased health-related quality of life in patients with Crohn disease and lead to lower adherence to provider recommendations. Assessment and management of stress, depression, and anxiety should be included as part of the comprehensive care of the Crohn disease patient.
  • Sulfasalazine is effective for treating symptoms of colonic Crohn disease that is mild to moderately active and can be used as treatment for this patient population.
  • Controlled ileal release budesonide at a dose of 9 mg once daily is effective and should be used for induction of symptomatic remission for patients with mild to moderate ileocecal Crohn disease.
  • Metronidazole is not more effective than placebo as therapy for luminal inflammatory Crohn disease and should not be used as primary therapy.
  • For patients with low risk of progression, treatment of active symptoms with antidiarrheals, other nonspecific medications, and dietary manipulation, along with careful observation for inadequate symptom relief, worsening inflammation, or disease progression, is acceptable.
  • Oral corticosteroids are effective and can be employed for short-term use in alleviating signs and symptoms of moderately to severely active Crohn disease. Thiopurines (azathioprine, 6-mercaptopurine) are effective and should be considered for use for steroid sparing in Crohn disease.
  • Azathioprine and 6-mercaptourine are effective therapies and should be considered for treatment of patients with Crohn disease for maintenance of remission
  • Thiopurine methyltransferase (TPMT) testing should be considered before initial use of azathioprine or 6-mercaptopurine to treat patients with Crohn disease.
  • Methotrexate (up to 25 mg once weekly intramuscularly [IM] or subcutaneously [SC]) is effective and should be considered for use in alleviating signs and symptoms in patients with steroid-dependent Crohn disease and for maintaining remission.
  • Anti–tumor necrosis factor (anti-TNF) agents (infliximab, adalimumab, certolizumab pegol) should be used to treat Crohn disease that is resistant to treatment with corticosteroids.
  • Anti-TNF agents should be given for Crohn disease refractory to thiopurines or methotrexate.
  • Combination therapy of infliximab with immunomodulators (thiopurines) is more effective than treatment with either immunomodulators alone or infliximab alone in patients who are naive to those agents.
  • For patients with moderately to severely active Crohn disease and objective evidence of active disease, anti-integrin therapy (with vedolizumab) with or without an immunomodulator is more effective than placebo and should be considered for use in induction of symptomatic remission in patients with Crohn disease.
  • Natalizumab is more effective than placebo and should be considered for use in induction of symptomatic response and remission in patients with active Crohn disease.
  • Natalizumab should be used for maintenance of natalizumab-induced remission of Crohn disease only if serum antibody to John Cunningham (JC) virus is negative. Testing for anti-JC virus antibody should be repeated every 6 months and treatment stopped if the result is positive.
  • Ustekinumab should be given for moderate to severe Crohn disease patients who failed previous treatment with corticosteroids, thiopurines, methotrexate, or anti-TNF inhibitors or who have had no prior exposure to anti-TNF inhibitors.
  • Intravenous corticosteroids should be used to treat severe or fulminant Crohn disease.
  • Anti-TNF agents (infliximab, adalimumab, certolizumab pegol) can be considered to treat severely active Crohn disease.
  • Infliximab may be administered to treat fulminant Crohn disease. Infliximab is effective and should be considered in treating perianal fistulas in Crohn disease. Infliximab may be effective and should be considered in treating enterocutaneous and rectovaginal fistulas in Crohn disease.
  • Adalimumab and certolizumab pegol may be effective and should be considered in treating perianal fistulas in Crohn disease.
  • Thiopurines (azathioprine, 6-mercaptopurine) may be effective and should be considered in treating fistulizing Crohn disease.
  • The addition of antibiotics to infliximab is more effective than infliximab alone and should be considered in treating perianal fistulas.
  • Drainage of abscesses (surgically or percutaneously) should be undertaken before treatment of fistulizing Crohn disease with anti-TNF agents.
  • Once remission is induced with corticosteroids, a thiopurine or methotrexate should be considered.
  • Anti-TNF therapy, specifically infliximab, adalimumab, and certolizumab pegol, should be used to maintain remission of anti-TNF–induced remission.
  • Anti-TNF monotherapy is effective at maintaining anti-TNF–induced remission, but because of the potential for immunogenicity and loss of response, combination with azathioprine/6-mercaptopurine or methotrexate should be considered.
  • Imidazole antibiotics (metronidazole and ornidazole) at doses between 1 and 2 g/day can be used after small intestinal resection in Crohn disease patients to prevent recurrence.
  • In high-risk patients, anti-TNF agents should be started within 4 weeks of surgery in order to prevent postoperative Crohn disease recurrence.
  • An intra-abdominal abscess should be treated with antibiotics and a drainage procedure, either radiographically or surgically.

