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05/14
2014 Decker Intellectual Properties Inc
gastrointestinal tract and abdomen
I N F L A M M A T O R Y B O W E L D I S E A S E
Tara M. Connelly, MB, BCh, MSc, Andrew Tinsley, MD, MS, and
Walter A. Koltun, MD, FACS, FASCRS
Historical Perspective
Although fi rst offi cially described as regional ileitis by
Burrill B. Crohn, Leon Ginzburg, and Gordon Oppenheimer in a case
series presented at the American Medical Associa-tion annual
meeting in 1932,1 reports of what was likely Crohn disease (CD)
have been noted as early as 1769, when Morgagni described the
autopsy fi ndings of a 20-year-old who, throughout his life, had
frequent bloody bowel move-ments and abdominal pain [see Figure
1].2 In 1923, the term nonspecifi c granulomata of the intestines
was used in the American Journal of Medicine by the pathologist
Moschowitz and his colleagues from Mount Sinai to describe what was
likely intestinal tissue from CD patients.3 The term Crohns disease
was fi rst offi cially used in the United States in 1933 by F.I.
Harris in the article entitled Chronic Cicatrizing Enteritis of the
Ileum: Regional Ileitis (Crohn).4 Initially, the disease was
believed to be confi ned to the ileum until, in
1934, R. Colp reported on a case in which infl ammation was
found in the terminal ileum, cecum and transverse colon, the fi rst
reported case of ileocolitis.5 Around the same time, the fi rst
recorded incidences of CD and the other main form of infl ammatory
bowel disease (IBD), ulcerative colitis (UC), were taken in
Rochester, Minnesota, in 1934. The rates of UC and CD were noted as
6 and 1.9 per 100,000, respectively.6 Prior to that date, no
incidence or prevalence fi gures were available. Awareness of IBD
was raised when, in 1956, the American president Dwight Eisenhower
underwent emergency surgery for intestinal obstruction secondary to
CD.7
UC was probably fi rst described by Wilks in 1859, in his
article entitled Morbid Appearances in the Intestines of Miss
Bankes.8 However, despite being recognized as two distinct
diseases, CD and UC were frequently considered one disease and/or
confused for each other until in 1952 the
Figure 1 Timeline of important dates in the history of infl
ammatory bowel disease, including the discovery and refi nement of
disease pheno-types, advent of medical treatments, and genomic
discoveries. ACTH = adrenocorticotropic hormone; 5-ASA =
5-aminosalicylic acid; CD = Crohn disease; IBD = infl ammatory
bowel disease; IPAA = ileal pouch-anal anastomosis; 6-MP =
6-mercaptopurine; TNF = tumor necrosis factor; UC = ulcerative
colitis.
1932Burrill B. Crohn andcolleagues present a caseseries of 14
patients withregional ileitis to theAmerican Medical Association at
their annualmeeting
1769 Morgagnidescribesautopsyfindingsof a 20-year-oldwholikely
hadIBD
1923Nonspecificgranulomataof the intestines isdescribed inthe Am
J of Med byMoschowitzet al
1859 Wilks 1st refers to UCby name inMorbid Appearancesin
theIntestines ofMiss Bankes
1933The termCrohnsdisease is1st usedin the USby F.I.Harris
inthearticleChronicCicatrizingEnteritisof
theIleum:RegionalIleitis(Crohn)
1945 GarlockandCrohnscriticalappraisal ofCD surgerypublishedin
JAMA
1952- CharlesWells(Liverpool)publisheson
thedifferentiationbetweenUC and CD- Brook
orspoutileostomydeveloped
1981Lee and Papianno appliedstrictureplasty techniquesto CD
based on the work ofIndian surgeons managingtuberculous
strictures
1996Ludwig KAet alpublish
onpreliminaryexperiencewithlaparoscopicsurgery for CD
1956PresidentEisenhowerundergoesemergency CD-relatedsurgery
1934- 1strecordedincidencesof UC andCD(Rochester,MN)- R Colp(Mt.
Sinai)1st reportsileocolitisin CD
1940 Sulfasalazinecreated byKarolinskabiochemists inSweden
1977Kahn andTruelovereport ontheadvantagesof
5-ASAcomponentofsulfasalzine
1962Bean uses 6-MP in thetreatment of IBD
1951Kirsner andPalmer report on theeffect ofACTHin chronicUC
1944 Strauss and Straussperform aproctocolectomywith end
ileostomyfor UC. Prior to this,ostomy andirrigation of thecolon
were thesurgical treatmentof choice.
1978Parkes andNichollsperform 1stIPAA in humans
1993 Dutchreport of12-year-oldgirl withmedicallyrefractoryCD
treatedwith anti-TNFs
1959/1960Brooke andLockart-Mummeryand Morsonmanuscripts provide
aframework forthe creation ofdiagnosticcriteria todistinguishCD vs
UC
2001 NOD2associationwith IBD
2003 HumanGenome Project
2007 The WellcomeTrust Case ControlConsortiumidentifies
novelloci asassociated withIBD (among 7studied diseases)
2005InternationalHaplotypeMap(HapMap)Project
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gastro infl ammatory bowel disease 2
tend to involve chronic bleeding and a toxic colitis picture
characterized by an atonic ahaustral colon, associated with fever
and an elevated white blood cell count (WBC).
The extent and location of disease in both UC and CD are
variable and can change within an individual patient with time,
particularly in the pediatric population and earlier in the disease
course of adults with IBD. Extension of disease from less than
pancolitis to pancolitis within 2 years has been documented in 39%
of pediatric CD cases and 46% of pediatric UC cases. Progression
from infl ammatory to stric-turing or penetrating disease within 4
years of diagnosis is seen in approximately 25% of pediatric
patients, and the incidence of perianal disease increases with time
(from 14 to 22% after 4 years of disease duration).13
histologic features
On microscopic examination, noncaseating granulomas (found in
< 50% of patients), focal crypt abscesses, and mononuclear cell
infi ltrate with or without the presence of neuronal hyperplasia
can be found in CD [see Figure 4]. However, granulomas are not
present in UC. Instead, tissue from UC patients is characterized by
goblet cell depletion, neutrophils in the lamina propria, and
diffuse crypt abscess with frequent crypt branching refl ecting
chronic disease [see Figure 5].
Symptoms
The overlapping and distinct symptoms of CD and UC are presented
in Table 2 [see Table 2].
Both CD and UC typically present with abdominal pain and
diarrhea. In CD, the abdominal pain tends to be more intermittent
in nature and symptoms relate to the site of dis-ease, with colitis
causing bloody diarrhea and small bowel or ileocolonic disease
leading to colicky pain with bloating and/or diarrhea. With UC,
pain often occurs on defecation because proctitis is usually
present. Bloody stools can be present in both diseases but are more
commonly found in UC, as is the presence of mucousy stools.
Systemic symp-toms such as weight loss, fever, and malaise are
present in both diseases but are slightly more common in CD.
Lastly, both diseases can be found with or without the presence of
extraintestinal manifestations such as skin lesions (erythema
nodosum, pyoderma gangrenosum), arthropathy, osteope-nia, and
primary sclerosing cholangitis (PSC, which is more common in UC)
and ophthalmologic manifestations such as uveitis, iritis, and
episcleritis. However, aphthous mouth
Liverpudlian surgeon Charles Wells fi rst formally
differenti-ated UC from CD.9 This was followed by hallmark articles
by Brooke and Lockhart-Mummery and Morson, written in 1959 and
1960, respectively, which provided a framework for the creation of
diagnostic criteria to distinguish the two diseases.10,11
Lockhart-Mummery and Morsons timeless description is still useful
when differentiating CD from UC: The distribution of the lymphoid
hyperplasia, oedema, and fi brosis, together with the appearance of
the mucosal ulcer-ation and the formation of deep fi ssures in the
bowel wall, make up a histological picture which can be diagnostic
of Crohns disease even in the absence of giant-cell systems.11
Disease Features
macroscopic features
CD and UC have distinct yet overlapping clinical and pathologic
features [see Table 1, Figure 2, and Figure 3]. The most
characteristic feature of CD is skiplike infl ammation involving
all layers of the gut wall, which may be found anywhere along the
alimentary tract, from the mouth to the anus. However, the disease
is most commonly distributed in the ileocolic region (approximately
60% of all patients), followed by the small bowel and colon
(approximately 15 to 20 and 30 to 35% of patients, respectively).
Isolated anal or upper gastrointestinal involvement is seen in less
than 4% of patients.12 In comparison, UC is characterized by
continuous mucosal infl ammation limited to the colon, most often
beginning in the rectum and progressing proximally. The infl
ammation of CD may be deeply ulcerating, leading to fi stulous
connections between the affected intestine and other parts of the
large or small bowel, skin, and/or adjacent viscera, as well as
strictures and/or abscesses. Ulcers are often described as if
gouged by a bear claw in appearance. Islands of normal tissue are
found between the ulcerations. Conversely, UC colonic tissue is
edematous and friable and bleeds easily on contact, and the infl
ammation is continu-ous. Areas of burnt-out colitis or chronic infl
ammation without bleeding or oozing may be seen on colonoscopy,
however. Pseudopolyps or areas of unaffected mucosa between areas
of infl ammation that give the false appear-ance of polyps are seen
in both diseases, although in UC, pseudopolyps are seen only in the
presence of severe disease. Due to these different macroscopic
features of the disease, CD emergencies tend to be obstructive in
nature secondary to strictures or due to an exsanguinating acute
hemorrhage when a large vessel is eroded. UC emergencies
Table 1 Gross and Microscopic Histologic Features of Crohn
Disease and Ulcerative ColitisAppearance Crohn Disease Ulcerative
Colitis
Gross appearance Aphthous ulcers/skip lesionsDeep bear claw
ulcerationsIslands of normal tissueFistulas, abscesses,
stricturesTransmural disease
Pancolonic inflammationLoss of vascular markings Friable mucosa
with easy bleeding on contactMucosal disease with normal
serosaEdematous mucosa
Microscopic appearance Occasional, focal crypt
abscessesGranulomas Mononuclear cell infiltrateNeuronal
hyperplasia
Uniform crypt abscessesGoblet cell depletionNeutrophils in
lamina propriaBranching crypts
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a b
c
Figure 2 Gross Crohn disease (CD) pathologic specimens. (a)
Intra-operative image of stricturing small bowel CD. Multiple
strictures cause the sausage-link appearance of small bowel CD.
