Classification and Reclassification of Inflammatory Bowel Diseases

Chapter 2

Classification and Reclassification of Inflammatory Bowel Diseases: From Clinical Perspective Shannon Chang1 and Bo Shen2 1

New York University Langone Medical Center, New York, NY, United States; 2The Cleveland Clinic Foundation, Cleveland, OH, United States

LIST OF ABBREVIATIONS AimD Autoimmune disorder AinD Autoinflammatory disorder ASC Adipose-derived stem cells ASCT Autologous hematopoietic stem-cell transplantation CARP Chronic antibiotic-refractory pouchitis CD Crohn’s disease EIM Extraintestinal manifestation FDA The Food and Drug Administration FMF Familial Mediterranean fever FMT Fecal microbiota transplantation G-CSF Granulocyte colony-stimulating factor GI Gastrointestinal GVHD Graft-versus-host disease GWAS Genome-wide association studies IBD Inflammatory bowel disease IBD-U Inflammatory bowel diseaseeunclassified IBD-V Inflammatory bowel diseaseevariant IC Indeterminate colitis IPAA Ileal pouch-anal anastomosis ITB Intestinal tuberculosis IL Interleukin IVIG Intravenous immunoglobulin MAP Mycobacterium avium paratuberculosis NAID NOD2-associated autoinflammatory disease NOD Nucleotide-binding oligomerization domain containing OLT Orthotopic liver transplantation PSC Primary sclerosing cholangitis TNF Tumor necrosis factor UC Ulcerative colitis

INTRODUCTION Classic inflammatory bowel disease (IBD) consists of Crohn’s disease (CD) and ulcerative colitis (UC), which

run chronic diseases with relapsing and remitting clinical courses. The diagnosis of IBD is made with histologic evidence of inflammatory and structural changes, with or without acute inflammation, combined with supporting clinical, endoscopic, and radiological features. The exact “triggers” for IBD are not entirely clear but the diseases are believed to be caused by a combination of genetic predisposition, abnormal immunity, and environmental exposures.1 Generally speaking, classic IBD has been considered to be idiopathic. As it is apparent in clinical practice, the phenotype IBD is far from uniform. Whereas one patient may have severe Crohn’s colitis with debilitating arthropathy, another patient may have mild UC with pyoderma gangrenosum (PG). The diagnosis may be unclear in 10%e15% of patients who will carry a disease entity of IBD-unclassified (IBD-U).2,3 To confuse the picture even further, infectious mimics to IBD such as intestinal tuberculosis (ITB) are frequently difficult to differentiate from CD.4 Inflammatory bowel disease can be associated with traditionally defined extraintestinal manifestation (EIM) such as primary sclerosing cholangitis (PSC) and PG. However, various autoimmune and autoinflammatory diseases occur concomitantly with IBD but are not considered to be classic IBD-associated EIMs. For example, IBD patients may have concurrent psoriasis, autoimmune hepatitis, or celiac disease. Those immune-mediated diseases have normally viewed as separate, distinct entities from IBD. However, those immune-mediated disorders, including classic, idiopathic IBD, may share part(s) of common pathways. Aside from the Montreal classification for CD and UC, multiple different classifications have been proposed.

Interventional Inflammatory Bowel Disease: Endoscopic Management and Treatment of Complications. http://dx.doi.org/10.1016/B978-0-12-811388-2.00002-6 Copyright © 2018 Elsevier Inc. All rights reserved.

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Interventional Inflammatory Bowel Disease: Endoscopic Management and Treatment of Complications

Vermeire et al.5 advocated for a molecular reclassification of IBD, noting that there is frequently a poor correlation between genetic-based subgroups and clinical phenotypes. Shen et al.6 proposed a systemic overlap syndrome of the gut (IBD) and liver. Cleynen et al.7 reported genetic evidence supporting a location-focused classification of IBD, for example, ileitis, colitis, ileocolitis, and proctitis. Levine et al.8 elaborated on the Montreal classification, advocating for pediatric IBD to be subdivided into diagnosis before or after age 10.9 We propose an adjustment from the traditional concept of IBD as a stand-alone field to IBD as a part of a spectrum of immune-mediated intestinal diseases and overlap syndromes. IBD can be further delineated into primary (“classic”) and secondary IBD. Variables such as the genome, exposome, microbiome, and immunome contribute to the variation in disease presentations, disease course, and outcomes.

CONVENTIONAL THEORIES OF PATHOGENESIS OF IBD The conventional theory in the pathogenesis of UC and CD begins with a dysbiotic shift followed by dysregulated innate and adaptive immunity in genetically susceptible hosts.10 Noticeable shifts in bacterial flora are apparent in IBD patients, with an overrepresentation of select bacterial taxa and decrease in overall diversity of the bacterial community.11 This dysbiosis leads to an inflammatory response. Genetic variants such as nucleotide-binding oligomerization domain containing 2 (NOD2), lead to alterations in host innate immunity such as defective sensing of bacteria and decreased production of antimicrobial peptides.12 Defects in innate immunity result in dysregulated T-cells of the adaptive immune system, chronic inflammation, and enterocyte apoptosis.13 The etiopathogenesis of UC and CD is also described in Chapter 1. Genetic factors, such as interleukin-10 (IL-10)/IL-10R

mutations may play a more important role in pathogenesis of infant or pediatric onset of IBD.

FEATURES OF CLASSIC IBD The definition of IBD has been traditionally limited to CD and UC. In some cases the diagnosis is unclear, despite clinical, endoscopic, radiographic, and gross pathologic evaluations. The label of IBD-indeterminate or indeterminate colitis (IC) is usually given in these cases.14 The Montreal classification is commonly used to categorize CD in terms of age, behavior (inflammatory, stricturing, penetrating), and location (ileal, colonic, ileocolonic, upper gastrointestinal (GI) tract, and perianal). In UC, patients are categorized based on the extent of disease (proctitis, left-sided colitis, and extensive colitis) and disease severity.15 The conventional discriminating features have been used to differentiate UC from CD for decades. CD may involve any part(s) of the GI tract, whereas UC is confined to the colon, rectum, and in some cases, distal ileum (backwash ileitis). Inflammation in CD (with or without granulomas) may extend transmurally, leading to a diverse array of complications including stricture, fistula, and abscess, whereas inflammation in UC is generally limited to the mucosa, muscularis, and up to the superficial submucosa (Fig. 2.1). In addition, a segmental distribution with skip lesions and rectal sparing are characteristics of CD, whereas the rectum is always affected in UC at presentation. Of interest, the disease location and extent of CD remain relatively stable,7 even after ileocolonic resection,16 whereas the disease extent of UC often migrates proximately. These phenomena suggest that etiopathogenetic pathways of CD and UC do not completely overlap. The treatment of IBD involves use of antiinflammatory agents such as mesalamines, corticosteroids, immunomodulators (e.g., thiopurines and methotrexate), anti-tumor

FIGURE 2.1 Depth of inflammation in various forms of immune-mediated chronic inflammatory bowel disease.

