Crohn's Disease - 2020 - Roda Et Al

PRIMER
Crohn’s disease
Giulia Roda1, Siew Chien Ng2, Paulo Gustavo Kotze3, Marjorie Argollo1, Remo Panaccione4,
Antonino Spinelli5,6, Arthur Kaser7, Laurent Peyrin-Biroulet8 and Silvio Danese1,6 ✉
Abstract | Crohn’s disease is an inflammatory bowel disease that is characterized by chronic
inflammation of any part of the gastrointestinal tract, has a progressive and destructive course
and is increasing in incidence worldwide. Several factors have been implicated in the cause
of Crohn’s disease, including a dysregulated immune system, an altered microbiota, genetic
susceptibility and environmental factors, but the cause of the disease remains unknown.
The onset of the disease at a young age in most cases necessitates prompt but long-term treatment
to prevent disease flares and disease progression with intestinal complications. Thus, earlier,
more aggressive treatment with biologic therapies or novel small molecules could profoundly
change the natural history of the disease and decrease complications and the need for
hospitalization and surgery. Although less invasive biomarkers are in development, diagnosis
still relies on endoscopy and histological assessment of biopsy specimens. Crohn’s disease is a
complex disease, and treatment should be personalized to address the underlying pathogenetic
mechanism. In the future, disease management might rely on severity scores that incorporate
prognostic factors, bowel damage assessment and non-invasive close monitoring of disease
activity to reduce the severity of complications.
The global prevalence of inflammatory bowel disease bowel damage at diagnosis, and half of these patients
(IBD) has been increasing since 2000, and IBD now require surgery in the 20 years following the diagnosis3,4.
affects up to 1 in 200 individuals in Western countries1. CD most often presents in patients younger than
IBD encompasses two distinct disorders, Crohn’s dis- 30 years, although the incidence is increasing in older
ease (CD) and ulcerative colitis (UC), which differ in individuals. Higher incidence has been reported for
pathophysiology, affected parts of the gastrointestinal Ashkenazi Jews, urban populations and those in north-
(GI) tract, symptoms, complications, disease course ern latitudes, with a peak between the second decade
and management. The cause of CD is still unclear but and the fourth decade of life. Many studies have failed
genetic, immunological and environmental factors con- to find any sex difference in incidence in Western coun-
tribute to risk of disease onset and progression2. CD is tries, whereas the incidence of CD is higher in men than
characterized by skip intestinal lesions (that is, areas of in women in Asian populations5–10.
inflammation interposed between normal-appearing Currently, mucosal healing is the preferred treatment
mucosa) anywhere in the GI tract, and involves chronic, target, as patients who achieve mucosal healing have
relapsing transmural inflammation that can lead to improved outcomes, including decreased risk of surgery,
chronic abdominal pain, diarrhoea, obstruction and/or lower relapse rates and improved QOL11. In the past two
perianal lesions2. UC affects only the colon, the lesions decades, the use of anti-inflammatory treatments, such
are continuous and inflammation is superficial, which as anti-tumour necrosis factor (anti-TNF) therapy (for
can lead to erosions, ulcers and bloody diarrhoea. CD is example, infliximab, adalimumab and certolizumab),
progressive and destructive — 21–47% of patients also has transformed the management of CD. These drugs
present with systemic, extraintestinal manifestations are being used earlier in the disease course and are now
(EIMs), which strongly affect patients in a multitude of considered the therapy of choice, especially for patients
ways, such as their quality of life (QOL) and long-term at high risk of disease progression. Although these tar-
outcomes, including risk of hospitalization, compli- geted biologic therapies are a notable advance in the
cations and surgery2. Furthermore, half of all patients treatment of CD, the requirement for parenteral admin-
✉e-mail: sdanese@ with CD develop intestinal complications, such as istration and the potential for immunogenicity are major
hotmail.com strictures or fistulae, within 10 years of diagnosis. drawbacks. Other biologic therapies for CD include the
https://doi.org/10.1038/ Population-based cohort studies have demonstrated gut-selective monoclonal anti-integrin antibody vedol-
s41572-020-0156-2 that up to 30% of patients with CD have evidence of izumab and an antagonist of IL-12 and IL-23 signalling,
NATURE REvIEwS | DisEAsE PRimERs | Article citation ID: (2020) 6:22 1
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Author addresses The rapid changes in CD epidemiology are a global

challenge for disease diagnosis, health care delivery
1
IBD Center, Department of Gastroenterology, Humanitas Clinical and Research Center – and disease prevention. In newly industrialized coun-
IRCCS –, Rozzano, Italy. tries (such as in Asia), the increasing incidence of CD
2
Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Science, reflects the influence of the Western lifestyle, par-
Chinese University of Hong Kong, Hong Kong, China.
ticularly diet, urbanization and industrialization, on
3
Colorectal Surgery Unit, Catholic University of Paraná, Curitiba, Brazil.
