Crohn disease

Crohn disease (CD) is an inflammatory bowel disease (IBD) of unclear etiology. Unlike ulcerative colitis, CD is not limited to the colon but can manifest anywhere in the gastrointestinal tract. Clinical features commonly include diarrhea, weight loss, and abdominal pain but differ according to disease severity. Extraintestinal manifestations may occur in the eyes, joints, and skin. Diagnosis is based primarily on characteristic endoscopic features (ulcerations, skip lesions, cobblestone appearance) and evidence of intestinal inflammation on imaging. Medical management aims to induce and maintain remission; it is tailored to the patient and influenced by the location and severity of CD. Acute flares are typically managed with corticosteroids but steroid-sparing regimes (e.g., thiopurine analogs, biologics) may also be used. Maintenance therapy (e.g., immunomodulators, biologics) focuses on limiting the frequency and duration of inflammatory episodes. Though surgery is ultimately required in up to half of patients with CD, surgical resection is generally not curative. Complications of CD include malabsorption, iron and vitamin deficiency, strictures, bowel obstruction, intraabdominal abscesses, and increased risk of bowel cancer.

• Prevalence: 1 case per 500 population
• Incidence: ∼ 6 cases per 100,000 population per year ^[1]
• Sex: ♂ = ♀
• Typical age of onset: bimodal distribution with one peak at 15–35 years and another one at 55–70 years ^[2][3]
• Populations with higher prevalence ^[4]
  • Individuals of Northern European descent
  • Individuals of Ashkenazi Jewish descent

Epidemiological data refers to the US, unless otherwise specified.

• Cause: Immune dysregulation and dysbiosis, which promotes chronic inflammation, the ultimate cause of which is not fully understood.
• Risk factors ^[4]
  • Familial aggregation
  • Genetic predisposition (e.g., mutation of the NOD2 gene, HLA-B27 association)
  • Tobacco smoke

Smoking tobacco is the primary modifiable risk factor for CD. Therefore, smoking cessation is especially important in patients with CD.

Inflammation

Inflammation is most likely caused by immune dysregulation.

• Dysregulation of IL-23-Th17 signaling → unrestrained Th17 cell function → inflammation → local tissue damage (edema, erosions/ulcers, necrosis) → obstruction, fibrotic scarring, stricture, and strangulation of the bowel ^[5]
• Mutations in the nucleotide oligomerization binding domain 2 (NOD2) protein are likely involved in the development of CD.

Abscess and fistula formation

• Intestinal aphthous ulcers → transmural fissures and inflammation of the intestinal walls → adherence of other organs or the skin → penetration of tissue → microperforation and abscess formation → macroperforation into these structures → fistula formation

CD typically has a chronic intermittent course with episodic acute flares and periods of remission. Clinical features differ according to the severity of CD. Patients with mild CD may be asymptomatic while patients with fulminant CD have severe symptoms.

Constitutional symptoms ^[6]

• Low-grade fever
• Weight loss
• Fatigue

Gastrointestinal symptoms ^[6]

CD most commonly affects the terminal ileum and colon, but involvement of any part of the GI tract (from mouth to anus) is possible. In contrast to ulcerative colitis, rectal involvement is uncommon.

• Chronic diarrhea
• Lower gastrointestinal bleeding (uncommon)
• Abdominal pain, typically in the RLQ
• Palpable abdominal mass in the RLQ
• Features of CD complications
  • Malabsorption (e.g., weight loss, anemia, failure to thrive)
  • Enterocutaneous or perianal fistulas, often associated with abscess formation ^[7]

Perianal fistulas and abscesses are often the first signs of CD.

Extraintestinal symptoms ^[8]

Extraintestinal manifestations of CD are present in 20–30% of patients with CD. ^[9]

• Joints
  • Enteropathic arthritis
    • A seronegative spondyloarthropathy that develops in association with inflammatory bowel disease
    • Typically affects joints of the lower extremities but can also involve the spine (e.g., sacroiliitis, spondylitis, inflammation of peripheral joints).
  • Nail clubbing ^[10]
• Eyes
  • Uveitis
  • Iritis
  • Episcleritis
• Liver/bile ducts: cholelithiasis
• Urogenital system: urolithiasis (mostly calcium oxalate stones)
• Oral mucosa
  • Oral aphthae
  • Pyostomatitis vegetans
• Skin
  • Erythema nodosum
  • Acrodermatitis enteropathica
  • Pyoderma gangrenosum: a neutrophilic dermatosis
    • Associated with various conditions (e.g., IBD, rheumatoid arthritis, and trauma)
    • Manifests with very painful, rapidly-progressive, red spots that can change into purulent pustules or deep ulcerated lesions with central necrosis
    • Commonly located at extensor side of the lower limbs
    • Treated with immunosuppressants (e.g., corticosteroids, cyclosporine A)

