Vous êtes sur la page 1sur 43



Crohn’s Disease

Epidemiology...........................................................................1990 Differential Diagnosis...............................................................2004
Etiology and Pathogenesis.......................................................1991 Establishing the Diagnosis and Evaluating
Initiating Events....................................................................... 1991 Disease Activity...................................................................2004
Genetics................................................................................. 1991 Differentiating Crohn’s Disease from UC................................... 2007
Environment............................................................................ 1995 Measuring Disease Activity...................................................... 2008
Adaptive Immune Response and Inflammation.......................... 1995 Treatment................................................................................2009
Pathology................................................................................1996 Goals...................................................................................... 2009
Early Findings......................................................................... 1997 Medical Therapy...................................................................... 2009
Later Findings......................................................................... 1997 Nutritional Therapy.................................................................. 2020
Other Findings........................................................................ 1998 Surgical Therapy..................................................................... 2020
Clinical Features......................................................................1998 Costs of Care...........................................................................2020
Disease Location..................................................................... 1998 Crohn’s Disease in the Life Cycle............................................2020
Clinical Presentation................................................................ 1998 Prognosis................................................................................2021
Disease Behavior..................................................................... 1999 Morbidity................................................................................ 2021
Classification of Disease.......................................................... 2000 Cancer.................................................................................... 2021
Pathophysiology of Common Symptoms and Signs................... 2001 Mortality................................................................................. 2021
Extraintestinal Manifestations................................................... 2002 Coping with Crohn’s Disease...................................................2022

Idiopathic IBD comprises conditions characterized by chronic

or relapsing immune activation and inflammation within the EPIDEMIOLOGY
GI tract. Crohn’s disease and UC are the 2 major forms of
idiopathic IBD; less common, but increasingly recognized, are Accurate comparisons of epidemiologic data on the incidence
the microscopic colitides, primarily collagenous colitis and and prevalence of Crohn’s disease are hampered by a lack of
lymphocytic colitis (see Chapter 128). Other chronic inflam- gold-standard criteria for diagnosis and inconsistent case
matory conditions of the intestine share some features of pre- ascertainment. Moreover, the invasiveness and expense of
sentation and pathogenesis with idiopathic IBD, but they have diagnostic modalities ensures that diagnosed cases represent
identifiable etiologies; examples of these disorders include only a fraction of the diseased population. Finally, studies that
diversion colitis, bypass enteropathy, radiation colitis, and rely on observations from large referral centers may be biased
drug-induced colitides. The 2 major forms of IBD share many toward reporting more aggressive forms of the disease,
clinical and epidemiologic characteristics, suggesting that thereby underestimating the true incidence of Crohn’s disease.
underlying causes may be similar. In approximately 10% of Misclassification of disease is problematic. Historically,
cases, Crohn’s disease cannot be distinguished from UC on unidentified infections, later recognized by improved culture
clinical grounds (see “Indeterminate Colitis” later), although and diagnostic techniques, might have accounted for some
the 2 diseases are distinct syndromes with divergent treatment portion of cases, particularly among persons with a single
and prognosis. episode of disease. At times, differentiating Crohn’s disease
Crohn’s disease is a chronic inflammatory disorder that from UC may be difficult, especially at the time of diagnosis,
may involve any part of the alimentary tract from mouth to and before the passage of time has allowed distinctive disease
anus, but with a propensity for the distal small intestine and characteristics to become manifest. Reassignment of a diagno-
proximal large bowel. Inflammation in Crohn’s disease often sis of Crohn’s disease or UC may be as high as 9% in the first
is discontinuous along the longitudinal axis of the intestine 2 years after diagnosis.1
and can involve all layers from mucosa to serosa. Affected Despite these methodologic limitations, distinct and
persons usually experience diarrhea and abdominal pain, fre- reproducible geographic and temporal trends in incidence
quently accompanied by weight loss. Common complications have been observed. A north-south gradient has reported in
include strictures and fistulas, which often necessitate surgery. France2 and the United States.3 This observation has been
Numerous extraintestinal manifestations also may be present. linked to variations in exposure to sunlight,4 with increasing
The etiology of Crohn’s disease is incompletely understood, levels of sunlight and vitamin D exposure inversely associ-
and therapy, although generally effective in alleviating the ated with epidemiologic and individual risk of Crohn’s
symptoms, is not curative. disease.5 Incidence rates as high as 20.2 and 12.7 per 100,000

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   1991

person-years have been reported in North America and reovirus, and many others. A proposed association between
Europe, respectively,6 whereas in Asia, the incidence rate has early measles vaccination and Crohn’s disease largely has
remained low, with a mean estimated incidence of 0.54 per been disproved.16 Another suggestion has been that the com-
100,000 person-years.7 Incidence rates in Australia and New mensal flora, although normal in speciation, possess more
Zealand are comparable to those found in other parts of the subtle virulence factors, such as enteroadherence, that cause
developed world, at 29.3 and 16.5 per 100,000 person-years.8,9 or contribute to IBD.17 Increasingly, evidence suggests that an
In all regions of the world where incidence has been recorded intestinal dysbiosis exists in Crohn’s disease, and which may
over time, the annual occurrence of new cases of Crohn’s precede the onset of disease. Primarily, there is a decrease in
disease is rising,6 including the United States. For example, in diversity of the microbial flora, with a notable reduction in
Olmsted County, Minnesota, rates had been steadily increas- Firmicutes.18 In particular, Faecalibacterium prausnitzii has been
ing from approximately 3 per 100,000 (1954-1963) to nearly 8 shown to be depleted in the ileocolonic mucosa of patients
per 100,000 (1964-1973), although since the late 1970s these with Crohn’s disease.18
rates have not changed significantly.10 Mortality trends for Among the most enduring hypotheses is that Mycobacte-
Crohn’s disease in the United States have followed a similar rium paratuberculosis is the causative agent of Crohn’s disease.
pattern, with rising mortality until the mid-1970s and a stable This notion dates to Dalziel’s observation in 1913 that idio-
rate since.11 Although improved diagnostic capabilities might pathic granulomatous enterocolitis in humans is similar to
have played some role in the rising incidence leading up to Johne’s disease, a granulomatous bowel disease of ruminants
the mid-1970s, the fact that Crohn’s-related mortality was caused by M. paratuberculosis.19 M. paratuberculosis is extremely
increasing in parallel argues against the theory that rising fastidious in its culture requirements, and some proponents of
Crohn’s diagnoses merely represented detection bias involv- this hypothesis have speculated that the presence of M. para-
ing mild cases. There is a paucity of epidemiologic data from tuberculosis as a spheroplast may have confounded efforts to
South America and Africa, and increasing access to health confirm this hypothesis by culture of the organism; to demon-
care may influence estimates from less affluent regions. Most strate it by immunohistochemistry, in situ hybridization, and
recently, the prevalence of Crohn’s disease in the United PCR methodology; and to treat it empirically with antimyco-
States was estimated to be 201 per 100,000 adults and 43 per bacterial antibiotics (see “Medical Therapy,” later). Most inves-
100,000 in children, adolescents, and adults younger than 20 tigation in this area, to date, has been inconclusive, providing
years of age.3 insufficient evidence to prove or reject the hypothesis.
Studies throughout the world have shown a small excess In light of the diversity of substances and bacteria within
risk of Crohn’s disease among women. Most reports show a the intestinal lumen, it is remarkable that the intestine is not
female-to-male ratio in adult patients between unity and perpetually inflamed. The presence of low-level physiologic
1.3 : 1.3,12,13 In the pediatric population this is reversed, with inflammation within the healthy intestinal mucosa represents
more boys having Crohn’s disease than girls.3 This slight a state of preparedness to deal with potentially harmful
difference in risk in adult-onset disease may be explained by agents. A more vigorous response would not be appropriate
hormonal or life-style factors and stands in contrast to the if directed toward the innocuous commensal flora of the intes-
nearly equal or even slight male predominance seen in UC. tine. Experiments in animal models of IBD suggest that in a
Crohn’s disease is diagnosed most often among persons 15 genetically susceptible host, a classic pathogen is not neces-
to 30 years of age, although the age at diagnosis can range sary to cause IBD, but rather nonpathogenic commensal
from early childhood throughout one’s lifespan. Population- enteric flora are sufficient to induce an inappropriate chronic
based studies have shown the median age of diagnosis to be inflammatory response. In diverse models, animals raised
approximately 30 years.10,12 Conflicting information may be under germ-free conditions show diminished or delayed
found regarding trends in the age of diagnosis. In Olmsted expression of the IBD phenotype.20 On introduction of defined
County, Minnesota, younger age groups have had a fairly bacterial flora, however, the expected phenotype of bowel
stable incidence over the past 20 years, with rising rates in inflammation becomes manifest.20 Such models suggest that a
patients aged 60 and older.10,12 These findings reflect diagnosis diversity of genetic alterations, including those that affect
in a larger proportion of patients older than 60 years. Indeed, intestinal barrier function and regulation of mucosal immu-
many12 studies have shown a smaller second peak in incidence nity, can result in intestinal inflammation. As in the animal
later in life, generally in the seventh decade. This second peak models of IBD, evidence in patients with Crohn’s disease also
may be the result of ascertainment bias because of more fre- points to an over-responsiveness of mucosal T cells to the
quent contact with medical care and more frequent evaluation enteric flora, manifest in part by the presence of antibodies
of older patients. The pathologic findings in young and old against an array of bacterial antigens. Patients with Crohn’s
patients are not different, although some studies have identi- disease who have disease-associated polymorphisms of the
fied a greater proportion of colonic and distal disease among NOD2 gene (see later) and their unaffected relatives have
older patients,14 compared with a predominance of ileocolonic increased levels of antibodies against bacterial antigens such
disease in younger patients.15 as Escherichia coli outer membrane porin C (OmpC) and


The argument for a genetic predisposition to IBD begins with
Initiating Events the observation that family members of affected persons are
In light of the nature of the pathologic findings in Crohn’s at greatly increased risk for developing IBD. The relative risk
disease (see later) and UC, it long has been clear that IBD among first-degree relatives is 8 to 10 times higher than that
represents a state of sustained immune response. The question of the general population.22 Roughly 1 of 5 patients with
arises as to whether this is an appropriate response to an Crohn’s disease report having at least 1 affected relative.
unrecognized pathogen or an inappropriate response to an Many families have more than 1 affected member, and
innocuous stimulus. Many infectious agents have been pro- although there is a tendency within families for either UC or
posed as the cause of Crohn’s disease, including chlamydia, Crohn’s disease to be present exclusively, mixed kindreds also
Listeria monocytogenes, cell-wall–deficient Pseudomonas species, occur; this suggests, and has recently been confirmed, the

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
1992   Section X  Small and Large Intestine

presence of some shared genetic traits as a basis for both insertion leading to early truncation of the protein (Leu1007­
diseases. fsinsC) and 2 missense mutations (Arg702Trp, Gly908Arg).
Ethnicity also plays a role. Eastern European (Ashkenazi) Carriage of disease-associated allelic variants on both chromo-
Jews are at a 2- to 4-fold higher risk of developing IBD than somes confers an odds ratio for Crohn’s disease of 17.1 (95%
non-Jews of the same geographic location, and they are at confidence interval [CI], 10.7 to 27.2), and heterozygous
greater risk of having multiple affected family members. persons have an odds ratio of 2.5 (95% CI, 2.0 to 2.9) for the
Studies of monozygotic and dizygotic twins suggest that disease.30 Genetic polymorphisms of NOD2/CARD15 have
genetic composition is a more powerful determinant of disease been associated with younger onset and ileal location of
for Crohn’s disease than for UC. Thus, the concordance rate disease and increased likelihood of stricture formation.30 It has
among monozygotic twins is as high as 67% for Crohn’s been estimated that as many as 20% to 30% of patients with
disease but only 13% to 20% for UC, although a lower rate of Crohn’s disease bear abnormal NOD2/CARD15. Nevertheless,
concordance for Crohn’s disease has been observed among the penetrance of NOD2/CARD15 is not more than 5% of indi-
monozygotic twins in a more recent study.22,23 Most studies viduals bearing 2 copies of disease-associated polymorphisms,
have suggested that concordance of disease location and and roughly 0.5% in heterozygous persons.31 This indicates
disease behavior are higher than one would expect by chance. that disease-related allelic variants of the gene may be found
As noted before, some subclinical markers of Crohn’s disease, in a large number of persons who do not have Crohn’s disease.
including anti-OmpC antibodies, are more common among The discovery of the association of NOD2/CARD15
apparently healthy family members of Crohn’s disease pro- with Crohn’s disease has opened a remarkable window into
bands than among the general population.24 the pathogenesis of Crohn’s disease. The gene product of
Only very rare forms of IBD are transmitted through NOD2/CARD15 is a cytosolic protein that functions as an intra-
Mendelian inheritance. These include autosomal recessive cellular sensor of bacteria. Specifically, the protein binds to
missense mutations of the interleukin (IL)-10 receptor gene, muramyl dipeptide (MDP; MurNAc-L-Ala-D-isoGln), a com-
which cause severe disease through loss of function and, ponent of bacterial peptidoglycan, found in Gram-positive
therefore, failure of IL-10 to down-regulate inflammation.25 and Gram-negative bacteria.32 The NOD2/CARD15 protein
Risk for common Crohn’s disease, however, is transmitted is expressed in a wide diversity of cells, including macro-
through non-Mendelian inheritance. Genome-wide associa- phages, lymphocytes, fibroblasts, and intestinal epithelial
tion (GWA) studies have been more successful in IBD than cells, specifically Paneth cells,22 which lie within the crypts and
in any other complex disease, and they have accelerated the produce endogenous antimicrobial peptides called defensins.
pace of gene discovery, providing unexpected insights into The NOD2/CARD15 gene consists of 2 CARD domains, a
pathogenesis.26 nucleotide binding domain (NBD), and 10 leucine-rich repeats
A landmark study provided deep insight into the genetic (LRR). NOD2/CARD15 variants associated with Crohn’s
architecture and causation of IBD by combining data from disease lie within the LRR and interfere with binding to MDP.
more than 75,000 cases of Crohn’s disease and UC, controls, In mononuclear cells, mutations in NOD2 result in decreased
and results from 15 GWA studies.27 Among 163 IBD loci identi- activation of nuclear factor (NF)-κB, whereas an excess of
fied, 110 were associated with both diseases, 30 were classified NF-κB expression is observed in tissue inflamed by Crohn’s
as Crohn’s disease–specific (Table 115-1), and 23 as UC-specific.27 disease. This apparent paradox has yet to be unraveled com-
Identified loci include regions with key genes validated in pletely, but it is clear that defects in NOD2 impair antibacterial
functional studies, others with multiple potential coding responses, particularly to oral exposure to pathogens. Notably,
regions, and still others with noncoding regions. The latter production of β-defensins, which are antibacterial proteins
may control expression of distant coding regions and thereby produced by Paneth cells, is defective in Crohn’s patients with
influence functional biology. The notable overlap of genetic variant NOD2.33 These findings strongly implicate defects in
loci suggests that Crohn’s disease and UC share many biologi- innate immunity—the immediate and nonspecific immune
cal mechanisms. However, biological differences are also sug- responses to microbial infection—in a subset of patients with
gested by the observation that 2 risk loci, NOD2 and PTPN22, Crohn’s disease, with subsequent chronic activation of adap-
are protective for UC. Additionally, 113 of the 163 risk loci are tive immunity, the antigen-specific responses mediated by
common to other complex immune-mediated diseases, such as antigen-presenting cells (APCs) and T cells.
type 1 diabetes, ankylosing spondylitis, and psoriasis.27 IBD Beyond NOD2, multiple genetic defects in the autophagy
loci also display enrichment for genetic loci associated with pathway, which is implicated in the pathogenesis of Crohn’s
primary immunodeficiencies of Mendelian inheritance, in con- disease, also provide a link to defective host-microbe interac-
cordance with the observation that individuals with a variety tions.34,35 Autophagy is an ancient cellular process, highly con-
of primary immunodeficiency syndromes have a higher than served in evolution, by which segments of cytoplasm are
expected rate of Crohn’s-like disease. GWA studies identify isolated within a membrane and delivered to lysosomes (or
genes associated with susceptibility to mycobacterial infec- “inflammasomes”) by mechanisms that do not involve trans-
tions, such as leprosy and Mycobacterium tuberculosis. The port through endocytic or vacuolar sorting pathways. This
Myco­bacterium tuberculosis susceptibility genes include VDR,27 unique process plays a role in cellular homeostasis by clearing
which encodes the vitamin D receptor, providing a possible proteins that are long-lived, misfolded, or aggregated, and by
link with epidemiologic data that associates risk of Crohn’s clearing apoptotic bodies, which might otherwise trigger
disease with sunlight and vitamin D exposure, as previously inflammation and autoimmunity. Autophagy has been shown
noted. to contribute directly to innate immunity through direct
The findings of GWA studies in Crohn’s disease and IBD killing of pathogens, activation of Toll-like receptors and
generally support a connection between disease susceptibility NOD-like receptors, which are pattern recognition receptors
and host interactions with microbes. This is exemplified most that activate the innate immune response, and elaboration of
strongly in the first described susceptibility locus for Crohn’s immunomodulatory cytokines such as interferon (IFN)-γ.
disease. The NOD2 (Nucleotide-binding Oligomerization Autophagy also stands at the interface of innate and adaptive
Domain containing 2) gene, also known as CARD15 (CAspase- immune responses, delivering antigen to HLA class II mole-
Recruitment Domain 15) was identified in 2001.28,29 The allelic cules in APCs for antigen-specific binding.35
variants most commonly associated with Crohn’s disease in GWA studies have identified variants that predispose to
European and American populations include 1 frameshift Crohn’s disease in at least 2 autophagy-related genes. The

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   1993

TABLE 115-1 Crohn’s Disease–Specific Loci

Key Genes (+no.

Position of additional
Chr. (Mb) SNP genes in locus) Product and Description of Candidate Genes, if Known

1 78.62 rs17391694 (5)

114.3 rs6679677 PTPN22 (8) Protein tyrosine phosphatase, nonreceptor type 22; gain-of-function
variant confers reduced risk for Crohn’s disease, while loss-of-function
variants promote autoimmune disorders
120.45 rs3897578 ADAM30 (5) ADAM (A Disintegrin And Metalloprotease domain) metallopeptidase
domain 30. Members of this family are membrane-anchored proteins
implicated in a variety of biological processes involving cell-cell and
cell-matrix interactions
172.85 rs9286879 FASLG, Fas ligand, causes apoptosis of some cell types, including lymphocytes
TNFSF18 (0) Tumor necrosis factor (ligand) superfamily, member 18. Modulates
T-lymphocyte survival in peripheral tissues, expressed in endothelial
cells, and believed to be important for interaction between T
lymphocytes and endothelial cells

2 27.63 rs1728918 UCN (23) Urocortin, a ligand for corticotropin-releasing factor type 2 receptors
62.55 rs10865331 (3)
231.09 rs6716753 SP140 (5) SP140 nuclear body protein; in lymphocytes, implicated in the innate
immune response to HIV1
234.15 rs12994997 ATG16L1 (8) Autophagy-related 16-like 1; involved in autophagy, by which there is
clearance of some intracellular pathogens, as well as integration of
innate and adaptive immune responses

4 48.36 rs6837335 (6)

102.86 rs13126505 (1)

5 55.43 rs10065637 IL6ST, IL31RA (1) Interleukin-6 signal transducer (gp130, oncostatin M receptor), a signal
transducer shared by interleukin 6, ciliary neurotrophic factor, leukemia
inhibitory factor, and oncostatin M, and activated when these cytokines
bind their receptors
Interleukin-31 receptor A; belongs to the type I cytokine receptor family,
with homology to gp130. Expressed on monocytes, and involved in
IL-31 signaling via activation of signal transducers and activators of
transcription (STAT-3) and STAT-5
72.54 rs7702331 (4)
173.34 rs17695092 CPEB4 (2) Cytoplasmic polyadenylation element binding protein 4

6 21.42 rs12663356 (3)

31.27 rs9264942 (22)
127.45 rs9491697 (3)
128.24 rs13204742 (2)
159.49 rs212388 TAGAP (5) T-cell activation Rho guanosine triphosphate (GTP) ase-activating protein;
locus reported to be protective for perianal sepsis in Crohn’s disease,
and a shared risk locus with celiac disease

7 26.88 rs10486483 (2)

28.17 rs864745 CREB5, JAZF1 (1) cAMP responsive element binding protein 5; binds to CRE as a
homodimer or a heterodimer with c-Jun or CRE-BP1, and functions as a
CRE-dependent trans-activator
JAZF zinc finger 1; encodes a nuclear protein with 3 C2H2-type zinc
fingers, and functions as a transcriptional repressor

8 90.87 rs7015630 RIPK2 (4) Receptor-interacting serine-threonine kinase 2; a member of the receptor-
interacting protein (RIP) family of serine/threonine protein kinases;
contains a C-terminal caspase activation and recruitment domain
(CARD). Implicated as a mediator of NOD2 signaling, and in
susceptibility to leprosy
129.56 rs6651252 0

13 44.45 rs3764147 LACC1 (3) Laccase (multicopper oxidoreductase) domain containing 1; implicated in
susceptibility to leprosy


Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
1994   Section X  Small and Large Intestine

TABLE 115-1 Crohn’s Disease–Specific Loci—cont’d

Key Genes (+no.

Position of additional
Chr. (Mb) SNP genes in locus) Product and Description of Candidate Genes, if Known

15 38.89 rs16967103 RASGRP1, Ras guanyl releasing protein 1 (calcium and DAG-regulated) activates the
SPRED1 (2) extracellular signal-regulated kinases (Erk)/mitogen-activated protein
(MAP) kinase cascade and regulates T-cell and B-cell development,
homeostasis, and differentiation
Sprouty-related, Ena/VASP Homology 1 (EVH1) domain containing 1 is
phosphorylated by tyrosine kinase in response to several growth factors,
and can act as a homodimer or as a heterodimer with SPRED2 to
regulate activation of the MAP kinase cascade

16 50.66 rs2066847 NOD2 (6) Nucleotide-binding Oligomerization Domain containing 2’s role in innate
immune response is through binding of intracellular muramyl dipeptide,
a component of bacterial cell walls

17 25.84 rs2945412 LGALS9, NOS2 Lectin, galactoside-binding, soluble, 9 is a S-type lectin, beta-galactoside-
(3) binding protein implicated in modulating cell-cell and cell-matrix
Nitric oxide synthase 2, inducible expressed in liver and is inducible by a
combination of lipopolysaccharide and certain cytokines; the protein is a
biologic mediator of antimicrobial and other processes

19 1.12 rs2024092 GPX4, HMHA1 Glutathione peroxidase 4 catalyzes the reduction of hydrogen peroxide,
(20) organic hydroperoxide, and lipid peroxides by reduced glutathione; it
also protects mitochondria from oxidative damage in intestinal epithelial
Histocompatibility (minor) HA-1
46.85 rs4802307 (9)
49.2 rs516246 FUT2 (25) Fucosyltransferase 2 is a Golgi stack membrane protein involved in
creating a precursor of the H antigen, which is required for the final step
in the soluble A and B antigen synthesis pathway

21 34.77 rs2284553 IFNGR2, IFNAR1 Interferon gamma receptor 2 (interferon gamma transducer 1) protein is
(10) the non-ligand-binding beta chain of the gamma interferon receptor.
Human interferon-gamma receptor is a heterodimer of IFNGR1 and
IFNGR2. Defects in IFNGR2 are a cause of Mendelian susceptibility to
mycobacterial disease (MSMD)
Interferon (alpha, beta and omega) receptor 1 forms one of the 2 chains of
a receptor for interferons alpha and beta. Binding and activation of the
receptor stimulates Janus protein kinases, which in turn phosphorylate
several proteins, including STAT 1 and STAT2
From GWA studies as reported in Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.
Nature 2012; 491:119-24. Descriptions of gene products adapted from NCBI (National Center for Biotechnology Information, US National Library of Medicine) Gene database,
http://www.ncbi.nlm.nih.gov/gene/. Accessed on June 30, 2013.

first, the autophagy-related 16-like 1 (ATG16L1) gene, was dendritic cells and macrophages, in response to diverse micro-
noted as having a disease-associated single nucleotide poly- bial signals. Naïve CD4+ T cells up-regulate IL-23 receptor
morphism (SNP) that encodes an amino acid substitution in when exposed to IL-6 and transforming growth factor (TGF)-
exon 8, resulting in a change from alanine to threonine34-36; this β, completing an autocrine loop in the generation of Th17 T
minor allele is protective against Crohn’s disease. ATG16L1 is cells, effector T cells that produce IL-17.39,40 A rare variant of
expressed by intestinal epithelial cells, APCs, and various the IL23R gene leading to a glutamine at position 381 rather
subsets of human T cells. The second autophagy gene associ- than an arginine is strongly protective for Crohn’s disease,
ated with Crohn’s disease is the IRGM (immunity-related with an odds ratio of 0.26 to 0.45; other, more common SNPs
GTPase [guanosine triphosphatase] family member M) gene are associated with increased risk for Crohn’s disease and
on chromosome 5q33.1.37 Careful study suggests that the UC.41 In the same pathway, variants of the IL12B gene, encod-
disease-associated variants of this gene do not affect the amino ing the p40 subunit common to IL-12 and IL-23, and of the
acid sequence of its product, but they more likely alter its JAK2 and STAT3 genes, with roles in IL23R signaling, as well
expression.37 IRGM appears to be important in resistance to as in Th17 differentiation in the case of STAT3, also have been
intracellular pathogens such as mycobacteria, Listeria monocy- associated with Crohn’s disease susceptibility.42 Together,
togenes, and Toxoplasma gondii.35 these findings support the pivotal role of this pathway in
A third pathway associated with Crohn’s disease is IL-23 maintaining mucosal homeostasis in the normal intestine. As
and other gene products associated with this protein.38 IL-23 the functional alterations associated with the many other iden-
is a heterodimeric cytokine comprising 2 linked subunits (p19 tified genetic risk loci are elucidated, it is certain that new
and p40). IL-23 is produced by many cell types, including insights into the causes of Crohn’s disease will arise.

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   1995

Environment however, and studies indicate that stress may be associated

with risk of relapse in Crohn’s disease.49
Even with notable progress in GWA studies, identified genetic
risk factors account at best for only 25% of disease variance.43
Additional, more rare genetic variants of new or already
Adaptive Immune Response and Inflammation
identified loci may yet be discovered, but it is clear that envi- The interaction between effector T cells and APCs is critical to
ronmental factors also are important. As noted earlier, the the pathogenesis of Crohn’s disease (Fig. 115-1). The antigens
rising incidence of Crohn’s disease over many decades, and that perpetuate the inflammatory response are taken up by
in developing countries, highly suggests an environmental APC. Degradation of antigen within proteasomes results in
contribution to the expression of disease. Epidemiologic presentation of an epitope in the context of major histocompat-
studies have examined numerous risk factors for Crohn’s ibility complex (MHC) class II. Interaction between MHC class
disease. Most studies have found breast-feeding to be pro­ II and the T-cell receptor (CD3) results in antigen-specific inter-
tective for IBD, presumably by playing a role in early pro- action between the macrophage and the CD4+ T cell. This event
gramming of immune responses in the developing GI tract is necessary, but not sufficient, to activate the T cell. A second
and in shaping the intestinal microbiome. Occupations associ- co-stimulatory signal is needed as well, because binding of
ated with outdoor physical labor are relatively under- CD3 to MHC class II without a co-stimulatory signal can result
represented among patients with Crohn’s disease. Crohn’s in anergy or apoptosis. Important co-stimulatory signals
disease has been associated with higher socioeconomic status, include binding of TNF to TNF receptor, CD40 to CD40 ligand,
presumably because of relative underexposure to diverse and B7 to CD28. Activation of T cells leads to production of
environmental antigens in the course of childhood—the IL-2, an important growth factor for T cells.
hygiene hypothesis as it relates to intestinal mucosal immu- Inflammation normally is kept in check through an active
nity in IBD. Many, but not all,5 studies have discerned an process termed immune tolerance. The nature of the
increased risk of Crohn’s disease among women who use oral co-stimulatory signal, the type of APC, and the cytokine
contraceptives. NSAIDs have been implicated not only in milieu influence the differentiation of T cells into populations
exacerbations of IBD but also as a potential precipitant of of effector T cells, which are involved in harmful immune
new cases, perhaps by increasing intestinal permeability. responses, and regulatory T cells, which ameliorate the
Increased intake of refined sugars and a paucity of fresh fruits immune response. Dendritic cells in the lamina propria
and vegetables in the diet have been associated with the devel- actively sample the luminal contents and play a particularly
opment of Crohn’s disease. It is conceivable that this observa- vital role as key APCs capable of shaping the immune response.
tion may be confounded by exacerbation of symptoms in As noted earlier, the p40 subunit is common to IL-12 and
patients with mild disease because of increased dietary fiber IL-23, each of which, in turn, is critical in shaping the Th1 and
intake and subsequent avoidance of these food items before Th17 responses that characterize Crohn’s disease. In addition
diagnosis. to IL-23, the presence of TGF-β and IL-6 facilitate differentia-
Antibiotic use, particularly in childhood, has been observed tion of naïve T cells into pathogenic Th17 cells.39 Activated
to be associated with subsequent risk of IBD.44-47 Such observa- APCs further shape and amplify the immune response by
tions are plausibly connected to the etiology of Crohn’s producing the T-cell growth factor IL-2 and the proinflamma-
disease, given the role of the microbiome in shaping the devel- tory cytokines IL-1 and TNF. Within mononuclear cells, the
oping immune system and host responses. However, caution key nuclear transcription factor is NF-κB, which regulates the
should be maintained in assuming that such associations are transcription of IL-1, IL-6, IL-8, TNF, and other peptides
causal, as an equally plausible explanation is that the genetic central to the inflammatory response.50
predisposition to Crohn’s disease also confers increased sus- In addition to being essential to the formation of granulo-
ceptibility to a variety of infections. mas, TNF causes neutrophil activation and, along with IFN-γ,
A virtually unexplored area is the connection between induces the expression of MHC class II on intestinal epithelial
environmental and genetic factors in the expression of disease. cells. Moreover, TNF and other proinflammatory cytokines
It is presumed that the most important environmental factors contribute to the expression of adhesion molecules on the
may be those that determine the composition of the intestinal endothelial cells of the intestinal vasculature.
flora, given its necessary role in the onset of IBD. Such factors Expression of adhesion molecules is critical to amplify the
might include breast-feeding, composition of the diet, hygiene, immune response because the resident populations of granu-
and many others. locytes and mononuclear cells alone do not account for the
Smoking is one of the more notable environmental factors vigorous inflammatory reaction characterizing IBD. Adhesion
for IBD. UC is largely a disease of ex-smokers and nonsmok- molecules on the leukocyte surface and their ligands on the
ers, whereas Crohn’s disease is more prevalent among endothelium of venules in the lamina propria interact in a
smokers. In addition, smokers have more surgery for their coordinated multistep process that permits trafficking of
disease and a greater risk of relapse after resection. The reasons inflammatory cells into the mucosa. First, a weak interaction
for the divergent effect of smoking on Crohn’s disease and UC between selectins on the leukocyte surface and the endothe-
are poorly understood, but they might include effects on intes- lium leads to rolling of the leukocytes along the endothelium.
tinal permeability, cytokine production, and clotting in the Second, in the presence of chemokines such as IL-8, activ­
microvasculature. More recently, studies have focused on the ation occurs, and integrins are expressed on the leukocyte
role of carbon monoxide in stimulating immunosuppressive surface. Third, interactions between leukocyte integrins and
effects mediated by heme oxygenase-1.48 Whether such bio- immunoglobulin-like cellular adhesion molecules on the
logic effects contribute to the different effects of smoking in endothelial surface lead to spreading of the cell and diapede-
Crohn’s disease and UC is unknown. sis.51 Specificity is conferred by the presence of tissue-specific
Many patients report a correlation between disease exac- cellular adhesion molecules. The integrins α4β7 and αEβ7 are
erbations and stress. Although depression and anxiety are a of special importance in IBD, because the corresponding
common reaction to illness, Crohn’s disease has not been ligands—mucosal addressin cellular adhesion molecule
shown to be caused by stress or by an anxious personality. and E-cadherin—are intestine specific. Mucosal addressin cel-
The mind-body connection between emotional states or stress lular adhesion molecule is expressed constitutively on the
and intestinal inflammation in IBD is slowly being revealed, endothelium of venules in the lamina propria,51 whereas