4
Inflammatory Bowel Disease Unit, Division of Gastroenterology and Hepatology, risk19. Furthermore, studies of migrants have shown
University of Calgary, Calgary, Alberta, Canada. that individuals who move from low-prevalence to
5
Humanitas Clinical and Research Center – IRCCS –, Rozzano, Italy. high-prevalence regions are at increased risk of devel-
6
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy. oping CD and that this risk is even more pronounced in
7
Division of Gastroenterology and Hepatology, Department of Medicine, University of the children of immigrants1.
Cambridge, Addenbrooke’s Hospital, Cambridge, UK. The incidence of CD has surpassed that of UC in
8
Department of Gastroenterology, University Hospital of Nancy, Nancy, France. many regions in the West. IBD in children younger
than 10 years, and especially those younger than 5 years
ustekinumab, for induction therapy and maintaining (very early onset IBD) is becoming more common, and
remission in patients with moderate-to-severe CD2. elderly individuals (older than 65 years) with IBD are
The chronic, unpredictable nature of the disease a rapidly rising population owing to new diagnoses in
and its debilitating effect on all aspects of life are major elderly patients and advancing age of those in whom
concerns for patients with CD. Health-related QOL IBD is diagnosed earlier in adulthood1. Owing to a lack
(HRQOL), disease activity and disease-associated mor- of population-based prospective studies to compare CD
bidity will soon be included as measures of treatment prevalence and environmental and genetic risk factors
outcomes in CD in clinical practice12,13. Optimizing care, for the disease in developing countries with those in
improving QOL, early disease treatment and predicting developed countries, it is difficult to predict how this
bowel damage are milestones that need to be achieved increase in incidence will affect phenotypic features of
soon and will require a concerted research effort. CD in developing countries.
In this Primer, we review the epidemiology, patho-
physiology, diagnosis and management of CD and the Risk factors
effect of the disease and therapies on patient QOL. The risk of CD onset and progression is influenced by
environmental factors in a genetically susceptible host1,2
Epidemiology (Fig. 1).
Incidence and prevalence
The incidence of IBD differs by region, ranging from Environmental factors. In Western countries, smoking
0.1 to 58 cases per 100,000 person-years, with the high- has been identified as the only modifiable risk factor for
est incidence reported in North America, northern and CD and doubles the risk of developing CD, although
western Europe and Oceania1. The incidence of CD is to a greater extent among females and also dependent
0–20.2 cases per 100,000 person-years in North America on age. Smoking is also associated with early disease
and 0.3–12.7 cases per 100,000 person-years in Europe1. onset, need for immunosuppression, increased need
The highest reported prevalence of CD was in Europe for surgical intervention and higher rates of post
(322 cases per 100,000 persons in Germany) and North operative disease recurrence2. Several meta-analyses have
America (319 cases per 100,000 persons in Canada)1. described a difference in the effect of smoking on CD
Since the turn of the twenty-first century, IBD inci- risk among different ethnicities20. Of interest, in Japan,
dence has increased globally, with rapidly increasing passive smoking is also associated with increased risk of
incidence reported in newly industrialized countries in developing CD20–23.
Asia, Africa and South America1. In China, following Gut dysbiosis is a feature of CD, and diet is the most
urbanization, IBD went from being a rare condition to likely environmental factor (of those that have changed in
one that is common and accounts for substantial use the past decade) to affect the intestinal microbiota.
of hospital beds14. CD incidence follows a south-to- In particular, the host–gut microbiota relationship has
north and east-to-west gradient in mainland China6. been altered by changes in the composition of food
In Korea, studies reported an incidence of 1.68 cases and a move from high-fibre, low-fat foods to processed
per 100,000 person-years in 2005, after which it reached a foods that contain food additives24. Reduced dietary
plateau8,9. Moreover, the incidence of CD in Asia has incr fibre intake and frequent dietary oscillations between
eased more rapidly than that of UC5–8, although the pre high-f ibre and low-f ibre foods lead to reduced gut
valence of IBD is lower than in Western countries. The microbiota diversity and are associated with the develop-
prevalence of CD in Asian populations has also increased. ment of CD1,2. As diet has a transient effect on the micro-
For example, the prevalence of CD in Taiwan increased bial composition, the involvement of dietary changes in
from 0.6 cases per 100,000 persons in 2001 to 3.9 cases the altered microbial diversity in CD is still the subject
per 100,000 persons in 2015, and the prevalence of CD in of debate. In two prospective studies in Sweden, greater
Hong Kong in 2014 was 18.6 cases per 100,000 persons15,16. adherence to a Mediterranean diet was associated with
Few studies have reported CD epidemiology data for a substantially lower risk of later-onset CD25.