Crohn Disease Activity Index (CDAI)

The CDAI is a validated system commonly used in clinical trials to categorize disease activity but with limited utility in clinical practice. ^[11][12]

Montreal classification

Classifies CD according to the course and phenotype. Primarily used to standardize and streamline communication between health care providers and facilitate epidemiological studies.

Endoscopy, cross-sectional imaging, and laboratory studies are required for the initial evaluation of suspected CD, evaluation of an acute flare, and monitoring response to therapy.

Approach ^[11][15]

• Conduct a thorough history and physical examination (including digital rectal examination).
  • Document any extraintestinal manifestations of CD.
  • Evaluate for the presence of perianal fistulas.
• Perform endoscopy and obtain intestinal biopsies.
• Obtain cross-sectional imaging to:
  • Establish location(s) and severity of disease
  • Identify complications (e.g., abscesses, fistulas, strictures)
• Obtain laboratory studies (blood and stool) to:
  • Rule out differential diagnoses of Crohn disease (e.g., infectious gastroenteritis)
  • Assess and monitor disease activity

Small bowel evaluation is an essential part of the initial diagnostic workup of CD. Almost one-third of patients with CD have only small bowel disease and this may not be visible on ileocolonoscopy. ^[11][16]

Endoscopy

Ileocolonoscopy ^[11]

• Indication: all patients with suspected CD
  • Assesses the distribution and severity of the disease
  • Aids differentiation of CD from other diseases (e.g., ulcerative colitis)
  • Monitors disease activity (e.g., active disease, remission)
  • Can be used therapeutically (e.g., stricture dilatation)
• Supportive findings ^[11][15][17]
  • Skip lesions: segmental and/or discontinuous pattern of involvement (interspersed with normal tissue)
  • Linear and/or serpiginous ulcerations
  • Small aphthous ulcerations
  • Cobblestone sign: inflamed edematous sections interspersed with deep ulcerations that resemble cobblestones
  • Erythema, fissures, strictures, and fistulas

Other endoscopic techniques ^[11]

• Upper endoscopy: if upper GI involvement is suspected ^[11][18]
• Video capsule endoscopy : Consider in patients with suspected small bowel CD (as an alternative to cross-sectional imaging).
• Deep enteroscopy (e.g., double-balloon enteroscopy): Consider for small bowel biopsy or stricture dilation. ^[11]

Discontinuous areas of inflammation, cobblestone appearance of the affected mucosa, and mucosal ulcerations are hallmark endoscopic findings of CD. ^[19]

Characteristic endoscopic features and evidence of chronic intestinal inflammation on histology are the most important factors to establish a diagnosis of CD. ^[20][21]

Imaging ^{[6][11][16][20]}

Cross-sectional imaging is preferred as it permits evaluation of the entire gastrointestinal tract (including the small bowel), can identify complications (e.g., bowel obstruction, abscess, fistula), and can assess for differential diagnoses of CD. ^[16]

Indications

• Suspected CD (part of initial evaluation)
• Localization of inflammation and assessment of severity ^[11][16]
• Evaluation of suspected acute flare or complications (e.g., abscess)
• Serial imaging to assess response to therapy

Modalities and supportive findings

• Cross-sectional enterography (MRE, CTE): preferred imaging modality for CD ; ^[11][16][20]
  • Edematous thickening of the intestinal wall
  • Mucosal enhancement, mesenteric fat stranding
  • Creeping fat: excessive mesenteric fat around the affected segments of bowel ^[22]
  • Can also identify:
    • Complications (e.g., strictures, fistulas, abscesses)
    • Extraluminal disease (e.g., cholelithiasis, urolithiasis)
    • Response to therapy (e.g., healing of ulcers)
• CT abdomen and pelvis (with IV contrast): preferred in acutely ill patients who cannot tolerate PO contrast
• Small bowel follow-through: : can identify luminal complications such as internal fistulas and narrowed segment(s) of bowel (string sign) ^[16]
• Additional modalities ^[11][16]
  • Ultrasound abdomen
    • Consider for initial evaluation of suspected CD and for disease monitoring. ^[16]
    • Supportive finding (of active disease): bowel wall thickening (> 4 mm)
  • Plain x-ray abdomen: Consider for expedited assessment of complications.
  • CT or MRI enteroclysis: Consider for evaluation of an acute flare or response to therapy. ^[16]
  • MRI abdomen and pelvis (with IV contrast) ^[16]
    • Preferred modality to evaluate for perianal fistulas.
    • Consider for stable patients with suspected intraabdominal abscesses.