Also depicted is creeping fat characteristic of CD. (b) Resected
strictured small bowel demonstrating mural thickening and
ulceration. (c) Ileocolic resection specimen. Loss of architecture,
severe ulcerations, and pseu-dopolyps are seen in the affected
tissue (red arrow). Normal mucosa distal and proximal to the
stricture in the terminal ileum and cecum are highlighted by black
arrows.
Figure 3 Gross ulcerative colitis (UC) colectomy specimens. (a)
Acute and chronic infl ammation. The acutely infl amed tissue
demonstrates ulceration and hemorrhage. The chronically infl amed
tissue demonstrates widespread loss of mucosal folds and colonic
architecture with dulling of the mucosa. (b) A resected colon from
an acute UC fl are. Hemorrhage, ulceration, and pseudopolyps, which
can at times be confused with Crohn colitis, are demonstrated.
ab
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gastro infl ammatory bowel disease 4
Figure 4 Histologic slides of Crohn disease (CD)-affected
colonic tissue. (a) This portion of the colonic mucosa has a
broad-based ulcer with granulation tissue (large blue arrow) (40
original magnifi cation). The retained colonic mucosa adjacent to
the ulcer retains nearly normal crypt architecture (red arrow),
supporting the impression of skipped infl ammation. (b) CD section
demonstrating a noncaseating granuloma in the mucosa (black arrow)
(200 original magnifi cation).
Figure 5 Histologic slides of ulcerative colitisaffected colonic
tissue. (a) The low-power photomicrograph demonstrates infl
ammation that is confi ned to the mucosa (20 original magnifi
cation). (b) Photomicrograph demonstrating mild crypt branching,
increased chronic lamina propria infl ammation and several crypt
abscesses (stars), and a focus of cryptitis (blue arrow and insert)
(400 original magnifi cation).
ulcers, dysphagia secondary to upper gastrointestinal
ulcer-ation, and anal disease in the form of fi stulas, abscesses,
fi ssures, and/or waxy skin tags are exclusive to CD.
Indeterminate Colitis
Despite the presence of characteristic features in the majority
of patients, approximately 5 to 15% of colitis cases have
overlapping features that make the differentiation between UC and
CD uncertain; then the term indeterminate colitis is used.14,15
Patients with rectal-sparing colitis or diffuse superfi cial
colitis with granuloma, which in UC may be due to foreign body infi
ltration, are examples of
indeterminate colitis. Classically, this term was used only
after a total abdominal colectomy had been performed. However,
presently, it is commonly used preoperatively because of its ramifi
cations for patients desirous of an ileal pouch-anal anastomosis
(IPAA). It is unclear if such patients represent occult CD or a
distinct entity separate from CD and UC. Such patients are more
likely to develop complica-tions such as anal disease and
ulceration or stricturing of their pouches post-IPAA.16 Thus,
surgical decision making is often diffi cult in these patients.
Every effort should be made to fully characterize such patients
before a defi nitive decision regarding pouch reconstruction is
made.
a b
a b
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Epidemiology
IBD is a relatively common disease, with UC affecting
approximately 500 per 100,000 people in Europe and 250 per 100,000
in North America. CD has a prevalence of approxi-mately 320 per
100,000 in both geographic locations.17 The Centers for Disease
Control and Prevention estimates that up to 1.4 million Americans
are currently living with IBD.18 Up to 10% of these patients are
under the age of 18,18 and approximately 25% of all worldwide IBD
is diagnosed in childhood.19 The majority of CD patients are
diagnosed in their 20s, whereas those with UC are most commonly
diag-nosed in their 30s. A second peak for the diagnosis of both
diseases has been suggested in the 60s and 70s. However, this
second peak may be due to misdiagnosis of other non-IBD colidites,
such as diverticulitis, ischemic colitis, or Clostridium diffi cile
colitis.20
The overall incidence of IBD is increasing, with the rate of CD
climbing faster than that of UC.17 UC is more common than CD in
adults; however, the opposite is seen in child-hood IBD.21 IBD is
more prevalent in urban areas, among higher socioeconomic
populations, and in more industrial-ized countries. It is also more
common in geographic regions further away from the equator, for
reasons unknown.2226 Although disease rates are far lower in less
industrialized areas such as Africa and Asia,17 incidence in these
previ-ously low IBD risk geographic locations is rising but at a
lesser rate than in geographic areas where IBD is more common.27,28
Additionally, specifi c ethnic groups manifest increased risk of
the development of IBD, with individuals of western European decent
demonstrating higher rates than Eastern Europeans, Africans, and
Asians, regardless of geographic location. Individuals of Jewish
descent have a particularly high prevalence, with documented rates
of IBD at least two to four times greater than those of any other
ethnic group irrespective of geographic location,24 with
individuals of Ashkenazi descent having the highest risk of all
Jewish groups.24,29
Diagnostic Testing
The diagnosis of IBD is made using clinical, radiographic,
pathologic, and endoscopic criteria. In the known IBD patient, such
testing may be routinely used to reassess disease severity,
recurrence, or response to therapy [see Treating to Target, below].
A panel of serum, radiographic, and endoscopic tests is frequently
required in most IBD patients, and the concept of staging the
illness, much as one might do for a cancer patient, is employed,
especially prior to surgery. Serum tests include the following:
Complete blood count. Assess hemoglobin and hematocrit for
microcytic anemia from blood loss or macrocytic anemia from vitamin
B12 defi ciency. An elevated WBC may refl ect stress, infection,
and/or dehydration.
Liver function tests. Aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) are elevated in PSC, bilirubin is
elevated if PSC is advanced, and albumin is used to assess
nutritional status.
Infl ammatory markers. C-reactive protein (CRP) is more commonly
elevated in CD and erythrocyte sedimentation rate (ESR) is more
commonly elevated in UC.
Vitamin B12 levels. In CD, particularly in small bowel dis-ease
and in patients with a history of ileal or ileocecal resection,
vitamin B12 levels may be below normal.
Serum antibodies. Perinuclear antineutrophil cytoplasmic
antibody (p-ANCA, more commonly elevated in UC) and
antiSaccharomyces cerevisiae antibodies (ASCA; more commonly
elevated in CD) can be used as an adjunct to distinguish UC from
CD.30
Radiographic examinations include the following:
CT enterography. Evaluate small bowel disease in known or
suspected CD using thin computed tomographic (CT) slices with
intravenous (IV) and oral contrast agents (such as water,
lactulose, polyethylene glycol) to expand the small bowel to assist
in visualization of the intestinal wall.
Table 2 Symptoms of Crohn Disease and Ulcerative ColitisSymptoms
Crohn Disease Ulcerative Colitis
Bowel symptoms Intermittent abdominal pain and crampingDiarrhea
blood
Increased stool frequencyBloody stoolsTenesmusUrge
incontinenceMucus per rectumAbdominal pain with defecation
Systemic symptoms Weight lossFeverBloatingPostprandial
nausea
All less common than CDWeight loss Fever
Other disease manifestations
Mouth aphthous ulcersDysphagia secondary to esophageal
ulcersAnal disease (fistula, abscess, fissures, waxy skin tags)Skin
manifestations (erythema nodosum, pyoderma
gangrenosum)OsteopeniaArthropathiesPrimary sclerosing
cholangitis (less common than UC)
OsteopeniaArthropathiesSkin manifestations (less common than in
CD:
erythema nodosum, pyoderma gangrenosum)Primary sclerosing
cholangitis Ophthalmologic manifestations: uveitis, iritis,
episcleritis (more common in UC than in CD)
CD = Crohn disease; UC = ulcerative colitis.
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gastro infl ammatory bowel disease 6
Magnetic resonance enterography. Similarly uses oral contrast
and gadolinium IV contrast to evaluate small bowel disease in known
or suspected CD; commonly used in younger patients to avoid
long-term or repetitive exposure to radiation. It is also used in
pregnancy.
Small bowel follow-through. For the evaluation of small bowel
disease in known or suspected CD using serial x-rays taken after
ingestion of an oral contrast agent (i.e., barium, Gastrograffi n).
Less detail is seen than in CT or magnetic resonance enterography
due to less distention of the bowel with contrast. However, x-ray
exposure is comparatively reduced.
CT of the abdomen and/or magnetic resonance imaging (MRI). These
modalities may be used to evaluate stricturing disease, fi stulas,
and abscesses. MRI is commonly used to evaluate severe perianal CD
and to detect the presence of occult fi stulous disease. Both
modalities are commonly used when severe stricturing CD precludes
endoscopy for evaluation of the colon.
Plain fi lm of the abdomen. This does not have a role in
diagnosis. However, it is indicated if obstruction or toxic colitis
is suspected and can show free air associated with perforation.
White blood cell scan. This is not commonly used due to limited
availability and risks inherent in the use of tech-nicium. However,
radiolabeled white blood cells can be used to identify the source
of infection or infl ammation, even in subclinical disease,
particularly in CD. White blood cell scanning has also been
suggested for use in the monitoring of treatment response.31
Endoscopic tests include the following:
Upper gastrointestinal endoscopy. This is used in CD to evaluate
for upper gastrointestinal disease.
Colonoscopy (with biopsy). Colonoscopy with biopsy is the gold
standard for the diagnosis and monitoring of IBD as biopsy is
required for a defi nitive diagnosis of UC versus CD in colitis.
Due to the high rates and younger age at onset of colorectal cancer
(CRC) with an increased risk of both synchronous and metachronous
neoplasia dem-onstrated in the IBD population, routine colonoscopic
surveillance is crucial in IBD colitic patients. New tech-niques
such as chromoendoscopy, which combines the application of an
absorptive blue dye with traditional colonoscopy, have increased
diagnostic yield. Chromoen-doscopy provides a three- to fourfold
increase in the detection of lesions (particularly diffi cult to
detect fl at lesions), with far fewer but targeted biopsies
compared with traditional colonoscopy due to the ability to
visually differentiate between neoplastic and nonneoplastic lesions
using pit pattern recognition.3235
Less accurate and less commonly used than chromoen-doscopy,
narrow-band imaging uses blue and green wavelengths to enhance
mucosal visualization without the application of dyes, and confocal
light endoscopy uses a miniature confocal scanner or probes in the
endo-scope to improve visual resolution and provide real-time
histology of the mucosal layer at a cellular level during
endoscopy. I-scan, a method of graphically enhancing endoscopy
images using specialized software, can decrease colonoscopy time
and increase yield without the
use of dyes but is not in large-scale use at this time.
