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Risk factors Symptoms/Pathology Diagnosis Clinical course / Sequelae / Extraintestinal disease Management
Known risk factors*
  • Genetics - 35% concordance among monozygotic twins
  • Cigarette smoking
  • Jewish descent
  • Race - Whites > Blacks > Asians > Hispanics

*Most patients with CD have no identifiable risk factor

Possible risk factors
  • Gastrointestinal infections
  • Mycobacterium infections
  • Altered intestinal flora
  • NSAID use
  • Geography - North > South;
    urban > rural [1,2,5]
Symptoms
  • Most patients develop symptoms in late adolescence and early adulthood
  • Symptom onset is typically insidious

    • Common symptoms include:
      • Abdominal pain
      • Diarrhea - may be bloody or nonbloody; may contain mucous; is often nocturnal
      • Weight loss
      • Fever
      • Rectal bleeding

  • In more severe disease, patients may present with intestinal strictures, perforations, or perianal fistulas
  • Extraintestinal involvement (e.g. arthritis, uveitis, pyoderma gangrenosum, erythema nodosum) as a presenting sign is uncommon but may occur

Pathology
  • The exact pathology of Crohn's disease is not entirely understood
  • Crohn's disease is believed to occur when defects in intestinal epithelial cells allow commensal bacteria in the intestinal lumen to come in contact with immune cells in the underlying tissue. Inflammatory responses are then elicited that lead to intestinal inflammation.
  • Intestinal epithelial defects occur through several mechanisms including decreased mucin secretion and leaky junctions between epithelial cells.
  • Disorders in the host immune response (e.g. imbalances in T-cell types) may also play a role in perpetuating CD
  • Inflammatory intestinal lesions in CD are transmural and may affect the entire gastrointestinal tract. CD is also characterized by skip lesions which is defined as sections of normal bowel in between diseased bowel. [1,2]

  • Intestinal involvement:
    • Terminal ileum and colon - 50%
    • Small bowel only - 30%
    • Colon involvement only - 20%
    • Rectum - rare [1]
Overview
  • CD is diagnosed based on a combination of clinical, endoscopic, histological, and radiological findings

Endoscopy
  • Endoscopy is the gold standard for establishing the diagnosis of CD
  • CD intestinal lesions are ulcerative, edematous, and erythematous. Strictures are also commonly seen.
  • Lesional biopsies show lymphoid-predominant transmural inflammation. This helps distinguish CD from ulcerative colitis which only has mucosal inflammation.
  • Noncaseating granulomas are considered pathognomonic for CD, but are infrequently seen [1]

Radiology
  • On CT scans, lesions consistent with CD include bowel wall thickening, fatty infiltration, and edema. CT scans are also useful for identifying complications of CD such as obstructions, strictures, fistulas, and abscesses.
  • MRI scan, ultrasound, and barium swallow with small bowel follow-through can also identify active disease, but these modalities are utilized less frequently
  • A variation of a CT scan called "CT enteroclysis" may be superior to standard CT scans in identifying small bowel lesions in CD. Enteroclysis involves running a tube down to the duodenum and infusing contrast before performing a CT scan. CT enteroclysis can be labor-intensive and uncomfortable for the patient so it is not widely performed. [1,2]

Laboratory
  • ESR and C-reactive protein - nonspecific inflammatory markers (e.g. erythrocyte sedimentation rate, C-reactive protein) are often elevated in CD
  • Fecal calprotectin - calprotectin is an antimicrobial substance released by polymorphonuclear granulocytes (PMNs). Fecal calprotectin concentrations are directly proportional to the number of PMNs migrating to the intestinal lumen. In patients with active inflammatory bowel disease, fecal calprotectin levels are typically very high. In studies involving adults with suspected inflammatory bowel disease (IBD) based on symptoms, the sensitivity and specificity of fecal calprotectin in detecting IBD (verified by endoscopy and histology) was 93% and 96%, respectively. In studies involving children and teenagers, the sensitivity was 92% and the specificity was 76%. The cutoff value typically used in the studies was > 50 mcg/g. [6,7]
  • Fecal lactoferrin - lactoferrin is an iron-binding protein that has antimicrobial activity. Lactoferrin is found in neutrophil granules. During intestinal inflammation, neutrophils migrate to the intestinal mucosa and secrete lactoferrin into the lumen. Because of this, fecal lactoferrin levels are often elevated in patients with active inflammatory bowel disease (IBD). In studies involving adults with suspected IBD, the sensitivity and specificity of fecal lactoferrin in detecting IBD (verified by endoscopy and histology) was 78% and 94%, respectively. The cutoff value used in most studies was 7.25 mcg/ml. [8]
Clinical course
  • A number of studies have looked at the clinical course of Crohn's disease
  • These studies were published before the widespread use of biological therapies (e.g. TNF inhibitors)
  • The clinical course of the disease is likely much different today

