*Crohn Disease

Chapter: Crohn Disease
McMaster Section Editor(s): Paul Moayyedi, John K. Marshall
Section Editor(s) in Interna Szczeklika: Witold Bartnik†, Małgorzata Szczepanek
McMaster Author(s): Neeraj Narula, Aiya Aboubakr
Author(s) in Interna Szczeklika: Witold Bartnik†, Małgorzata Szczepanek
† Deceased.
Additional Information

Definition, Etiology, PathogenesisTop

Crohn disease (CD) is an inflammatory disease process that may affect any part of the gastrointestinal (GI) tract from the oral cavity to the anus. The disease is characterized by the presence of segments of predominantly granulomatous transmural inflammatory lesions separated by healthy sections of the intestine. The etiology is unknown. The inflammatory process starts in the mucosa and gradually involves all layers of the intestinal wall, leading to its destruction, fibrosis, and the formation of fistulas and strictures.

Clinical Features and Natural HistoryTop

1. General symptoms: Fatigue, fever (in ~30% of patients), and weight loss (~60%; secondary to malabsorption or malnutrition).

2. Symptoms dependent on the location, extent, and severity of the GI lesions:

1) Classic form involving the terminal ileum (40%-50% of patients): The onset is usually insidious, although in rare cases it may be acute and resemble appendicitis. The presenting symptoms include abdominal pain (~80%; often localized to the right lower quadrant of the abdomen and worsened postprandially), diarrhea, anemia, fever of unknown origin. Hematochezia and melena are infrequent. In patients with a retrocecal abscess, guarded movement of the right hip is seen. Extensive involvement of the small intestine leads to malabsorption syndrome with fatty diarrhea, anemia, hypoproteinemia, vitamin deficiency (particularly cobalamin), and electrolyte disturbances. With time patients develop malnutrition and cachexia, as well as edema in the case of hypoalbuminemia.

2) Colon (in 20% of patients lesions are isolated; in 30%-40% lesions are also present in the small intestine): Symptoms may resemble ulcerative colitis (UC). Diarrhea is the most frequent manifestation (sometimes with visible blood). Abdominal pain is also common, particularly in patients with involvement of the cecum and ileum.

3) Mouth: Pain, aphthous ulcers, sores.

4) Esophagus: Dysphagia, odynophagia.

5) Stomach and duodenum: Abdominal pain, vomiting (symptoms may resemble peptic ulcer disease or pyloric stenosis).

6) Perirectal area: Large hemorrhoidal tags, ulcers, fissures, perianal abscesses and fistulas; these occur in 50% to 80% of patients with involvement of the colon and may be the presenting symptoms of CD.

7) Symptoms of intestinal and extraintestinal complications: see Complications, below.

3. Natural history: CD has a chronic course typically lasting several decades, usually with alternating periods of flares and remissions. Frequently the symptoms are persistent, cause significant disability, and require surgery because of complications (60% of patients after 10 years). Endoscopic recurrence rates after surgery are ~70% at 1 year after resection, and clinical recurrence occurs in 30% to 50% of patients 5 years after resection.


Diagnostic Tests

The diagnosis of CD requires correlation and integration of clinical, biochemical, imaging, endoscopic, and histopathologic information.

1. Laboratory tests:

1) Routine studies may reveal anemia, leukocytosis, thrombocytosis, elevated erythrocyte sedimentation rate (ESR), elevated C-reactive protein (CRP) levels, hypoproteinemia with hypoalbuminemia, and electrolyte abnormalities such as hypokalemia. Results of these studies are useful in detecting and determining the severity of disease and degree of malabsorption.

2) Serologic testing, such as anti–Saccharomyces cerevisiae antibodies (ASCAs) and antineutrophil cytoplasmic antibodies (ANCAs), may be used as adjunct testing, but generally it is ineffective in routine diagnosis and in differentiating colonic CD from UC.

