IBD
Crohn's Disease
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Crohn's Disease
, Terminal Ileitis, Regional Enteritis, Crohn's Colitis, Crohns Disease
See Also
Inflammatory Bowel Disease
Gynecologic Manifestations of Crohn's Disease
Epidemiology
Prevalence
(U.S.)
Child: 58 per 100,000
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
First degree relative confers 2-4 fold risk
Second degree relative confers less increased risk
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
Related to defective
Bacteria
l sensing by
Monocyte
s
Results in hyper-immune response to
Bacteria
l LPS
References
Ahmad (2002) Gastroenterology 122:854 [PubMed]
Chronic granulomatous inflammation
Transmural extension to entire bowel wall
Ulcerative Colitis
only affects mucosa
Effects entire Gastrointestinal tract, mouth to anus
Distal ileum and proximal colon most often involved
Isolated colonic involvement in 25% of cases
Irregular involvement ("Skip lesions")
Risk Factors
Tobacco Abuse
Oral Contraceptive
s
Antibiotics
Frequent
NSAID
s
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 Sign
s (identify unstable patients)
Heart Rate
Blood Pressure
Temperature
Respiratory Rate
Body weight
Abdominal examination
Abdominal tenderness
Abdominal Distention
Abdominal mass
Anorectal Exam
Anal Fissure
Perirectal fistula
Perirectal Abscess
Symptoms
Gene
ral (insidious in most cases)
Fever
Weight loss
Fatigue
Nausea
Anorexia
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
Symptoms
Most suggestive of Crohns Disorder in chronic
Abdominal Pain
history
Adult (strongest association first)
Perianal lesions other than
Hemorrhoid
s
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)
Anemia
Hematochezia
Weight loss
El-Chammas (2013) J Pediatr 162(4): 783-7 [PubMed]
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
Arthralgia
s
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
Signs
Gastrointestinal
Stool Occult Blood
positive
Anal Disease(20%)
Perirectal fistula
Anal
Skin Tag
Anal Ulcer
ation or
Anal Fissure
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
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
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
Comprehensive metabolic panel (
Liver Function Test
s,
Renal Function
tests)
Serum
Alkaline Phosphatase
increased in
Primary Sclerosing Cholangitis
(in addition to more common causes)
Acute phase reactants
C-Reactive Protein
(
C-RP
)
Erythrocyte Sedimentation Rate
(ESR)
Stool
studies
Stool Culture
or Enteric Nucleic Acid Test
Ova and Parasite
s
Clostridium difficile Toxin
Markers of nutritional status
Serum Ferritin
Serum Iron
Total Iron Binding Capacity
Serum
Vitamin B12
Serum Folate
Serum Albumin
Serum Prealbumin
Vitamin D
Serum Calcium
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]
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)
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]
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
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
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)
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
Gene
ral Measures
No immunosuppressants if
Infectious Colitis
possible
Tobacco Cessation
Update
Vaccination
s
Hepatitis B Vaccine
Influenza Vaccine
Pneumococal
Vaccine
Avoid exacerbating factors
Pregnancy
NSAID
s
Oral Contraceptive
s
Consider baseline
DEXA Scan
and
Vitamin D
level
Consider concurrent
Vitamin Supplement
ation
Folic Acid
Vitamin B12
Vitamin D
Supplementation
Fat soluble
Vitamin
s
Calcium Supplementation
Prior to starting an
Anti-TNF Agent
Chest XRay
Tuberculosis Screening
with
Purified Protein Derivative
(PPD) or Quantiferon
Management
Acute Crohns Flare
Endoscopy is preferred evaluation if available
Discuss with gastroenterology if
Corticosteroid
s are planned
Fluid
Resuscitation
Analgesic
s
Antibiotics may be indicated in ill or toxic appearing patients
Obtain
Clostridium difficile
stool
Antigen
Obtain
Enteric Pathogens Nucleic Acid Test Panels
(PCR)
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
References
Swaminathan and Shoenberger in Herbert (2020) EM:Rap 20(6): 18-9
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
Moderate to Severe (Significant systemic symptoms)
Step 1:
Systemic Corticosteroid
s
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
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 Factor
s
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
Vaccine
s and screen for
Tuberculosis
before starting therapy
Agents
Adalimumab
(
Humira
, $73,000/year in 2018)
Start 160 mg SQ once initially
Then 80 mg SQ once at week 2
Then 40 mg every 2 weeks
Certrolizumab pegol (Cimzia, $121,000/year in 2018)
Start 400 mg SQ once at weeks 0, 2, and 4
Then 400 mg every 4 weeks
Infliximab
(
Remicade
, $37,000/year in 2018)
Start 5 mg/kg IV once at weeks 0, 2, and 6
Then 5 mg/kg every 8 weeks
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
Step 5: Anti-
Interleukin
-12/23p40
Antibody
Ustekinumab (Stelera)
Consider in refractory disease
Step 6:
Enteral Nutrition
First-line option in children with Crohns Disease (and may be effective in adults)
References
(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]
Management
Available preparations
Similar to
Ulcerative Colitis
Management
Antiinflammatory agents
Corticosteroid
s
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
6-Mercaptopurine
Azathioprine
Methotrexate
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
Belluzzi (1996) N Engl J Med 334:1557-60 [PubMed]
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
Probiotic
s
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
Delaney (2003) J Am Coll Surg 196:714-21 [PubMed]
Approach
Segmental resection is preferred over total resection
Prevent recurrence by starting
Anti-TNF Agent
with other agents as above (e.g. immunomodulators)
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
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
Bernell (2000) Ann Surg 231:38-45 [PubMed]
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
Immunization
s (if on immunosuppressants)
Annual
Influenza Vaccine
Prevnar 13
Pneumovax 23
Avoid
Live Vaccine
s
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
Immunization
s
References
Botoman (1998) Am Fam Physician 57(1):57-72 [PubMed]
Cummings (2008) BMJ 336(7652): 1062-6 [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]
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