REVIEW

Crohn Disease: Epidemiology, Diagnosis, and

Management
Joseph D. Feuerstein, MD, and Adam S. Cheifetz, MD

Abstract

Crohn disease is a chronic idiopathic inflammatory bowel disease condition characterized by skip lesions
and transmural inflammation that can affect the entire gastrointestinal tract from the mouth to the anus.
For this review article, we performed a review of articles in PubMed through February 1, 2017, by using
the following Medical Subject Heading terms: crohns disease, crohn’s disease, crohn disease, inflammatory
bowel disease, and inflammatory bowel diseases. Presenting symptoms are often variable and may include
diarrhea, abdominal pain, weight loss, nausea, vomiting, and in certain cases fevers or chills. There are
3 main disease phenotypes: inflammatory, structuring, and penetrating. In addition to the underlying
disease phenotype, up to a third of patients will develop perianal involvement of their disease. In addition,
in some cases, extraintestinal manifestations may develop. The diagnosis is typically made with endoscopic
and/or radiologic findings. Disease management is usually with pharmacologic therapy, which is deter-
mined on the basis of disease severity and underlying disease phenotype. Although the goal of manage-
ment is to control the inflammation and induce a clinical remission with pharmacologic therapy, most
patients will eventually require surgery for their disease. Unfortunately, surgery is not curative and patients
still require ongoing therapy even after surgery for disease recurrence. Importantly, given the risks of
complications from both Crohn disease and the medications used to treat the disease process, primary care
physicians play an important role in optimizing the preventative care management to reduce the risk of
complications.
ª 2017 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2017;92(7):1088-1103

From the Department of rohn disease (CD) was first described
Medicine and Division of
Gastroenterology, Beth Israel
Deaconess Medical Center,
Harvard Medical School, Bos-
ton, MA.
C by Dr Burrill B. Crohn and colleagues
in 1932.1 Along with ulcerative colitis
(UC), it falls under the spectrum of chronic
idiopathic inflammatory bowel disease
(IBD).2 A recent estimate suggests that 1.3%
(3 million individuals) of the US population
has a diagnosis of IBD.3 Crohn disease is a
chronic disease with an annual incidence
ranging from 3 to 20 cases per 100,000.4
The median onset of disease is age 30 years
and it has 2 peaks, first between age 20 and
30 years and then a smaller peak around age
50 years. Crohn disease is characterized by
discontinuous skip lesions affecting any part
of the gastrointestinal tract from the mouth
to the anus. The inflammation is classically
transmural and on pathology granulomas
may be present on biopsies.5 Presenting symp-
toms are variable but can include diarrhea,
abdominal pain, weight loss, nausea, vomit-
ing, and sometimes fevers or chills.6 The
natural history of the disease is one of periods
of remission and flares. There are multiple
different phenotypes of disease including
inflammatory, stricturing, and penetrating. Pa-
tients can have 1 or more of these disease phe-
notypes during the course of their disease, and
patients often progress from inflammatory to
stricturing or penetrating. Unfortunately, there
is no cure for CD and most patients require
at least 1 surgical resection.5 The goal of med-
ical therapy is to achieve a steroid-free clinical
and endoscopic remission with the hopes
of preventing complications and surgery.
Until recently, medication options were
limited to thiopurines, methotrexate (MTX),
natalizumab, and antietumor necrosis factor
(anti-TNF) agents. Of late, drugs with novel
mechanisms of action have been approved
including a gut-selective antiintegrin (a4b7)
inhibitor and a monoclonal antibody to
IL-12/IL-23. For this review article, we per-
formed a review of articles in PubMed through
February 1, 2017, by using the following Med-
ical Subject Heading terms: crohns disease,

1088 Mayo Clin Proc. n July 2017;92(7):1088-1103 n http://dx.doi.org/10.1016/j.mayocp.2017.04.010

www.mayoclinicproceedings.org n ª 2017 Mayo Foundation for Medical Education and Research
CROHN DISEASE: EPIDEMIOLOGY, DIAGNOSIS, AND MANAGEMENT
crohn’s disease, crohn disease, inflammatory
bowel disease, and inflammatory bowel
diseases.
EPIDEMIOLOGY
The prevalence of CD has an incidence of 3 to
20 cases per 100,000.4 Crohn disease is more
common in the industrialized world, particu-
larly in North America and Western Europe,
though the incidence is rising in Asia and South
America.7,8 There may be a slightly higher pre-
dominance of CD in women and it is more
common in individuals of Ashkenazi Jewish
origin than in non-Jews. The exact pathogen-
esis of CD is unknown, although there are a
number of genetic and environmental factors
that have been shown to increase the risk of
the disease and lead to the aberrant gut im-
mune response characteristic of the disease.7
RISK FACTORS
Risk factors for the development of CD appear
to be related to changes in the gut microbiome
or disruptions to the intestinal mucosa and
genetics.
Environmental Risk Factors
Crohn disease appears to be triggered by alter-
ations in the gut microbiome or disruption in
the intestinal mucosa.8 Patients with IBD often
have a dysbiosis that results in a reduction in
the diversity of the gut microbiome.9 Although
the literature surrounding the specifics is
evolving, the exact mechanism by which alter-
ations in the gut microbiome predispose to
CD is still not fully understood.
Gastrointestinal infections, nonsteroidal
anti-inflammatory drugs, and antibiotics have
all been implicated in the development of
IBD.7,8,10-12 However, none of these associa-
tions has been substantiated with large epide-
miological studies. In one study, patients with
enteric infections from salmonella or campylo-
bacter had an increased risk of developing
IBD within the first year of their illness.10
Also, sustained use of nonsteroidal anti-
inflammatory drugs, especially in women,
may increase the risk of IBD.11 Antibiotic
exposure early in life has also been associated
with an increased risk of developing CD.13 In
women, both hormone replacement therapy
and oral contraceptives may increase the risk
of IBD.12,14,15
Mayo Clin Proc. n July 2017;92(7):1088-1103 n http://dx.doi.org/10.1016/j.mayocp.2017.04.010
www.mayoclinicproceedings.org
ARTICLE HIGHLIGHTS
d Crohn disease is a chronic condition characterized by skip
lesions affecting any part of the gastrointestinal tract from the
mouth to the anus.
d Presenting symptoms are variable but include diarrhea,
abdominal pain, weight loss, nausea, vomiting, and sometimes
fevers or chills.
d Diagnosis is made in the right clinical setting via endoscopic and/
or radiologic findings.
d Treatment is based on severity of symptoms and underlying
disease phenotype. The most effective therapies are the biologic
therapies (antietumor necrosis factor, anti-integrin, and IL-12/
IL-23 inhibitors).
d Primary care physicians are critical in optimizing the overall care
of these patients and limiting potential complications.
The best-studied environmental risk
factor, cigarette smoking, doubles the risk of
developing CD.16 This risk is increased in
both current and former smokers.17 Studies
have also suggested that appendectomy may
increase the risk of CD but this may be due
to inaccurate classification of appendicitis
which in truth was actually CD.18 The role
of diet in the development of CD also remains
unclear. Some studies have suggested that
diets high in sugar, omega-6 fatty acids, poly-
unsaturated fatty acids, total fat, oil, and meat
increase the risk of CD whereas a diet high in
fiber and fruit decreased the risk of CD.19-21
However, further studies are still needed to
clarify the role of diet and the risk of devel-
oping CD.
Genetic Risk Factors
Although family history does portend an
increased risk, only 10% to 25% of patients
with IBD have a first-degree relative with the
disease.7 In twin studies, concordance rates
for CD in monozygotic twins range from
20% to 50% compared with 10% in dizygotic
twins.22-25 Crohn disease is more common in
patients of Ashkenazi Jewish origin than in
non-Jews and is less frequently seen in African
Americans or Hispanics.7 Although genetic
risk factors are still being elucidated, there
are more than 200 genes that have been
1089