Crohn disease radiologic evaluation

In 2017, an expert panel, which included contributors from the Society of Abdominal Radiology Crohn’s Disease–Focused Panel, the Society of Pediatric Radiology, and the American Gastroenterological Association, issued the following guidelines on the use of computed tomography enterography (CTE) and magnetic resonance enterography (MRE) in patients with small bowel Crohn disease[149, 150] :

  • The number of involved bowel segments and their location, as well as the length and degree of upstream dilatation of Crohn strictures, should be reported by radiologists to help gastroenterologists and surgeons determine the best therapeutic plan.
  • Radiologists should state if mural inflammation is present when describing areas with stricture or penetrating disease.
  • Cross-sectional enterography should be performed at Crohn disease diagnosis.
  • Consider cross-sectional enterography for disease monitoring in patients with small bowel disease or penetrating complications.
  • While a dedicated pelvic magnetic resonance (MR) study is needed in patients with perianal disease, all CTEs and MREs should also include imaging of the anus.
  • Radiologists should comment on and describe intramural T2 hyperintensity, restricted diffusion, perienteric stranding, wall thickness, and mural ulcerations seen on imaging, because they typically correlate with disease severity.
  • MRE is preferred over CTE to estimate response to medical treatment in patients with asymptomatic disease.
  • Noncontrast MRE with T2-weighted and diffusion-weighted imaging is an “acceptable alternative” when intravenous contrast agents cannot be used.
  • Radiologists should evaluate CTE and MRE examinations for signs of mesenteric venous thrombosis, occlusions, or small bowel varices.
 

Medication

Medication Summary

The goals of pharmacotherapy in patients with Crohn disease are to reduce morbidity, to prevent complications, and to maintain nutritional status.

Management of diarrhea

Chronic diarrhea in Crohn disease responds well to antidiarrheal agents such as loperamide (2-4 mg), diphenoxylate with atropine (1 tablet), and tincture of opium (8-15 drops). Such agents may be administered up to 4 times daily, but they should not be given to patients with active colitis, because of the risk of developing toxic megacolon.

Patients with terminal ileal disease may not absorb bile acids normally, which can lead to secretory diarrhea in the colon. These patients may benefit from bile acid sequestrants such as cholestyramine (2-4 g) and colestipol (5 g 2 or 3 times daily before meals).

Abdominal cramps may be reduced with propantheline (30 mg before meals and at bedtime), dicyclomine (10-20 mg), or hyoscyamine (0.125 mg). These drugs should not be used if there is the possibility of a bowel obstruction.

Management of bowel inflammation

For colon and small bowel inflammation, anti-inflammatory drugs or antibiotics are helpful. Neither sulfasalazine nor balsalazide alleviates small bowel disease. Products such as mesalamine, which releases 5-aminosalicylic acid (5-ASA) in the distal small bowel secondary to pH changes are more useful in patients with small intestinal Crohn disease.

According to a systematic review, antituberculosis therapy, macrolides, fluoroquinolones, 5-nitroimidazoles, and rifaximin (alone or in combination) have been shown to induce remission in active Crohn disease and ulcerative colitis.[151] Further trials of antibiotic therapy are necessary in order to determine the best course of single or combination antibiotic therapy.

Long-term maintenance with mesalamine (800 mg 3 times daily) may delay clinical relapse. Prednisone (40-60 mg/day) is generally helpful in acute inflammation. Oral glucocorticoid preparations such as budesonide are useful for patients with isolated terminal ileal inflammation and may reduce systemic side effects.

Steroids are not indicated for maintenance therapy, because of serious complications, such as aseptic necrosis of the hip, osteoporosis, cataract, diabetes, and hypertension. Accordingly, once remission is achieved, the agent is slowly tapered (5-10 mg every 1-2 weeks).