Celiac Lymphocytic Collagenous Autoimmune disease colitis colitis enteropathy Ulcerative colitis

Autoinflammatory disorders

Depth of Gut Involvment

Idiopathic colon/small bowel ulcer syndrome

Behcet’s

Crohn’s disease

Intestinal tuberculosis

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necrosis factor a (TNFa; e.g., infliximab, adalimumab, golimumab, and certolizumab pegol), anti-integrins (e.g., vedolizumab and natalizumab), anti-ILs (e.g., ustekinumab), and pathway-targeted small molecules (e.g., ozanimod). The newer agents have been developed to target various etiopathogenetic pathways involved in IBD.

CONVENTIONAL CLASSIFICATION OF IBD Inflammatory bowel disease has traditionally been classified into UC and CD. The term of IC has been used by the GI pathologist to describe transmural inflammation in severely inflamed colon, which precludes the diagnosis of UC or CD. Patients with clinical, endoscopic, and histologic features, which do not completely fit the diagnosis of UC or CD, may be labeled as IBD-U. Both UC and CD are then further subclassified based on the age of onset, disease location/extent, and disease phenotype and severity. The most commonly used is the Montreal classification (see Chapter 1). However, the current classification systems are not able to cover the spectrum of immune-mediated IBD and IBDlike conditions, with a wide range of etiopathogenesis, disease course, phenotypes, and histopathologic features.

GENETIC CONTRIBUTIONS IN DEVELOPMENT OF IBD The classic boundary between UC and CD is frequently obscured. Up to 9% of patients diagnosed with either UC or CD may have their diagnosis changed within the first 2 years after diagnosis.17 Approximately 23%e35% of patients with CD have disease limited to the large bowel, that is, Crohn’s colitis.18 The distinction between Crohn’s colitis and UC can be challenging, especially if the colon has severe inflammation, leading to a histopathologic diagnosis of IC (Fig. 2.2). It has also been reported that some patients with UC may have duodenal involvement,19 especially in those with concurrent PSC. These ill-defined “gray zones” have posed a great challenge for clinicians in the diagnosis and management of IBD. Attempts have been made to further define these “gray zones” based on genetics. It is known that of the 163 confirmed IBD susceptibility loci, many are dually associated with both UC and CD, making the majority of IBD polygenic.20 Moreover, a recent genetic-phenotype profiling study redefined IBD into three groups, ileal CD, colonic CD, and UC, noting that disease location has a strong association with genetics. In contrast, traditional distinctions (UC and CD) or disease behavior (penetrating, stricturing, inflammatory) do not match up well with predictive models of genetic risk.7

FIGURE 2.2 Severe underlying ulcerative colitis with transmural lymphocyte infiltration leading to a later diagnosis of indeterminate colitis.

Single-gene mutations, rather than gene profiling, can also define phenotype in pediatric IBD. Monogenic mutations in IL-10RA and IL-10RB determine phenotype in a very early-onset IBD.9,21e25 In very early-onset IBD, infants develop symptoms of perianal fistulas, diarrhea, oral ulcers, and folliculitis within the first year of life. The defect in IL-10 signaling in this special form of IBD has a Mendelian inheritance pattern with complete penetrance.9 Owing to the unique genetic defect leading to disease, patients with very early-onset IBD do not usually respond to conventional IBD therapy and require alternative treatments such as allogeneic stem-cell transplants.25 Thus in many forms of IBD, there are genetically driven (monogenic and polygenic) disease phenotypes.

IBD WITH EIMS Inflammatory Bowel Disease frequently presents with EIMs involving the skin, eyes, joints, liver, lungs, or pancreas.26 The classic EIMs include erythema nodosum, PG, uveitis, episcleritis, iritis, ankylosing spondylitis, sacroiliitis, and PSC. The gut disease activity of IBD may or may not be associated with the presence of and severity of those EIMs. The treatment of the underlying IBD is a key to controlling many of these EIMs. In contrast the severity of some EIMs is not driven by underlying intestinal inflammation. For example, the disease courses PG, ankylosing spondylitis, and PSC are independent of bowel inflammation.27 This is particularly apparent in the disease course of PSC in postcolectomy UC patients. It is unclear why certain diseases have been labeled as EIMs of IBD, whereas other commonly IBD-associated disorders are referred to as separate disease entities. For

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Interventional Inflammatory Bowel Disease: Endoscopic Management and Treatment of Complications

TABLE 2.1 Examples of Arbitrary Classification of Extraintestinal Manifestations and Concurrent Autoimmune Disorders of Inflammatory Bowel Disease Classic Extraintestinal Manifestations of Inflammatory Bowel Disease

Examples of “Concurrent” Autoimmune Disorders of Inflammatory Bowel Disease

Skin

Pyoderma gangrenosum, erythema nodosum

Psoriasis, Hashimoto thyroiditis, celiac disease

Liver

Primary sclerosing cholangitis

Primary biliary cirrhosis, autoimmune hepatitis

Joint

Ankylosing spondylitis

Rheumatoid arthritis

Vascular

Thromboembolism

Autoimmune vasculitis

instance, ankylosing spondylitis is considered an EIM of IBD, whereas rheumatoid arthritis is regarded as a concurrent autoimmune disorder (AimD) (Table 2.1). In fact, patients with IBD were shown to have comparably high odds ratios of having ankylosing spondylitis (odds ratio ¼ 5.1) or rheumatoid arthritis (odds ratio ¼ 3.5).28 As another example, unlike erythema nodosum or PG, psoriasis is not considered a dermatologic EIM of IBD, despite the known association between psoriasis and IBD.29,30 In fact, ustekinumab, an agent for psoriasis, was recently approved for the treatment of CD in the United States.31,32 Other immune-mediated diseases, such as autoimmune thyroiditis and autoimmune hepatitis, which occur concomitantly with IBD, are considered as concurrent AimDs but as classic EIMs of IBD. Up to now, we have taken this traditional classification system at face value, which has created confusion in clinical practice. This is now leading to our proposal for reclassification of IBD and its associated disorders (Table 2.2).