associated with the development of IBD. The
first gene discovered was the NOD2 locus on
chromosome 16.26-28 Homozygotic changes
at NOD2 have a 20 to 40 times higher risk
of developing CD, while being heterozygous
increases the risk by 2 to 4 times.26-28 A num-
ber of other genetic foci involving multiple
different pathways (eg, autophagy, adaptive
immunity, and epithelial function) have also
been associated with CD.29-31
LOCATION OF DISEASE, DISEASE SUBTYPE,
AND SEVERITY OF DISEASE
Crohn disease is characterized on the basis of
disease location and phenotype.
Location of Disease
Crohn disease can affect any part of the gastro-
intestinal tract.5 Fifty percent of patients have
involvement of the terminal ileum and the co-
lon, 30% have only small-bowel involvement,
and in 20% of cases it is isolated to the colon.
In addition, 25% of patients suffer from peri-
anal complications including fissures and fis-
tula. Much less frequently (<10%), patients
may present with isolated perianal complaints,
upper gastrointestinal disease, or extraintesti-
nal manifestations (EIMs) of disease.5
Disease Phenotype
For research and treatment purposes, CD has
been divided into phenotypic subtypes: in-
flammatory, stricturing, and fistulizing. In-
flammatory CD is characterized by
inflammation of the gastrointestinal tract
with no evidence of stricturing or fistulizing
disease. This inflammation can eventually
lead to fibrosis and luminal narrowing and
these patients become classified as having
stricturing disease. Once fibrostenotic changes
occur, there is no process that reverses this
aside from surgical intervention. Ongoing
transmural inflammation can also result in
the development of a sinus or fistulous tract
characteristic of fistulizing CD. Fistulae can
develop between the bowel and any adjacent
organ (including the vagina, bladder, and
other areas of the bowel). If the sinus tract is
not complete between the bowel and an adja-
cent organ, an intraabdominal abscess may
develop. In addition to these subtypes, pa-
tients can develop perianal complications.
Perianal disease is not considered its own
n n
1090 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
phenotype but rather a complication that can
develop regardless of the underlying luminal
disease phenotype.5 To standardize disease
classification, the Montreal Classification is
used (Table 1). This system factors in the age
at diagnosis, location of the CD, and behavior
(phenotype) of the disease.
Signs and Symptoms
Presenting symptoms are quite variable but
may correlate with disease phenotype and
location to some extent. Some patients may
have symptoms for years before the diagnosis
of CD.32 Patients with inflammatory disease
often present with abdominal pain and diar-
rhea, though they may develop more systemic
symptoms including weight loss, low-grade
fevers, and fatigue. Often patients with stric-
turing disease develop bowel obstructions
(most commonly, small bowel). Bowel ob-
structions are characterized by lack of flatus
and bowel movements, hyperactive bowel
sounds, and nausea and vomiting. Patients
with penetrating CD can develop fistula or ab-
scesses. When an abscess is present, in addi-
tion to abdominal pain, patients can have
systemic symptoms such as fever and chills.
Patients may also present with signs of acute
peritonitis. Penetrating disease may also result
in symptoms related to the fistula location:
diarrhea in cases of enteroenteric fistula, uri-
nary tract infection from enterovesicular or
enterouretheral fistula, or passage of stool
from the vagina in cases of enterovaginal fis-
tula, or drainage from the skin in enterocuta-
neous fistula. In cases of severe CD colitis,
bloody stool may be present but classically
TABLE 1. Montreal Classification of Crohn
Disease5
Age at A1:
16
diagnosis (y) A2: 17-40
A3: Over 40
Location L1: Ileal
L2: Colonic
L3: Ileocolonic
L4: Isolated upper gastrointestinal
Behavior B1: Nonstricturing/nonpenetrating
B2: Stricturing
B3: Penetrating
Modifier P: Perianal disease
July 2017;92(7):1088-1103 http://dx.doi.org/10.1016/j.mayocp.2017.04.010
www.mayoclinicproceedings.org
CROHN DISEASE: EPIDEMIOLOGY, DIAGNOSIS, AND MANAGEMENT
this is more commonly associated with UC.5,33
However, symptoms alone should not be the
sole guide for management decisions. Subjec-
tive findings should be correlated with objec-
tive findings of disease activity from
biochemical markers, endoscopy, or radiologic
findings.
Laboratory Testing
Although there is no laboratory test that defi-
nitely rules out CD or is diagnostic of CD,
findings on serum and stool testing can assist
with making a diagnosis. Stool studies should
be obtained to rule out other causes of gastro-
intestinal symptoms and diarrhea. Laboratory
abnormalities are seen more frequently with
a longer duration and more severe disease.34
Patients may have an anemia from iron defi-
ciency anemia, chronic inflammation, and
B12 deficiency. Inflammatory markers
including erythrocyte sedimentation rate and/
or c-reactive protein may be elevated, but
normal levels do not rule out CD activity.34
Multiple tests have been evaluated to assess
for inflammation in the gastrointestinal tract
including fecal calprotectin or fecal lactofer-
rin.35 However, none of these tests is unique
to IBD and can be elevated with any intestinal
infection or inflammatory condition.34
EIMs of Disease
Crohn disease is associated with EIMs that can
affect the skin, joints, eyes, liver, blood vessels,
and kidneys.36
Arthritis is the most common EIM
affecting up to 25% of patients with CD. It
can involve both the peripheral and axial skel-
eton. The peripheral arthropathies are further
categorized as type I and type II arthritis.36
Type I is an acute, pauciarticular arthritis
involving fewer than 6 joints that usually flares
with luminal disease activity. This type of
arthritis is self-limited and improves with
treating the underlying CD. Type II arthritis
involves more than 6 joints and can be chronic
in nature. Although symptoms may start with
luminal disease flares, it is usually indepen-
dent of disease activity and can persist after
the luminal CD is treated. These symptoms
are often migratory. There is no synovial
destruction associated with IBD-associated
arthritis.36 Axial arthropathies include anky-
losing spondylitis and sacroiliitis.36 These
Mayo Clin Proc. n July 2017;92(7):1088-1103 n http://dx.doi.org/10.1016/j.mayocp.2017.04.010
www.mayoclinicproceedings.org
conditions limit spinal flexion and can be
very debilitating. Presenting symptoms are
morning stiffness and pain, which are relieved
with exercise.37-39
The 2 most common skin lesions associ-
ated with CD are erythema nodosum and
pyorderma gangrenosum. In most cases, ery-
thema nodosum mirrors the luminal disease
activity, whereas pyorderma gangrenosum is
independent of luminal disease activity.37,40,41
Primary sclerosing cholangitis is also asso-
ciated with IBD and more commonly seen in
UC but may also occur in CD.42 It does not
parallel luminal disease. Primary sclerosing
cholangitis can be a progressive disease with
complications including cirrhosis, portal hy-
pertension, cholangiocarninoma, and colon
cancer.43
Multiple other conditions have been asso-
ciated with CD including uveitis, scleritis,
osteoporosis, psoriasis, depression, nephroli-
thiasis, B12 deficiency, deep vein thrombosis,
chronic bronchitis, bronchiectasis, and
impaired growth in children.36,37,40,41
DIFFERENTIAL DIAGNOSIS
Many conditions can mimic CD. All patients
with diarrhea should be assessed for infection,
IBD, and in certain cases celiac disease as well.
Other conditions that may present similar to
CD include appendicitis, Behcet disease, and
UC. It is important to rule out infection and
other causes of gastrointestinal symptoms
even when patients with known CD are having
“flares.”
DIAGNOSIS
The diagnosis of CD is a clinical one and can
be quite difficult given that the presenting
symptoms can be insidious and nonspecific.5
Red flag symptoms that require further evalu-
ation include weight loss, bloody diarrhea,
iron deficiency, and night-time awakenings.
Similarly, significant family history of IBD, un-
explained elevations in the c-reactive protein
level, sedimentation rates, or other acute-
phase reactants (eg, ferritin and platelets), or
low B12 should prompt further investigation
for possible CD.
The diagnosis of CD is made on the basis
of symptoms and endoscopic and radiologic
findings.5,33 Pathology can be confirmatory.
In cases of colonic or ileal CD, endoscopic
1091