If steroid withdrawal proves difficult, immunosuppressants such as azathioprine (2 mg/kg/day) or its active metabolite, 6-mercaptopurine (6-MP), may be considered. Response is usually observed within 3-6 months. Mycophenolate mofetil 500 mg twice daily in 2 divided doses is well tolerated by patients and can be used to reduce the steroid dose.[2, 85]

Management of fistulae

Fistulae between bowel loops (eg, ileoileal, ileocecal, or ileosigmoid) are usually benign and may not produce any major problems. Medical management is used to treat underlying infections and symptoms with oral metronidazole (1 g/day) for at least 1-2 months.

Infliximab is effective in patients who have refractory perianal and enterocutaneous fistulae. Current clinical practice is to give it 5 mg/kg by intravenous (IV) infusion at 0 weeks, 2 weeks, and 6 weeks, followed by maintenance IV infusions every 8 weeks. On average, the effect lasts for 12 weeks.

5-Aminosalicylic Acid Derivatives

Class Summary

The 5-ASA derivative agents are used to treat mild-to-moderate Crohn disease and to maintain remission.

Mesalamine rectal (Canasa, Rowasa)

Rectal mesalamine is a formulation of mesalamine that specifically releases 5-ASA in the distal colon. This agent elicits an anti-inflammatory effect by an unknown mechanism.

Mesalamine (Asacol, Lialda, Apriso)

Products such as mesalamine, which releases 5-ASA in the distal small bowel secondary to pH changes, are more useful in patients with small intestinal Crohn disease. Long-term maintenance with mesalamine may delay clinical relapse. This agent is better tolerated than sulfasalazine and has fewer adverse effects.

Sulfasalazine (Azulfidine)

Sulfasalazine is useful mainly in colonic disease because the active compound, 5-ASA, is released in the large bowel by bacterial degradation of the parent compound. Sulfasalazine does not alleviate small bowel disease; it acts locally in the colon to reduce the inflammatory response and systemically inhibits prostaglandin synthesis. It has no additive or steroid-sparing effects when used in conjunction with corticosteroids. In contrast to its action in ulcerative colitis, sulfasalazine does not seem to maintain remission in Crohn disease.

Balsalazide (Colazal)

Balsalazide is an active component of sulfasalazine and is metabolized to mesalamine by intestinal flora. It has an anti-inflammatory effect, but its exact mechanism of action is not known. Balsalazide is used to treat ulcerative colitis.

Corticosteroids

Class Summary

Corticosteroids are used to treat active moderate to severe Crohn disease. They are not indicated for maintenance therapy. A short course of corticosteroid therapy is indicated in patients with severe systemic symptoms (eg, fever, nausea, and weight loss) and in those whose condition does not respond to anti-inflammatory agents.

Budesonide is available in an ileal controlled-release form and is used for the treatment of ileal or right-side colonic disease. Budesonide induces remission in active Crohn disease but is less effective than other standard glucocorticosteroids and is of no benefit in preventing relapse.[89]

Prednisone

Prednisone exerts anti-inflammatory effects through decreased capillary permeability, impaired neutrophil chemotaxis, release of anti-inflammatory cytokines, decrease of production of eicosanoids, and stabilization of lysosomal membranes. This agent is generally helpful in acute inflammation.

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

Methylprednisolone exercises anti-inflammatory effects through decreased capillary permeability, impaired neutrophil chemotaxis, release of anti-inflammatory cytokines, decreased production of eicosanoids, and stabilization of the lysosomal membrane.

Budesonide (Entocort EC)

Budesonide alters levels of inflammation in tissues by inhibiting multiple types of inflammatory cells and decreasing the production of cytokines and other mediators involved in inflammatory reactions.

Hydrocortisone (Cortenema, Anusol-HC, Cortifoam)

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.

Prednisolone (Pediapred, Prelone, Orapred)

Prednisolone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity. It is a commonly used oral agent. Prednisolone is used for an oral taper of steroids, which may reduce the emotional effects of steroid withdrawal and the risk of the development of adrenocortical insufficiency. However, these risks are not very high after only 3 days of treatment with high-dose steroids, and most neurologists do not use a prednisone taper.

Immunosuppressants

Class Summary

Immunosuppressant agents are used off label to treat moderate-to-severe Crohn disease, to treat steroid-dependent or steroid-refractory disease, and to maintain remission.

