Crohn's disease

Essential Evidence

Authors:
Kristen H. Goodell, MD, Clinical Assistant Professor, Tufts University School of Medicine

Editor:Mark H. Ebell, MD, MS, Professor, College of Public Health, University of Georgia

Last updated: 2018-08-08 © 2018 John Wiley & Sons, Inc.

Overall Bottom Line

 Consider Crohn’s when patients present with chronic (>6 weeks) or nocturnal diarrhea, abdominal pain,
weight loss, fever, or symptoms indicating an intestinal blockage or fistula. C
 Initial studies if Crohn’s is suspected should include CBC, C-reactive protein, or sedimentation rate, stool
for lactoferrin and clostridium difficile, and colonoscopy. C
 Treatment is based on disease severity and can involve salicylates, steroids, and immunomodulators for
induction and maintenance of remission. A
 Complications are common and include fistulae, abscesses, and obstructions, which may require surgical
intervention and/or IV antibiotics. B Systemic complications include osteoporosis and colon cancer. C
 Crohn’s is rarely curable; management is focused on symptom control and minimizing complications. C

Background
Crohn’s disease is a chronic inflammatory disease that usually affects the ileum and colon but can occur in any part
of the intestinal tract. It causes transmural, discontinuous lesions in the bowel that are often complicated by
obstruction, abscess, and fistulae. It has the potential for systemic complications.

Incidence

 Incidence is 5/100,000 persons per year in the United States.1

Prevalence

 Prevalence is approximately 50/100,000 in the United States.1

Economic Impact

 The cost of medical and surgical therapy was estimated at up to 2 billion dollars annually in the United
States in 1999.2

Causes of the Condition

  Genetic and environmental risk factors are probably equally important in the appearance and progression.
 Studies demonstrate a 15% prevalence in first-degree relatives of Crohn’s patients and 70% concordance in
monozygotic twins. 6
 A Danish population-based study found incidence rate ratios of 7.8 for first-degree relatives, 2.4 for
second-degree relatives, and 1.9 for third-degree relatives of patients with Crohn's disease.82
 Smoking and oral contraceptive use increase the risk of recurrence.4
 Intercurrent infections (including respiratory and enteric infections) and NSAID use exacerbate disease.55
 There may be an association between diet and intestinal permeability in Crohn’s disease, but these have not
been well established or translated into practical considerations for management.
 A systematic review of 6 observational studies found an association between cesarean delivery and later
diagnosis of Crohn's disease (95% CI, 1.1-1.7).75
 A systematic review of 8 case-control and 3 cohort studies found an association between Crohn's disease
and previous antibiotic use, especially metronidazole and fluoroquinolones. Causality has not been
demonstrated, and it is possible that antibiotics were given for early symptoms of CD in these patients.76
 There is no association between measles vaccination and the development of inflammatory bowel
disease.37

Pathophysiology

 The pathophysiology of Crohn’s disease has not been definitively described, but is believed to result from
impaired immunity within the intestine that leads to a chronic inflammatory state.
 The resulting overproduction of pro-inflammatory cytokines leads to well-demarcated, discontinuous,
transmural lesions with a tendency to form fistulae.
 There is a clear genetic component, given 70% concordance in monozygotic twins. 6

Risk Factors

Risk Factor Odds Ratio

Oral contraceptive use (ever users) 3.0

Smoking current vs not current 2.1

Screening and Prevention

Bottom Line

 Colorectal cancer is more common in patients with inflammatory bowel disease, and there is indirect
evidence that surveillance may improve outcomes (primarily stage at diagnosis). However, this could
represent lead-time bias.34 Screening in this group is not addressed by the USPSTF., ACS, or the Multi-
Society guidelines.C
 Oral contraceptives increase the likelihood of relapse in patients with Crohn’s disease (HR 3.0, 95% CI,
1.5-5.9); women should consider alternative forms of birth control.40B
 Smoking increases the risk of recurrence (HR 2.1, 95% CI, 1.1-4.2); patients who smoke should be
encouraged to quit.404B
  A cost-effectiveness analysis found that chemoprophylaxis against pneumocystis jiroveci pneumonia is not
helpful.83