Latin America and Africa. In both regions, CD incidence Several studies have shown that the composition
and prevalence have been reported as low, although a few of the gut microbiota can change in response to diet24.
studies have reported a high incidence of CD in Brazil17,18. In addition, dietary components can have effects
2 | Article citation ID: (2020) 6:22 www.nature.com/nrdp
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Epithelial cell Insight into geographical variations, especially related

to diet and urbanization, and disease progression is
important to prepare the clinical infrastructure and
health care resources necessary to mitigate the burden
Bacteria Intestinal lumen of CD. As potentially relevant environmental factors
differ in different populations, selective intervention
for disease prevention may need to be targeted towards
specific populations. Modifying smoking, judicious use
Intestinal of antibiotics, promoting breastfeeding and appropriate
↑ NOD2
↑ NF-κB
lamina dietary advice might be a reliable approach to reduce CD
propria
development and improve long-term outcomes5. While
Macrophage APC better clinical trials are awaited, dietary interventions
Pro-inflammatory
IL-12 IL-12 cytokines and newer elimination diets have the potential to better
IL-23 IL-23 IL-23 control disease or avoid complications30. Future research
IL-6
IL-17 should focus on identifying environmental factors dur-
NK cell IL-21
IL-22 ing the early stages of industrialization that increase dis-
IL-21 IL-23 ease risk and designing specific interventions that can
TH0 cell TH17 IL-12
cell IL-21 IFNγ prevent disease development and improve outcomes in
Activated
NK cell TNF patients with CD (Table 1).
IL-4 IFNγ TH1
TNF cell Genetic factors. Compared with environmental fac-
TH2 tors, much more progress has been made in delineating
Recruitment cell genomic variation that determines disease risk. Familial
of leukocytes Endothelial cell inheritance of CD is recognized, with concordance rates
amongst monozygotic twins that are higher for CD
Systemic (~50%) than for UC (~15%)2,31.
circulation Following the seminal discovery in 2001 of coding
variation in the intracellular pattern recognition receptor
gene NOD2 (also known as CARD15), which is selectively
Fig. 1 | Causes of Crohn’s disease. Intestinal homeostasis is maintained by the equilibrium associated with CD risk, genome-wide association stud-
between the luminal content and the mucosal immune system in the lamina propria. ies in more than 70,000 individuals identified more than
The intestinal epithelium orchestrates this equilibrium because of its mechanical function
200 loci associated with CD risk32–35. As in most other dis-
(as a physical barrier) but also its role in immune responses. Specialized intestinal epithelial
cells (IECs) have important roles in intestinal immunity. For example, Paneth cells (not shown) eases, most CD risk loci individually only very modestly
are IECs present at the base of crypts of Lieberkühn and constitutively produce antimicrobial increase relative risk (typical odds ratios of 1.1–1.2),
peptides, whereas microfold cells are IECs present in the gut-associated lymphoid tissue and these variants are present mostly in regulatory
(not shown) that sample luminal antigens and present them to cells of the adaptive regions of the genome35. Most minor risk loci for CD are
immune system. After contact with an antigen, antigen-presenting cells (APCs) such as shared with a wide range of immunomediated diseases36.
dendritic cells present antigen to T cells and B cells to initiate a controlled inflammatory Importantly, a substantial fraction of aggregate herita-
response. In inflammatory conditions such as Crohn’s disease, epithelial barrier dysfunction ble risk is explained by variance at a few loci, including
(owing to, for example, polymorphisms in NOD2 and nuclear factor-κB (NF-κB) signalling NOD2 and the autophagy gene ATG16L1 (both specific
pathway genes) results in the luminal contents entering the lamina propria, leading to for CD), and the IL-23 receptor gene IL23R (which
dendritic cells activating inflammatory T cell types, such as naive T helper (TH0) cells,
increases the risk of CD and UC)35–37. The discovery of
T helper 1 (TH1) cells, TH17 cells and TH2 cells, which produce proinflammatory cytokines,
such as IFNγ and tumour necrosis factor (TNF). Furthermore, in response to luminal some variants has identified novel disease mechanisms;
contents, macrophages produce the proinflammatory cytokines IL-12 and IL-23, which for example, NOD2 c.3019–3020insC and ATG16L1
activate natural killer (NK) cells, resulting in perpetuation of the intestinal inflammation p.Thr300Ala have implicated impaired bacterial recog-
with production of proinflammatory cytokines. Luminal contents include dietary nition and autophagy, respectively, in CD pathogenesis37.
components and the gut microbiota. IL-4, IL-6, IL-21 and IL-22 are also produced by Of note, genome-wide association studies showed that
TH0 cells in response to activation of dendritic cells. NOD2 is one of the most important genetic factors asso-
ciated with the risk of ileal CD38, and intestinal epithe-
on epigenetic modifications and thereby produce lial cells (IECs) in Nod2-deficient mice have impaired
long-lasting phenotypic changes24. Unravelling the com- bacteria-killing ability, leading to perturbed interactions
plex interaction between diet and the gut dysbiosis in between the ileal microbiota and mucosal immunity39.