Mercaptopurine (Purinethol)

6-MP and its prodrug azathioprine are purine analogues; they interfere with protein synthesis and nucleic acid metabolism and have cytotoxic effect on lymphoid cells. If steroid withdrawal proves difficult, immunosuppressants such as 6-MP may be considered.

Azathioprine (Imuran, Azasan)

Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. It may decrease proliferation of immune cells, which lowers autoimmune activity.

Methotrexate (Trexall, Rheumatrex)

Methotrexate is used for the treatment of moderate-to-severe Crohn disease and maintenance of remission. It is effective in inducing and maintaining remission in chronic Crohn disease in adults and has been shown to be effective and well tolerated for maintenance of remission in children. Methotrexate is a structural analogue of folic acid that inhibits binding of dihydrofolic acid to the enzyme dihydrofolate reductase. It impairs DNA synthesis, induces apoptosis, and reduces interleukin (IL)-1 production.

Tacrolimus (Prograf, Hecoria)

Tacrolimus is an immunomodulator produced by the bacteria Streptomyces tsukubaensis. Its mechanism of action is similar to that of cyclosporine. Tacrolimus may be effective in treating Crohn disease.

Monoclonal Antibodies

Class Summary

Monoclonal antibodies are used in the treatment of moderate-to-severe active Crohn disease or fistulizing disease that is unresponsive to other medical therapy.

Infliximab (Inflectra, Remicade)

Infliximab is a chimeric mouse-human monoclonal antibody against tumor necrosis factor (TNF)-α that shows promise in the treatment of Crohn disease. This agent blocks TNF-α in the serum and at the cell surface, leading to the lysis of TNF-producing macrophages and T cells. Infliximab has been approved for the treatment of pediatric Crohn disease.

Adalimumab (Humira, Amjevita, adalimumab-atto)

Adalimumab is indicated for the induction and remission of moderate-to-severe active inflammatory Crohn disease. This agent is a recombinant human immunoglobulin (Ig) G1 monoclonal antibody specific for human TNF. It binds specifically to TNF-α and blocks interaction with p55 and p75 cell-surface TNF receptors. This interferes with the cytokine driven inflammatory processes. Adalimumab also lyses surface TNF-expressing cells in vitro in the presence of complement, but it does not bind to TNF-β (lymphotoxin).

Certolizumab pegol (Cimzia)

Certolizumab pegol is indicated for moderate-to-severe Crohn disease in individuals whose condition has not responded to conventional therapies. It is a pegylated anti–TNF-α blocker, and its action results in disruption of the inflammatory process.

Ustekinumab (Stelara)

Ustekinumab inhibits interleukin (IL)-12 and IL-23 cytokines, which play a key role in inflammatory and immune responses. It is indicated for adults with moderately to severely active Crohn disease who have failed or were intolerant to immunomodulators or corticosteroids, but never failed treatment with a tumor necrosis factor (TNF) blocker. It is also indicated for those who failed or were intolerant to treatment with 1 or more TNF blockers.

Alpha 4 Integrin Inhibitors

Class Summary

Integrin inhibitors are emerging as options for moderate-to-severe active 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 indicated for moderate-to-severe Crohn disease in patients who have had inadequate responses to other therapies. It is a monoclonal antibody that binds α4β7 and α4β1 that results in inhibition of leukocyte adhesion and migration to areas of inflammation.

Vedolizumab (Entyvio)

Vedolizumab is a recombinant humanized monoclonal antibody that binds specifically to α4β7 integrin. It blocks the interaction of α4β7 integrin with mucosal 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.

Antibiotics

Class Summary

Antibiotics are used in the treatment of mild-to-moderate, fistulizing, and perianal disease. Antibiotics may change the microbial flora of the intestine and have a potential effect on the cell-mediated immune system.

Metronidazole (Flagyl)

Metronidazole is an imidazole ring–based antibiotic that is active against various anaerobic bacteria and protozoa. It is sometimes used in combination with other antimicrobial agents (except for Clostridium difficile enterocolitis). Metronidazole also possesses immunosuppressive and anti-inflammatory properties.

Ciprofloxacin (Cipro)

A fluoroquinolone, ciprofloxacin has activity against pseudomonads, streptococci, methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, and most gram-negative organisms, but it has no activity against anaerobes. Ciprofloxacin inhibits bacterial DNA synthesis and, consequently, growth.