Diagnosis
Bottom Line

 Consider Crohn’s disease when patients present with chronic (>6 weeks) or nocturnal diarrhea, abdominal
pain, weight loss, fever, or symptoms indicating an intestinal blockage or fistula. C
 Initial labs should include CBC, sed rate or CRP, and a stool sample for Clostridium difficile and
lactoferrin. Fecal calprotectin is useful when negative for ruling out Crohn's disease in adults and
children.647C
 Diagnosis is based on clinical presentation and confirmed with endoscopic (including histologic)
findings. C
 Crohn’s disease is classified into mild-moderate, moderate-severe, or severe-fulminant depending on
clinical presentation, treatment response, and complications (see Table 1). C

Differential Diagnosis

Diagnosis Features

Ulcerative colitis Mainly distinguished by endoscopic and histologic findings

Irritable bowel syndrome Negative lactoferrin, negative ESR, negative guaiac

Gastroenteritis Usually resolves within 1 week

Less frequently presents with diarrhea, but mostly distinguished by

Colorectal carcinoma
endoscopy

Celiac disease Positive serum IgA-TTG, remission with gluten-free diet

Radiation Exposure history plus endoscopic findings

Clostridium difficile or other enteric

Presence of toxin in stool
pathogens

No bleeding or systemic symptoms, diarrhea typically less severe, normal

Microscopic (collagenous) colitis
gross appearance of colon

Using the History and Physical

 Consider Crohn’s when a patient presents with chronic (>6 weeks) or nocturnal diarrhea, abdominal pain,
weight loss, fever, or symptoms indicating an intestinal blockage or fistula.
 A study of 1981 adults with lower GI symptoms presenting to a gastroenterologist for evaluation, of whome
302 had CD or UC, found that signs and symptoms had low predictive value. Absence of bloody stools had
a LR− of 0.7, while passage of stools more than 4 times a day had a LR+ of 2.3.69
 The medical history should include symptom onset, duration, recent travel, food intolerance, sick contacts,
medication use, smoking, and family history. Typical historical findings include abdominal pain (70% of
patients), diarrhea (particularly nocturnal or lasting longer than 6 weeks), weight loss (60% of patients),
fatigue, fever, or rectal bleeding (40%-50% of patients).7
  Measure weight and and perform a rectal exam with occult blood testing. The physical exam may show
pallor, cachexia,8 abdominal tenderness or mass, perianal fissures (10% of patients), fistulae, or
abscess. Clubbing may be present.
 Extraintestinal manifestations may be present even in the absence of the typical signs/symptoms and
include inflammation of eyes, skin, or joints; or delay of growth or puberty in children.
 See Table 1 for severity classification.