findings are classically characterized by skip
lesions, with varying degrees of inflammation
(including erythema, friability, erosions, and
ulcers) next to areas of normal-appearing mu-
cosa. During endoscopy, luminal strictures,
and less commonly fistulae, may be seen. On
pathology, the classic finding of CD is a non-
caseating granuloma (Figure 1). However,
these are rare, occurring in less than 25% of
cases and are not unique or pathognomonic
to CD.44,45 More common pathologic findings
include varying degrees of infiltrates from lym-
phocytes, plasma cells, granulocytes, basal
lymphoplasmacytosis, distortion of the crypt
architecture with shortening and disarray of
the crypts, crypt atrophy, crypt abscesses,
and crypt branching. The pathologic finding
of chronicity is also supported by the presence
of paneth cell metaplasia.5 In certain cases,
such as isolated jejunal disease, the affected
area may not be amenable to easy endoscopic
evaluation. In these cases, balloon enteroscopy
or capsule endoscopy can be performed to
assess the small-bowel mucosa.46 Although
capsule endoscopy is a very sensitive test for
finding abnormal mucosa, it has low speci-
ficity for diagnosing CD and has the risk of
becoming retained or impacted in cases of
stricturing CD.47,48 The risk of capsule reten-
tion in cases of suspected CD is quite low at
1.6%, but this risk increases to 13% in cases
of known CD.48 To mitigate this risk, small-
bowel imaging and a patency capsule should
be placed before performing a capsule endos-
copy. The patency capsule is specially
designed to disintegrate within 48 to 72 hours.
Imaging is obtained 24 hours after placement
FIGURE 1. Crohn granuloma.
n n
1092 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
to identify the radiopaque markers on the
patency capsule to determine whether it
passed through the small bowel. If this passed
through, then the regular capsule endoscopy
can likely be performed without significant
risk of being retained.49
Imaging can also be used to diagnose CD.
Both computed tomography enterography
(CTE) and magnetic resonance enterography
(MRE) allow for visualization of the bowel
wall, mucosa, and extraluminal complications
(Figure 2). The CTE and MRE have sup-
planted small-bowel barium studies as the cri-
terion standard for the diagnosis and
assessment of CD.50 Compared with CTE,
MRE is more expensive but importantly, it
avoids radiation exposure and does not use
iodinated contrast.
Although a number of studies have evalu-
ated the use of serologic markers in diagnosing
CD,51,52 no marker or panel of markers is sen-
sitive or specific enough to establish or rule
out the diagnosis of CD.
TREATMENT
The treatment of CD depends on disease
severity, location of disease, and subtype of
disease (ie, inflammatory, stricturing, or pene-
trating). We now also attempt to determine
who is at risk for aggressive CD and who
may require earlier and more aggressive thera-
pies. Risk factors for aggressive disease activity
include age of diagnosis less than 30 years,
extensive anatomic involvement, perianal dis-
ease, deep ulcers, prior surgery, and strictur-
ing and/or penetrating disease.53 One of the
biggest challenges associated with CD is that
after 20 years of disease activity 80% of pa-
tients will require a surgery and approximately
30% will require surgery within 5 years of
diagnosis.5,54 Although the goal of medical
therapy is to maintain remission without the
need for surgery, once stricturing and/or fistul-
izing complications occur, surgery may be
required. Unfortunately, because surgery is
not curative for CD, many patients will require
multiple surgeries over their lifetime.54
There are a number of different drugs used
to treat CD. Mesalamine has been evaluated in
a number of studies but has not been shown
to effectively induce or maintain remission in
CD. The perceived benefit of mesalamine is
likely related to its safety profile.5 Antibiotics
July 2017;92(7):1088-1103 http://dx.doi.org/10.1016/j.mayocp.2017.04.010
www.mayoclinicproceedings.org
CROHN DISEASE: EPIDEMIOLOGY, DIAGNOSIS, AND MANAGEMENT
FIGURE 2. A, Phlegmon (black arrows) from Crohn disease. B, Hyperenhancing mural thickening
(red arrows) associated with active inflammation from Crohn disease.
are also used in CD, but the evidence supporting
their use is also limited.55 The main role of anti-
biotics is to treat the suppurative or perianal
complications of CD.56 The immunosuppres-
sants azathioprine (AZA)/mecaptopurine (MP)
and MTX have been used for many years to treat
CD but because of slow onset of action they are
typically used to maintain remission. However,
more recent studies question the overall efficacy
of AZA/MP as monotherapy and their use in
early CD.57-59 More recently, these drugs are
used in combination with anti-TNF drugs to
decrease their immunogenicity and increase
anti-TNF drug concentrations. The mainstay
of therapy for CD has been anti-TNF agents.
More recently approved drugs are monoclonal
antibodies directed against certain integrins
(a4 or a4b7) or interleukins (IL-12/IL-23).
The first antiintegrin approved for CD was nata-
lizumab, but this is associated with progressive
multifocal leukoencephalopathy (PML), a fatal
brain infection.60,61 Vedolizumab is a gut-
selective antiintegrin that has not been associ-
ated with PML and is used mostly to maintain
remission in moderate to severe CD with only
modest effectiveness at induction of remis-
sion.62 In contrast, the most recently approved
agent, ustekinumab, an IL-12/IL-23 inhibitor,
has been shown to be as effective as anti-TNF
therapy at inducing and maintaining remission
in moderate to severe CD.63
Ultimately, the goal of medical therapy is
to induce and maintain a steroid-free clinical
remission, prevent complications and surgery,
and improve the patient’s quality of life.64 For
typical medication, complications, and moni-
toring recommendations, see Table 2.
Mayo Clin Proc. n July 2017;92(7):1088-1103 n http://dx.doi.org/10.1016/j.mayocp.2017.04.010
www.mayoclinicproceedings.org
5-Aminosalycilates
In general, studies suggest that mesalamine is
ineffective in the treatment of CD and should
not be used.65 Although there are some data
that sulfasalazine may be modestly effective
for induction of remission in colonic CD, it
has not been shown to maintain remission.66
Despite this finding, mesalamine is still one
of the most commonly prescribed drugs for
CD.67 Although studies are lacking, some phy-
sicians do use mesalamine in patients with
mild colonic CD that appears similar to UC.
The data supporting this technique are limited
but the safety profile of mesalamine makes it
quite intriguing to use.5 If the drug is going
to be efficacious, symptoms should start to
improve in 2 to 4 weeks.68 If induction of
remission is achieved, mesalamine should be
continued to maintain remission. However, if
ineffective after a few weeks, other therapies
should be initiated. Patients should not be
kept on an ineffective medication just because
it is perceived to be safe. Side effects are rare.
In less than 5% of cases, patients may have a
paradoxical reaction causing increased diar-
rhea, in which case the drug should be
stopped and no other mesalamine agent
should be used, because this is a class effect.
In less than 1% of patients treated with mesal-
amine, interstitial nephritis may occur and
episodic checking of renal function is
recommended.69
Antibiotics
Similar to mesalamine, antibiotics have not
been shown to be effective for induction and
1093
 1094

TABLE 2. Medications, Monitoring, and Adverse Eventsa

Adverse events to be aware of
Medications Drugs Available routes Efficacy Routine testing recommended (not all inclusive)
5-Aminosalycilates Mesalamine Oral Induction and maintenance but not Cr  urinalysis Headache
Balsalazide Rectal FDA approved for Crohn disease CBC, LFTsc Nausea
Sulfasalazineb Diarrhea
Paradoxical worsening of symptoms
Interstitial nephritis
Hemolytic anemia,c leukopenia,c
hepatitisc
Corticosteroids Prednisone Oral Induction only Consider checking hemoglobin A1c Osteopenia/porosis
Budesonide Rectal and vitamin D levels Avascular necrosis
Methylprednisolone IV If prolonged steroid >3 mo: DEXA Serious infection
scan and ophthalmology Weight gain
evaluation Insomnia
Mood changes
Delirium
Cataracts
Mayo Clin Proc.

Glaucoma
Skin changes
Delayed wound healing
Adrenal insufficiency
n

Thiopurines Azathioprine Oral Maintenance TPMT enzyme activity or genetics Nausea

July 2017;92(7):1088-1103

Mercaptopurine before initiation Vomiting

CBC, LFTs Transaminitis
Skin examinations Bone marrow suppression
Yearly Pap smear in women Pancreatitis
Infection
Non-Hodgkin lymphoma
Nonmelanoma skin cancer
n

Cervical dysplasia
http://dx.doi.org/10.1016/j.mayocp.2017.04.010

Methotrexateb Methotrexate Subcutaneous or intramuscular Induction and maintenance CBC, LFTs Infection

MAYO CLINIC PROCEEDINGS

(limited efficacy of oral route) Cytopenias
Transaminitis
www.mayoclinicproceedings.org

Cirrhosis
Nausea/vomiting
Flu-like symptoms
Oral ulcers
Pulmonary toxicity
Contraindicated in pregnancy
Continued on next page
www.mayoclinicproceedings.org
Mayo Clin Proc. n July 2017;92(7):1088-1103

CROHN DISEASE: EPIDEMIOLOGY, DIAGNOSIS, AND MANAGEMENT

TABLE 2. Continued
Adverse events to be aware of
Medications Drugs Available routes Efficacy Routine testing recommended (not all inclusive)
Anti-TNF Infliximab IV Induction and maintenance Latent TB and hepatitis B before Infusion/injection- site reaction
Adalimumab Subcutaneous initiation Infection
Certolizumab pegol CBC, LFTs Non-Hodgkin lymphoma (mostly if
Skin examinations combined with a thiopurine)
HSTC-L (if combined with a
thiopurine)
Melanoma
Reactivation of latent TB and
n

hepatitis B
http://dx.doi.org/10.1016/j.mayocp.2017.04.010

Drug-induced lupus erythematosus

Demyelinating disease
Psoriasform and eczema reactions
Worsening of CHF
Adhesion molecule Natalizumab IV Induction and maintenance Natalizumab: JC virus checking Infusion reactions
inhibitors Vedolizumab before initiation and yearly Infection
monitoring for JC virus Nasopharyngeal polyps
Vedolizumab and natalizumab: PML (natalizumab only with positive
Consider CBC JC virus)
IL-12/IL-23 inhibitors Ustekinumab IV/subcutaneous Induction and maintenance Latent TB before initiation Infusion reactions
Consider CBC, LFTs Skin cancer
Reversible posterior
leukoencephalopathy
TB
a
Anti-TNF ¼ antietumor necrosis factor; CBC ¼ complete blood cell count; CHF ¼ congestive heart failure; Cr ¼ creatinine; DEXA ¼ dual energy-x-ray absorptiometry; FDA ¼ Food and Drug Administration; HSTLC ¼
hepatosplenic T-cell lymphoma; IV ¼ intravenous; JC ¼ John Cunningham; LFT ¼ liver function test; Pap ¼ papanicolaou; PML ¼ progressive multifocal leukoencephalopathy; TB ¼ tuberculosis; TPMT ¼ thiopurine
methyltransferase.
b
Patients should be given 1 g of folic acid with the medication to reduce side effects.
c
Sulfasalazine only.
1095