Antidiarrheals

Class Summary

Chronic diarrhea in Crohn disease responds well to antidiarrheal agents such as loperamide (2-4 mg), diphenoxylate with atropine (1 tablet), and tincture of opium (8-15 drops). Such agents may be administered up to 4 times daily, but they should not be given to patients with active colitis, because of the risk of developing toxic megacolon.

Loperamide (Imodium, Diamode)

Loperamide, which is available over the counter, acts on intestinal muscles to inhibit peristalsis and to slow intestinal motility. It prolongs the movement of electrolytes and fluid through the bowel and increases the viscosity and loss of fluids and electrolytes. Loperamide improves stool frequency and consistency, reduces abdominal pain and fecal urgency, and may exacerbate constipation.

Diphenoxylate-atropine (Lomotil)

The combination of diphenoxylate with atropine consists of 2.5 mg of diphenoxylate, which is a constipating meperidine congener, and 0.025 mg of atropine to discourage abuse. The preparation inhibits excessive gastrointestinal (GI) propulsion and motility, but it may exacerbate constipation.

Bile Acid Sequestrants

Class Summary

Patients with terminal ileal disease may not absorb bile acids normally, which can lead to secretory diarrhea in the colon. These patients may benefit from bile acid sequestrants such as cholestyramine and colestipol.

Cholestyramine (Prevalite, Questran, Questran Light)

Cholestyramine is used for diarrhea associated with Crohn disease. It binds bile acids, thereby reducing damage to the intestinal mucosa. Cholestyramine also reduces the induction of colonic fluid secretion. It forms a nonabsorbable complex with bile acids in the intestine, thereby, in turn, inhibiting 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.

Anticholinergic Agents

Class Summary

Abdominal cramps may be reduced with anticholinergic agents such as propantheline, dicyclomine, or hyoscyamine. These drugs should not be used if there is the possibility of a bowel obstruction.

Dicyclomine (Bentyl)

Dicyclomine treats GI motility disturbances. It blocks the action of acetylcholine at parasympathetic sites in secretory glands, smooth muscle, and the central nervous system (CNS). Adverse effects are dose-dependent.

Hyoscyamine (Levsin, Levbid, Anaspaz, Symax, NuLev)

Hyoscyamine blocks the action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the CNS, thereby exerting antispasmodic effects. This agent decreases fecal urgency and pain.

Propantheline

Propantheline is a quaternary ammonium antimuscarinic agent with peripheral effects that are similar to those of atropine. It inhibits GI motility and decreases gastric acid secretion.

 

Questions & Answers

Overview

What is Crohn disease?

What are the signs and symptoms of Crohn disease?

Which physical exams should be performed if Crohn disease is suspected?

Which routine lab studies are useful in the diagnosis and management of Crohn disease?

Which imaging studies are useful for Crohn disease?

Which procedures may be useful in the evaluation of Crohn disease?

Which medications are used in the treatment of Crohn disease?

Which surgical procedures may be performed for the management of Crohn disease?

What is Crohn disease?

Which factors may trigger Crohn disease?

Which parts of the GI tract are involved in Crohn disease?

What are the characteristics of Crohn disease?

What is the role of lab tests in Crohn disease?

Which imaging studies are performed in the diagnosis of Crohn disease?

What are the goals of treatment in Crohn disease?

How is therapy for Crohn disease typically administered?

What is the role of surgery in the treatment of Crohn disease?

What is the pathogenesis of Crohn disease?

What is the role of granuloma in the pathogenesis of Crohn disease?

What causes bowel obstruction in Crohn disease?

Where are fistulae found in Crohn disease?

Which factors may increase the risk of developing Crohn disease?

Is Crohn disease genetic?

What are the roles of the genes IBD1 and NOD2 (CARD15) in the etiology of Crohn disease?

What the role of the gene IL23R in the etiology of Crohn disease?

What are the roles of the genes CCR6, IL12B, STAT3, JAK2, LRRK2, CDKAL1, and PTPN22 in the etiology of Crohn disease?

What are the roles of the genes ITLN1, ATG16L1, IRGM, and PTGER4 in the etiology of Crohn disease?