Selecting Diagnostic Tests

 There is no single gold standard available for diagnosis. It is confirmed by a combination of clinical
evaluation, radiologic, endoscopic and histologic findings.
 Serum c-reactive protein or sedimentation rate14 (especially if >100 mm/h) helps establish acute
inflammation and is recommended at first presentation.7 However, patients with Crohn's may have a
normal CRP, so a normal value does not exclude the disease. CRP is a useful test to monitor disease
progression and response to treatment, though.56 Because anemia and thrombocytosis are common
findings at presentation, order a CBC as well.
 Clostridium difficile infection is part of the differential diagnosis of Crohn’s disease and can be comorbid
with it; this may obscure the diagnosis initially. Stool examination for Clostridium difficile toxin is
recommended.7
 Several novel blood tests accurately distinguish Crohn’s disease (or other inflammatory bowel disease)
from irritable bowel syndrome. They include fecal lactoferrin (LR+ 45, LR− 0.1), fecal calprotectin (LR+
10.6, LR− 0.1), and anti-Saccaromyces cerevisiae antibodies (ASCA).80 Note that anti-neutrophil
cytoplasm antibodies (ANCA) suggest ulcerative colitis, not Crohn's disease. Thus, the combination of
positive ASCA and negative pANCA strongly suggests Crohn's disease. A systematic review of 8 studies of
fecal calprotectin in children found that it had a very good sensitivity (95%-100%) and negative predictive
value (3% with pretest probability of 50%).64
 For suspected Crohn’s, endoscopy with multiple biopsies is the first-line procedure to establish the
diagnosis.7
 In patients with evidence of Crohn’s disease based on a single endoscopic study, additional endoscopic or
radiologic studies (such as small bowel follow-through (SBFT), capsule endoscopy, or complete
colonoscopy) may be helpful to determine the extent and locations of disease.7 A barium study or CT
enterography are also helpful when the diagnosis is in doubt after colonoscopy. SBTF is better than
enteroclysis for Crohn’s disease staging.389 Capsule endoscopy is a newer technology that provides
excellent accuracy for detecting the extent of Crohn’s disease.
 Small intestine contrast ultrasonography is sensitive and specific for the detection of small bowel lesions in
patients with Crohn's (88% sensitive, 86% specific, AUROCC 0.93).88
 When extramural complications are suspected (such as abscess or fistula), an imaging study such as
ultrasound, CT, or MR colonography15 should be performed.7 In the United States, CT (or pelvic MRI to
assess perianal fistula disease) are the most commonly selected imaging studies.
 Mean platelet volume measured at week 14 of treatment and the difference between baseline and 14 week
MPV is associated with a sustained response to infliximab in patients with CD.79

Approach to the Patient

  Consider Crohn’s when patients present with chronic (>6 weeks) or nocturnal diarrhea, abdominal pain,
weight loss, fever, or symptoms indicating an intestinal blockage or fistula. The general diagnostic
approach is to rule out other causes of diarrhea before using endoscopy to identify characteristic lesions.
When diarrhea is present, rule out enteric pathogens by testing a stool sample for lactoferrin and
Clostridium difficile.7
 Initial laboratory investigations should include c-reactive protein and CBC to evaluate degree of
inflammation, anemia, and whether infection is present. Also order fecal lactoferrin or fecal calprotectin,
and consider ASCA IgA and IgG.7
 Refer patients for endoscopy to confirm the diagnosis, to obtain samples for histopathologic evaluation, and
to assess disease location and severity.
 Disease is classified into mild-moderate, moderate-severe, or severe-fulminant depending on clinical
presentation, treatment response, and complications (Table 1).

History and Physical Tests

 Bowel symptoms -> Crohn's disease

Diagnostic Tests

 Screening (any) -> serious inflammatory disease

 IBD suspected (child) -> UC or Crohns disease
 IBD suspected (adult) -> UC or Crohns disease

Treatment
Bottom Line

 Treatment is based on the severity of disease and response to earlier treatment modalities. C55
 Sulfasalazine and mesalamine are of limited value for induction of remission; mesalamine is more effective
in colonic than small bowel disease. Controlled ileal release budesonide is effective for more distal disease,
as are metronidazole and ciprofloxacin.55A
 Systemic steroids should be used to treat moderate-severe disease once peritonitis or serious infection are
excluded, and as a bridge to more definitive therapy with an immunemodulator or anti-TNF agent.2324A
 Immunomodulators or TNF-alpha monoclonal antibodies should be used for patients with steroid-resistant
or fulminant disease.25262728A
 Fistulae should be treated with antibiotics and perirectal abscesses should be treated with surgical drainage.
Obstruction treatment depends on the type of obstruction but surgical consultation is warranted. B