CD might improve our understanding of the role of diet Remarkably, whereas non-synonymous, coding risk
in CD pathogenesis and lead to the development of novel variants in NOD2, ATG16L1 and IL23R predominate in
therapeutic agents. white populations, the risk variants of these genes are
Antibiotic exposure in childhood increases the risk monomorphic in Asian cohorts2,40. In Asians, TNFSF15
of developing CD20. Furthermore, oral contraceptives, is the predominant risk locus that is selectively associ-
aspirin and NSAIDs have been reported to increase the ated with CD17, and its effect size exceeds that of NOD2
risk of CD20,26–28. Among environmental factors asso- in white populations41. A meta-analysis of genome-wide
ciated with reduced risk of CD, breastfeeding reduce association studies assessed genetic loci associated
CD risk, albeit inconsistently, and statins are linked to with IBD in East Asian populations and identified new
decreased risk20,29. loci involved in B cell function42. By contrast, the large
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Table 1 | Environmental risk factors for Crohn’s disease luminal contents. A defect in any of these barrier com-
ponents can lead to inflammation. Susceptibility poly-
Environmental factor Association Refs morphisms in genes encoding junctional proteins, such
Smoking Strong positive association with disease onset and 2,7
as E-cadherin, guanine nucleotide-binding protein
worse disease course subunit-α12 and zonula occludens 1 in IECs, defective
Appendectomy Positive association with disease onset and no 2,7
production of antimicrobial peptides by innate immune
association with disease course cells and IELs, and altered expression of junctional pro-
Low dietary vitamin D Positive association with disease onset and course 8,9 teins, such as E-cadherin, β-catenin and claudins, by
Oral contraceptive use Strong positive association with disease onset and no 2 IECs result in the increased permeability that is a fea-
association with disease course ture of IBD47,48. Specifically, reduced expression of the
sealing tight junction proteins claudin 5 and claudin 8
Postmenopausal No association with disease onset and no association 2,7
hormone use with disease course and increased expression of the pore-forming claudin 5
in IECs occur in active CD47,48.
NSAID use Positive association with disease onset and strong 2,7
positive association with disease course An emerging organizing principle of the mucosal
immune response relates to the single layer of IECs.
Antibiotic use Positive association with disease onset and with 2,7
The term ‘intestinal barrier’ has been used to refer to the
disease course
mucus layer or the underlying mucosal immune sys-
Depression and Positive association with disease onset and no 2,7,10
tem49. CD-associated polymorphisms in several genes,
psychosocial stress association with disease course
such as NOD2, ATG16L1, IRGM and LRRK2, manifest
Low dietary fibre Negative association with disease onset and no 8,9
themselves as abnormalities in the secretory activity of
association with disease course
Paneth cells, specialized IECs that are present at the base
High dietary fat No association with disease onset or with disease course 8,9
of the crypts of Lieberkühn in the small intestine50–53.
High dietary protein No association with disease onset or with disease course 8,9 Endoplasmic reticulum stress within IECs, which can
be triggered by a wide range of environmental cues,
can elicit a pathological unfolded protein response (UPR)
number of CD risk loci with individually small contribu- and initiate intestinal inflammation54–56. ATG16L1 poly
tions seem to be better correlated between ethnicities40. morphisms (such as p.Thr300Ala) in IECs set the
Of note, this transethnic association study showed that threshold for tolerable endoplasmic reticulum stress
most risk loci are shared among diverse ancestry groups, by determining the activation level of the UPR sensor
with the few that affect population specificity related to inositol-requiring enzyme 1α (IRE1α); hyperactivation
heterogeneity in risk allele frequency (NOD2) or effect of IRE1α can trigger spontaneous ileitis in mice, which
size (TNFSF15 and TNFSF8)41. Moreover, patients with phenocopies key features of CD56. STAT3 signalling and
early-onset IBD have mutations in IL-10 receptor genes nuclear factor-κB (NF-κB) signalling in IECs are simi-
that show highly penetrant, Mendelian-like inheritance43. larly important, and defects in these two pathways favour
As only 13.1% of disease heritability is explained by the development of colitis57. Inhibitor of NF-κB kinase-α
genetic factors2,44, non-genetic environmental factors (IKKα) phosphorylates ATG16L1 and thereby prevents
and epigenetic factors also have important effects on its degradation, in the absence of which IRE1α accumu-
CD risk. Moreover, genetic variation alone does not lates and relays a pathological UPR, which highlights one
explain disease variance and phenotypes, including age of many levels of cross-regulation of these key pathways58.