What are the roles of the genes BSN, MST1, NKX2-3, and PTPN2 in the etiology of Crohn disease?

Which infectious agents may have a role in the etiology of Crohn disease?

What are the roles of interleukins and tumor necrosis factor (TNF) in the etiology of Crohn disease?

Do environmental factors such as smoking, high-fat diet, and measles vaccine increase the risk of developing Crohn disease?

What is the prevalence of Crohn disease in the US?

What is the global incidence of Crohn disease?

At what age does the onset of Crohn disease typically occur?

Is Crohn disease more common in males or females?

Does Crohn disease have a racial predilection?

What is the prognosis of Crohn disease?

What is the life expectancy of patients with Crohn disease?

What is the relapse rate for Crohn disease?

Which patients with Crohn disease are at a higher risk of mortality?

How is acute Crohn disease diagnosed and treated?

Which guidelines have been released for the diagnosis and management of colorectal cancer in patients with IBD?

Are specific genes prognostic factors in Crohn disease?

Where can families and patients obtain educational materials about Crohn disease?

Presentation

What factors determine the clinical presentation of Crohn disease?

What is the focus of medical history in adults and children with suspected Crohn disease?

What is the initial presentation of Crohn disease?

What is the usual presentation of Crohn disease of the small intestine?

What are the signs and symptoms of enterovesical fistulae in Crohn disease?

How often is the terminal ileum involved in Crohn disease in children?

What areas of the GI tract do cases of Crohn disease affect and which complications may precede the development of intestinal symptoms?

What should be the focus of the physical exam for suspected Crohn disease?

Which abdominal findings suggest Crohn disease?

Which findings of the perineal and rectal exams suggest Crohn disease?

What are the possible extraintestinal manifestations (EIMs) that suggest Crohn disease?

Which skin and oral mucosa findings suggest Crohn disease?

How are growth abnormalities detected in children with suspected Crohn disease?

What is the etiology of major intestinal complications of Crohn disease?

Where does microperforation typically occur in Crohn disease?

What are the signs and symptoms of frank perforation in Crohn disease?

Is colon cancer a possible complication of Crohn disease?

What is the cumulative risk of colon cancer in Crohn disease?

What is the standard of care for colon cancer prevention in Crohn disease?

What is the risk of small bowel cancer in Crohn disease?

Which extraintestinal manifestations (EIMs) are the most common in adults and children with Crohn disease?

When is arthritis likely to occur in adults with Crohn disease?

How often do dermatologic extraintestinal manifestations (EIMs) occur in Crohn disease?

What is the presentation of erythema nodosum in Crohn disease?

What are the dermatologic manifestations of Crohn disease?

What is the most common oral manifestation of Crohn disease?

When do ophthalmologic manifestations of Crohn disease occur?

What are the less common ophthalmologic manifestations of Crohn disease?

What are the urologic extraintestinal manifestations (EIMs) of Crohn disease?

How are gallstones formed in patients with Crohn disease?

What is the most common extraintestinal manifestation (EIM) of Crohn disease?

Which manifestations of liver disease occur in children with Crohn disease?

How common is cholelithiasis (gallstones) in patients with Crohn disease?

What are the symptoms of primary sclerosing cholangitis in patients with Crohn disease?

Does primary sclerosing cholangitis increase the risk of developing Crohn disease?

What are pancreatic or hepatobiliary manifestations of Crohn disease?

What is the etiology of thromboembolic disease in Crohn disease?

What are the risk factors for thromboembolism in Crohn disease?

What are the hematologic and genitourinary manifestations of Crohn disease?

What is the role of malabsorption in Crohn disease?

How is inflammatory bowel disease (IBD) classified?

How is disease activity in adults with Crohn disease assessed?

Which indices are used to assess disease activity in adults with Crohn disease?

DDX

How is Crohn disease differentiated from ulcerative colitis?

What percentage of patients have an undetermined type of IBD with features of both Crohn disease and ulcerative colitis and what are other diagnostic considerations?

What are the differential diagnoses for Crohn Disease?

Workup

How is Crohn disease diagnosed?

What is the role of imaging studies in the diagnosis of Crohn disease?

Has a risk model for complications of Crohn disease based on levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) been validated?

Are patients with complicated Crohn disease at increased risk for excessive radiation exposure from multiple radiologic studies?