Drug Therapy

 Mild-moderate active disease

 Mesalamine 3.2 to 4 g daily and sulfasalazine (ileocolonic or colonic only) 3 to 6 g daily have traditionally
been recommended. However, recent systematic reviews have found that they are little better than
placebo8745 and are less effective than budesonide.55 Controlled ileal release budesonide 9 mg/day is the
preferred therapy for patients with disease primarily in the ileum and right colon.55 Oral prednisone 40
 mg/day and budesonide 3 mg tid given orally are effective but have more side effects, and should be
reserved for patients with moderate disease activity.24 Ciprofloxacin 1 g daily and metronidazole are
options for mild to moderate disease and appear to be similar in effectiveness to mesalamine, although
based largely on small trials.22 Anti-tubercular therapies are not effective,86 and the evidence base is
insufficient for disease limited to the upper GI tract. If treatment is unsuccessful, advance to treatment for
moderate to severe disease.55Azathioprine and 6-mercaptopurine are no more effective than placebo at
inducing remission or improving clinical symptoms.25
 A Cochrane review found that high dose methotrexate (25 mg IM per week) but not low dose were
effective at inducing remission and withdrawal from steroids in patients with refractory Crohn's disease.26
 Moderate-severe active disease
 Begin with an oral corticosteroid. Both oral prednisone 40 to 60 mg daily and oral budesonide 3 mg tid are
effective compared with placebo, and are generally given for 1 to 4 weeks.4955 A Cochrane review of 9
studies with 779 patients found that budesonide is slightly less effective than prednisone, but has fewer side
effects.2324 Azathioprine, 6-mercaptopurine, and methotrexate (parenteral) can help maintain remission
that has been induced by steroids .
 For patients who do not respond to steroids or immunosuppressants, consider treatment with an anti tumor
necrosis factor (TNF) monoclonal antibody such as infliximab, adalimumab or certolizumab pegol. A
network meta-analysis concluded (based largely on indirect comparisons between placebo controlled trials)
that infliximab was the most effective at inducing remission in patients who had not been on a previous
anti-TNF drug.73 Infliximab can be given with azathioprine, and the anti-TNF drugs are appropriate in
patients who cannot take corticosteroids. An RCT randomized 508 patients
to infliximab monotherapy, azathioprinemonotherapy, or both. At 26 weeks, rates of steroid-free remission
were 57% for combination therapy, 44% for infliximab alone, and 30%
for azathioprine alone.63 Finally, natalizumab is an option for patients that have not responded to or do not
tolerate the above drugs, although can rarely cause progressive multifocal leukoencephalopathy (PML) and
is therefore not considered first-line therapy.552728
 An RCT of 244 adults with active Crohn's disease (CDAI 150 to 450 and Crohn's Disease Endoscopic
Index of Severity >6) compared a strategy of escalation to adalimumab based on biomarkers plus clinical
judgement versus clinical judgment alone. At one year, outcomes were better in the former group.92 A
similar but smaller trial using infliximab, however, did not find an advantage to adding biomarkers to the
decision-making process.93
 Severe-fulminant disease
 Hospitalize patients with severe of fulminant disease, or patients presenting with fever or other evidence of
serious infection, inability to take oral fluids or medication, or evidence of peritonitis or obstruction. CT is
recommended to exclude peritonitis or abscess, as well as consultation with a gastroenterologist. If serious
infection is excluded, these patients should receive parenteral steroids (equivalent dose to 60
mg prednisoneper day), and non-responders should consider tacrolimus or cyclosporine (although not of
proven effectiveness).5554 Azathioprine or 6-mercaptopurine have been used to induce remission. Optimal
dosing has not been determined for these medications, and 17 or more weeks may be needed to elicit a
response. A 2013 Cochrane review found no evidence that they were more effective at inducing remission