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
1996   Section X  Small and Large Intestine

Bacteria Barrier

Th17 Th1
Innate Th2
immunity Defensins IL-12
IL-23 DC
Paneth Th0
cells Mϕ
NOD2 Autophagosome
TNF Adaptive Treg
Mϕ ATG16L1



FIGURE 115-1. Pathogenesis of Crohn’s disease. Animal models of IBD, studies of human genetics, and clinical trials with targeted thera-
peutic agents suggest that Crohn’s disease is a complex, polygenic disease driven by disturbances in distinct physiologic pathways;
however, not all defects or pathways appear to be aberrant in all patients. Thus, patients with allelic variants in NOD2 have defective
sensing of intracellular bacteria, as well as reduced production of defensins, which are natural antimicrobial products produced by
Paneth cells in the base of the intestinal crypts. The net result is excessive activation of adaptive immune responses to compensate
for defective innate immunity. Similarly, variant loci of the ATG16L1 and IRGM genes are associated with defective autophagy, a
process that is involved in defense against microbes and that stands at the interface of innate and adaptive immunity in the processing
of intracellular pathogens and presentation of antigens to T cells. Adaptive immunity also may be deranged along the interleukin (IL)-12/
IL-23 pathway, thereby shaping the expression of the helper T-cell response toward the spectrum of T helper Th17. Together, Th17
and Th1 responses, most closely associated with Crohn’s disease, account for up-regulation of effector T-cell responses in Crohn’s
disease. Defects in regulatory T cells (Treg) of a few varieties also may be a factor in expression of disease. Dendritic cells (DCs) are
active participants in maintaining immunologic tolerance within the intestine, continuously sampling luminal contents via podocytes
extending through the epithelium. Activation of DCs and macrophages (Mϕs) result in the expression of TNF within the mucosa. This
pleiotropic cytokine has many downstream, proinflammatory effects that contribute to disease, and anti-TNF antibodies are effective
in treating Crohn’s disease. Antigen presenting cells (APCs), including Mϕs and DCs, also lead to activation of T cells when antigen is
presented to the T cell in the context of major histocompatibility complex (MHC) class II, along with a co-stimulatory signal. Defects
in the barrier function of the intestinal mucosa (e.g., through variant PTGER4) can lead to increased microbial and antigenic penetration
of the mucosa, also resulting in immune activation. Leukocyte trafficking is a necessary element in amplification of the mucosal immune
response. Integrins are heterodimeric proteins that facilitate adhesion of leukocytes to the endothelium and recruitment into tissue.
Integrins containing α4, such as α4β1 and α4β7, bind respectively to intercellular adhesion molecule 1 (ICAM-1) in the endothelium of
inflamed tissues throughout the body and to mucosal addressin cellular adhesion molecule 1 (MAdCAM-1), which is specific to the
intestinal endothelium. Blocking these interactions interferes with adhesion and recruitment of inflammatory cells, thereby disrupting

binding of αEβ7 on intestinal lymphocytes to E-cadherin on

intestinal epithelium permits localization of intraepithelial PATHOLOGY
lymphocytes. Antibodies to the α4 subunit of integrin have
proved to be therapeutic in Crohn’s disease.52 Focal intestinal inflammation is the hallmark pathologic
Once recruited to the lamina propria, mononuclear cells finding in Crohn’s disease. This tendency for inflammation to
and granulocytes elaborate a variety of injurious and proin- be focal is evident in focal crypt inflammation, focal areas of
flammatory substances that ultimately cause tissue destruc- marked chronic inflammation, the presence of aphthae and
tion. These substances include prostaglandins, reactive oxygen ulcers on a background of little or no chronic inflammation,
metabolites, nitric oxide, leukotrienes, and proteases. Collage- and the interspersing of segments of involved bowel with
nase and matrix metalloproteinases play a pivotal role in the segments of uninvolved bowel. Even within a single biopsy
tissue destruction and complications, such as fistula and stric- specimen, one can see a pronounced variability in the degree
ture, seen in Crohn’s disease.53 Counterbalancing these destruc- of inflammation. The presence of focally enhanced gastritis,
tive substances are other substances that promote epithelial characterized by a focal perifoveolar or periglandular lympho-
restitution and repair, including IL-11, trefoil peptides, and monocytic infiltrate, is a common finding in patients with
growth factors such as EGF and keratinocyte growth factor. Crohn’s disease. This finding underscores the focal nature of

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   1997

the inflammation, despite the strong potential for inflamma-

tion to occur anywhere along the entire longitudinal axis of
the GI tract. To a certain extent, the nature of the findings and
the depth of inflammatory changes depend on the chronicity
of the inflammation.

Early Findings
Because of the variable and often long delay between the onset
of the disease process and its diagnosis, it rarely is possible to
observe the evolution of pathology from the earliest events.
Studies of recurrent Crohn’s disease after ileal resection have
offered a window into the sequence of pathologic changes in
the disease.54

Aphthous Ulcers
The earliest characteristic lesion of Crohn’s disease is the aph-
thous ulcer. These superficial ulcers are minute, ranging in
size from barely visible to 3 millimeters, and are surrounded
by a halo of erythema. In the small intestine, aphthous ulcers
arise most often over lymphoid aggregates, with destruction
of the overlying M cells. In the colon, aphthae can occur
without an endoscopically visible central erosion and may be
associated with lymphoepithelial complexes. Crohn’s aphthae
typically occur in normal mucosa, although villus blunting FIGURE 115-2. Photomicrograph of a typical Crohn’s disease gran-
may be seen in the surrounding small intestinal mucosa. uloma found in an endoscopic biopsy specimen. Note the loosely
Aphthous ulcers represent focal areas of immune activa- formed collection of cells, consisting of multinucleated giant cells
tion. The M cells and underlying lymphoid aggregates are (not always observed) and mononuclear cells, including T cells,
primary locations for antigen sampling and antigen presenta- and epithelioid macrophages. Central caseation is not noted.
tion, and HLA-DR is strongly expressed on the follicle- (Courtesy Dr. Gregory Lauwers, Boston, Mass.)
associated epithelium of the aphthous ulcer.55 Contact with
luminal contents is a key factor in the development of aph-
thous ulcers in Crohn’s disease. an injured crypt. The latter represent a response to mucin
Aphthous ulcers heal in bowel excluded from the fecal released from injured goblet cells and may be found in UC
stream by ileostomy, whereas reestablishing intestinal conti- and other conditions.57
nuity leads to their recurrence56; these observations provide Regardless of whether granulomas are found, the granu-
strong evidence for the role of luminal factors in the early lomatous inflammation of Crohn’s disease represents a
pathogenesis of Crohn’s disease. particular process involving characteristic cell types and
regulation by specific cytokines and adhesion molecules. TNF
is the key cytokine in the formation of granulomas. Apprecia-
Granulomas tion of this fact led to the concept of anti-TNF therapies as a
The presence of granulomas (Fig. 115-2), while highly charac- treatment for Crohn’s disease (see later).
teristic of Crohn’s disease, is neither unique to Crohn’s disease
nor universally found.57 Non-caseating granulomas, like aph-
thous lesions, are believed to be an early finding. Estimates of
Later Findings
the prevalence of granulomas in Crohn’s disease have varied Resected specimens of intestine may show localized foci of
greatly, ranging from 15% in endoscopic series to as high as architectural distortion unaccompanied by chronic inflamma-
70% in surgical series. Whether granulomas are found appears tion, an observation that suggests early superficial lesions
to be, in part, a matter of how hard one looks and how much such as aphthae may be transient and reversible. When the
tissue is available to examine; the more tissue sampled, the disease becomes chronic, however, aphthae can coalesce into
larger the specimen, and the more levels taken for histopathol- larger ulcers with a stellate appearance. Linear or serpiginous
ogy, the more likely granulomas will be found. ulcers can form when multiple ulcers fuse in a longitudinal
Granulomas may be discovered in involved and unin- direction. The classic cobblestoned appearance of Crohn’s
volved bowel, in any layer of the intestine, and in mesenteric disease results when linear and transverse ulcers intersect and
lymph nodes. Granulomas also may be found outside the GI networks of ulcers surround areas of relatively normal mucosa
tract—for example, in skin, eye, and liver—but extraintestinal and prominent submucosal edema. Ulcers also can extend
granulomas are rare; occasionally, they may be recognized as down to the muscularis propria.
millet seed–like nodules on the serosal surface of the bowel at A prevailing generalization is that intestinal inflammation
laparotomy. The granulomas of Crohn’s disease are sarcoid- in Crohn’s disease is a transmural process, in contrast to the
like, consisting of collections of epithelioid histiocytes and a more superficial inflammation of UC. The transmural nature
mixture of other inflammatory cells, including lymphocytes of the inflammation, however, cannot be appreciated on
and eosinophils; giant cells occasionally are seen. The granu- superficial endoscopic biopsy specimens, and in resected spec-
lomas usually are sparse, scattered, and not well formed. In imens it tends to be focal. Transmural involvement is observed
contrast to the granulomas of TB, there is little or no central less commonly than is disease of the mucosa and submucosa,
necrosis, and acid-fast stains and mycobacterial cultures are but to the extent that transmural disease is noted, it is
negative. It also is important to distinguish the granulomas of highly consistent with a diagnosis of Crohn’s disease. Dense
Crohn’s disease from those that can occur in association with lymphoid aggregates can enlarge the submucosa. At times,

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
1998   Section X  Small and Large Intestine

lymphoid aggregates also may be seen just outside the mus-

cularis propria. The presence of lymphoid aggregates in the CLINICAL FEATURES
submucosa and external to the muscularis propria is a reliable
sign of Crohn’s disease even when granulomas are not seen. Disease Location
Lymphoid aggregates occasionally may be seen within the
muscularis propria, most often adjacent to the myenteric Crohn’s disease has a predilection for the distal small intestine
plexus. and proximal colon. One third to one half of all patients have
Large ulcers, sinus tracts, and strictures are late features of disease affecting both ileum and colon. Another one third
Crohn’s disease. Sinuses and fistulas represent extensions of have disease confined to the small intestine, primarily the
fissures; sinus tracts end blindly, and fistulas enter epithelial- terminal ileum, and there may be an increasing group with
lined organs, such as bowel, skin, bladder, or vagina. Intramu- isolated colonic disease.61,62 Isolated jejunal involvement is
ral sinus tracts are recognized easily on barium studies. With rare. Gross involvement of the esophagus, stomach, or duode-
penetration of inflammation to the serosa, serositis can occur, num also is rare and almost always is seen in association with
resulting in adhesion of bowel to loops of small intestine, disease of the distal small intestine or colon. Focally enhanced
colon, or other adjacent organs. As a result of the chronicity acute and chronic inflammation may be seen in gastric biopsy
of the inflammatory process and adhesions, free perforation specimens of patients with Crohn’s disease either with or
is much less common than walled-off or contained intra- without gross involvement of the stomach.63 The discontinu-
abdominal abscesses or fistula formation. Fissures and fistulas ous nature of the disease makes possible many variations in
are lined by neutrophils and surrounded by histiocytes and a disease location, leading to considerable differences in clinical
mononuclear cell infiltrate; partial epithelialization also is presentation. The disease usually stays confined to the segment
often observed, perhaps reflecting incomplete healing. in which it begins, but anatomic localization can vary over
Fibrosis is another transmural aspect of the disease. Fibro- time, generally by involvement of additional segments of the
sis may be evident grossly as irregular thickening of the bowel alimentary tract, with a disease that has the potential to affect
wall and, along with hypertrophy of the muscularis mucosa, any segment of the GI tract.
can contribute to the development of strictures. TGF-β is
released locally in the presence of inflammation and is a cyto-
kine that is critical for restitution and healing. In Crohn’s
Clinical Presentation
disease, however, TGF-β may be a double-edged sword. The presentation of Crohn’s disease may be subtle and varies
Fibroblasts isolated from the lamina propria produce primar- considerably. Factors contributing to this variability include
ily type III collagen in response to TGF-β1, and in the inflamed the location of disease, the intensity of inflammation, and pres-
tissues of Crohn’s disease, significantly greater amounts of ence of specific intestinal and extraintestinal complications.
type III collagen are produced in response to this cytokine.58 Compared with UC, abdominal pain is a more frequent and
Thus, a cytokine essential to the healing process also is impli- persistent complaint. Pain is attributable to inflammation,
cated in the fibrogenesis of Crohn’s disease. abscess, or obstruction and may be intermittent and colicky or
sustained and severe. Some patients experience symptoms that
are mild but long-standing or that are atypical. Such patients
Other Findings are more likely to experience a delay in diagnosis that exceeds
At the anatomic level, one of the most characteristic findings 1 year. Patients with Crohn’s disease have a longer mean time
of Crohn’s disease is the presence of fat wrapping, a term that to diagnosis than patients with UC, and as many as 25% of
refers to the creeping of mesenteric fat onto the serosal surface patients have a delay in diagnosis of over 2 years from onset
of the bowel. Surgeons have long taken fat wrapping as a of symptoms.64 With improved diagnostic methods, and
reliable indicator of the presence of diseased tissue. Mesen- perhaps heightened awareness of the disease, more recent
teric adipose tissue hypertrophy and creeping fat are recog- series have described typical delays of less than 1 year.61 A
nized early in the course of disease at laparotomy or prodromal period is common in Crohn’s disease (not typically
laparoscopy. Locally, fat wrapping correlates with the pres- seen in UC) and might contribute to a delayed diagnosis, as
ence of underlying acute and chronic inflammation, as well as does a prior diagnosis of IBS and older age at onset of symp-
transmural inflammation in the form of lymphoid aggregates. toms.65 Occasionally, radiologic and endoscopic findings are
It is intriguing that patients with an increased ratio of visceral subtle, precluding definitive diagnosis even among patients
to subcutaneous fat are at significantly increased risk for with typical symptoms. Fecal occult blood may be found in
complicated disease behavior.59 Expression of peroxisome approximately one half of patients, but in contrast to UC, gross
proliferator-activated receptor (PPAR)γ, a pivotal mediator in rectal bleeding is uncommon, and acute hemorrhage is rare.
the regulation of adipose tissue homeostasis, is increased Constitutional symptoms, particularly weight loss and fever,
greatly in the tissues of patients with Crohn’s disease.60 In or growth retardation in children, may be prominent and occa-
turn, adipocytes may participate in the inflammatory process sionally are the sole presenting features of Crohn’s disease.
of Crohn’s disease by producing TNF and other inflammatory
At the microscopic level, the finding of pyloric metaplasia, Typical Presentations
normally a response to peptic ulcer disease when found in the Disease of the ileum, often accompanied by involvement of the
duodenum, strongly suggests a diagnosis of Crohn’s disease cecum, can manifest insidiously. Some patients present with a
when found in the terminal ileum. Careful descriptive immu- small bowel obstruction, perhaps precipitated by impaction of
nopathology of areas of pyloric metaplasia reveals the pres- indigestible foods, such as raw vegetables or fruit. Many years
ence of an ulcer-associated cell lineage. Bud-like glandular of subclinical inflammation can progress to fibrotic stenosis,
structures arise adjacent to areas of ulceration and are distin- with the subsequent onset of intermittent colicky pain,
guished by production of epidermal growth factor in acinar sometimes accompanied by nausea and vomiting. Physical
cells of the nascent gland and by trefoil proteins in the more examination can reveal fullness or a tender mass in the right
superficial cells lining the tract. Epidermal growth factor and hypogastrium, which may be more prominent during obstruc-
trefoil proteins, in turn, can promote restitution of the epithe- tive episodes. Patients with an active inflammatory component
lium in adjacent mucosal ulceration. to their disease more often present with anorexia, loose or

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   1999

frequent stools, and weight loss; their examination might distinct condition that occasionally responds to a gluten-free
reveal fever or evidence of malnutrition. Occasionally, a patient diet (see Chapters 107 and 119). Frank malabsorption and
presents with acute right lower quadrant pain, mimicking steatorrhea often occur. If the disease is confined to a short
appendicitis. segment of intestine or has features consistent with Crohn’s
Colonic disease can involve mainly the right colon or can disease, initial management should be based on the presumed
extend distally to involve most or all of the colon (extensive diagnosis of Crohn’s disease.
or total colitis). In patients with Crohn’s colitis, tenesmus is a Controversy continues to surround the diagnosis of
less common complaint than in patients with UC, because the Crohn’s disease of the appendix. When idiopathic granuloma-
rectum often is not involved or may be less severely inflamed tous inflammation is confined to the appendix, the presenta-
than other colonic segments. Nevertheless, proctitis may be tion most often resembles that of acute appendicitis and
the initial presentation in some cases, especially in older indi- occasionally periappendiceal abscess. The condition is rare,
viduals (see later). The typical presenting symptom of colonic and the lack of disease in other locations of bowel portends a
disease is diarrhea, occasionally with passage of obvious favorable prognosis, with a postoperative recurrence rate as
blood. The severity of the diarrhea tends to correlate with both low as 6%.68
the extent of colitis and the severity of inflammation, and the
presentation may range from minimally altered bowel habits
to fulminant colitis. Abdominal pain is often present to a
Disease Behavior
greater extent than is seen in UC. Systemic manifestations Clinical observation suggests that disease behavior in Crohn’s
such as weight loss and malaise also may be prominent. disease may be divided roughly into 2 categories: aggressive
Perianal disease is another common presentation of fistulizing disease and indolent cicatrizing disease; a third
Crohn’s disease. In as many as 24% of patients with Crohn’s subset of patients appear to develop neither of these disease
disease, perianal disease precedes intestinal manifestations, behaviors over long periods of observation. Moreover, these
with a mean lead time of 4 years.66 More often, however, peri- distinctions are not always neat. Both fistula and stricture can
anal disease occurs concomitantly with or after the onset of occur simultaneously in the same patient, such as in the
symptoms of luminal disease. Perianal findings may be cate- patient with a fistula arising behind a terminal ileal stricture,
gorized as skin lesions, anal canal lesions, and perianal or at different times.
fistulas. Skin lesions include maceration, superficial ulcers, Genetic factors are important in determining disease
abscesses, and skin tags. Skin tags are generally of 2 types: behavior, with NOD2 variants being associated with strictur-
type 1 (“elephant ears”) are typically soft and painless and can ing or fistulizing disease, and hence, increased risk for
be quite large; type 2, which often arise from healed fissures, surgery.69 In addition, serologic antibody responses to micro-
ulcers or hemorrhoids, are typically edematous, hard, and bial antigens and carbohydrates are associated with certain
tender.67 Anal canal lesions include fissures, ulcers, and steno- disease phenotypes.70-72 Specifically, the presence of antiglycan
sis. The anal fissures of Crohn’s disease tend to be located antibodies to mannan (a constituent of the cell wall of baker’s
more eccentrically than the usual idiopathic fissures, which yeast anti-Saccharomyces cerevisiae antibody [ASCA]) correlates
generally occur in the midline (see Chapter 129). In most cases, with small intestinal disease; identification of anti-CBir1 (anti-
anal stricture is asymptomatic, but pain and occasionally flagellin) is associated with internal penetrating and strictur-
obstruction occurs, particularly if stool consistency improves ing disease; and anti-Escherichia coli outer membrane porin C
in the course of treatment. Deeper abscesses can arise second- (anti-OmpC) predicts internal perforations. When perinuclear
ary to fistulas, especially when the internal opening is located antineutrophil cytoplasmic antibodies (pANCA) are present
high in the rectum. in a patient with Crohn’s disease, the phenotype is often that
of an inflammatory “UC-like” Crohn’s disease.
Unusual Presentations
Upper GI tract Crohn’s disease is uncommon in the absence Fistula and Abscess
of disease beyond the ligament of Treitz. Approximately one Fistulas are frequent manifestations of the transmural nature
third of patients with proximal Crohn’s disease do not have of Crohn’s disease. Immune activation triggers the release of
evidence of distal Crohn’s disease at the time of diagnosis, but a variety of proteases and matrix metalloproteinases that can
virtually all develop distal disease in time. Patients with proxi- contribute directly to tissue destruction, sinus tract formation,
mal Crohn’s disease tend to be younger at the time of diagno- and, finally, penetration to adjacent tissues. Perianal fistulas
sis and more often present with abdominal pain and malaise; are common and are estimated to occur in 15% to 35% of
they do not undergo surgery more often than do patients with patients (Fig. 115-3). When the fistula arises from an anal
lower tract disease alone, but the length of bowel that is gland, a low-lying perianal fistula is the most common result.
resected tends to be greater. Such fistulas often are minimally symptomatic and can resolve
Gastroduodenal Crohn’s disease manifests as Hp-negative with local care alone. Surprisingly, not all perianal fistulas
peptic ulcer disease, with dyspepsia or epigastric pain as the occur in the setting of active rectal inflammation. In some
primary symptom. When outflow obstruction occurs because cases, perianal fistulization may be extensive, forming a
of stricture formation or edema, early satiety, nausea, vomit- network of passages and extending to multiple openings that
ing, and weight loss can predominate. can include not only the perianal region but also the labia or
Esophageal Crohn’s disease is rare, occurring in less than scrotum, buttocks, or thighs.
2% of patients. Presenting symptoms can include dysphagia, Fistulas from 1 segment of the GI tract to another also
odynophagia, substernal chest pain, and heartburn. These occur commonly. Enteroenteric, enterocolonic, and colocolonic
symptoms may be progressive and lead to profound weight fistulas often are asymptomatic. Much more rarely, colonic
loss. Aphthous ulcers sometimes are found in the mouth and disease penetrates normal duodenum or stomach to form a
posterior pharynx. Esophageal stricture and even esophago- coloduodenal or cologastric fistula, respectively; affected
bronchial fistula can complicate the course of disease. patients might have feculent vomiting, or diarrhea from SIBO.
Crohn’s disease that is confined solely to the jejunum and If the fistula tracks posteriorly from the terminal ileum to
ileum is unusual and may be impossible to differentiate from the retroperitoneum, the ensuing phlegmon can ensnare the
ischemic jejunitis (See Chapter 118) ulcerative jejunoileitis, a ureter (usually the right ureter), causing noncalculous

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
2000   Section X  Small and Large Intestine


FIGURE 115-3. Perianal fistulas in Crohn’s disease. A, Multiple complex fistulas in a man with Crohn’s disease. Several are active and
draining. The scrotum, perianal skin, and buttocks are discolored and hardened by healed fistulas and abscesses. B, A simple fistula
in a woman with Crohn’s disease. The purplish discoloration surrounding the fistula is from an abscess that drained spontaneously
through the fistula. (Courtesy Dr. Lawrence J. Brandt, Bronx, New York.)

hydronephrosis; such patients often present with thigh pain abscess also are taking glucocorticoids, which are notorious
or a limping gait. Deeper penetration yields the classic, but for suppressing peritoneal signs and fever and masking the
fortunately rare, psoas abscess. Affected patients typically presentations of infection; therefore, a high level of suspicion
present with right flank discomfort, fever, and a gait similar must be maintained. When free perforation and peritonitis
to those with ureteral entrapment. occur, the situation is life-threatening.
Fistula to the vagina can occur with penetration from a
severely inflamed rectal vault anteriorly (rectovaginal fistula)
or from the small intestine. Rectovaginal fistulas tend to occur Stricture
among women who have had a hysterectomy, permitting Stricture is another characteristic complication of Crohn’s
direct extension to the adjacent vaginal cuff without the inter- disease. Strictures represent long-standing inflammation and
posing presence of a uterus. Patients present with foul, persis- can occur in any segment of the GI tract in which inflamma-
tent vaginal discharge and occasionally with passage of flatus tion has been active. Strictures do not develop in all patients
or frank stool per vagina. Patients also might complain of with inflammatory disease, but are likely to recur, most often
dyspareunia or perineal pain. The vaginal os of the fistula may at the anastomosis, in patients who undergo bowel resection
be difficult to identify, but palpation might elicit tenderness of because of a stricture. These observations suggest that addi-
the posterior vaginal wall. Fistulas arising from terminal ileal tional unidentified factors play a role in stricture formation.
disease often occur in the setting of an ileal stricture, back Strictures usually are silent until the luminal caliber is small
pressure and stasis perhaps contributing to the process. enough to cause relative obstruction. Symptoms can include
Enterovesicular or colovesicular fistulas can manifest as recur- colicky, postprandial abdominal pain and bloating, punctu-
rent polymicrobial urinary tract infection or as frank pneuma- ated by more severe episodes, and often culminating in com-
turia and fecaluria. These fistulas are notoriously difficult to plete obstruction.
heal by nonsurgical means, although the resulting cystitis may Not all obstructive presentations, however, are caused by
be controlled with antibiotics. Enterocutaneous fistulas to the fibrotic strictures. The classic radiologic “string sign” of a
anterior abdomen, often occurring after surgery, may be espe- markedly narrowed bowel segment amid widely spaced
cially troublesome. A classic presentation of Crohn’s disease bowel loops (Fig. 115-4) is a result of spasm and edema associ-
is the onset of an enterocutaneous fistula after appendectomy ated with active inflammation rather than fibrostenosis; the
for what had been presumed to be appendicitis. Often the tract typical string sign transiently resolves with administration of
of the fistula follows the planes of dissection to the abdominal glucagon, which relieves smooth muscle spasm.
surface. Short of demonstrating a clear response to anti-
It has been estimated that as many as one fourth of all inflammatory therapy or reviewing a surgical specimen, the
patients with Crohn’s disease present with an intra-abdominal clinician may find it extremely difficult to differentiate a
abscess at some time in their lives73; this figure is much less fibrostenotic from an inflammatory stricture. All strictures
than one would imagine in light of the high incidence of fis- must be considered with suspicion, and biopsies of a stricture
tulas. For the most part, inflamed serosal surfaces adhere to need to be pursued vigorously, because some strictures harbor
innocent serosa, thereby containing what would be an other- cancer.
wise free perforation. Another common scenario is a perfora-
tion and abscess formation around the site of a surgical
anastomosis. The classic presentation of an intra-abdominal
Classification of Disease
abscess is that of a patient with spiking fevers and focal A major need in the clinical investigation of Crohn’s disease
abdominal tenderness or localized peritoneal signs. Unfortu- is the ability to define subgroups of patients with distinctive,
nately, many of the patients at highest risk for perforation or if not unique, characteristics. The ability to define such

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   2001


FIGURE 115-4. Films from an upper GI series and small bowel follow-through in a patient with Crohn’s disease. A, Multiple areas of
narrowed small bowel are evident (arrows), with a classic cobblestoned appearance of the mucosa. Note also the separation of bowel
loops. B, Small bowel follow-through that demonstrates a string sign in the right lower quadrant. The classic radiologic string sign
(arrows) of a markedly narrowed bowel segment amidst widely spaced bowel loops is a result of spasm and edema associated with
active inflammation rather than fibrostenosis; thus, the typical string sign transiently resolves with administration of glucagon, which
relieves smooth muscle spasm. (Courtesy Dr. Jack Wittenberg, Boston, Mass.)

subgroups could add tremendous power to the investigation can result in exudation of protein and fluids. Increased
of new therapies and to genetic studies. In light of the wide production of prostaglandins, biogenic amines, cytokines,
heterogeneity of demographic, anatomic, and disease behav- neuropeptides, and reactive oxygen metabolites all contribute
ior characteristics, however, distilling the numerous possible to these alterations. An imbalance in the luminal concentration
phenotypes into simple categories is a formidable task. of bile salts relative to dietary fat can result in either bile salt–
The Montreal Classification of Crohn’s Disease is 1 pro- induced diarrhea or steatorrhea in the setting of ileal dysfunc-
posed scheme that incorporates the patient’s age at diagnosis tion or resection (see Chapter 102). Bacterial overgrowth can
(A1, 16 years and younger; A2, 17 to 40 years; A3, >40 years), occur behind strictured bowel and contribute to malabsorp-
disease location (L1, ileal: L2, colonic; L3, ileocolonic), and tion (see Chapter 105). Disordered colonic motility is seen in
disease behavior (B1, non-stricturing, non-penetrating; B2, the setting of chronic inflammation and also contributes to
stricturing; B3, penetrating).74 In addition, modifiers for upper diarrhea. Occasionally, medications used to treat Crohn’s
tract disease location (L4) and for perianal disease (p) may be disease can exacerbate diarrhea. Thus, secretory diarrhea can
added to the other categories. Increasingly, other associated occur with olsalazine, and any of the 5-aminosalicylates rarely
characteristics such as serologic markers and genetic profiles can induce a paradoxical increase in diarrhea, usually a result
may be used for their prognostic value in projecting outcomes of salicylate sensitivity.
in this heterogeneous disease.75
Abdominal Pain
Pathophysiology of Common The pathophysiology of abdominal pain in Crohn’s disease is
not well understood. Numerous lines of investigation have
Symptoms and Signs provided tantalizing clues about the connection between the
nervous system and Crohn’s disease, although the relation-
Diarrhea ship among the enteric nervous system, inflammation, and
Diarrhea is the most common complaint among patients with immune activation in Crohn’s disease is quite complex. Stretch
Crohn’s disease. Increased stool frequency and decreased receptors in the intestinal wall may be stimulated as a food
stool consistency arise through alterations in mucosal function bolus passes through stenotic bowel, leading to abdominal
and intestinal motility. In any given patient, multiple factors pain and possibly vomiting. Visceral pain can result from
are likely to contribute to diarrhea. Altered fluid and electro- serosal inflammation and local pain from abscess formation.
lyte absorption and secretion can decrease stool consistency. The ganglia of the myenteric plexuses in the intestine in
Increased mucosal permeability from mucosal inflammation Crohn’s disease are increased in size and number, possibly