maintenance of remission for active CD.70 The
best data for antibiotics are in the short-term
treatment of perianal fistula and in combina-
tion with anti-TNF for perianal CD.71 Aside
from these indications, antibiotics should
really be used to treat the suppurative compli-
cations of CD.55,71 The most commonly used
agents are ciprofloxacin and metronida-
zole.55,72 The main limitations to using these
agents long-term are antibiotic resistance and
side effect profile.
Corticosteroids
Steroids are used to induce remission but are
not an effective maintenance agent.73,74 Multi-
ple steroid formulations are available
including intravenous steroids, prednisone,
and the less systemically absorbed budesonide
(enteric coated).75,76 Although budesonide is
ideal to use given its improved side effect pro-
file, its efficacy is limited to mild-moderate
ileal and right-sided colonic CD.77 Steroids
have a quick onset of action and are generally
effective at inducing remission in CD but have
no role in the maintenance of disease remis-
sion. In addition, steroids are also ineffective
in treating perianal CD.55,78 Patients treated
with systemic steroids should be transitioned
to a medication proven to maintain remission
in CD, and prolonged courses of steroids
should be avoided. Unfortunately, steroids
have numerous side effects including adrenal
insufficiency, obesity, cataracts, glaucoma, hy-
pertension, diabetes, and so forth
(Table 2).5,55,78,79 In addition, several studies
have demonstrated that systemic corticoste-
roids increase the risk of serious infection
and mortality in patients with moderate to se-
vere CD.79-81
Immunosuppressants
Thiopurines. Thiopurines (AZA and MP) are
more commonly used to maintain remission
as opposed to induction of remission.53,58,82,83
A Cochrane review of the literature found that
both AZA and MP were no better than placebo
for induction of remission or clinical
improvement in ongoing active CD.83,84 In
addition, more recent data question the overall
efficacy of earlier use of thiopurines in CD,
which may not be effective in altering the
natural history of the disease.57,59 Although
recent studies cast doubt on the overall
n n
1096 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
efficacy of thiopurines in CD, the most recent
American Gastroenterological Association
(AGA) guidelines for drug therapy in CD
include them as an option for maintaining
remission in moderate CD.53,57,59 However, in
a head-to-head trial, AZA was shown to be less
effective than infliximab monotherapy or the
combination of AZA and infliximab at main-
taining a steroid-free remission.85
Because thiopurines do not work quickly
and take approximately 6 to 12 weeks to
achieve response, steroids are typically used
to induce remission and steroids are continued
during this time to ensure that the patient will
not flare while transitioning to a thiopurine.
Importantly, before thiopurines are started,
thiopurine methyltransferase (TPMT) enzy-
matic activity should be assessed to evaluate
how the patient’s liver metabolizes the
drug.86-88 If a patient has intermediate TPMT
enzymatic activity, then the initial dose of
AZA or MP should be lower by 25% to 50%.
For the 0.3% of the population that lacks all
TPMT activity, AZA and MP should be
avoided.89 In addition, in patients younger
than 25 years, Epstein-Barr virus should be
checked and if negative then the drug should
probably be avoided given an increased risk
of hemophagocytic lymphohistiocytosis and
primary thyroid lymphoma.90,91
The use of thiopurines is limited by their
side effect profile. Around 15% to 20% of
patients discontinue the drug because of side
effects.91,92 See Table 2 for full details. Both
cytopenias and transaminitis can be seen at
any point in time and routine laboratory testing
to screen for this is recommended. These side
effects are typically related to the drug meta-
bolism, and drug metabolites can be clinically
checked in these situations.93 Other side effects
that may occur at the time of initiation include
nonspecific nausea and vomiting and an
allergy or acute pancreatitis. Thiopurines also
increase the risk of nonmelanoma skin cancers,
cervical dysplasia, lymphoma, and heptos-
plenic T-cell lymphoma.91,93,94
Methotrexate. Methotrexate can be used both
for induction of remission and for mainte-
nance of remission.83,95,96 For induction of
remission, only the subcutaneous injection
was found to be effective.96 For maintenance
of remission, MTX appears to be slightly more
July 2017;92(7):1088-1103 http://dx.doi.org/10.1016/j.mayocp.2017.04.010
www.mayoclinicproceedings.org
CROHN DISEASE: EPIDEMIOLOGY, DIAGNOSIS, AND MANAGEMENT
effective than AZA or MP.83 Onset of action is
within 8 to 16 weeks.97
Side effects are not uncommon with the
use of MTX. In one study, MTX was discontin-
ued in 17% of patients as a result of adverse
effects.95 Methotrexate is associated with a
number of nonspecific symptoms including
nausea, vomiting, headaches, and fatigue.
Similar to thiopurines, it can be hepatotoxic
and in rare cases cause myelosuppression.
Routine laboratory testing is recommended
to monitor for these potential adverse events.
Methotrexate also has an antifolate effect that
can result in anemia and stomatitis. When tak-
ing MTX, concomitant administration of daily
folic acid is recommended.97 Similar to thio-
purines, MTX appears to be associated with
an increased risk of both nonmelanoma skin
cancer and lymphoma.98,99 In addition, MTX
is contraindicated during pregnancy because
it is both an abortifacient and teratogenic.5
Anti-TNF Agents. To date, anti-TNF therapy
appears to be our most effective therapy for
moderate to severe CD and can be used alone
or in combination with an immunomodulator
to induce and maintain remission.5,33,85,100
Currently, 3 anti-TNF agents are Food and
Drug Administration (FDA) approved for
moderate to severe CD: infliximab, adalimu-
mab, and certolizumab pegol.101-103 Inflix-
imab is a chimeric anti-TNF antibody that is
administered intravenously. Adalimumab is a
fully humanized monoclonal antibody that is
administered subcutaneously by self-injec-
tion.104 Certolizumab pegol is an FaB anti-
body fragment of a humanized anti-TNF
molecule that is also self-administered subcu-
taneously. Before an anti-TNF agent can be
started, patients need to have latent tubercu-
losis and hepatitis B infection ruled out.105 If
either infection is identified, then the patient
should be referred to a specialist before start-
ing anti-TNF therapy.
There have not been any head-to-head tri-
als of anti-TNF agents, but there are some data
suggesting that infliximab is associated with
fewer hospitalizations, surgeries, and steroid
use compared with other anti-TNF agents in
CD.106 In general, patient and physician pref-
erence should decide which anti-TNF agent
is chosen. However, insurance companies
often have a preferred anti-TNF agent that
Mayo Clin Proc. n July 2017;92(7):1088-1103 n http://dx.doi.org/10.1016/j.mayocp.2017.04.010
www.mayoclinicproceedings.org
ultimately dictates which agent is used. Never-
theless, for fistulizing CD, infliximab is the
only agent with a phase 3 study demonstrating
efficacy and a specific FDA indication. This is
why many physicians consider infliximab the
preferred agent for fistulizing CD, particularly
for perianal fistulizing disease.102 Anti-TNF
agents work quickly and some response may
be seen within the first week of treatment
(eg, infliximab) but the therapeutic effect
may take up to 6 weeks.
If the patient’s disease flares while taking
an anti-TNF agent, drug concentrations and
antidrug antibodies (ADAs) can be checked
to determine whether patients require more
drug (low drug concentrations and no/low
ADAs), a switch to another anti-TNF agent
(high ADAs), or need to be switched to a
different drug class (adequate anti-TNF drug
concentrations).107 This treatment paradigm
has been shown to better direct care and is
more cost-effective than empiric dose escala-
tion.107 Furthermore, there is some evolving
evidence that proactive dose optimization
and treating to a therapeutic window may
improve outcomes and be cost-effective.107,108
Current AGA guidelines advocate for the
use of combining an anti-TNF agent with a
thiopurine or MTX.53 This combination has
been shown to increase the anti-TNF drug
concentrations while also minimizing the risk
of developing ADA.60,61 However, this combi-
nation is associated with an increased risk of
side effects including opportunistic infec-
tion.5,33 To assist in determining in whom
combination therapy is appropriate, the
BRIDGe group has developed an algorithm
that incorporates the risks and benefits of
combination therapy (http://www.bridgeibd.
com/mono-versus-combo-therapy).109
The 3 anti-TNF agents have similar safety
profiles.104 The most common side effects
are injection-site/infusion reactions and an
increased risk of infection.110,111 Although
less common than with thiopurines and
MTX, there are rare cases of cytopenias and
liver toxicity and routine laboratory testing is
recommended. Although there is a slightly
increased risk of melanoma with anti-TNF
use, the risk of other malignancies is un-
clear.112 When anti-TNF and thiopurines or
MTX are used in combination, side effects
related to both anti-TNF and thiopurine or
1097

