II. Epidemiology
- Worldwide Prevalence: 3-20 per 100,000
- U.S. Prevalence
- Child: 58 per 100,000
- Adult: 119-241 per 100,000
- Peak onset: 15-30 years
- Bimodal peak in age 20s and age 50s
- However most have onset before age 40 years
- Women more often affected than men
- More common in caucasian patients and northern latitudes
- Familial aggregation
- First degree relative confers 2-4 fold risk
- Identical twins have greater concordance
- Second degree relative confers less increased risk
III. Pathophysiology
- Etiology unknown
- Related genetic mutation: NOD2 (Chromosome 16 in IBD1)
- Associated with increased Crohn's Relative Risk
- One NOD 2 mutation: 2 fold Relative Risk
- Two NOD 2 mutations: 15-35 fold Relative Risk
- Proposed mechanism
- References
- Associated with increased Crohn's Relative Risk
- Chronic Granulomatous inflammation
- Ulcers form over lymphoid aggregates; ulcers may then coalesce into larger ulcerations
- Transmural extension may extend through entire bowel wall
- Contrast with Ulcerative Colitis which only affects mucosa
- Full, transmural extension through the bowel wall may result in fistulas, sinuses, abscesses or bowel perforation
- Secondary fibrosis may result in strictures
- May affect entire Gastrointestinal Tract, mouth, Esophagus, Stomach, small and Large Bowel to anus
- Distal ileum (33% of cases) and proximal colon most often involved
- Isolated colonic involvement in 25% of cases
- Irregular involvement ("Skip lesions")
- Discontinuous transmural lesions are a hallmark of Crohn Disease
- Resulting cobblestoning on endoscopy is of patches of ulceration scattered among normal mucosa
IV. Risk Factors
-
Tobacco Abuse
- Associated with greater risk of flares
- Oral Contraceptives
- Antibiotics
- Frequent NSAIDs
- Urban environment
- NOT associated with Vaccination
- Possible Protective Factors (anti-Risk Factors)
- Pet or farm animal exposure
- Bedroom sharing
- More than 2 siblings
- High fiber intake
- Fruit intake
- Physical Activity
V. 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)
VI. Exam
- Vital Signs (identify Unstable Patients)
- Abdominal examination
- Abdominal tenderness
- Abdominal Distention
- Abdominal mass
-
Anorectal Exam
- Anal Fissure
- Perirectal fistula
- Perirectal Abscess
VII. Symptoms: General (insidious in most cases)
- Fever
- Anorexia
- Weight loss
- Fatigue
- Nausea
- Abdominal Pain (Low abdominal ache or cramp)
- Diarrhea (85%)
-
Rectal Bleeding
- Much less prominent than in Ulcerative Colitis
- Non-bloody Diarrhea is typical for Crohn's Disease
VIII. Symptoms: Most suggestive of Crohns Disorder in chronic Abdominal Pain History
- Adult (strongest association first)
- Perianal lesions other than Hemorrhoids
- First degree relative with Inflammatory Bowel Disease
- Weight loss (5% of usual body weight) in the past 3 months
- Abdominal Pain >3 months
- Nocturnal Diarrhea
- Fever
- Abdominal Pain subsides for 30-45 minutes after meals
- No rectal urgency
- Danese (2015) J Crohns Colitis 9(8): 601-6 [PubMed]
- Child (strongest association first)
IX. Symptoms: Based on Location
- Ileum and colon (35%)
- Diarrhea
- Abdominal cramping or Abdominal Pain
- Weight loss
- Colon only (32%)
- Diarrhea
- Rectal Bleeding
- Perirectal Abscess
- Fistula
- Perirectal ulcer
- Associated with skin lesions and Arthralgias
-
Small Bowel only (28%)
- Diarrhea
- Abdominal cramping or Abdominal Pain
- Weight loss
- Associated with fistulas and abscesses
- Gastroduodenal region (5%)
- Anorexia