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
2002   Section X  Small and Large Intestine

indicating neural dysfunction. Substance P binding can par- activity alone without superimposed illness or even abscess
ticipate in the expression of pain, and substance P receptors formation.
have been found in increased numbers around lymphoid fol-
licles, in the microvasculature, and on enteric neurons in
Crohn’s disease, even in locations distant from active inflam- Anemia
mation; there also is increased binding of substance P to its Anemia is found in one third of patients with Crohn’s
receptors in the setting of an inflamed mucosa.76,77 disease, primarily as a consequence of iron deficiency from
blood loss. Macrocytic anemia can result from vitamin B12
deficiency because of ileal disease or resection, from SIBO or,
Weight Loss and Malnutrition less commonly, from folate deficiency because of proximal
Weight loss and malnutrition often are seen in patients small intestinal disease or sulfasalazine therapy. Overproduc-
with Crohn’s disease and contribute to the complaints of tion of IFN-γ, TNF, or IL-1 can inhibit erythropoietin pro­
weakness, irritability, malaise, and easy fatigability that are so duction, contributing to anemia that is resistant to
common. In children, malnutrition can manifest as growth iron supplementation.80
retardation. A host of specific nutritional deficiencies may be
found even among patients whose disease has been in long-
standing remission, including iron, folic acid, vitamin B12,
Extraintestinal Manifestations
calcium, magnesium, zinc, and, particularly in the setting of In addition to penetrating and cicatrizing complications that
malabsorption from small intestinal disease, fat-soluble vita- can arise in patients with Crohn’s disease, numerous compli-
mins. Potential contributing factors for these deficiencies are cations can occur distant from the bowel. Depending on the
numerous and include inadequate intestinal absorption definition, it is estimated that between 6% and 25% of all
among patients with extensive small intestinal disease or patients with Crohn’s disease have an extraintestinal manifes-
resection and increased protein losses through exudation from tation (EIM) of IBD.81 Many of these EIMs are common to
inflamed intestine. Specific medications can cause absorption Crohn’s disease and UC and indeed to other non-idiopathic
problems, including decreased calcium absorption with glu- inflammatory conditions of the intestine. For example, patients
cocorticoids; malabsorption of fat, fat-soluble vitamins, and with ileal Crohn’s disease are at increased risk for cholelithia-
calcium with cholestyramine; and folate malabsorption with sis, but patients with extensive UC are at nearly the same risk.
sulfasalazine. In Crohn’s disease, however, the major risk factor for this
The catabolic state induced by intense inflammation can complication appears to be the extent of ileal resections. In
increase energy and protein requirements. Unrecognized large series, EIMs are found to occur more often in Crohn’s
infection can be a major contributing factor beyond the catabo- disease than in UC and are more common among patients
lism induced by the disease itself. Bypassing of small intestine with colonic involvement than in patients with no colonic
by enteroenteric or enterocolonic fistulas also can contribute inflammation. One fourth of those affected have more than 1
to undernutrition. EIM.82 Some EIMs occur as a direct result of the bowel disease
The most important factor in weight loss, however, is poor (e.g., nephrolithiasis resulting from oxalate malabsorption). In
oral intake. Most often, poor intake results from fear of eating the case of inflammatory mucocutaneous, joint, and ocular
because of postprandial abdominal pain or diarrhea. This EIMs, the pathogenesis is an influx of mononuclear cells acti-
concern may be accentuated when in social situations, and it vated in the intestine but homing aberrantly to the involved
can contribute to a patient’s lack of interest in being outside extraintestinal organs.
of the home. Decreased intake occasionally may be a conse-
quence of unnecessarily restrictive diets imposed by the phy-
sician or the patient in an effort to control symptoms. Weight Musculoskeletal
loss disproportionate to the burden of disease, however, Among the most common EIMs are disorders of the bones and
should raise the suspicion of occult malignancy. joints. Clubbing of the fingernails is a common and innocuous
Anorexia, nausea, and vomiting also can contribute to EIM. More consequential are arthritic manifestations, which
weight loss and poor nutrition. As with other symptoms of are observed more commonly in patients with Crohn’s disease
Crohn’s disease, diverse mechanisms may be contributory. than in those with UC. In a study of 976 patients with UC and
TNF originally was discovered as a cytokine capable of induc- 483 patients with Crohn’s disease, pauciarticular arthropathy
ing cachexia in patients with malignancy and sepsis. Indeed, (type I, affecting ≤ 4 joints) occurred in 3.6% of patients with
serum levels of TNF in severely ill patients with Crohn’s UC and in 6.0% of those with Crohn’s disease.83 In most
disease may be high enough to contribute to anorexia. Delayed patients, joint symptoms occurred in the setting of a relapse
gastric emptying of solids may be a causative factor for dys- of intestinal symptoms. Polyarticular arthropathy (type II, ≥ 5
pepsia in individuals with Crohn’s disease, even when the joints affected) occurred in 2.5% of patients with UC and 4.0%
disease is inactive.78,79 Finally, anorexia, nausea, or vomiting of those with Crohn’s disease.83 Among patients with Crohn’s
also may be caused by drugs used to treat the disease, includ- disease, nearly one half had joint symptoms in association
ing metronidazole, sulfasalazine, 6-mercaptopurine, azathio- with a relapse in intestinal disease.
prine, and methotrexate. Peripheral arthralgias occur in one fifth of patients with
Crohn’s disease, most strongly in association with colonic
disease.82 Patients tend to have waxing and waning joint pain
Fever and stiffness in association with flares of intestinal disease.
Fever associated with active Crohn’s disease usually is Joints may be involved in an asymmetrical or migratory
low grade and occasionally is the presenting complaint, espe- fashion. With rare exception, the disease is non-deforming and
cially in children; increased production of proinflammatory often is accompanied by skin (erythema nodosum) and eye
cytokines, including IL-1, IL-6, and TNF, likely are contribu- (uveitis) complications. Rheumatoid factor typically is nega-
tory. When spiking, high, or persistent fevers occur, the clini- tive. Knee and ankle joints often are affected first, but elbows,
cian needs to consider an infectious etiology and undertake wrists, proximal interphalangeal, metacarpophalangeal, and
an evaluation appropriate to the clinical picture. Rarely, metatarsophalangeal joints may be involved subsequently.
such fever patterns are manifestations of Crohn’s disease Patients who have undergone ileocecal resection for their

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   2003

disease tend to have fewer arthritic complications after their are associated with EN, including Streptococcus or Yersinia
surgery. infection, TB, leprosy, fungal infections, Behçet’s syndrome,
Axial arthropathies are less common than peripheral and sarcoidosis. The classic appearance of EN is tender sub-
arthropathies and occur in 3% to 10% of patients with IBD.84 cutaneous nodules with an erythematous or dusky appear-
Spondylitis associated with IBD, like idiopathic ankylosing ance, most often on the pretibial region. There is a strong
spondylitis, manifests as insidious low back pain and morning association of EN with arthropathy. EN often manifests during
stiffness that is improved by exercise. As many as 75% of exacerbations of intestinal disease and tends to improve with
patients with Crohn’s disease and spondylitis are positive for treatment of the underlying bowel disease. Whenever possi-
HLA-B27.85 Iritis can occur in association with this manifesta- ble, EN lesions should not be biopsied because biopsied
tion. Bilateral symmetrical sacroiliitis without progression to lesions tend to scar; spontaneously resolving lesions heal
spondylitis is more common than spondylitis and is reported without forming a scar.
to occur in 4% to 18% of patients.86 In 1 study, sacroiliitis was Aphthous ulcers of the mouth are common among patients
found on MRI among 39% of patients, with two thirds report- with Crohn’s disease and UC but also are often seen among
ing low back pain; 11% of patients with negative scans reported otherwise healthy persons. As the most cephalad part of the
low back pain.87 GI tract, the mouth rarely may be involved directly by the
Rarer rheumatologic complications include granuloma- granulomatous inflammation of Crohn’s disease. Features
tous vasculitis, periostitis, and amyloidosis. In addition, a may include lip or facial swelling, angular cheilitis and oral
septic joint, although a rare complication of Crohn’s disease, mucosal cobblestoning.93
should be kept in mind. A septic hip joint is a striking, devas- A rare EIM is metastatic Crohn’s disease (i.e., granuloma-
tating, and fortunately rare complication of a psoas abscess tous inflammation of the skin remote from the GI tract but
that extends directly to the acetabular capsule. histologically identical to the primary intestinal lesion).94
Glucocorticoids used to treat Crohn’s disease may be a Described cases have included lesions behind the ears, in the
cause of joint pain. Withdrawal of glucocorticoids can lead to perineum, or on the feet, legs, penis, and vulva. Other rare
pseudoarthritis, with diffuse joint aches that gradually resolve; skin manifestations of Crohn’s disease include leukocytoclas-
adrenal insufficiency should be considered in such patients. tic vasculitis, Sweet’s syndrome (neutrophilic dermatosis),
Aseptic necrosis of the hip and other joints can occur with or cutaneous polyarteritis nodosa, and epidermolysis bullosa
without the use of glucocorticoids and may be disabling. acquisita. An increased occurrence of psoriasis among patients
Osteomyelitis can occur as a result of direct extension by a with Crohn’s disease is in concordance with the reported
fistula, usually to the pelvis, or it may be a recurrent problem genetic overlap between these diseases.27,95
distant to the site of inflammation, presumably through hema-
togenous spread of bacteria.
Metabolic bone disease is common in Crohn’s disease; Ocular
osteopenia (T score on dual energy x-ray absorptiometry Ocular EIMs are estimated to occur in 6% of patients with
between −2.49 and −1.0) or osteoporosis (T score −2.5 and Crohn’s disease.96 Episcleritis is more common in Crohn’s
lower) occurs in 30% to 60% of patients. Morbidity, as a con- disease than in UC, consists of injection of the sclera and con-
sequence of increased susceptibility to bone fractures, includes junctiva, and does not affect visual acuity. Episodes tend to
debilitating and painful vertebral crush fractures, which can occur in association with active intestinal disease. Scleritis
occur even in children with Crohn’s disease. Although gluco- involves deeper layers of the eye, also occurs most often in
corticoid use is the main risk factor for this metabolic bone parallel with active intestinal disease, and i can cause lasting
disease in UC, low bone mineral density is a feature of Crohn’s damage if untreated. Uveitis usually manifests with headache,
disease even upon diagnosis in both adults and children.88,89 deep eye pain, lacrimation, blurred vision, and photophobia,
Contributing factors include malabsorption of calcium and as a consequence of iridospasm. Physical examination find-
vitamin D, smoking, and perhaps the effects of proinflamma- ings of uveitis include meiosis and ciliary flush. Visual acuity
tory cytokines such as TNF.90 Low BMI may be the most is preserved unless the posterior segment becomes involved.
important risk factor for developing osteoporosis.91 Sarcope- In contrast to the uveitis associated with ankylosing spondy-
nia (decreased muscle mass) is closely associated with litis, the presentation of uveitis in patients with IBD often is
decreased bone density and is seen in up to 60% of patients insidious, with bilateral involvement and extension to the
with Crohn’s disease.92 posterior segment. Slit-lamp examination demonstrates an
inflammatory flare in the anterior chamber. Of all the ocular
EIMs, uveitis is the one that demands emergent ophthalmo-
Mucocutaneous logic consultation. Other ocular complications of Crohn’s
The most common skin lesions associated with IBD are pyo- disease include a particular corneal injury referred to as kera-
derma gangrenosum and erythema nodosum. Neither condi- topathy and night blindness resulting from malabsorption of
tion is found solely in IBD, and the finding of 1 or the other vitamin A.
lesion is not specific for either major form of IBD.
Pyoderma gangrenosum (PG) appears first as a papule,
pustule, or nodule. It can occur virtually anywhere on the Hepatobiliary
body but most often it occurs on the leg or occasionally around Gallstones occur in 14.35/1000 patient-years of follow-up
a stoma, and progresses to an ulcer with undermined borders. among people with Crohn’s disease, roughly twice the rate of
The PG ulcer typically has a violaceous rim and crater-like the general population.97 Asymptomatic and mild elevations
holes pitting its base. The phenomenon of pathergy, or the of liver biochemical tests often are seen in Crohn’s disease, but
development of large ulcers at the site of minor trauma, is only few of these patients develop clinical evidence of cirrho-
characteristic of PG and also the skin lesions of Behçet’s syn- sis. PSC more often is associated with UC, but it occurs in
drome. Healing typically is associated with a cribriform, or patients with Crohn’s disease, and is more often small duct
pocked, scar. In Crohn’s disease, PG often occurs without an disease associated with colonic involvement.98 Recent GWA
associated flare of intestinal symptoms. studies in PSC indicated that 6 of 12 significant associations
Erythema nodosum (EN) is seen much more commonly outside the human leukocyte antigen complex are more
in women than in men. Like PG, many other diseases strongly associated with PSC than with IBD (rs7426056, 2q33,

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
2004   Section X  Small and Large Intestine

CD28; rs5625822, 16q15*, BACH2; rs4147359, 10p15*, IL2RA; patients with marked malabsorption. Pleuropericarditis, myo-
rs7937682, 11q23, SIK2; rs3184504, 12q24, SH2B3; rs60652743, carditis, and endocarditis occur rarely. Acute pancreatitis is
19q13*, PRKD2), despite the observation that nearly three uncommon, though may occur spontaneously or as a result of
quarters of PSC patients have comorbid IBD.99 As the findings treatment with mesalamine or a thiopurine agent. Granuloma-
are more often confined to the small biliary radicals, the pre- tous pancreatitis and pancreatic insufficiency are rare.
sentation is usually one of abnormal liver biochemical tests,
pericholangitis on liver biopsy, and a normal cholangiogram.
Other hepatobiliary complications of Crohn’s disease include DIFFERENTIAL DIAGNOSIS
fatty liver and autoimmune hepatitis.
Establishing a diagnosis of Crohn’s disease usually is straight-
forward once it is considered. Nevertheless, a large number of
Renal and Genitourinary alternative diagnoses may be considered during various
In addition to the direct complications of perforating Crohn’s stages of the evaluation. Reports are legion of other diseases
disease with encroachment on the bladder and other genito- mistakenly diagnosed as Crohn’s disease and of Crohn’s
urinary structures, and inflammatory entrapment of the disease mistaken for other diseases. Misdiagnoses may be
ureter, uric acid and oxalate stones are common in patients attributed to the protean presentations of Crohn’s disease,
with Crohn’s disease.100 In the setting of fat malabsorption which include considerable variation among patients with dis-
resulting from intestinal resection or extensive small intestinal tinct anatomic distributions of disease, different degrees of
disease, the malabsorbed free fatty acids bind luminal calcium, inflammation, and the variable presence of intestinal compli-
thereby decreasing the calcium that is available to bind with cations and EIMs.
and clear oxalate via intestinal excretion. Oxalate that remains There are a number of clinical situations in which Crohn’s
in the intestinal lumen binds to sodium and as sodium oxalate disease should enter the differential diagnosis, including diar-
has increased absorption compared with calcium oxalate, the rhea or abdominal pain, especially when localized to the right
result is hyperoxaluria and calcium oxalate stone formation. lower quadrant; evidence of intestinal inflammation on radio-
Uric acid stones are believed to result from volume depletion logic or endoscopic studies; discovery of an intestinal stricture
and a hypermetabolic state. Rare intrinsic renal complications or fistula arising from the intestine; and evidence of inflam-
include membranous nephropathy, glomerulonephritis, and mation or granulomas on intestinal histology. Categories of
renal amyloidosis. Interstitial nephritis has been associated causation that overlap with Crohn’s disease in clinical pre­
with mesalamine use, but it is not clear if it is a direct result sentation include functional bowel disorders, primarily IBS;
of the medication or of the disease itself. Penile and vulvar immune-mediated diseases, particularly other colitides and
edema also have been reported, but the mechanism for these most importantly UC; medications, especially NSAIDs; vascu-
occurrences is unknown. lar disorders, notably ischemic bowel disease and collagen
vascular diseases; neoplasia, including carcinoma and lym-
phoma; infectious diarrheas, intestinal inflammation, or gran-
Vascular ulomas; and miscellaneous other diseases and syndromes,
A prothrombotic tendency has been noted in both UC and including diverticular disease. Once the presence of bowel
Crohn’s disease. Patients might present with venous throm- inflammation has been confirmed, the differential diagnosis
boembolism or, much less commonly, arterial thrombosis.101 may focus on presentation according to the anatomic location
The incidence of venous thromboembolism increases with of the findings (Box 115-1).
age, but a higher relative risk is observed in younger patients.102
The hypercoagulable state can arise from many possible con-
tributing causes: thrombocytosis, increased levels of fibrino-
gen, fibrinopeptide A, factor V, and factor VIII, antithrombin ESTABLISHING THE DIAGNOSIS AND
III deficiency, and free protein S deficiency, all related to EVALUATING DISEASE ACTIVITY
active bowel inflammation. Circulating immune complexes,
increased levels of plasminogen activator inhibitors, decreased No single symptom, sign, or diagnostic test establishes the
levels of tissue plasminogen activator, and spontaneous diagnosis of Crohn’s disease. Rather the diagnosis is estab-
platelet aggregation may be present independent of bowel lished through a total assessment of the clinical presentation
inflammation. Defective methylenetetrahydrofolate reductase with confirmatory evidence from radiologic, endoscopic, and,
(MTHFR), along with folate and vitamin B12 deficiency, is in most cases, pathologic findings.
linked to hyperhomocysteinemia, which in turn may predis- Initial evaluation includes a thorough history-taking,
pose to thrombosis. Reports of increased prevalence of the physical examination, and basic laboratory tests. History-
factor V Leiden mutation and MTHFR have been observed by taking focuses on the key symptoms and their severity and
some but not other investigators.103 In more than half of duration. Specific points to be covered should include recent
patients who experience thrombosis, no predisposing factor travel history, use of antibiotics and other medications, diet,
can be identified. and sexual preference and activity. A family history of IBD
can raise the level of suspicion but does not guarantee the
diagnosis. The review of systems should focus on eliciting
Other EIMs and weight loss. Fever may be associated with the
Clinically significant disease of the lungs,104 heart, pancreas, underlying disease or a suppurative complication. A careful
and nervous system105 in association with Crohn’s disease is examination of the abdomen for signs of obstruction, tender-
unusual but reported. Subclinical lung involvement may be ness, or a mass should be undertaken. Thorough inspection of
much more common than is apparent, perhaps reflecting the the perineum and a rectal examination might disclose findings
commonality of bronchus-associated lymphoid tissue and highly suggestive of the underlying diagnosis or gross or
gut-associated lymphoid tissue.104 Patients with IBD are more occult blood.
at risk to develop asthma, and there also may be an association Laboratory data may be normal. Anemic patients should
with chronic obstructive pulmonary disease.95,106 Cardiomy- undergo further evaluation to define the contributions of iron,
opathy can result from a variety of nutrient deficiencies in folate, or vitamin B12 deficiencies. The WBC count may be

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   2005

BOX 115-1 Differential Diagnosis of Crohn’s Disease

Differential Diagnosis of Ileitis Vasculitis: Henoch-Schönlein purpura, polyarteritis nodosa,

Backwash ileitis in UC eosinophilic granulomatosis with polyangiitis (EGPA,
Drug-related Churg-Strauss syndrome), SLE, Takayasu’s arteritis,
Ectopic pregnancy granulomatosis with polyangiitis, lymphomatoid
Endometriosis granulomatosis, giant cell arteritis, rheumatoid
Gynecologic disorders vasculitis, thromboangiitis obliterans
Ileitis associated with spondyloarthropathy
Infection Differential Diagnosis of Colitis
Actinomycosis israelii Acute self-limited colitis
Anisakis simplex Behçet’s disease
Cryptococcus neoformans Chronic granulomatous disease
Cytomegalovirus Diversion colitis
Histoplasma capsulatum Diverticulitis
Mycobacterium avium complex Drug-induced colitis (NSAIDs, gold, penicillamine)
Mycobacterium tuberculosis Eosinophilic gastroenteritis
Neutropenic enterocolitis Graft-versus-host disease
Salmonella spp. Indeterminate colitis
Yersinia enterocolitica Infections
Yersinia pseudotuberculosis Aeromonas spp.
Infiltrative disorders Campylobacter spp.
Amyloidosis Clostridium difficile
Eosinophilic gastroenteritis Cytomegalovirus
Lymphoid nodular hyperplasia Entamoeba histolytica
Neoplasms Escherichia coli (enterohemorrhagic, enteroinvasive)
Carcinoid tumor Mycobacterium tuberculosis
Cecal or ileal adenocarcinoma Salmonella spp.
Lymphoma Schistosoma mansoni
Metastatic cancer Shigella spp.
NSAID-related ulcer or stricture Strongyloides stercoralis
Other inflammatory disorders Yersinia enterocolitica
Appendicitis/appendiceal abscess Ischemic colitis
Cecal diverticulitis Chronic ischemic colitis
Ovarian cyst or tumor Ischemic stricture
Ovarian torsion Ischemic colitis with toxic megacolon
Pelvic inflammatory disease Transient ischemic colitis
Radiation enteritis Microscopic colitis
Torsion of the appendiceal epiploica Collagenous colitis
Tubo-ovarian abscess Lymphocytic colitis
Vascular disorders Radiation colitis
Behçet’s disease Sarcoidosis
Intestinal ischemia: focal segmental ischemia: acute Segmental colitis associated with diverticular disease
enteritis, chronic enteritis, stricture; chronic mesenteric (SCAD)
ischemia; drug-induced (e.g., oral contraceptives, Solitary rectal ulcer syndrome
ergotamine, amphetamines, phenylephrine, cocaine) UC

From Sands BE. From symptom to diagnosis: Clinical distinctions among various forms of intestinal inflammation. Gastroenterology 2004; 126:1518-32, with permission.

normal or elevated; an increased number of band forms sug- Submucosal edema may be evident as thickening or flattening
gests the possibility of a pyogenic complication. In the patient of the valvulae conniventes, whereas transmural edema mani-
with vague symptoms suggesting IBS, an elevated C-reactive fests as widening of the separation between bowel loops.
protein or erythrocyte sedimentation rate, although not spe- Ulcers most often occur on the mesenteric border, with conse-
cific for IBD, can prompt further investigation. Stool studies quent pseudosacculation of the antimesenteric border because
should include culture, examination for ova and parasites, and of shortening of the mesenteric portion of bowel. Later find-
testing for Clostridium difficile infection and should be per- ings include a cobblestone appearance resulting from edema
formed before endoscopy or barium studies. Serology for Ent- and inflammation of relatively spared islands of mucosa sepa-
amoeba histolytica should be considered in selected patients. rated by intersecting longitudinal and transverse knife-like
Ultimately, the diagnosis of Crohn’s disease is confirmed clefts of ulceration. Still later, one can discern fistulas, sinus
by findings on imaging studies, endoscopy, and usually histo- tracts, and fixed strictures; all but the finest and earliest details
pathology. Barium studies had been the mainstay of imaging may now be seen with cross-sectional imaging modalities.
Crohn’s disease for many years, and they accurately define the Standard CT studies do not demonstrate mucosal detail
anatomic location of disease and can reveal evidence of active and often appear normal early in the course of disease. The
inflammation (see Fig. 115-4). However, the small bowel advent of CT enterography, however, has allowed fine mucosal
follow-through study has largely been replaced at most centers changes to be evaluated along with extraluminal features (and
with CT or MRI (see later). Fine details from barium studies complications of Crohn’s disease). CT enterography differs
are instructive in describing the anatomical findings of the from routine CT by the use of a high-resolution multidetector
disease, even if rarely used. Early findings include aphthous scanner, IV contrast, and large volumes of oral contrast (either
ulcers, a coarse villus mucosal pattern, and thickened folds. dilute barium or negative water-based contrast) to improve

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
2006   Section X  Small and Large Intestine

FIGURE 115-5. CT enterography in a patient with Crohn’s disease

showing an intestinal stricture with pre-stenotic dilatation. The
stricture is partly inflammatory, with increased enhancement,
mural thickening, and peri-enteric inflammation. (Courtesy Dr.
Edward Loftus and Dr. Joel Fletcher, Rochester, Minn.)

visualization of the small intestinal wall and reveal luminal

details (Fig. 115-5). Radiologic findings that are significantly
correlated with endoscopic evidence of Crohn’s activity
include mural enhancement (segmental enhancement of all or
part of the small intestinal wall); increased density of peri- FIGURE 115-6. MR enterography with gadolinium contrast in a
enteric fat (focal increased inhomogeneous attenuation in the patient with Crohn’s disease. This coronal view shows mural
peri-enteric fat, compared with the appearance of subcutane- hyperenhancement, mural thickening, and the comb sign
ous or peri-enteric fat in adjacent non-inflamed intestinal (engorged peri-enteric vasculature) involving the terminal ileum.
loops); and the comb sign (segmental dilatation of the vasa The vessels are seen medial to the inflamed loop and resemble
recta involving an intestinal loop).107 Mural enhancement may the teeth of a comb. (Courtesy Dr. Edward Loftus and Dr. Jeffrey
be the most useful finding and can be quantified in a semi- Fidler, Rochester, Minn.)
automated fashion using dedicated software.107,108 When com-
pared with a consensus diagnosis of Crohn’s disease based on
clinical presentation and 4 different imaging modalities, the some interest in using EUS to differentiate Crohn’s disease
sensitivity of CT enterography was 82%, specificity was 89%, (transmural) from UC, but its major value is still to help evalu-
and accuracy was 85%.109 The safety of radiation exposure ate and guide therapy of perianal disease.115 Pelvic MRI,
associated with the routine use of CT is a matter of much however, remains the preferred imaging modality to evaluate
debate, and needs to be taken into careful consideration if this suspected pelvic, perirectal or perianal abscess or fistula.
technology is to replace other diagnostic modalities, especially Doppler vascular flow studies to evaluate Crohn’s disease
in children.110,111 activity have been investigated with mixed results.116 US-
As an alternative to CT, MRI is approaching equivalent and CT-guided percutaneous drainage of intra-abdominal
image quality in evaluating the intestine. MR enterography abscesses is a safe and effective alternative to surgical drain-
has the advantages of providing high soft tissue contrast, age in well-selected patients.117 Early findings suggest that US
obtaining static and dynamic images, and avoiding ionizing elasticity imaging may be useful to detect intestinal fibrosis in
radiation.112 Similar to CT enterography, patients drink an oral strictures.118 99mTc leukocyte scintigraphy has an accuracy of
contrast agent before the procedure. Some European centers 84% compared with the gold standard of intraoperative find-
incorporate enteroclysis with nasoduodenal intubation to ings,119 although it is used seldom in clinical practice. Early
administer the contrast, which might increase the yield for data suggest a possible role for PET/CT scanning to help in
subtle mucosal lesions but is likely to be less acceptable to evaluating the activity level and distribution of Crohn’s
most patients.112 Findings of intestinal wall thickening, sub- disease.120,121
mucosal edema, vasa recta engorgement, and lymphadenopa- Because it allows direct inspection of the mucosa and
thy are signs of active disease (Fig. 115-6). Using dynamic permits biopsy for histopathology, endoscopy complements
FIESTA (fast imaging employing steady state acquisition), radiologic techniques. Typical mucosal features recognized on
images can add information regarding the functional status of endoscopy include aphthous ulcers, stellate and other discrete
fibrotic segments. A scoring system was developed for assess- ulcers, mucosal edema, cobblestoning, and luminal narrowing
ing small intestinal Crohn’s disease and gives higher scores (Fig. 115-7). The visual impression of demarcated lesions on a
for details such as increased wall thickness and contrast background of normal mucosa is most easily recognized in
enhancement, stenosis and mucosal abnormalities, absence of early or mild disease. Rectal sparing is more specific before
peristalsis and distensibility, and extraintestinal findings.113 treatment has been initiated. The discontinuous segmental
Using these criteria, compared with the gold standard of ileo- nature of the disease is an important clue to the diagnosis.
colonoscopy with biopsies, the MRI images yielded a diagnos- Intubation and biopsy of the terminal ileum should be
tic accuracy of 91%. attempted in all patients having colonoscopy and greatly
Other potentially useful diagnostic modalities include US increase the sensitivity and specificity of the examination. In
and scintigraphy. Transabdominal US is used mainly to general, the diagnostic accuracy of colonoscopy and histologic
exclude other causes of abdominal pain (e.g., biliary and gyne- interpretation is increased substantially by obtaining multiple
cologic disorders), but it can also be effective in evaluating biopsies from both involved and uninvolved sites. The use of
disease activity of luminal Crohn’s disease.114 There has been jumbo forceps should be considered to improve submucosal

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   2007



FIGURE 115-7. Endoscopic appearance of Crohn’s disease. A wide variety of findings may be visualized on endoscopy, in part depend-
ing on the duration and severity of the inflammation. A, Typical aphthous ulcers (arrows), consisting of a central white depression
surrounded by a slightly elevated, erythematous rim only a few millimeters in diameter. B, Findings more typical of advanced disease,
with erythema, edema, and a cobblestoned appearance. C, Stellate ulcers (arrows) in the terminal ileum. D, Discrete ulcers (arrows)
with normal intervening mucosa, typical of the patchy inflammation seen in Crohn’s disease.

sampling. Balloon dilation of strictures is another application various ways among different centers. As many as 10% of
of endoscopy in Crohn’s disease that might delay surgery or patients presenting with IBD are considered to have indeter-
eliminate the need for it, but balloon dilation is associated with minate colitis. A diagnosis of indeterminate colitis has particu-
a measurable complication rate. lar implications for surgical therapy. Patients undergoing
Video capsule endoscopy (VCE) has become routine for ileoanal pouch construction for indeterminate colitis have a
detecting the small intestinal lesions of Crohn’s disease. relatively high likelihood of developing Crohn’s-like compli-
Although VCE may be very sensitive in identifying lesions cations of the pouch, although the rate of pouch failure is not
(even if standard endoscopy has been unrevealing),122 its low significantly different from those with UC.128 Histology, when
specificity limits its use as a first-line study to diagnose small applied without attention to clinical features, is highly likely
intestinal Crohn’s disease.109 The presence of significant bowel to be unable to differentiate Crohn’s disease from UC. There-
stricture should be excluded radiologically or by patency fore, the entire clinical picture must be considered for accurate
capsule123,124 before attempting VCE, because capsule retention diagnosis (Table 115-2). Discriminating features for Crohn’s
and obstruction may occur in 2.6% of patients.125 Nonetheless, disease include the presence of small intestinal disease, pre-
capsule retention can be clinically useful to localize occult dominantly right-sided colonic disease, rectal sparing, fistuli-
strictures pre- and intraoperatively.126 Increasingly, single- and zation (with the exception of rare rectovaginal or perianal
double-balloon enteroscopy is being used to address jejunal fistulas in UC), major perineal complications, and granulo-
and proximal ileal Crohn’s disease,127 allowing for biopsy and mas. In cases initially labeled as indeterminate, the true diag-
balloon dilation of strictures. nosis usually becomes clear with the passage of time.
With an incomplete understanding of the environmental
and genetic determinants that produce a clinical phenotype of
Differentiating Crohn’s Disease from UC Crohn’s disease or UC, the immunologic markers noted previ-
When IBD is confined to the colon, the main diagnostic dis- ously are being explored as a means of differentiating the 2
tinction is between Crohn’s colitis and UC. As noted earlier, diseases. pANCA (perinuclear antineutrophil cytoplasmic
UC and Crohn’s disease share many similarities in epidemiol- antibodies) and ASCA (anti-Saccharomyces cerevesiae antibod-
ogy, genetics, and clinical manifestations, and the distinction ies) were the first such markers shown to correlate with the
between them is becoming increasingly important with regard diagnosis of UC and Crohn’s disease, respectively. ASCA has
to choices of surgical and medical therapies. Patients with relatively high specificity, above 95%, but sensitivity is less
features of both diseases are said to have indeterminate colitis than 50%.129 To improve the test characteristics, the prediction
(also referred to as IBD, unclassified), a vague term applied in model has added anti-OmpC and anti-CBir1 to pANCA and

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
2008   Section X  Small and Large Intestine

TABLE 115-2 Differentiation of Crohn’s Colitis from UC

Feature Crohn’s Colitis Ulcerative Colitis

Mucosal lesions Aphthous ulcers are common in early Micro-ulcers are more common, but larger ulcers are seen
disease; late disease is notable for stellate, Pseudopolyps are more common
rake, bear-claw, linear, or serpiginous
ulcers and cobblestoning

Distribution Often discontinuous and asymmetric, with Continuous, symmetric, and diffuse, with granularity or
skipped segments of normal intervening ulceration found in the entirety of involved segments;
mucosa, especially in early disease however, peri-appendiceal inflammation (cecal patch) is
common, even when the cecum is not involved

Rectum Complete, or more often relative, rectal Typically involved with variable proximal distribution

Ileum Often involved (≈75% of cases) Not involved, except as backwash ileitis in panulcerative

Depth of inflammation Mucosal, submucosal, and transmural Mucosal; transmural only in fulminant disease

Serosal findings Marked erythema and creeping fat (the latter Absent except in severe colitis or toxic megacolon
is virtually pathognomonic)

Perianal complications Often prominent, including large anal skin Not prominent (fissure or fistula if present, should be
tags, deep fissures, perianal fistulas, that uncomplicated)
are often complex

Strictures Often present Rarely present; when present, suggests adenocarcinoma

Fistulas Perianal, enterocutaneous, rectovaginal, Absent, except for the rare occurrence of rectovaginal or
enterovesicular, and other fistulas may be perianal fistula

Histopathology Granulomas are present in 15%-60% of Granulomas should not be present (microgranulomas may
patients (higher frequency in surgical be associated with ruptured crypt abscess)
specimens than in mucosal pinch biopsies)
Crypt abscesses may be present Crypt abscesses and ulcers are the defining lesion
Focally enhanced inflammation, often on a Ulceration on a background of inflamed mucosa
normal background, is the hallmark

Serology pANCA in 20%-25%, ASCA in 41%-76% pANCA in 60%-65%, ASCA in 5%

ASCA, anti-Saccharomyces cerevisiae antibody; pANCA, perinuclear antineutrophil cytoplasmic antibody.

