Crohn's Disease

See Also

Epidemiology

Prevalence (U.S.)
1. Child: 58 per 100,000
2. Adult: 119-241 per 100,00
Peak onset: 15-30 years (onset up to age 40 years, and some older than 40 years)
Women more often affected than men
More common in caucasian patients
Familial aggregation
1. First degree relative confers 2-4 fold risk
2. Second degree relative confers less increased risk

Pathophysiology

Etiology unknown
Related genetic mutation: NOD2 (Chromosome 16 in IBD1)
1. Associated with increased Crohn's Relative Risk
  1. One NOD 2 mutation: 2 fold Relative Risk
  2. Two NOD 2 mutations: 15-35 fold Relative Risk
2. Proposed mechanism
  1. Related to defective Bacterial sensing by Monocytes
  2. Results in hyper-immune response to Bacterial LPS
3. References
  1. Ahmad (2002) Gastroenterology 122:854 [PubMed]
Chronic granulomatous inflammation
1. Transmural extension to entire bowel wall
2. Ulcerative Colitis only affects mucosa
Effects entire Gastrointestinal tract, mouth to anus
1. Distal ileum and proximal colon most often involved
2. Isolated colonic involvement in 25% of cases
Irregular involvement ("Skip lesions")

Risk Factors

Tobacco Abuse
Oral Contraceptives
Antibiotics
Frequent NSAIDs
Urban environment
NOT associated with Vaccination

Protective Factors

Pet or farm animal exposure
Bedroom sharing
More than 2 siblings
High fiber intake
Fruit intake
Physical Activity

History

Gastrointestinal and constitutional symptoms (see below)
Nocturnal symptoms
Stool urgency
Food intolerance (e.g. gluten intolerance)
Travel history
Medications (e.g. antibiotics)
Family history Inflammatory Bowel Disease
Extra-intestinal symptoms (eye, joint, skin)

Exam

Vital Signs (identify unstable patients)
1. Heart Rate
2. Blood Pressure
3. Temperature
4. Respiratory Rate
5. Body weight
Abdominal examination
1. Abdominal tenderness
2. Abdominal Distention
3. Abdominal mass
Anorectal Exam
1. Anal Fissure
2. Perirectal fistula
3. Perirectal Abscess

Symptoms
General (insidious in most cases)

Fever
Weight loss
Fatigue
Nausea
Anorexia
Abdominal Pain (Low abdominal ache or cramp)
Diarrhea (85%)
Rectal Bleeding
1. Much less prominent than in Ulcerative Colitis
2. Non-bloody Diarrhea is typical for Crohn's Disease

Symptoms
Most suggestive of Crohns Disorder in chronic Abdominal Pain history

Adult (strongest association first)
1. Perianal lesions other than Hemorrhoids
2. First degree relative with Inflammatory Bowel Disease
3. Weight loss (5% of usual body weight) in the past 3 months
4. Abdominal Pain >3 months
5. Nocturnal Diarrhea
6. Fever
7. Abdominal Pain subsides for 30-45 minutes after meals
8. No rectal urgency
9. Danese (2015) J Crohns Colitis 9(8): 601-6 [PubMed]
Child (strongest association first)
1. Anemia
2. Hematochezia
3. Weight loss
4. El-Chammas (2013) J Pediatr 162(4): 783-7 [PubMed]

Symptoms
Based on location

Ileum and colon (35%)
1. Diarrhea
2. Abdominal cramping or Abdominal Pain
3. Weight loss
Colon only (32%)
1. Diarrhea
2. Rectal Bleeding
3. Perirectal Abscess
4. Fistula
5. Perirectal ulcer
6. Associated with skin lesions and Arthralgias
Small Bowel only (28%)
1. Diarrhea
2. Abdominal cramping or Abdominal Pain
3. Weight loss
4. Associated with fistulas and abscesses
Gastroduodenal region (5%)
1. Anorexia
2. Weight loss
3. Nausea and Vomiting
4. Associated with Bowel Obstruction

Signs
Gastrointestinal

Stool Occult Blood positive
Anal Disease(20%)
1. Perirectal fistula
2. Anal Skin Tag
3. Anal Ulceration or Anal Fissure
4. Perirectal Abscess
Right Lower Quadrant abdominal palpable mass (common)
Minimal increased Colon Cancer risk (contrast with Ulcerative Colitis)

Signs
Extra-abdominal manifestations (10% Incidence)