than placebo, although the overall number of patients was small and the difference was nearly statistically
significant (RR 1.23, 95% CI, 0.97-1.55).25 Methotrexate 25 mg IM once weekly can be used as an
alternative to induce remission for patients previously treated with steroids, based primarily on a single
 large study (NNT = 5).26However, data are insufficient to recommend it for routine use as a maintenance
drug.42
 If immunomodulators are ineffective, infliximab 5 mg/kg IV infusions may be effective.27 This should not
be used in patients with obstructing symptoms. Some experts suggest treating with infliximab before using
other immune modulators, but there is no evidence to support a specific order of treatment for these
medications. NICE guidelines recommend that it be used for 12 months or until treatment failure,
whichever is shorter. The NICE guidelines also recommend adalimumab as an alternative for patients with
severe active Crohn's disease. Natalizumab 300 mg is a relatively new agent that is effective for induction
and maintenance of remission in patients who have failed to respond to conventional treatments. However,
it’s use is restricted to to concerns about causing progressive multifocal leukoencephalopathy
(PML).28 Vedolizumab is another monoclonal antibody to integrin that has been shown in a RCT to induce
remission better than placebo (14% vs 6% at 6 weeks, NNT = 12) but also higher rates of serious adverse
events and serious infections (5.5% vs 3.0%). No cases of PML were identified during one year of follow-
up.62 In another RCT, patients with moderately severe active CD who had failed therapy with a TNF
antagonist were randomized to vedolizumab or placebo. There was no difference in outcomes at 6 weeks,
but a greater likelihood of remission was seen at 10 weeks (27% vs 12%, p = 0.001, NNT = 7).68
 Maintenance therapy
 Once symptoms are in remission, patients should be treated with maintenance therapy. Salicylates and
corticosteroids are not effective for maintenance of medically induced remission85 , and long-term use of
corticosteroids such as budesonide have important adverse effects.77 A Cochrane review identified 12
studies with 1273 patients, and concluded that budesonide was not effective for maintenance of remission,
other than minor benefits for lower CDAI scores and somewhat longer time to recurrence, and that these
small benefits must be considered in the context of significant harms.4831 Azathioprine (2.0-2.5
mg/kg/day) and to a lesser extent 6-mercaptopurine (1.0-1.5 mg/kg) are effective in maintaining remission,
but have significant adverse effects including pancreatitis, leukopenia, and infection.29 A trial of patients
with quiescent Crohn's who had been on azathioprine maintenance for at least 4 years found that
withdrawal increased the risk of relapse after one year (31% vs 15%).65 Methotrexate given 15 mg/week
IM (but not orally) also reduces relapse (NNT = 4).52 TNF inhibitors (infliximab 5-10 mg/kg q 8
wks, adalimumab 40 mg every 1-2 wks, and certolizumab pegol 400 mg q 4 wks) are effective at
maintaining remission but are considerably more expensive.53 A RCT of 741 patients with moderately to
severely active Crohn's found that IV ustekinumab was more effective than placebo at inducing remission
(NNT = 4-10) and maintaining remission (NNT =
5).90 Metronidazole, mesalamine,46 azathioprine/mercaptopurine, and infliximab are recommended by
ACG guidelines to reduce the likelihood of recurrence following ileocolonic resection.6055
 Interleukin 10, thalidomide and its analogues, and sargramostim are not effective for induction or
maintenance of remission in Crohn’s, based on systematic reviews.414350 A RCT with 280 patients found
no significant benefit of tofacitinib for induction and maintenance of Crohn's disease.89
 A network meta-analysis concluded based on indirect comparisons between clinical trials
that adalimumaband the combination of infliximab + azathioprine were the most effective therapies for
induction and maintenance of remission in patients with CD.72