- Weight loss
- Nausea and Vomiting
- Associated with Bowel Obstruction
X. Signs: Gastrointestinal
- Stool Occult Blood positive
- Anal Disease(20%)
- Perirectal fistula
- Anal Skin Tag
- Anal Ulceration or Anal Fissure
- Perirectal Abscess
- Right Lower Quadrant abdominal palpable mass (common)
- Minimal increased Colon Cancer risk (contrast with Ulcerative Colitis)
XI. Signs: Extra-abdominal manifestations (10% Incidence)
- See Gynecologic Manifestations of Crohn's Disease
- Similar findings in Ulcerative Colitis
- However extraintestinal findings are more common with Crohn's Disease
- 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%)
XII. Labs
-
Complete Blood Count with Platelet
- Mild Anemia: Chronic blood loss
- Anemia is more common in Ulcerative Colitis
- Mild Leukocytosis: Crohn's Disease exacerbation
- Marked Leukocytosis
- Severe colitis
- Toxic Megacolon
- Intra-abdominal abscess
- Mild Anemia: Chronic blood loss
- Comprehensive metabolic panel (Liver Function Tests, Renal Function tests)
- Serum Alkaline Phosphatase increased in Primary Sclerosing Cholangitis (in addition to more common causes)
- Acute phase reactants
-
Stool studies
- Stool Culture or Enteric Nucleic Acid Test
- Ova and Parasites
- Clostridium difficile Toxin
- Markers of nutritional status
- First-line Diagnostic labs
- Fecal Calprotectin
- Test Sensitivity: 83-100% in adults (95-100% in children)
- Test Specificity: 60-100% in adults (44-93% in children)
- Kallel (2010) Eur J Gastroenterol Hepatol 22(3): 340-5 [PubMed]
- Waugh (2013) Health Technol Assess 17(55):1-211 [PubMed]
- Fecal Calprotectin
- Other diagnostic labs
- Fecal lactoferrin
- Marker of Crohns Disease activity
- Sidhu (2010) Aliment Pharmacol Ther 31(12): 1365-70 [PubMed]
- Escherichia coli outer membrane porin Antibody
- Saccharomyces cerevisiae Antibody
- Perinuclear Antineutrophil Cytoplasmic Antibody (pANCA)
- Fecal lactoferrin
XIII. Differential Diagnosis
- See Inflammatory Bowel Disease
-
Ulcerative Colitis
- Continuous lesions that start in the Rectum, and are typically limited to the colon
- Typically involves only the mucosal and submucosal layers
- 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]
XIV. Diagnostics
-
Colonoscopy with Ileoscopy (first-line study in most patients)
- Focal ulcerations: aphthous, stellate, or linear
- Skip areas
- Rectal sparing
- Cobblestone appearance
- Strictures
- Upper endoscopy
- Consider in children (more common to have isolated upper gastrointestinal involvement)
- Other studies
- Capsule Endoscopy
- Enteroscopy
XV. Imaging
- First Line imaging studies
- CT Abdomen (with enterography is preferred)
- MRI Abdomen (with enterography is preferred)
- Older studies with lower Test Sensitivity and Test Specificity
- Small Bowel follow-through
- Barium Enema with retrograde terminal ileum filling
- May show classic thumbprinting
- Defect protrudes into lumen
XVI. Diagnosis
- Crohn Disease often has a delayed diagnosis (mean 7 years of symptoms prior to correct diagnosis)
- Step 1: History, physical and labs are inconclusive for Crohn's Disease
- Obtain Fecal Calprotectin and unlikely to be Crohn's Disease if negative
- Step 2: Fecal Calprotectin positive OR Crohn's Diseases diagnosis thought likely
- Toxic presentation
- Obtain CT Abdomen with contrast
- Non-toxic presentation
- Ileocolonoscopy with biopsy
- CT or MRI with enterography (defines disease extent and adjunct to inconclusive endoscopy)
- Toxic presentation
XVII. Grading: Severity