Colonoscopy should be performed with caution in severe disease,
particularly in stricturing CD and fulminant coli-tis.
Sigmoidoscopy or proctoscopy may be appropriate for evaluation of
distal UC; however, full colonoscopy is still required for the
surveillance of CRC.
Enteroscopy. Balloon enteroscopy has essentially replaced push
enteroscopy. Balloon enteroscopy uses a fl exible endoscope with
overtubes with a balloon at each of their ends. A push-and-pull
technique is used while infl ating and defl ating the balloons to
visualize the entire small bowel in up to 40% of patients and over
150 cm past the ligament of Treitz in the majority of patients.
When used in conjuction with spiral enteroscopy (which uses an
overtube with helical spirals at the end, which is rotated to
improve visualization), the entire small bowel is seen in up to 75%
of patients.36
Capsule endoscopy. This may be used for the evaluation of small
bowel involvement in CD. The patient ingests a small coated camera
that relays images to a media source. The main advantage of capsule
endoscopy is in visualiza-tion of the entire small intestine.
However, biopsies cannot be taken and all mucosa is not fully
visualized.37 Additionally, unlike enteroscopy, the capsule moves
distally with peristalsis and cannot be directed toward areas of
interest. This mode of investigation should be used with caution in
stricturing disease as, infrequently, the camera may become
impacted by the presence of a stricture, necessitating surgical
extraction. If stricture is suspected, a dissolvable patency pill
is administered prior to capsule endoscopy to determine if the
capsule will subsequently pass through the intestine.
Etiology
Because of IBDs propensity to affect multiple family members, at
one time, it was thought to possibly have an infectious cause, with
Mycobacterium avium subspecies paratuberculosis (MAP) as one of the
earliest important organisms to be considered. MAP causes a CD-like
illness known as Johne disease in hoofed livestock. This hypothesis
has since been refuted,38 but other infectious organisms, including
over 20 bacteria, six viruses (including Epstein-Barr virus and
cytomegalovirus), and at least two yeasts have been documented by
patient survey, serum antibodies, and/or medical records to be
associated with the develop-ment of IBD.39 Some bacteria, such as
adherent invasive Escherichia coli (AIEC), have been shown to have
a positive association, whereas Bacteroides fragilis and
Faecalibacterium prausnitzii have been correlated with protection
from the disease.4042 Additionally, commonly tested serum
antibacte-rial and antifungal antibodies are present in IBD, with
higher titers found in CD patients. Such antibodies include
anti-I2, anti-CBir, anti-OmpC, and ASCA.21 However, it is unclear
if this is due to causative infection or simply an immune response
to pathogen entry through an ulcerated and compromised intestinal
epithelium.
Host immune status is key to the development of IBD. Exposure to
a variety of commonly encountered environ-mental antigens, some
from enteric pathogens, particularly in early life, is necessary
for the development of a healthy
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gastro infl ammatory bowel disease 7
immune system. The hygiene hypothesis suggests that the lack of
exposure of the immune system to common environ-mental antigens
early in life leads to a lack of tolerance and an exaggerated
immune response later in life.27 IBD disease clustering and a
decreased IBD incidence in less urban areas supports this theory,
as does the overall failure to induce IBD-like colitis in mice kept
in germ-free environments, even if predisposing genetic mutations
in key immunologic pathways are present.43 In Western countries
where IBD rates are highest, several pathogens, including
helminths, are rarely found in the general population. Helminths
have been shown to improve infl ammation in experimental colitis in
animal models and trials administering helminths, such as the
porcine whipworm Trichurus suis, to CD patients have shown an
improvement in disease symptoms.44 However, the degree of infl
uence of such local pathogenic exposure early in childhood in an
IBD etiology model is questioned by immigration studies that have
demonstrated that indi-viduals who migrate from low-risk geographic
areas (where they would have been exposed to local pathogens as
chil-dren) to higher-risk areas nonetheless acquire an increased
risk of developing IBD near that of the native population.4548
Although the exact etiology of CD is unknown, the current
working hypothesis is that of a multifactorial patho-physiology
involving a combination of host and environ-mental factors in the
setting of a genetic predisposition rep-resented by a defect in
either the immune system or intestinal mucosal barrier function or
both.20,49,50 Because of the variability in a possible multitude of
host genetic factors combined with numerous differing potential
environmental effectors, the specifi c etiology of IBD and
resulting pheno-types may be variable among individuals [see Figure
6].
Microbiota
Recent insights have suggested a role for an individuals
intestinal microfl ora in the development of IBD, with dys-biosis
or bacterial imbalance a highly studied possible risk factor. The
role for microbiota is supported by the observa-tion of reduced
diversity of intestinal microbiota seen in IBD patients when
compared with non-IBD controls, but this may be an epiphenomenon
because IBD patients are fre-quently treated with medications that
alter bacterial pres-ence, such as antibiotics, laxatives, bowel
preparations, and steroids.5157 However, both medical and surgical
clinicians clearly recognize the improvement in IBD with stomal
diversion of the fecal stream, which implicates intestinal luminal
contents as having a role in precipitating illness.41 There is
presently a rigorous research effort to characterize the intestinal
microfl ora in the diseased patient, suggesting that this microbial
second genome is critical to the development of disease in the host
genetically susceptible individual.
Smoking
Of all environmental factors, tobacco smoking has the strongest
association with the risk of developing IBD. How-ever, it has a
paradoxical effect, with former or current smokers having a
decreased risk of UC but an increased risk of developing and
aggravating CD.5860 In CD patients,
smoking has been associated with a more aggressive disease
course, higher rates of clinical recurrence, and an increased need
for surgery.6164 Conversely, in UC patients, smoking is correlated
with less disease incidence, a decreased require-ment for
medication, and a lower hospitalization rate.65
Nonsteroidal Antiinfl ammatory Drugs
Nonsteroidal antiinfl ammatory drug (NSAID) use has been
consistently associated with an increased risk of developing IBD.66
However, data on the role of NSAIDs in relapses/fl ares are confl
icting. Aspirin is an exception, with no data supporting its
association with disease fl ares.67,68
Appendectomy
The role or association of appendectomy and the develop-ment of
IBD has been debated for several decades. Meta-analysis suggests an
elevated rate of CD diagnosis within the fi rst year following
appendectomy, but that rate decreas-es to that of the general
population within 5 years.69 Propo-nents of such an association
argue that loss of this lymphoid organ, particularly if early in
life, leads to an impaired ability of the colon to defend against
pathogens, allowing for antigenic invasion and the commencement of
an infl amma-tory process. Others debate that the excision of the
lymphoid tissue in which antigens are sequestered is preventive of
the development of IBD. In CD in particular, what is interpreted to
be appendicitis at an early age may, in fact, be the fi rst but
undiagnosed manifestation of CD.70 A separate meta-analysis
suggested more of a protective role for appendec-tomy in UC.71
However, mesenteric adenitis, an appropriat e immune response to
pathogenic invasion, has also been suggested to have a protective
role in UC.72
Genetics
familial studies
The number one risk factor for the development of IBD is the
presence of a family member with IBD [see Table 3]. A genetic
association for IBD has been confi rmed by family studies, twin
studies, and genome-wide association studies (GWAS). The majority
of data obtained from twin studies originate from Scandinavia due
to these countries meticu-lously maintained national twin
registries. Such familial studies have concluded the following:
Approximately 15 to 35% of IBD patients have an affected family
member.73
An individual incurs 17 times the normal population risk if a
sibling has IBD.
The lifetime risk of developing IBD for a fi rst-degree relative
of a CD patient is 5 to 16% and 8 to 14% for a UC patient.74
Fifty percent and 10% concordance for IBD (either UC or CD)
exists in mono- and dizygotic twins, respectively.75
When broken down by disease (CD versus UC), monozy-gotic twin
concordance rates range from 20 to 50% for CD and 14 to 19% for
UC.
In dizygotic twins, both CD and UC concordance rates range from
0 to 7%.74
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gastro infl ammatory bowel disease 8
Figure 6 This diagram illustrates how the interplay between
genetics and environment leads to multiple, individual phenotypes
of infl amma-tory bowel disease (IBD). NSAID = nonsteroidal
antiinfl ammatory drug.
Table 3 Genetic and Demographic Factors Affecting IBD Risk
Genetic and Demographic Factor IBD Risk (%)
Monozygotic twin affected 3750
2 affected family members 30
Dizygotic twin affected 710
Jewish (all groups) 6.6
White with one first-degree relative affected 3.3
IBD = infl ammatory bowel disease.
Only a single type of colitis, either CD or UC, is found in 75%
of IBD families, whereas in the remaining 25%, both CD- and
UC-affected members can be found.45,76
IBD families are generally concordant for age at onset,
location, and behavior.7780
In UC, a familial concordance for extraintestinal
manifes-tations has been noted.74
from candidate studies to gwas
Similar to the majority of other immune-mediated dis-eases, such
as systemic lupus erythematosus (SLE), type 1 diabetes mellitus,
and rheumatoid arthritis, IBD is a complex, multigenic disease and
does not follow a typical mendelian pattern of inheritance.