MTX must be reviewed with the patient as
well as the increased risk of opportunistic
infection.91,100,113 In addition, there is a rare
risk of hepatosplenic T-cell lymphoma with
the combination of thiopurines and anti-
TNF.114 Although extremely rare, this risk is
greatest in male patients younger than 35 years
and after 2 years of combination therapy.33
Selective Adhesion Molecule Inhibitors.
Vedolizumab is the first gut-selective adhesion
molecule inhibitor for use in moderate to se-
vere CD.62 It is a humanized monoclonal
IgG antibody that targets the adhesion mole-
cule a4b7-heterodimer, inhibiting leukocyte
migration.115 A similar agent, natalizumab,
was the first adhesion molecule approved for
moderate to severe CD. However, natalizumab
blocks the a4 integrin, which is not gut spe-
cific, and carries a risk of PML, a viral brain
infection that results in severe disability and
death. In contrast, no cases of PML have
been reported to date with vedolizumab.62,115
Vedolizumab can be used for induction of
remission, but the onset of action is quite
slow and its efficacy is quite limited.62 Howev-
er, patients who have an initial response to
therapy will then maintain this remission at
1 year.62 An initial response is typically seen
within 12 weeks of starting the drug.62 In
addition, because vedolizumab is gut selective,
there does not appear to be an increased risk
of serious adverse events or infections other
than nasopharyngitis.62
Interleukin Inhibitor. Ustekinumab is the lat-
est drug approved for moderate to severe CD
(October 2016) though it has been FDA
approved for psoriasis since 2009. Ustekinu-
mab is a fully humanized monoclonal anti-
body to the p-40 subunit of IL-12 and IL-23.
The drug is administered as a one-time
weight-based infusion followed by subcu-
taneous injections every 8 weeks. Similar to
anti-TNF agents, before starting this drug,
patients should be tested for latent tubercu-
losis and hepatitis B. Its overall efficacy ap-
pears to be on par with anti-TNF therapy for
both induction of remission and maintenance
of remission.63,102,104,116 Ustekinumab also
seems to have a similar onset of action and
response is usually seen within 6 weeks.
Based on the trials to date in CD and the
n n
1098 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
postmarketing data for psoriasis, ustekinumab
does not appear to increase the risk of serious
infection.117 However, the studies in CD are
relatively short-term and the dose used
for psoriasis is less than the dose approved
for CD.
Surgery
Most patients with CD will undergo surgery
during the course of their disease.5,33,118 Sur-
gery is indicated in a number of situations
including stricturing CD with obstructive
symptoms, fistulizing or perianal CD with in-
fectious complications or issues related to the
drainage of the fistula, failure of medical ther-
apy, steroid dependence, dysplasia, or can-
cer.119 The exact surgical procedure depends
on the underlying indication for the surgery.
Stricturing CD. No medical therapy reverses
the fibrostenotic changes that cause strictures.
In patients who have ongoing obstructive
symptoms, surgical resection of the stricture
may be indicated.78 Because surgery is not
curative, the goal is to remove the smallest
amount of bowel possible and perform a pri-
mary anastomosis. When there are numerous
strictures, removal of all of them may not be
feasible. In these cases, the most prominent
stricture may be resected while the others may
either be dilated intraoperatively or a stric-
turoplasty may be performed.78,119
Fistulizing CD. For enteroenteric fisulae, as
long as the fistula is not causing a direct
complication, it is rarely intervened upon.
However, in cases of enterovesicular fistulae,
enterovaginal fisulae, or enterocutaneous
fistulae, bowel resection and fistulotomy are
often required.120 Also, if a sinus tract is pre-
sent and an abscess forms, then radiologic or
surgical drainage of the abscess may be
required as well.120
Perianal CD. Perianal CD can present as an
anal fissure, perianal fistula, or perirectal ab-
scess. Both perianal fistula and abscess often
require surgical intervention with drainage
and placement of a seton. Anal fissures are
typically treated medically with therapy for
CD but if they do not respond then a fissurot-
omy can be considered or in some cases botu-
linum toxin injections may also be used.72,121
July 2017;92(7):1088-1103 http://dx.doi.org/10.1016/j.mayocp.2017.04.010
www.mayoclinicproceedings.org
CROHN DISEASE: EPIDEMIOLOGY, DIAGNOSIS, AND MANAGEMENT
Postoperative Medical Therapy. Unfortu-
nately, about 50% of patients will develop a
clinical recurrence within 5 years of their sur-
gery and as many as 40% will require a second
surgery within 10 years.5,33 Ideally, drug
therapy is used to prevent this clinical recur-
rence.122 However, the overall efficacy of us-
ing pharmacologic therapy to prevent clinical
recurrence of CD following surgery is un-
clear.122,123 The most robust data are with the
use of anti-TNF therapy.124 Classically,
patients will undergo a colonoscopy 6 to 12
months after surgery to assess for endoscopic
recurrence and to perform a Rutgeerts scoring
system to predict the likelihood of clinical
recurrence in the next 1 to 5 years
(Table 3).125 However, in patients who are at
high risk of early clinical recurrence (Table 4),
some physicians opt to place patients on
immediate postoperative medication.126
Regardless, ongoing colonoscopic assessment
for recurrence is recommended.
OTHER DISEASE COMPLICATIONS
Patients with CD colitis involving at least one-
third of the colon are at an increased risk of
colon cancer and require ongoing surveil-
lance.33 If colonic disease is present, then cur-
rent guidelines from the AGA recommend
initiating screening 8 years after diagnosis.127
Surveillance colonoscopy is necessary only in
those with more than one-third of their colon
involved. This is performed every 1 to 3 years
with segmental biopsies throughout the co-
lon.127 Patients with ileal disease are also at a
significantly increased risk of small-bowel car-
cinoma, but the overall risk is still low, and no
screening is recommended.128
Quality Measures in CD and the Role of the
Primary Care Physician
Crohn disease can be associated with signifi-
cant morbidity and many patients require
pharmacologic therapy to suppress the im-
mune system to maintain disease-free remis-
sion. To minimize the risk of iatrogenic
complications, primary care physicians and
gastroenterologists need to comanage these
patients to optimize their management. In
2011, the AGA developed a list of quality mea-
sures to improve the care of patients with
IBD.105 Eight of the 10 measures focus on
Mayo Clin Proc. n July 2017;92(7):1088-1103 n http://dx.doi.org/10.1016/j.mayocp.2017.04.010
www.mayoclinicproceedings.org
TABLE 3. Rutgeerts Score Assessment125
i0 No lesions seen Low risk: 80%-85% in remission in 3 y
i1
5 aphthous ulcers Low risk: 80%-85% in remission in 3 y
i2 >5 aphthous ulcers with normal 15%-20% chance of recurrence in 3 y
mucosa between lesions or lesions
confined to ileocolonic anastomosis
that is <1 cm in length
i3 Diffuse aphthous ileitis with diffusely 40% chance of recurrence in 3 y
inflamed mucosa
i4 Diffuse inflammation with large ulcers, 90% chance of recurrence in 3 y
nodules, and/or narrowing
Adapted with permission from Gastroenterology.125
the management of outpatients with IBD. Mul-
tiple quality measures can be comanaged by
gastroenterology and primary care: screening
for tobacco abuse and counseling patients to
quit if they are smoking, yearly influenza
vaccination, pneumococcal vaccination, and
assessment for bone loss with a bone density
scan in those patients exposed to the equiva-
lent of prednisone 10 mg/d or more for
60 days or more.105 In a recent study, our
group noted that compliance with these qual-
ity measures was poor across different practice
types including academic practice, community
practice, and private practice.129 The impor-
tance of preventing iatrogenic complications
is of utmost importance when treating patients
with immunosuppressants. At our institution
we also recommend that patients be optimized
with all relevant vaccinations including
tetanus, diphtheria, acellular pertussis, human
papilloma virus, hepatitis A and B vaccination,
varicella, and zoster vaccination after age
50 years.130-133 However, live vaccines, vari-
cella and zoster, should not be administered
to those on immunosuppressive or biologic
therapies. Likewise, in our practice to further
mitigate the risk of drug-related complications,
TABLE 4. Risk Factors for Clinical Recurrence
After Surgery126
Risk factors
Stricturing or fistulizing disease
Active tobacco abuse
Prior intestinal resection (especially >50 cm)
Early age of onset of disease
Perianal disease
Adapted with permission from Alimentary Pharmacology and
Therapeutics.126
1099

