INFLAMMATORY BOWEL DISEASE - acreditacion … · INFLAMMATORY BOWEL DISEASE Tara M. Connelly, MB,...

Scientifi c American SurgeryDOI 10.2310/7800.2267

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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

Scientifi c American Surgery

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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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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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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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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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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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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


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.


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.


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


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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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

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