OVERLAP OF IBD AND AIMDS Inflammatory bowel disease and other AimDs are known to occur together in a subset of patients. The list of AimDs overlapping with IBD is extensive, including celiac disease, microscopic colitis, Hashimoto thyroiditis, psoriasis, rheumatoid arthritis, and autoimmune hepatitis. For example, two common immune-mediated bowel diseases, celiac disease and IBD, can occur concurrently.33e35 CD and UC have a reported prevalence of 4% and 3.2%, respectively, in patients with celiac disease,33 which is higher than the prevalence of 1%e2% in the general population.36 Interestingly, patients with coexisting celiac disease and UC were more likely to have extensive colitis.33,37 This more extensive clinical phenotype suggests that overlap of celiac disease and UC may represent a distinct phenotype of IBD. In addition, lymphocytic colitis and collagenous colitis can also be present in IBD patients.38,39 In the majority of reported cases, older patients with microscopic colitis, usually collagenous colitis, later on may develop UC.38 One of

explanations for the overlap between IBD and those AimDs is from genetic association. AimDs, such as psoriasis, systemic lupus erythematosus, type 1 diabetes mellitus, multiple sclerosis, and vitiligo, have been clinically as well as genetically linked with IBD in genome-wide association studies (GWAS).40 GWAS highlight the genetic contribution to IBD overlap with autoinflammatory disorders (AinDs). The genetic studies are the first step for the molecular classification of the spectrum of immune-mediated disorders.

OVERLAP OF IBD AND AINDS Autoinflammatory disorders are diseases with episodes of unprovoked inflammation without known high-titer antibodies or antigen-specific T-cells.41 The overlap between CD and other AinD is, in part, being elucidated with genetic sequencing studies. The association between CD and NOD2 gene was discovered in 2001, paving the way for the discovery of other AimD associated with NOD2 variants such as NOD2-associated autoinflammatory disease (NAID), Blau syndrome, and familial Mediterranean fever (FMF).42e45 For example, a patient with CD has been reported to have FMF and chronic idiopathic urticarial with angioedema without identified NOD2 mutations.46 NOD2-associated autoinflammatory disease is a recently described disease with a constellation of inflammatory symptoms including periodic fever, dermatitis, arthritis, abdominal pain, non-bloody diarrhea, lower extremity swelling, and sicca-like symptoms.47 Yao et al.47 described a cohort of 54 adults with identified NOD2 variants and low titers of antinuclear antibody (ANA) without coexisting AimD, AinD, and classic IBD. Although NAID and IBD may represent separate disease entities, there are shared clinical manifestations such as arthritis and colitis. The colitis in NAID usually is not severe and does not have histologic changes of classic IBD.47 As with UC and CD, genetic association may be partially responsible for the overlap seen between IBD and AinD.

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TABLE 2.2 Proposed Classification of Inflammatory Bowel Diseases Criteria

Class

Description

Examples

Disease location, extent and depth þ/ granulomas

Ulcerative colitis

Classic ulcerative colitis

Crohn’s disease

Classic Crohn’s disease

Age of onset

Very early onset

Age 0

Early onset

Age 0e10 years

Indeterminate colitis IL-10/ILR mutations

Age 10e17 years

Phenotype

Locations

Regular onset

Age 17e40 years

Late onset

Age >50 years

Inflammatory

Inflammatory Crohn’s disease; classic ulcerative colitis

Stricturing

Stricturing Crohn’s disease; ulcerative colitis with stricture

Penetrating

Fistulizing Crohn’s disease

Oral Upper gastrointestinal Jejunum Ileum Colon Rectum Perianal

Concurrent or immunemediated disorders

Extraintestinal

Metastatic Crohn’s disease of the skin, lung, liver

IBD

Isolated ulcerative colitis or Crohn’s disease of the gut

IBDvariant

IBDþ

IBD þ classic extraintestinal manifestations

Ulcerative colitis with concurrent primary sclerosing cholangitis

IBDþþ

IBD þ autoimmune and/or autoinflammatory disorders  classic extraintestinal manifestations

IBD with concurrent microscopic colitis, celiac disease, hidradenitis suppurativa

IBDþ/

Diseases sharing clinical features and possible etiopathogenetic pathways with classic IBD  classic extraintestinal manifestations of IBD, autoimmune disorders or autoinflammatory disorders

Lymphocytic colitis, collagenous colitis; Behcet’s disease, cryptogenic multifocal ulcerous stenosing enteritis, ulcerative jejunitis

Monogenic

IL-10, IL-10RA, IL-10RB mutations Very earlyeonset IBD

Polygenic

Classic ulcerative colitis; classic Crohn’s disease

Identifiable pathogens

Mycobacterium avium paratuberculosis

Medication-induced

Mycophenolate-associated colitis; Ipilimumabassociated colitis

Organ transplantation-induced

Post-solid organ transplant IBD-like conditions, cord colitis syndrome;

Surgery-induced

Pouchitis, Crohn’s disease-like conditions of the pouch, postcolectomy enteritis, bariatric surgeryassociated IBD



Etiology of IBD

Primary or idiopathic

Secondary

Continued

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Interventional Inflammatory Bowel Disease: Endoscopic Management and Treatment of Complications

TABLE 2.2 Proposed Classification of Inflammatory Bowel Diseasesdcont’d Criteria Genetic etiology

Disease spread process

Class

Description

Examples

Monogenic

IL-10/IL-R mutations, familial Mediterranean fever

Polygenic

Classic Crohn’s disease and classic ulcerative colitis

Intrinsic (“insideout”)

Starting from the lymphatic system or mesentery, spreading to gut mucosa

Subset of obese Crohn’s disease patients; subset of sclerosing mesenteritis or lymphangitis

Extrinsic (“outside-in”)

External trigger (e.g. bacteria) leading to mucosal inflammation

Fulminant ulcerative colitis: from mucosal disease to transmural inflammation

IBD, inflammatory bowel disease.

SPECTRUM OF IMMUNE-MEDIATED DISORDERS OF THE GUT Diverging from the Montreal classification of CD and UC,15 the different clinical phenotypes of IBD could be organized into alternative classifications based on available, emerging data (Table 2.2). The spectrum of immunemediated disorders can be categorized according to the clinicopathological features.