at diagnosis, location and complications45. However, data IELs are predominantly antigen-experienced T cells
from the largest genotype–phenotype study in patients that reside within the gut epithelium and have a cru-
with IBD showed a possible distinction between ileal cial role in maintaining gut homeostasis, although their
CD, colonic CD and UC on the basis of genetic risk fac- role in CD pathogenesis is poorly understood and some
tors45. This study showed that NOD2 variants are asso- studies are in contrast with its role in maintaining gut
ciated only with disease location in patients with CD but homeostasis and have shown a proinflammatory role
not with stricturing disease, suggesting that location is of IELs in CD. CD8αα-expressing CD4+ IELs are a sub-
patient specific (that is, influenced by genetic factors), type of CD4+ IELs that modulate the activity of other
whereas disease behaviour, including complications, is immune cells by, among other mechanisms, producing
a marker of disease progression45. the anti-inflammatory cytokines IL-10 and transform-
ing growth factor-β (TGFβ), but also directly respond
Mechanisms/pathophysiology to epithelial injury or microbial infection in their role as
Inflammation of the GI tract in CD involves impaired cytotoxic T lymphocytes59. Recently, increased produc-
intestinal barrier function and dysregulation of innate tion of IL-17A, IFNγ and TNF was identified in IELs
and adaptive immune responses and possibly also the from patients with CD60. Consequently, IEL dysfunction,
gut microbiota. such as excessive activity of cytotoxic T lymphocytes
or pathological reduction in their anti-inflammatory
Intestinal barrier function activity, might contribute to CD61.
The intestinal barrier, comprising IECs, innate immune
cells, intraepithelial lymphocytes (IELs) and the mucus The immune response
layer, is the first physical and chemical barrier encoun- IECs communicate with innate and adaptive immune
tered by intestinal bacteria, pathogens and food anti- cells by multiple mediators; for example, endoplas-
gens46 and is in constant homeostasis with the intestinal mic reticulum stress upregulates NKG2D ligands and
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activates natural killer cells and group 1 innate lym- colon of patients with CD contain increased numbers
phoid cells (ILC1s)62, which is notable, as NKG2D of ILC3s, and ILC1s are more abundant in the ileum of
blockade may be effective in inducing remission in patients with CD than in patients without ileal inflam-
CD63. Conversely, IECs receive crucial signals from mation73. Furthermore, the inflamed areas contain an
various leukocytes, including the cytokines IL-22 and increased abundance of IFNγ-producing ILC1s at the
IL-17 derived from IL-17-producing T helper cells expense of ILC3s (which produce the anti-inflammatory
(TH17 cells), ILC3s and γδ T cells, which promote IEC cytokines IL-17 and IL-22), suggesting that increased
regeneration and barrier fortification64,65. ILC3-to-ILC1 plasticity may be involved in CD patho-
genesis. The proinflammatory cytokine IL-12 seems to
Innate immunity. Neutrophils, dendritic cells, mono- drive ILC1 differentiation from ILC3s74. Importantly, the
cytes, macrophages and ILCs are components of the damaged epithelium activates ILCs to restore epithelial
innate immune response. Mutations in various genes, barrier function75.
such as NOD2, ATG16L1, LRRK2, XBP1 and IRGM, lead
to alterations in Paneth cell survival and function, includ- Adaptive immunity. Most lymphocytes are activated
ing dysregulated secretion of antimicrobial proteins66. in the gut-associated lymphoid tissue and are recruited
NOD-like receptors are innate immune proteins that to sites of inflammation. Integrins, such as αLβ2, α4β1,
can initiate NF-κB-dependent and mitogen-activated α4β7 and αEβ7 integrins, on the surface of leukocytes are
protein kinase-dependent gene transcription, result- pivotal in the ‘rolling phase’ of leukocyte extravasation,
ing in the production of protective anti-inflammatory as they enable leukocytes to bind to cellular adhesion
cytokines64,65. Dendritic cells in inflammatory states molecules on the surface of endothelial cells. Studies
express TLR2, TLR4 and co-stimulatory receptors; in mice established that the binding of the adhesion
signalling through these molecules results in the pro- molecule MADCAM1 on intestinal endothelial cells to
duction of proinflammatory cytokines. In homeostatic α4β7 integrin on T cells is a crucial intestinal homing
conditions, IECs produce TGFβ, which promotes the mechanism, with this gut tropism imprinted on T cells
production of the anti-inflammatory cytokine IL-10 by by Peyer’s patch dendritic cells76,77. Indeed, a monoclonal
dendritic cells to maintain tolerance. Thus, dendritic anti-α4β7 integrin antibody78 and an anti-α4 integrin
cells control crosstalk between innate and adaptive antibody that also blocks α4β1 integrin79 are efficacious
immunity to maintain homeostasis46. Neutrophils have in treating CD.