Surgical Therapy

 Because Crohn’s disease occurs in discontinuous lesions throughout the GI tract, surgical cure is not
possible.
  Surgical consultation should be obtained if there is evidence (usually by CT, MR, or ultrasound) of abscess,
fistula, abdominal mass, malignancy, or obstruction, if symptoms are refractory to medical therapy, or there
is perianal disease.55
 A systematic review identified 7 studies of 1125 patients comparing stapled with handsewn methods for
ileocolic anastomosis. Staples resulted in fewer leaks.4447
 A systematic review of population-based observational studies found that the 5 year risk of requiring a
second surgery was 29% (95% CI, 23%-37%). The 10 year risk was 35% (95% CI, 32%-39%). Newer
studies had a lower likelihood of requiring a second surgery, probably due to improved medical therapy
options.74

Complementary/Alternative Therapy

 Enteral nutrition therapy is inferior to corticosteroids for induction of remission of Crohn’s disease,
regardless of the protein or fat composition of the formula.32 A systematic review identified two trials that
support use of enteral nutrition to maintain remission.51
 There is no evidence to support the use of probiotics for the maintenance of remission.33
 An RCT with over 700 patients found that omega-3 free fatty acids are no more than placebo in preventing
relapse of Crohn's disease.36 A Cochrane review came to a similar conclusion, based on 2 RCTs.57

Rehabilitation and Physical Therapy

 Exercise has been shown to decrease rates of bone loss in patients with Crohn’s disease.

Behavioral Medicine and Psychotherapy

 The effect of psychotherapy, group therapy, and relaxation has been studied on Crohn’s disease with
respect to medical and psychosocial outcomes, however the results appear to be inconsistent.

Other Treatment

 A randomized trial of hematopoietic stem cell transplantation for patients with refractory Crohn's disease
who were not surgical candidates found no benefit and significant harms.78 A systematic review identified
only a single RCT plus 4 observational studies, and found high rates of transplant associated mortality
(6.4%) and febrile neutropenia (83%). 95
 A Cochrane review of 10 RCTs concluded that enteral nutrition was similarly effective to steroids for
induction of remission.91

Duration of Treatment

 A multidisciplinary European expert panel has made recommendations regarding the duration of therapy,
and when clinicians can consider stopping drugs in patients with clinical remission and normal CRP and
fecal calprotectin levels.
 They concluded that azathioprine, 6-mercaptopurine, and methotrexate could be withdrawn after 4 years of
clinical remission and normal blood tests, while anti-tumor necrosis factor (TNF) drugs could be withdrawn
 after 2 years of clinical remission and normal endoscopy. For patients taking both an anti-TNF drug and an
immunomodulator, the anti-TNF drug could be withdrawn after 2 years of clinical remission.61

When to Refer or Hospitalize

 Patients should be hospitalized if they develop high fever, frequent vomiting, GI bleeding, severe
abdominal pain, evidence of intestinal obstruction or abscess.

Management of Complications

 Complications of Crohn’s disease include fistulae, abscesses, strictures, and obstructions.

 Obstructions should be assessed with imaging studies to determine if they are adhesive obstructions or
fibrotic strictures. The former can be treated with NG suction and bowel rest, the latter with corticosteroids
and bowel rest. They occasionally require surgery.
 Inflammatory masses require IV antibiotics and steroids, while abscesses require surgical or percutaneous
drainage.
 Perianal fistulae can be treated medically, with ciprofloxacin and metronidazole, and if symptoms persist
immunomodulators or anti-TNF agents can be added. These generally improve with medical therapy but
occasionally require surgery.
 A randomized trial of 212 patients with perianal fistula found better healing with allogenic expanded
adipose derived stem cells than placebo (56% vs 39% remission, p = 0.021, NNT = 6).94
 Osteopenia and osteoporosis are common, particularly in patients taking steroids; however, there is no
evidence that favors a particular screening regimen.
 The risk of colon cancer is increased, but there is only indirect evidence that routine screening decreases
mortality from colon cancer.34

Managing the Hospitalized Patient

 Correct fluid and electrolyte imbalances.

 Patients without severe pain or obstruction may be fed orally as tolerated. Patients who cannot tolerate oral
feeding should receive enteral elemental feedings or parenteral nutrition after 5 to 7 days.
 Ciprofloxacin 400 mg IV twice daily and metronidazole 500 mg IV every 8 hours should be used for
patients with suspected perforation, abscess, or fistula.