2. Imaging studies:

1) Depending on which part of the GI tract is investigated, barium radiography (eg, small bowel follow-through [SBFT] and contrast barium enema) can reveal segmental lesions in the small intestine or colon, solitary or multiple strictures, characteristic deep “rose-thorn” or “collar-button” ulcers, or fistulas. SBFT has a sensitivity of ~70% for the diagnosis and detection of complications in CD. Because barium radiography is less sensitive than magnetic resonance or computed tomography (CT) enterography, intestinal ultrasonography, and small bowel capsule endoscopy, it is not the recommended diagnostic method when these alternatives are available.

2) Ultrasonography, CT, and magnetic resonance imaging (MRI) can reveal abscesses and fistulas. These studies also visualize the intestinal wall and allow for the assessment of its thickness and the diameter of the lumen. Administration of luminal contrast by enteroclysis or enterography improves small bowel visualization. The sensitivity of CT and MRI in the diagnosis of CD is about 80% to 90%. Small intestine contrast ultrasonography (with oral contrast) offers a better detection rate of strictures and associated dilation. Its sensitivity and specificity are comparable to magnetic resonance enterography and CT enterography.

3. Endoscopy: Ileocolonoscopy (colonoscopy with evaluation of the terminal ileum) with ≥2 biopsy specimens from the ileum and from 5 sites around the colon (including the rectum) is suggested to establish the diagnosis of CD. The earliest lesions are small aphthous mucosal ulcers, with subsequent irregular edema and deep ulcers of varying shapes. Typical lesions are transverse and longitudinal linear ulcers with a characteristic “cobblestone” appearance.

1) Rectoscopy reveals irregular rectal strictures, islets of mucosal lesions separated by portions of normal mucosa, and ulcers. In ~50% of patients with involvement of the colon, rectal mucosa has a normal appearance but histologic examination of rectal mucosa biopsy specimens may reveal granulomas or a granulomatous reaction in the submucosa.

2) Ileocolonoscopy is used to assess the type and extent of inflammatory lesions in the colon and terminal ileum (collecting multiple specimens is recommended).

3) Capsule endoscopy is used in patients with suspected inflammatory lesions in the small intestine that are not accessible using classic endoscopy and radiography.

4. Histologic examination: While CD has no pathognomonic histologic features, 60% of patients have noncaseating epithelioid granulomas, giant multinucleated Langerhans-type cells, and lymphocytes in the intestinal wall. However, granulomas are detected only in 10% of patients with CD who have intestinal biopsies.

5. Stool examination:

1) Microbiology: In patients with recently diagnosed active CD or a CD exacerbation, microbiological testing of the stool including assessment for Clostridium (now Clostridioides) difficile infection should be performed.

2) Fecal inflammation markers: Fecal calprotectin and lactoferrin can be useful in distinguishing inflammatory bowel disease (IBD) from irritable bowel syndrome (IBS) and in predicting relapse. Patients with a calprotectin level <40 microg/g have ≤1% chance of IBD. Fecal lactoferrin has similar utility, as patients with lactoferrin levels ≤10 microg/g have a 2% chance of IBD.Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Menees SB, Powell C, Kurlander J, Goel A, Chey WD. A meta-analysis of the utility of C-reactive protein, erythrocyte sedimentation rate, fecal calprotectin, and fecal lactoferrin to exclude inflammatory bowel disease in adults with IBS. Am J Gastroenterol. 2015 Mar;110(3):444-54. doi: 10.1038/ajg.2015.6. Epub 2015 Mar 3. Review. PubMed PMID: 25732419.

Diagnostic Criteria

No strict diagnostic criteria exist for CD. The diagnosis is based on endoscopic, radiologic, and histologic confirmation of segmental inflammatory lesions involving the entire thickness of the intestinal wall, as described in detail above.

There are also no unequivocal criteria for the differentiation between CD and UC; however, several findings may suggest CD over UC, including presence of granulomatous lesions on biopsy, presence of perianal disease, rectal sparing, and involvement of the small bowel. Nonetheless, in about 10% of patients a diagnosis of indeterminate colitis (IC) or inflammatory bowel disease unclassified (IBDU) is made.