Initially, genetic analysis of IBD was slow moving, using tedious
linkage analysis to investigate sibling pairs, searching for
allelic sharing
incidences greater than those found solely by coincidence,81 and
candidate gene studies limited largely by relatively small groups
of patients and a small number of known IBD-associated genes at
that time. Since the completion of the HapMap Project and the
development of GWAS, where thousands of genes in thousands of
patients can be studied simultaneously, the fi eld has rapidly
advanced, and over 160 genetic loci and over 350 IBD-associated
single nucleo-tide polymorphisms (SNPs) have been identifi ed as
associ-ated with IBD [see Table 4].15,82,83 Interestingly, some of
the genes mapped to these loci are associated with CD, others with
UC, and some with both, confi rming the two diseases overlapping
and yet distinct pathologic and clinical features. Additionally,
several gene associations are shared between IBD and other
immune-related diseases, such as rheumatoid arthritis, multiple
sclerosis, and even leprosy.83
The role of several of these genes in IBD can be intuitively
correlated with the disease due to their known function in the
immune system and/or intestinal barrier function [see Figure 7].49
The majority of IBD-associated genes play a role in four main
categories of physiologic functioning: (1) innate immunity,
including autophagy (NOD2/CARD15, ATG16L1, IRGM); (2) adaptive
immunity (T cell differentiation/anti-gen presentation, L23R, JAK2,
STAT3, CCR6, ICOSLG); (3) epithelial barrier function (IBD5, DLG5,
PTGER4, ECM1, CDH1); and (4) cytokine/cell signaling (IL10, IL6,
IL23) [see Table 5]. Several of these genes have overlapping roles
in more than one pathway. For example, TNFSF15 has a role in T cell
differentiation and vascular endothelial growth.
IBD Phenotype IBD Phenotype IBD Phenotype IBD Phenotype1 2 3
4
GeneticFactors
EnvironmentalFactors
EpithelialBarrier
Dysfunction
Gut Microbiome
Miscellaneous FactorsDiet, Smoking,
NSAID Use
ImmuneDysregulation
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Similarly, STAT5 is involved in tight junctions and T cell
differentiation.
Innate Immunity
IBD-associated innate immunity defects involve the congenital
ability to recognize as foreign certain enteric organismrelated
antigens and autophagy or the auto-digestion and recycling of
cellular components.58 Although several IBD-associated genes are
found in this pathway, the three that play the greatest role and
are thus most commonly known are NOD2, ATG16L1, and IRGM.
autophagy
ATG16L1
The ATG16L1 gene is found on chromosome 2q37, and its protein
product is involved in the formation of the autopha-gosome and is
commonly expressed in intestinal epithelial cells, lymphocytes, and
macrophages. It has been shown to be immunopreciptated with NOD2.
Both NOD2 and ATG16L1 must be functional in dendritic cells for
autophagy to be induced in response to MDP stimulation.75 CD
patients with mutations in ATG16L1 have been demonstrated to have
Paneth cell abnormalities and increased levels of infl ammatory
cytokines.
IRGM
Discovered to be associated with IBD at the same time as
ATG16L1, the IRGM (immunity related guanosine triphos-phatase
family M protein) gene located on chromosome 5 encodes
immunity-related guanosine triphosphatases, which are required for
the interferon gammamediated clearance of intracellular pathogens.
Knockdown of IRGM has been
shown to cause defective autophagy and increased survival of
several pathogens, including Toxoplasma gondii, Listeria
monocytogenes, and Mycobacterium tuberculosis.84,85
pathogen recognition
NOD2/CARD15
Early genetic fi ne mapping led to the identifi cation of the fi
rst IBD-associated gene, NOD2 (nucleotide-binding oligo-merization
domain-containing protein 2), also known as CARD15 (caspase
recruitment domain-containing protein 15), located on chromosome
16, in 2001 [see Figure 8].86 The NOD2/CARD15 gene is expressed in
several cell types, such as monocytes, dendritic cells, Paneth
cells, and intestinal epithelial cells. Its protein product is
involved in the recog-nition of muramyl dipeptide (MDP), found in
the bacterial cell wall.87 Activation of NOD2 results in activation
of the mitogen-activated protein kinase (MAPK) and nuclear factor
aB (NF-kB) pathways.58 NF-kB plays a key role in infl ammatory and
immune responses and is involved in the regulation of several genes
responsible for the production of proinfl ammatory cytokines,
including interleukins 1, 6, 8, and 12; tumor necrosis factora
(TNF-a); adhesion molecules; chemokines; and growth factors. TNF-a
is a potent proinfl ammatory cytokine highly involved in the
pathogenesis of IBD and thus is a pharmacologic target.
The NOD2 gene has the strongest, most commonly repli-cated
association with IBD.87 The three SNPs most commonl y associated
with IBD (R702W, G908R, and 1007fs) have been found in up to 40% of
European and North American CD patients, compared with 10 to 15% of
the healthy popula-tion.88 These three polymorphisms are all
located within or near the leucine-rich repeat sequence part of the
gene that
Table 4 Common Infl ammatory Bowel DiseaseAssociated GenesUC
Genes UC and CD Genes CD Genes
CALM3CREMDAGLBDAPEXOC3GNA12GPR35HNF4AIBD7IL7RIP6K3IRF5ITGALLAMB1MST1RMUC21CDH1S1007HLA-DQA/B
BTNL2ADAP11P36BRDMAML2MANBASKIV2LECM1SMURF1ULK4ZNF90C2NOX3ORMDL3ORVPARD3ARPC2TNFSFR14PSORS1C1ZFP90
1q24BACH2
C11orf30KIF21BC2ORF74C6ORF85CAPN10CCL2/7/11/8CCNYATG16L1CR6CGNCDKAL1CLDN1/3/4CSDAZNF365DLG5ECM1F11RFCGR2AGALCGCKRGL1
IBD5ISOCLGIKZF1IL10IL12BIL17RIL18IL2IL23RIL27IL8CYCSP4IRF5IRGMITLN1JAK2KFL2KIFLRRK2LSP1LYRM4MAG12MAP3K
MEP1AMST1TJP2PTPNNKX2.3ORMDL3PARD3PDRMPER2NOD1/2PPARyPRDM1PSMG1PTGER4HERC2HORMADTLR1/10/6PUS10RAB3BSERPINASFPDSLC2RTNFSF15/TL1A
SAMD3STAT3SYMPKTAGAPMTMRYCJCZMIZTREM1ZO
1-3U6/7THADACPA5MUC19MY88MYO9BNCF4NELL1GPR12GPX4SMAD3STAT5DAP
PXRAGTATG4A/DC7ORFCCL7/12CD24/MUC1CLDN3CPEB4DPEB4DEFB1DENND1BDNMT3ADRAPERAP2FAS1FNBP1LFUT2HLA11IL2RAIL4/6LACC1NLRP3
NOD1OPNPLCL1POU5F1PTPN22RIPK2SLC22SP140SPP1TGFB1TLR4TGFB1TLR4TMEM17TNFAIP3TNFSF11/14TNDSF18TRAIPTRPV3UBE2ZFP36L1
CD = Crohn disease; UC = ulcerative colitis.These tables
demonstrate several of the more than 150 genes associated with UC,
CD, or both UC and CD.
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Figure 7 Genes involved in innate and adaptive immunity in Crohn
disease (CD). This fi gure illustrates the interplay between the
bacterial recognition gene NOD2, with its effect on nuclear
factorkB (NF-kB) activation, and the autophagy genes IRGM and
ATG16L1 in the innate arm of the immune system. Also demonstrated
are the STAT3/NKX2-3 and IL23 pathways leading to the activation of
T helper type 17 (Th17) cells and downregulation of T regulatory
(Treg) cells characteristic of CD. IFN-c = interferon gamma; MDP =
muramyl dipeptide; TNF-a = tumor necrosis factora.
OCTN1/2
CLDN
DLG5Zo
CellCell
NOD2
ORMDL3
ATG16L1IRGM
NF-B
NF-BActivation
IL-23R/JAK2
STAT3
NKX2-3TNFSF15
IL-10R
Th1 Cell
Th17 Cell
Lamina Propria
IL-10
Treg Cell
CD4+ T Cell
ADAPTIVE IMMUNE RESPONSE
ImmuneActivation
IFN
IL-12B/23
Activation andDifferentiationof Th1/Th17
Lymphocytesand Downregulation
of Treg Cells
Ca2+
Regulation
CELLULAR ANDMETABOLIC PROCESSES
TIGHT JUNCTION/EPITHELIAL
BARRIERFUNCTION
INNATE IMMUNE RESPONSE
Secretion ofAntimicrobial
PeptidesMDP
BacterialRecognition
IntestinalLumen
AutophagosomeDegradation of
Bacteria
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senses MDP, and the presence of any of these mutations leads to
impaired activation of NF-kB and the subsequent altered production
of infl ammatory cytokines,89 refl ecting a host defi cit in
recognizing enteric antigens that might be present early in
life.
Toll-Like Receptors
The main role of Toll-like receptors (TLRs) in innate immunity
is in distinguishing self from non-self by usin g pattern
recognition receptors (PRRs) to detect pathogen-associated
molecular patterns (PAMPs) on the surface of pathogens. Although
several of the TLR subtypes are involved in the pathogenesis of
IBD, TLR2, which detects bacterial proteins, and TLR4, which
detects the gram-negative bacterial outer membrane component
lipopolysac-charide (LPS), are most commonly associated with the
disease. These TLRs, once stimulated, activate the adapter protein
myeloid differentiation factor 88 (MyD88)-dependen t pathway,
leading to the production of several proinfl amma-tory cytokines.
However, TLR4, located on chromosome 9, can also activate an
MyD88-independent pathway, leading to a more direct activation of
interferons, TNF-a, and several proinfl ammatory interleukins.
Functional studies have shown that IBD patients have a signifi
cantly higher expression of TLR4 within the intestine, especially
when comparing infl amed colonic mucosa with noninfl amed
controls.90
epithelial barrier function
OCTN1, OCTN2
The IBD5 locus is located on chromosome 5. Two organic cation
transporter genes (OCTN1 and OCTN2) are located in this region.91
OCTN1 is also known as the solute carrier family 22, member 4
(SLC22A4), and OCTN2 is also known as SLC22A5. Although highly
replicated as associated with IBD through multiple GWAS, the exact
mechanism through which these mutations contribute to the
pathophysiology of either CD or UC is not yet clear. However,
mutations have been associated with colonic involvement and anal
disease.91
The Adaptive Immune System
The adaptive immune system refers to the clinical response of T
and B lymphocytes to the presence of anti-gens, ultimately leading
to pathogenic elimination through direct killing, cytokine-mediated
pathways, and antibodies. These pathways are initiated by the
interaction between antigenic peptides sequestered onto the major
histocompat-ibility complexes (MHCs) of antigen-presenting cells
(APCs), such as dendritic cells, which are then presented to the T
cells via the T cell receptors in the presence of costimulatory
signals, leading to T cell activation and differentiation into
different subsets, such as T helper types 1, 2, and 17 and T
regulatory (Treg) cells.