Prognosis
Bottom Line

 Crohn’s disease is characterized by intermittent episodes of pain, diarrhea, and other symptoms.
Medications may decrease the severity and frequency of these episodes, but generally do not prevent them
entirely. C
 Mortality is slightly increased in Crohn’s patients, and surgery is likely at some point.10B
 Patients are at increased risk for osteoporosis and colon CA, but screening protocols are not well defined. C

Prognosis
  About 80% of patients10 will require surgery at some point.
 Overall mortality is thought to be slightly higher than the normal population and is greatest in the first 2
years after diagnosis. However, a 20 year follow-up of 237 patients in Norway found no increase in overall
mortality (HR 1.35, 95% CI, 0.94-1.94), and no difference in GI cancers, other cancers, or cardiovascular
disease.58
 Crohn’s disease is characterized by intermittent episodes of pain, diarrhea, and other symptoms.
Medications seek to decrease the severity and frequency of these episodes, but generally do not prevent
them entirely.
 Current evidence does not support an increased risk of lymphoma in patients with IBD at the present
time.39

Follow-up tests and monitoring

 Activity of disease is monitored by clinical signs and symptoms.

 Surveillance guidelines for colon cancer, osteoporosis, and vitamin/mineral deficiencies have not been
determined.
 In patients taking a TNF antagonist, fecal calprotectin was somewhat helpful at predicting endoscopic
recurrence (sensitivity 90%, specificity 80%), but less accurate at predicint clinical recurrence (sensitivity
70%, specificity 65).70
 Following surgery, patients with fecal calprotectin levels <100 mcg/g were unlikely to have a recurrence.81

Management of Special Populations

Pregnancy

 Methotrexate is absolutely contraindicated in pregnancy.

 An observational study found no association between mode of delivery and long-term risk of perineal
disease. Women receiving cesarean section tended to be older and have more complicated CD.71
 A systematic review concluded that women with UC or Crohn's had small increases in the risk for preterm
birth (OR 1.9, 95% CI, 1.7-2.0), still birth (OR 1.6, 95% CI, 1.03-2.4), and congenital anomalies (OR 1.3,
95% CI, 1.05-1.58).84

Infants and Children

 Children may develop growth delay, delayed puberty, bone demineralization, and malnutrition in addition
to the typical signs and symptoms of Crohn’s disease. Good control of inflammation may reduce this
adverse impact on growth, but clinical trials are lacking.
 Presentation and diagnosis in children is similar to that in adults.
 One Cochrane review evaluated the various treatment modalities with respect to their effect on growth. 6-
MP was not found to adverse effect growth compared to placebo. Enteral feedings were studied in two
lower quality trials, and increased growth relative to corticosteroid treatment.35

References and Additional Resources

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Additional Resources

 Crohn's and Colitis Foundation of America. [www.ccfa.org]

Tables
Table 1: Classification of Crohn's Disease.

Severity CDAI* Description

Mild to 150- Ambulatory patients who can tolerate oral intake and do not have evidence of abdominal
moderate 220 mass, high fevers, obstruction, or significant weight loss

Moderate to 220- Patients who have failed to respond to treatment for mild disease or those with more
severe 450 prominent systemic symptoms (fever, weight loss, vomiting)

Severe to Patients with persistent symptoms despite the use of oral steroids, or with evidence of
>450
fulminant intestinal obstruction or abscess, acute abdomen, or cachexia

Article ID: eee0178

Azathioprine and 6-mercaptopurine appear not to be effective in inducing
remission in Crohn's disease compared with placebo. Infliximab appears to be more
effective than azathioprine for induction of remission.