Differential Diagnosis

1. CD of the ileum:

1) Intestinal tuberculosis: Difficult to differentiate from CD because of the similar histologic appearance (granulomas) and similar location of lesions in the ileocecal region. Microbiological findings and the presence or absence of caseating necrosis are decisive for the final diagnosis.

2) Acute ileitis: A sudden onset with symptoms suggestive of appendicitis. The diagnosis is frequently established during laparotomy. Acute ileitis may be caused by parasites or Yersinia spp.

2. CD of the colon:

1) UC (see Table 2 in Ulcerative Colitis).

2) Ischemic colitis: Advanced age, GI hemorrhage as a presenting symptom, rapid course of disease, typical location of lesions near the splenic flexure.

3) Segmental colitis associated with diverticulosis (SCAD): Appearance of localized area of colitis around diverticula with a typical location of disease near the sigmoid colon.

4) Infectious colitis: Commonly acute onset, may be associated with symptoms of vomiting and diarrhea.

5) IBS: Patients may have some similar manifestations but lack red flag symptoms (weight loss), have normal laboratory test results (no anemia or elevated CRP levels), and the appearance of the bowel on cross-sectional imaging or colonoscopy is unchanged.

6) Colorectal cancer: Cancer may resemble CD when it causes longer intestinal strictures. Most commonly it affects elderly persons without local or general symptoms of inflammation and no lesions typical of CD in the mucosa of the strictures.


General Management

1. Cessation of tobacco smoking is of great importance in the prevention of relapses in active smokers with CD. Previous studies have demonstrated an association of current smoking and CD.Evidence 2Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data. Mahid SS, Minor KS, Soto RE, Hornung CA, Galandiuk S. Smoking and inflammatory bowel disease: a meta-analysis. Mayo Clin Proc. 2006 Nov;81(11):1462-71. Erratum in: Mayo Clin Proc. 2007 Jul;82(7):890. PubMed PMID: 17120402. Smoking also increases the risk of recurrence after surgery for CD, especially in women and heavy smokers. Smoking cessation likely lowers the risk of symptomatic relapse compared with patients who continue to smoke.Evidence 3Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data and increased due to effect size. Cosnes J, Beaugerie L, Carbonnel F, Gendre JP. Smoking cessation and the course of Crohn's disease: an intervention study. Gastroenterology. 2001 Apr;120(5):1093-9. PubMed PMID: 11266373.

2. Avoidance of other factors causing exacerbations, such as infections, nonsteroidal anti-inflammatory drugs (NSAIDs), and stress. High perceived stress levels have been associated with an increased risk of IBD flare.Evidence 4Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational and subjective nature of data. Bernstein CN, Singh S, Graff LA, Walker JR, Miller N, Cheang M. A prospective population-based study of triggers of symptomatic flares in IBD. Am J Gastroenterol. 2010 Sep;105(9):1994-2002. doi: 10.1038/ajg.2010.140. Epub 2010 Apr 6. PubMed PMID: 20372115. Evidence regarding other potential triggers, including NSAIDs, infections, or antibiotic use, is weaker.

3. Correction of metabolic disturbances: Treatment of dehydration; correction of electrolyte disturbances, hypoalbuminemia, and anemia; treatment of cobalamin deficiency in patients with involvement of the ileum or after ileum resection.

Nutritional Management

Nutritional interventions can be used in patients with active disease complicated by malnutrition. Enteral nutrition (EN) with elemental or polymeric formulas is recommended; in patients in whom this is impossible or insufficient (because of GI obstruction, fistulas, or short bowel syndrome), supplementary or total parenteral nutrition should be used.

