- ACRONYMS AND DEFINITIONS
- ACG - American College of Gastroenterology
- AGA - American Gastroenterological Association
- ASGE - American Society for Gastrointestinal Endoscopy
- CD - Crohn's disease
- CDAI - Crohn's disease activity index
- CRP - C-reactive protein
- ESR - Erythrocyte sedimentation rate
- RCT - Randomized controlled trial
- TNF - Tumor necrosis factor
- 6-MP - Mercaptopurine
- EPIDEMIOLOGY
- In 2015, the estimated prevalence of inflammatory bowel disease (Crohn's and ulcerative colitis) was 1.3% in the adult U.S. population. Women were affected slightly more than men (57% of cases), and Whites and Hispanics were affected more than blacks [17]
- RISK FACTORS
- Known risk factors
- Genetics - 35% concordance among monozygotic twins
- Cigarette smoking
- Jewish descent
- Race: Whites > Blacks > Asians > Hispanics
- Possible risk factors
- Gastrointestinal infections
- Mycobacterium infections
- Altered intestinal flora
- NSAID use
- Geography: North > South | Urban > rural [1,2,5]
- SYMPTOMS
- Overview
- Most patients develop symptoms in late adolescence and early adulthood. Symptom onset is typically insidious.
- 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
- Common symptoms include:
- Abdominal pain
- Diarrhea - may be bloody or nonbloody; may contain mucous; is often nocturnal
- Weight loss
- Fever
- Rectal bleeding
- PATHOPHYSIOLOGY
- Overview
- 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 are 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]
- DIAGNOSIS
- Overview
- CD diagnosis is 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]
- Laboratories
- ESR and C-reactive protein - nonspecific inflammatory markers (e.g. erythrocyte sedimentation rate, C-reactive protein) are often elevated in CD, but they are nonspecific and up to 40% of IBD patients with mild inflammation may have a normal ESR and CRP. [15]
- 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
- Overview
- A number of studies have looked at the clinical course of Crohn's disease. Most of the studies were published before the widespread use of biologic therapies. Biologics are typically more effective and less toxic than traditional therapies so the clinical course of Crohn's disease has likely improved in recent years.
- 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%
- Bowel surgery - in some studies, up to 50% of patients required surgery within 10 years of diagnosis. Factors associated with an increased risk of surgery include tobacco use, Clostridium difficile infection, and perianal disease. After surgery, about 50% of patients relapse within 5 years. Biologic therapies appear to decrease the risk of bowel surgery. [1,3,18]
- 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
- Overview
- 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
- Extraintestinal diseases
- 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
- See features of different arthritis syndromes for a comparison of different types of arthritis including IBD-associated arthritis
- 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]
Crohn's disease drugs | |
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Biologicals
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Immunosuppressants
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ACG 2018 Crohn's Disease Treatment Recommendations |
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Mild-to-moderate active disease
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Moderate-to-severe active disease
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Severe/fulminant active disease
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Fistulizing disease
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Maintenance of remission
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AGA 2014 Crohn's Disease Treatment Recommendations |
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Initial therapy
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Maintenance of remission
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Refractory disease
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- TNF inhibitor failure
- In 2017, the AGA issued recommendations for evaluating treatment failure in patients with IBD who are being treated with TNF inhibitors (infliximab, adalimumab, certolizumab, golimumab)
- The guidelines recommend checking for the presence of anti-drug antibodies and trough levels of TNF inhibitors
- The table below outlines their recommendations
Evaluating patients who fail treatment while on TNF inhibitor therapy |
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Step 1 - Check trough TNF inhibitor levels
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Step 2
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- 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]
- The parameters and calculations for the CDAI are presented in the table below. An online calculator is available at this link - online CDAI calculator
CDAI SCORE | |
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|
|
Item | Weight |
Total number of liquid or very soft stools over last 7 days | 2 |
Degree of abdominal pain over last 7 days
|
5 |
General well-being over last 7 days
|
7 |
Presence of the following (one point for each):
|
20 |
Use of antidiarrheal in last week (Yes - 1, No - 0) | 30 |
Abdominal mass
|
10 |
Hematocrit (Hct) below normal
|
6 |
Percent weight loss (Healthy weight - current weight)/Healthy weight X 100 | 1 |
CDAI score interpretation | |
---|---|
CDAI score | Disease activity |
< 150 | Remission |
150 - 220 | Mild-moderate disease |
220 - 450 | Moderate-severe disease |
> 450 | Severe-fulminant |
- STUDIES
- The study enrolled 526 adults with Crohn's Disease who had failed TNF inhibitor therapy
Main inclusion criteria
- Crohn’s disease of at least 3 months’ duration
- Disease confirmed by radiography and/or endoscopy
- Failed infliximab, adalimumab, or certolizumab pegol
- Active disease, defined as CDAI score of ≥ 220
Main exclusion criteria
- Crohn’s complications (e.g. strictures, stenoses, short gut syndrome)
- Bowel resection, diversion, or placement of a stoma within 6 months
Baseline characteristics
- Average age - 39 years
- Average duration of disease - 12 years
- Average CDAI - 323
- Receiving corticosteroids at baseline - 50%
Randomized treatment groups
- Group 1 (131 patients): Ustekinumab 1 mg/kg IV one time
- Group 2 (132 patients): Ustekinumab 3 mg/kg IV one time
- Group 3 (131 patients): Ustekinumab 6 mg/kg IV one time
- Group 4 (132 patients): Placebo
- Patients were permitted to continue other drug therapies for Crohn's disease
- After 6 weeks, 145 patients who had a response to ustekinumab underwent a second randomization to receive ustekinumab 90 mg SQ or placebo at weeks 8 and 16
Primary outcome: Clinical response (defined as ≥100-point decrease from the baseline CDAI score) at week 6
Results
Duration: 6 weeks | |||||
Outcome | Ust 1mg | Ust 3mg | Ust 6mg | Placebo | Comparisons |
---|---|---|---|---|---|
Primary outcome | 36.6% | 34.1% | 39.7% | 23.5% | 1 vs 4 p=0.02 | 2 vs 4 p=0.06 | 3 vs 4 p=0.005 |
Remission at 22 weeks (maintenance phase) | Ustekinumab - 41.7%, Placebo - 27.4%, (p=0.03) |
Findings: Patients with moderate-to-severe Crohn’s disease that was resistant to TNF antagonists had an increased rate of response to induction with ustekinumab, as compared
with placebo. Patients with an initial response to ustekinumab had significantly increased rates of response and remission with ustekinumab as maintenance therapy.