Pattern of Disease Extent: Small and Large Bowels Disorders of the gut could be described as a range of diseases involving the colon to the small bowel (Fig. 2.3). Typical disease phenotypes vary from UC proctitis to ileal CD. Cleynen et al.7 recently published data on genetic risk scores for corresponding phenotypes in 35,000 patients with IBD.7 Comparing the Montreal classifications, patient samples were genotyped using the Immunochip array (Illumina, San Diego, CA) to evaluate for 195,806 polymorphisms associated with IBD. The authors noted incongruence between genetic-based subgroups and clinical subphenotypes. Rather than finding correlations with the disease classifications, CD versus UC, the location of disease was found to have the strongest genetic association. The genetic substructure of IBD was divided into UC, colonic IBD-U, colonic CD, ileocolonic CD, and ileal CD. Stricturing CD, a behavioral classification, did not have a FIGURE 2.3 Range of “classic” IBD from the rectum to distal ileum. IBD, inflammatory bowel disease; UC, ulcerative colitis.

strong genetic association. Similar findings were described when examining gene expression and regulation whereby CD could be clearly divided into colon and ileal subclasses.48 These findings point toward location as a fundamental biological aspect of disease over behavior, which is likely a marker of disease progression.7 There are variants for the classified pattern of disease extent. UC with duodenitis is an example.

Pattern of Disease Spread: Extrinsic Versus Intrinsic Immune-mediated gut disorders have a wide range of histopathologic features. Classic mucosal disease, such as lymphocytic colitis, collagenous colitis, and celiac disease, has disease involvement limited to the epithelium, glands, and lamina propria. UC can involve the mucosa, muscularis, and superficial submucosa. However, severe or fulminant UC can present with deep fissure-like ulcers and transmural inflammation with lymphoid aggregate (Fig. 2.2). These diseases are classic examples for the extrinsic or “outside-in” theory of immune-mediated gut disorders, that is, from the mucosa to deeper layers of the bowel wall (Fig. 2.4). The theory of dysbiosis as a trigger for IBD fits the clinical and histopathologic picture for these disease processes. Logically speaking, the change in gut microbiome may be the primary event in spread of disease from the outside to inside. Supporting this theory, patients with CD or UC may have a preceded viral or

Colonic to Small Bowel IBD

UC Proctitis

UC pancolitis

UC pancolitis/ backwash ileitis

Crohn’s colitis

Crohn’s Ileocolitis

Crohn’s Ileitis

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(A)

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(B)

(C) (D)

FIGURE 2.4 Features suggestive intrinsic theory of Crohn’s disease. (A and B) Fat wrapping; (C) Fistula opening with minimum adjacent mucosal inflammation; (D) Extensive fistula with thick mesenteric adipose tissues.

bacterial gastroenteritis and some patients with CD may respond to luminally active antimicrobial agents. In contrast, the “inside-out” theory or the intrinsic pathway of IBD implies that the disease process starts from within the mesentery, serosa, or deep bowel wall, subsequently outward to the mucosa. In these diseases, inflammation may not always follow the route from the lumen to serosa; mucosal ulceration may be a terminal event rather than the first event .49 CD and Behcet’s disease are classic examples of transmural, segmental, inflammatory disorders of the gut.50,51 CD-associated gene mutations in NOD2, ATG16L1, and IRGM lead to defective immune response to intracellular bacteria, the bacteria not invading from the gut lumen.15 In our clinical practice, we have noticed that mucosa-active agents, such as mesalamines, are not effective to treating patients with transmural CD. Furthermore, the mesentery is hypothesized to harbor the source for chronic intestinal inflammation, which may play a key role in the development of intrinsic IBD. Spanning from the duodenum to rectum, the mesentery comprises a continuous network of lymphatics, nerves, vasculature, connective tissue, and adipose tissue.52,53

Owing to its anatomic complexity and functional role in regulating local and systemic homeostasis, Coffey et al.53 postulated that the mesentery is a distinct organ, playing an important role in pathogenesis in various diseases. Mesenteric lymph and adipose tissue have been implicated in the early pathogenesis of CD, with bacterial invasion into lymph nodes leading to lymphangitis, lymphangiectasia, and mesenteric adenitis development before any apparent mucosal pathology.49,54,55 The deep, linear ulcers’ characteristics of CD are seen on the mesentery side of the bowel, supporting a model of mesenteric adenitis and lymphangitis in mucosal inflammation. Indeed, the mesentery, including lymphatic, vascular, and neural systems, may help explain the patchy, “skip-lesion” distribution of inflammation in CD .56 In addition the available body of evidence suggests that the adipose tissue in the mesentery plays an important role in CD and maybe IBD in general. Mesenteric adipose tissue produces proinflammatory cytokines, including TNF.57 Increased mesenteric fat hypertrophy is seen in obesity and CD.58 The characteristic intestinal adipose tissue proliferation known as “fat wrapping” of inflamed bowel is a

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Interventional Inflammatory Bowel Disease: Endoscopic Management and Treatment of Complications

hallmark of CD. In postoperative CD patients, increased visceral fat area is associated with endoscopic recurrence of CD .56 If this is true, the prevention of postoperative CD recurrence may depend upon surgical handling of the mesentery (Fig. 2.4). In clinical practice, we have noticed a growing number of obese patients with CD, in stark contrast to the more typical, underweight, malnourished CD patients. Obese CD patients with increased mesenteric fat, particularly African Americans59 or Hispanic Americans,60,61 often present with severe fistulizing perianal disease.62 Obese CD patients have been shown to have a higher risk for postoperative complications63 and postoperative disease recurrence.56 Malnourished CD patients often have severe mucosal inflammation, along with strictures or fistulae, whereas obese CD patients may have severe enteroenteric or perianal fistulae with minimal mucosal disease (Fig. 2.4). Given that increased visceral adipose mass is also associated with insulin resistance and the metabolic syndrome, it is possible that as the obesity epidemic continues, there may be a unique phenotype of obese CD patients with more severe inflammation that is driven by the mesentery outward to the mucosa rather than by mucosal inflammation extending inward to deeper layers of bowel wall. CD may even be considered as part of metabolic syndrome. Thus, two models of CD spread exist: extrinsic or “outside-in” and intrinsic or “inside-out.” The currently accepted “outside-in” model does not explain the clinical presentation of all CD patients. The “inside-out” theory suggests that signals from mesenteric adipose tissues, lymphatic system, and possible vascular and neural system contribute to the initiation of (the “inside-out” theory) or exacerbation of CD .55