Which procedures may be useful in the diagnosis of Crohn disease?

What is the role of lab testing in Crohn disease?

What is the role of a CBC count in the diagnosis of Crohn disease?

Which common abnormalities observed on a chemistry panel suggest Crohn disease?

Which acute inflammatory markers may indicate disease activity in Crohn disease?

What is the role of stool sample testing in the evaluation of Crohn disease?

Which serologic tests are useful in differentiating ulcerative colitis from Crohn disease?

Which serologic test results indicate that ulcerative colitis is more likely than Crohn disease?

What are the limitations of serologic testing to differentiate between ulcerative colitis and Crohn disease?

In addition to ASCAs and p-ANCA, which serologic markers may suggest Crohn disease?

What is the role of abdominal radiography in the diagnosis of Crohn disease?

What is the role of barium contrast studies in the diagnosis of Crohn disease?

What is the role of small bowel follow-through (SBFT) in the diagnosis of Crohn disease?

Is enteroclysis or small bowel follow-through (SBFT) more accurate in the diagnosis of Crohn disease?

What is the role of barium enema in the diagnosis of Crohn disease?

What is the role of CT scanning in the diagnosis of Crohn disease?

What is the role of CT enterography in the diagnosis of Crohn disease?

Why is CT scanning the study of choice for the diagnosis of Crohn disease?

What is the role of MRI in the diagnosis of Crohn disease?

Why is MRI the study of choice for evaluation and management of perianal Crohn disease?

Which studies are used for the evaluation of the small bowel in the diagnosis of Crohn disease?

What is the role of ultrasonography in the diagnosis and management of Crohn disease?

Can ultrasonography be used to assess perianal Crohn disease?

What is the role of colonoscopy in the diagnosis and management of Crohn disease?

How effective is an ileocolonoscopy in the assessment of Crohn disease?

What is the role of upper GI endoscopy in the diagnosis of Crohn disease?

What is the role of ERCP in the diagnosis and management of Crohn disease?

What is the role of small bowel enteroscopy or capsule endoscopy in the diagnosis Crohn disease?

What is the role of radionucleotide scanning in the diagnosis and management Crohn disease?

Which test is performed to assess active bowel inflammation in IBD?

What are the common characteristics of inflammation in Crohn disease?

How is upper GI tract Crohn disease typically characterized?

Treatment

What are the general goals of Crohn disease treatment?

How has the development of new therapies affected the treatment of Crohn disease?

When is surgical intervention for Crohn disease indicated, and what if pharmacotherapy or nutritional therapy is ineffective or unadaptable for those with active colonic disease?

Is stem cell transplantation an effective treatment for Crohn disease?

When is resection of malignant bowl strictures indicated in the management of Crohn disease?

When is hospitalization indicated in the management of Crohn disease?

What are the therapy options for mild Crohn disease?

What is the treatment approach for moderate to severe Crohn disease?

In which patient groups is a top-down therapy indicated for the management of Crohn disease?

What are causes of diarrhea in Crohn disease and how is it treated?

Which patients with Crohn disease may benefit from bile acid sequestrants (cholestyramine) (colestipol)?

How are abdominal cramps reduced in Crohn disease?

How is colon and small bowel inflammation treated in Crohn disease?

What are the indications for corticosteroid therapy in Crohn disease?

What are the possible complications of corticosteroid therapy in Crohn disease?

Which treatments are effective for ileal and cecal Crohn disease?

When are immunosuppressants useful in the treatment of Crohn disease?

What is the role of thiopurine methyltransferase (TPMT) activity measurement in the treatment of Crohn disease?

What is the role of methotrexate in inducing and maintaining remission in Crohn disease?

Which patients with Crohn disease are most likely to benefit from tumor necrosis factor (TNF) therapy?

What are the risks of tumor necrosis factor (TNF) medications in patients with Crohn disease, and how effective are these agents with or without an immunomodulator?

When is infliximab indicated in the treatment of Crohn disease?

Is infliximab effective in the treatment of Crohn disease?

What are the possible adverse effects of infliximab in the treatment of Crohn disease?

What are the risk factors for relapse of Crohn disease after successful treatment with infliximab?

Are adalimumab and certolizumab pegol effective in the treatment of Crohn disease?

What is the efficacy of adalimumab in the treatment of Crohn disease?