patients on thiopurines, MTX, or anti-TNF
should see a dermatologist yearly given the
increased risks of skin cancer.94,98,134 Finally,
in females on a thiopurine, an yearly pap
smear is recommended given the increased
risk of cervical dysplasia.135
CONCLUSION
Crohn disease is a chronic IBD that can affect
any portion of the gastrointestinal tract. It is
typically medically managed, but a significant
percentage of patients will require surgery.
The goals of care are to induce and maintain
a steroid-free remission, decrease the risk of
complications and surgery, and also improve
the overall quality of life. To this end, patients
with CD are best comanaged with primary
care physicians to help optimize their primary
prevention and reduce their risk of complica-
tions. Being aware of the subtypes and natural
history of CD as well as the potential compli-
cations of the disease and the medication used
to treat the disease is critical to optimizing the
health care of patients with CD.
ACKNOWLEDGMENTS
Special thanks to Martin Smith, MD, for pro-
viding the computed tomography scan images
and to Robert Najarian, MD, for providing the
pathology images.
Abbreviations and Acronyms: ADA = antidrug antibody;
AGA = American Gastroenterological Association; Anti-
TNF = antietumor necrosis factor; AZA = azathioprine;
CD = Crohn disease; CTE = computed tomography enter-
ography; EIM = extraintestinal manifestation; FDA = Food
and Drug Administration; IBD = inflammatory bowel dis-
ease; MP = mercaptopurine; MRE = magnetic resonance
enterography; MTX = methotrexate; PML = progressive
multifocal leukoencephalopathy; TPMT = thiopurine meth-
yltransferase; UC = ulcerative colitis
Potential Competing Interests: Dr Cheifetz is a consultant
for Abbvie, Janssen Pharmaceuticals, Pfizer, Takeda, Sam-
sung, and Miraca Laboratories. J.D. Feuerstein reports no
competing interests.
Correspondence: Address to Joseph D. Feuerstein, MD,
110 Francis St, 8E Gastroenterology, Boston, MA 02215
(jfeuerst@bidmc.harvard.edu).
REFERENCES
1. Wilks S. Morbid appearances in the intestine of Miss Bankes.
London Med Times Gazette. 1859;2:264.
2. Loftus EV Jr, Silverstein MD, Sandborn WJ, Tremaine WJ,
Harmsen WS, Zinsmeister AR. Crohn’s disease in
n n
1100 Mayo Clin Proc. July 2017;92(7):1088-1103
MAYO CLINIC PROCEEDINGS
Olmsted County, Minnesota, 1940-1993: incidence, prev-
alence, and survival. Gastroenterology. 1998;114(6):1161-
1168.
3. Dahlhamer JM, Zammitti EP, Ward BW, Wheaton AG,
Croft JB. Prevalence of inflammatory bowel disease among
adults aged 18 yearsdUnited States, 2015. MMWR Morb
Mortal Wkly Rep. 2016;65(42):1166-1169.
4. Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence
and prevalence of the inflammatory bowel diseases with time,
based on systematic review. Gastroenterology. 2012;142(1):46-
54:e42; quiz e30.
5. Cheifetz AS. Management of active Crohn disease. JAMA.
2013;309(20):2150-2158.
6. Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med. 2011;
365(18):1713-1725.
7. Ng SC, Bernstein CN, Vatn MH, et al; Epidemiology and Nat-
ural History Task Force of the International Organization of
Inflammatory Bowel Disease (IOIBD). Geographical variability
and environmental risk factors in inflammatory bowel disease.
Gut. 2013;62(4):630-649.
8. Loftus EV Jr. Clinical epidemiology of inflammatory bowel dis-
ease: incidence, prevalence, and environmental influences.
Gastroenterology. 2004;126(6):1504-1517.
9. Kostic AD, Xavier RJ, Gevers D. The microbiome in inflamma-
tory bowel disease: current status and the future ahead.
Gastroenterology. 2014;146(6):1489-1499.
10. Gradel KO, Nielsen HL, Schønheyder HC, Ejlertsen T,
Kristensen B, Nielsen H. Increased short- and long-term
risk of inflammatory bowel disease after salmonella or
campylobacter gastroenteritis. Gastroenterology. 2009;
137(2):495-501.
11. Ananthakrishnan AN, Higuchi LM, Huang ES, et al. Aspirin,
nonsteroidal anti-inflammatory drug use, and risk for Crohn
disease and ulcerative colitis: a cohort study. Ann Intern Med.
2012;156(5):350-359.
12. García Rodríguez LA, González-Pérez A, Johansson S,
Wallander MA. Risk factors for inflammatory bowel disease
in the general population. Aliment Pharmacol Ther. 2005;
22(4):309-315.
13. Kronman MP, Zaoutis TE, Haynes K, Feng R, Coffin SE. Anti-
biotic exposure and IBD development among children: a
population-based cohort study. Pediatrics. 2012;130(4):e794-
e803.
14. Cornish JA, Tan E, Simillis C, Clark SK, Teare J, Tekkis PP. The
risk of oral contraceptives in the etiology of inflammatory
bowel disease: a meta-analysis. Am J Gastroenterol. 2008;
103(9):2394-2400.
15. Khalili H, Higuchi LM, Ananthakrishnan AN, et al. Hormone
therapy increases risk of ulcerative colitis but not Crohn’s dis-
ease. Gastroenterology. 2012;143(5):1199-1206.
16. Mahid SS, Minor KS, Soto RE, Hornung CA, Galandiuk S.
Smoking and inflammatory bowel disease: a meta-analysis.
Mayo Clin Proc. 2006;81(11):1462-1471.
17. Higuchi LM, Khalili H, Chan AT, Richter JM, Bousvaros A,
Fuchs CS. A prospective study of cigarette smoking and the
risk of inflammatory bowel disease in women. Am J Gastroen-
terol. 2012;107(9):1399-1406.
18. Kaplan GG, Jackson T, Sands BE, Frisch M, Andersson RE,
Korzenik J. The risk of developing Crohn’s disease after an ap-
pendectomy: a meta-analysis. Am J Gastroenterol. 2008;
103(11):2925-2931.
19. Amre DK, D’Souza S, Morgan K, et al. Imbalances in dietary
consumption of fatty acids, vegetables, and fruits are associ-
ated with risk for Crohn’s disease in children. Am J Gastroen-
terol. 2007;102(9):2016-2025.
20. Sakamoto N, Kono S, Wakai K, et al; Epidemiology Group of
the Research Committee on Inflammatory Bowel Disease in
Japan. Dietary risk factors for inflammatory bowel disease: a
multicenter case-control study in Japan. Inflamm Bowel Dis.
2005;11(2):154-163.
http://dx.doi.org/10.1016/j.mayocp.2017.04.010
www.mayoclinicproceedings.org
CROHN DISEASE: EPIDEMIOLOGY, DIAGNOSIS, AND MANAGEMENT
21. Hou JK, Abraham B, El-Serag H. Dietary intake and risk of
developing inflammatory bowel disease: a systematic review
of the literature. Am J Gastroenterol. 2011;106(4):563-573.
22. Halfvarson J, Bodin L, Tysk C, Lindberg E, Järnerot G. Inflam-
matory bowel disease in a Swedish twin cohort: a long-term
follow-up of concordance and clinical characteristics. Gastro-
enterology. 2003;124(7):1767-1773.
23. Yang H, McElree C, Roth MP, Shanahan F, Targan SR, Rotter JI.
Familial empirical risks for inflammatory bowel disease: differ-
ences between Jews and non-Jews. Gut. 1993;34(4):517-524.
24. Thompson NP, Driscoll R, Pounder RE, Wakefield AJ.
Genetics versus environment in inflammatory bowel disease:
results of a British twin study. BMJ. 1996;312(7023):95-96.
25. Orholm M, Binder V, Sørensen TI, Rasmussen LP, Kyvik KO.
Concordance of inflammatory bowel disease among Danish
twins: results of a nationwide study. Scand J Gastroenterol.
2000;35(10):1075-1081.
26. Hugot JP, Chamaillard M, Zouali H, et al. Association of
NOD2 leucine-rich repeat variants with susceptibility to
Crohn’s disease. Nature. 2001;411(6837):599-603.
27. Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in
NOD2 associated with susceptibility to Crohn’s disease.
Nature. 2001;411(6837):603-606.
28. Philpott DJ, Viala J. Towards an understanding of the role of
NOD2/CARD15 in the pathogenesis of Crohn’s disease.
Best Pract Res Clin Gastroenterol. 2004;18(3):555-568.
29. Wang MH, Achkar JP. Geneeenvironment interactions in
inflammatory bowel disease pathogenesis. Curr Opin Gastroen-
terol. 2015;31(4):277-282.
30. Cleynen I, Boucher G, Jostins L, et al. Inherited determinants of
Crohn’s disease and ulcerative colitis phenotypes: a genetic as-
sociation study. Lancet. 2016;387(10014):156-167.
31. Ventham NT, Kennedy NA, Nimmo ER, Satsangi J. Beyond
gene discovery in inflammatory bowel disease: the emerging
role of epigenetics. Gastroenterology. 2013;145(2):293-308.
32. Burgmann T, Clara I, Graff L, et al. The Manitoba Inflammatory
Bowel Disease Cohort Study: prolonged symptoms before
diagnosisehow much is irritable bowel syndrome? Clin Gastro-
enterol Hepatol. 2006;4(5):614-620.
33. Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. 2012;
380(9853):1590-1605.
34. Vermeire S, Van Assche G, Rutgeerts P. Laboratory markers
in IBD: useful, magic, or unnecessary toys? Gut. 2006;55(3):
426-431.
35. Vermeire S, Van Assche G, Rutgeerts P. Serum sickness,
encephalitis and other complications of anti-cytokine therapy.
Best Pract Res Clin Gastroenterol. 2009;23(1):101-112.
36. Harbord M, Annese V, Vavricka SR, et al; European Crohn’s
and Colitis Organisation. The first European evidence-based
consensus on extra-intestinal manifestations in inflammatory
bowel disease. J Crohns Colitis. 2016;10(3):239-254.
37. Williams H, Walker D, Orchard TR. Extraintestinal manifesta-
tions of inflammatory bowel disease. Curr Gastroenterol Rep.
2008;10(6):597-605.
38. Rudwaleit M, Baeten D. Ankylosing spondylitis and bowel dis-
ease. Best Pract Res Clin Rheumatol. 2006;20(3):451-471.
39. Wordsworth P. Arthritis and inflammatory bowel disease. Curr
Rheumatol Rep. 2000;2(2):87-88.
40. Ott C, Schölmerich J. Extraintestinal manifestations and com-
plications in IBD. Nat Rev Gastroenterol Hepatol. 2013;10(10):
585-595.
41. Timani S, Mutasim DF. Skin manifestations of inflammatory
bowel disease. Clin Dermatol. 2008;26(3):265-273.
42. Feuerstein JD, Tapper EB. Primary sclerosing cholangitis: an
update. OA Hepatol. 2013;1(1):6.
43. Hirschfield GM, Karlsen TH, Lindor KD, Adams DH. Primary
sclerosing cholangitis. Lancet. 2013;382(9904):1587-1599.
44. Chambers T, Morson B. The granuloma in Crohn’s disease.
Gut. 1979;20(4):269-274.
Mayo Clin Proc. n July 2017;92(7):1088-1103 n http://dx.doi.org/10.1016/j.mayocp.2017.04.010
www.mayoclinicproceedings.org
45. Heresbach D, Alexandre JL, Branger B, et al; ABERMAD
(Association Bretonne d’Etude et de Recherche sur les Mala-
dies de l’Appareil Digestif). Frequency and significance of gran-
ulomas in a cohort of incident cases of Crohn’s disease. Gut.
2005;54(2):215-222.
46. Tukey M, Pleskow D, Legnani P, Cheifetz AS, Moss AC. The
utility of capsule endoscopy in patients with suspected
Crohn’s disease. Am J Gastroenterol. 2009;104(11):2734-2739.
47. Fireman Z, Mahajna E, Broide E, et al. Diagnosing small bowel
Crohn’s disease with wireless capsule endoscopy. Gut. 2003;
52(3):390-392.
48. Cheifetz AS, Kornbluth AA, Legnani P, et al. The risk of reten-
tion of the capsule endoscope in patients with known or
suspected Crohn’s disease. Am J Gastroenterol. 2006;101(10):
2218-2222.
49. Signorelli C, Rondonotti E, Villa F, et al. Use of the Given
Patency System for the screening of patients at high risk for
capsule retention. Dig Liver Dis. 2006;38(5):326-330.
50. Dambha F, Tanner J, Carroll N. Diagnostic imaging in Crohn’s
disease: what is the new gold standard? Best Pract Res Clin Gas-
troenterol. 2014;28(3):421-436.
51. Peeters M, Joossens S, Vermeire S, Vlietinck R, Bossuyt X,
Rutgeerts P. Diagnostic value of anti-Saccharomyces cerevi-
siae and antineutrophil cytoplasmic autoantibodies in
inflammatory bowel disease. Am J Gastroenterol. 2001;
96(3):730-734.
52. Zholudev A, Zurakowski D, Young W, Leichtner A,
Bousvaros A. Serologic testing with ANCA, ASCA, and anti-
OmpC in children and young adults with Crohn’s disease
and ulcerative colitis: diagnostic value and correlation with dis-
ease phenotype. Am J Gastroenterol. 2004;99(11):2235-2241.
53. Dassopoulos T, Sultan S, Falck-Ytter YT, Inadomi JM,
Hanauer SB. American Gastroenterological Association Insti-
tute technical review on the use of thiopurines, methotrexate,
and antieTNF-a biologic drugs for the induction and mainte-
nance of remission in inflammatory Crohn’s disease. Gastroen-
terology. 2013;145(6):1464-1478:e1-e5.
54. Bernstein CN, Loftus EV Jr, Ng SC, Lakatos PL, Moum B;
Epidemiology and Natural History Task Force of the Interna-
tional Organization for the Study of Inflammatory Bowel Dis-
ease (IOIBD). Hospitalisations and surgery in Crohn’s disease.
Gut. 2012;61(4):622-629.
55. Gomollón F, Dignass A, Annese V, et al; ECCO. 3rd European
Evidence-based Consensus on the Diagnosis and Manage-
ment of Crohn’s Disease 2016, part 1: Diagnosis and Medical
Management. J Crohns Colitis. 2017;11(1):3-25.
56. Rahimi R, Nikfar S, Rezaie A, Abdollahi M. A meta-analysis of
broad-spectrum antibiotic therapy in patients with active
Crohn’s disease. Clin Ther. 2006;28(12):1983-1988.
57. Cosnes J, Bourrier A, Laharie D, et al; Groupe d’Etude Thér-
apeutique des Affections Inflammatoires du Tube Digestif
(GETAID). Early administration of azathioprine vs conven-
tional management of Crohn’s disease: a randomized
controlled trial. Gastroenterology. 2013;145(4):758-765:e2;
quiz e14-e15.
58. Chande N, Patton PH, Tsoulis DJ, Thomas BS, MacDonald JK.
Azathioprine or 6-mercaptopurine for maintenance of remis-
sion in Crohn’s disease. Cochrane Database Syst Rev. 2015:
Issue 10:Art. No. CD000067.
59. Panés J, López-SanRomán A, Bermejo F, et al; AZTEC Study
Group. Early azathioprine therapy is no more effective than
placebo for newly diagnosed Crohn’s disease. Gastroenter-
ology. 2013;145(4):766-774:e761.
60. Sandborn WJ, Colombel JF, Enns R, et al; International Efficacy
of Natalizumab as Active Crohn’s Therapy (ENACT-1) Trial
Group; Evaluation of Natalizumab as Continuous Therapy
(ENACT-2) Trial Group. Natalizumab induction and mainte-
nance therapy for Crohn’s disease. N Engl J Med. 2005;
353(18):1912-1925.
1101