- Crohn Disease Activity Index (CDAI)
- https://www.mdcalc.com/calc/3318/crohns-disease-activity-index-cdai
- The CDAI is not typically used in clinical practice (instead used for research study patient classification)
- Disease in Remission (CDAI <150)
- Asymptomatic without Corticosteroid use
- Mild to Moderate Disease (CDAI 150 to 220)
- Ambulatory, eating and maintaining hydration
- No systemic toxicity, abdominal tenderness, painful mass, Intestinal Obstruction
- Weight loss <10%
- Moderate to Severe Disease (CDAI 220-450)
- Refractory to mild to moderate disease management
- Prominent symptoms (fever, weight loss, Abdominal Pain or tenderness, Nausea or Vomiting, significant Anemia)
- Severe to Fulminant Disease (CDAI>450)
- Symptoms persist despite Corticosteroids and Biologic Agents
- High fever, persistent Vomiting, Intestinal Obstruction, peritoneal signs, Cachexia or abscess
XVIII. 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]
XIX. Management: General Measures
- No Immunosuppressants if Infectious Colitis possible
- Tobacco Cessation
- Update Vaccinations
- Hepatitis B Vaccine
- Influenza Vaccine
- Pneumococal Vaccine
- Avoid exacerbating factors
- Pregnancy
- NSAIDs
- Oral Contraceptives
- Consider baseline DEXA Scan and Vitamin D level
- Consider concurrent Vitamin Supplementation
- Folic Acid
- Vitamin B12
- Vitamin D Supplementation
- Fat soluble Vitamins
- Calcium Supplementation
- Prior to starting an Anti-TNF Agent
- Chest XRay
- Tuberculosis Screening with Purified Protein Derivative (PPD) or Quantiferon
XX. Management: Acute Crohns Flare
- Evaluate for Crohns Flare versus other gastrointestinal disorder or new complication
- Ask the patient if the Abdominal Pain, Diarrhea or other acute symptom is consistent with prior flares
- Perform a complete exam including Vital Signs
- Obtain labs (e.g. CBC, Chem18, Lipase, C-RP, C Diff, enteric Bacteria)
- Obtain CT Abdomen imaging if concerned for Small Bowel Obstruction, infection or peritonitis
- Supportive care
- Fluid Resuscitation
- Analgesics
- Avoid antidiarrheal agents (e.g. Imodium) in acute flares
- VTE Prophylaxis for admitted patients (Crohns is associated with VTE Risk)
- Endoscopy is preferred evaluation if available
- Discuss with gastroenterology if Corticosteroids (e.g. Prednisone, budesonide) are considered
-
Antibiotics may be indicated in ill, febrile or toxic appearing patients
- Obtain Clostridium difficile stool Antigen
- Obtain Enteric Pathogens Nucleic Acid Test Panels (PCR)
- Consider Ciprofloxacin with Metronidazole or with Amoxicillin-clavulanate
-
Abdominal Pain often requires CT Imaging in Crohns Disease
- Contrast with Ulcerative Colitis in which perforation and abscess are uncommon
- Griffey (2017) Ann Emerg Med 69(5): 587-99 [PubMed]
- Avoid starting maintenance medications during a Crohns flare
- Do not initiate Salicylate preparations (e.g. Mesalamine) during a flare
- Management of new fistula
- Refer to gastroenterology or colorectal surgery
- Initiate Antibiotics (e.g. Amoxicillin-clavulanate or Ciprofloxacin with Metronidazole)
- References
- Stannard, Rogers and Kernen (2023) Crit Dec Emerg Med 37(7): 24-9
- Swaminathan and Shoenberger in Herbert (2020) EM:Rap 20(6): 18-9
XXI. Management: Longterm Protocol Based on Severity
- Approach
- Trend in 2018 is to start Biologic Agents (e.g. TNF Inhibitor) as first-line management
- Best efficacy of TNF agents is when started within first 2 years of onset
- Mild to Moderate (Weight loss <10%, tolerating P.O.)