phenotype and disease behavior, which extends beyond classic IBD and classic EIM. Analogous to the local overlap syndrome of GI system is that in the hepatopancreaticobiliary system. PSC may exist as an isolated disease but may occur concurrently with primary biliary cholangitis and/or autoimmune hepatitis.64e66 In fact, PSC per se represents a spectrum of diseases ranging from classic PSC to immunoglobulin G4 (IgG4)-related sclerosing cholangitis to autoimmune sclerosing cholangitis with varying clinical presentations, natural history, and disease course.6 At times, the diagnosis is unclear with overlap of clinical, histologic, and immunologic features of multiple diseases. The establishment of the correct diagnoses is important because treatment may be targeted to multiple diseases or a common “denominator.” The mechanisms for the development of overlap syndromes are not well defined, hence optimal treatments for overlap syndromes are also not well defined. The understanding of systemic overlap syndromes involving IBD may lead to more efficacious treatment options for these unique phenotypes.

Overlap Syndrome of Gut Similar to the liver diseases, a subset of IBD patients will develop an overlap syndrome of immune-mediated disorders in the gut. A classic example is concurrent UC or CD and microscopic colitis, celiac disease, or autoimmune enteritis (Fig. 2.5).

Systemic Overlap Syndromes The inflammatory and autoimmune features of IBD tend to overlap with extraintestinal disorders. Diseases that involve the gut are not always confined to the gut (Fig. 2.5). A classic example of gut-and-body overlap syndromes is UC and PSC. Although approximately 5% of UC patients have PSC, 60%e80% of patients with PSC have UC or Crohn’s colitis.67 There is a well-established overlap between the two diseases, but both diseases may exist independently. Of

Overlap Syndrome of Immune-Mediated Disorders Overlap syndromes can be defined as multiple disease states occurring together to produce a unique clinical

FIGURE 2.5 Range of overlap syndrome from isolated gut disorder to multi-organ involvement of immune-mediated disorders. CD, Crohn’s disease; IBD, inflammatory bowel disease; ITB, intestinal tuberculosis; UC, ulcerative colitis

Lymphocytic colitis Collagenous colitis

IBD + extra-intestinal manifestations

UC

Autoimmune disorders

GI and multi-organ involvement

Idiopathic colon/small bowel ulcer/stricture syndrome

Celiac disease

CD ITB

Behcet’s

Autoinflammatory disorders

Systemic overlap syndrome

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interest, concurrent PSC may adversely impact the disease location and course (e.g., colitis-associated neoplasia) in UC, but the disease severity of UC has a minimum impact on the disease course of PSC (e.g., risk for development of cholangiocarcinoma or the need for orthotopic liver transplantation [OLT]).68 Patients with PSC and UC have a fivefold increased risk of colonic neoplasia as compared to patients with UC alone.69 PSC patients undergoing ileal pouch-anal anastomosis (IPAA) are at an increased risk for the development of chronic antibiotic-refractory pouchitis (CARP).70,71 As such, PSC-UC patients can be thought of as a unique phenotype in the spectrum of systemic overlap syndromes. Using pouchitis as another model, we have found that pouchitis can overlap with AimD.71 Pouchitis patients with more complicated, severe phenotypes such as CARP tend to exhibit autoimmune overlap with concomitant AimD such as PSC, psoriasis, idiopathic thrombocytopenic purpura, or type 1 diabetes. In addition, patients with CARP are prone to having positive autoantibodies including ANA, antimicrosomal antibody, and celiac serology; classic EIM of IBD; and tissue infiltration by IgG4-expressing plasma cells. We are currently investigating this model in IBD.

Overlaps Between Chronic Gut Infection and Inflammation Host immune systems are deeply influenced by the microbiota to which they are exposed. There is a close association between chronic inflammatory disorders and chronic infectious disorders, of the gut. The contribution of gut microbiota to chronic intestinal diseases can be (1) dysbiosis or alteration in the quantity and/or quality of commensal bacteria or fungi; and (2) infection by pathogenic bacteria, viruses, or fungi. To illustrate, a preceding acute, infectious gastroenteritis increases the risk of IBD two- or three-folds, particularly in the first year after gastroenteritis.72 The exposure to Campylobacter and Salmonella species may be associated with an increased risk for developing CD or UC.73 There is considerable overlap between the mycobacterial infections, leprosy and tuberculosis (TB), and IBD. Clinically, histologically, and radiographically, we have found that the distinction between ileal TB and Crohn’s ileitis is often difficult,74,75 while this distinction is critical for the treatment. A common scenario seen in clinical practice is a CD patient with persistently positive TB skin tests or serum assays despite anti-TB treatment. The possibility of latent TB cannot be completely excluded, and clinicians are hesitant to start anti-TNF therapy. It is possible that longstanding latent TB may become an etiopathogenetic factor for CD. This notion has been supported by evidence of genetic studies. It has been shown that the genetic susceptibility loci are shared by CD and

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mycobacterial infections. Near the NOD2 genes on chromosome 16, there is a cluster of IBD genes that are linked with Mycobacterium tuberculosis response.20 Similarly, four loci linked to Mycobacterium leprae are also linked to IBD. Mycobacterium avium paratuberculosis (MAP) infection has been hypothesized to cause CD, although treatment of MAP infection to induce remission in CD has yielded mixed results to date.76 Further genetic and microbiome studies are needed to elucidate the relationship between IBD and possible infectious mechanisms of disease.

TRIGGERING FACTORS FOR DE NOVO IBD: CONCEPT OF SECONDARY IBD Aside from the classic theory of dysbiosis, other triggers may alter the immune system homeostasis. To make a metaphor, the immune thermostat is “reset” or “turned on” after a stimulus. For reasons not yet understood, an intervention that beneficially alters the immune thermostat for one patient may conversely trigger IBD flare-up in others. Fecal microbiota transplantation (FMT) is one example. Other treatments and interventions also alter the immune thermostat, for better or worse, including medications, organ transplantation, and abdominal surgeries.