Laboratory studies ^[6][11]

• To rule out differential diagnoses of CD
  • Stool analysis: to identify ova, cysts, or C. difficile infection in symptomatic patients
  • Serology: not routinely recommended due to low sensitivity ^[23]
    • ↑ Anti-Saccharomyces cerevisiae antibodies (ASCA): more commonly elevated in CD than in UC
    • pANCA: more commonly elevated in UC than in CD
• To monitor disease activity
  • Fecal calprotectin and/or fecal lactoferrin: proteins associated with neutrophil activation ; ^[21]
    • Used as noninvasive markers of intestinal inflammation to monitor disease activity and response to therapy
    • Also used to differentiate IBD from irritable bowel syndrome
  • Inflammatory markers: CRP, ESR, platelets
    • CRP correlates with disease activity better than ESR; both may be normal in patients with mild CD. ^[11][24]
    • ↑ Thrombocytes may be an indicator of active disease (reactive thrombocytosis) ^[11][25]
• To identify complications
  • CMP: to identify malnutrition (↓ total protein), end-organ damage (↑ creatinine), and/or dehydration
  • CBC, iron studies, vitamin B₁₂, folate: to evaluate for anemia and micronutrient deficiency ^[24]

Anemia in CD may result from chronic disease, iron deficiency, and/or vitamin B₁₂ deficiency.

• Transmural inflammation: all mucosal layers of the intestinal wall are involved
  • Noncaseating granulomas ^[26]
  • Giant cells
  • Distinct lymphoid aggregates of the lamina propria
• Creeping fat
• Hypertrophic lymph nodes

Management of CD is complex and includes medications with potentially significant adverse effects.

General principles ^[11][20]

• Tailor therapy to the severity of CD, phase of the disease (acute flare or remission), and risk of progression of CD.
• Surgery may be required to manage complications and is an option for isolated short-segment disease.
• Lifestyle modifications (e.g., smoking cessation) may decrease the incidence of complications.
• Regular monitoring of disease activity and screening for complications are essential aspects of long-term management.

Management of acute flare of CD

• Hemodynamic support as needed (e.g., for severe to fulminant CD): IV fluids, electrolyte repletion
• Consult gastroenterology early to determine choice of induction therapy.
• Screen for and administer prophylaxis against common infectious diseases.
• Patients with severe or fulminant CD typically require hospitalization.
• Initiate thromboprophylaxis as needed (e.g., presence of risk factors for VTE, hospitalization). ^[20][27]
• Identify and treat malnutrition and micronutrient deficiency.

Infectious disease screening and prophylaxis ^[20]

Perform prior to initiating therapy if feasible as most medications for CD can cause immunosuppression.

• Update immunization status at diagnosis: See “ACIP immunization schedule” for details.
• Screen for viral infections (hepatitis B, hepatitis C, HIV, Epstein-Barr virus) and tuberculosis. ^[20][24]
• Consult infectious disease before initiating therapy if screening tests are positive. ^[20]

Pharmacotherapy ^[11][28]

• Induction phase
  • Used to manage acute flares.
  • Agents that have a rapid onset of action (e.g., corticosteroids, biologics) are used.
  • Should be continued until there is objective evidence of remission (typically < 3 months) ^[11]
    • Endoscopic evidence of remission (e.g., healing ulcers) is currently the best indicator of remission of colonic CD. ^[11][29]
    • Noninvasive markers of intestinal inflammation (fecal calprotectin, cross-sectional imaging) are suitable alternatives to evaluate for remission.
• Maintenance phase
  • Used to maintain remission, typically in patients with moderate or severe CD and those at high risk of progression of CD. ^[30]
  • Biologics and immunomodulators are the principal agents of maintenance therapy.
  • Typically continued for a prolonged period of time. ^[31]

Symptoms do not accurately correlate with disease activity. Use objective markers of disease severity (e.g., biomarkers, imaging, endoscopy) to assess the severity of CD, guide treatment, and verify remission. ^[11][20]