    • Clinical course of Crohn's disease after initial diagnosis:
      • No relapse - 13%
      • Yearly relapse - 20%
      • Combination of years of relapses and years of remission - 67%
      • Continuous active disease - < 5%
      • In some studies, up to 50% of patients will require surgery within 10 years of initial diagnosis
      • After surgery, about 50% of patients relapse within 5 years [1,3]


Sequelae

  • Fistulas - fistulas including enterovesical (bowel to bladder), enteroenteric (bowel to bowel), and enterocutaneous (bowel to skin) occur in 20 - 40% of patients. Perianal fistulas are the most common type of fistula seen in CD. [3]
  • Bowel strictures - seen in up to 50% of patients in some studies [9]
  • Bowel resection - in some studies, up to 50% of patients require bowel resection within 10 years of initial diagnosis. The most common indication for surgery is disease that is uncontrolled with medical therapy. Newer therapies (e.g. TNF inhibitors) have likely lowered the probability of surgery. [1,3]
  • Abdominal perforations and abscesses
  • Colon cancer - in the past, patients with CD had a higher risk of colon cancer. More recent studies suggest that the risk may no longer be elevated. This is likely due to newer therapies (e.g. TNF inhibitors) and better disease control. See colon cancer screening for recommendations on screening in Crohn's disease [10]
  • Osteoporosis - patients with Crohn's may be at increased risk of osteoporosis secondary to malabsorption and/or prolonged steroid use [2]
  • Anemia - anemia may occur secondary to decreased iron absorption [3]

Extraintestinal disease
  • A number of organ systems may be affected by Crohn's disease
  • In up to 25% of patients, extraintestinal disease occurs before the diagnosis of inflammatory bowel disease

  • Arthritis - occurs in 10 - 20% of patients
    • Pauciarticular (affecting < 5 large joints) - knee is commonly involved; typically associated with intestinal disease activity; improves with treatment of bowel disease; does not typically cause joint destruction
    • Polyarticular (affecting ≥ 5 small joints) - MCP joints are commonly involved; typically not associated with intestinal disease activity; may be treated with steroids and COX-2 inhibitors; does not typically cause joint destruction
    • Axial arthropathy - ankylosing spondylitis and sacroiliitis; less common; typically not associated with intestinal disease activity
  • Erythema nodosum - occurs in up to 15% of patients; typically coincides with acute flares; improves with disease treatment
  • Oral disease - aphthous ulcers and periodontitis; occur in up to 10% of patients
  • Eye disease - episcleritis, scleritis, and uveitis; occurs in 3 - 7% of patients
  • Pyoderma gangrenosum - rare; associated with severe disease; typically affects the shin
  • Hepatobiliary disease - gallstones, autoimmune hepatitis, cholestasis, fatty liver disease, primary sclerosing cholangitis - all may be more common in CD patients [11]
Initial treatment

  • Mild disease - no systemic symptoms; CDAI 150 - 220

    • Ileum and/or proximal colon involvement

    • Diffuse or left colon
      • *Prednisone 40 - 60 mg once daily ± azathioprine 2 - 3 mg/kg/day

    • *Prednisone is given until resolution of symptoms which typically occurs within 7 - 28 days. It is then tapered by 5 - 10 mg/week down to 20 mg. From 20 mg, it is tapered by 2.5 - 5 mg/week until stopped.




References [3,14]
Maintenance of remission

  • Mild disease - no systemic symptoms; CDAI 150 - 220

    • Option 1 - stop therapy; this option has a high relapse rate
    • Option 2 - budesonide 6 mg/day; time to relapse is prolonged; remission rates are similar to placebo at 1 year
    • Option 3



  • Moderate - severe disease - CDAI 220 - 450


References [3,14]
Refractory disease






Drug Dosage form Dosage Generic/Price Mechanism/FDA-approved
indications
Side effects
P = % of patients on placebo who experienced side effect
Drug Interactions Contraindications/
Precautions
Budesonide

(Entocort®)
Budesonide enteric-coated capsules
  • 3 mg
Adults
Mild to moderate Crohn's disease involving the ileum and/or the ascending colon

  • Initial treatment: 9 mg once daily for up to 8 weeks
  • Maintenance of remission: 6 mg once daily for up to 3 months
  • Treatment beyond 3 months has not been shown to be effective in clinical trials
  • When switching from oral steroids like prednisone to budesonide, prednisone tapering should begin concomitantly with initiating budesonide