From Sands BE. From symptom to diagnosis: Clinical distinctions among various forms of intestinal inflammation. Gastroenterology 2004; 126:1518-32, with permission.

ASCA.72,130 Other antiglycan antibodies, such as antilaminari- subject the patient to repeated radiologic studies or colonos-
bioside (ALCA) and antichitobioside (ACCA) have also been copies to ascertain disease activity; disease location tends to
associated with Crohn’s disease.131 Limited data are available be stable over time. Repeat studies are undertaken when
to establish the predictive value of serologic markers in cases symptoms have increased substantially or have changed and
of indeterminate colitis observed over long periods of time.132 are suspected to arise not from persistent intestinal inflamma-
Thus, serologic testing currently is an adjunct to diagnosis in tion but from other causes, such as infection, complication, or
selected cases—one additional piece of evidence to be consid- a functional disorder. In clinical research, however, more
ered but not definitive in establishing the diagnosis. Genetic quantitative evaluations are needed.
research has led to great strides over the past few years, and Composite scoring systems, most commonly the Crohn’s
CARD15/NOD2 testing is available commercially. Owing to its Disease Activity Index (CDAI [Table 115-3]), are used in an
low diagnostic accuracy, this test is not currently recom- attempt to integrate the many possible features of the disease.
mended as part of the diagnostic algorithm for Crohn’s Other disease activity indices include the van Hees index,133
disease. Preliminary data suggest that models combining the Cape Town index,134 the Harvey-Bradshaw index,135 the
NOD2 genotyping with serologic biomarkers such as ASCA, International Organization of IBD (or Oxford) index,136 the St.
anti-OmpC, anti-CBir1 pANCA and anti-I2, have acceptable Marks Crohn’s index,137 De Dombal’s index,138 the Talstad
receiver-operator characteristics for predicting complicated index,139 and a Crohn’s disease activity index for survey
disease behavior such as stricture or fistula.130 research.140 Specialized indices also have been developed for
use in children with Crohn’s disease.141,142 All these indices
vary in the features included in the scoring system, but most
Measuring Disease Activity include a combination of subjective symptoms and objective
In daily practice, usually it is sufficient to follow the patient’s findings on examination and laboratory testing. A great deal
symptoms and signs with treatment. Rarely is it necessary to of interobserver and methodological variation has been noted,

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   2009

TABLE 115-3 Crohn’s Disease Activity Index (CDAI)*

Variable Scale Weight

Liquid or very soft stools Stool count summed daily for 7 days 2

Abdominal pain Sum of 7 days of daily ratings as: 0 = none, 1 = mild, 2 = moderate, 3 = severe 5

General well-being Sum of 7 days of daily ratings as: 0 = generally well, 1 = slightly below par, 7
2 = poor, 3 = very poor, 4 = terrible

Features of extraintestinal disease Any of the following present during the 7 days of daily ratings: 20 each
a. Arthritis or arthralgia
b. Skin or mouth lesions, including pyoderma gangrenosum, erythema
nodosum, aphthous stomatitis
c. Iritis or uveitis
d. Anal fissure, fistula, or perirectal abscess
e. Other external fistula
f. Fever > 100°F

Opiate use for diarrhea 0 = no, 1 = yes 30

Abdominal mass 0 = none, 2 = questionable, 5 = definite 10

Hematocrit value (%): Males: 47 – hematocrit 6

Females: 42 – hematocrit

% Body weight below standard 100 × [1 – (body weight/standard weight)] 1

*To calculate the CDAI, the scale is multiplied by the weighting factor for each variable, and then all 8 weighted variables are added.
From Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study. Gastroenterology 1976;
70:439-44, with permission.

even among experienced researchers,143 and in fibrostenotic

disease, indices that rely more heavily on subjective measure- TREATMENT
ments can poorly reflect bowel inflammation as a cause of
symptoms. Other approaches have included use of disease- Goals
activity indices that focus on a specific outcome, such as peri-
anal disease,144,145 endoscopic findings,146,147 or achieving an Because neither medical nor surgical therapy provides a cure
individual goal of therapy.148 Each of these approaches has for Crohn’s disease, the primary goals of therapy are to induce
advantages and disadvantages, but all have their application and maintain remission. The definition of remission is evolv-
in research rather than in clinical practice. ing, and has moved beyond the CDAI and other subjective
Another approach with some merit is the measurement of disease activity indices to include mucosal and histologic
biological markers of disease inflammation. The erythrocyte healing, which are more closely associated with improved
sedimentation rate and serum acute phase response proteins long-term treatment goals and preventing bowel damage.151,152
(e.g., C-reactive protein and orosomucoid) may be useful in In achieving these goals, the intention is to ameliorate symp-
tracking disease activity, but lack sensitivity and specificity. toms and improve the patient’s quality of life. Therefore, it is
Direct measurements of intestinal immune activation in a essential to consider the adverse consequences of therapy,
mucosal sample could enhance sensitivity and specificity but particularly with regard to any durable consequences of short-
are inconvenient, invasive, and, if dependent on biopsy, term treatment and adverse effects of maintenance therapy.
subject to variability and poor standardization. Fecal excretion Other goals may be specific to the individual patient, such as
of calprotectin (a calcium- and zinc-binding protein found in healing a fistula or achieving normal growth in a child. Main-
neutrophils) and of lactoferrin (an iron-binding glycoprotein taining adequate nutrition can at times be a challenge and is
secreted by most mucosal membranes) have been shown to be an important goal in all patients.
sensitive markers of intestinal inflammation149 that also might
correlate with relapse of quiescent disease and response to
therapy with biologics.129
Medical Therapy
Ultimately, it is desirable to measure the patient’s overall
state of well being, or subjective health status. Health-related Aminosalicylates
quality of life may be measured with generic instruments, In the United States, aminosalicylates (ASAs) are used in the
which focus on various domains of health common to many treatment of UC and in mild to moderate Crohn’s disease.
disease states, or with disease-specific instruments, which Sulfasalazine, the parent compound of all ASAs used in IBD,
focus on specific domains relevant to the disease of interest. was developed by the Swedish physician Nana Svartz in 1938-
The Inflammatory Bowel Disease Questionnaire is the most 1939 as a treatment for RA. In 1941-1942 sulfasalazine was
widely accepted disease-specific instrument and measures serendipitously found to improve the intestinal symptoms of
separate domains for bowel, social, systemic, and emotional patients with colitis who were being treated for associated
function.150 arthropathy.

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
2010   Section X  Small and Large Intestine

Most of the adverse effects of sulfasalazine are due to prophylactic effect on endoscopic and clinical recurrence at 1
its sulfapyridine moiety, which serves as a carrier for the year, with numerical but not statistical advantages at 2 and 3
5-ASA portion of the molecule. After a classic experiment by years of follow-up.165 In this study, as in clinical use, side
Azad Khan and colleagues implicated 5-aminosalicylate effects, including GI upset, nausea, dysgeusia, and peripheral
(5-ASA, mesalamine) rather than sulfapyridine as the thera- neuropathy, were common. A study using ornidazole, also a
peutic moiety of sulfasalazine,153 other formulations were nitroimidazole antibiotic, showed similar results.166 Ornidizole
developed. might have fewer side effects than metronidazole, but toxicity
These delivery systems include enemas or suppositories, was still a problem with this formulation. A meta-analysis
which provide the drug to the rectum and left colon; coating concluded that nitroimidazole antibiotics are effective in the
with protective materials that release the drug in a prevention of postoperative Crohn’s disease, but that their
pH-dependent manner to achieve controlled (Pentasa) or side effect profile limits acceptability.167
delayed (Asacol and Lialda) delivery; and diazo-bonding the Open-label experience suggests that metronidazole
drug to a second 5-ASA molecule (olsalazine) or to an inert 20 mg/kg/day is beneficial in healing perineal fistulas.168 Ran-
carrier (balsalazide). domized controlled trial (RCT) data are limited, preventing
Most studies have shown sulfasalazine to be superior to further conclusions. Fistulas tend to recur with cessation
placebo in inducing remission in active Crohn’s disease, when of therapy, and long-term use is limited by side effects.
the colon is the primary site affected.154,155 Efficacious doses, as Studies of metronidazole in active luminal Crohn’s disease
used in the National Cooperative Crohn’s Disease Study generally have not demonstrated benefit, but they have sug-
(NCCDS), are in the range of 4 to 6 g/day (1 g/15 kg body gested better outcomes in subgroups of patients with colonic
weight).154 The European Cooperative Crohn’s Disease Study involvement.169,170
(ECCDS) found sulfasalazine 3 g/day to provide no signifi- Ciprofloxacin is increasingly used to treat Crohn’s disease.
cant benefit in achieving remission.156 For perianal fistulas, ciprofloxacin may be similar in efficacy
Early studies with controlled-release mesalamine (Pentasa) to metronidazole and with fewer side effects,171 and its addi-
at doses less than 2 g/day failed to show efficacy in the treat- tion might improve the response to infliximab and adalim-
ment of mild to moderately active Crohn’s disease.157,158 A umab.172,173 In the treatment of luminal disease, 1 study found
much larger study of 466 patients with mild to moderate ciprofloxacin 1 g/day to be equivalent to mesalamine 4 g/day
Crohn’s disease compared daily doses of 1, 2, and 4 g with in achieving remission of mild to moderately active Crohn’s
placebo for 16 weeks. The 43% remission rate on 4 g mesala- disease at week 6, with more than half of the patients in each
mine was statistically and clinically superior to the placebo group achieving remission.174 In a longer-term study using
response rate of 18%.159 Notably, patients responding best to ciprofloxacin 500 mg twice daily for 6 months in patients with
the 4 g/day dose were those with ileum-only disease, suggest- moderately active disease, those who were given ciprofloxacin
ing that mesalamine provides a potential benefit over sul- had a statistically significantly lower CDAI at 6 months com-
fasalazine in treating this subgroup of patients. Subsequent pared with placebo (P < 0.001).175 Another study compared the
trials of similar design, however, failed to show benefit over combined use of ciprofloxacin and metronidazole, 1 g each,
placebo; although the treatment effect was of similar magni- against methylprednisolone for active Crohn’s disease. The
tude, the placebo response was larger than the originally antibiotic combination was comparable with glucocorticoids
observed 18%. A meta-analysis failed to demonstrate a clini- in achieving remission over 12 weeks.176 A more recent study
cally significant benefit of Pentasa 4 g/day in patients with failed to detect additional efficacy of the same dual antibiotic
mild to moderate Crohn’s disease.160 Numerous studies with regimen over placebo when added to controlled ileal-release
a variety of preparations have failed to demonstrate preven- budesonide; however, a trend toward benefit was noted in the
tion of relapses of Crohn’s disease with 5-ASA compounds.155,161 subgroup of patients with colonic disease.177
Therefore, although maintenance therapy with mesalamine Preliminary evidence suggested that clarithromycin mono-
often is prescribed in Crohn’s disease, little data justify the therapy was useful in treating active disease,178 but a follow-up
expense and inconvenience of this practice, and mesalamine- randomized trial did not confirm the open label experience.179
based products have been excluded from recent evidence- Additional interest in clarithromycin is sparked by its role as
based treatment algorithms.162 part of a highly effective treatment regimen for atypical myco-
In summary, sulfasalazine 4 to 6 g/day may be useful for bacterial infection. As reviewed earlier, M. paratuberculosis has
inducing remission of mild to moderate colonic Crohn’s been the most extensively studied infectious agent thought to
disease, whereas the role of mesalamine is uncertain.163 The be important in the etiology of Crohn’s disease. Studies of
small margin of benefit and relatively slow onset of effect (4 antimycobacterial therapy, however, have not shown consis-
to 8 weeks) must be weighed against the excellent safety tent benefit. A large recent study of triple antibiotic therapy
profile of these agents (Table 115-4). (clarithromycin, rifabutin, and clofazimine) combined with
prednisolone showed an early clinical benefit, but when fol-
lowed for 2 more years, this benefit was not sustained.180 The
Antibiotics authors concluded that the treatment regimen might have con-
Antibiotics have a clear role in treating pyogenic complica- tributed to nonspecific antibacterial effects and improvement
tions of Crohn’s disease. On the basis of relatively little evi- during the course of therapy, but the findings did not support
dence, antibiotics also are used to treat perineal disease, a significant role for M. paratuberculosis in the pathogenesis of
fistulas, and active luminal Crohn’s disease. The largest Crohn’s disease.
reported experience has been with metronidazole and the Rifaximin is a nonabsorbable oral rifamycin antibiotic that
anaerobic flora affected by metronidazole might have particu- is approved for the treatment of traveler’s diarrhea, and it has
lar importance in the pathogenesis of Crohn’s disease.164 shown success in the treatment of IBS. An RCT for treating
Perhaps the clearest demonstration of this principle is a mildly to moderately active Crohn’s disease showed a numeri-
study of postsurgical prophylaxis after ileal resection. In this cal advantage for rifaximin 800 mg twice daily compared with
disease model, which in some ways might replicate the earli- once-daily dosing or placebo, but this difference was not sta-
est events in the initiation of Crohn’s disease, high-dose met- tistically significant.181 Treatment failures in the placebo group
ronidazole (20 mg/kg/day for 3 months) demonstrated a were significantly higher, and patients with an elevated

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   2011

TABLE 115-4 Safety Profiles of Agents Used to Treat Crohn’s Disease

Agent Adverse Effects Pregnancy* Nursing*

5-Aminosalicylates (5-ASA)
Sulfasalazine Anorexia, dyspepsia, nausea and No evidence of teratogenicity; Negligible amounts found in
vomiting, hemolysis, neutropenia, normal fetal growth; give with breast milk; safe for term
agranulocytosis, folate deficiency, folic acid neonates
reversible male infertility, neuropathy;
see also sulfa-free 5-ASAs
Sulfa-free 5-ASAs Headache, drug fever, rash, paradoxical No evidence of teratogenicity in Found in breast milk in low
(mesalamine, disease exacerbation, pancreatitis, humans, normal fetal growth concentrations; rare
olsalazine, hepatitis, pericarditis, pneumonitis, Branded Asacol and Asacol HD watery diarrhea in
balsalazide) nephritis with dibutyl phthalate coating breast-fed infants
Secretory diarrhea (olsalazine) is associated with
teratogenicity in animals

Metronidazole Anorexia, nausea and vomiting, Questionable teratogenicity, Found in breast milk; with
dysgeusia, disulfiram-like effect, normal fetal growth rare exception, should not
peripheral neuropathy, reversible be used
Ciprofloxacin Nausea and vomiting, headache, Theoretical teratogenic potential; Found in breast milk, should
restlessness, rash, insufficient data in humans not be used
pseudomembranous colitis, elevated
serum aminotransferase levels,
spontaneous tendon rupture

Classic Sleep and mood disturbance, acne, No evidence of teratogenicity in Safe for breast-feeding
striae, hirsutism, adrenal suppression, humans, more frequent
proximal myopathy, glucose stillbirths and reduced fetal
intolerance, hypertension, narrow- birth weight when used for
angle glaucoma, cataracts, other diseases; may be used
pseudotumor cerebri, infection, as indicated by severity of
edema, impaired wound healing, disease
growth retardation, bone loss, aseptic
Novel Controlled ileal-release budesonide: Limited human data but probably No data available, probably
adrenal suppression at doses of low risk safe for breast feeding
9 mg daily and higher in 2 divided
doses, but occurrence of classic
glucocorticoid adverse effects are
similar to placebo

Immune Modulators
6-Mercaptopurine, Nausea, drug fever, rash, arthralgias, Teratogenic in animals, but large Small amounts excreted in
azathioprine leukopenia, thrombocytopenia, bone series in renal transplantation breast milk; not
marrow suppression, pancreatitis, and other diseases do not recommended
hepatitis, infection; lymphoma? show an increase in birth
defects; evidence for fetal
growth retardation and
prematurity; isolated cases of
neonatal immune and bone
marrow suppression; outcomes
appear favorable in limited
series of patients with IBD;
may be used when indicated
because of disease severity
Methotrexate Anorexia, nausea and vomiting, Highly teratogenic, particularly in Small amounts excreted in
leukopenia, megaloblastic anemia, the first trimester; abortifacient breast milk; not
alopecia, hepatic fibrosis, interstitial recommended
pneumonitis, neuropathy


Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
2012   Section X  Small and Large Intestine

TABLE 115-4 Safety Profiles of Agents Used to Treat Crohn’s Disease—cont’d

Agent Adverse Effects Pregnancy* Nursing*

Cyclosporine Reversible or irreversible decrease in Significant levels in fetal Excreted in breast milk; not
renal function, hypertension, tremor, circulation; does not appear recommended
headache, paresthesias, seizure, to be teratogenic; intrauterine
gingival hyperplasia, hypertrichosis, growth retardation and
hepatotoxicity, infection, lymphoma premature delivery are
increased, especially at higher
doses; little reported
experience in IBD

Biological Response Modifiers

Anti-TNF Upper respiratory tract and other Growing amount of evidence Minimal levels in breast milk
antibodies infections, disseminated TB, supporting safety, but still
(infliximab, increased risk of systemic fungal relatively limited data in
adalimumab, infection and other intracellular humans. Infliximab and
certolizumab pathogens, acute or delayed adalimumab can freely cross
pegol) hypersensitivity reactions, antinuclear the placenta and lead to high
antibodies, anti–double-stranded DNA levels in newborns, whereas
antibodies, lupus-like reaction, certolizumab pegol only
demyelinating disease, lymphoma; crosses the placenta in very
contraindicated in heart failure limited quantities
because of increased mortality
Natalizumab Headache, flushing, infections, Teratogenic in animals Unknown safety in nursing
progressive multifocal
leukoencephalopathy, jaundice, liver
*From Connell WR. Safety of drug therapy for inflammatory bowel disease in pregnant and nursing women. Inflamm Bowel Dis 1996; 2:33-47, with permission. Updated
based on Ng S, Mahadevan U. Management of inflammatory bowel disease in pregnancy. Expert Rev Clin Immunol 2013; 9:161-73.
Adapted from Sands BE. Therapy of inflammatory bowel disease. Gastroenterology 2000; 118(2 Suppl 1):S72, with permission.

C-reactive protein did have a significantly better response. To supports this efficacy of traditional steroids over 5-ASA
follow up on these findings, an RCT was performed in over therapy and placebo.185
400 patients with moderately active Crohn’s disease. With the Patients with severely active disease usually respond to IV
extended intestinal release formulation using 800 mg twice administration of glucocorticoids.186 Options for IV glucocor-
daily, significantly more subjects in the rifaximin group were ticoid formulation include hydrocortisone (100 mg IV every 8
in remission at 12 weeks compared with placebo (62% vs. 43%, hours), prednisolone (30 mg IV twice daily), or methylpred-
P = 0.005).182 nisolone (16 to 20 mg IV every 8 hours). Hydrocortisone can
In summary, antibiotics can play an adjunctive role in the cause slightly more salt retention and sodium wasting, but it
treatment of Crohn’s disease and, in selected patients, they is likely to be equally effective. In a randomized double-blind
may be useful in treating perineal disease, enterocutaneous trial with UC patients, continuous infusion was no better than
fistulas, or active colonic disease. As the antigenic determi- divided dosing for efficacy and safety.187
nants of the intestinal flora are elucidated further, more Unfortunately, the beneficial effects of glucocorticoids
directed antibiotic approaches might be feasible. come at the expense of frequent and often severe adverse
effects (see Table 115-4). The most common side effects are
troubling neuropsychiatric symptoms, including mood distur-
Glucocorticoids bance and insomnia, and cosmetic effects, including acne,
Glucocorticoids play a central yet vexing role in the treatment cushingoid appearance, hair loss, and hirsutism. Still more
of Crohn’s disease. Early favorable series of glucocorticoid serious are metabolic consequences, including adrenocortical
treatment led to the validation of their short-term efficacy in suppression, glucose intolerance, myopathy, and bone loss.
the NCCDS (prednisone 0.5 to 0.75 mg/kg/day for initial The risk of infectious complications is increased, particularly
treatment of active disease, with the dose adjusted according at doses of prednisone higher than 40 mg; doses lower than
to CDAI)154 and the ECCDS (6-methylprednisolone 48 mg/ 10 mg confer no appreciable increased risk of infection.188
day in the first week, tapered to 12 mg by week 6, and held at Among patients taking immunomodulators or infliximab, the
8 mg for remission up to 2 years).156 concomitant use of prednisone appears to lead to more fre-
In usual practice, patients with mild to moderate disease quent serious infections and higher rates of mortality than
that does not respond to primary therapy and patients with when these agents are used alone.189-191 The unfavorable
moderately severe symptoms are treated initially with 40 to risk profile of glucocorticoids makes their prolonged use
60 mg of prednisone, the dose then being tapered off over 6 hazardous.
to 12 weeks. Response rates are approximately 80% by 1 Glucocorticoids are not effective as long-term therapy. A
month.183 When doses are pushed as high as 1 mg/kg/day for meta-analysis of maintenance glucocorticoid therapy in
up to 7 weeks, 92% of patients can achieve clinical remission.184 Crohn’s disease failed to detect benefit in the prevention of
The onset of response is rapid, usually within the first 3 relapse at 6, 12, or 24 months.192 Conversely, once glucocorti-
weeks of treatment. A Cochrane review of the use of cortico- coids are introduced, they cannot be discontinued without
steroids for the induction of remission of Crohn’s disease recurrent symptoms in many patients, even with gradual

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   2013

tapering; this problem is referred to as glucocorticoid depen- maintenance effect is consistent for both novel and traditional
dence. Among patients with Crohn’s disease who received glucocorticoids.
glucocorticoids for the first time, no response (glucocorticoid In light of the superior response in comparison with mesa-
resistance) was seen in 20% in the first 30 days.183 Among the lamine and its relative safety, budesonide may be considered
80% who were complete or partial responders, 55% had a as first-line therapy for patients with active ileal, ileocecal,
prolonged response, and 45% relapsed or could not have treat- or right colonic disease. In addition, some patients who
ment tapered off within 1 year.183 Similar results were seen in are dependent upon conventional glucocorticoids may be
both adult and pediatric populations in a cohort from Olmsted switched successfully to budesonide, with the potential ben-
County, Minnesota.193,194 Clinical factors associated with glu- efits of decreased systemic glucocorticoid exposure.203
cocorticoid dependence include smoking, younger age at In summary, glucocorticoids are effective for the short-
onset, colonic location, and non-fibrostenotic disease.195 Mech- term control of symptoms of Crohn’s disease, but they are
anisms that can contribute to glucocorticoid resistance include neither effective nor safe for long-term maintenance of
up-regulation of the multidrug resistance (mdr) gene196,197 and response. In patients with disease that is refractory to or
increased serum levels of glucocorticoid-binding globulin.198 dependent on glucocorticoids, steroid-sparing strategies
Moreover, only 29% of patients who achieve clinical remission should be considered, including immune modulators or
on glucocorticoids also achieve endoscopic remission.184 This surgery.
finding suggests that the effect of glucocorticoid treatment in
most patients is to suppress symptoms when given in doses
above a threshold that can vary among patients and even in Thiopurine Agents
the same patient over time. The thiopurine antimetabolites azathioprine (AZA) and
There are several principles of glucocorticoid use in 6-mercaptopurine (6-MP) have been used to treat Crohn’s
Crohn’s disease: disease since the initial report of Brooke and colleagues
Use an effective dose. Underdosing at the start of therapy typi- describing healing of fistulas with AZA.204 Another decade
cally leads to dose escalation and prolonged dosing to would pass, however, before the efficacy of this class of drugs
achieve a response. was demonstrated in an RCT by Present and colleagues148;
Do not overdose. Patients who do not benefit from 40 to 60 mg earlier studies were marred by either insufficient power or
are unlikely to benefit from increased or prolonged oral incomplete understanding of adequate dosing and the slow
dosing. Such patients require IV dosing or treatment with onset of action of these agents.
another rapidly acting agent, such as an anti-TNF agent A Cochrane meta-analysis of studies of AZA and 6-MP in
(see later). Crohn’s disease has provided the best summary of the effects
Do not treat for excessively short periods. Doses should not be of these drugs.205 For active disease, thiopurine treatment pro-
tapered too quickly once symptoms have been controlled. duced a higher remission rate of 47% compared with a 37%
Very brief courses of glucocorticoids (3 weeks or less) are placebo rate, but this corresponded to a non-significant rela-
likely to result in a rebound flare. tive risk of 1.23 (95% CI, 0.97 to 1.55). The outcome of remis-
Do not treat for excessively long periods. Patients in whom a sion or clinical response similarly yielded a higher but not
glucocorticoid taper fails should be considered candidates statistically significant result compared with placebo (48% vs.
for glucocorticoid-sparing immune modulators. Glucocor- 36%; RR 1.26; 95% CI, 0.98 to 1.62). The odds ratio for response
ticoids should not be begun without a strategy in mind for increases after 17 weeks of therapy, suggesting the minimum
terminating treatment. duration for a trial of 6-MP or AZA. A steroid-sparing effect
Anticipate side effects. Bone loss in particular may be antici- was significant (RR, 1.34; 95% CI, 1.02 to 1.77), and the number
pated with even short-term use. (See later, “Adjunctive needed to treat (NNT) was about 6. Only 18 patients with
Therapies.”) fistulas were included, but a 54% rate of fistula response was
In an attempt to limit the unintended systemic effects of noted, compared with a 29% healing rate on placebo; this,
glucocorticoid therapy, novel glucocorticoids have been however, was not statistically significant (RR, 2.00; 95% CI,
developed. Budesonide possesses glucocorticoid receptor 0.67 to 5.93), most likely the result of a type II error. There is
affinity superior to that of traditional glucocorticoids and also more convincing evidence of the benefit of thiopurines for
takes advantage of enhanced first-pass metabolism by the maintenance of remission. The OR for maintenance of remis-
liver to limit systemic exposure. A controlled ileal-release for- sion with AZA was 2.32 (95% CI, 1.55 to 3.49; NNT = 6) and
mulation of budesonide targets the terminal ileum and right with 6-MP 3.32 (95% CI, 1.40 to 7.87; NNT = 4).206 The OR for
colon. Studies have demonstrated that 9 mg/day of this AZA maintaining remission increased from 1.20 at 1 mg/kg
preparation are superior to placebo and mesalamine and up to 4.13 (95% CI, 1.59 to 10.71) at 2.5 mg/kg, demonstrating
about 15% less effective than prednisolone in achieving remis- the importance of appropriate dosing.
sion, but with fewer side effects.199 Pushing the dose higher Overall, approximately one half of patients may respond
results in better efficacy but at the expense of increasing adre- to thiopurine therapy, and once in remission about half to two
nocortical suppression and side effects.200 To evaluate the effi- thirds of patients will maintain that response. In earlier
cacy of budesonide for maintenance of remission, an RCT studies, mucosal healing was seen in approximately half of the
compared 6 mg to 9 mg at 12 months.201 Both doses were patients who received thiopurines,207 however, in a more
associated with relatively low relapse rates (24% and 19%, recent large study, this was seen in only 16.5% of patients at
respectively) that were not significantly different, but a placebo 26 weeks.208 In children, early administration of 6-MP soon
comparison group was not included, which limits the ability after diagnosis was associated with steroid sparing and main-
to understand the relevance of this study. Adverse events tenance of remission.209 However, this was not reproduced in
were not different in these 2 dosage groups, supporting the adults in a recently published trial.210
safety of the 9-mg dose over a 1-year period. A meta-analysis In clinical practice, AZA and 6-MP are used virtually inter-
reviewed all studies that evaluated budesonide for the treat- changeably, with the exception of dosing. AZA generally is
ment of active luminal Crohn’s disease, and concluded that used in doses of 2 to 2.5 mg/kg/day, and 6-MP is given in
budesonide was superior to placebo for inducing remission doses of 1 to 1.5 mg/kg/day. The introduction of thiopurine
(RR = 0.73; 95% CI, 0.63 to 0.84) but not in preventing relapse medications should be timed with their slow onset of action
(RR = 0.93; 95% CI, 0.82 to 1.04).202 Therefore, lack of a in mind; many patients require a tapering regimen of

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
2014   Section X  Small and Large Intestine