- Step 1: Start Salicylate (5-ASA preparations)
- Mesalamine (Rowasa, Pentasa, Asacol) or
- Sulfasalazine (Azulfidine)
- Step 2: Treat as moderate to severe if refractory
- See below
- Previously Metronidazole or Ciprofloxacin was used for refractory cases
- These Antibiotics have limited role in treating abscesses and fistulas
- Step 3: Maintenance therapy for remission
- Mesalamine (Rowasa) 3.2 to 4 grams per day
- Step 1: Start Salicylate (5-ASA preparations)
- Moderate to Severe (Significant systemic symptoms)
- Step 1: Systemic Corticosteroids
- Prednisone tapered over 8-12 weeks
- Indicated for diffuse of left colon disease
- Start at 40-60 mg orally daily
- Taper by 5 mg/week initially, then at 2.5-5 mg/week once dose <20 mg
- Consider Budesonide instead of Prednisone for
- Budesonide (Entocort EC)
- Indicated for ileal and proximal colon disease
- Minimal absorption and may be preferred over Prednisone as first line agent
- Dose: 9 mg PO qAM for up to 8 weeks
- Methylprednisolone IV for severe fulminant disease
- Taper once control is achieved
- Initial: Taper by 5-10 mg weekly
- Below 20 mg: Taper by 2.5 to 5 mg weekly
- Prednisone tapered over 8-12 weeks
- Step 2: Consider immunosuppresant for maintenance (in combination with TNF agent)
- Start while tapering Corticosteroid off
- Not typically used as monotherapy (TNF agent usually added)
- Azathioprine 50 mg orally daily (maximum 2-2.5 mg/kg/day) or
- 6-Mercaptopurine 60 mg orally daily (maximum 1.5 mg/kg/day)
- Other immunomodulators to consider
- Methotrexate 25 mg weekly
- Tacrilimus and Cyclosporine have also been used
- Step 3: Anti-Tumor Necrosis Factors (TNF-alpha blockers)
- Indicated if refractory to Steps 1 and 2
- However, in 2018 these agents are used as first line agents
- Precautions
- See Tumor Necrosis Factor Inhibitor
- Risk of infection, Skin Cancer and require monitoring and frequent labs
- Update Vaccines and screen for Tuberculosis before starting therapy
- Agents
- Adalimumab (Humira, $36,000/year in 2023)
- Start 160 mg SQ once initially
- Then 80 mg SQ once at week 2
- Then 40 mg every 2 weeks
- Infliximab (Remicade, $10,400/year plus infusion cost in 2023)
- Start 5 mg/kg IV once at weeks 0, 2, and 6
- Then 5 mg/kg every 8 weeks
- Certrolizumab pegol (Cimzia, $121,000/year in 2018)
- Less evidence of benefit than other TNF-alpha blockers
- Start 400 mg SQ once at weeks 0, 2, and 4
- Then 400 mg every 4 weeks
- Adalimumab (Humira, $36,000/year in 2023)
- Indicated if refractory to Steps 1 and 2
- Step 4: Anti-Integrin agents (target Leukocyte trafficking)
- Vedolizumab (Entyvio)
- Preferred agent of class (no risk of Progressive Multifocal Leukoencephalopathy)
- High efficacy, Specificity for gut Leukocyte trafficking
- Natalizumab (Tysabri)
- Risk of Progressive Multifocal Leukoencephalopathy
- Do not use in patients seropositive for anti-John Cunningham Virus
- Vedolizumab (Entyvio)
- Step 5: Anti-Interleukin
- Consider these agents in disease refractory to other agents (esp. TNF-alpha blockers and Immunosuppressants)
- Risankizumab (Skyrizi)
- Targets IL-23, p19 subunit
- Costs $98,700/year in 2023
- Ustekinumab (Stelera)
- Antibody targets 12/23p40
- Costs $159,000/year in 2023
- Step 6: Janus Kinase Inhibitors (JAK Inhibitor)
- Upadacitinib (Rinvoq)
- Once daily oral medication for moderate to severe Crohns Disease refractory to other measures
- Costs $73,500/year in 2023
- Upadacitinib (Rinvoq)
- Step 7: Enteral Nutrition
- First-line option in children with Crohns Disease (and may be effective in adults)
- Step 1: Systemic Corticosteroids
- References
- (2023) Presc Lett 30(8): 47
- (2018) Presc Lett 25(7): 40
- Knutson (2003) Am Fam Physician 68(4):707-14 [PubMed]
- Wall (1999) Pharmacotherapy 19:1138-52 [PubMed]
- Hanauer (2003) Gastroenterology 125:906-10 [PubMed]
XXII. Management: Available Preparations
- Similar to Ulcerative Colitis Management
- Antiinflammatory agents
- Corticosteroids
- Prednisone
- Budesonide
- Oral 5 ASA preparations
- Not effective for small bowel Crohn's Disease
- Sulfasalazine (Azulfidine)
- Inexpensive but significant side effects
- Olsalazine (Dipentum)
- Diarrhea commonly occurs
- Mesalamine (Asacol, Pentasa, Canasa, Rowasa)
- Balsalazide (Colazal)
- Immunosuppressive Agents
- Corticosteroids
- Fish Oil (Enteric Coated)
- Dose: 2.7 g qd
- Marked reduction in relapse in 1 year (28% vs 69%)
- Serum markers of inflammation also reduced
- Reference
- Anti-Tumor Necrosis Factor agents
- Adalimumab (Humira)
- Certrolizumab pegol (Cimzia)
- Infliximab (Remicade)
- Anti-Integrin agents (target Leukocyte trafficking)
- Vedolizumab (Entyvio)
- Natalizumab (Tysabri, PML risk!)