What is the recommended dosage regimen for adalimumab in the treatment of Crohn disease?

What is the efficacy of certolizumab in the treatment of Crohn disease?

Is natalizumab effective in the treatment of Crohn disease and how is it administered?

Are there restrictions on the use of natalizumab for the treatment of Crohn disease?

What are the risk factors for developing progressive multifocal leukoencephalopathy (PML) in patients with Crohn disease?

When is natalizumab therapy indicated for patients with Crohn disease?

Is vedolizumab effective for the treatment of Crohn disease?

When is ustekinumab indicated for the treatment of Crohn disease?

Is tacrolimus an effective treatment for Crohn disease?

What is the dosing for mycophenolate mofetil in the treatment of Crohn disease?

What is the role of T suis in the treatment of Crohn disease?

Is low-dose oral naltrexone effective for treatment of Crohn disease?

How are fistulae managed in Crohn disease?

How is systemic sepsis managed in Crohn disease?

How are perianal fistulae managed in Crohn disease?

What is the role of nutritional therapy in the treatment of Crohn disease?

Which nutritional therapies are effective in the treatment of Crohn disease?

How is appetite suppression managed in Crohn disease?

Which nutritional supplements are beneficial for patients with Crohn disease?

What is the most common duration of exclusive enteral nutrition (EEN) in children with Crohn disease?

Which diets are most beneficial for patients with Crohn disease who undergo resection of the terminal portion of ileum?

When is surgery indicated in the management of Crohn disease?

How often is surgical intervention performed in Crohn disease?

What are the ASCRS guidelines for surgical procedures for Crohn disease?

What is the most common complication of Crohn disease and when is surgical intervention required?

How is strictureplasty performed in patients with Crohn disease?

Which complications of Crohn disease may require surgical intervention?

How are abscesses in Crohn disease treated?

How are fistulae treated in Crohn disease?

How are toxic megacolon and massive hemorrhage treated in Crohn disease?

Does segmental bowel resection increase the risk of recurrence of Crohn disease?

What are the possible complications of perianal Crohn disease?

What is the role of a seton in the management of Crohn disease?

What is the efficacy of a laparoscopic surgical approach in Crohn disease?

How does the laparoscopic approach compare to open resection for management of Crohn disease?

What are preoperative steps for resection in patients with Crohn disease?

What is the goal of surgical resection in Crohn disease?

How is laparoscopic resection performed in Crohn disease?

What is the postoperative management of Crohn disease?

What are the most common complications of surgical intervention in Crohn disease?

Which specialists should be involved in the treatment of Crohn disease?

What are the American College of Gastroenterology guidelines on preventive care in inflammatory bowel disease (IBD)?

Guidelines

What are the American College of Gastroenterology treatment guidelines for Crohn disease?

What are the guidelines for use of CTE and MRE in patients with small bowel Crohn disease?

Medications

What are the goals of pharmacotherapy in Crohn disease?

How is chronic diarrhea managed in Crohn disease?

When are bile acid sequestrants indicated in the management of Crohn disease?

Which medications may be used to reduce abdominal cramps in Crohn disease?

Which medications may be used to reduce inflammation in Crohn disease?

Which medications have been shown to induce remission in active Crohn disease?

What is the role of mesalamine in the treatment of Crohn disease?

What are the possible complications of steroids in Crohn disease?

How are fistulae between bowel loops managed in Crohn disease?

When is infliximab indicated in the management of Crohn disease?

Which medications in the drug class 5-Aminosalicylic Acid Derivatives are used in the treatment of Crohn Disease?

Which medications in the drug class Corticosteroids are used in the treatment of Crohn Disease?

Which medications in the drug class Immunosuppressants are used in the treatment of Crohn Disease?

Which medications in the drug class Monoclonal Antibodies are used in the treatment of Crohn Disease?

Which medications in the drug class Alpha 4 Integrin Inhibitors are used in the treatment of Crohn Disease?

Which medications in the drug class Antibiotics are used in the treatment of Crohn Disease?

Which medications in the drug class Antidiarrheals are used in the treatment of Crohn Disease?

Which medications in the drug class Bile Acid Sequestrants are used in the treatment of Crohn Disease?

Which medications in the drug class Anticholinergic Agents are used in the treatment of Crohn Disease?