6-TU Inactive shunting. Shunting refers to high TPMT activity that results in
low 6-TG levels and high 6-methylmercaptopurine (MMP)
XO levels (see Fig. 115-8); a 6-MMP:6-TG ratio of greater than 10
HPRT IMPDH GMPS has been suggested as a profile of metabolism that is unlikely
AZA 6-MP 6-TIMP 6-TXMP 6-TGN to lead to clinical benefit.213,218 In these patients, it may be pos-
sible to add allopurinol and take advantage of the drug inter-
TPMT TPMT Active action noted earlier. A study testing this hypothesis showed
that by decreasing the thiopurine dose to 25% to 50% of the
6-MMP 6-MMPR original dose and adding a low dose of allopurinol, 6-TG
Active levels rose significantly, with a coincident drop in 6-MMP
levels and an improvement in clinical outcomes.219 Although
FIGURE 115-8. Metabolism of azathioprine (AZA) and 6- this strategy requires careful following of the WBC count, it
mercaptopurine (MP). 5-ASA, 5-aminosalicylate; 6-MMP, 6- has been shown to be well tolerated and safe in 1 study with
methylmercaptopurine; 6-MMPR, 6-methylmercaptopurine a median follow-up period of 19 months.220
ribonucleotides; 6-TGN, 6-thioguanine nucleotides; 6-TIMP, In a Cochrane analysis, adverse events severe enough to
6-thioinosine 5′-monophosphate; 6-TU, 6-thiouric acid; 6-TXMP, result in drug withdrawal were seen in 10% of patients.205
6-thioxanthosine 5′-monophosphate; GMPS, guanosine mono- Adverse events that lead to drug discontinuation typically
phosphate synthetase; HPRT, hypoxanthine phosphoribosyl- occur soon after drug initiation, with a median time of 1
transferase; IMPDH, inosine monophosphate dehydrogenase; month.221 Nausea within the first few weeks of treatment is
TPMT, thiopurine methyltransferase; XO, xanthine oxidase. reported in approximately 8% of patients, but typically will
subside gradually. Allergic reactions consisting of fever, rash,
or arthralgias are seen in 1% to 2% of patients, usually within
a few weeks of introducing the drug. Pancreatitis, observed in
glucocorticoids to bridge the time period until the thiopurines 3% to 4%, is another idiosyncratic reaction and usually occurs
have taken effect. Thiopurine therapy also may be considered in the first month of therapy. The presentation is typically
for the postsurgical prophylaxis of Crohn’s disease,211 although classic with epigastric pain that radiates to the back, but may
conflicting data exist about their efficacy. be atypical and subtle, with nausea and vague dyspepsia.
Much is known about the metabolism of 6-MP and AZA When symptoms are recognized promptly, discontinuation of
(Fig. 115-8). AZA is a prodrug that is converted in part to 6-MP the drug leads to resolution of pancreatitis. Rechallenge with
through non-enzymatic means and into a variety of other either drug should not be attempted, because recurrent pan-
immunologically active and inert metabolites. Xanthine creatitis is certain to occur. Elevated serum aminotransferase
oxidase (XO) converts 6-MP to 6-thiouric acid, in competition levels develop in approximately 3% of patients and have been
with hypoxanthine phosphoribosyltransferase. The former correlated with the presence of very high levels of 6-MMP.222
enzymatic pathway accounts for an important drug reaction Mild elevations of liver tests can often revert to normal without
with allopurinol, a XO inhibitor (see later). Thiopurine meth- any intervention, or with dose reduction. An exception is in
yltransferase (TPMT) plays a key role in the metabolic the rare occurrence of cholestatic hepatitis or nodular regen-
pathway. Persons who are homozygous for a recessive muta- erative hyperplasia (NRH), in which case thiopurine therapy
tion that results in inactivation of TPMT (≈1 in 300 persons) should be withdrawn.
produce exceedingly high levels of 6-thioguanine (6-TG) Bone marrow suppression is another concern with thiopu-
nucleotides. These persons are unlikely to tolerate thiopurine rine agents. A 27-year, retrospective, single-center study of 739
agents and tend to develop profound leukopenia and other IBD patients treated with AZA found 28 patients (3.8%) devel-
limiting adverse effects. In contrast, persons who are TPMT oped leukopenia (WBC < 3 × 109 cells/L [<3000 cells/mm3]), 9
heterozygous (≈10% of the population) are likely to have mod- of whom (1.2%) had severe leukopenia (WBC count < 2 × 109
erately high levels of 6-TG nucleotides.212,213 They usually cells/L [<2000 cells/mm3])223; 3 of these patients became pan-
require lower doses of drug but are much more likely to cytopenic, and 2 died of sepsis. A review of 66 studies that
respond. A steady state in the production of erythrocyte 6-TG included over 8000 patients had a similar rate of myelotoxicity
nucleotides may be reached as early as 14 days after dosing,214 and, fortunately, a low risk (<0.1%) of death attributable to
but has recently been reported at a median time of 55 days in treatment.224 Although leukopenia occurs early among patients
pediatric patients.215 with low TPMT activity, it might not be related solely to TPMT
There have been mixed results reported of the correlation genotype and can occur at any time during therapy.224 For this
between 6-TG nucleotide levels and response to therapy, but reason, it is advisable to continue monitoring the complete
a meta-analysis of 6 studies did find an overall significant blood count every 1 to 3 months for the duration of therapy
relationship.216 A threshold of 230 to 260 pmol/8 × 1010 red and more frequently (every 2 weeks if TPMT activity is normal,
blood cells corresponded to a 62% rate of remission, compared weekly if it is heterozygous) in the 8 to 12 weeks after intro-
with a rate of 36% in those with lower levels (OR, 3.27; 95% ducing the drug or increasing dosage. Temporary cessation of
CI, 1.71 to 6.27) of 6-TG. Correlations between higher levels of therapy for a week or 2 and an adjustment in dose usually
6-TG nucleotides and leukopenia, and between metabolite suffice to bring the leukocyte count back within normal range.
levels and response to therapy, might explain the clinical Careful monitoring of the leukocyte count also should be per-
observation that patients who achieve mild leukopenia are formed during a tapering regimen of glucocorticoids. Concur-
more likely to respond to such therapy.217 Conversely, rent treatment with glucocorticoids can raise the leukocyte
however, leukopenia is not necessary to achieve a therapeutic count, but as the glucocorticoid is discontinued, leukopenia
response. It is not clear if routine measurement of thiopurine can develop.
metabolite levels and directed dose adjustment would contrib- Infections can occur in the setting of thiopurine therapy.
ute to improved management of Crohn’s disease, as opposed Serious infections are reported to occur approximately 2%
to the standard weight-based dose approach. to 6% of the time, not necessarily in the setting of leukope-
When a patient is not responding to thiopurine therapy nia.208,221 Patients treated concurrently with glucocorticoids
after 3 to 4 months, it is useful to measure metabolite levels to may be at greater risk of serious infection, including cyto-
identify patients who are noncompliant, under-dosed, or megalovirus. Treatment should be interrupted when serious

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   2015

infections occur, although the effect of the drug will endure with some patients in selected practices treated successfully
for weeks. for over 4 years. Although 15-mg intramuscular dosing was
Malignancy associated with thiopurines has been a long- studied for maintenance, many continue on 25 mg weekly
standing concern of patients and providers. Immunosuppres- without dose reduction. Pharmacokinetic studies in RA have
sive regimens given to patients after organ transplantation shown equivalency for subcutaneous and intramuscular
and for other immune-mediated conditions are associated dosing, and therefore most gastroenterologists administer
with an excess risk of malignancy, particularly non-Hodgkin’s MTX subcutaneously.233,234 Although oral dosing would be
lymphoma (NHL). Such regimens have included AZA, often more convenient for long-term administration, a Cochrane
administered in higher doses than for IBD and in conjunction review did not find evidence of efficacy when compared to
with other immunosuppressive agents. In IBD, there does placebo.235 This may be explained by the variable intestinal
appear to be an association between thiopurine exposure and absorption of MTX,236 particularly in the presence of small
lymphoma, specifically NHL. The rate of NHL is reported to intestinal disease.
be approximately 4 to 9 per 10,000 patient-years.225,226 Data Although MTX is a folate antagonist, the drug often is
suggest that once stopping thiopurines, the risk of lymphoma given with folic acid (1 to 2 mg/day) to prevent nausea and
returns to the patient’s baseline risk. Non-melanoma skin stomatitis, and so other modes of action are likely responsible
cancer appears to have a clear association with thiopurine for its efficacy. In addition to stomatitis and nausea, diarrhea,
exposure, but not melanoma.227,228 No other solid tumors have hair loss, and mild leukopenia can occur with MTX. Serum
been found to be associated with thiopurines when used for aminotransferase elevations sometimes occur, but correlate
the treatment of IBD.229 poorly with the complication of hepatic fibrosis. Liver biopsy
Once treatment with a thiopurine agent has proved to be is performed routinely in patients with psoriasis after cumula-
effective, the question of how long to continue such therapy tive doses of 1.5, 3, and 5 g have been administered, but these
inevitably arises. One RCT demonstrated a clinical relapse rate guidelines have not been widely adopted in patients with RA,
of 21% 18 months after withdrawal of AZA in patients who in whom the risk of hepatic fibrosis appears to be lower. In 1
had been in remission for at least 3.5 years on the drug,230 series of IBD patients who received a mean cumulative dose
compared with a relapse rate of only 8% in the group who of methotrexate greater than 2.5 g and had liver biopsy, only
continued AZA. The authors concluded, and most authorities minimal hepatic toxicity was evident.237 Obesity, diabetes,
agree, that AZA maintenance therapy should be continued and alcohol intake correlate with hepatic fibrosis. MTX inter-
longer than 3.5 years. The decision to withdraw thiopurine acts with sulfa medications and with AZA and 6-MP to cause
therapy should only be undertaken after discussion between severe leukopenia. Rare but potentially life-threatening inter-
doctor and patient of possible risks and benefits. stitial pneumonitis can manifest as cough and dyspnea
of insidious onset. Early detection, cessation of MTX, and
prompt treatment with glucocorticoids is essential. MTX is
Methotrexate toxic to sperm, and men should wait 3 months after stopping
Methotrexate (MTX) has long been used to treat psoriasis MTX before trying to conceive.238 Finally, MTX is a potent
and RA. An RCT studied patients with chronically active abortifacient and is strongly teratogenic. Women of child­
Crohn’s disease despite at least 3 months of prednisone (at bearing capacity must use MTX only with highly effective
least 12.5 mg/day) and with at least 1 failed attempt to taper contraception.
off treatment.231 All patients were brought to a 20 mg/day MTX may be considered as an alternative to the thiopurine
dose of prednisone to standardize therapy, with separate analogs, particularly among patients who do not tolerate these
stratification for patients in whom the dose of prednisone was drugs. Studies comparing MTX to thiopurines in a head-to-
increased and for those in whom the dose had dropped to head protocol have been too small to make definitive conclu-
20 mg before entry. Subjects then received either weekly injec- sions of superiority or equivalency.235 Some patients who do
tions of MTX 25 mg intramuscularly or placebo while execut- not respond to 6-MP might respond to MTX.239 In addition to
ing a tapering prednisone regimen over 16 weeks. Overall, its proved role as a glucocorticoid-sparing agent, MTX may be
39.4% of patients assigned to MTX achieved remission off considered as a treatment for active disease, although its value
prednisone compared with 19.1% of placebo-treated patients.231 for this indication is less clear.240
Most patients responded by the eighth week of treatment.
Although the remission rates in the MTX-treated high- and
low-prednisone group were nearly equal (39.0% and 40.0%, Other Immune Modulators
respectively), the remission rate for placebo-treated patients There appears to be little role for cyclosporine in Crohn’s
in the high-prednisone dose group was 10.0%, compared with disease. Series of uncontrolled RCTs have shown high doses
35.3% in the low-dose group.231 This result often is miscon- of cyclosporine to be efficacious in treating IBD and fistulas,
strued as showing that MTX works well for patients on high but at an unacceptably high cost of adverse effects.241 More-
doses of prednisone but not for those on low doses of predni- over, lower doses, although somewhat safer, are not effective
sone, but it merely shows an unexpectedly high placebo in maintaining remission.242 One uncontrolled study sug-
response rate among patients dependent on low doses of gested a benefit for hospitalized patients with Crohn’s colitis,
glucocorticoids. many of whom had been previously exposed to anti-TNF
MTX also is beneficial in maintaining remission. A agents, but further data are required to understand its benefit
follow-up study randomized patients who achieved remission to risk profile.243 For virtually all Crohn’s indications, equally
by week 16 on MTX 25 mg intramuscularly once weekly to effective and less hazardous medications are available.
receive either weekly injections of placebo or MTX at a dose Tacrolimus is absorbed more reliably from the intestine
of 15 mg. At week 40, 65% of patients treated with MTX were than is cyclosporine and has a similar mode of action via
still in remission, compared with 39% of placebo-treated inhibition of calcineurin, thereby diminishing T-cell activa-
patients (P = 0.04).232 Treatment was well tolerated. Among tion.244 Preliminary data suggest that tacrolimus may be useful
patients who relapsed on the maintenance dose, more than in treating glucocorticoid-resistant disease, and an RCT has
half were able to achieve remission again with resuming a demonstrated efficacy in healing fistulas.245,246 The drug
25-mg dose. If the 16 weeks of induction therapy were also may be effective as a topical agent for oral and perianal
included, the combined duration of therapy was nearly 1 year, ulcerating disease247,248; long-term application of 0.1%

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
2016   Section X  Small and Large Intestine

tacrolimus applied to broken skin and mucosa was safe and subcutaneously at week 0, 80 mg at week 2, and then 40 mg
serum levels were undetectable.249 every other week.
Thalidomide may have a role for some patients with Certolizumab pegol, initially known as CDP870, is a
Crohn’s disease through the mechanism of down-regulation polyethylene-glycolated Fab fragment of a humanized anti-
of TNF-α and inhibition of NFκB activity. It has been shown TNF antibody. An exploratory study of a single dose in
to be effective in small studies of patients naïve to biologics, patients with Crohn’s disease was promising261 and led to a
and also in whom thiopurine, MTX, and anti-TNF therapy series of large RCTs. In the first, although clinical benefit
have failed.250 The most frequent long-term toxicity is periph- clearly was evident, the primary endpoint of clinical response
eral neuropathy, which is typically reversible, but not in all at 12 weeks missed statistical significance.262 Post hoc analysis
cases. Careful contraceptive measures are critical owing to exposed a high placebo rate in subjects with low CRP levels,
well-known teratogenicity. Lenalidomide, an analog of tha- and subsequent recalculation limiting analysis to patients with
lidomide with similar immunomodulatory properties but an elevated CRP showed a significant difference. In 2 follow-up
with less toxicity (specifically neuropathy), was studied in an studies that stratified patients based on CRP levels, certoli-
RCT, but did not show a response significantly different from zumab pegol 400 mg, administered subcutaneously at weeks
placebo.251 0, 2, and 4 weeks and then every 4 weeks, proved to be effec-
tive to induce and maintain clinical response and remission
out to 26 weeks.263,264 Interestingly, patients responded equally
Biological Therapy regardless of their CRP status.
Infliximab, adalimumab, and certolizumab pegol are all
Anti-TNF Agents effective for treating moderately to severely active Crohn’s
Infliximab is the first biological response modifier shown to disease.265 Although it is impossible to compare the response
be effective in Crohn’s disease. This chimeric monoclonal TNF and remission rates of these agents because of different study
antibody had an unsuccessful history as an investigational designs and patient populations, all appear to have similar
antisepsis agent before its use in Crohn’s disease was explored. rates of initial response (≈60%) and maintenance of that
Despite conflicting reports regarding the importance of TNF response between 6 and 12 months (≈40% of the initial
in IBD, the Dutch investigator van Deventer posited that in responders). Differences may be found over the longer term
light of the critical role of TNF in granuloma formation, an based on specific modes of action, pharmacokinetics, develop-
anti-TNF agent might prove efficacious for granulomatous ment of antibodies, and side effects. Although these 3 medica-
bowel disease. Open-label trials subsequently demonstrated tions are similar, all anti-TNF agents are not equivalent, as
rapid and prolonged improvement in disease activity, accom- illustrated by etanercept (a human soluble TNF receptor Fc
panied in many cases by mucosal healing.252-254An early short- fusion protein) and CDP571 (a humanized monoclonal anti-
term (12-week) RCT provided strong confirmation of the body to TNF), both of which failed to show significant efficacy
initial impression of efficacy.255 Coincidental healing of entero- for Crohn’s disease.266,267
cutaneous fistulas in some patients led to a separate successful The mode of action of anti-TNF agents is likely to be more
RCT of infliximab for this indication. involved than just its nominal binding of TNF. The antibody
Limited information regarding the efficacy of repeated can bind and clear soluble TNF, but it also binds to cell-bound
dosing was available before the commercial release of inflix- TNF. Through the latter mechanism, infliximab and adalim-
imab in the United States. Maintenance dosing every 8 weeks umab have been shown to induce apoptosis of cells expressing
at 5 mg/kg IV after a 0-, 2- and 6-week induction regimen was membrane TNF. Etanercept does not induce apoptosis, an
demonstrated to maintain response in patients with fistulizing observation thought to be the explanation for its lack of effi-
and non-fistulizing disease.256,257 In these studies, although sig- cacy,268,269 although neither does certolizumab pegol induce
nificant differences were seen at the primary endpoints, the apoptosis,270 and, as mentioned earlier, it has efficacy similar
treatment effect was not as robust as with initial therapy. to that of these other agents. Therefore, the mechanism of
Approximately 60% of patients with luminal disease initially action is most likely multifactorial, all pointing toward the
respond to therapy and 40% of those individuals maintain that ability to control the mucosal immune response.
response at 1 year. Other important observations from these Treatment with the anti-TNF agents usually is well toler-
studies included the steroid-sparing effect of infliximab, and ated. In the largest and longer-term clinical trials, between 4%
sustained improvement in quality of life out to the 54-week and 16% of patients withdrew from study because of an
duration of these trials. adverse event.257,271 Injection site and infusion reactions occur
Infliximab was approved for the treatment of moderate to at variable rates. They are higher with infliximab than with
severe pediatric Crohn’s disease by the FDA in 2006. Fortu- adalimumab or certolizumab pegol.272 Infusion reactions with
nately, children had even higher response and remission rates infliximab typically are associated with antibodies to inflix-
than adults, which likely reflects the early nature of disease in imab (ATI), also referred to as HACA (human anti-chimeric
children compared with adults and a different phenotype antibodies). ATI developed in 13% of infliximab-treated
(e.g., inflammatory) at young age. patients with Crohn’s disease. Patients in whom ATI develop
Since the success of infliximab, 2 additional anti-TNF are more likely, although not uniformly so, to experience
agents have been approved for treating Crohn’s disease. acute infusion reactions, which can consist of chest tightness,
Adalimumab is a subcutaneously administered human immu- dyspnea, rash, and hypotension. ATI are less likely to develop
noglobulin G1 (IgG1) monoclonal antibody that targets TNF. in patients treated concomitantly with glucocorticoids or
After success in RA, an early open-label study was performed immune modulators, providing a justification for continu­
of patients with Crohn’s disease who had lost response to or ing MTX, AZA, or 6-MP, even when these treatments
become intolerant to infliximab. In this study, 59% responded have failed.
to adalimumab therapy and 29% of patients were in remission Delayed hypersensitivity reactions, consisting of severe
at 12 weeks.258 Importantly, no patients experienced acute or polyarthralgia, myalgia, facial edema, urticaria, or rash, are
delayed hypersensitivity reactions to adalimumab. This paved unusual complications that can occur 2 to 12 days after an
the way to larger RCTs that showed efficacy for inducing infusion.273 High ATI concentrations appear in such patients
remission259 and maintenance at 1 year.260 Based on results after the occurrence of such reactions, but they are not neces-
from these studies, the recommended adult dosing is 160 mg sarily found before reinfusion. The major risk factor for

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   2017

delayed hypersensitivity appears to be a long delay (probably A reasonable conclusion is that both immunomodulators and
≥ 6 months) between infusions, thereby priming an amnestic anti-TNF agents increase the absolute risk of NHL to a real
antibody response. Delayed hypersensitivity appears to be but small extent. It is not clear if combination therapy increases
less common when a standard induction regimen is used and this risk to any clinically meaningful extent.
when an immune modulator is given concurrently.274 Hepatosplenic T-cell lymphoma (HSTCL) has been
Antibody formation is not unique to infliximab. For adali- described in patients with Crohn’s disease who have been
mumab, human anti-human antibodies (HAHAs) can form. treated with anti-TNF agents in combination with immuno-
They were seen in only 2.6% of patients in a 1-year mainte- modulators and with immunomodulators alone (6-MP and
nance study of adalimumab in Crohn’s disease271 but in up to AZA).277 This nearly universally fatal form of NHL predomi-
17% in patients with RA.275 Antibodies to certolizumab were nantly affects young men, but its incidence is unknown; for-
seen in approximately 10% of patients in the induction and tunately it appears to be rare, and more often occurs in the
maintenance trials.262,264 The clinical significance of the pres- setting of combination therapy. This, in addition to the uncer-
ence of anti-drug antibodies is a matter of debate, but data tain magnitude of benefit of combination therapy for all
demonstrate an association with lower infliximab serum levels patients, has led some authorities to recommend anti-TNF
in the setting of episodic therapy, where ATI formation is monotherapy, particularly in young male patients.282 Because
highest,276 and a decreased response rate to adalimumab it appears that the risk of HSTCL does not begin until approxi-
among patients with HAHAs.277 mately 2 years of thiopurine exposure,272 another approach to
Antinuclear antibodies are common and appear in approx- reduce risk would be to use combination therapy to induce
imately 50% of patients receiving infliximab after 2 years. Of and maintain remission, with plans to consider withdrawing
patients who develop antinuclear antibodies, approximately the thiopurine if a stable remission is maintained.
30% develop anti–double-stranded DNA.276 Actual drug- Infliximab, adalimumab, and certolizumab pegol are class
induced lupus is rare but can occur. Treatment with certoli- B agents for use in pregnancy. Most of the clinical data in
zumab pegol has been observed to induce a lower rate of Crohn’s disease comes from experience with infliximab, but
antinuclear antibodies than does infliximab or adalimumab, there are now similar data available for adalimumab and cer-
perhaps a result of this agent’s inability to induce T-cell tolizumab. Infliximab and adalimumab cross the placenta in
apoptosis. The clinical significance of these autoantibodies is the third trimester and may be detectable in the infant up to
unclear. 6 months after birth.283 Certolizumab pegol can cross the pla-
In clinical trials, infections were reported in up to 57% of centa in the first trimester in low levels, but has the lowest
anti-TNF treated patients, but typically the rate of infections level of placental transfer in the third trimester, leading to very
seen with placebo is similar to those in the intervention low exposure to the newborn infant. The rate of birth defects
groups.271 Serious infections fortunately were unusual, occur- does not appear to be elevated in pregnancies that have
ring in only 2% to 4% of patients, which was consistent for all occurred while the mother is on anti-TNF therapy, but safety
3 anti-TNF agents.256,260,263 In the course of treatment of patients is not clearly established and use during pregnancy has not
with enterocutaneous fistulas, but especially with perineal been routine.284
disease, abscesses formation can arise from superficial healing Optimizing Anti-TNF Response.  Proper selection of patients is
and closure of an infected pocket. Any patient with a sus- the key to using anti-TNF agents safely, effectively, and appro-
pected pyogenic complication of Crohn’s disease or any priately. Patients without objective findings of inflammation
serious infection should undergo adequate drainage and treat- or with fibrostenotic disease are unlikely to benefit, and treat-
ment with antibiotics before starting or continuing infliximab. ing patients who have an undrained abscess is likely to be
A systematic review found that sepsis had a mortality rate of unsafe. In addition to proper patient selection, opportunities
0.4% in anti–TNF–treated patients.278 Patients with sepsis typi- to optimize the response to anti-TNF treatment include
cally were older and had comorbidities. Primary contributing dose modification, avoidance of smoking, using concomitant
factors included the concomitant use of narcotics, prednisone, immunomodulators, administering early intensive therapy,
and other immune suppressing agents, which can indepen- and the use of drug and antibody levels to guide therapeutic
dently increase the risk of serious infections and death.190,279 decisions.
Reactivation of TB has been observed with anti-TNF therapies, Dose intensification often is required to regain response.
and has resulted in disseminated disease and death. The rate For infliximab, this means increasing the dose from 5 mg/kg
of occurrence of TB was estimated to be 0.2% in a recent meta- to 10 mg/kg or increasing the maintenance frequency from
analysis of anti-TNF exposed patients with IBD.280 All patients every 8 weeks to every 6 weeks. This tactic works in the major-
should be screened for pulmonary TB before starting anti-TNF ity of patients and allows therapy to be continued after an
therapy. attenuated response.285 Increasing adalimumab dosing to
Since the early days of infliximab use, there has been 40 mg weekly (or 80 mg every 2 weeks) or giving an addi-
concern of an increased risk of lymphoproliferative disorders, tional certolizumab pegol dose can yield similar results.260,286
specifically non-Hodgkin’s lymphoma. A meta-analysis of Because the response rate to a second anti-TNF agent is lower
patients with Crohn’s disease treated with anti-TNF agents than the first, dose intensification is favored before moving on
reported the rate of NHL as 6.1 per 10,000 patient-years,281 to a different anti-TNF drug. Smoking is a strong negative
which compared with the background rate in the general predictor of response to anti-TNF therapy, and all patients
population of 1.9 per 10,000 patient-years, corresponds to a need to be informed of the poor initial and long-term out-
standardized incidence ratio of 3.23 (95% CI, 1.5 to 6.9). Com- comes associated with smoking.287
pared with the rate of NHL in Crohn’s patients seen in the The value of the concomitant use of immunomodulators
meta-analysis of immunomodulators noted earlier (4 to 9 per (6-MP, AZA, or MTX) to improve the anti-TNF initial response
10,000),225 the standardized incidence ratio is 1.7 (95% CI, 0.5 and maintenance effect is still somewhat controversial. As
to 7.1). Because most of the anti-TNF treated patients also were noted earlier, immunomodulators appear to decrease the pro-
exposed to immunomodulators, however, it is not possible to duction of anti-drug antibodies, thereby increasing serum
determine the magnitude of risk contributed by the anti-TNF drug levels, but the clinical significance of such increased
treatment alone. As described above, the absolute risk of lym- levels is uncertain. A prospective study that addressed this
phoma in IBD patients treated with thiopurines alone observed question and used infliximab with or without MTX showed
in the French CESAME cohort was 9 per 10,000 patient-years.226 no difference in outcomes at the end of 1 year.288 In support of

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
2018   Section X  Small and Large Intestine

this, post hoc analyses of RCTs also did not show a benefit of Low or undetectable drug levels without antibody (or low-
combination immunomodulator and anti-TNF therapy over level antibody) present should lead to an increase in dose or
anti-TNF therapy alone. Most of these patients, however, had shortening of the dosing interval. Low or undetectable drug
already failed an immunomodulator to be entered into these levels with high antibody titer should prompt a change to a
studies. To evaluate the effect of AZA or infliximab mono- different anti-TNF agent. High drug levels should prompt an
therapy compared with combination therapy in patients objective evaluation for disease activity. If there is no active
without prior exposure to these agents, the Study of Biologic disease, then an alternative explanation for symptoms should
and Immunomodulator Naïve Patients with Crohn’s Disease be sought. If there is active disease with circulating drug at
(SONIC) study was performed. SONIC found that 57% of trough, then there should be a consideration for switching to
patients receiving combination therapy were in steroid-free an agent with a different mechanism of action than anti-TNF.
clinical remission at 6 months, compared with 44% receiving The other time to consider checking levels is to optimize
infliximab alone and 30% receiving azathioprine alone.208 In dosing preemptively before infusion reactions or loss of
addition, mucosal healing occurred more often in the combi- response occurs. The hypothesis is that anti-drug antibodies
nation therapy group. This landmark study has pushed the form when there is no circulating drug, and these antibodies
field to strongly consider combination therapy, particularly in can lead to infusion reactions and/or increased drug clear-
immunomodulator and anti-TNF naïve patients. It is not clear ance. Therefore, by optimizing the dose to prevent time
if these results can be extrapolated to other anti-TNFs. The without circulating drug, antibody formation can be sup-
value of continuing immunomodulators after their use as pressed, thereby leading to better and more sustained anti-
monotherapy has failed is still uncertain; a recent meta- TNF response.
analysis showed that it may be important for infliximab, but Another emerging concept is that once antibodies develop,
not adalimumab or certolizumab pegol.289 The decision to use they may resolve.295 If there are low levels of antibodies to the
anti-TNF mono- or combination therapy has to be made based drug, dose optimization (to increase the trough level) and the
on an individual patient basis, taking their expected benefits addition of an immunomodulator if not already prescribed
and risks into account.290 could be considered. This may salvage the current anti-TNF
The strategy of early aggressive therapy for Crohn’s drug before having to move onto another agent in its class.
disease has gained much attention because of the enthusiasm High levels of antibodies to anti-TNF agents typically cannot
of this approach in RA, and favorable results have been be overcome and, if present, a switch to a different agent
reported in Crohn’s disease.291 In the study by D’Haens, 133 within class is recommended.
patients with recent-onset active Crohn’s disease were ran- In addition to optimizing treatment, there is also an effort
domized to receive early combined immunosuppression with to better define the goals of therapy. There has been focus on
AZA and infliximab (followed by maintenance AZA and mucosal healing, both as a treatment goal and a predictive
on-demand infliximab) or conventional treatment with the factor for disease progression. The hypothesis is that persis-
sequential use of prednisone, AZA, and then infliximab.291 At tent inflammatory change, even if not causing symptoms, will
the end of 1 year, 62% of patients in the early-combination lead to structural damage of the bowel, and ultimately lead to
therapy group were in remission compared to 42% in the complications of Crohn’s disease. Data from the pre-biologic
conventional group. By study design, all patients in the con- and biologic era support better long-term outcomes if mucosal
ventional group received glucocorticoids, but no patients in healing is achieved.292 Because we are unable to achieve com-
the early-combination group required glucocorticoids. Finally, plete healing in most patients, we need to understand how far
at 2 years, 73% of patients in the early-combination group had to push the therapeutic regimen to achieve a possibly unat-
complete mucosal healing, compared with 30% in the conven- tainable goal. It is hoped that new disease indices that look at
tional group. The authors concluded that more intensive treat- cumulative bowel damage will help us understand how
ment early in the course of Crohn’s disease could lead to better mucosal healing and other endpoints should be used in clini-
outcomes. There are significant limitations in this open-label cal trials and in practice.152
study, including the lack of an arm of early immunomodulator
treatment alone. Also, the use of episodic infliximab therapy
is not standard of care, although it must be acknowledged that Natalizumab
this strategy might yet prove effective in disease of recent Natalizumab is humanized monoclonal antibody against α4-
onset. Despite these and other limitations, an important point integrin that inhibits leukocyte adhesion and migration into
is made that aggressive treatment early in the course of inflamed tissue. Also used for the treatment of multiple scle-
Crohn’s disease can prevent the need for glucocorticoids and rosis (MS), natalizumab is the first new class of drug approved
lead to a high rate of mucosal healing. Post-hoc studies of for the treatment of Crohn’s disease since approval of inflix-
adalimumab and certolizumab clinical trials corroborate the imab in 1998. It is administered IV at a dose of 300 mg every
premise of early aggressive therapy, showing increased 4 weeks. The large RCTs, Efficacy of Natalizumab as Active
response and remission rates in patients who received anti- Crohn’s Therapy (ENACT)-1 and ENACT-2,52 confirmed its
TNF therapy within 2 years of diagnosis.292 Although this efficacy in both induction and maintenance of remission in
work has highlighted the potential benefit of early aggressive moderate to severely active disease.
therapy and intuitively makes sense to effectively treat an Unfortunately, in the open-label extension portion of the
inflammatory condition before the onset of fibrosis and perfo- ENACT studies, 1 patient died from progressive multifocal
rating disease, we still need to keep in mind that this paradigm leukoencephalopathy (PML),296 a progressive degenerative
shift is not yet supported by the strongest of evidence. neurologic disease caused by infection with John Cunningham
The newest tool in the armamentarium to optimize anti- virus (JCV); it typically is seen in patients with AIDS. This
TNF therapy is the ability to measure anti-TNF drug and information, together with 2 additional reports of PML in
antibody levels.293 Previously, reliant on symptoms alone, natalizumab-treated patients with MS led to a temporary
empiric changes were made for drug dose or switch to another withdrawal of natalizumab from the market for MS (for which
agent within class. Now, the availability of drug and antibody it had already been approved) and suspension of further clini-
levels can guide our decision making. The most intuitive time cal studies in Crohn’s disease. After careful scrutiny and
to check drug levels is in the setting of loss of response. In this follow-up of all treated patients,297 natalizumab was returned
scenario, drug and antibody levels are checked at trough.293,294 for use in MS and approved by the FDA in 2008 for treating