See Gynecologic Manifestations of Crohn's Disease
Similar findings in Ulcerative Colitis
1. See Ulcerative Colitis extraintestinal manifestations
Anemia (>9%)
Anterior Uveitis (17%)
Episcleritis (29%)
Aphthous Stomatitis (>4%)
Cholelithiasis (>13%)
Erythema Nodosum (>2%)
Inflammatory Arthropathy (>10%)
Nephrolithiasis (>8%)
Osteoporosis (>2%)
Pyogenic gangrenosum (>0.5%)
Scleritis (18%)
Venous Thromboembolism (>10%)

Labs

Complete Blood Count with platelet
1. Mild Anemia: Chronic blood loss
  1. Anemia is more common in Ulcerative Colitis
2. Mild Leukocytosis: Crohn's Disease exacerbation
3. Marked Leukocytosis
  1. Severe colitis
  2. Toxic Megacolon
  3. Intra-abdominal abscess
Comprehensive metabolic panel (Liver Function Tests, Renal Function tests)
1. Serum Alkaline Phosphatase increased in Primary Sclerosing Cholangitis (in addition to more common causes)
Acute phase reactants
1. C-Reactive Protein (C-RP)
2. Erythrocyte Sedimentation Rate (ESR)
Stool studies
1. Stool Culture or Enteric Nucleic Acid Test
2. Ova and Parasites
3. Clostridium difficile Toxin
Markers of nutritional status
First-line Diagnostic labs
1. Fecal Calprotectin
  1. Test Sensitivity: 83-100% in adults (95-100% in children)
  2. Test Specificity: 60-100% in adults (44-93% in children)
  3. Kallel (2010) Eur J Gastroenterol Hepatol 22(3): 340-5 [PubMed]
  4. Waugh (2013) Health Technol Assess 17(55):1-211 [PubMed]
Other diagnostic labs
1. Fecal lactoferrin
  1. Marker of Crohns Disease activity
  2. Sidhu (2010) Aliment Pharmacol Ther 31(12): 1365-70 [PubMed]
2. Escherichia coli outer membrane porin Antibody
3. Saccharomyces cerevisiae Antibody
4. Perinuclear Antineutrophil Cytoplasmic Antibody (pANCA)

Differential Diagnosis

See Inflammatory Bowel Disease
Ulcerative Colitis
1. Continuous lesions that start in the Rectum, and are typically limited to the colon
2. Typically involves only the mucosal and submucosal layers
3. Rectal Bleeding and Anemia are more common and Abdominal Pain is less prominent than in Crohns Disease
Celiac Sprue
Chronic Pancreatitis
Colorectal Cancer
Diverticulitis
Yersinia infection
Mycobacterium infection
Irritable Bowel Syndrome
Ischemic Colitis
Small Bowel Lymphoma
Sarcoidosis
Cummings (2008) BMJ 336(7652): 1062-6 [PubMed]

Diagnostics

Colonoscopy with Ileoscopy (first-line study in most patients)
1. Focal ulcerations: aphthous, stellate, or linear
2. Skip areas
3. Rectal sparing
4. Cobblestone appearance
5. Strictures
Upper endoscopy
1. Consider in children (more common to have isolated upper gastrointestinal involvement)
Other studies
1. Capsule Endoscopy
2. Enteroscopy

Imaging

First Line imaging studies
1. CT Abdomen (with enterography is preferred)
2. MRI Abdomen (with enterography is preferred)
Older studies with lower Test Sensitivity and Test Specificity
1. Small Bowel follow-through
2. Barium Enema with retrograde terminal ileum filling
  1. May show classic thumbprinting
  2. Defect protrudes into lumen

Diagnosis

Step 1: History, physical and labs are inconclusive for Crohn's Disease
1. Obtain Fecal Calprotectin and unlikely to be Crohn's Disease if negative
Step 2: Fecal Calprotectin positive OR Crohn's Diseases diagnosis thought likely
1. Toxic presentation
  1. Obtain CT Abdomen with contrast
2. Non-toxic presentation
  1. Ileocolonoscopy with biopsy
  2. CT or MRI with enterography (defines disease extent and adjunct to inconclusive endoscopy)

Evaluation
Moderate to High Risk patient criteria

Age at initial diagnosis >30 years old
Extensive involvement
Ileal or ileocolonic involvement
Perianal or severe rectal disease
Deep ulcers
Prior surgical resection
Strictures or penetrating involvement
Sandborn (2014) Gastroenterology 147(3): 702-5 [PubMed]