Fecal Microbiota Transplantation Clinical and experimental evidence supports the theory that dysbiosis exists in UC and CD patients77,78 and FMT may reverse dysbiosis and its consequences, leading to the improvement or resolution of infections such as Clostridium difficile79,80 or diseases such as UC.81 FMT yields conflicting results in the treatment of IBD. Moayyedi et al.82 reported a higher rate of UC remission with 6 weeks of fecal retention enemas for active UC than placebo. In a small study by Rossen et al.,83 there were higher rates of clinical and endoscopic remission in UC patients who received FMT via nasoduodenal infusion. A meta-analysis of 18 studies (with a total of 122 IBD patients) found that 45% achieved clinical remission with FMT.84 In these studies, resetting the dysbiosis potentially attenuated the aberrant immune response. However, in other patients, FMT triggered flares85e87 or possibly new IBD.88 The alteration of the microbiome may be a double-edged sword. As there are only small numbers of IBD patients studied in treatment with FMT, more investigation is needed to understand how FMT alters gut microbiome and immune system of the host.

Immunosuppressive Medications It is well known that medications used to treat AimD can paradoxically trigger autoinflammatory and autoimmune

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Interventional Inflammatory Bowel Disease: Endoscopic Management and Treatment of Complications

conditions. TNFa inhibitors are a good example. TNFa inhibitors are a mainstay for treating IBD and its EIMs, such as arthritis, PG, and erythema nodosum.89 However, antiTNFa such as infliximab can cause autoimmune hepatitis or drug-induced lupus with corresponding autoantibody formation.90e92 TNFa inhibitors are also associated with a risk for the development of multiple sclerosis, as overexpression of TNFa in the brain is associated with demyelination syndromes.93 Another example is that the use of TNFa inhibitors commonly improves arthralgia in IBD, while paradoxical, painful arthropathy may also develop.94 Furthermore, TNFa inhibitors have been routinely used to treat psoriasis. Adverse events with paradoxical skin disorders occur in 20%e25% of patients receiving anti-TNFa, with the majority being psoriasiform lesions.95 Patients who develop these skin lesions tend to respond to anti-TNFa therapy; approximately 70% of IBD patients are without active luminal disease, despite the development of cutaneous lesions.95e97 The reason for these paradoxical psoriasiform eruptions is unclear, but there are known genetic loci such as IL23R and IL12B shared between IBD and psoriasis.95 The development of antibodies such as ANA and dsDNA (double-stranded DNA) occurs more frequently in patients with known risk loci.98 In patients without a history of psoriasis before TNFa inhibitor exposure but with a genetic propensity, those agents may be an environmental trigger leading to immunological changes. The classic example of drug-induced IBD is mycophenolate mofetileassociated colitis. In multiple small trials, mycophenolate mofetil with or without corticosteroids had favorable short-term clinical efficacy in CD, including perianal disease.99,100 On the other hand, mycophenolate, especially in a postorgan transplant setting, is known to cause a colitis that is histologically similar to graft-versushost disease (GVHD) or IBD.101 Similarly, calcineurin inhibitors such as cyclosporine and tacrolimus are treatments for UC.102 However, tacrolimus, also a calcineurin inhibitor, has been shown to cause de novo IBD-like colitis in patients after renal transplantation.103 A new generation of anti-ILs is undergoing clinical trials for the treatment of IBD. The Food and Drug Administration approved ustekinumab, an anti-IL-12/23 antibody, for the treatment of CD, in addition to psoriasis. Secukinumab, an anti-IL-17A agent, for the treatment of psoriasis, can result in paradoxical worsening of CD.104

Immune-Boosting Medications While immunosuppressive agents are the mainstay in the treatment of IBD and other immune-mediated disorders, other schools of thought have advocated for the treatment focused on boosting the innate and adaptive immune systems. It has been postulated that CD can result from an

immune deficiency rather than from overactive or dysregulated immune system.49 For example, granulocyte colony-stimulating factor (G-CSF) has been reported to heal recalcitrant enterocutaneous and perianal fistulas in an adolescent CD patient previously treated with mercaptopurine, metronidazole, prednisone, and even fecal diversion.105 Sargramostim, a G-CSF, significantly improved clinical response in CD patients compared with placebo.106 G-CSF is hypothesized to boost the function of neutrophils in CD.107 Intravenous immunoglobulin (IVIG) has also been used in various autoimmune conditions characterized by ineffective immune responses to provide antiinflammatory and immunomodulatory benefits.108 Small cohorts of patients receiving IVIG have shown clinical improvement in the disease course of IBD,108 multiple sclerosis,109 systemic sclerosis,110 and chronic inflammatory demyelinating polyneuropathy.111 IVIG may help reset the immune thermostat, especially in patients refractory IBD who have been treated with aggressive immunosuppressive medications.

Stem Cell and Solid Organ Transplantations Organ transplantation may be beneficial for resetting the immune thermostat and clinically is being used in the treatment of IBD. In refractory IBD, stem cell and organ transplantations have been used as a “final-line” therapy. The intended results of transplantation for refractory CD are to reset or restore the peripheral T-cell tolerance that is lost in CD. In clinical practice, autologous hematopoietic stem-cell transplantation (ASCT) has been used as a salvage therapy for severe refractory CD.112 In addition to ASCT, results using adipose-derived stem cells have shown efficacy in the closure of perianal fistulas and rectovaginal fistulas in CD.113e115 Finally, small bowel transplantation is a life-saving treatment for CD patients with intestinal failure. In the largest cohort of 65 CD patients receiving intestinal transplantation, the recurrence of CD after small bowel transplantation was remarkably low (7.7%).116 The findings suggest that small bowel transplantation may also reset the body’s immune thermostat, helping eradicate the disease, despite the development of various transplantrelated issues. On the other hand, organ transplantation can result in “IBD-like” conditions. For example, colitis syndromes develop de novo after stem-cell transplantation. Cord colitis syndrome, which develops after umbilical cord blood transplantation, can present with a delayed, culturenegative diarrheal illness that is distinct from GVHD.117 Cord colitis syndrome may have granulomatous or lymphohistiocytic inflammation, Paneth cell metaplasia, and crypt architectural distortion, similar to histology seen in classic CD.118 Cord colitis syndrome may represent a new

Classification and Reclassification of Inflammatory Bowel Diseases Chapter | 2

form of secondary IBD, which is distinct from GVHD, mycophenolate-induced colitis, or classic (primary) IBD.101,119,120 Unlike classic IBD and GVHD, cord colitis syndrome typically responds to a short course of antibiotics rather than corticosteroids.118 De novo IBD occasionally occurs after solid organ transplant.121 The 10-year cumulative risk of de novo IBD after OLT has been reported to be as high as 30%.122 Although, as expected, the majority of patients who developed de novo IBD after OLT had PSC, there were also cases reported after transplantation for autoimmune hepatitis, alcoholic liver disease, primary biliary cholangitis, and other diseases not classically associated with IBD.121 It is of interest that IBD develops after transplantation despite the use of immunosuppressive, antirejection medications. Transplantation, in some cases, changes the immune thermostat, leading to the development of secondary IBD.