important functions in maintaining gut homeostasis and Several studies have reported a persistent T cell
in the inflammatory process. Initially in IBD, neutrophils immune activation in IBD67. CD results from exces-
phagocytose pathogenic microorganisms to maintain sive T helper 1 (TH1) and TH17 cell responses to pro
homeostasis, but later their subsequent accumulation inflammatory cytokines, such as IL-12, IL-18 and IL-23,
within the gut epithelium compromises epithelial bar- which are produced by antigen-presenting cells and
rier function and leads to the production of inflam- macrophages68. In turn, TH1 and TH17 cells secrete the
matory mediators that perpetuate gut inflammation67. proinflammatory cytokines IL-17, IFNγ and TNF, which
Macrophages in the healthy human gut mucosa seem perpetuate inflammation by stimulating production of
to be in a tolerant state and control tissue remodelling TNF, IL-1, IL-6, IL-8, IL-12 and IL-18 by other cells, such
through the clearance of apoptotic or senescent cells67. as macrophages, endothelial cells and monocytes68.
Current effective CD therapies act to block inflamma- IL-12 and IL-23 are heterodimeric cytokines that
tory mediator production and signalling and, therefore, share the p40 subunit while pairing with p35 and p19
are perceived as inhibiting unrestrained inflammation. subunits, respectively. They are produced by innate
However, several lines of evidence suggest that defects immune cells (such as macrophages, dendritic cells and
in phagocytic function and an immunodeficiency ele- possibly neutrophils) and have emerged as central driv-
ment are also important in CD pathogenesis68. Impaired ers of intestinal inflammation and major mediators of
neutrophil NADPH oxidase activity has been described inflammation in IBD. Studies in T cell-dependent and
in very early onset CD69. CD-associated risk variants innate immune cell-driven models of experimental
of NOD2 and ATG16L1 are hypomorphic, and NOD2 colitis demonstrate that IL-23 is especially important.
and ATG16L1 functionally and, in some contexts, also IL-23 signals through a heterodimeric receptor consist-
physically interact to promote autophagy in dendritic ing of IL-23R and IL-12Rβ1 to activate JAK2–STAT3
cells, macrophages and neutrophils, thereby increasing signalling and is expressed by αβ T cells, γδ T cells and
their antimicrobial function70,71. Furthermore, neutro- ILC3s. A monoclonal anti-p40 antibody (targeting both
phil inflammatory responses to killed Escherichia coli IL-12 and IL-23) is effective in CD treatment, and sev-
are reduced in patients with CD but not in those with eral anti-p19 antibodies (which specifically target IL-23)
UC or rheumatoid arthritis, supporting the view that showed efficacy in CD treatment in phase II trials79.
neutrophil antimicrobial defences are defective in CD72. Whereas TH17 cells in the intestine (which contribute
ILCs have an important role in the maintenance of to mucosal homeostasis by producing barrier-protective
gut homeostasis by producing cytokines that bridge the IL-17 and IL-22) develop independently of IL-23, IL-23
innate and adaptive immune systems. ILCs are classified activates pathogenic CD4+ lymphocytes that produce
into natural killer cells, ILC1s, ILC2s, ILC3s and lym- granulocyte–macrophage colony-stimulating factor
phoid tissue inducer cells. The increased abundance of and IFNγ and can also inhibit intestinal regulatory
ILC1s and ILC2s in patients indicates a potential role for T cells (Treg cells) in experimental model systems 68.
these cells in IBD pathogenesis73. Inflamed ileum and Polymorphisms in the coding sequence of IL23R that
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are associated with CD and UC risk are hypermorphic80, and biopsy tissues of paediatric patients with CD and
suggesting that this immune pathway is indeed close to might be a potential biomarker of early-onset CD93. A
the core immunogenetic mechanism of both diseases81. meta-analysis showed a lower diversity of both the viral
The activity of effector T cells is regulated by Treg cells, community and the microbiota (but variability between
a suppressive subset of CD4+ T cells that have a role samples was higher) in patients with CD compared
in maintaining immune homeostasis in the gut and with healthy individuals, with increased abundance of
other tissues and organs. Mucosal effector T cells from Synechococcus phage S CBS1 and viruses of the family
patients with IBD may be resistant or less responsive Retroviridae in CD samples94. Moreover, in a Japanese
to Treg cell-mediated suppression82. IL-10 production by cohort, the overall structure of the fungal microbiota in
Treg cells is essential to prevent intestinal inflammation in patients with CD seemed to differ completely from that
mice43. Of note, mutations in the genes encoding IL-10 of healthy individuals or patients with UC, with an abun-
and IL-10 receptor have been associated with very early dance of Candida spp. in patients with CD compared
onset IBD43. with healthy individuals95.