61. Van Assche G, Van Ranst M, Sciot R, et al. Progressive multi-
focal leukoencephalopathy after natalizumab therapy for
Crohn’s disease. N Engl J Med. 2005;353(4):362-368.
62. Sandborn WJ, Feagan BG, Rutgeerts P, et al; GEMINI 2 Study
Group. Vedolizumab as induction and maintenance therapy
for Crohn’s disease. N Engl J Med. 2013;369(8):711-721.
63. Sandborn WJ, Gasink C, Gao LL, et al; CERTIFI Study Group.
Ustekinumab induction and maintenance therapy in refractory
Crohn’s disease. N Engl J Med. 2012;367(16):1519-1528.
64. Panaccione R, Rutgeerts P, Sandborn WJ, Feagan B,
Schreiber S, Ghosh S. Review article: treatment algorithms
to maximize remission and minimize corticosteroid depen-
dence in patients with inflammatory bowel disease. Aliment
Pharmacol Ther. 2008;28(6):674-688.
65. Lichtenstein GR, Hanauer SB, Sandborn WJ; Practice Parame-
ters Committee of American College of Gastroenterology.
Management of Crohn’s disease in adults. Am J Gastroenterol.
2009;104(2):465-483:quiz 464, 484.
66. Steinhart AH, Hemphill D, Greenberg GR. Sulfasalazine and
mesalazine for the maintenance therapy of Crohn’s disease:
a meta-analysis. Am J Gastroenterol. 1994;89(12):2116-2124.
67. Gearry RB, Ajlouni Y, Nandurkar S, Iser JH, Gibson PR.
5-Aminosalicylic acid (mesalazine) use in Crohn’s disease: a
survey of the opinions and practice of Australian gastroenter-
ologists. Inflamm Bowel Dis. 2007;13(8):1009-1015.
68. Gisbert JP, Gomollón F, Maté J, Pajares JM. Role of
5-aminosalicylic acid (5-ASA) in treatment of inflammatory
bowel disease: a systemic review. Dig Dis Sci. 2002;47(3):
471-488.
69. Cunliffe RN, Scott BB. Review article: monitoring for drug
side-effects in inflammatory bowel disease. Aliment Pharmacol
Ther. 2002;16(4):647-662.
70. Prantera C, Zannoni F, Scribano ML, et al. An antibiotic
regimen for the treatment of active Crohn’s disease: a ran-
domized, controlled clinical trial of metronidazole plus cipro-
floxacin. Am J Gastroenterol. 1996;91(2):328-332.
71. Schwartz DA, Loftus EV Jr, Tremaine WJ, et al. The natural
history of fistulizing Crohn’s disease in Olmsted County, Min-
nesota. Gastroenterology. 2002;122(4):875-880.
72. Gecse KB, Bemelman W, Kamm MA, et al; World Gastroen-
terology Organization; International Organisation for Inflam-
matory Bowel Diseases IOIBD; European Society of
Coloproctology and Robarts Clinical Trials. A global
consensus on the classification, diagnosis and multidisciplinary
treatment of perianal fistulising Crohn’s disease. Gut. 2014;
63(9):1381-1392.
73. Steinhart AH, Ewe K, Griffiths AM, Modigliani R,
Thomsen OO. Corticosteroids for maintenance of remission
in Crohn’s disease. Cochrane Database Syst Rev. 2003;(4):
CD000301.
74. Rutgeerts P. Review article: the limitations of corticosteroid
therapy in Crohn’s disease. Aliment Pharmacol Ther. 2001;
15(10):1515-1525.
75. Rutgeerts P, Löfberg R, Malchow H, et al. A comparison of
budesonide with prednisolone for active Crohn’s disease.
N Engl J Med. 1994;331(13):842-845.
76. Hanauer SB, Sandborn W. Management of Crohn’s disease in
adults. Am J Gastroenterol. 2001;96(3):635.
77. Rezaie A, Kuenzig ME, Benchimol EI, et al. Budesonide for in-
duction of remission in Crohn’s disease. Cochrane Database
Syst Rev. 2015;(6):CD000296.
78. Rieder F, Latella G, Magro F, et al. European Crohn’s and Co-
litis Organisation Topical Review on Prediction, Diagnosis and
Management of Fibrostenosing Crohn’s Disease. J Crohns Coli-
tis. 2016;10(8):873-885.
79. Akerkar GA, Peppercorn MA, Hamel MB, Parker RA. Cortico-
steroid-associated complications in elderly Crohn’s disease
patients. Am J Gastroenterol. 1997;92(3):461-464.
80. Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infec-
tions and mortality in association with therapies for Crohn’s
n n
1102 Mayo Clin Proc. July 2017;92(7):1088-1103
MAYO CLINIC PROCEEDINGS
disease: TREAT registry. Clin Gastroenterol Hepatol. 2006;
4(5):621-630.
81. Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infec-
tion and mortality in patients with Crohn’s disease: more
than 5 years of follow-up in the TREAT registry. Am J Gas-
troenterol. 2012;107(9):1409-1422.
82. Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB,
Pasternack BS. Treatment of Crohn’s disease with 6-
mercaptopurine: a long-term, randomized, double-blind study.
N Engl J Med. 1980;302(18):981-987.
83. Patel V, Wang Y, MacDonald JK, McDonald JW, Chande N.
Methotrexate for maintenance of remission in Crohn’s dis-
ease. Cochrane Database Syst Rev. 2014;(8):CD006884.
84. Chande N, Townsend CM, Parker CE, MacDonald JK. Azathi-
oprine or 6-mercaptopurine for induction of remission in
Crohn’s disease. Cochrane Database Syst Rev. 2016;(10):
CD000545.
85. Colombel JF, Sandborn WJ, Reinisch W, et al; SONIC Study
Group. Infliximab, azathioprine, or combination therapy for
Crohn’s disease. N Engl J Med. 2010;362(15):1383-1395.
86. Swaminath A, Kornbluth A. Optimizing drug therapy in inflam-
matory bowel disease. Curr Gastroenterol Rep. 2007;9(6):513-
520.
87. Black AJ, McLeod HL, Capell HA, et al. Thiopurine methyl-
transferase genotype predicts therapy-limiting severe toxicity
from azathioprine. Ann Intern Med. 1998;129(9):716-718.
88. Lichtenstein GR. Use of laboratory testing to guide 6-mercap-
topurine/azathioprine therapy. Gastroenterology. 2004;127(5):
1558-1564.
89. Dewit O, Starkel P, Roblin X. Thiopurine metabolism moni-
toring: implications in inflammatory bowel diseases. Eur J Clin
Invest. 2010;40(11):1037-1047.
90. Beaugerie L, Brousse N, Bouvier AM, et al; CESAME Study
Group. Lymphoproliferative disorders in patients receiving
thiopurines for inflammatory bowel disease: a prospective
observational cohort study. Lancet. 2009;374(9701):1617-
1625.
91. Smith MA, Irving PM, Marinaki AM, Sanderson JD. Review
article: malignancy on thiopurine treatment with special refer-
ence to inflammatory bowel disease. Aliment Pharmacol Ther.
2010;32(2):119-130.
92. Qiu Y, Mao R, Zhang SH, et al. Safety profile of thiopurines in
Crohn disease: analysis of 893 patient-years follow-up in a
Southern China cohort. Medicine (Baltimore). 2015;94(41):
e1513.
93. Gilissen LP, Wong DR, Engels LG, et al. Therapeutic drug
monitoring of thiopurine metabolites in adult thiopurine
tolerant IBD patients on maintenance therapy. J Crohns Colitis.
2012;6(6):698-707.
94. Setshedi M, Epstein D, Winter TA, Myer L, Watermeyer G,
Hift R. Use of thiopurines in the treatment of inflammatory
bowel disease is associated with an increased risk of non-
melanoma skin cancer in an at-risk population: a cohort study.
J Gastroenterol Hepatol. 2012;27(2):385-389.
95. Feagan BG, Fedorak RN, Irvine EJ, et al. A comparison of
methotrexate with placebo for the maintenance of remission
in Crohn’s disease. North American Crohn’s Study Group In-
vestigators. N Engl J Med. 2000;342(22):1627-1632.
96. McDonald JWD, Wang Y, Tsoulis DJ, MacDonald JK,
Feagan BG. Methotrexate for induction of remission in refrac-
tory Crohn’s disease. Cochrane Database Syst Rev. 2014;(8):
CD003459.
97. Feldman PA, Wolfson D, Barkin JS. Medical management of
Crohn’s disease. Clin Colon Rectal Surg. 2007;20(4):269-281.
98. Long MD, Herfarth HH, Pipkin CA, Porter CQ, Sandler RS,
Kappelman MD. Increased risk for non-melanoma skin cancer
in patients with inflammatory bowel disease. Clin Gastroenterol
Hepatol. 2010;8(3):268-274.
99. Whitmore SE. Methotrexate and risk for lymphoma. Arch Der-