Bowel-Altering Surgery Abdominal surgery can “cure” some patients of UC or CD, whereas the same surgery can also either trigger or exacerbate IBD. For example, some CD patients with the distal small bowel, large bowel, or perianal disease, and most UC patients, may be “cured” by proximal fecal diversion with ileostomy without the need of further medical therapy for IBD .123 In addition, in a small cohort of 11 patients diagnosed preoperatively with Crohn’s colitis (with presence of granulomas on biopsy or perianal fistulas) who

(A)

underwent restorative proctocolectomy and IPAA, four patients did not develop recurrent CD over a median follow-up of 7 years.124 The CD was considered “cured” by surgery, but on the other hand, bowel-altering surgery can trigger the development of IBD-like conditions or de novo IBD (see below). There are multiple layers of evidence suggesting that surgery may trigger the development of IBD-like conditions. For example, a postcolectomy enteritis syndrome has been described wherein diffuse chronic active enteritis, distinct from the segmental disease of CD, develops within months after colectomy for UC125,126 (Fig. 2.6). In addition, there have also been cases of de novo CD or CD-like conditions reported after bariatric surgery (Roux-en-Y gastric bypass).127,128 Furthermore, celiac disease, another immune-mediated disorder, can also develop after pancreaticoduodenectomy,129 Billroth II,130 pyloroplasty,130 and even IPAA.131 Finally, de novo CD may develop after restorative proctocolectomy with IPAA for the initial diagnosis of UC. It is estimated that 2.7%e13% after colectomy for UC or IC may develop de novo CD anytime from weeks to years after IPAA.132 Other IBD-like conditions may develop postoperatively. Pouchitis, especially CARP, may be considered as a unique form of IBD after restorative proctocolectomy for UC. Patients with CARP respond favorably to standard immunosuppressive therapies for IBD, such as TNFa inhibitors133 and anti-integrins.134 Also after restorative proctocolectomy for UC, fecal diversion with the creation

(B)

(E)

(C)

27

(D)

FIGURE 2.6 Postcolectomy (for ulcerative colitis) enteritis syndrome. Diffuse enteritis on endoscopy (via stoma) (AeD) and histology (E).

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Interventional Inflammatory Bowel Disease: Endoscopic Management and Treatment of Complications

of an ileostomy often results in inflammation of the out-ofcircuit bowel, called diversion pouchitis. The favorable response to short-chain fatty acids suggests that the diversion pouchitis along with diversion colitis and diversion proctitis may represent variants for classic IBD.135 Surgical alteration of bowel anatomy may alter response to medical therapy. In a retrospective cohort of 85 patients with history of CD requiring ileocolonic resection after preoperative anti-TNF treatment, patients were either continued on the same anti-TNF or switched to a different anti-TNF agent, postoperatively. There were similar numbers of patients requiring a subsequent ileocolonic resection in the consistent and switch groups.136 Therefore we hypothesized that bowel surgery may alter factors influencing the body’s “immune thermostat,” resulting in a restored response to previously inefficacious medication. The mechanisms for the thermostat changes induced by surgery are not clear. The composition of the microbiome is known to be altered after colectomy.137 Changes in the microbiome may induce inflammation after surgical alteration of the bowel. For example, in patients who undergo IPAA, preoperative abundance of certain bacteria such as Ruminococcus granus, Bacteroides vulgatus, and Clostridium perfringens is associated with a higher risk of postoperative pouchitis.138 Although it has not been proven why CD develops after IPAA, there has been speculation that surgery enables a “CD-friendly” environment with operation-related ischemia, fecal stasis in the small bowel, and subsequent shifts in composition of commensal bacteria.132 Other potential contributors to the development of CD in IPAA include environmental causes (smoking) and genetic propensity (family history of CD or the presence of single-nucleotide polymorphisms associated with CD).139 However, it could be argued that these environmental and genetic contributions were present before the surgery itself and are not the major determinants of development of CD of the pouch. Surgery, in these examples, can be a trigger that results in subsequent activation of chronic inflammation.

THE TWO-HIT THEORY There is a delicate homeostasis in the human body, affected by genetic, environmental, infectious, and immunologic factors. Various factors can redial or reset the “thermostat.” How can we make sense of the vast overlap among infectious, inflammatory, and autoimmune diseases with IBD? Rather than considering IBD as an isolated disease state, IBD should be considered part of a broader set of overlapping disease states. To offer a unified theory of pathogenesis, we propose a two-hit theory. Variables such as the genome, exposome (the sum total of environmental exposures), microbiome, and immunome (immune system regulation and response) bring to fruition the wide range of