EN is not regularly used to induce remission in adult patients with CD; however, it can be considered in certain populations (eg, pediatric). A meta-analysis of 10 studies that compared EN with glucocorticoids suggests that glucocorticoid therapy may be more effective than EN for induction of clinical remission in adults with active CD and equally effective for induction of remission in children with active CD.Evidence 5Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and imprecision. Narula N, Dhillon A, Zhang D, Sherlock ME, Tondeur M, Zachos M. Enteral nutritional therapy for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2018 Apr 1;4:CD000542. doi: 10.1002/14651858.CD000542.pub3. Review. PubMed PMID: 29607496. Maintenance with EN is typically not performed because of issues with compliance and acceptability.

Specific Pharmacologic Treatment

Treatment of CD is usually directed by gastroenterologists, possibly with interdisciplinary involvement from other allied health-care professionals such as nutritionists. Colorectal and general surgeons are also essential for patients with particular phenotypes of CD, including those with perianal fistulas or structuring disease causing bowel obstructions.

1. Anti-inflammatory drugs:

1) Glucocorticoids: Oral prednisone or prednisolone 40 to 60 mg/d. In patients with lesions involving the ileocecal region, use oral budesonide 9 mg/d. In patients with very active disease, use IV hydrocortisone 300 mg/d or methylprednisolone 60 mg/d. Once an acute flare of CD is under control, taper off the glucocorticoid dose over 2 to 3 months; discontinuation is not always possible.

2) Aminosalicylates (5-aminosalicylic acid [5-ASA]): Oral sulfasalazine 3 to 4 g/d is sometimes used in mild cases of colonic CD without clear evidence of benefit.Evidence 6Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and sparse data. Lim WC, Wang Y, MacDonald JK, Hanauer S. Aminosalicylates for induction of remission or response in Crohn's disease. Cochrane Database Syst Rev. 2016 Jul 3;7:CD008870. doi: 10.1002/14651858.CD008870.pub2. Review. PubMed PMID: 27372735.

2. Immunomodulating agents are used in patients with response to glucocorticoids as maintenance of remission therapy:

1) Oral azathioprine 1.5 to 2.5 mg/kg/d, oral mercaptopurine 0.75 to 1.5 mg/kg/d. These agents have not been demonstrated to be beneficial for induction but can maintain a glucocorticoid-induced remission.

2) IM methotrexate: For induction treatment, use 25 mg/wk; for maintenance treatment, use 15 mg/wk. Studies examining oral methotrexate have not demonstrated benefit.

3. Biologic agents (standard doses):

1) Infliximab: Induction treatment: 3 administrations of 5 mg/kg once a week in a 2-hour IV infusion at weeks 0, 2, and 6; maintenance treatment: repeat the infusion every 8 weeks.

2) Adalimumab: Induction treatment: 160 mg subcutaneously followed by 80 mg after 2 weeks; maintenance treatment: 40 mg every 2 weeks.

3) Vedolizumab: Induction treatment: 3 administrations of 300 mg once a week in a 30-minute IV infusion at weeks 0, 2, and 6; maintenance treatment: repeat the infusion every 8 weeks.

4) Ustekinumab: Induction treatment: 1 weight-based infusion between 260 mg and 520 mg; maintenance treatment: 90 mg subcutaneously every 8 to 12 weeks.

4. Antibiotics: In patients with septic complications and draining perianal fistulas with or without an abscess, you can use metronidazole, ciprofloxacin, or both.

Symptomatic Treatment

1. Analgesics: Acetaminophen (INN paracetamol). In patients with continuous pain who require opioids, use opioids with little effect on motility (eg, tramadol). Cannabinoids may also play a role in the management of patients with CD who have chronic abdominal pain.

2. Antidiarrheal drugs: Diphenoxylate with atropine 2.5 to 5 mg (1-2 tablets) bid or tid or loperamide 2 to 6 mg as needed. In patients with diarrhea caused by impaired absorption of bile acids after resection of the small intestine, use cholestyramine 4 g (1 teaspoon) with main meals.

Treatment Options Depending on CD Location and Severity

Disease severity (based on the 2010 European Crohn’s and Colitis Organisation [ECCO] consensus):

1) Remission: The patient is asymptomatic, may have responded to medical or surgical therapy, and has no residual active disease. This category does not include patients who require ongoing glucocorticoid treatment.