matol. 2007;143(5):663-664.
http://dx.doi.org/10.1016/j.mayocp.2017.04.010
www.mayoclinicproceedings.org
CROHN DISEASE: EPIDEMIOLOGY, DIAGNOSIS, AND MANAGEMENT
100. Dulai PS, Siegel CA, Colombel JF, Sandborn WJ, Peyrin-
Biroulet L. Systematic review: monotherapy with antitumour
necrosis factor a agents versus combination therapy with an
immunosuppressive for IBD. Gut. 2014;63(12):1843-1853.
101. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human antietumor
necrosis factor monoclonal antibody (adalimumab) in Crohn’s
disease: the CLASSIC-I trial. Gastroenterology. 2006;130(2):323-
333:quiz 591.
102. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the
treatment of fistulas in patients with Crohn’s disease. N Engl
J Med. 1999;340(18):1398-1405.
103. Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol
for the treatment of Crohn’s disease. N Engl J Med. 2007;
357(3):228-238.
104. Nielsen OH, Ainsworth MA. Tumor necrosis factor inhibitors
for inflammatory bowel disease. N Engl J Med. 2013;369(8):
754-762.
105. American Gastroenterological Association. Adult Inflam-
matory Bowel Disease Physician Performance Measures Set.
Vol 20132011. http://www.gastro.org/practice/quality-initiatives/
IBD_Measures.pdf. Accessed February 1, 2017.
106. Singh S, Heien HC, Sangaralingham LR, et al. Comparative
effectiveness and safety of anti-tumor necrosis factor agents
in biologic-naive patients with Crohn’s disease. Clin Gastroen-
terol Hepatol. 2016;14(8):1120-1129:e1126.
107. Velayos FS, Kahn JG, Sandborn WJ, Feagan BG. A test-based
strategy is more cost effective than empiric dose escalation
for patients with Crohn’s disease who lose responsiveness
to infliximab. Clin Gastroenterol Hepatol. 2013;11(6):654-666.
108. Vaughn BP, Martinez-Vazquez M, Patwardhan VR, Moss AC,
Sandborn WJ, Cheifetz AS. Proactive therapeutic concentration
monitoring of infliximab may improve outcomes for patients
with inflammatory bowel disease: results from a pilot observa-
tional study. Inflamm Bowel Dis. 2014;20(11):1996-2003.
109. Melmed GY, Spiegel BM, Bressler B, et al. The appropriateness
of concomitant immunomodulators with antietumor necrosis
factor agents for Crohn’s disease: one size does not fit all. Clin
Gastroenterol Hepatol. 2010;8(8):655-659.
110. Cheifetz A, Smedley M, Martin S, et al. The incidence and
management of infusion reactions to infliximab: a large center
experience. Am J Gastroenterol. 2003;98(6):1315-1324.
111. Feuerstein JD, Cullen G, Cheifetz AS. Immune-mediated reac-
tions to anti-tumor necrosis factors in inflammatory bowel
disease. Inflamm Bowel Dis. 2015;21(5):1176-1186.
112. Targownik LE, Bernstein CN. Infectious and malignant compli-
cations of TNF inhibitor therapy in IBD. Am J Gastroenterol.
2013;108(12):1835-1842:quiz 1843.
113. Dulai PS, Siegel CA, Peyrin-Biroulet L. Antietumor necrosis
factor-a monotherapy versus combination therapy with an
immunomodulator in IBD. Gastroenterol Clin North Am.
2014;43(3):441-456.
114. Kotlyar DS, Osterman MT, Diamond RH, et al. A systematic
review of factors that contribute to hepatosplenic T-cell lym-
phoma in patients with inflammatory bowel disease. Clin Gas-
troenterol Hepatol. 2011;9(1):36-41:e31.
115. Cominelli F. Inhibition of leukocyte trafficking in inflammatory
bowel disease. N Engl J Med. 2013;369(8):775-776.
116. Sandborn WJ, Feagan BG, Fedorak RN, et al; Ustekinumab
Crohn’s Disease Study Group. A randomized trial of usteki-
numab, a human interleukin-12/23 monoclonal antibody,
in patients with moderate-to-severe Crohn’s disease.
Gastroenterology. 2008;135(4):1130-1141.
117. Papp K, Gottlieb AB, Naldi L, et al. Safety surveillance for uste-
kinumab and other psoriasis treatments from the Psoriasis
Longitudinal Assessment and Registry (PSOLAR). J Drugs Der-
matol. 2015;14(7):706-714.
Mayo Clin Proc. n July 2017;92(7):1088-1103 n http://dx.doi.org/10.1016/j.mayocp.2017.04.010
www.mayoclinicproceedings.org
118. Frolkis AD, Dykeman J, Negrón ME, et al. Risk of surgery for
inflammatory bowel diseases has decreased over time: a sys-
tematic review and meta-analysis of population-based studies.
Gastroenterology. 2013;145(5):996-1006.
119. Yamamoto T, Watanabe T. Surgery for luminal Crohn’s dis-
ease. World J Gastroenterol. 2014;20(1):78-90.
120. Gionchetti P, Dignass A, Danese S, et al. 3. EUROPEAN
Evidence-based consensus on the diagnosis and management
of Crohn’s disease 2016, part 2: surgical management and spe-
cial situations. J Crohns Colitis. 2017;11(2):135-149.
121. Schwartz DA, Ghazi LJ, Regueiro M. Guidelines for
medical treatment of Crohn’s perianal fistulas: critical
evaluation of therapeutic trials. Inflamm Bowel Dis. 2015;
21(4):737-752.
122. Regueiro M, Velayos F, Greer JB, et al. American Gastroenter-
ological Association technical review on the management of
Crohn’s disease after surgical resection. Gastroenterology.
2017;152(1):277-295:e3.
123. De Cruz P, Kamm MA, Hamilton AL, et al. Crohn’s disease
management after intestinal resection: a randomised trial. Lan-
cet. 2015;385(9976):1406-1417.
124. Herfarth HH. Antietumor necrosis factor therapy to prevent
Crohn’s disease recurrence after surgery. Clin Gastroenterol
Hepatol. 2014;12(9):1503-1506.
125. Rutgeerts P, Geboes K, Vantrappen G, Beyls J, Kerremans R,
Hiele M. Predictability of the postoperative course of Crohn’s
disease. Gastroenterology. 1990;99(4):956-963.
126. Buisson A, Chevaux JB, Allen PB, Bommelaer G, Peyrin-
Biroulet L. Review article: the natural history of postoperative
Crohn’s disease recurrence. Aliment Pharmacol Ther. 2012;
35(6):625-633.
127. Farraye FA, Odze RD, Eaden J, et al; AGA Institute Medical
Position Panel on Diagnosis and Management of Colorectal
Neoplasia in Inflammatory Bowel Disease. AGA medical
position statement on the diagnosis and management
of colorectal neoplasia in inflammatory bowel disease.
Gastroenterology. 2010;138(2):738-745.
128. Jess T, Gamborg M, Matzen P, Munkholm P, Sørensen TI.
Increased risk of intestinal cancer in Crohn’s disease: a meta-
analysis of population-based cohort studies. Am J Gastroenterol.
2005;100(12):2724-2729.
129. Feuerstein JD, Castillo NE, Siddique SS, et al. Poor documen-
tation of inflammatory bowel disease quality measures in aca-
demic, community, and private practice. Clin Gastroenterol
Hepatol. 2016;14(3):421-428:e422.
130. Wasan SK, Calderwood AH, Long MD, Kappelman MD,
Sandler RS, Farraye FA. Immunization rates and vaccine be-
liefs among patients with inflammatory bowel disease: an
opportunity for improvement. Inflamm Bowel Dis. 2014;
20(2):246-250.
131. Boroujerdi-Rad L, Melmed GY. Vaccination considerations for
patients with inflammatory bowel disease. Pract Gastroenterol.
2011:33-40.
132. Wasan SK, Coukos JA, Farraye FA. Vaccinating the inflamma-
tory bowel disease patient: deficiencies in gastroenterologists
knowledge. Inflamm Bowel Dis. 2011;17(12):2536-2540.
133. Wasan SK, Baker SE, Skolnik PR, Farraye FA. A practical guide
to vaccinating the inflammatory bowel disease patient. Am J
Gastroenterol. 2010;105(6):1231-1238.
134. Long MD, Martin CF, Pipkin CA, Herfarth HH, Sandler RS,
Kappelman MD. Risk of melanoma and nonmelanoma skin
cancer among patients with inflammatory bowel disease.
Gastroenterology. 2012;143(2):390-399:e391.
135. Farraye FA, Melmed GY, Lichtenstein GR, Kane SV. ACG
Clinical Guideline: Preventive Care in Inflammatory Bowel
Disease. Am J Gastroenterol. 2017;112(2):241-258.
1103