- Anti-Interleukin-12/23p40 Antibody
- Ustekinumab (Stelera)
-
Antibiotics for perianal fistula or abscess
- Previously used for refractory disease, but now limited to infection
- Metronidazole (Flagyl) 10-20 mg/kg/day up to 500 mg orally four times daily
- Ciprofloxacin 500 mg orally twice daily
- Other agents currently being researched
- Thalidomide (not used in women who can conceive)
- Mycophenalate (Cellcept)
- Tacrolimus
- IL-10, 11 and 18
- Probiotics
XXIII. Management: Intestinal resection (57% of patients)
- Indications
- Fistula
- Abscess
- Perianal disease
- Perforation
- Stricture
- Consider Strictureplasty or endoscopic dilation instead of resection
- Dysplasia or cancer
- Persistent bleeding
- Colon obstruction
- Refractory disease
- Intractable pain or other symptoms
- Efficacy
- Not Curative (unlike for Ulcerative Colitis)
- Symptoms nearly always recur after surgery
- Five years: 30% symptoms recur
- Ten years: 50% symptoms recur
- Fifteen years: 70% symptoms recur
- Surgery associated with improved quality of life
- Approach
- Segmental resection is preferred over total resection
- Prevent recurrence by starting Anti-TNF Agent with other agents as above (e.g. immunomodulators)
XXIV. Complications: Gastrointestinal
-
Colon Cancer
- 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)
- Treatment with Antibiotics (Ciprofloxacin, Metronidazole) and surgery
- Rectal Fissure
- Rectocutaneous fistula
- Perirectal Abscess
XXV. Prognosis: Risk for intestinal resection
- Poor prognostic indicators (relapse)
- Crohn's involving Small Intestine
- Perianal fistulas
- Favorable prognostic indicators
- Ileocecal disease
- Colorectal disease
- Relapse-free period of 10 years
- References
XXVI. Prevention
-
Colon Cancer screening
- Periodic Colonoscopy after 15 years of disease (annual in some cases)
- Lower Colon Cancer risk than Ulcerative Colitis (but still increased, esp. if more than a third colon involved)
-
Cervical Cancer Screening
- Annual Pap Smear and consider HPV screening if on Immunosuppression
-
Skin Cancer screening
- Increased risk of Melanoma (TNF agents) and non-Melanoma (thioprines) Skin Cancer
-
Anemia Screening
- Screen every 3-12 months
- See labs as above
- Other cancer risks (if on Immunosuppressants)
- Lymphoma of the gastrointestinal and genitourinary tract
- Cholangiocarcinoma
- Lung Cancer
-
Immunizations (if on Immunosuppressants)
- Annual Influenza Vaccine
- Prevnar 13
- Pneumovax 23
- Avoid Live Vaccines
- Other prevention
- Major Depression screening (higher risk)
- Nutritional deficiency
- Osteoporosis
- See Corticosteroid Associated Osteoporosis
- Also increased risk with Vitamin D Deficiency and chronic inflammation
- Tobacco Cessation
- Venous Thromboembolism Risk
- Immunizations
XXVII. References
- Kleinmann (2023) Crit Dis Emerg Med 37(2): 22-9
- Botoman (1998) Am Fam Physician 57(1):57-72 [PubMed]
- Cummings (2008) BMJ 336(7652): 1062-6 [PubMed]
- Lichtenstein (2009) Am J Gastroenterol 104(2): 465-83 [PubMed]
- Moses (1998) Postgrad Med 103(5):77-84 [PubMed]
- Sands (2000) Gastroenterology 118(2 Suppl 1):S68-82 [PubMed]
- Stein (2001) Surg Clin North Am 81(1):71-101 [PubMed]
- Veauthier (2018) Am Fam Physician 98(11): 661-9 [PubMed]
- Wilkins (2011) Am Fam Physician 84(12):1365-75 [PubMed]