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   2019

patients who have moderate to severe Crohn’s disease with role. As noted earlier, low vitamin D levels may be associated
evidence of active inflammation refractory to prior treatment, with an increased risk of developing Crohn’s disease.5 Taken
including anti-TNF. A mandatory patient registry, Tysabri a step further, there is some suggestion that replacing vitamin
Outreach Unified Commitment to Health (TOUCH), tracks all D can be helpful as an adjunctive therapy to decrease Crohn’s
treated patients in the United States. Since return to the market, disease activity level.303 We still need to learn more about the
additional cases of PML have been reported, almost all of importance of vitamin D and Crohn’s disease, but a general
whom had MS, but additional cases have been reported in recommendation is to keep vitamin D, specifically 24(OH)D3,
patients Crohn’s disease as well. above 32-40 ng/ml.
Progress had been made to understand who is at most risk
for PML. Three risk factors were identified, including treat-
ment beyond 2 years, prior exposure to immunosuppressants, Novel Therapies
and the presence of anti-JCV antibodies. Because all Crohn’s Progress in understanding the pathogenesis of Crohn’s disease
disease patients receiving natalizumab have prior immuno- has borne fruit in the development of a wide variety of novel
suppressant exposure, the risk factors to consider in this therapeutic agents. In addition to holding real promise for
patient population are anti-JCV status and duration of treat- safer and more effective therapy in the future, clinical trials of
ment. An anti-JCV virus assay is commercially available, and novel therapeutics offer access to these agents for patients
the recommendation is to perform this test before determining whose disease has exhausted approved therapies.
if natalizumab is an appropriate treatment for a particular Promising agents under investigation include antibodies
patient. Data show that if a patient has all 3 risk factors listed directed against the shared p40 subunit of IL-12 and IL-23. The
above, the risk of developing PML is approximately 1 in 100.298 human anti IL-12/23 monoclonal antibody ustekinumab was
Because this risk is higher than most patients and providers studied in a blinded crossover trial involving 104 patients with
will tolerate, natalizumab is not recommended to patients moderate to severe Crohn’s disease.304 Although the primary
with a positive anti-JCV antibody, unless under extraordinary endpoint of clinical response at 8 weeks was not achieved,
circumstances. If anti-JCV antibody is negative, however, the significant differences compared with placebo were seen at
PML risk may be close to zero, and, therefore, treatment with other time points, with the largest differences seen in patients
natalizumab may be considered, with repeat anti-JCV anti- who had previously received infliximab. This prompted an
body testing every 6 months. RCT of over 500 patients.305 In this study, patients were treated
In addition to PML, severe hepatic toxicity that could lead with a single IV induction dose of 1 mg/kg, 3 mg/kg, 6 mg/
to death or the need for liver transplantation has been reported, kg, or placebo. The patients who had a response at 6 weeks
but this also appears to be very rare.297,299 Typically, natali- were then randomized to a subcutaneous dose of either 90 mg
zumab is very well tolerated: approximately 10% of patients or placebo. At the time of the primary endpoint at 6 weeks,
in the treatment arm of ENACT withdrew because of an 40% of patients had responded to therapy compared with 24%
adverse event, and serious infections were reported at a rate in the placebo group (P = 0.005). Of the responders, 42% were
of 2% to 3%, which is no different from the rate in placebo- in remission at week 22 compared with 27% in the placebo
treated patients. The future of natalizumab for the treatment group (P = 0.03). Treatment was well tolerated. Serious adverse
of Crohn’s disease is uncertain. Although risk can be managed events were rare and primarily related to active Crohn’s
with the use of anti-JCV antibody testing, newer medications disease.
with a similar mechanism of action, but without PML risk may Vedolizumab is an anti-integrin molecule similar to natali-
take its place (see vedolizumab below). zumab, but in contrast to natalizumab, which targets both
α4β1 and α4β7, vedolizumab only targets α4β7. This is impor-
tant because there are no α4β7 receptors in the brain, and
Adjunctive Therapies therefore PML theoretically is not a concern with vedolizumab;
Many other therapies are used to control the symptoms and animal models and experience in humans have supported this
adverse consequences of Crohn’s disease. Antidiarrheal and claim. Vedolizumab was studied in patients with Crohn’s
anticholinergic agents can help to alleviate diarrhea and disease using an IV dose of 300 mg given at baseline and again
cramping. Patients with ileal disease or resection can require 2 weeks later.306 There was a statistically significant rate of
parenteral vitamin B12 supplementation or the addition of cho- clinical remission at week 6 (15% treatment group vs. 7%
lestyramine (1 to 4 g/day) or colesevelam (625 to 3800 mg/ placebo group, P = 0.02). Patients without prior failure to anti-
day) to control bile salt diarrhea. Iron supplementation also TNF did better than those in whom anti-TNF therapy previ-
may be needed. Smoking cessation should be vigorously ously failed. Although the week 6 data were somewhat
pursued as a means of improving long-term outcomes.300 disappointing, the maintenance data were significantly
Bone loss should be anticipated as a potentially serious better.307 By week 52, there were statistically significant differ-
complication in all patients. 301 Bone density should be checked ences for treatment with vedolizumab (administered every 4
at diagnosis and at regular intervals thereafter, with appropri- or 8 weeks) compared with placebo for the outcomes of clini-
ate medical management of bone loss. Strategies to preserve cal remission, clinical response, and corticosteroid-free remis-
bone density include smoking cessation and, at a minimum, sion. As was also seen in UC, vedolizumab may prove to be 1
daily supplementation of calcium and vitamin D; 1000 mg/day of our most effective and durable maintenance medications
of elemental calcium is enough for younger men and premeno- for Crohn’s disease. Based on these results, vedolizumab was
pausal women, whereas men and women older than 50 years approved in the United States for both Crohn’s disease and
should have as a goal elemental calcium intake of 1500 mg/day. ulcerative colitis in 2014.
For most people, 400 to 800 IU of vitamin D daily is adequate. Inhibition of Janus kinase (JAK) is another pathway
In patients at the highest risk and without contraindications, showing promise for the treatment of Crohn’s disease. When
bisphosphonates should be considered at the time corticoste- cytokines bind to the cell surface, receptors lead to polymer-
roids are initiated. One study showed that a single-dose of ization and activation of JAK. Activated JAK in turn phos-
zoledronate could be effective to prevent bone loss when phorylates signal transducer and activator of transcription
administered during a flare requiring corticosteroids.302 (STAT) protein, which dimerizes and moves to the cell nucleus
Aside from its role in preventing bone loss, vitamin D has to activate new gene transcription.308 The oral JAK inhibitor
also gained interested for its potential immunomodulatory tofacitinib is showing promise for both UC and Crohn’s

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
2020   Section X  Small and Large Intestine

disease. In a phase 2 study of 139 patients with moderate to have had some surgical procedure.318 Depending on the preva-
severe Crohn’s disease, there was a dose-dependent treatment lent medical culture in the country of study, the rate of surgery
effect on CRP levels and on clinical response.309 There was also within 3 years of diagnosis varies from 25% to 45%. Approxi-
a dose-dependent increase in LDL cholesterol, so this safety mately 30% of patients require a second surgery by 5 years
signal will have to be monitored in future trials of this agent. after the first, and about one third of patients who need a
Probiotic therapies have been examined as a safe means of second surgery eventually require a third.319 These percent-
modulating the intestinal immune response in IBD, but studies ages stayed fairly stable from 1950-2000, but likely have
in pediatrics and in the setting of postoperative prophylaxis decreased since the introduction of biologic agents.318 Because
have been disappointing.310,311 of the high likelihood of recurrence after segmental resection,
Some novel agents defy conventional approaches to the the guiding principle of surgery in Crohn’s disease is preser-
treatment of Crohn’s disease. Porcine whipworm (Trichuris vation of intestinal length and function. Taking wide margins
suis) has been administered as a possible treatment for both does not reduce the likelihood of recurrent disease and, with
Crohn’s disease and UC, with promising effect and excellent repeated resection, can contribute to short bowel syndrome
safety and tolerability.312 Theoretically, this iatrogenic helmin- and intestinal failure.
thic infestation might prove effective through the induction of Indications for surgery include complications such as
regulatory T cells. intra-abdominal abscess, medically intractable fistula, fibrotic
Although the hypotheses underlying these unusual thera- stricture with obstructive symptoms, toxic megacolon, hemor-
pies have yet to be proved, the excitement over the novel rhage, and cancer. Patients with symptoms refractory to
mechanisms and how they inform us of the pathophysiology medical therapy also should be considered for surgery, par-
of Crohn’s disease continue to stimulate enthusiasm. ticularly when they remain dependent on or refractory to glu-
cocorticoids despite optimal medical therapy. Some patients
prefer to consider a limited small bowel resection as opposed
Nutritional Therapy to a trial of immunomodulator or biologic therapy.320 A well-
Nutritional therapy in Crohn’s disease conceivably has 2 timed bowel resection may be indicated for children with
purposes: repletion of nutrients and treatment of the primary growth failure. In patients with indeterminate colitis for whom
disease (see Chapter 6). Specific deficits should be iden­ colectomy is required, ileal pouch–anal anastomosis (IPAA)
tified and corrected. Protein-calorie malnutrition should be can be considered, but pouch-related complications are seen
addressed, preferably with enteral supplementation. Many, at a higher rate than in patients with UC.128 In patients with
but not all, patients with Crohn’s disease are lactose intolerant Crohn’s disease, there is a high rate of pouch failure and IPAA
and may need increased calcium supplementation. TPN may typically is avoided. In selected patients with rectal sparing
be considered for patients with severe malnutrition before and lack of fistulizing disease, however, IPAA or ileorectal
surgery or for selected patients with severe Crohn’s disease as anastomosis may be considered (see Chapter 117).321,322 Increas-
a primary therapy in combination with bowel rest. Patients ing facility with minimally invasive laparoscopic approaches
with short bowel syndrome from numerous small bowel and enhanced recovery pathways for Crohn’s disease
resections can require enteral nutrition with defined diets; might reduce operative morbidity, reduce hospital stays, and
rarely, patients with severe short bowel syndrome require improve outcomes.323-326
lifelong TPN.
A meta-analysis has found defined enteral diets to be infe-
rior to glucocorticoids in achieving clinical response,313 but COSTS OF CARE
defined enteral or polymeric diets still may be useful in some
children for whom glucocorticoids are undesirable.314 Elemen- Substantial medical and societal costs are incurred in the
tal diets do not appear to be superior to polymeric diets.313 course of Crohn’s disease. One study estimated the total cost
Children may be taught to receive nocturnal feedings after in the United States for patients with Crohn’s disease exceeds
self-intubation with an NG tube. Long-term tolerance may be $2 billion annually.327 Studies from the United States and
poor, however, and disease tends to recur when the patient’s Canada estimate the average cost of hospitalization for a
usual diet is reintroduced. patient with Crohn’s disease to be approximately $10,000 to
A number of dietary interventions have been evaluated. $15,000 and annual costs of anti-TNF agents to be $25,000
Most of the focus has been on elimination diets, dietary fiber to $30,000.328,329 Despite the expense of the anti-TNF drugs,
including prebiotics, glutamine, fish oil, and carbohydrates. analyses have shown that these agents improve quality of life
Although patients frequently report associations between diet and are cost-effective because of prevention of hospitaliza-
and symptoms,315 none of these interventions to date have tions and surgery.330
consistently shown benefit in clinical trials.316 Patients with a
stricture might tolerate raw fruits and vegetables poorly or
might experience complete intestinal obstruction.
A compelling newer avenue of research is to study the CROHN’S DISEASE IN THE LIFE CYCLE
impact of diet on the intestinal microbiome. Because the
microbiome may contribute to disease manifestations through Approximately 25% of new Crohn’s disease diagnoses are
host-microbe interactions, alteration of the microbiome with made in persons younger than 20 years of age. In most respects,
diet may be a strategy to prevent or manage Crohn’s disease. Crohn’s disease has the same pathophysiology and clinical
Much work in this area is needed, but early data confirm features in children as it does in adults. The special conse-
a link between dietary patterns and intestinal microbial quences of Crohn’s disease in children and adolescents
enterotype.317 relate to the vulnerability of this population to disturbances
in physical growth, sexual maturation, and psychosocial
Surgical Therapy Crohn’s disease affects many persons in the peak of their
Surgery plays an integral role in the treatment of Crohn’s reproductive years. Studies have varied in the assessment of
disease to control symptoms and to treat complications. By the female fertility in Crohn’s disease, showing either no differ-
20th year from the onset of symptoms, roughly 75% of patients ence from the general population or a slight decrease. Studies

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   2021

that have detected diminished fertility generally have corre- antigens ASCA, anti-CBir, and anti-OmpC have higher rates
lated this finding with increased disease activity. Contributing of complicated disease.339 Furthermore, the highest antibody
factors can include true infertility or a conscious decision to sum group has the most rapid disease progression. Similar
avoid childbearing. In men and women, decreased libido results also have been seen in adults, and with other serologic
because of symptoms (e.g., diarrhea, abdominal pain, fatigue) antibody markers (antibodies to carbohydrates).71,340,341 There
are not uncommon; in women, dyspareunia and rectovaginal have been mixed results regarding the utility of genetic
fistulas can play additional roles. Except for reversible sperm polymorphisms in predicting the natural history of disease,
abnormalities caused by sulfasalazine and MTX, men with perhaps reflecting our currently incomplete understanding of
Crohn’s disease have normal fertility. the genetic and environmental factors that shape disease
The effect of pregnancy on the course of Crohn’s disease expression.339,342 In the future, predictive models will most
depends on the status of the disease at conception.331 Women likely use a combination of clinical, serologic, and genetic
with quiescent disease at conception have the same rate of markers to help prognosticate disease severity and course.343
relapse during pregnancy as nonpregnant women. Among
women with active disease at conception, the one-third rule
applies: one third improve, one third worsen, and one third
have unchanged symptoms during their pregnancy.332 The estimated risk of colorectal cancer (CRC) in Crohn’s
Most pregnancies carried by women with Crohn’s disease disease has varied widely, ranging from no more risk than that
are normal, but there appears to be an increased rate of adverse of the general population to an estimated standardized inci-
conception outcomes (i.e., spontaneous abortion), adverse dence ratio as high as 26.6 (see Chapter 127).344 One meta-
pregnancy outcomes (e.g., preterm birth, child small for ges- analysis estimated the absolute risk at 10, 20, and 30 years
tational age, stillbirth) and pregnancy-related complications.333 to be 2.9%, 5.6%, and 8.3%, respectively. For patients with
Other than preterm birth, the contribution of disease activity Crohn’s colitis, this was higher than expected in the general
to these outcomes may be lower than previously thought.333,334 population, but not different from what was reported for
For a review of the safety of medical therapies in pregnancy patients with UC. For patients with isolated ileal disease, the
and nursing, see Table 115-4. relative risk of colon cancer was not statistically higher than
Compared with younger patients who have Crohn’s those without IBD. The overall rate of colon cancer in Crohn’s
disease, older patients are more likely to have disease of the disease over the past 30 years may have decreased.345
colon, particularly of the distal colon. As with children, the The general recommendation for CRC surveillance for
presentation may be subtle; extraintestinal symptoms can pre- patients with Crohn’s disease that involves the colon is to
dominate, and diagnosis may be delayed. Medical manage- follow the same guidelines as for UC.346 Segments of bowel
ment is essentially no different for the older patient, but the excluded by diversion procedures are at greatly increased risk
clinician more often must consider the variety of other condi- for developing CRC and present a great challenge to screening
tions prevalent among older patients when choosing thera- and surveillance.
pies. As expected, older IBD patients who are hospitalized Little controversy surrounds the increased risk of small
have a higher morbidity and mortality than younger patients,335 bowel adenocarcinoma associated with long-standing disease
and are at a higher risk of adverse events from immune sup- or in bypassed loops of small intestine. Small intestinal cancers
pressive therapy.336 are rare in Crohn’s disease, but in comparison to the extremely
low incidence of this disease in the general population, there
is a high associated relative risk.345 The association between
PROGNOSIS Hodgkin’s and non-Hodgkin’s lymphomas and Crohn’s
disease remains unclear. Studies relying on cases at referral
centers have found an increased risk of lymphoma, whereas
Morbidity population-based studies have not.229 The most likely explana-
The natural history of Crohn’s disease is a moving target, tions are either a referral bias or an increased risk confined to
continuously changing as therapeutic strategies improve.318 patients with more severe disease. Squamous cell carcinomas
The course of disease is highly variable and difficult to predict can arise in association with a chronic fistula to the skin and
for a given patient. Population-based studies from Scandina- in anal Crohn’s disease. Some studies also have found an
via provide the best information regarding the course of association between Crohn’s disease and respiratory cancers,347
disease. In the first year after diagnosis, the cumulative relapse perhaps attributable to smoking behavior.
rate is high, approaching 50%, with 10% of patients having a
chronic relapsing course.337 Thereafter, patients generally are
true to their own history: The rate of relapse in the first 2 years
of the disease correlates with the risk of relapse in the ensuing Whether having Crohn’s disease conveys an increased mortal-
5 years.338 Symptomatically active disease in the preceding ity is debated. Older population-based studies from the 1980s-
year yields a high likelihood of active disease in the following 1990s generally showed a modestly increased mortality rate
year. Conversely, a year in which symptoms are quiescent has in Crohn’s disease. A U.S. population-based study reporting
an 80% probability of being followed by another year without on the years 1996 to 2003 demonstrated a 40% increase in the
exacerbation.338 Over a 4-year period, the same analysis has standardized mortality rate among patients with Crohn’s
shown that 22% of patients remain in remission, 25% experi- disease compared with controls, but the absolute difference in
ence chronically active symptoms, and 53% have a course that death rates was still small.348 Specifically, the standardized
fluctuates between active and inactive disease.338 Although mortality rate among Crohn’s disease patients was 66.9 deaths
most persons continue to lead productive lives, the course of per 10,000 person-years compared with 49.7 deaths per 10,000
the disease may be punctuated by periods of poor productiv- person-years in the general population, and representing an
ity. Over time, approximately 10% of patients are disabled by excess of 17 deaths per 10,000 person-years attributable to
their disease. Crohn’s disease. More recently, European population-based
Increasingly, serologic markers are recognized as provid- studies did not show a difference in mortality compared with
ing prognostic information. Pediatric patients with Crohn’s the general population.349-351 A recent meta-analysis continues
disease who have higher immune responses to the microbial this debate, with the report of an increased mortality rate,

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
2022   Section X  Small and Large Intestine

driven by CRC, pulmonary disease and nonalcoholic steato- 54. Rutgeerts P, Geboes K, Vantrappen G, et al. Natural history
hepatitis.352 These data are not conclusive, but a reasonable of recurrent Crohn’s disease at the ileocolonic anastomosis
explanation is that Crohn’s disease may be associated with a after curative surgery. Gut 1984; 25:665-72.
slightly higher mortality rate. 152. Pariente B, Cosnes J, Danese S, et al. Development of the
Crohn’s disease digestive damage score, the Lemann score.
Inflamm Bowel Dis 2011; 17:1415-22.
COPING WITH CROHN’S DISEASE 161. Akobeng A, Gardener E. Oral 5-aminosalicylic acid for
maintenance of medically induced remission in Crohn’s
Although the old myths surrounding psychopathology as an Disease. Cochrane Database Syst Rev 2005; CD003715.
underlying cause of IBD have long been debunked, coping 206. Prefontaine E, Sutherland LR, Macdonald JK, et al.
with diarrhea, pain, malaise, and decreased energy takes a toll Azathioprine or 6-mercaptopurine for maintenance of
on all persons who suffer from Crohn’s disease, as well as on remission in Crohn’s disease. Cochrane Database Syst Rev
their families. Depression and anxiety often diminish daily 2009; CD000067.
functioning that already may be impaired by the physical 208. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab,
manifestations of the disease; psychosocial functioning, of azathioprine, or combination therapy for Crohn’s disease.
course, has a large impact on the patient’s quality of life, even N Engl J Med 2010; 362:1383-95.
in the absence of active disease.353,354 Patients cite concerns 226. Beaugerie L, Brousse N, Bouvier AM, et al.
about lack of energy, loss of control, body image, fear and Lymphoproliferative disorders in patients receiving
isolation, feeling unclean, and not reaching their full poten- thiopurines for inflammatory bowel disease: A prospective
tial.355 The medical provider can help greatly in alleviating observational cohort study. Lancet 2009; 374:1617-25.
these concerns by providing accurate and plentiful informa- 281. Siegel C, Marden S, Persing S, et al. Risk of lymphoma
tion. Lay organizations such as the Crohn’s and Colitis Foun- associated with anti-TNF agents for the treatment of
dation of America provide valuable resources in support of Crohn’s disease: A meta-analysis. Gastroenterology 2008;
affected persons and their families (http://www.ccfa.org). An 134:A14.
attitude of hopefulness is warranted because an astounding 291. D’Haens G, Baert F, van Assche G, et al. Early combined
number of therapeutic innovations—and someday perhaps a immunosuppression or conventional management in
cure—continue to unfold. patients with newly diagnosed Crohn’s disease: An open
randomised trial. Lancet 2008; 371:660-7.
293. Ordas I, Feagan BG, Sandborn WJ. Therapeutic drug
KEY REFERENCES monitoring of tumor necrosis factor antagonists in
inflammatory bowel disease. Clin Gastroenterol Hepatol
Full references for this chapter can be found on 2012; 10:1079-87; quiz e85-6.
www.expertconsult.com. 318. Cosnes J, Gower-Rousseau C, Seksik P, et al. Epidemiology
and natural history of inflammatory bowel diseases.
22. Cho JH, Brant SR. Recent insights into the genetics of Gastroenterology 2011; 140:1785-94.
inflammatory bowel disease. Gastroenterology 2011; 331. Mahadevan U, Cucchiara S, Hyams JS, et al. The London
140:1704-12. Position Statement of the World Congress of
43. Franke A, McGovern DPB, Barrett JC, et al. Genome-wide Gastroenterology on Biological Therapy for IBD with
meta-analysis increases to 71 the number of confirmed the European Crohn’s and Colitis Organisation: Pregnancy
Crohn’s disease susceptibility loci. Nat Genet 2010; and pediatrics. Am J Gastroenterol 2011; 106:214-23;
42:1118-25. quiz 24.

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   2022.e1

identified by gut microbiota analysis of Crohn disease

REFERENCES patients. Proc Natl Acad Sci U S A 2008; 105:16731-6.
19. Mendoza JL, Lana R, Diaz-Rubio M. Mycobacterium
1. Henriksen M, Jahnsen J, Lygren I, et al. Change of avium subspecies paratuberculosis and its relationship
diagnosis during the first five years after onset of with Crohn’s disease. World J Gastroenterol 2009;
inflammatory bowel disease: Results of a prospective 15:417-22.
follow-up study (the IBSEN Study). Scand J Gastroenterol 20. Sartor R. Microbial influences in inflammatory bowel
2006; 41:1037-43. diseases. Gastroenterology 2008; 134:577-94.
2. Nerich V, Monnet E, Etienne A, et al. Geographical 21. Devlin SM, Yang H, Ippoliti A, et al. NOD2 variants and
variations of inflammatory bowel disease in France: A antibody response to microbial antigens in Crohn’s disease
study based on national health insurance data. Inflamm patients and their unaffected relatives. Gastroenterology
Bowel Dis 2006; 12:218-26. 2007; 132:576-86.
3. Kappelman M, Rifas-Shiman S, Kleinman K, et al. The 22. Cho JH, Brant SR. Recent insights into the genetics of
prevalence and geographic distribution of Crohn’s disease inflammatory bowel disease. Gastroenterology 2011;
and ulcerative colitis in the United States. Clin 140:1704-12.
Gastroenterol Hepatol 2007; 5:1424-9. 23. Halfvarson J. Genetics in twins with Crohn’s disease: Less
4. Nerich V, Jantchou P, Boutron-Ruault MC, et al. Low pronounced than previously believed? Inflamm Bowel Dis
exposure to sunlight is a risk factor for Crohn’s disease. 2011; 17:6-12.
Aliment Pharmacol Ther 2011; 33:940-5. 24. Mei L, Targan S, Landers C, et al. Familial expression of
5. Ananthakrishnan AN, Khalili H, Higuchi LM, et al. Higher anti–Escherichia coli outer membrane porin C in relatives of
predicted vitamin D status is associated with reduced risk patients with Crohn’s disease. Gastroenterology 2006;
of Crohn’s disease. Gastroenterology 2012; 142:482-9. 130:1078-85.
6. Molodecky NA, Soon IS, Rabi DM, et al. Increasing 25. Glocker EO, Kotlarz D, Boztug K, et al. Inflammatory
incidence and prevalence of the inflammatory bowel bowel disease and mutations affecting the interleukin-10
diseases with time, based on systematic review. receptor. N Engl J Med 2009; 361:2033-45.
Gastroenterology 2012; 142:46-54.e42; quiz e30. 26. Xavier R, Rioux J. Genome-wide association studies: A new
7. Ng SC, Tang W, Ching J, et al. Incidence and phenotype of window into immune-mediated diseases. Nature Rev
inflammatory bowel disease based on results from the Immunol 2008; 8:631-43.
Asia-Pacific Crohn’s and Colitis Epidemiology Study. 27. Jostins L, Ripke S, Weersma RK, et al. Host-microbe
Gastroenterology 2013; 145:158-65. interactions have shaped the genetic architecture of
8. Gearry RB, Richardson A, Frampton CM, et al. High inflammatory bowel disease. Nature 2012; 491:119-24.
incidence of Crohn’s disease in Canterbury, New Zealand: 28. Hugot J, Chamaillard M, Zouali H, et al. Association of
Results of an epidemiologic study. Inflamm Bowel Dis NOD2 leucine-rich repeat variants with susceptibility to
2006; 12:936-43. Crohn’s disease. Nature 2001; 411:599-603.
9. Wilson J, Hair C, Knight R, et al. High incidence of 29. Ogura Y, Bonen D, Inohara N, et al. A frameshift mutation
inflammatory bowel disease in Australia: A prospective in NOD2 associated with susceptibility to Crohn’s disease.
population-based Australian incidence study. Inflamm Nature 2001; 411:603-6.
Bowel Dis 2010; 16:1550-6. 30. Economou M, Trikalinos T, Loizou K, et al. Differential
10. Loftus C, Loftus EVJ, Harmsen W, et al. Update on the effects of NOD2 variants on Crohn’s disease risk and
incidence and prevalence of Crohn’s disease and ulcerative phenotype in diverse populations: A meta-analysis. Am J
colitis in Olmsted County, Minnesota, 1940-2000. Inflamm Gastroenterol 2004; 99:2393-404.
Bowel Dis 2007; 13:254-61. 31. Brant SR, Wang MH, Rawsthorne P, et al. A population-
11. Sonnenberg A. Time trends of mortality from Crohn’s based case-control study of CARD15 and other risk factors
disease and ulcerative colitis. Int J Epidemiol 2007; 36:890-9. in Crohn’s disease and ulcerative colitis. Am J
12. Bernstein C, Wajda A, Svenson L, et al. The epidemiology Gastroenterol 2007; 102:313-23.
of inflammatory bowel disease in Canada: A population- 32. Strober W, Kitani A, Fuss I, et al. The molecular basis of
based study. Am J Gastroenterol 2006; 101:1559-68. NOD2 susceptibility mutations in Crohn’s disease. Mucosal
13. Jacobsen B, Fallingborg J, Rasmussen H, et al. Increase in Immunol 2008; 1(Suppl 1):S5-9.
incidence and prevalence of Gastroenterol Hepatol 2006; 33. Wehkamp J, Schmid M, Fellermann K, et al. Defensin
18:601-6. deficiency, intestinal microbes, and the clinical phenotypes
14. Charpentier C, Salleron J, Savoye G, et al. Natural history of Crohn’s disease. J Leukoc Biol 2005; 77:460-5.
of elderly-onset inflammatory bowel disease: A population- 34. Rioux J, Xavier R, Taylor K, et al. Genome-wide association
based cohort study. Gut 2013. [Epub ahead of print]. study identifies new susceptibility loci for Crohn disease
15. Castro M, Papadatou B, Baldassare M, et al. Inflammatory and implicates autophagy in disease pathogenesis.
bowel disease in children and adolescents in Italy: Data Nat Genet 2007; 39:596-604.
from the pediatric national IBD register (1996-2003). 35. Xavier R, Huett A, Rioux J. Autophagy as an important
Inflamm Bowel Dis 2008; 14:1246-52. process in gut homeostasis and Crohn’s disease
16. Davis R, Kramarz P, Bohlke K, et al. Measles-mumps- pathogenesis. Gut 2008; 57:717-20.
rubella and other measles-containing vaccines do not 36. Hampe J, Franke A, Rosenstiel P, et al. A genome-wide
increase the risk for inflammatory bowel disease: A association scan of nonsynonymous SNPs identifies a
case-control study from the Vaccine Safety Datalink project. susceptibility variant for Crohn disease in ATG16L1.
Arch Pediatr Adolesc Med 2001; 155:354-9. Nat Genet 2007; 39:207-11.
17. Barnich N, Carvalho F, Glasser A, et al. CEACAM6 acts as 37. Parkes M, Barrett J, Prescott N, et al. Sequence variants in
a receptor for adherent-invasive E. coli, supporting ileal the autophagy gene IRGM and multiple other replicating
mucosa colonization in Crohn disease. J Clin Invest 2007; loci contribute to Crohn’s disease susceptibility. Nat Genet
117:1566-74. 2007; 39:830-2.
18. Sokol H, Pigneur B, Watterlot L, et al. Faecalibacterium 38. Neurath M. IL-23: A master regulator in Crohn disease.
prausnitzii is an anti-inflammatory commensal bacterium Nat Med 2007; 13:26-8.