- The GEMINI 2 study enrolled 1093 patients with CD
Main inclusion criteria
- ≥ 18 years old
- 3 months of moderate to severe disease (CDAI 220 - 450)
- No response or unacceptable side effects from steroids, immunosuppressants, or TNF inhibitors
- 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
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%
Randomized treatment groups:
Induction phase
Induction phase
- Patients were randomized to one of two groups:
- Group 1 (148 patients) - Placebo infusion
- Group 2 (220 patients) - Vedolizumab 300 mg at Weeks 0 and 2
- Patients were randomized to one of three groups:
- 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
Primary outcome:
- Induction phase - clinical remission (CDAI score of ≤ 150 points) at week 6
- Maintenance phase - clinical remission (CDAI score of ≤ 150 points) at week 52
Results
Duration: Induction phase - 6 weeks | Maintenance phase - 52 weeks | ||||
Outcome | Placebo | Ved q8wk | Ved q4wk | Comparisons |
---|---|---|---|---|
Primary outcome (induction phase) | 6.8% | 14.5% | N/A | p=0.02 |
Primary outcome (maintenance phase) | 21.6% | 39% | 36.4% | 1 vs 2: p<0.001 | 1 vs 3: p=0.004 |
≥ 100-point decrease in CDAI at week 6 | 25.7% | 31.4% | N/A | p=0.23 |
|
Findings: Vedolizumab-treated patients with active Crohn's disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab.
- The ENACT 1 and 2 studies enrolled 905 patients with CD
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
- Average age 38 years
- Average CDAI score - 302
- Treatment with steroids only - 38%
- Treatment with immunosuppressants only - 33%
- Treatment with steroids + immunosuppressants - 14%
Randomized treatment groups
- 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 outcome:
- 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.
Results
Duration: ENACT 1 - 10 weeks | ENACT 2 - 36 weeks | |||
Outcome | Natalizumab | Placebo | Comparisons |
---|---|---|---|
Primary outcome (ENACT 1) | 56% | 49% | p=0.05 |
Primary outcome (ENACT 2) | 61% | 28% | p=0<0.001 |
|
Findings: Induction therapy with natalizumab for Crohn's disease resulted in small, nonsignificant improvements in response and remission rates.
Patients who had a response had significantly increased rates of sustained response and remission if natalizumab was continued every four weeks. The benefit of natalizumab
will need to be weighed against the risk of serious adverse events, including progressive multifocal leukoencephalopathy.
- The SONIC study enrolled 508 patients with moderate-to-severe CD
Main inclusion criteria
- ≥ 21 years old
- Moderate-to-severe disease (CDAI 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
- Average CDAI score - 287
- Median disease duration - 2.3 years
- Treatment with oral steroids - 27%
- Receiving budesonide - 14%
- Receiving 5-Aminosalicylic compounds - 54%
Randomized treatment groups
- 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
Results
Duration: 26 weeks | ||||
Outcome | Azathioprine | Infliximab | Both | Comparisons |
---|---|---|---|---|
Primary outcome | 30% | 44% | 57% | 1 vs 2, p=0.006 | 1 vs 3, p<0.001 | 2 vs 3, p=0.02 |
|
Findings: Patients with moderate-to-severe Crohn's disease who were treated with infliximab plus azathioprine or infliximab monotherapy were
more likely to have a corticosteroid-free clinical remission than those receiving azathioprine monotherapy.
- BIBLIOGRAPHY
- 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
- 15 - PMID 29610508 - ACG Clinical Guideline: Management of Crohn’s Disease in Adults, Am J Gastroenterol (2018)
- 16 - PMID 28780013 - Therapeutic Drug Monitoring in Inflammatory Bowel Disease, AGA Clinical Guidelines Committee (2017)
- 17 - CDC website
- 18 - PMID 33065311 - Rates of Intestinal Resection and Colectomy in Inflammatory Bowel Disease Patients after Initiation of Biologics: A Cohort Study, Clin Gastroenterol Hepatol (2020)