Overview of commonly used medications ^[11]

• Corticosteroids
  • Primarily used to induce remission
  • Agents used (depending on severity of CD):
    • Controlled ileal release budesonide
      • A formulation of the synthetic steroid budesonide that is released in environments with a pH ≥ 5.5, which facilitates drug delivery distal to the proximal small bowel
      • Used to treat Crohn disease that involves sites of inflammation in the ileum and/or ascending colon
    • Oral prednisolone
    • IV methylprednisolone
• Biologics
  • Anti-TNF-α antibodies: e.g., adalimumab, infliximab, certolizumab
    • Increasingly used as a primary agent to induce remission.
    • Also used to maintain remission and manage CD refractory to immunomodulators
  • Anti-leukocyte trafficking antibody (vedolizumab) and anti-p40 antibody; (ustekinumab) : used mainly to induce and maintain remission in moderate to severe CD
• Immunomodulators: e.g., thiopurine analogs (azathioprine, 6-mercaptopurine), methotrexate
  • Primarily used to maintain remission
  • Can be used as a steroid-sparing regimen to induce remission
• 5-aminosalicylic acid derivative: sulfasalazine (mesalamine is not routinely recommended)
  • May be considered to induce remission of mild to moderate colonic or ileocolonic CD
  • Not effective in isolated small bowel disease
• Antibiotics: no longer recommended for the primary treatment of CD
  • Metronidazole may be beneficial in the prevention of postoperative recurrence of CD.
  • Broad-spectrum antibiotics are used for the treatment of abscesses and systemic infections.

Corticosteroids can be used to induce remission but should be discontinued once the acute flare has been managed. Immunomodulators and biologics are the mainstays of maintenance therapy but can also be used to induce remission. ^[11][20]

Treatment regimens based on disease severity

Almost 20% of patients with CD are steroid refractory. ^[11]

Do not use corticosteroids for maintenance therapy in CD. They do not promote mucosal healing and potentially increase the risk of complications. ^[11]

Supportive therapy

• Pain management ^[34][35]
  • Use multimodal therapy before using opioids.
  • Use atypical opioids (e.g., tramadol) if opioids are necessary.
  • Consult pain specialists early.
• Antidiarrheal therapy: loperamide OR cholestyramine ^[36]
• Lifestyle modifications ^[11]
  • Smoking cessation
  • NSAID avoidance ^[11]
  • Stress, depression, and anxiety management
• Dietary optimization
  • Enteral nutrition is preferred over parenteral nutrition. ^[21]
  • Identify and treat micronutrient deficiency: Iron deficiency, vitamin D deficiency, and vitamin B₁₂ deficiency are common. ^[20]
  • Identify and treat malabsorption syndrome: E.g., supplement calories, protein, and micronutrients (vitamins, zinc, calcium, iron).

Poor pain control and/or increased opioid use may indicate inadequate disease management. ^[34]

Antidiarrheals should not be used in patients with bowel obstruction, abdominal tenderness, or signs of systemic infection (e.g., fever). ^[37]

Surgery ^[11]

Half of patients with CD require major abdominal surgery within 10 years of diagnosis. ^[11][21]

• Indications
  • Severe complications (e.g., bowel obstruction; , intraabdominal abscess, perianal abscess) ^[11]
  • Unsuccessful medical therapy
  • Symptom control in disease localized to a short segment of the bowel ^[11][38]
• Procedures ^[38]
  • Surgical drainage of abscess ^[11][38]
  • Laparoscopic or open resection of the diseased bowel segment (small bowel resection, segmental colectomy) ^[38]
  • Strictureplasty (bowel-sparing technique) ^[11][38]

Surgery can lead to remission but is not curative, and short bowel syndrome may occur following multiple procedures.

• Assess severity of CD.
• Obtain IV access and initiate IV fluid therapy as needed (e.g., severe dehydration, acute complications)
• Maintain NPO status until workup is complete.
• Obtain laboratory studies: CBC, CMP, CRP, ESR, blood culture
• Obtain stool studies: stool culture, Clostridium difficile toxin, ova and parasite study, fecal calprotectin
• Order appropriate imaging.
• Consult gastroenterology to discuss management.
• Consult surgery if intraabdominal complications are suspected (e.g., bowel obstruction, bowel perforation).
• Start broad-spectrum antibiotics if an abscess or systemic infection is identified (e.g., empiric antibiotic therapy for intra-abdominal infections).
• Avoid antidiarrheal medication if the patient is acutely ill.
• Initiate DVT prophylaxis as needed.