2) Mild: The patient is able to walk, eat, and drink; has lost <10% of body weight; may have mild symptoms but has no GI obstruction, no fever, no dehydration, no palpable mass, and no abdominal tenderness; serum CRP levels may be slightly elevated.

3) Moderate: Intermittent vomiting without obstructive findings or >10% body weight loss; ineffective treatment of mild disease or a painful abdominal mass found on physical examination with no clinically overt GI obstruction; usually elevated serum CRP levels.

4) Severe: Cachexia (body mass index <18 kg/m2), GI obstruction, or abscess; symptoms persisting despite intensive treatment; usually elevated serum CRP levels.

Disease Limited to the Ileocecal Region

1. Mild disease: Oral budesonide 9 mg/d. The efficacy of mesalamine is low. In patients with mild or no symptoms, no pharmacotherapy may be considered.

2. Moderate disease: Oral budesonide 9 mg/d or oral prednisone/prednisolone 1 mg/kg/d (remission rates after 7 weeks of treatment are >90% but adverse effects are more frequent than with budesonide). Azathioprine/mercaptopurine or methotrexate in combination with glucocorticoids are also appropriate. In patients with glucocorticoid resistance, dependence, or intolerance, biologic drugs may be considered.

3. Severe disease: Use a glucocorticoid, starting from IV methylprednisolone. In case of relapse introduce a biologic drug, alone or in combination with an immunomodulator; restarting glucocorticoids with an immunomodulator may also be appropriate. In patients with treatment failure, consider surgery.


1. Systemic glucocorticoids: Although sulfasalazine is recommended by the American College of Gastroenterology (ACG) guidelines for treating symptoms of colonic CD that is mild to moderately active, it has not been demonstrated to be more effective than placebo for achieving mucosal healing. Sulfasalazine is not recommended by the ECCO guidelines.

2. Recurrent disease of moderate or severe activity: A biologic agent alone or in combination with an immunomodulator. For some patients restarting glucocorticoids with an immunomodulator may also be appropriate.

3. Surgery should be considered before starting treatment with biologic or immunosuppressive agents.

Diffuse Disease of the Small Intestine (>100 cm)

If disease activity is moderate or severe, use oral prednisone/prednisolone 1 mg/kg combined with azathioprine, mercaptopurine, or methotrexate. Start nutritional therapy. In selected patients consider early biologic agents or surgical treatment. Aim to avoid surgical treatment in patients with extensive small bowel disease because of the risk of short bowel syndrome.

Disease of the Esophagus, Stomach, and Duodenum

If disease activity is moderate or severe, use oral prednisone/prednisolone 1 mg/kg combined with azathioprine, mercaptopurine, or methotrexate. In patients with no response to treatment consider biologic agents.

Disease With Fistulas

1. Simple perianal fistulas: If the fistulas are asymptomatic, no intervention is needed. If they cause discomfort, seton insertion with or without fistula dissection (fistulotomy) is performed and treatment with metronidazole 750 to 1500 mg/d, ciprofloxacin 1000 mg/d, or both is started.

2. Complex perianal fistulas: First-line treatment includes antibiotics, azathioprine, or mercaptopurine, all combined with surgical treatment. In the case of perianal abscesses, drainage is performed. Second-line treatment includes biologic agents. Biologics are often necessary in patients with complex fistulas because of low response rates to nonbiologic therapies.

3. Enterovaginal fistulas: Low and asymptomatic fistulas may require no surgical treatment, whereas in symptomatic fistulas surgery is usually necessary. Symptomatic rectovaginal fistulas that do not respond to medical treatment also warrant surgical treatment. In fistulas originating in the small intestine or the sigmoid colon resection of the affected segment of the intestine is required.

4. Enterovesical fistulas require surgical treatment. In high-risk patients (after several surgical interventions or with a significantly shortened intestine) medical treatment should be attempted first.