Microbial dysbiosis Diagnosis, screening and prevention

In the past 10 years, gut dysbiosis (pathological altera- Although the natural history of CD is well understood,
tion of the gut microbial composition) has been exten- diagnosis can be challenging, as it is not based on a sin-
sively investigated in patients with IBD. However, no gle specific finding and there are no pathognomonic
microbiota composition or marker microorganisms that features. Instead, diagnosis requires a complete assess-
are specific to CD have been identified. ment based on clinical history, physical examination
and complementary diagnostic tests, such as assays for
Gut bacterial composition. The gut microbiota has been serological and faecal biomarkers, cross-sectional and
evaluated in different intestinal conditions, including endoscopic imaging, and histological evaluation of
IBD and irritable bowel syndrome (IBS)83, and both biopsy specimens96,97.
overlaps and differences in composition were found. Gut
microbial dysbiosis promotes intestinal inflammation in Natural history
experimental model systems84. A reduced representation Disease phenotype. CD has different presentations or
of Firmicutes and Bacteroidetes and an overrepresenta- phenotypes: stricturing disease due to fibrosis; pen-
tion of enterobacteria in the microbiota of patients with etrating disease due to fistulas between the gut and
CD has been described67,85. Moreover, adherent–invasive other structures; disease lacking these features, which
E. coli and Faecalibacterium prausnitzii have been asso- is termed inflammatory or non-s tricturing, non-
ciated with promotion of CD (by overcolonization of penetrating disease; and stricturing, penetrating dis-
epithelial cells) and protection against CD (by butyrate ease. Disease phenotype can change from inflammatory
production), respectively86–88. Adherent–invasive E. coli disease to stricturing, penetrating disease, as repeated
can cause granulomatous colitis in boxer dogs, which can cycles of inflammation can lead to bowel damage.
be cured by antibiotic treatment89. No robust clinical trial
data are yet available for the efficacy of faecal microbiota Disease location. Disease location usually remains stable
transplantation in treating CD. Studies have identified over time. Approximately one third of patients with CD
specific taxa whose abundance is altered (lowered or present with large-bowel disease, one third with ileo
increased) in patients with poor prognosis, no therapeu- colonic disease and one third with small-bowel dis-
tic response to conventional or biologic treatments, poor ease. The prevalence of upper GI tract involvement in
lifestyle or likelihood of relapse after surgery or in rela- CD differs substantially among studies. Upper GI tract
tionship to short-chain fatty acid production through dif- involvement was initially considered of low prevalence
ferent metabolic pathways90. Furthermore, patients with (0.3–5%), but higher prevalence (30–75%) has been
CD who have active disease showed an altered micro- reported in the past two decades98,99. ‘Upper GI tract
bial community compared with healthy individuals or involvement’ refers to involvement of the oesophagus,
patients with inactive CD, with enrichment in Escherichia stomach, duodenum and jejunum either in isolation or
spp. and a decrease in abundance of Firmicutes, prob- together with other locations98,99.
ably linked to increased vascular and paracellular per- Up to one third of patients have evidence of strictur-
meability91. Of note, Enterococcus spp., Escherichia spp., ing or penetrating intestinal complications at diagnosis,
Fusobacterium spp., Streptococcus spp. and Veillonella and half of all patients experience an intestinal compli-
spp. have been identified as promising, specific, cross- cation in the 20 years after diagnosis100. A substantial
disease markers for bile duct obstruction and GI inflam- proportion of patients (40%) have bowel damage within
mation, highlighting their role in concomitant biliary 1 year of diagnosis (when the first cross-sectional imag-
disease, such as primary sclerosing cholangitis92. ing analysis is done). Having bowel damage at diagnosis
is associated with worse outcomes, including high rates
Gut viral and fungal composition. In the past 5 years, of surgery and hospitalization101. These findings confirm
research into the role of the gut viral community in the need to stratify patients at early stages of the disease
IBD has increased. Several studies have shown a role on the basis of the risk of progression101. Treatment with
of the gut viral community and fungal microbiota in immunomodulators or TNF antagonists within the first
IBD pathogenesis93. Of interest, Caudovirales bacterio- 2 years of CD diagnosis reduces the risk of developing
phage sequences have been detected in intestinal washes bowel strictures when compared with starting treatment
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with these drugs more than 2 years after diagnosis. anaemia and recurrent fistulas or other perianal findings
Furthermore, early immunomodulator treatment is (ulcers or fissures). Bowel obstructions in patients with
associated with reduced risk of intestinal surgery, per- stricturing disease result in lack of bowel movements,
ianal surgery and any complication102. The cumulative which can lead to hyperactive bowel sounds, nausea
risk of developing perianal disease during the course of and vomiting. Fistulas or abscesses can be a manifes-
CD is 30% at 1 year after diagnosis103. tation of penetrating disease103,104. When an abscess is
Female sex and EIMs are associated with increased present, patients can have systemic symptoms, such as
risk of perianal lesions other than fistulas, whereas older fever and chills. The symptoms resulting from fistulas
age at diagnosis is associated with a slightly decreased depend on the location of the fistula: diarrhoea in the
risk of these lesions104. Data from a population-based case of enteroenteric fistulas, urinary tract infections
inception cohort of patients with CD indicated a cumu- in the case of enterovesicular (between the intestine
lative incidence of perianal or rectovaginal fistulas of and the bladder) or enterouretheral fistulas, passage of
24% at 30–40 years after a CD diagnosis and a decreased stool to the vagina in the case of enterovaginal fistulas
cumulative incidence of perianal or rectovaginal fistu- or drainage of stomach or intestinal contents from the
las and proctectomy in the biologic era compared with skin in the case of enterocutaneous fistula. Symptoms are
the prebiologic era. The decreased incidence might be similar in patients with early-onset CD and in patients
explained by a change in the treatment paradigm from with late-onset CD, but there are some differences. For
a conventional step-up (escalation-as-needed) approach example, EIMs are less common, the disease is less pro-
to a top-down (intense-therapy-first) approach105. gressive and a family history is less common in patients
CD is characterized by periods of remission inter- with late-onset CD than in patients with early-onset CD.