Children (8 - 17 years who weigh > 25 kg)
Mild to moderate Crohn's disease involving the ileum and/or the ascending colon

  • Initial treatment: 9 mg once daily for up to 8 weeks, followed by 6 mg once daily for 2 weeks
YES/$$$$ Mechanism
  • Budesonide is a corticosteroid. See corticosteroids for general information.
  • Budesonide enteric-coated capsules differ from other oral corticosteroids in that systemic absorption of the steroid is greatly reduced. Budesonide coated granules do not dissolve until they reach the small intestine. In theory, this provides localized delivery of budesonide to affected sections of the ileum and ascending colon.
  • Budesonide also undergoes a very high rate of first-pass metabolism in the liver (80 - 90%) further reducing its systemic availability.

FDA-approved indications
  • Mild to moderate active Crohn's disease involving the ileum and/or the ascending colon - treatment and maintenance of remission
NOTE: Only side effects that occurred at an incidence of ≥ 5% and ≥ 2% more than placebo are listed. Data are from short-term trials with 9 mg dose.

  • Headache - 21%, P - 18%
  • Acne - 15%, P - 13%
  • Easy bruising - 15%, P - 11%
  • Moon face - 11%, P - 4%
  • Respiratory infections - 11%, P - 7%
  • Nausea - 11%, P - 9%
  • Dizziness - 7%, P - 5%
  • Dyspepsia - 6%, P - 4%
  • Hirsutism - 5%, P - 2%
  • CYP3A4 inhibitors - budesonide is a CYP3A4 sensitive substrate. Systemic exposure to budesonide is increased when taken with CYP3A4 inhibitors.
  • Corticosteroid precautions - see corticosteroids for general precautions regarding corticosteroids. Systemic exposure with budesonide is reduced compared to other oral steroids, so the risks with budesonide therapy are also likely reduced. [12]
  • Hypothalamus-pituitary-adrenal (HPA) axis suppression - HPA suppression is a side effect of oral corticosteroids. Budesonide has reduced systemic exposure compared to other oral steroids, but some exposure does occur. In studies lasting 13 weeks, 59 - 84% of budesonide-treated patients had normal, unstimulated, plasma cortisol levels. In another study, 92% of budesonide-treated patients had normal adrenal function at one year compared to 75% of prednisone-treated patients (15 mg/day). The risk of HPA suppression appears to be lower with budesonide than with other oral steroids. [12]
  • Kidney disease - manufacturer makes no specific recommendation
  • Liver disease - since budesonide undergoes extensive first-pass metabolism, patients with moderate to severe liver disease may have increased systemic exposure to budesonide. Consider dose reductions in these patients.




Study Criteria Intervention Outcomes Results

Infliximab
vs
Azathioprine
vs
Combination therapy

SONIC study

NEJM 2010

PubMed abstract
Main inclusion criteria:
  • ≥ 21 years old
  • CDAI score of 220 - 450
  • One of the following:
    • Corticosteroid-dependent
    • Considered for 2nd course of steroids within 12 months
    • No response to mesalamine after 4 weeks
    • No response to budesonide after 4 weeks
Main exclusion criteria:
  • Previous treatment with azathioprine, 6MP, methotrexate, or anti-TNF
  • Decreased TPMT activity
  • Abdominal surgery within the previous 6 months

Baseline characteristics
  • Median age 34 years
  • Median disease duration - 2.3 years
  • Average CDAI - 287
  • Receiving steroids (prednisone-equivalent): 0 - 73%, < 20 mg - 9%, ≥ 20 mg - 18%
  • Receiving budesonide: 14%
  • Receiving 5-Aminosalicylic compounds: 54%
Group 1 (170 patients)
  • Azathioprine 2.5 mg/kg/day

Group 2 (169 patients)
  • Infliximab 5 mg/kg at Weeks 0, 2, and 6, then every 8 weeks

Group 3 (169 patients)
  • Azathioprine + infliximab

  • Oral mesalamine was continued at a stable dose
  • Steroids (oral and budesonide) could be used up to Week 14, then they had to be tapered
  • Colonoscopy was performed at baseline and Week 26
  • At Week 30, patients were given the option to continue on current treatment while maintaining blinding to Week 50
Primary outcome
  • Rate of corticosteroid-free clinical remission (CDAI < 150) at week 26