Table 5 Common IBD-Associated Genes Involved in Epithelial
Barrier Dysfunction, Innate Immunity, Antigen Presentation, T Cell
Differentiation, Cytokine Production, and Cell Signaling
Epithelial Barrier Dysfunction Innate Immunity Antigen
Presentation and T Cell Differentiation Cytokine Production and
Cell Signaling
IBD5DLG5PTGER4ECM1CDH1STAT5MMP18DLG5
NOD2/CARD15NFkBATG16L1IRGM
IL23RJAK2STAT3TNFSF15/TL1ACCR6ICOSLGTAGAPHLA class II
IL10 (downregulatory)IL6CCR5
IBD = infl ammatory bowel disease.
CARD1 CARD2
Nucleotide-Binding DomainCaspase RecruitmentDomains 1 and 2
Leucine-Rich Repeat Region(Bacterial Recognition)
NBD LRR
29 124 127 220 273 577 744 1020
1007
FS
G90
8R
R70
2W
Figure 8 NOD2/CARD15. Demonstrated are the three components of
the gene key to bacterial recognition and activation of downstream
anti-antigenic pathways, the capsase recruitment domains, the
nucleotide-binding domain (NBD), and the leucine-rich repeat (LRR)
region, where bacterial recognition is initiated. The most common,
most universally found Crohn diseaseassociated NOD2 single
nucleotide polymorphisms, R702W, G908R, and 1007fs, are found in
this region.
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hla
The human leukocyte antigen (HLA) region, a highly polymorphic
gene complex located on chromosome 6, is the most extensively
studied region in IBD.103 IBD-associated HLA genes fall into two
categories: class I and class II. Class I genes are expressed in fi
broblasts, endothelial cells, and dendritic cells. Expression rises
during viral and bacterial infections. Class II genes are expressed
in activated T cells, macrophages, and dendritic, endothelial, and
epithelial cells. The majority of IBD studies have focused on the
role of HLA type II (with a particular focus on HLA-DRB1) as these
genes play an important role in presenting antigens to T
lympho-cytes, which subsequently leads to B cell production of
anti-bodies against that particular antigen. Notably, this gene has
been associated with the extraintestinal manifestations of IBD.104
Meta-analysis has revealed DR2, DR9, and DRB1 to be associated with
UC and DR7, DRB3, and DQ4 to be associated with CD.105 Also found
in this region is the TNF-a gene.106
Cytokine Signaling
il10
Although several genes implicated in the pathogenesis of IBD are
associated with cytokine signaling, the most inves-tigated genes
are the IL10 pathway. IL10 is most famously known from the 2009
Royal Free Hospital case study, where IL10 receptor (IL10R)
mutations were detected in a small cohort of patients with
early-onset colitis. Bone marrow transplantation was then
successfully used as treatment for a case of particularly severe,
medically refractory CD with dramatic anal involvement.107 IL10 is
an antiinfl ammatory cytokine; thus, mutations affecting it or its
receptor result in infl ammation.
Medical Management
Traditionally, the medical management of IBD has been guided by
three general principles: (1) rapid and effective treatment of
acute fl ares to achieve clinical remission, (2) maintenance of
remission and prevention of clinical relapse, and (3) avoidance of
complications of therapy, especially those related to long-term
corticosteroid use [see Figure 9]. Although these guiding
principles still hold true today, additional treatment strategies
and end points have recently emerged (with the advent of biologic
therapy) that may offer an opportunity to impact the natural
history of both CD and UC. One of the key aspects of this new
medical management paradigm involves adoption of an earlier, more
aggressive approach with an increased reliance on objective
measures of infl ammation to guide therapeutic decision making.
Concepts such as top-down approach, combination therapy, treating
to target, and drug-level monitoring are now becoming part of the
IBD providers lexicon. For the surgeon who cares for IBD patients,
familiarity with these new concepts is important, as is an
understanding of the indica-tions, effi cacy, and side-effect profi
le of drugs routinely used to treat CD and UC [see Table 6].
In the pathophysiology of IBD, the role for T cellmediated
adaptive immune responses is best characterized, with the role of B
cells less well understood.92 A bias toward T helper type 1 (Th1)
cell differentiation with subsequent interleukin-12 (IL-12),
interferon gamma, and TNF produc-tion and abnormal Treg cells has
been well documented in CD, whereas a Th2 cell bias (with
subsequent production of IL-4, -5, and -13) has been demonstrated
in UC. Th17 cells have been associated with both UC and CD but have
a slightly stronger association with CD.83,93
tnfsf15
The tumor necrosis factor superfamily member 15 (TNFSF15) gene,
also known as TNFSF ligand A (TL1A) and the vascular endothelial
growth inhibitor (VEGI) gene, is found on chromosome 9q32 and acts
as a ligand binding to death domain receptor 3 (DR3), which is
mainly expressed on T lymphocytes. The TNFSF15 gene was among the
fi rst genes to be identifi ed as being associated with both CD and
UC through GWAS.94 Its gene product, TL1A, is produced by dendritic
cells and monocytes and is expressed in macrophages, endothelial
cells, and gut lamina propria lymphocytes.95 This gene has both
immunoregulatory and angiostatic functions.96 Stimulation is
through the NF-kB pathway and leads to a preferential increase in T
helper cells during T cell differentiation94,97 and enhanced
interferon gamma and IL-2 production by T cells in IBD
patients.97,98 Also key to the pathogenesis of IBD, particularly
CD, are Treg cells, which function as suppressors of immune
responses and promote tolerance to gut microbiota and dietary
antigens.94 Overexpression of TL1A in T cells has also been
associated with increased numbers of Treg cells.99,100 Additional
downstream effects of TL1A include angiostasis, apoptosis, and the
induction of metalloproteinases, which are involved in intestinal
barrier function.100,101
il23r
Like many IBD-associated genes, the IL23R (interleukin-23
receptor) gene has been linked to other autoimmune condi-tions,
such as rheumatoid arthritis and ankylosing spondy-litis, and has
been associated with mucosal infl ammation in the gastrointestinal
tract.92 IL23R plays an important role in the IL-23/Th17 infl
ammatory pathway.102 This pathway is particularly important in the
pathogenesis of IBD, as evidenced by the association of multiple
polymorphisms located within several genes in this pathway as
associated with the disease.92
IL23R messenger RNA is expressed by natural killer cells and
CD4+ and CD8+ T cells. In CD4+, it is expressed in par-ticularly
high levels in the Th17 subset.92 Activated macro-phages and
dendritic cells produce IL-23, which binds to the receptor, thus
activating the Janus kinase 2 gene (JAK2) with the downstream
recruitment and dimerization of the sub-units of the signal
transducer and activator of transcription 3 (STAT3) transcription
activator. STAT3 is then able to translocate into the nucleus and
promote the transcription of proinfl ammatory mediators.102 This
signaling pathway plays an important role in CD4+ T helper cell
differentiation via activation of another pathway, the retinoic
acidbinding orphan receptor-ct (ROR-ct) pathway, and the production
of IL-17A, IL-17F, IL-6, and TNF-a cytokines, leading to infl
ammation and differentiation of Th17 cells.102
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Drug Classes
systemic corticosteroids
Systemic corticosteroids represent the oldest, least expen-sive,
and perhaps most rapidly acting antiinfl ammatory treatment for
IBD. They are most often used in treating mod-erate to severe
disease fl ares in an effort to induce clinical remission in
patients with both UC and CD.108 In this role, they have been shown
to be very effective, with short-term clinical remission rates as
high as 70%.108110 However, they are not considered appropriate
maintenance agents, nor have they consistently demonstrated the
ability to achieve mucosal healing. With the introduction of
numerous biologic agents that can be used for both disease
induction and maintenance of remission, the use of systemic
corticosteroids is diminishing.
For the hospitalized patient with severe UC (a scenario that
mandates a close collaboration between the gastroenter-ologist and
the surgeon), IV corticosteroids typically remain a fi rst-line
approach in those who do not choose to undergo surgery [see Figure
10]. Although such patients often respond to IV steroids within 5
days, those who do not should either undergo surgery or be switched
to an alternative therapy, such as cyclosporine or infl
iximab.111,112
In addition to traditional systemic corticosteroids, oral
topically active steroids are available and offer signifi cant effi
cacy with a more appealing side-effect profi lethe result of high
fi rst-pass metabolism of the drug.113 Budesonide (a synthetic
analogue of prednisolone) exists in two common formulations that
predominantly target either the distal small bowel (Entocort EC,
AstraZeneca) or colon (Uceris, Santarus). Although these
medications have been shown to
Figure 9 Typical course of Crohn disease (CD). CD typically
progresses from an infl ammatory predominant phenotype (blue shaded
area) to a stricturing phenotype (yellow shaded area) with or
without fi stulas or abscesses (green shaded area). Medical
treatment aims to halt this process and reduce the likelihood of
strictures or penetrating disease requiring surgical
intervention.