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
2022.e2   Section X  Small and Large Intestine

39. Bettelli E, Carrier Y, Gao W, et al. Reciprocal Crohn’s disease. Clin Gastroenterol Hepatol 2011;
developmental pathways for the generation of pathogenic 9:684-7.e1.
effector TH17 and regulatory T cells. Nature 2006; 60. Peyrin-Biroulet L, Chamaillard M, Gonzalez F, et al.
441:235-8. Mesenteric fat in Crohn’s disease: A pathogenetic hallmark
40. Izcue A, Hue S, Buonocore S, et al. Interleukin-23 restrains or an innocent bystander? Gut 2007; 56:577-83.
regulatory T cell activity to drive T cell-dependent colitis. 61. Jess T, Riis L, Vind I, et al. Changes in clinical
Immunity 2008; 28:559-70. characteristics, course, and prognosis of inflammatory
41. Duerr R, Taylor K, Brant S, et al. A genome-wide bowel disease during the last 5 decades: A population-
association study identifies IL23R as an inflammatory based study from Copenhagen, Denmark. Inflamm Bowel
bowel disease gene. Science 2006; 314:1461-3. Dis 2007; 13:481-9.
42. Barrett J, Hansoul S, Nicolae D, et al. Genome-wide 62. Jiang L, Xia B, Li J, et al. Retrospective survey of 452
association defines more than 30 distinct susceptibility loci patients with inflammatory bowel disease in Wuhan city,
for Crohn’s disease. Nat Genet 2008; 40:955-62. central China. Inflamm Bowel Dis 2006; 12:212-7.
43. Franke A, McGovern DPB, Barrett JC, et al. Genome-wide 63. Annunziata ML, Caviglia R, Papparella LG, et al. Upper
meta-analysis increases to 71 the number of confirmed gastrointestinal involvement of Crohn’s disease: A
Crohn’s disease susceptibility loci. Nat Genet 2010; prospective study on the role of upper endoscopy in the
42:1118-25. diagnostic work-up. Dig Dis Sci 2012; 57:1618-23.
44. Shaw SY, Blanchard JF, Bernstein CN. Association between 64. Vavricka SR, Spigaglia SM, Rogler G, et al. Systematic
early childhood otitis media and pediatric inflammatory evaluation of risk factors for diagnostic delay in
bowel disease: An exploratory population-based analysis. inflammatory bowel disease. Inflamm Bowel Dis 2012;
J Pediatr 2013; 162:510-4. 18:496-505.
45. Shaw SY, Blanchard JF, Bernstein CN. Association between 65. Burgmann T, Clara I, Graff L, et al. The Manitoba
the use of antibiotics and new diagnoses of Crohn’s disease Inflammatory Bowel Disease Cohort Study: Prolonged
and ulcerative colitis. Am J Gastroenterol 2011; 106:2133-42. symptoms before diagnosis—How much is irritable bowel
46. Shaw SY, Blanchard JF, Bernstein CN. Association between syndrome? Clin Gastroenterol Hepatol 2006; 4:614-20.
the use of antibiotics in the first year of life and pediatric 66. Baker W, Milton-Thompson G. The anal lesion as the sole
inflammatory bowel disease. Am J Gastroenterol 2010; presenting symptom of intestinal Crohn’s disease. Gut
105:2687-92. 1971; 12:865.
47. Margolis DJ, Fanelli M, Hoffstad O, et al. Potential 67. Bonheur J, Braunstein J, Korelitz B, et al. Anal skin tags in
association between the oral tetracycline class of inflammatory bowel disease: New observations and a
antimicrobials used to treat acne and inflammatory bowel clinical review. Inflamm Bowel Dis. 2008; 14:1236-9.
disease. Am J Gastroenterol 2010; 105:2610-6. 68. Richards M, Aberger F, Landercasper J. Granulomatous
48. Hegazi R, Rao K, Mayle A, et al. Carbon monoxide appendicitis: Crohn’s disease, atypical Crohn’s or not
ameliorates chronic murine colitis through a heme Crohn’s at all? J Am Coll Surg 1997; 185:13-7.
oxygenase 1–dependent pathway. J Exp Med 2005; 69. Adler J, Rangwalla SC, Dwamena BA, et al. The prognostic
202:1703-13. power of the NOD2 genotype for complicated Crohn’s
49. Bitton A, Dobkin P, Edwardes M, et al. Predicting relapse disease: A meta-analysis. Am J Gastroenterol 2011;
in Crohn’s disease: A biopsychosocial model. Gut 2008; 106:699-712.
57:1386-92. 70. Papadakis K, Yang H, Ippoliti A, et al. Anti-flagellin
50. Atreya I, Atreya R, Neurath M. NF-κB in inflammatory (CBir1) phenotypic and genetic Crohn’s disease
bowel disease. J Intern Med 2008; 263:591-6. associations. Inflamm Bowel Dis 2007; 13:524-30.
51. Van Assche G, Rutgeerts P. Physiological basis for novel 71. Papp M, Altorjay I, Dotan N, et al. New serological
drug therapies used to treat the inflammatory bowel markers for inflammatory bowel disease are associated
diseases. I. Immunology and therapeutic potential of with earlier age at onset, complicated disease behavior, risk
antiadhesion molecule therapy in inflammatory bowel for surgery, and NOD2/CARD15 genotype in a Hungarian
disease. Am J Physiol Gastrointest Liver Physiol 2005; IBD cohort. Am J Gastroenterol 2008; 103:665-81.
288:G169-74. 72. Targan S, Landers C, Yang H, et al. Antibodies to CBir1
52. Sandborn W, Colombel J, Enns R, et al. Natalizumab flagellin define a unique response that is associated
induction and maintenance therapy for Crohn’s disease. independently with complicated Crohn’s disease.
N Engl J Med 2005; 353:1912-25. Gastroenterology 2005; 128:2020-8.
53. Warnaar N, Hofker HS, Maathuis MHJ, et al. Matrix 73. Feagins LA, Holubar SD, Kane SV, et al. Current strategies
metalloproteinases as profibrotic factors in terminal ileum in the management of intra-abdominal abscesses in Crohn’s
in Crohn’s disease. Inflamm Bowel Dis 2006; 12:863-9. disease. Clin Gastroenterol Hepatol 2011; 9:842-50.
54. Rutgeerts P, Geboes K, Vantrappen G, et al. Natural history 74. Satsangi J, Silverberg MS, Vermeire S, et al. The Montreal
of recurrent Crohn’s disease at the ileocolonic anastomosis classification of inflammatory bowel disease: Controversies,
after curative surgery. Gut 1984; 25:665-72. consensus, and implications. Gut 2006; 55:749-53.
55. Rutgeerts PJ. From aphthous ulcer to full-blown Crohn’s 75. Silverberg M, Satsangi J, Ahmad T, et al. Toward an
disease. Dig Dis 2011; 29:211-4. integrated clinical, molecular and serological classification
56. Rutgeerts P, Goboes K, Peeters M, et al. Effect of faecal of inflammatory bowel disease: Report of a Working Party
stream diversion on recurrence of Crohn’s disease in the of the 2005 Montreal World Congress of Gastroenterology.
neoterminal ileum. Lancet 1991; 338:771-4. Can J Gastroenterol 2005; 19:5-36.
57. Yantiss RK, Odze RD. Pitfalls in the interpretation of 76. Michalski C, Autschbach F, Selvaggi F, et al. Increase in
nonneoplastic mucosal biopsies in inflammatory bowel substance P precursor mRNA in noninflamed small-bowel
disease. Am J Gastroenterol 2007; 102:890-904. sections in patients with Crohn’s disease. Am J Surg 2007;
58. Burke JP, Mulsow JJ, O’Keane C, et al. Fibrogenesis in 193:476-81.
Crohn’s disease. Am J Gastroenterol 2007; 102:439-48. 77. ter Beek W, Biemond I, Muller E, et al. Substance P
59. Erhayiem B, Dhingsa R, Hawkey CJ, et al. Ratio of visceral receptor expression in patients with inflammatory bowel
to subcutaneous fat area is a biomarker of complicated disease. Determination by three different techniques, i.e.,

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   2022.e3

storage phosphor autoradiography, RT-PCR and disease: A population-based study. Gastroenterology 2005;
immunohistochemistry. Neuropeptides 2007; 41:301-6. 129:827-36.
78. Keller J, Beglinger C, Holst JJ, et al. Mechanisms of gastric 96. Lanna C, Ferrari Mde L, Rocha S, et al. A cross-sectional
emptying disturbances in chronic and acute inflammation study of 130 Brazilian patients with Crohn’s disease and
of the distal gastrointestinal tract. Am J Physiol Gastrointest ulcerative colitis: Analysis of articular and ophthalmologic
Liver Physiol 2009; 297:G861-8. manifestations. Clin Rheumatol 2008; 27:503-9.
79. Nobrega AC, Ferreira BR, Oliveira GJ, et al. Dyspeptic 97. Parente F, Pastore L, Bargiggia S, et al. Incidence and risk
symptoms and delayed gastric emptying of solids in factors for gallstones in patients with inflammatory bowel
patients with inactive Crohn’s disease. BMC Gastroenterol disease: A large case-control study. Hepatology 2007;
2012; 12:175. 45:1267-74.
80. Kulnigg S, Gasche C. Systematic review: Managing 98. Halliday JS, Djordjevic J, Lust M, et al. A unique clinical
anaemia in Crohn’s disease. Aliment Pharmacol Ther 2006; phenotype of primary sclerosing cholangitis associated
24:1507-23. with Crohn’s disease. J Crohn Colitis 2012; 6:174-81.
81. Peyrin-Biroulet L, Loftus EV Jr, Colombel JF, et al. Long- 99. Liu JZ, Hov JR, Folseraas T, et al. Dense genotyping of
term complications, extraintestinal manifestations, and immune-related disease regions identifies nine new risk
mortality in adult Crohn’s disease in population-based loci for primary sclerosing cholangitis. Nat Genet 2013;
cohorts. Inflamm Bowel Dis 2011; 17:471-8. 45:670-5.
82. Farmer R, Hawk W, Turnbull RBJ. Clinical patterns in 100. Kane S. Urogenital complications of Crohn’s disease. Am J
Crohn’s disease: A statistical study of 615 cases. Gastroenterol 2006; 101:S640-3.
Gastroenterology 1975; 68:627-35. 101. Bernstein C, Wajda A, Blanchard J. The incidence of arterial
83. Orchard T, Wordsworth B, Jewell D. Peripheral thromboembolic diseases in inflammatory bowel disease: A
arthropathies in inflammatory bowel disease: Their population-based study. Clin Gastroenterol Hepatol 2008;
articular distribution and natural history. Gut 1998; 6:41-5.
42:387-91. 102. Kappelman MD, Horvath-Puho E, Sandler RS, et al.
84. Turkcapar N, Toruner M, Soykan I, et al. The prevalence of Thromboembolic risk among Danish children and adults
extraintestinal manifestations and HLA association in with inflammatory bowel diseases: A population-based
patients with inflammatory bowel disease. Rheumatol Int nationwide study. Gut 2011; 60:937-43.
2006; 26:663-8. 103. Bernstein C, Sargent M, Vos H, Rosendaal F. Mutations in
85. Jacques P, Mielants H, Coppieters K, et al. clotting factors and inflammatory bowel disease. Am J
The intimate relationship between gut and joint in Gastroenterol 2007; 102:338-43.
spondyloarthropathies. Curr Opin Rheumatol 2007; 104. Basseri B, Enayati P, Marchevsky A, et al. Pulmonary
19:353-7. manifestations of inflammatory bowel disease: Case
86. Gravallese E, Kantrowitz F. Arthritic manifestations of presentations and review. J Crohns Colitis 2010;
inflammatory bowel disease. Am J Gastroenterol 1988; 4:390-7.
83:703-9. 105. Zois CD, Katsanos KH, Kosmidou M, et al. Neurologic
87. Orchard TR, Holt H, Bradbury L, et al. The prevalence, manifestations in inflammatory bowel diseases: Current
clinical features and association of HLA-B27 in sacroiliitis knowledge and novel insights. J Crohns Colitis 2010;
associated with established Crohn’s disease. Aliment 4:115-24.
Pharmacol Ther 2009; 29:193-7. 106. Ekbom A, Brandt L, Granath F, et al. Increased risk of both
88. Sylvester F, Wyzga N, Hyams J, et al. Natural history of ulcerative colitis and Crohn’s disease in a population
bone metabolism and bone mineral density in children suffering from COPD. Lung 2008; 186:167-72.
with inflammatory bowel disease. Inflamm Bowel Dis 2007; 107. Colombel J, Solem C, Sandborn W, et al. Quantitative
13:42-50. measurement and visual assessment of ileal Crohn’s
89. Ghosh S, Cowen S, Hannan W, et al. Low bone mineral disease activity by computed tomography enterography:
density in Crohn’s disease, but not in ulcerative colitis, at Correlation with endoscopic severity and C reactive
diagnosis. Gastroenterology 1994; 107:1031-9. protein. Gut 2006; 55:1561-7.
90. Turk N, Cukovic-Cavka S, Korsic M, et al. Proinflammatory 108. Bodily K, Fletcher J, Solem C, et al. Crohn disease: Mural
cytokines and receptor activator of nuclear factor kappaB- attenuation and thickness at contrast-enhanced CT
ligand/osteoprotegerin associated with bone deterioration enterography—Correlation with endoscopic and histologic
in patients with Crohn’s disease. Eur J Gastroenterol findings of inflammation. Radiology 2006; 238:505-16.
Hepatol 2009; 21:159-66. 109. Solem C, Loftus EVJ, Fletcher J, et al. Small-bowel imaging
91. Noble C, McCullough J, Ho W, et al. Low body mass not in Crohn’s disease: A prospective, blinded, 4-way
vitamin D receptor polymorphisms predict osteoporosis in comparison trial. Gastrointest Endosc 2008; 68:255-66.
patients with inflammatory bowel disease. Aliment 110. Brenner D, Hall E. Computed tomography—An increasing
Pharmacol Ther 2008; 27:588-96. source of radiation exposure. N Engl J Med 2007;
92. Schneider S, Al-Jaouni R, Filippi J, et al. Sarcopenia is 357:2277-84.
prevalent in patients with Crohn’s disease in clinical 111. Peloquin J, Pardi D, Sandborn W, et al. Diagnostic ionizing
remission. Inflamm Bowel Dis 2008; 14:1562-8. radiation exposure in a population-based cohort of patients
93. Howell JL, Bussell RM, Hegarty AM, et al. Service with inflammatory bowel disease. Am J Gastroenterol 2008;
evaluation of patients with orofacial granulomatosis and 103:2015-22.
patients with oral Crohn’s disease attending a paediatric 112. Masselli G, Casciani E, Polettini E, et al. Comparison of MR
oral medicine clinic. Eur Arch Paediatr Dent 2012; enteroclysis with MR enterography and conventional
13:191-6. enteroclysis in patients with Crohn’s disease. Eur Radiol
94. Palamaras I, El-Jabbour J, Pietropaolo N, et al. Metastatic 2008; 18:438-47.
Crohn’s disease: A review. J Eur Acad Dermatol Venereol 113. Girometti R, Zuiani C, Toso F, et al. MRI scoring system
2008; 22:1033-43. including dynamic motility evaluation in assessing the
95. Bernstein C, Wajda A, Blanchard J. The clustering of other activity of Crohn’s disease of the terminal ileum. Acad
chronic inflammatory diseases in inflammatory bowel Radiol 2008; 15:153-64.

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
2022.e4   Section X  Small and Large Intestine

114. Tarjan Z, Toth G, Gyorke T, et al. Ultrasound in Crohn’s 133. van Hees P, van Elteren P, van Lier H, et al. An index of
disease of the small bowel. Eur J Radiol 2000; 35:176-82. inflammatory activity in patients with Crohn’s disease. Gut
115. Spradlin N, Wise P, Herline A, et al. A randomized 1980; 21:279-86.
prospective trial of endoscopic ultrasound to guide 134. Wright J, Marks I, Parfitt A. A simple clinical index of
combination medical and surgical treatment for Crohn’s Crohn’s disease activity—The Cape Town index. S Afr Med
perianal fistulas. Am J Gastroenterol 2008; 103:2527-35. J 1985; 68:502-3.
116. Sjekavica I, Barbaric-Babic V, Krznaric Z, et al. Assessment 135. Harvey R, Bradshaw J. A simple index of Crohn’s disease
of Crohn’s disease activity by Doppler ultrasound of activity. Lancet 1980; 1:514.
superior mesenteric artery and mural arteries in thickened 136. Myren J, Bouchier I, Watkinson G, et al. The O.M.G.E.
bowel wall: Cross-sectional study. Croat Med J 2007; Multinational Inflammatory Bowel Disease Survey
48:822-30. 1976-1982. A further report on 2,657 cases. Scand J
117. Gutierrez A, Lee H, Sands B. Outcome of surgical versus Gastroenterol Suppl 1984; 95:1-27.
percutaneous drainage of abdominal and pelvic abscesses 137. Willoughby J, Kumar P, Beckett J, et al. A double-blind trial
in Crohn’s disease. Am J Gastroenterol 2006; 101:2283-9. of azathioprine in Crohn’s disease. Gut 1971; 12:864.
118. Stidham RW, Xu J, Johnson LA, et al. Ultrasound elasticity 138. De Dombal F, Burton I, Clamp S, et al. Short-term course
imaging for detecting intestinal fibrosis and inflammation and prognosis of Crohn’s disease. Gut 1974; 15:435-43.
in rats and humans with Crohn’s disease. Gastroenterology 139. Talstad I, Gjone E. The disease activity of ulcerative
2011; 141:819-26 e1. colitis and Crohn’s disease. Scand J Gastroenterol 1976;
119. Almer S, Granerus G, Strom M, et al. Leukocyte 11:403-8.
scintigraphy compared to intraoperative small bowel 140. Sandler R, Jordan M, Kupper L. Development of a Crohn’s
enteroscopy and laparotomy findings in Crohn’s disease. index for survey research. J Clin Epidemiol 1988; 41:451-8.
Inflamm Bowel Dis 2007; 13:164-74. 141. Hyams J, Ferry G, Mandel F, et al. Development and
120. Louis E, Ancion G, Colard A, et al. Noninvasive assessment validation of a pediatric Crohn’s disease activity index.
of Crohn’s disease intestinal lesions with (18)F-FDG PET/ J Pediatr Gastroenterol Nutr 1991; 12:439-47.
CT. J Nucl Med 2007; 48:1053-9. 142. Lloyd-Still J, Green O. A clinical scoring system for chronic
121. Meisner R, Spier B, Einarsson S, et al. Pilot study using inflammatory bowel disease in children. Dig Dis Sci 1979;
PET/CT as a novel, noninvasive assessment of disease 24:620-4.
activity in inflammatory bowel disease. Inflamm Bowel Dis 143. Sands B, Ooi C. A survey of methodological variation in
2007; 13:993-1000. the Crohn’s disease activity index. Inflamm Bowel Dis 2005;
122. Triester S, Leighton J, Leontiadis G, et al. A meta-analysis 11:133-8.
of the yield of capsule endoscopy compared to other 144. Allan A, Linares L, Spooner H, et al. Clinical index to
diagnostic modalities in patients with non-stricturing small quantitate symptoms of perianal Crohn’s disease. Dis
bowel Crohn’s disease. Am J Gastroenterol 2006; Colon Rectum 1992; 35:656-61.
101:954-64. 145. Irvine E. Usual therapy improves perianal Crohn’s disease
123. Cohen SA, Ephrath H, Lewis JD, et al. Pediatric capsule as measured by a new disease activity index. McMaster
endoscopy: Review of the small bowel and patency IBD Study Group. J Clin Gastroenterol 1995; 20:27-32.
capsules. J Pediatr Gastroenterol Nutr 2012; 54:409-13. 146. Mary J, Modigliani R. Development and validation of
124. Yadav A, Heigh RI, Hara AK, et al. Performance of the an endoscopic index of the severity for Crohn’s disease:
patency capsule compared with nonenteroclysis radiologic A prospective multicentre study. Groupe d’Etudes
examinations in patients with known or suspected Thérapeutiques des Affections Inflammatoires du Tube
intestinal strictures. Gastrointest Endosc 2011; 74:834-9. Digestif (GETAID). Gut 1989; 30:983-9.
125. Liao Z, Gao R, Li F, et al. Fields of applications, diagnostic 147. Daperno M, D’Haens G, Van Assche G, et al. Development
yields and findings of OMOM capsule endoscopy in 2400 and validation of a new, simplified endoscopic activity
Chinese patients. World J Gastroenterol 2010; 16:2669-76. score for Crohn’s disease: The SES-CD. Gastrointest Endosc
126. Cheifetz A, Lewis B. Capsule endoscopy retention: Is it a 2004; 60:505-12.
complication? J Clin Gastroenterol 2006; 40:688-91. 148. Present D, Korelitz B, Wisch N, et al. Treatment of Crohn’s
127. Wiarda BM, Heine DG, Mensink P, et al. Comparison of disease with 6-mercaptopurine. A long-term, randomized,
magnetic resonance enteroclysis and capsule endoscopy double-blind study. N Engl J Med 1980; 302:981-7.
with balloon-assisted enteroscopy in patients with obscure 149. Langhorst J, Elsenbruch S, Koelzer J, et al. Noninvasive
gastrointestinal bleeding. Endoscopy 2012; 44:668-73. markers in the assessment of intestinal inflammation in
128. Brown C, Maclean A, Cohen Z, et al. Crohn’s disease and inflammatory bowel diseases: Performance of fecal
indeterminate colitis and the ileal pouch–anal anastomosis: lactoferrin, calprotectin, and PMN-elastase, CRP, and
Outcomes and patterns of failure. Dis Colon Rectum 2005; clinical indices. Am J Gastroenterol 2008; 103:162-9.
48:1542-9. 150. Guyatt G, Mitchell A, Irvine E, et al. A new measure of
129. Lewis JD. The utility of biomarkers in the diagnosis and health status for clinical trials in inflammatory bowel
therapy of inflammatory bowel disease. Gastroenterology disease. Gastroenterology 1989; 96:804-10.
2011; 140:1817-26 e2. 151. Allen PB, Peyrin-Biroulet L. Moving towards disease
130. Lichtenstein GR, Targan SR, Dubinsky MC, et al. modification in inflammatory bowel disease therapy.
Combination of genetic and quantitative serological Curr Opin Gastroenterol 2013; 29:397-404.
immune markers are associated with complicated Crohn’s 152. Pariente B, Cosnes J, Danese S, et al. Development of the
disease behavior. Inflamm Bowel Dis 2011; 17:2488-96. Crohn’s disease digestive damage score, the Lemann score.
131. Dotan I, Fishman S, Dgani Y, et al. Antibodies against Inflamm Bowel Dis 2011; 17:1415-22.
laminaribioside and chitobioside are novel serologic 153. Azad Khan A, Piris J, Truelove S. An experiment to
markers in Crohn’s disease. Gastroenterology 2006; determine the active therapeutic moiety of sulphasalazine.
131:366-78. Lancet 1977; 2:892-5.
132. Joossens S, Reinisch W, Vermeire S, et al. The value of 154. Summers R, Switz D, Sessions JTJ, et al. National
serologic markers in indeterminate colitis: A prospective Cooperative Crohn’s Disease Study: Results of drug
follow-up study. Gastroenterology 2002; 122:1242-7. treatment. Gastroenterology 1979; 77:847-69.

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   2022.e5

155. Ford AC, Kane SV, Khan KJ, et al. Efficacy of A randomised, double-blind, placebo controlled trial
5-aminosalicylates in Crohn’s disease: Systematic (ADAFI). Gut 2013 Mar 23. [Epub Ahead of Print].
review and meta-analysis. Am J Gastroenterol 2011; 173. West R, van der Woude C, Hansen B, et al. Clinical and
106:617-29. endosonographic effect of ciprofloxacin on the treatment of
156. Malchow H, Ewe K, Brandes J, et al. European Cooperative perianal fistulae in Crohn’s disease with infliximab: A
Crohn’s Disease Study (ECCDS): Results of drug treatment. double-blind placebo-controlled study. Aliment Pharmacol
Gastroenterology 1984; 86:249-66. Ther 2004; 20:1329-36.
157. Rasmussen S, Lauritsen K, Tage-Jensen U, et al. 174. Colombel J, Lemann M, Cassagnou M, et al. A controlled
5-Aminosalicylic acid in the treatment of Crohn’s trial comparing ciprofloxacin with mesalazine for the
disease. A 16-week double-blind, placebo-controlled, treatment of active Crohn’s disease. Groupe d’Etudes
multicentre study with Pentasa. Scand J Gastroenterol Thérapeutiques des Affections Inflammatoires Digestives
1987; 22:877-83. (GETAID). Am J Gastroenterol 1999; 94:674-8.
158. Mahida Y, Jewell D. Slow-release 5-amino-salicylic acid 175. Arnold GL, Beaves MR, Pryjdun VO, et al. Preliminary
(Pentasa) for the treatment of active Crohn’s disease. study of ciprofloxacin in active Crohn’s disease. Inflamm
Digestion 1990; 45:88-92. Bowel Dis 2002; 8:10-5.
159. Singleton J, Hanauer S, Gitnick G, et al. Mesalamine 176. Prantera C, Zannoni F, Scribano M, et al. An antibiotic
capsules for the treatment of active Crohn’s disease: Results regimen for the treatment of active Crohn’s disease: A
of a 16-week trial. Pentasa Crohn’s Disease Study Group. randomized, controlled clinical trial of metronidazole plus
Gastroenterology 1993; 104:1293-301. ciprofloxacin. Am J Gastroenterol 1996; 91:328-32.
160. Hanauer S, Stromberg U. Oral Pentasa in the treatment of 177. Steinhart A, Feagan B, Wong C, et al. Combined
active Crohn’s disease: A meta-analysis of double-blind, budesonide and antibiotic therapy for active Crohn’s
placebo-controlled trials. Clin Gastroenterol Hepatol 2004; disease: A randomized controlled trial. Gastroenterology
2:379-88. 2002; 123:33-40.
161. Akobeng A, Gardener E. Oral 5-aminosalicylic acid for 178. Leiper K, Morris A, Rhodes J. Open label trial of oral
maintenance of medically-induced remission in Crohn’s clarithromycin in active Crohn’s disease. Aliment
Disease. Cochrane Database Syst Rev 2005:CD003715. Pharmacol Ther 2000; 14:801-6.
162. Sandborn W, Feagan B, Lichtenstein G. Medical 179. Leiper K, Martin K, Ellis A, et al. Clinical trial: Randomized
management of mild to moderate Crohn’s disease: study of clarithromycin versus placebo in active Crohn’s
Evidence-based treatment algorithms for induction and disease. Aliment Pharmacol Ther 2008; 27:1233-9.
maintenance of remission. Aliment Pharmacol Ther 2007; 180. Selby W, Pavli P, Crotty B, et al. Two-year combination
26:987-1003. antibiotic therapy with clarithromycin, rifabutin, and
163. Lichtenstein GR, Hanauer SB, Sandborn WJ, et al. clofazimine for Crohn’s disease. Gastroenterology 2007;
Management of Crohn’s disease in adults. Am J 132:2313-19.
Gastroenterol 2009; 104:465-83; quiz 4, 84. 181. Prantera C, Lochs H, Campieri M, et al. Antibiotic
164. Duchmann R, May E, Heike M, et al. T cell specificity and treatment of Crohn’s disease: Results of a multicentre,
cross reactivity towards enterobacteria, Bacteroides, double blind, randomized, placebo-controlled trial with
Bifidobacterium, and antigens from resident intestinal flora rifaximin. Aliment Pharmacol Ther 2006; 23:1117-25.
in humans. Gut 1999; 44:812-8. 182. Prantera C, Lochs H, Grimaldi M, et al. Rifaximin-extended
165. Rutgeerts P, Hiele M, Geboes K, et al. Controlled trial of intestinal release induces remission in patients with
metronidazole treatment for prevention of Crohn’s moderately active Crohn’s disease. Gastroenterology 2012;
recurrence after ileal resection. Gastroenterology 1995; 142:473-81 e4.
108:1617-21. 183. Munkholm P, Langholz E, Davidsen M, et al. Frequency of
166. Rutgeerts P, Van Assche G, Vermeire S, et al. Ornidazole glucocorticoid resistance and dependency in Crohn’s
for prophylaxis of postoperative Crohn’s disease disease. Gut 1994; 35:360-2.
recurrence: A randomized, double-blind, placebo-controlled 184. Modigliani R, Mary J, Simon J, et al. Evolution on
trial. Gastroenterology 2005; 128:856-61. prednisolone. Groupe d’Etude Thérapeutique des
167. Doherty GA, Bennett GC, Cheifetz AS, et al. Meta-analysis: Affections Inflammatoires Digestives. Gastroenterology
Targeting the intestinal microbiota in prophylaxis for 1990; 98:811-18.
post-operative Crohn’s disease. Aliment Pharmacol Ther 185. Benchimol EI, Seow CH, Steinhart AH, et al. Traditional
2010; 31:802-9. corticosteroids for induction of remission in Crohn’s
168. Brandt L, Bernstein L, Boley S, et al. Metronidazole therapy disease. Cochrane Database Syst Rev 2008; 2:CD006792.
for perineal Crohn’s disease: A follow-up study. 186. Shepherd H, Barr G, Jewell D. Use of an intravenous
Gastroenterology 1982; 83:383-7. steroid regimen in the treatment of acute Crohn’s disease.
169. Sutherland L, Singleton J, Sessions J, et al. Double blind, J Clin Gastroenterol 1986; 8:154-9.
placebo controlled trial of metronidazole in Crohn’s 187. Bossa F, Fiorella S, Caruso N, et al. Continuous infusion
disease. Gut 1991; 32:1071-5. versus bolus administration of steroids in severe attacks of
170. Ursing B, Alm T, Barany F, et al. A comparative study of ulcerative colitis: A randomized, double-blind trial. Am J
metronidazole and sulfasalazine for active Crohn’s disease: Gastroenterol 2007; 102:601-8.
The cooperative Crohn’s disease study in Sweden. II. 188. Stuck A, Minder C, Frey F. Risk of infectious complications
Result. Gastroenterology 1982; 83:550-62. in patients taking glucocorticosteroids. Rev Infect Dis 1989;
171. Thia K, Mahadevan U, Feagan B, et al. Ciprofloxacin or 11:954-63.
metronidazole for the treatment of perianal fistulas in 189. Lewis J, Gelfand J, Troxel A, et al. Immunosuppressant
patients with Crohn’s disease: A randomized, double-blind, medications and mortality in inflammatory bowel disease.
placebo-controlled pilot study. Inflamm Bowel Dis 2009; Am J Gastroenterol 2008; 103:1428-35.
15:17-24. 190. Lichtenstein G, Feagan B, Cohen R, et al. Serious infections
172. Dewint P, Hansen BE, Verhey E, et al. Adalimumab and mortality in association with therapies for Crohn’s
combined with ciprofloxacin is superior to adalimumab disease: TREAT registry. Clin Gastroenterol Hepatol 2006;
monotherapy in perianal fistula closure in Crohn’s disease: 4:621-30.