conditions included in the spectrum of diseases associated with IBD. The first hit relates to genetics of the individual. The second hit involves contributions from one or all of the exposome (e.g., smoking, medications, toxins, and foods), microbiome, and immunome. It is intuitive that genetics is the first hit. Genome-wide association scans have identified 163 loci associated with IBD, many of which are shared loci common to both CD and UC.20 There have also been genetic links discovered between IBD and other immune-mediated disorders. IBD and psoriasis are strongly genetically associated with IL-12 and IL-23.140 Behcet’s disease shares the IL-23 and IL-10 loci with IBD.40 CD and mycobacterial infections share genetic susceptibility loci. The list of genetic overlaps illustrates the importance of the “first hit” in the pathogenesis of diseases. Genetic susceptibility to a disease does not mean a person will develop the disease. In sibling studies in IBD, although the relative risk of developing disease is higher, there is not complete penetrance.141 There must be a “second hit” promoting disease development. The microbiome may be altered whereby the intestinal flora alters intestinal homeostasis, leading to changes in immune functioning with aberrantly aggressive immune responses in genetically susceptible individuals .142 Intestinal flora may be altered by surgery, antibiotics, or probiotics. Changes in the microbiome induced by probiotic administration can result in modulation in levels of inflammatory cytokines. At times, the immune modulation of inflammation may even be dependent on genetic composition. For example, in mouse models of colitis, Lactobacillus salivarius probiotics demonstrated a protective capacity against colitis only in NOD2-positive mice.143 This antiinflammatory effect of Lactobacillus correlated with local production of the antiinflammatory cytokine IL-10. This experiment demonstrates how the genome (the “first hit”) combined with a change in the microbiome (the “second hit”) leads to changes in the immunome. When evaluated altogether, there is a spectrum of immune-mediated disorders of the gut that share many common pathways with IBD. The large variation in clinical presentation, endoscopy, imaging, and histopathology may be attributed to a complex interplay of genetics combined with varying weighted contributions from the microbiome, immunome, and exposome. For example, the genome may play a heavier role in the Ashkenazi Jewish cohort where there is more familial inheritance.144 In contrast, the microbiome may play a stronger role in pathogenesis in Asian patients who are exposed more frequently to Mycobacterium where genetic factors likely play a lesser role.145,146 Finally, as the world obesity epidemic continues, the exposome may be more influential in certain ethnicities (Hispanic or African Americans) with increased mesenteric adipose tissue,60 which may contribute to the

Classification and Reclassification of Inflammatory Bowel Diseases Chapter | 2

development of aggressive CD.61 Thus the conventional thought on IBD as a specific disease entity with a uniform pathogenesis should be transformed into more of a spectrum of immune-mediated disorders of the gut with various etiopathogenetic pathways.

29

IBD++

IBD+

RECLASSIFICATION OF IBD AND IBDLIKE CONDITIONS A disease spectrum is ideally classified based on known etiology, such as ITB, ischemic colitis, celiac disease, nonsteroidal antiinflammatory drugeinduced enteropathy or based on characteristic pathological features, such as lymphocytic colitis and collagenous colitis. However, immune-mediated disorders have been difficult to be classified, largely due to the complexity of disease process and interplay of genetic, environmental, microbial, immunological, and vascular factors, at different age and different stages of diseases. Based on our clinical observation and currently available literature, we would like to propose a reclassification of the spectrum of IBD and IBD-like conditions. The classification of a wide spectrum of disease is not an easy task. In addition to the traditional classifications based on age at onset, disease location, extent, and phenotype, here we classify a spectrum of IBD, based on disease location and the degree of shared etiopathogenetic pathways, causative factors, and disease processes. We believe that genetic, environmental, immunological, and vascular factors play varied roles in the pathogenesis of infant- or very earlye onset IBD versus early-onset versus elderly-onset IBD (Fig. 2.7). Based on the degree of extraintestinal organ involvement and pathogenetic pathways, we categorize classic IBD (UC and CD) and IBD-variants (IBD-V). Within IBD-V categories, there are IBDþ (IBD with classic EIM, e.g., IBD with PSC and PG); IBDþþ (IBD with concurrent AimD and/or AinD with or without classic EIM, e.g., classic IBD with ankylosing spondylitis and celiac

Environmental Fat and Mesentery Incidence

Immune Dysregulation Genetics

0

20

40

60

100

Age of onset FIGURE 2.7 The three-peak incidences of inflammatory bowel disease and relative contribution of etiopathogenic factors.

IBD

IBD+/-

FIGURE 2.8 Range and overlaps of IBD and IBD-like conditions. IBD, inflammatory bowel disease.

disease); and IBDþ/, which shares some clinical presentations, histopathologic features, and possible pathways with IBD, IBDþ or IBDþþ (e.g., microscopic colitis and Behcet’s disease) (Table 2.2) (Fig. 2.8). Different forms of IBD share similar clinical presentations, histopathologic features, and treatment strategies. Predominantly mucosal diseases such as microscopic colitis, celiac disease, and UC, often present with diarrhea. Predominantly transmural diseases, such as CD and Behcet’s disease, often present with abdominal pain, nausea, vomiting, and abdominal fistula or abscess. To fit the diagnosis of IBD and IBD-V, at least two of the following histopathologic criteria should be met: (1) infiltration of mononuclear cells (including lymphocytes, plasma cells, monocytes, and macrophages) in the lamina propria or epithelium; (2) basal lymphoplasmacytosis; (3) crypt distortion; (4) Paneth cell and/or pyloric gland metaplasia; and (5) mucin depletion or increase crypt apoptosis. Additional features, such as non-caseating granuloma, neuronal hyperplasia, and transmural infiltration of lymphocytes, may further support the diagnosis of IBD and IBD-V. Some degree of tissue eosinophilia, lymphangitis and vasculopathy may be present in IBD and IBD-V. Medical management of IBD and IBD-V is mainly antiinflammatory medications and immunosuppressive agents. In this classification, we also propose the concept of secondary IBD, which differs from primary or idiopathic IBD. In primary IBD, there may be no clear triggers or identified etiological factor(s). In secondary IBD, a triggering factor can be clearly pinpointed (such as medications, surgery, or transplantation). Finally, IBD is classified into extrinsic versus intrinsic IBD, corresponding to the

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Interventional Inflammatory Bowel Disease: Endoscopic Management and Treatment of Complications

“outside-in” versus “inside-out” theory of disease mechanisms. This proposed new classification system is largely based on clinical, genetic, and histologic evidence. As new data for an advanced molecular basis with genetic and serological studies are emerging, we must try to elucidate some common clinical and histopathologic features of IBD versus IBD-V, primary versus secondary IBD, and intrinsic versus extrinsic IBD, to provide guidance to clinicians and researchers in the investigation, diagnosis, and management of these diseases.

SUMMARY AND CONCLUSION There are innumerable clinical phenotypes of IBD. The concept of classic or idiopathic IBD has evolved into a disease spectrum with various clinical, endoscopic, imaging, and histologic presentations of the gut and various types of EIMs. The classification of secondary IBD is proposed, which encompasses the subset of IBD with identifiable triggers. The proper diagnosis and categorization of IBD or IBD-like condition will surely be useful for proper management, medical versus endoscopic versus surgical, or combination and for improvement in prognosis. No doubt, our understanding of disease process goes handin-hand with the evolution of technology. Therefore the classification process of a wide disease spectrum is not static, and we anticipate that newer classifications will emerge in near future.

ACKNOWLEDGMENTS Dr. Bo Shen is supported by the Ed and Joey Story Endowed Chair.

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