Table 6 Overview of the Medical Treatment of Infl ammatory Bowel
Disease
TreatmentShort-Term
UseLong-Term
Use Effi cacy Selected Side Effects
Corticosteroids Yes No Short-term reduction of
inflammationLimited efficacy in maintaining
remission short term (particularly in nonfibrostenosing
ileocolic CD)
Glucose intolerance, glaucoma, opportunistic infection, bone
loss, skin changes, depression, dependence
5-ASA Yes Yes Induction of remissionMaintenance of remission
GI disturbances, rash, liver dysfunction, lupus syndrome, bone
marrow dysfunction, reversible male infertility
AZA/6-MP No Yes Steroid reduction/weaningmaintenance of
remission (i.e., more
effective in quiescent IBD)Can be interchanged if loss of
response
or allergic reaction
GI disturbances, bone marrow suppression, pancreatitis,
opportunistic infection
Tumor necrosis factor antagonists
Yes Yes Induction of remissionMaintenance of remissionRole in
mucosal healing
Infusion/allergic reactions, increased risk of malignancy,
reactivation of TB
Methotrexate No Yes Maintenance of remissionCD > UC
GI upset, hepatotoxicity, CNS disturbances
Cyclosporine Yes No Induction of remissionMaintenance of
remissionUC > CD
Skin infections, pulmonary infections, renal toxicity,
hyperkalemia, hypertension
5-ASA = 5-aminosalicylic acid; AZA = azathioprine; CD = Crohn
disease; CNS = central nervous system; GI = gastrointestinal; IBD =
infl ammatory bowel diseae; 6-MP = 6-mercaptopurine; TB =
tuberculosis; UC = ulcerative colitis.
Time
Infl
amm
atio
n
Diagnosis
RemissionFlare
Flare
Diagnosis
Flare
e
Remission
FFlare
Remission
Flare
Inflammation Stricturing Fistula or Abscess
*Surgery required
*Surgery required
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be effective induction agents in the treatment of active CD,
they are not thought to be suitable for the prevention of clinical
relapse.114116
Finally, rectal steroid preparations may be benefi cial in IBD
patients with proctitis. If the patient can retain them for an
adequate period of time, hydrocortisone enemas have been
demonstrated to work well.117119 A foam formulation is also
available.
Side Effects and Complications
The utility of prolonged use of systemic corticosteroids is
limited by a profi le of unfavorable side effects, including
diabetes, osteoporosis, osteonecrosis, glaucoma, and infec-tions.
Furthermore, in data from the Crohns Therapy, Resource, Evaluation
and Assessment Tool (TREAT) regis-try, prednisone was the only CD
medication found to be associated with an increased risk of
mortality after adjusting for other potential confounding
factors.120
Of particular interest to the surgeon is that high doses of
corticosteroids appear to have detrimental effects on tissue
integrity and may negatively impact operative outcomes,
including wound breakdown, anastomotic leak, and infectious
complications.121124
The need for systemic corticosteroids often indicates severe
disease and has been shown to be a predictor of the need for
surgery. There is a 30% colectomy rate in UC, and approximately 40%
of CD patients will require surgery within 1 year of steroid
commencement.125
5-aminosalicylates
5-Aminosalicylates (5-ASAs) are typically fi rst-line agents in
mild to moderate UC, whereas their effi cacy and use in CD
(particularly for isolated small bowel disease) are more
controversial. They exist in various preparations (oral,
sup-pository, and enema) and formulations, designed to target
specifi c sites of active infl ammation [see Table 7]. A 2012
Cochrane review of 48 studies involving over 7,000 UC patients
found 5-ASAs to be more effective than placebo for inducing
clinical remission.126 Of note, the authors found once-daily dosing
to be as effi cacious and safe as
Figure 10 Suggested treatment algorithm for a severe fl are in
the hospitalized ulcerative colitis patient. AZA = azathioprine; IV
= intravenous; 6-MP = 6-mercaptopurine; TNF = tumor necrosis
factor. *If the patient deteriorates at any time in the course of
the hospitalization, emergent surgery should be considered. Due to
the likelihood of severe adverse reactions, only cyclosporine or
infl iximab should be instituted. If the patient is already taking
cyclosporine or infl iximab prior to the fl are, the other drug
should not be trialed.
ORCommence Maintenance
TherapyAnti-TNF vs AZA/6-MP
IV Cyclosporine
Colectomy
Response within 5 days*
Yes No
IV Infliximab
IV Steroids
NoYes
Response within 23 days*
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gastro infl ammatory bowel disease 15
conventional dosing of these agents. Supporting the role of
5-ASAs in maintaining UC remission, a recent meta-analysis
demonstrated superior effi cacy of 5-ASAs over placebo, with no
differences between the various formulations. In additional
studies, nonadherence to long-term 5-ASA was found to be associated
with an approximate fi vefold increase in the likelihood of a
disease fl are when compared with adherent patients.127,128
The effi cacy of 5-ASAs in CD is questionable based on several
studies showing nonsuperiority to placebo for both induction and
maintenance of remission.129,130 However, 5-ASAs currently remain
in the CD therapeutic armamen-tarium for a variety of reasons,
including a high safety profi le and concerns that disease
heterogeneity and differing drug formulations may have impacted
study results.
For management of proctitis, topical 5-ASA preparations have
been shown to be effective.131 In fact, a meta-analysis suggested
superiority of topical over oral 5-ASAs.132 For maintenance of
remission in distal disease, the combination of an oral and topical
agent is likely the most effective approach.133
Side Effects and Complications
Generally, the 5-ASAs are well tolerated and considered low-risk
medications. Although not used often anymore, sulfasalazine, which
is composed of aminosalicylates cova-lently bonded to a
sulfapyridine moiety, has been associated with a signifi cant rate
of side effects, which can limit its utility. This is thought to be
the result of the sulfapyridine component of the drug and can lead
to allergic hypersensi-tivity and sperm abnormalities.
Additionally, sulfasalazine also appears to impair folate
absorption, so folic acid is typically prescribed concurrently with
the drug. Use of other 5-ASA compounds may also lead to
hypersensitivity reactions, although these occur much less often
than with sulfasalazine.134 Periodic monitoring of kidney function
is recommended with this class of medications given the potential
for the development of nephrotoxicity (most often interstitial
nephritis).135
immunomodulators
Thiopurine Analogues
The role of the thiopurine analogues azathioprine (AZA) and
mercaptopurine (6-MP) has been well established for the treatment
of both CD and UC, the result of controlled trials, meta-analyses,
and extensive clinical experience.136
Traditionally, the use of these agents has been reserved for
prevention of clinical relapse or cases of corticosteroid
dependency. Over the last few years, their use has expanded to
include prevention of postoperative recurrence and as an adjunct to
anti-TNF therapy.137 In UC, they have demon-strated superior effi
cacy over 5-ASAs, with patients being almost fi ve times more
likely to achieve steroid-free clinical remission at 6 months. A
meta-analysis of CD studies reported an odds ratio of over 2 for
maintenance of remission with AZA in patients with quiescent
disease.138
Early use of AZA as monotherapy is controversial.139,140
Evidence from several large studies has shown that the use of
combination therapy (AZA and anti-TNFs) in CD patients is effective
in achieving steroid-free remission.137,141,142 It appears likely
that this combination therapy approach will also be effective in
UC.
Side Effects and Complications
As with any drug, prior to initiation of either AZA or 6-MP,
details of the potential risks of therapy need to be fully
explained to the patient. Patients also need to be informed of the
requirement and importance of regular laboratory monitoring
(complete blood counts and liver biochemical tests). Finally,
before prescribing the drug, it is recommended that a thiopurine
S-methyltransferase (TPMT) enzymatic activity level be checked. If
it is found to be low (0.3% of individuals), then an alternate
medication should be chosen given the high risk of a rapid and
severe leukopenia.
Common side effects include nausea, headache, abdomi-nal
discomfort, hypersensitivity reactions (in up to 5% of patients),
and pancreatitis (in approximately 3%). In cases of
hypersensitivity or pancreatitis, the medication should be stopped
immediately. Mild elevations in liver tests (amino-transferases)
are often seen and frequently resolve without the need for
permanent drug discontinuation. However, a rare and potentially
serious immunomodulator-induced cholestasis has been reported.143
An increased risk of cancer, particularly nonmelanoma skin cancer
and lymphoma, has been associated with thiopurine use, particularly
of more than 5 years duration.144 Opportunistic infection can be a
life-threatening side effect of AZA/6-MP, particularly
postoperatively.145,146
methotrexate
Methotrexate (MTX) is an antifolate drug and is more effi
cacious in the treatment of CD versus UC.138 Its use is
Table 7 5-ASA Derivatives and Their Sites of Action5-ASA
Derivative Preparation Site of Action
Mesalamine (Pentasa) Oral Jejunum to colon
Mesalamine (Lialda/Asacol/Apriso) Oral Ileum to colon
Balsalazide (Colazal) Oral Colon only
Mesalamine (Rowasa) Enema Distal colon (to splenic flexure)
Mesalamine (Canasa) Suppository Rectum
5-ASA = 5-aminosalicylic acid.
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limited by side effects, which include gastrointestinal upset,
bone marrow suppression, and central nervous system effects. Up to
40% of CD patients on MTX treatment experi-ence at least one side
effect, with hepatotoxicity seen in approximately 30%. Remission
rates after 3 years are low at less than 50%.147 Thus, MTX use is
generally limited to those intolerant to anti-TNF use.
cyclosporine
The role of cyclosporine in the treatment of IBD is essen-tially
reserved for salvage therapy in the hospitalized patient with
severe UC who is failing to respond adequately to IV
corticosteroids if he or she has chosen not to undergo immediate
surgery. In this setting, several studies have confi rmed the
initial fi ndings of Lichtiger of an 80% rate of colectomy
avoidance.148 However, over the long term, a signifi cant
proportion of these patients may still require surgery.
Cyclosporine should only be used in centers with experience using
this drug and where drug levels can be monitored.149 If a patient
ultimately responds to IV cyclospo-rine and is discharged, he or
she is transitioned to an oral formulation with a plan to replace
this over the long term with a more appropriate maintenance agent
(typically an immunomodulator). Therefore, patients who have
already been treated unsuccessfully with an immunomodulator are
unlikely to maintain long-term remission.