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
2022.e6   Section X  Small and Large Intestine

191. Toruner M, Loftus EV Jr, Harmsen WS, et al. Risk factors 211. Doherty G, Bennett G, Patil S, et al. Interventions for
for opportunistic infections in patients with inflammatory prevention of post-operative recurrence of Crohn’s disease.
bowel disease. Gastroenterology 2008; 134:929-36. Cochrane Database Syst Rev 2009; CD006873.
192. Steinhart AH, Ewe K, Griffiths AM, et al. Corticosteroids 212. Ansari A, Arenas M, Greenfield SM, et al. Prospective
for maintenance of remission in Crohn’s disease. Cochrane evaluation of the pharmacogenetics of azathioprine in the
Database Syst Rev 2003:CD000301. treatment of inflammatory bowel disease. Aliment
193. Faubion WAJ, Loftus EV Jr, Harmsen W, et al. The natural Pharmacol Ther 2008; 28:973-83.
history of corticosteroid therapy for inflammatory bowel 213. Gearry RB, Barclay ML. Azathioprine and
disease: A population-based study. Gastroenterology 2001; 6-mercaptopurine pharmacogenetics and metabolite
121:255-60. monitoring in inflammatory bowel disease. J Gastroenterol
194. Tung J, Loftus EV Jr, Freese DK, et al. A population-based Hepatol 2005; 20:1149-57.
study of the frequency of corticosteroid resistance and 214. Sandborn W, Tremaine W, Wolf D, et al. Lack of effect of
dependence in pediatric patients with Crohn’s disease intravenous administration on time to respond to
and ulcerative colitis. Inflamm Bowel Dis 2006; azathioprine for steroid-treated Crohn’s disease. North
12:1093-100. American Azathioprine Study Group. Gastroenterology
195. Franchimont D, Louis E, Croes F, et al. Clinical pattern of 1999; 117:527-35.
corticosteroid dependent Crohn’s disease. Eur J 215. Pozler O, Chladek J, Maly J, et al. Steady-state of
Gastroenterol Hepatol 1998; 10:821-5. azathioprine during initiation treatment of pediatric
196. Farrell R, Murphy A, Long A, et al. High multidrug inflammatory bowel disease. J Crohns Colitis 2010; 4:623-8.
resistance (P-glycoprotein 170) expression in inflammatory 216. Osterman M, Kundu R, Lichtenstein G, et al. Association of
bowel disease patients who fail medical therapy. 6-thioguanine nucleotide levels and inflammatory bowel
Gastroenterology 2000; 118:279-88. disease activity: A meta-analysis. Gastroenterology 2006;
197. Krupoves A, Mack D, Seidman E, et al. Associations 130:1047-53.
between variants in the ABCB1 (MDR1) gene and 217. Colonna T, Korelitz B. The role of leukopenia in the
corticosteroid dependence in children with Crohn’s disease. 6-mercaptopurine–induced remission of refractory Crohn’s
Inflamm Bowel Dis 2011 Nov; 17:2308-17. disease. Am J Gastroenterol 1994; 89:362-6.
198. Mingrone G, DeGaetano A, Pugeat M, et al. The steroid 218. Dubinsky M, Yang H, Hassard P, et al. 6-MP metabolite
resistance of Crohn’s disease. J Investig Med 1999; profiles provide a biochemical explanation for 6-MP
47:319-25. resistance in patients with inflammatory bowel disease.
199. Seow C, Benchimol E, Griffiths A, et al. Budesonide for Gastroenterology 2002; 122:904-15.
induction of remission in Crohn’s disease. Cochrane 219. Sparrow M, Hande S, Friedman S, et al. Effect of
Database Syst Rev 2008; CD000296. allopurinol on clinical outcomes in inflammatory
200. Greenberg G, Feagan B, Martin F, et al. Oral budesonide bowel disease nonresponders to azathioprine or
for active Crohn’s disease. Canadian Inflammatory Bowel 6-mercaptopurine. Clin Gastroenterol Hepatol 2007;
Disease Study Group. N Engl J Med 1994; 331:836-41. 5:209-14.
201. de Jong D, Bac D, Tan G, et al. Maintenance treatment with 220. Hoentjen F, Seinen ML, Hanauer SB, et al. Safety and
budesonide 6 mg versus 9 mg once daily in patients with effectiveness of long-term allopurinol-thiopurine
Crohn’s disease in remission. Neth J Med 2007; 65:339-45. maintenance treatment in inflammatory bowel disease.
202. Ford AC, Bernstein CN, Khan KJ, et al. Glucocorticosteroid Inflamm Bowel Dis 2013; 19:363-9.
therapy in inflammatory bowel disease: Systematic review 221. Chaparro M, Ordas I, Cabre E, et al. Safety of thiopurine
and meta-analysis. Am J Gastroenterol 2011; 106:590-9; quiz therapy in inflammatory bowel disease: Long-term
600. follow-up study of 3931 patients. Inflamm Bowel Dis 2013;
203. Cortot A, Colombel J, Rutgeerts P, et al. Switch from 19:1404-10.
systemic steroids to budesonide in steroid dependent 222. Gisbert JP, Gonzalez-Lama Y, Mate J. Thiopurine-induced
patients with inactive Crohn’s disease. Gut 2001; 48:186-90. liver injury in patients with inflammatory bowel disease: A
204. Brooke B, Hoffmann D, Swarbrick E. Azathioprine for systematic review. Am J Gastroenterol 2007; 102:1518-27.
Crohn’s disease. Lancet 1969; 2:612-4. 223. Connell W, Kamm M, Ritchie J, et al. Bone marrow toxicity
205. Chande N, Tsoulis DJ, MacDonald JK. Azathioprine or caused by azathioprine in inflammatory bowel disease: 27
6-mercaptopurine for induction of remission in Crohn’s years of experience. Gut 1993; 34:1081-5.
disease. Cochrane Database Syst Rev 2013; 4:CD000545. 224. Gisbert JP, Gomollon F. Thiopurine-induced myelotoxicity
206. Prefontaine E, Sutherland LR, Macdonald JK, et al. in patients with inflammatory bowel disease: A review.
Azathioprine or 6-mercaptopurine for maintenance of Am J Gastroenterol 2008; 103:1783-800.
remission in Crohn’s disease. Cochrane Database Syst Rev 225. Kandiel A, Fraser A, Korelitz B, et al. Increased risk of
2009; CD000067. lymphoma among inflammatory bowel disease patients
207. D’Haens G, Geboes K, Ponette E, et al. Healing of severe treated with azathioprine and 6-mercaptopurine. Gut 2005;
recurrent ileitis with azathioprine therapy in patients with 54:1121-5.
Crohn’s disease. Gastroenterology 1997; 112:1475-81. 226. Beaugerie L, Brousse N, Bouvier AM, et al.
208. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, Lymphoproliferative disorders in patients receiving
azathioprine, or combination therapy for Crohn’s disease. thiopurines for inflammatory bowel disease: A prospective
N Engl J Med 2010; 362:1383-95. observational cohort study. Lancet 2009; 374:1617-25.
209. Markowitz J, Grancher K, Kohn N, et al. A multicenter trial 227. Peyrin-Biroulet L, Khosrotehrani K, Carrat F, et al.
of 6-mercaptopurine and prednisone in children with Increased risk for nonmelanoma skin cancers in patients
newly diagnosed Crohn’s disease. Gastroenterology 2000; who receive thiopurines for inflammatory bowel disease.
119:895-902. Gastroenterology 2011; 141:1621-28 e1-5.
210. Panes J, Lopez-Sanroman A, Bermejo F, et al. Early 228. Peyrin-Biroulet L, Chevaux JB, Bouvier AM, et al. Risk of
azathioprine therapy is no more effective than placebo for melanoma in patients who receive thiopurines for
newly diagnosed Crohn’s disease. Gastroenterology 2013. inflammatory bowel disease is not increased. Am J
[Epub Ahead of Print]. Gastroenterol 2012; 107:1443-4.

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   2022.e7

229. Mason M, Siegel CA. Do inflammatory bowel disease randomized controlled trial. Inflamm Bowel Dis 2007;
therapies cause cancer? Inflamm Bowel Dis 2013; 13:245-53.
19:1306-21. 249. Rice SA, Woo PN, El-Omar E, et al. Topical tacrolimus 0.1%
230. Lemann M, Mary J, Colombel J, et al. A randomized, ointment for treatment of cutaneous Crohn’s Disease. BMC
double-blind, controlled withdrawal trial in Crohn’s Res Notes 2013; 6:19.
disease patients in long-term remission on azathioprine. 250. Ng SC, Chan FK, Sung JJ. Review article: The role of
Gastroenterology 2005; 128:1812-18. non-biological drugs in refractory inflammatory bowel
231. Feagan B, Rochon J, Fedorak R, et al. Methotrexate for the disease. Aliment Pharmacol Ther 2011; 33:417-27.
treatment of Crohn’s disease. The North American Crohn’s 251. Mansfield J, Parkes M, Hawthorne A, et al. A randomized,
Study Group Investigators. N Engl J Med 1995; 332:292-7. double-blind, placebo-controlled trial of lenalidomide in
232. Feagan B, Fedorak R, Irvine E, et al. A comparison of the treatment of moderately severe active Crohn’s disease.
methotrexate with placebo for the maintenance of Aliment Pharmacol Ther 2007; 26:421-30.
remission in Crohn’s disease. North American Crohn’s 252. Derkx B, Taminiau J, Radema S, et al. Tumour-necrosis-
Study Group Investigators. N Engl J Med 2000; 342:1627-32. factor antibody treatment in Crohn’s disease. Lancet 1993;
233. Brooks P, Spruill W, Parish R, et al. Pharmacokinetics of 342:173-4.
methotrexate administered by intramuscular and 253. van Dullemen H, van Deventer S, Hommes D, et al.
subcutaneous injections in patients with rheumatoid Treatment of Crohn’s disease with anti–tumor necrosis
arthritis. Arthritis Rheum 1990; 33:91-4. factor chimeric monoclonal antibody (cA2).
234. Jundt J, Browne B, Fiocco G, et al. A comparison of low Gastroenterology 1995; 109:129-35.
dose methotrexate bioavailability: Oral solution, oral tablet, 254. Baert F, D’Haens G, Peeters M, et al. Tumor necrosis factor
subcutaneous and intramuscular dosing. J Rheumatol 1993; alpha antibody (infliximab) therapy profoundly down-
20:1845-9. regulates the inflammation in Crohn’s ileocolitis.
235. McDonald JW, Tsoulis DJ, Macdonald JK, et al. Gastroenterology 1999; 116:22-8.
Methotrexate for induction of remission in refractory 255. Targan S, Hanauer S, van Deventer S, et al. A short-term
Crohn’s disease. Cochrane Database Syst Rev 2012; study of chimeric monoclonal antibody cA2 to tumor
12:CD003459. necrosis factor alpha for Crohn’s disease. Crohn’s
236. Kurnik D, Loebstein R, Fishbein E, et al. Bioavailability of Disease cA2 Study Group. N Engl J Med 1997;
oral vs. subcutaneous low-dose methotrexate in patients 337:1029-35.
with Crohn’s disease. Aliment Pharmacol Ther 2003; 256. Hanauer S, Feagan B, Lichtenstein G, et al. Maintenance
18:57-63. infliximab for Crohn’s disease: The ACCENT I randomised
237. Te H, Schiano T, Kuan S, et al. Hepatic effects of long-term trial. Lancet 2002; 359:1541-9.
methotrexate use in the treatment of inflammatory bowel 257. Sands B, Anderson F, Bernstein C, et al. Infliximab
disease. Am J Gastroenterol 2000; 95:3150-6. maintenance therapy for fistulizing Crohn’s disease. N Engl
238. Morris L, Harrod M, Menter M, et al. Methotrexate and J Med 2004; 350:876-85.
reproduction in men: Case report and recommendations. 258. Sandborn W, Hanauer S, Loftus EVJ, et al. An open-label
J Am Acad Dermatol 1993; 29:913-16. study of the human anti-TNF monoclonal antibody
239. Mack D, Young R, Kaufman S, et al. Methotrexate in adalimumab in subjects with prior loss of response or
patients with Crohn’s disease after 6-mercaptopurine. intolerance to infliximab for Crohn’s disease. Am J
J Pediatr 1998; 132:830-5. Gastroenterol 2004; 99:1984-9.
240. Lemann M, Chamiot-Prieur C, Mesnard B, et al. 259. Hanauer S, Sandborn W, Rutgeerts P, et al. Human
Methotrexate for the treatment of refractory Crohn’s anti–tumor necrosis factor monoclonal antibody
disease. Aliment Pharmacol Ther 1996; 10:309-14. (adalimumab) in Crohn’s disease: The CLASSIC-I trial.
241. McDonald JW, Feagan BG, Jewell D, et al. Cyclosporine for Gastroenterology 2006; 130:323-33.
induction of remission in Crohn’s disease. Cochrane 260. Colombel J, Sandborn W, Rutgeerts P, et al. Adalimumab
Database Syst Rev 2005:CD000297. for maintenance of clinical response and remission in
242. Feagan B, McDonald J, Rochon J, et al. Low-dose patients with Crohn’s disease: The CHARM trial.
cyclosporine for the treatment of Crohn’s disease. The Gastroenterology. 2007; 132:52-65.
Canadian Crohn’s Relapse Prevention Trial Investigators. 261. Winter T, Wright J, Ghosh S, et al. Intravenous CDP870, a
N Engl J Med 1994; 330:1846-51. PEGylated Fab’ fragment of a humanized antitumour
243. Lazarev M, Present DH, Lichtiger S, et al. The effect of necrosis factor antibody, in patients with moderate to
intravenous cyclosporine on rates of colonic surgery in severe Crohn’s disease: An exploratory study. Aliment
hospitalized patients with severe Crohn’s colitis. J Clin Pharmacol Ther 2004; 20:1337-46.
Gastroenterol 2012; 46:764-7. 262. Schreiber S, Rutgeerts P, Fedorak R, et al. A randomized,
244. Gerber D, Bonham C, Thomson A. Immunosuppressive placebo-controlled trial of certolizumab pegol (CDP870) for
agents: Recent developments in molecular action and treatment of Crohn’s disease. Gastroenterology 2005;
clinical application. Transplant Proc 1998; 30:1573-9. 129:807-18.
245. Sandborn W, Present D, Isaacs K, et al. Tacrolimus for the 263. Sandborn W, Feagan B, Stoinov S, et al. Certolizumab pegol
treatment of fistulas in patients with Crohn’s disease: A for the treatment of Crohn’s disease. N Engl J Med 2007;
randomized, placebo-controlled trial. Gastroenterology 357:228-38.
2003; 125:380-8. 264. Schreiber S, Khaliq-Kareemi M, Lawrance I, et al.
246. McSharry K, Dalzell AM, Leiper K, et al. Systematic review: Maintenance therapy with certolizumab pegol for Crohn’s
The role of tacrolimus in the management of Crohn’s disease. N Engl J Med 2007; 357:239-50.
disease. Aliment Pharmacol Ther 2011; 34:1282-94. 265. Behm BW, Bickston SJ. Tumor necrosis factor-alpha
247. Casson D, Eltumi M, Tomlin S, et al. Topical tacrolimus antibody for maintenance of remission in Crohn’s disease.
may be effective in the treatment of oral and perineal Cochrane Database Syst Rev 2008; CD006893.
Crohn’s disease. Gut 2000; 47:436-40. 266. Sandborn W, Feagan B, Radford-Smith G, et al. CDP571, a
248. Hart A, Plamondon S, Kamm M. Topical tacrolimus in the humanised monoclonal antibody to tumour necrosis factor
treatment of perianal Crohn’s disease: Exploratory alpha, for moderate to severe Crohn’s disease: A

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
2022.e8   Section X  Small and Large Intestine

randomised, double blind, placebo controlled trial. Gut patients with inflammatory bowel disease. Am J
2004; 53:1485-93. Gastroenterol 2013; 108:433-40.
267. Sandborn W, Hanauer S, Katz S, et al. Etanercept for active 285. Regueiro M, Siemanowski B, Kip K, et al. Infliximab dose
Crohn’s disease: A randomized, double-blind, placebo- intensification in Crohn’s disease. Inflamm Bowel Dis 2007;
controlled trial. Gastroenterology 2001; 121:1088-94. 13:1093-9.
268. Van den Brande J, Braat H, van den Brink G, et al. 286. Lichtenstein G, Mitchev K, D’Haens G. Re-induction with
Infliximab but not etanercept induces apoptosis in lamina certolizumab pegol following disease exacerbation during
propria T-lymphocytes from patients with Crohn’s disease. maintenance therapy is effective to regain response and
Gastroenterology 2003; 124:1774-85. remission. Gastroenterology 2008; 134:A-488.
269. Hanauer S, Rutgeerts P, D’Haens G, et al. Delayed 287. Triantafillidis JK, Mantzaris G, Karagiannis J, Papet AL.
hypersensitivity to infliximab (Remicade) re-infusion after Similar response to adalimumab in patients with active
2-4 year interval without treatment. Gastroenterology 1999; Crohn’s disease either naive to biologic agents or with
116:A731. prior loss of response or intolerance to infliximab. Rev Med
270. Nesbitt A, Fossati G, Bergin M, et al. Mechanism of action Chir Soc Med Nat Iasi 2010; 114:85-90.
of certolizumab pegol (CDP870): In vitro comparison with 288. Feagan B, McDonald J, Panaccione R, et al. A randomized
other anti–tumor necrosis factor alpha agents. Inflamm trial of methotrexate in combination with infliximab for the
Bowel Dis 2007; 13:1323-32. treatment of Crohn’s disease. Gastroenterology 2008;
271. Sandborn W, Hanauer S, Rutgeerts P, et al. Adalimumab 135:294-5.
for maintenance treatment of Crohn’s disease: Results of 289. Jones JL, Kaplan GG, Peyrin-Biroulet L, et al. Impact of
the CLASSIC II trial. Gut 2007; 56:1232-9. concomitant immunomodulator treatment on efficacy and
272. Clark M, Colombel JF, Feagan BC, et al. American safety of anti-TNF therapy in Crohn’s disease: A meta-
Gastroenterological Association consensus development analysis of placebo controlled trials with individual
conference on the use of biologics in the treatment of patient-level data. A-Tu979, presented at DDW, May 21,
inflammatory bowel disease, June 21-23, 2006. 2013.
Gastroenterology 2007; 133:312-39. 290. Melmed GY, Spiegel BM, Bressler B, et al. The
273. Miehsler W, Novacek G, Wenzl H, et al. A decade of appropriateness of concomitant immunomodulators with
infliximab: The Austrian evidence based consensus on anti-tumor necrosis factor agents for Crohn’s disease: One
the safe use of infliximab in inflammatory bowel disease. size does not fit all. Clin Gastroenterol Hepatol 2010;
J Crohns Colitis 2010; 4:221-56. 8:655-9.
274. Moss AC, Fernandez-Becker N, Jo Kim K, et al. The impact 291. D’Haens G, Baert F, van Assche G, et al. Early combined
of infliximab infusion reactions on long-term outcomes in immunosuppression or conventional management in
patients with Crohn’s disease. Aliment Pharmacol Ther patients with newly diagnosed Crohn’s disease: An open
2008; 28:221-7. randomised trial. Lancet 2008; 371:660-7.
275. Bartelds G, Wijbrandts C, Nurmohamed M, et al. Clinical 292. Fasci Spurio F, Aratari A, Margagnoni G, et al. Early
response to adalimumab: Relationship to anti-adalimumab treatment in Crohn’s disease: Do we have enough evidence
antibodies and serum adalimumab concentrations in to reverse the therapeutic pyramid? J Gastrointest Liver Dis
rheumatoid arthritis. Ann Rheum Dis 2007; 66:921-6. 2012; 21:67-73.
276. Vermeire S, Noman M, Van Assche G, et al. Effectiveness 293. Ordas I, Feagan BG, Sandborn WJ. Therapeutic drug
of concomitant immunosuppressive therapy in suppressing monitoring of tumor necrosis factor antagonists in
the formation of antibodies to infliximab in Crohn’s inflammatory bowel disease. Clin Gastroenterol Hepatol
disease. Gut 2007; 56:1226-31. 2012; 10:1079-87; quiz e85-6.
277. West R, Zelinkova Z, Wolbink G, et al. Immunogenicity 294. Afif W, Loftus EV Jr, Faubion WA, et al. Clinical utility of
negatively influences the outcome of adalimumab measuring infliximab and human anti-chimeric antibody
treatment in Crohn’s disease. Aliment Pharmacol Ther concentrations in patients with inflammatory bowel
2008; 28:1122-6. disease. Am J Gastroenterol 2010; 105:1133-9.
278. Siegel C, Hur C, Korzenik J, et al. Risks and benefits of 295. Vande Casteele N, Gils A, Singh S, et al. Antibody response
infliximab for the treatment of Crohn’s disease. Clin to infliximab and its impact on pharmacokinetics can be
Gastroenterol Hepatol 2006; 4:1017-24. transient. Am J Gastroenterol 2013; 108:962-71.
279. Toruner M, Loftus EVJ, Harmsen W, et al. Risk factors for 296. Van Assche G, Van Ranst M, Sciot R, et al. Progressive
opportunistic infections in patients with inflammatory multifocal leukoencephalopathy after natalizumab therapy
bowel disease. Gastroenterology 2008; 134:929-36. for Crohn’s disease. N Engl J Med 2005; 353:362-8.
280. Ford AC, Peyrin-Biroulet L. Opportunistic infections with 297. Sands B, Francis G, Belcher G, et al. The Touch program
anti-tumor necrosis factor-alpha therapy in inflammatory and risk management plan for the administration of
bowel disease: Meta-analysis of randomized controlled natalizumab: Lessons and updated safety results from the
trials. Am J Gastroenterol 2013; 108:1268-76. use of natalizumab in patients with relapsing multiple
281. Siegel C, Marden S, Persing S, et al. Risk of lymphoma sclerosis and implications for potential use in Crohn’s
associated with anti-TNF agents for the treatment of disease. Gastroenterology 2008; 134:Abstract S1232.
Crohn’s disease: A meta-analysis. Gastroenterology 2008; 298. Bloomgren G, Richman S, Hotermans C, et al. Risk of
134:A14. natalizumab-associated progressive multifocal
282. Rosh J, Oliva-Hemker M. Infliximab use and hepatosplenic leukoencephalopathy. N Engl J Med 2012; 366:1870-80.
T cell lymphoma: Questions to be asked and lessons 299. Natalizumab (Tysabri) for Crohn’s disease. Med Lett Drugs
learned. J Pediatr Gastroenterol Nutr 2007; 44:165-7. Ther 2008; 50:34-6.
283. Mahadevan U, Wolf DC, Dubinsky M, et al. Placental 300. Lawrance IC, Murray K, Batman B, et al. Crohn’s disease
transfer of anti-tumor necrosis factor agents in pregnant and smoking: Is it ever too late to quit? J Crohns Colitis
patients with inflammatory bowel disease. Clin 2013. [Epub Ahead of Print].
Gastroenterol Hepatol 2013; 11:286-92; quiz e24. 301. Lichtenstein GR, Sands BE, Pazianas M. Prevention and
284. Casanova MJ, Chaparro M, Domenech E, et al. Safety of treatment of osteoporosis in inflammatory bowel disease.
thiopurines and anti-TNF-alpha drugs during pregnancy in Inflamm Bowel Dis 2006; 12:797-813.

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 115  Crohn’s Disease   2022.e9

302. Klaus J, Haenle MM, Schroter C, et al. A single dose of Crohn’s disease? A Markov analysis Dis Colon Rectum
intravenous zoledronate prevents glucocorticoid therapy- 2004; 47:2120-30.
associated bone loss in acute flare of Crohn’s disease, a 321. Joyce MR, Fazio VW. Can ileal pouch anal anastomosis be
randomized controlled trial. Am J Gastroenterol 2011; used in Crohn’s disease? Adv Surg 2009; 43:111-37.
106:786-93. 322. Le Q, Melmed G, Dubinsky M, et al. Surgical outcome of
303. Yang L, Weaver V, Smith JP, et al. Therapeutic effect of ileal pouch-anal anastomosis when used intentionally for
vitamin D supplementation in a pilot study of Crohn’s well-defined Crohn’s disease. Inflamm Bowel Dis 2013;
patients. Clin Transl Gastroenterol 2013; 4:e33. 19:30-6.
304. Sandborn W, Feagan B, Fedorak R, et al. A randomized 323. Spinelli A, Bazzi P, Sacchi M, et al. Short-term outcomes of
trial of ustekinumab, a human interleukin-12/23 laparoscopy combined with enhanced recovery pathway
monoclonal antibody, in patients with moderate to after ileocecal resection for Crohn’s disease: A case-
severe Crohn’s disease. Gastroenterology 2008; matched analysis. J Gastrointest Surg 2013; 17:126-32;
135:1130-41. discussion p 32.
305. Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab 324. Maartense S, Dunker M, Slors J, et al. Laparoscopic-assisted
induction and maintenance therapy in refractory Crohn’s versus open ileocolic resection for Crohn’s disease: A
disease. N Engl J Med 2012; 367:1519-28. randomized trial. Ann Surg 2006; 243:143-9.
306. Sandborn W, Sands BE, Colombel JF, et al. Vedolizumab 325. Gardenbroek TJ, Tanis PJ, Buskens CJ, et al. Surgery for
induction therapy for Crohn’s disease: Results of GEMINI Crohn’s disease: New developments. Dig Surg 2012;
II, a randomized, placebo-controlled, double-blind, 29:275-80.
multicenter phase 3 trial. Am J Gastroenterol 2012; 326. Dasari BV, McKay D, Gardiner K. Laparoscopic versus
107:S624-5. open surgery for small bowel Crohn’s disease. Cochrane
307. Sandborn W, Sands BE, Colombel JF, et al. Vedolizumab Database Syst Rev 2011:CD006956.
maintenance therapy for Crohn’s disease: Results of 327. Gunnarsson C, Chen J, Rizzo JA, et al. Direct health care
GEMINI II, a randomized, placebo-controlled, double- insurer and out-of-pocket expenditures of inflammatory
blind, multicenter phase 3 trial. Am J Gastroenterol 2012; bowel disease: Evidence from a US national survey. Dig
107:S620. Dis Sci. 2012; 57:3080-91.
308. Shuai K, Liu B. Regulation of JAK-STAT signalling in the 328. Bernstein CN, Longobardi T, Finlayson G, et al. Direct
immune system. Nat Rev Immunol 2003; 3:900-11. medical cost of managing IBD patients: A Canadian
309. Sandborn W, Ghosh S, Panes J, et al. Phase 2 randomized population-based study. Inflamm Bowel Dis 2012;
study of CP-690,550, an oral Janus kinase inhibitor, in active 18:1498-508.
Crohn’s disease. Digestive Disease Week; 2011:Su795. 329. Tang DH, Armstrong EP, Lee JK. Cost-utility analysis of
310. Bousvaros A, Guandalini S, Baldassano R, et al. A biologic treatments for moderate to severe Crohn’s disease.
randomized, double-blind trial of Lactobacillus GG versus Pharmacotherapy 2012; 32:515-26.
placebo in addition to standard maintenance therapy for 330. Lindsay J, Punekar YS, Morris J, et al. Health-economic
children with Crohn’s disease. Inflamm Bowel Dis 2005; analysis: Cost-effectiveness of scheduled maintenance
11:833-9. treatment with infliximab for Crohn’s disease—Modelling
311. Van Gossum A, Dewit O, Louis E, et al. Multicenter outcomes in active luminal and fistulizing disease in adults.
randomized-controlled clinical trial of probiotics Aliment Pharmacol Ther 2008; 28:76-87.
(Lactobacillus johnsonii, LA1) on early endoscopic recurrence 331. Mahadevan U, Cucchiara S, Hyams JS, et al. The London
of Crohn’s disease after ileo-caecal resection. Inflamm Position Statement of the World Congress of
Bowel Dis 2007; 13:135-42. Gastroenterology on Biological Therapy for IBD with the
312. Summers R, Elliott D, Urban JFJ, et al. Trichuris suis therapy European Crohn’s and Colitis Organisation: pregnancy and
in Crohn’s disease. Gut 2005; 54:87-90. pediatrics. Am J Gastroenterol 2011; 106:214-23; quiz 24.
313. Zachos M, Tondeur M, Griffiths AM. Enteral nutritional 332. Korelitz B. Inflammatory bowel disease and pregnancy.
therapy for induction of remission in Crohn’s disease. Gastroenterol Clin North Am 1998; 27:213-24.
Cochrane Database Syst Rev 2007:CD000542. 333. Mahadevan U, Sandborn W, Li D, et al. Pregnancy
314. Dziechciarz P, Horvath A, Shamir R, et al. Meta-analysis: outcomes in women with inflammatory bowel disease: A
Enteral nutrition in active Crohn’s disease in children. large community-based study from Northern California.
Aliment Pharmacol Ther 2007; 26:795-806. Gastroenterology 2007; 133:1106-12.
315. Cohen AB, Lee D, Long MD, et al. Dietary patterns and 334. Norgard B, Hundborg H, Jacobsen B, et al. Disease activity
self-reported associations of diet with symptoms of in pregnant women with Crohn’s disease and birth
inflammatory bowel disease. Dig Dis Sci 2013; 58:1322-8. outcomes: A regional Danish cohort study. Am J
316. Yamamoto T, Nakahigashi M, Saniabadi AR. Review Gastroenterol 2007; 102:1947-54.
article: Diet and inflammatory bowel disease— 335. Ananthakrishnan A, McGinley E, Binion D. Inflammatory
Epidemiology and treatment. Aliment Pharmacol Ther bowel disease in the elderly is associated with worse
2009; 30:99-112. outcomes: A national study of hospitalizations. Inflamm
317. Wu GD, Chen J, Hoffmann C, et al. Linking long-term Bowel Dis 2009; 15:182-9.
dietary patterns with gut microbial enterotypes. Science 336. Ha CY, Katz S. Clinical outcomes and management of
2011; 334:105-8. inflammatory bowel disease in the older patient. Curr
318. Cosnes J, Gower-Rousseau C, Seksik P, et al. Epidemiology Gastroenterol Rep 2013; 15:310.
and natural history of inflammatory bowel diseases. 337. Moum B, Ekbom A, Vatn M, et al. Clinical course during
Gastroenterology 2011; 140:1785-94. the 1st year after diagnosis in ulcerative colitis and Crohn’s
319. Whelan G, Farmer R, Fazio V, et al. Recurrence after disease. Results of a large, prospective population-based
surgery in Crohn’s disease. Relationship to location of study in southeastern Norway, 1990-93. Scand J
disease (clinical pattern) and surgical indication. Gastroenterol 1997; 32:1005-12.
Gastroenterology 1985; 88:1826-33. 338. Munkholm P, Langholz E, Davidsen M, et al. Disease
320. Kennedy E, Urbach D, Krahn M, et al. Azathioprine or activity courses in a regional cohort of Crohn’s disease
ileocolic resection for steroid-dependent terminal ileal patients. Scand J Gastroenterol 1995; 30:699-706.

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
2022.e10   Section X  Small and Large Intestine

339. Dubinsky M, Kugathasan S, Mei L, et al. Increased immune 348. Hutfless S, Weng X, Liu L, et al. Mortality by
reactivity predicts aggressive complicating Crohn’s disease medication use among patients with inflammatory
in children. Clin Gastroenterol Hepatol 2008; 6:1105-11. bowel disease, 1996-2003. Gastroenterology 2007;
340. Arnott I, Landers C, Nimmo E, et al. Sero-reactivity to 133:1779-86.
microbial components in Crohn’s disease is associated with 349. Manninen P, Karvonen AL, Huhtala H, et al. Mortality
disease severity and progression, but not NOD2/CARD15 in ulcerative colitis and Crohn’s disease. A population-
genotype. Am J Gastroenterol 2004; 99:2376-84. based study in Finland. J Crohns Colitis 2012;
341. Dotan I. New serologic markers for inflammatory bowel 6:524-8.
disease diagnosis. Dig Dis 2010; 28:418-23. 350. Hovde O, Kempski-Monstad I, Smastuen MC, et al.
342. Seiderer J, Schnitzler F, Brand S, et al. Homozygosity for Mortality and causes of death in Crohn’s disease: Results
the CARD15 frameshift mutation 1007fs is predictive of from 20 years of follow-up in the IBSEN study. Gut 2013.
early onset of Crohn’s disease with ileal stenosis, entero- [Epub ahead of print].
enteral fistulas, and frequent need for surgical intervention 351. Romberg-Camps M, Kuiper E, Schouten L, et al. Mortality
with high risk of re-stenosis. Scand J Gastroenterol 2006; in inflammatory bowel disease in the Netherlands 1991-
41:1421-32. 2002: Results of a population-based study: The IBD
343. Siegel CA, Siegel LS, Hyams JS, et al. Real-time tool to South-Limburg cohort. Inflamm Bowel Dis 2010;
display the predicted disease course and treatment 16:1397-410.
response for children with Crohn’s disease. Inflamm Bowel 352. Bewtra M, Kaiser LM, TenHave T, et al. Crohn’s disease
Dis 2011; 17:30-8. and ulcerative colitis are associated with elevated
344. Lewis J, Deren J, Lichtenstein G. Cancer risk in patients standardized mortality ratios: A meta-analysis. Inflamm
with inflammatory bowel disease. Gastroenterol Clin North Bowel Dis 2013; 19:599-613.
Am 1999; 28:459-77, x. 353. Graff L, Walker J, Lix L, et al. The relationship of
345. Canavan C, Abrams KR, Mayberry J. Meta-analysis: inflammatory bowel disease type and activity to
Colorectal and small bowel cancer risk in patients with psychological functioning and quality of life. Clin
Crohn’s disease. Aliment Pharmacol Ther 2006; 23:1097-104. Gastroenterol Hepatol 2006; 4:1491-501.
346. Itzkowitz SH, Present DH, Crohn’s, et al. Consensus 354. Lix L, Graff L, Walker J, et al. Longitudinal study of quality
conference: Colorectal cancer screening and surveillance in of life and psychological functioning for active, fluctuating,
inflammatory bowel disease. Inflamm Bowel Dis 2005; and inactive disease patterns in inflammatory bowel
11:314-21. disease. Inflamm Bowel Dis 2008; 14:1575-84.
347. Persson P, Karlen P, Bernell O, et al. Crohn’s disease and 355. Casati J, Toner B, de Rooy E, et al. Concerns of patients
cancer: A population-based cohort study. Gastroenterology with inflammatory bowel disease: A review of emerging
1994; 107:1675-9. themes. Dig Dis Sci 2000; 45:26-31.

Downloaded for Stanislaus Hatta Alinudinputra (stanislaushatta@yahoo.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on December 11, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.