Secondary outcomes
  • Rate of corticosteroid-free clinical remission (CDAI < 150) at week 50
  • Proportion of patients with mucosal healing after 26 weeks
Primary outcome:
  • Group 1: 30%
  • Group 2: 44%
  • Group 3: 57%
  • Group 3 significantly better than Group 2 (p=0.02) and Group 1 (p<0.001)
  • Group 2 significantly better than Group 1 (p=0.006)

Secondary outcomes:
  • Mucosal healing after 26 weeks: Group 1 - 16.5%, Group 2 - 30%, Group 3 - 44%
  • Clinical remission at Week 50 (only patients who entered extension):
    • Group 1 (N=75) - 55%
    • Group 2 (N=97) - 61%
    • Group 3 (N=108) - 72%

Adverse events
  • There was no significant difference in the incidence of serious infections between the groups (Group 1 - 5.6%, Group 2 - 5%, Group 3 - 4%)
  • There were significantly fewer serious adverse events in Group 3 than in Group 1 and 2 (Group 1 - 27%, Group 2 - 24%, Group 3 - 15%)


Study Criteria Intervention Outcomes Results

Natalizumab
vs
Placebo

ENACT-1 and 2 studies

NEJM 2005

PubMed abstract
Main inclusion criteria:
  • ≥ 18 years old
  • 6 months of moderate to severe disease (CDAI 220 - 450)
  • Disease confirmed within previous 36 months by endoscopy, surgery, or imaging

Main exclusion criteria:
  • TNF inhibitors within previous 3 months
  • Active obstructing stricture, fistula, or abscess

Baseline characteristics (ENACT-1)
  • Average age 38
  • Average CDAI score - 302
  • Treatment with corticosteroids only - 38%
  • Treatment with immunosuppressants only - 33%
  • Treatment with corticosteroids + immunosuppressants - 14%
Group 1 (724 patients)
  • Natalizumab 300 mg IV every 4 weeks

Group 2 (181 patients)
  • Placebo IV every 4 weeks

  • Immunosuppressants were continued at current doses
  • Steroids were continued until Week 10, at which point, patients were required to attempt tapering
  • ENACT-1 lasted 12 weeks
  • In ENACT-2, patients from ENACT-1 who had a response were randomized to natalizumab or placebo for an additional 44 weeks
Primary outcomes
  • ENACT-1 - proportion of patients with response (defined by a decrease in the Crohn’s Disease Activity Index (CDAI) score of at least 70 points) at week 10

  • ENACT-2 - proportion of patients with sustained response through Week 36. Loss of response was defined by an increase in the CDAI score of at least 70 points after Week 12 and by an absolute score of at least 220 or the need for intervention after Week 12.

Secondary outcomes
  • Both trials - disease remission (CDAI < 150) at Week 10 (ENACT-1) and Week 36 (ENACT-2)
ENACT-1
Primary outcome:
  • Group 1: 56%
  • Group 2: 49%
  • Group 1 vs Group 2 (p=0.05)

ENACT-2
Primary outcome:
  • Group 1 (N=168): 61%
  • Group 2 (N=170): 28%
  • Group 1 vs Group 2 (p<0.001)

Secondary outcomes:
ENACT-1
  • Remission: Group 1 - 37%, Group 2 - 30%, (p=0.12)

ENACT-2
  • Remission: Group 1 - 44%, Group 2 - 26%, (p=0.003)

Adverse events
  • The rates of serious infections were similar between groups in both studies
  • In an open-label extension study, one patient treated with Natalizumab died of PML

Study Criteria Intervention Primary outcome Results

Vedolizumab
vs
Placebo

GEMINI 2 study

NEJM 2013

PubMed abstract
Main inclusion criteria:
  • ≥ 18 years old
  • 3 months of moderate to severe disease (CDAI 220 - 450)
  • One of the following:
    • C-reactive protein > 2.87 mg/L
    • Colonoscopy showing ≥ 3 large ulcers or ≥ 10 aphthous ulcers
    • Fecal calprotectin > 250 mcg/g + radiological findings of CD
  • No response or unacceptable side effects from steroids, immunosuppressants, or TNF inhibitors

Main exclusion criteria:
  • Adalimumab within previous 30 days
  • Infliximab or certolizumab within 60 days
  • History of extensive intestinal surgery

Baseline characteristics
  • Average age 36 years
  • Average CDAI score - 324
  • Treatment with steroids only - 34%
  • Treatment with immunosuppressants only - 16%
  • Treatment with steroids + immunosuppressants - 17%
  • No steroids or immunosuppressants - 33%
  • Prior TNF inhibitor - 62%
Induction phase
Group 1 (148 patients)
  • Placebo infusion