Side Effects and Complications
Long-term cyclosporine use is limited by its toxicity, including
renal failure and hypertension. There is also an associated
increased risk of infection, including skin infec-tions and
potentially fatal Pneumocystis jiroveci (formerly Pneumocystis
carinii) pneumonia.150 Administration requires monitoring of levels
to avoid potential abnormalities such as hypomagnesaemia and renal
damage. Additionally, hyper-trichosis and hypertension may result
from administration.
anti-tnf therapy
Infl iximab, adalimumab, certolizumab pegol, and golim-umab are
anti-TNF agents approved for use in CD and/or UC. With the
exception of certolizumab pegol (pegylated fragment of an anti-TNF
antibody), they are all recombinant antibodies designed to bind to
TNF-a, a proinfl ammatory cytokine expressed in both the mucosa and
systemic circula-tion. Infl iximab is administered as an IV
infusion, whereas the other anti-TNFs are given via subcutaneous
injection. Infl iximab was the fi rst approved TNF antagonist, with
two early trials demonstrating that this medication was superior to
placebo in terms of clinical response and remission rates for
patients with moderate to severe CD receiving other ongoing
therapy.151,152 Infl iximab was also shown to be effective in the
treatment of fi stulas.153 In CD, adalimumab and certolizumab pegol
were subsequently studied and approved for use in moderate to
severe disease, with similar effi cacy seen in induction and
maintenance trials.154,155 Post hoc analyses of the maintenance
trials also suggest a role for adalimumab and certolizumab pegol in
the management of CD-related fi stulas.156,157
In UC, the fi rst large randomized controlled trials on infl
iximab in ambulatory patients with moderate to severe disease
demonstrated signifi cantly higher clinical response
and remission rates at 8 and 54 weeks compared with placebo (at
week 54, 16.5% in clinical remission in the placebo group versus
34.7% in those receiving infl iximab).158 Although not the primary
end point in these studies, mucosal healing rates were also signifi
cantly higher in the infl iximab-treated patients. Induction and
maintenance trials comparing adalimumab with placebo also found
signifi cantly higher clinical response and remission rates at 1
year in ambulatory anti-TNF-naive patients with moderate to severe
UC.159 Golimumab was recently approved for use in UC and shows
similar effi cacy when given as an induction or maintenance
agent.160
Infi ximab is also often used as a rescue therapy in the
hospitalized patient with severe UC not responding to IV steroids
as an alternative to cyclosporine. Although studies have shown that
this strategy may be effective, we await full publication of the
large randomized clinical trial that appears to suggest that infl
iximab is noninferior to IV cyclosporine in this setting.
Anti-TNF therapy has been suggested to be very effective in the
prevention of postoperative recurrence of CD, which is particularly
important in the patient with an aggressive disease
phenotype.161,162 It is important to understand that with
increasing use of biologic anti-TNF therapy, data have begun to
suggest the possibility that the natural course of IBD may be
favorably impacted. Hospitalization, surgical interventions, and
CRC rates may be declining, with improved long-term outcomes more
likely when anti-TNF therapy is initiated early in the disease
course.163,164
Side Effects and Complications
Given their duration of use in large numbers of patients across
various disease states, the side-effect profi les of anti-TNF drugs
are relatively well characterized. This drug class has a propensity
to lose effectiveness over time. Gener-ally, after approximately 1
years use, 30% of patients will retain benefi t.165 Besides being
expensive, anti-TNFs have a moderate rate of acute infusion
reactions and have been associated with an increased risk of
lymphoma and serious infections.166
Increased risk of the development of solid tumors is not proven.
However, an increased likelihood of skin cancer and possibly
cervical dysplasia has been suggested.144 Rates of lymphoma among
anti-TNF users with rheumatoid arthritis have been reported to be
greater than fi ve times that of the general population.167
Treatment can also lead to the reacti-vation of latent
tuberculosis, and a purifi ed protein deriva-tive (PPD) skin test
is recommended prior to commencing treatment.
Several systematic reviews and meta-analyses have been performed
to evaluate the risk of anti-TNFs and postopera-tive complications.
However, patients treated with anti-TNFs generally have more severe
disease and, as such, are prone to more complications regardless of
treatment. The results are confounding, particularly in CD, which
is more studied in regard to anti-TNF treatment.168173
antibiotics
There is an increasing evidence base supporting a role for
bacteria and the microbiome in the pathogenesis of IBD. For this
reason, antibiotic use for the treatment of both luminal
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CD and UC has persisted in clinical practice despite the fact
that controlled trials have not consistently demonstrated a benefi
t.174 Current guidelines do not recommend the use of routine
antibiotics in luminal CD or UC (unless concurrent infection is
suspected or in patients with severe toxic colitis). However,
specifi c situations exist in the medical manage-ment of the IBD
patient, where antibiotics are indicated based on available data.
Metronidazole therapy alone or in combination with ciprofl oxacin
has shown effi cacy in perianal CD.175 Unfortunately, long-term use
appears to be required to prevent recurrent drainage, which
necessitates monitoring for side effects of these medications.
Metronida-zole can lead to a peripheral neuropathy, whereas ciprofl
ox-acin treatment can be complicated by tendon damage.
anti-integrin therapy
Natalizumab is a monoclonal antibody that modulates intestinal
and brain lymphocyte migration by antagonizing a4 integrins,
glycoproteins expressed on the surface of most leukocytes. It is
approved by the Food and Drug Adminis-tration for CD (as
monotherapy) but not UC. In the Effi cacy of Natalizumab as Active
Crohns Therapy (ENACT)-1 trial, patients with moderate to severe CD
and a CRP level above the upper limit of normal demonstrated
signifi cantly superior remission rates at week 10 (40% natalizumab
versus 28% in placebo).176 A subsequent randomized
placebo-controlled trial also demonstrated the effi cacy of
natalizuma b as an induction agent in a similar population of CD
patients.177 In addition, data clearly support natalizumab use for
maintenance therapy (sustained response rates of 54% at 60 weeks
compared with 20% in the placebo group).176
Despite the demonstrate d effi cacy of natalizumab in CD, its
use in clinical practice has been limited by the develop-ment, in a
small number of patients, of progressive multifo-cal
leukoencephalopathy (PML), an opportunistic brain infection thought
to be caused by reactivation of a latent JC virus.178 Use of this
drug is usually limited to severely diseased CD patients and must
be preceded by a negative JC virus antibody test.
new medical therapies and emerging treatment paradigms
Several new medications with differing mechanisms of action are
on the horizon for use in either CD or UC. This is especially
important as approximately one third of IBD patients may not
respond at all to anti-TNF therapy. Furthermore, in those who do
derive a clinical benefi t, many subsequently lose response to
anti-TNFs over time.152,155,179
Vedolizumab (Millennium Pharmaceuticals) is a monoclo-nal
antibody to a4b7 integrin and therefore modulates gut, but not
brain (unlike natalizumab), lymphocyte traffi cking. This specifi
city should, in theory at least, ensure that patients treated with
this medication are not at an increased risk for PML. In a large
clinical trial, patients with moderate to severe CD who responded
initially to vedolizumab had close to a 40% clinical remission rate
at 52 weeks compared with just over 20% who received placebo.180 In
this study, vedolizumab use was associated with a higher rate of
adverse events and infections. In a large clinical trial of
sim-ilar design in UC, in patients who responded to induction
dosing with vedolizumab, 44.8% were in clinical remission at 1
year compared with 15.9% in those who received placebo.181
Ustekinumab is another monoclonal antibody that blocks the
biologic activity of interleukin-12 and interleukin-23 (cytokines
implicated in the pathophysiology of CD) by binding to the common
p40 subunit on receptors for these two cytokines found on various
immune cells. In a large multicenter clinical trial of moderate to
severe CD, patients who had failed to respond to anti-TNF therapy,
those who responded to ustekinumab and began maintenance therapy
with the drug, had signifi cantly higher rates of clinical
remission compared with placebo (41.7% versus 27.4%).182
Additional studies targeting proinfl ammatory cytokines are
ongoing. Another therapeutic target currently being explored
involves the inhibition of Janus kinases (JAKs), proteins that are
involved in important signal transduction pathways affecting
cytokines and therefore the immune response. Tofacitinib is one
such JAK inhibitor that has been studied in patients with moderate
to severely active UC. Patients treated with tofacitinib were more
likely to have clinical response and remission than those receiving
placebo in a phase II trial.183
emerging treatment paradigms
Top-Down Approach
The renewed impetus for adopting an earlier, more aggressive
approach to IBD therapy (in particular for CD) arose as the result
of the limited long-term effi cacy and safety profi le of systemic
corticosteroids when compared with anti-TNF therapy. Therefore, the
introduction of an anti-TNF agent earlier in the treatment
algorithm of CD is appealing [see Figure 11]. Furthermore,
anti-TNFs have been shown to be associated with mucosal healing, an
end point that has not been demonstrated with steroids. Ultimately,
the effi cacy of a top-down versus a step-up approach was evaluated
in a prospective, randomized, controlled trial of newly diagnosed
CD patients, naive to all immunosuppres-sive medications
(corticosteroids, immunomodulators, and anti-TNFs). At week 52, a
signifi cantly higher percentage of patients in the top-down group
(infl iximab and AZA) achieved steroid-free clinical remission
compared with the conventional step-up group (61.5% versus
42.2%).141 Furthermore, a follow-up study of these patients
revealed that those who were able to achieve mucosal healing (a
higher proportion in the top-down group) had signifi cantly higher
steroid-free remission rates 4 years after therapy was
initiated.184
Treating to Target
An additional emerging concept in the medical treatment of IBD
is the concept of treating to target. The target may be endoscopic,
serologic (including infl ammatory markers or drug levels), or
radiologic. The key to this approach is that the same target is
used at all time points. This method allows for appropriate dose
adjustment, identifi es patients who may be developing antibodies,
and leads to individual-ized therapy. A common target is mucosal
healing. The attainment of mucosal healing is predictive of a more
benign
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future disease course.184 Serum measurements of infl iximab
concentration and antibodies can also help guide treatment and
determine if a patient is underdosed or nonresponsive due to
antibody formation.185
The Future of IBD Surgery
Despite the effi cacy of IBD drugs, up to 70% of IBD patients
require surgery for their disease. Surgical interven-tion is more
common for CD than UC at all time periods after diagnosis due to
the recurring nature of CD and, conversely, the curative nature of
a total proctocolectomy (TPC) in UC.186 Although the incidence of
IBD is increasing,17 rates of surgery for IBD have been decreasing
worldwide over the past fi ve decades, as evidenced by a
meta-analysis of over 25 articles.186,187 This was also illustrated
in a Danish study of approximately 50,000 patients diagnosed with
IBD between 1979 and 2011, where the 5-year cumulative probability
of fi rst major surgery decreased from 44.7% in CD and 11.7% for UC
between 1979 and 1986 to 19.6% and 7.5%, respectively, between 2003
and 2011, the same time period when a signifi cant increase in the
use of anti-TNF and thiopurine treatment was seen.188 The
likelihood of dis-ease recurrence in CD and the unpredictable
response to medical and surgical treatment in both CD and UC remain
challenging, however. A paradigm shift toward the institu-tion of
personalized medicine using genetic analysis prom-ises to address
many of the clinical uncertainties associated with these diseases.