A Cochrane review [1] 1 included 13 RCTs (n=1211) of azathioprine and 6-mercaptopurine

therapy in adult patients with Crohn's disease. There was a trend favouring azathioprine or
6-mercaptopurine but no statistically significant difference in clinical remission rates or
improvement compared with placebo (table [1] ). A steroid sparing effect (prednisone dose
less than 10 mg/day while maintaining remission) was seen with azathioprine (table [1] )
There was no difference in adverse events requiring withdrawal. Azathioprine was inferior to
infliximab for induction of steroid-free clinical remission and mucosal healing (table [2] ). The
combination of azathioprine and infliximab was significantly superior to infliximab alone for
induction of steroid-free clinical remission (table [3] ). Azathioprine or 6-mercaptopurine
therapy was found to be no better at inducing steroid free clinical remission compared to
methotrexate and 5-aminosalicylate or sulfasalazine. There were no statistically significant
differences in withdrawals due to adverse events between azathioprine or 6-mercaptopurine
and methotrexate; between azathioprine or 6-mercaptopurine and 5-aminosalicylate or
sulfasalazine; between azathioprine and infliximab; or between the combination of
azathioprine and infliximab and infliximab.

Relative Assumed risk - Corresponding risk - No of Participants

Outco
effect (95% Control - Intervention: AZA or 6-MP (studies), Quality of
me
CI) Placebo (95%CI) evidence

Clinica
l 1.23 (0.97
372 / 1000 458 / 1000 (361 to 577) 380 (5), Moderate
remiss to 1.55)
ion

Clinica
l
remiss
1.26 (0.98
ion or 359 / 1000 452 / 1000 (352 to 582) 434 (8), Moderate
to 1.62)
impro
vemen
t

Steroi
d
1.34 (1.02
sparin 457 / 1000 612 / 1000 (466 to 809) 143 (4), Moderate
to 1.77)
g
effect

Withdr
awals
due to 1.70 (0.94
53 / 1000 90 / 1000 (50 to 163) 510 (8), Moderate
advers to 3.08)
e
events

Relative Corresponding risk - No of Participants

Outco Assumed risk -
effect (95% Intervention: IFX (95% (studies) Quality of
me Control - AZA
CI) CI) evidence

Clinica
l 0.66 (0.51 to
479 / 1000 316 / 1000 (244 to 417) 339 (1), Moderate
remiss 0.87)
ion

Clinica
l
remiss 0.68 (0.51 to
444 / 1000 302 / 1000 (226 to 400) 339 (1), Moderate
ion off 0.90)
steroid
s
 Relative Corresponding risk - No of Participants
Outco Assumed risk -
effect (95% Intervention: IFX (95% (studies) Quality of
me Control - AZA
CI) CI) evidence

Mucos
al 0.55 (0.33 to
283 / 1000 156 / 1000 (93 to 266) 214 (1), Moderate
healin 0.94)
g

Withdr
awals
due to 1.47 (0.96 to
178 / 1000 262 / 1000 (171 to 397) 324 (1), Moderate
advers 2.23)
e
events

Relative Corresponding risk - No of Participants

Outco Assumed risk -
effect (95% Intervention: AZA + IFX (studies) Quality of
me Control: IFX
CI) (95% CI) evidence

Clinica
l 1.26 (1.03
479 / 1000 603 / 1000 (493 to 738) 338 (1), Moderate
remiss to 1.54)
ion

Clinica
l
remiss 1.23 (1.02
482 / 1000 593 / 1000 (492 to 708) 383 (2), Moderate
ion off to 1.47)
steroi
ds

Mucos
al 1.50 (1.02
283 / 1000 424 / 1000 (289 to 620) 210 (1), Moderate
healin to 2.19)
g

Withd
rawals
due to 1.16 (0.75
178 / 1000 206 / 1000 (134 to 320) 342 (1), Moderate
adver to 1.80)
se
events

References
1. Chande N, Townsend CM, Parker CE et al. Azathioprine or 6-mercaptopurine for induction of
remission in Crohn's disease. Cochrane Database Syst Rev 2016;(10):CD000545.