Management
General Measures

No immunosuppressants if Infectious Colitis possible
Tobacco Cessation
Update Vaccinations
1. Hepatitis B Vaccine
2. Influenza Vaccine
3. Pneumococal Vaccine
Avoid exacerbating factors
1. Pregnancy
2. NSAIDs
3. Oral Contraceptives
Consider baseline DEXA Scan and Vitamin D level
Consider concurrent Vitamin Supplementation
1. Folic Acid
2. Vitamin B12
3. Vitamin D Supplementation
4. Fat soluble Vitamins
5. Calcium Supplementation
Prior to starting an Anti-TNF Agent
1. Chest XRay
2. Tuberculosis Screening with Purified Protein Derivative (PPD) or Quantiferon

Management
Protocol based on severity

Approach
1. Trend in 2018 is to start biologic agents (e.g. TNF Inhibitor) as first-line management
2. Best efficacy of TNF agents is when started within first 2 years of onset
Mild to Moderate (Weight loss <10%, tolerating P.O.)
1. Step 1: Start Salicylate (5-ASA preparations)
  1. Mesalamine (Rowasa, Pentasa, Asacol) or
  2. Sulfasalazine (Azulfidine)
2. Step 2: Treat as moderate to severe if refractory
  1. See below
  2. Previously Metronidazole or Ciprofloxacin was used for refractory cases
    1. These antibiotics have limited role in treating abscesses and fistulas
3. Step 3: Maintenance therapy for remission
  1. Mesalamine (Rowasa) 3.2 to 4 grams per day
Moderate to Severe (Significant systemic symptoms)
1. Step 1: Systemic Corticosteroids
  1. Prednisone tapered over 8-12 weeks
    1. Indicated for diffuse of left colon disease
    2. Start at 40-60 mg orally daily
    3. Taper by 5 mg/week initially, then at 2.5-5 mg/week once dose <20 mg
    4. Consider Budesonide instead of Prednisone for
  2. Budesonide (Entocort EC)
    1. Indicated for ileal and proximal colon disease
    2. Minimal absorption and may be preferred over Prednisone as first line agent
    3. Dose: 9 mg PO qAM for up to 8 weeks
  3. Methylprednisolone IV for severe fulminant disease
  4. Taper once control is achieved
    1. Initial: Taper by 5-10 mg weekly
    2. Below 20 mg: Taper by 2.5 to 5 mg weekly
2. Step 2: Consider immunosuppresant for maintenance (in combination with TNF agent)
  1. Start while tapering Corticosteroid off
  2. Not typically used as monotherapy (TNF agent usually added)
  3. Azathioprine 50 mg orally daily (maximum 2-2.5 mg/kg/day) or
  4. 6-Mercaptopurine 60 mg orally daily (maximum 1.5 mg/kg/day)
  5. Other immunomodulators to consider
    1. Methotrexate 25 mg weekly
    2. Tacrilimus and Cyclosporine have also been used
3. Step 3: Anti-tumor necrosis factors
  1. Indicated if refractory to Steps 1 and 2
    1. However, in 2018 these agents are used as first line agents
  2. Precautions
    1. See Tumor Necrosis Factor Inhibitor
    2. Risk of infection, skin cancer and require monitoring and frequent labs
    3. Update Vaccines and screen for Tuberculosis before starting therapy
  3. Agents
    1. Adalimumab (Humira, $73,000/year in 2018)
      1. Start 160 mg SQ once initially
      2. Then 80 mg SQ once at week 2
      3. Then 40 mg every 2 weeks
    2. Certrolizumab pegol (Cimzia, $121,000/year in 2018)
      1. Start 400 mg SQ once at weeks 0, 2, and 4
      2. Then 400 mg every 4 weeks
    3. Infliximab (Remicade, $37,000/year in 2018)
      1. Start 5 mg/kg IV once at weeks 0, 2, and 6
      2. Then 5 mg/kg every 8 weeks
4. Step 4: Anti-integrin agents (target Leukocyte trafficking)
  1. Vedolizumab (Entyvio)
    1. Preferred agent of class (no risk of Progressive Multifocal Leukoencephalopathy)
    2. High efficacy, Specificity for gut Leukocyte trafficking
  2. Natalizumab (Tysabri)
    1. Risk of Progressive Multifocal Leukoencephalopathy
    2. Do not use in patients seropositive for anti-John Cunningham Virus
5. Step 5: Anti-interleukin-12/23p40 Antibody
  1. Ustekinumab (Stelera)
    1. Consider in refractory disease
6. Step 6: Enteral Nutrition
  1. First-line option in children with Crohns Disease (and may be effective in adults)
References
1. (2018) Presc Lett 25(7): 40
2. Knutson (2003) Am Fam Physician 68(4):707-14 [PubMed]
3. Wall (1999) Pharmacotherapy 19:1138-52 [PubMed]
4. Hanauer (2003) Gastroenterology 125:906-10 [PubMed]