Additionally, expansion of surgical treatment options; improvements
in techniques of ileocolec-tomy and fi stula repair; the
introduction of single-site, robotic, and natural orifi ce
surgeries; and the concept of
coordinated multidisciplinary care have already led to the
evolution of the surgical treatment of the IBD, and this will
continue into the future.
Personalized Medicine: The Role of Genetics in Customizing
Medical and Surgical IBD Care
Due to the dramatic improvement in genotyping, includ-ing the
use of GWAS, a large group of IBD-associated genes has been
identifi ed [see Etiology, above], with several of these genes
either having a disease-predisposing and/or signifi -cant
disease-modifying effect.189 This has led, over the past several
years, to the identifi cation of the major immunologic pathways
involved in the pathogenesis of IBD. The individ-ual components of
these pathways are now being more closely investigated. These
IBD-associated genes are being used to further characterize both CD
and UC to offer more accurate prognosis to patients, predict
disease behavior, and assist in surgical decision making, which may
be very different from patient to patient based on an individual
characteristic genotype. Advantages to using genetic markers to
characterize a patients disease and thus predict disease course
include the following: (1) markers are present at birth; (2)
markers do not fl uctuate with disease course, unlike radiographic,
serum, and endoscopic fi ndings; (3) noninvasive methods can be
used for DNA acquisition (e.g., a cheek swab); (4) the patient, the
diagnostic modality, and the person who interprets the results need
not be in the same geographic location; and (5) the recent
exponential drop in the cost of genotyping due to advances in
genotyping techniques has led to affordable whole genome or exome
sequencing in the near future [see Table 8].
Bottom Up
+ 5-ASA
+ AZA or 6-MP
+ Steroids
Anti-TNF*
5-ASA
Steroids
AZA or 6-MP
Anti-TNF
Surgery
Surgery
Top Down
Figure 11 Top-down versus bottom-up treatment of infl ammatory
bowel disease. The top-down algorithm (left) advocates the use of
biologics (antitumor necrosis factors [anti-TNFs]) early in the
disease course. If surgery is necessary early in the disease
course, institution of anti-TNFs is required early in the top-down
algorithm. However, as shown in the bottom-up pyramid (right),
others advocate a gradual progression in treatment, commencing with
drugs with a smaller side-effect profi le and culminating in
anti-TNF treatment surgical intervention. 5-ASA = 5-aminosalicylic
acid; AZA = azathioprine; 6-MP = 6-mercaptopurine. * surgical
intervention.
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Such routine individual genotyping will lead to the more
accurate characterization of the IBD patient, allowing for the
tailoring of medical and surgical treatment [see Table 9]. Such a
personalized medical approach will likely involve initial
genotyping of IBD patients to obtain a genetic signature of sorts
that will subcategorize the patient, followed by the use of serum
markers, endoscopy, and radiographic imaging to monitor treatment
response.
Disease Classifi cation
The clinical phenotype of the individual IBD patient is
presently derived from a combination of clinical and ana-tomic
features such as disease duration, location, and sever-ity. For
example, one patient may have isolated stricturing small bowel
disease, whereas another may have fi stulizing colonic disease with
concomitant arthropathy. However, both have CD. The Montreal
classifi cation and other similar systems have attempted to provide
a phenotypic categoriza-tion system based on age at onset, anatomic
location, and disease behavior190; however, such classifi cation
systems are very imperfect. Additionally, when all possible
observations of disease behavior are considered, hundreds of
different clinical CD phenotypes are theoretically possible. In
addi-tion, as time passes, such classifi cations can change (e.g.,
the infl ammatory phenotype can become stricturing). Genotyp-ing
promises a more quantitative and objectively defi ned patient
classifi cation schema. As a fi rst pass, the very recog-nition
that there are unique genetic alleles associated with one or the
other of UC or CD suggests a possible diagnostic as well as
subclassifi cation role for genotyping.
Predicting the Development of CRC
Infl ammation is a known risk factor for the development of
cancer. Patients with the chronic infl ammation of IBD
have increased rates of CRC, with risk correlating with disease
extent and duration.191193 This risk is signifi cant as
approximately 15% of IBD patients die from CRC.194 Presently,
colonoscopy is the standard of care, but it is very imperfect, with
a 50% discordance between colonoscopic biopsy and postcolectomy
pathology. A more reliable marke r for CRC in UC is needed. A
genetic marker to predict pro-gression from UC to CRC could prompt
prophylactic colec-tomy in high-risk patients and potentially alter
surveillance colonoscopy frequency. However, to date, there has
been relatively little research in the area of CRC in UC, and,
gen-erally, studies are small and have had confl icting
results.195,196 Both distinct and overlapping genetic mutations
have been found when comparing IBD-associated CRC with sporadic
CRC, such as the cellular adhesionmodulating E-cadherin gene.
However, no clinical test using these mutations is currently in
clinical use.
Surgical Genetics
Several recent studies have attempted to identify genetic
markers to predict the need for surgery and/or surgical out-come in
IBD, and the term surgical genetics has been created to describe
such. A recent study used genotyping results at over 70 known IBD
loci and genome-wide association in 1,115 CD patients, discovering
three CD susceptibility loci independently associated with the need
for surgery within 5 years of CD diagnosis (IL23R, IL12B, and
C11orf30) and two loci, 7q21 and 9q34, associated with early
surgery.197 One area of particular clinical importance is
postileocolec-tomy recurrence, which occurs in up to 60% of
ileocolectomy patients, typically within 5 years of ileocolectomy
and as the result of a stricturing process.198200 A genetic
association between recurrent ileocolectomy and IRGM-associated
poly-morphisms has been demonstrated in multiple studies,201 with
patients with an SNP associated with this gene demon-strated to
have more frequent ileocolectomies and earlier time to
reoperation.202
Up to 60% of IPAA patients develop pouchitis or infl am-mation
of the ileal pouch of varying degrees post-IPAA.203 Depending on
severity, pouchitis can lead to prolonged courses of antibiotics or
pouch failure and pouchectomy, with permanent stoma in up to
15%.204 The ability to identify which patients will develop
recurrent debilitating pouchitis would offer the opportunity to
perform alternative surgical procedures on such patients (i.e., TPC
with a permanent ileostomy). In a recent multicenter study of 714
individuals, a NOD2insC risk variant SNP was signifi cantly
associated with chronic pouchitis and CD-like pouch complications
such as fi stula and abscess,205 suggesting that the pouchitis
patients with this mutation may have compromised host defense
against enteric bacteria.203
Presently, as disease behavior is widely variable in both UC and
CD and each goes through fl ares and remissions and includes
subsets of patients at both extremes of the dis-ease spectrum of
behavior and severity, being able to predict the natural history of
the disease using genetic criteria would greatly aid in therapeutic
decision making. An example is the TNFSF15 gene product, TL1A,
which is involved in immunoregulation and angiostasis. SNPs
associated with
Table 8 Advantages of Using Genetic Markers to Predict Disease
Course in IBD
Present at birth (before disease manifests)Do not fluctuate with
disease behavior/severity/flaresObjective measurements (not user
dependent like
colonoscopy)Obtainable by noninvasive methods (cheek swab)Can be
tested remotely from patient (i.e., at another site if
patient is remote)Relative affordability (inexpensive to
genotype a limited
number of SNPs)
IBD = infl ammatory bowel disease; SNP = single nucleotide
polymorphism.
Table 9 Areas of Surgical Application of Personalized
Medicine/Genetic Information
in IBD1. Subclassifying patients by their IBD genotype2.
Predicting response to medical treatment and postoperative outcomes
(e.g., CD recurrence, IPAA failure/pouchitis) 3. Identifying
patients destined to progress to colorectal cancer
CD = Crohn disease; IBD = infl ammatory bowel disease; IPAA =
ileal pouch-anal anastomatosis.
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gastro infl ammatory bowel disease 20
this gene have been associated with severe, medically
refrac-tory UC that requires surgery.206 Such genetic factors may
then identify subsets of patients with genes/SNPs of possi-ble
surgical relevance [see Table 10],107,197,200203,205219 and their
role in the pathophysiology of IBD is listed in Table 9 [see Table
9]. Due to the potential curative effect of total abdominal
colectomy or TPC, genetic research in UC has focused not on
characterizing disease but on predicting the need for surgery and
surgical outcomes.
The Future of Surgical Techniques in IBD
laparoscopy/single-incision laparoscopic surgery
Due to the tissue fragility of steroid-treated IBD patients and
the fi stulizing and stricturing nature of CD, laparoscopi c
procedures in the IBD population had a high conversion to open
laparoscopic procedures in the early era of laparoscopi c
surgery.220,221 However, as surgeon experience expanded,
laparoscopic outcomes improved, and such treatment has evolved to
become the current mainstay of the surgical treat-ment of CD and UC
in the majority of institutions.222225 Thus, it is likely that a
similar trend will be seen in single-site, natural orifi ce, and
robotic surgery. Single-incision laparo-scopic surgery (SILS) is
attractive due to the improved cos-mesis resulting from fewer and
smaller scars. IBD patients have been included in larger SILS
studies, and complica-tions and reoperation rates were not signifi
cantly different between the SILs and laparoscopic groups.226 Case
studies and series citing success in the use of SILS in the
treatment of
a complex ileovesical CD fistula,227 ileocolic resection
inclu-sive of an enterocutaneous fi stula,228 treatment of
abscessing or fi stulizing CD, and IPAA for UC are
available.229231
natural orifice transluminal endoscopic surgery
Several colorectal natural orifi ce transluminal endoscopic
surgery (NOTES) resections for cancer and motility disor-ders have
been performed to date. However, extensive trial of the pr