Group 2 (220 patients)
  • Vedolizumab 300 mg at Weeks 0 and 2

Maintenance phase
Group 1 (153 patients)
  • Placebo infusion

Group 2 (154 patients)
  • Vedolizumab 300 mg every 8 weeks

Group 3 (154 patients)
  • Vedolizumab 300 mg every 4 weeks

  • Stable doses of oral prednisone (≤30 mg per day) or budesonide (≤9 mg per day), immunosuppressive agents, mesalamine, and antibiotics were permitted
  • The induction phase also had an open-label vedolizumab arm that included 747 patients
  • Vedolizumab-responders from the induction phase (randomized and open-label) were re-randomized into the maintenance phase
Induction phase
  • Endpoint 1 - clinical remission (CDAI score of ≤150 points) at week 6

  • Endpoint 2 - CDAI-100 response defined as ≥ 100-point decrease in the CDAI score at week 6

Maintenance phase - clinical remission (CDAI score of ≤ 150 points) at week 52
Induction phase
  • Endpoint 1 - Group 1 - 6.8%, Group 2 - 14.5% (p=0.02)
  • Endpoint 2 - Group 1 - 25.7%, Group 2 - 31.4% (p=0.23)

Maintenance phase
  • Primary endpoint - Group 1 - 21.6%, Group 2 - 39%, Group 3 - 36.4%
  • Group 1 vs Group 2 p<0.001; Group 1 vs Group 3 p=0.004

Adverse events
  • More serious adverse events occurred in the vedolizumab groups than in the placebo groups (24.4% vs 15.3%)
  • More serious infections occurred in the vedolizumab groups than in the placebo groups (5.5% vs 3%%)



  • Crohn's Disease Activity Index (CDAI) score

  • Overview
    • The CDAI is a measure of Crohn's disease activity that is often integrated into guidelines and used as an outcome measure in trials
    • The CDAI uses mostly subjective parameters, and in studies, it has had inconsistent correlation with objective measures of disease activity (e.g. direct endoscopic or microscopic mucosal examination). Despite this, it has become the gold standard for assessing Crohn's disease activity. [13]

      • Reference [13]
      CDAI parameters
      Item Weight
      (multiply score by this number)
      Number of liquid or
      very soft stools in past week
      2
      Degree of abdominal pain over a week
      (0 - none, 1 - mild, 2 - moderate, 3 - severe)
      5
      General well-being over last week
      (0 - well, 1 - below normal, 2 - poor,
      3 - very poor, 4 - terrible)
      7
      Presence of the following (one point for each):
      • Arthritis/arthralgia
      • Mucocutaneous lesions (e.g. erythema nodosum,
        aphthous ulcers)
      • Iritis/Uveitis
      • Anal disease (e.g. fistula, fissure, etc.)
      • Fistula (cutaneous, vesicular, vaginal, etc.)
      • Fever (> 100.04°F, 37.8°C) in past week
      20
      Use of antidiarrheal in last week 30
      Abdominal mass
      (0 - none, 2 - questionable, 5 - definite)
      10
      Hematocrit (Hct) below normal
      Males
      • 47 minus current Hct
      Females
      • 42 minus current Hct
      6
      Percent weight loss
      (Healthy weight - current weight)/Healthy weight X 100
      1
  • Score interpretation

      • Reference [3]
      CDAI score Disease activity
      < 150 Remission
      150 - 220 Mild-moderate disease
      220 - 450 Moderate-severe disease
      > 450 Severe-fulminant



  • PRICING

    • $ = 0 - $50
    • $$ = $51 - $100
    • $$$ = $101 - $150
    • $$$$ = > $151

    • Pricing based on one month of therapy at standard dosing in an adult
    • Pricing based on survey of GoodRX.com®, HEB®, and Costco®, [accessed 11/2015]
    • Pricing may vary by region and availability



  • References:
  • 1 - PMID 23695484 - JAMA review
  • 2 - PMID 22914295 - Lancet review
  • 3 - PMID 19174807 - ACGE 2009 GL
  • 4 - PMID 24267474 - AGA 2013 treatment GL
  • 5 - PMID 17499605 - Risk factors for IBD
  • 6 - PMID 20634346 - Calprotectin MA in BMJ
  • 7 - LabCorp website
  • 8 - PMID 25002150 - Lactoferrin MA
  • 9 - PMID 25691840 - Stricture incidence
  • 10 - PMID 22522090 - Colon cancer risk
  • 11 - PMID 26154136 - Extraintestinal dx
  • 12 - PMID 19035972 - Budesonide side effects
  • 13 - PMID 10099817 - CDAI review
  • 14 - PMID 25046160 - AGA treatment algorithm