Management
Available preparations

Similar to Ulcerative Colitis Management
Antiinflammatory agents
1. Corticosteroids
  1. Prednisone
  2. Budesonide
2. Oral 5 ASA preparations
  1. Not effective for small bowel Crohn's Disease
  2. Sulfasalazine (Azulfidine)
    1. Inexpensive but significant side effects
  3. Olsalazine (Dipentum)
    1. Diarrhea commonly occurs
  4. Mesalamine (Asacol, Pentasa, Canasa, Rowasa)
  5. Balsalazide (Colazal)
3. Immunosuppressive agents
  1. 6-Mercaptopurine
  2. Azathioprine
  3. Methotrexate
Fish Oil (Enteric Coated)
1. Dose: 2.7 g qd
2. Marked reduction in relapse in 1 year (28% vs 69%)
3. Serum markers of inflammation also reduced
4. Reference
  1. Belluzzi (1996) N Engl J Med 334:1557-60 [PubMed]
Anti-tumor necrosis factor agents
1. Adalimumab (Humira)
2. Certrolizumab pegol (Cimzia)
3. Infliximab (Remicade)
Anti-integrin agents (target Leukocyte trafficking)
1. Vedolizumab (Entyvio)
2. Natalizumab (Tysabri, PML risk!)
Anti-interleukin-12/23p40 Antibody
1. Ustekinumab (Stelera)
Antibiotics for perianal fistula or abscess
1. Previously used for refractory disease, but now limited to infection
2. Metronidazole (Flagyl) 10-20 mg/kg/day up to 500 mg orally four times daily
3. Ciprofloxacin 500 mg orally twice daily
Other agents currently being researched
1. Thalidomide (not used in women who can conceive)
2. Mycophenalate (Cellcept)
3. Tacrolimus
4. IL-10, 11 and 18
5. Probiotics

Management
Intestinal resection (57% of patients)

Indications
1. Fistula
2. Abscess
3. Perianal disease
4. Perforation
5. Stricture
  1. Consider Strictureplasty or endoscopic dilation instead of resection
6. Dysplasia or cancer
7. Persistent bleeding
8. Colon obstruction
9. Refractory disease
  1. Intractable pain or other symptoms
Efficacy
1. Not Curative (unlike for Ulcerative Colitis)
2. Symptoms nearly always recur after surgery
  1. Five years: 30% symptoms recur
  2. Ten years: 50% symptoms recur
  3. Fifteen years: 70% symptoms recur
3. Surgery associated with improved quality of life
  1. Delaney (2003) J Am Coll Surg 196:714-21 [PubMed]
Approach
1. Segmental resection is preferred over total resection
2. Prevent recurrence by starting Anti-TNF Agent with other agents as above (e.g. immunomodulators)

Complications
Gastrointestinal

Colon Cancer
1. Much lower risk than with Ulcerative Colitis, but increased risk if more than one third colon involved
Rectal disease (50% of Crohn's Disease patients)
1. Treatment with antibiotics (Ciprofloxacin, Metronidazole) and surgery
2. Rectal Fissure
3. Rectocutaneous fistula
4. Perirectal Abscess

Prognosis
Risk for intestinal resection

Poor prognostic indicators (relapse)
1. Crohn's involving Small Intestine
2. Perianal fistulas
Favorable prognostic indicators
1. Ileocecal disease
2. Colorectal disease
3. Relapse-free period of 10 years
References
1. Bernell (2000) Ann Surg 231:38-45 [PubMed]

Prevention

Colon Cancer screening
1. Periodic Colonoscopy after 15 years of disease (annual in some cases)
2. Lower Colon Cancer risk than Ulcerative Colitis (but still increased, esp. if more than a third colon involved)
Cervical Cancer Screening
1. Annual Pap Smear and consider HPV screening if on immunosuppression
Skin cancer screening
1. Increased risk of Melanoma (TNF agents) and non-Melanoma (thioprines) skin cancer
Anemia Screening
1. Screen every 3-12 months
2. See labs as above
Other cancer risks (if on immunosuppressants)
1. Lymphoma of the gastrointestinal and genitourinary tract
2. Cholangiocarcinoma
3. Lung Cancer
Immunizations (if on immunosuppressants)
1. Annual Influenza Vaccine
2. Prevnar 13
3. Pneumovax 23
4. Avoid Live Vaccines
Other prevention
1. Major Depression screening (higher risk)
2. Nutritional deficiency
3. Osteoporosis
  1. See Corticosteroid Associated Osteoporosis
  2. Also increased risk with Vitamin D Deficiency and chronic inflammation
4. Tobacco Cessation
5. Venous Thromboembolism Risk
6. Immunizations

References