5. Enterocutaneous fistulas: For fistulas developing after surgery, start with medical treatment (including nutritional management); surgery is performed once a normal nutritional status is restored. For primary fistulas, use surgery (resection of the affected segment of the intestine) or medical treatment.

Remission Maintenance Treatment

1. The use of 5-ASA or glucocorticoids in maintenance treatment is not recommended. In some patients maintenance treatment can be avoided.

2. If remission was achieved with glucocorticoids, maintenance treatment should be considered with azathioprine, mercaptopurine, or methotrexate.

3. In glucocorticoid-dependent patients use azathioprine, mercaptopurine, or methotrexate alone or in combination with infliximab, adalimumab, vedolizumab, or ustekinumab.

4. In case of relapse in the course of maintenance treatment with azathioprine or mercaptopurine, first make sure that the patient has been adherent to the prescribed regimen, and then consider switching to methotrexate or a biologic agent.

5. If remission was achieved using infliximab, adalimumab, vedolizumab, or ustekinumab, the same drug should be used for maintenance therapy. Episodic biologic use is likely a less effective strategy compared with regular scheduled use because of sensitization against the biologic.Evidence 7Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Rutgeerts P, Diamond RH, Bala M, et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn's disease. Gastrointest Endosc. 2006 Mar;63(3):433-42; quiz 464. PubMed PMID: 16500392. Rutgeerts P, Feagan BG, Lichtenstein GR, et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease. Gastroenterology. 2004 Feb;126(2):402-13. PubMed PMID: 14762776.

6. Discontinuation of azathioprine may be considered after 2 to 4 years of continuous complete remission. No sufficient data are available to define the duration of maintenance treatment with methotrexate or a biologic drug (our practice is to continue).

7. The need for surgical treatment should be evaluated based on the frequency, extent, and severity of relapses, as well as for adverse effects or failure of maintenance treatments.

8. In patients after resection of the small intestine, use maintenance treatment to prevent relapses; the most effective drugs are anti–tumor necrosis factor agents like infliximab or adalimumab. Azathioprine and mercaptopurine could be considered for initial postoperative recurrence.

9. For maintenance treatment in patients with perianal fistulas, use azathioprine, mercaptopurine, or a biologic drug for ≥1 year.

Surgical Treatment

1. Indications:

1) Emergency (acute surgery): Total GI obstruction due to small intestinal stricture, massive hemorrhage, or intestinal perforation with diffuse peritonitis.

2) Urgent: Lack of significant improvement after 7 to 10 days of intensive medical treatment of a severe episode of extensive disease of the colon.

3) Elective (most common): Internal and external fistulas, intraabdominal infectious complications, extensive perianal lesions, confirmed or suspected cancer, chronic disability due to persistent troublesome symptoms despite adequate medical treatment, delayed physical development with growth retardation in children.

2. Types of surgical operations:

1) Disease of the small intestine: Resection of as small a portion as possible or surgical dilation of small intestinal strictures (strictureplasty).

2) Disease of the left or right colon: Hemicolectomy.

3) More extensive lesions of the colon: Colectomy with ileoanal anastomosis or proctocolectomy with permanent ileostomy.


Local Complications

External fistulas (perianal, enterocutaneous) and internal fistulas (communicating between the small intestine and the cecum, another loop of the small intestine, sigmoid, bladder, and vagina), interloop abscesses and significant intestinal strictures with symptoms of partial obstruction; rarely acute intestinal obstruction, massive hemorrhage, perforation with diffuse peritonitis. The risk of colorectal cancer is increased in CD but lower than in UC. Many guidelines recommend endoscopic screening for dysplasia be performed in all patients with Crohn colitis involving more than one-third of the colon after 8 to 10 years from the time of disease onset. Regular surveillance should be considered at 1- to 3-year intervals after the initial screening colonoscopy.

Extraintestinal Complications

As in ulcerative colitis. Additional common complications include cholelithiasis (30% of patients with involvement of the ileum), clubbing of digits (40%-60% of patients with severe CD flares), and nephrolithiasis (10%).

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