Vaccinations ^[6]

• Ensure immunizations are up to date at each follow-up (see “ACIP immunization schedule” for details).
• Recommend pneumococcal vaccine and yearly influenza vaccine (inactivated).
• Consider herpes zoster vaccination.

Live vaccines should be avoided in patients receiving immunosuppressive therapy. ^[6][20]

Monitoring of disease activity ^[11][20]

• Endoscopic monitoring
  • Schedule an endoscopic exam 6–9 months after treatment is initiated. ^[39]
  • Routine monitoring endoscopy is not recommended in the remission phase. ^[40]
• Periodic cross-sectional imaging (MRE, CTE) : especially in patients with small bowel disease. ^[11]
• Serial CRP and fecal calprotectin: to assess inflammatory status and treatment efficacy (treating-to-target) ^[11][29]

Screening for complications and malignancies ^[6][20]

• Intestinal cancer
  • Chronic inflammation increases the risk of intestinal cancer. ^[20]
  • Schedule surveillance colonoscopy with biopsies ^[11]
    • After 8 years after CD onset in patients with ≥ 30% colonic involvement.
    • At diagnosis in patients with primary sclerosing cholangitis
• Skin cancer: periodic thorough skin examinations ^[6][20]
• Cervical cancer: annual pap smear ^[20]
• Anemia and malnutrition: e.g., CBC, iron-binding studies, folate, vitamin B₁₂, LDH, vitamin D, albumin ^[6]
• Osteoporosis: DXA in patients with > 3 months cumulative lifetime exposure to corticosteroids ^[20]

Crohn disease vs. ulcerative colitis

The crone and the fat granny skipped over the wrecked cobblestones: the most important features of Crohn disease are creeping fat, granuloma, skip lesions, rectal sparing, and cobblestone sign.

Other differential diagnoses

• Acute appendicitis
• Infectious gastroenteritis/colitis
• Noninfectious colitis (ischemic, after radiation therapy, after ingestion of drugs, etc.)
• Diverticulitis
• Irritable bowel syndrome
• Gastrointestinal tuberculosis
• Malignant intestinal transformations

The differential diagnoses listed here are not exhaustive.

Fistulizing CD ^[43]

• Overview
  • Occur in one-third of patients with CD
  • Typically involve the perianal region
  • Internal fistulas may involve the bladder, vagina, and/or another portion of the intestine.
  • Recurrences are common
• Clinical features: depend on location of the fistula (see “Fistulas”)
• Management: Interdisciplinary management including gastroenterology and surgery is required. ^[44]
  • Anal fistula
    • Fistulotomy or seton placement
    • Biologic PLUS antibiotic in addition to surgery
  • Internal fistula
    • Medical therapy (typically a biologic ± an antimetabolite) to reduce bowel inflammation ^[11]
    • Consider surgery when the patient is medically optimized.

Other intestinal complications

• Colorectal cancer (especially in the case of pancolitis)
• Short bowel syndrome and associated issues after surgery
• Stenosis/strictures → bowel obstruction/(sub)ileus
• Intestinal perforation → peritonitis
• Primary sclerosing cholangitis
• Impaired bile acid reabsorption
  • Bile acid diarrhea
  • Bile acid malabsorption → steatorrhea and deficiencies in fat-soluble vitamins
• Abscess formation/phlegmons

Systemic complications

• Signs of malabsorption syndrome
  • Weight loss
  • Failure to thrive and growth failure in children
  • Anemia
    • Iron deficiency anemia
    • Anemia of chronic disease
    • Megaloblastic anemia (vitamin B₁₂ deficiency due to impaired absorption in the chronically inflamed ileum)
  • Osteoporosis
• Amyloidosis

We list the most important complications. The selection is not exhaustive.

Crohn disease in pregnancy

See “Inflammatory bowel disease in pregnancy.”

CD is a chronic disease that is currently not curable. Patients with any of the following features are at high risk of progression to severe disease and may require more aggressive treatment to prevent complications of CD. ^[11][12][20]

• Young age at diagnosis (< 30 years of age)
• Early need for steroid use
• Small bowel involvement
• Perianal or rectal disease
• Previous stenosis, fistula, and/or abscess
• Visceral adiposity

Failure to achieve and maintain remission on therapy is associated with worse clinical outcomes, including stricture and fistula formation and the need for surgery. ^[29]