spersed between flares of intestinal inflammation.
Disease flares occur randomly and are mostly unpredict- Extraintestinal manifestations. Overall, EIMs are pres-
able. Stable and prolonged endoscopic remission occurs ent in 43% of patients with CD, and can affect multi-
in 10% of patients106. Up to 50% of patients require intes- ple body systems, including musculoskeletal (axial and
tinal resection within 10 years of a CD diagnosis owing peripheral arthropathy, arthritis and ankylosing spondy-
to intestinal complications12. litis), oral (aphthous stomatitis), ocular (uveitis, scleritis
and episcleritis), dermatological (pyoderma gangreno-
Symptoms. Symptoms can be insidious, can be non- sum, psoriasis and erythema nodosum) and hepatobil-
specific and can depend on disease location and severity, iary (primary sclerosing cholangitis) systems108 (Fig. 2).
and some patients may have symptoms for years before These EIMs may be present even before GI symptoms
a CD diagnosis107. Diarrhoea and abdominal pain are appear, and the presence and/or persistence of some
the cardinal symptoms reported by patients with CD97. EIMs is linked to intestinal disease activity. For exam-
Other symptoms include fatigue, weight loss, fever, ple, axial arthropathy (including ankylosing spondylitis
and sacroiliitis) and erythema nodosum track intestinal
disease activity104 and typically disappear when luminal
Dermatological Ocular inflammation is successfully treated. Conversely, periph-
• Aphthous stomatitis • Uveitis eral arthropathy (type 2 polyarticular), the symptoms
• Erythema nodosum • Scleritis of which are often migratory, and pyoderma gangreno-
• Psoriasis • Episcleritis
sum are usually independent of disease activity (except
• Pyoderma gangrenosum
for type 1 pauciarticular arthropathy) and can persist
Vascular Respiratory after the luminal inflammation is treated109. Primary
• Portal hypertension • Obstructive sleep sclerosing cholangitis is more common in patients with
• Thromboembolism apnoea UC than in patients with CD104. However, because of the
• Thrombosis • Chest infections progressive nature of primary sclerosing cholangitis, fur-
• Pulmonary embolism
ther extraintestinal complications can occur, including
cirrhosis, portal hypertension, cholangiocarcinoma and
Arthropathy Hepatobiliary colon cancer104. Patients with CD have an increased risk
• Arthritis • Primary sclerosing
• Ankylosing spondylitis of developing colorectal cancer and small-bowel cancers
cholangitis
• Sacroiliitis • Cirrhosis compared with the general population109.
• Colorectal cancer A slightly increased risk of lymphoma, despite treat-
Inflammatory
• Small-bowel cancer ment such as with immunosuppressive drugs, was
• Asthma reported in a meta-analysis of population-based stud-
• Bronchitis ies104. Overall mortality is slightly increased in patients
• Pericarditis Other with CD (standardized mortality ratio 1.4)110. Additional
• Rheumatoid arthritis • Metabolic bone
• Multiple sclerosis disease
EIMs have also been described, such as metabolic bone
disease and thromboembolic diseases98,104, including
threefold increased risk of deep venous thrombosis
Fig. 2 | Extraintestinal manifestations and complications in Crohn’s disease. Crohn’s
disease is associated with various manifestations and complications beyond those in the and pulmonary embolism compared with the general
affected areas of the gastrointestinal tract. Many of these conditions result from immune population108.
system dysfunction, including inflammatory conditions in the skin, eyes, joints and EIMs can also result from treatment of CD; for
respiratory, musculoskeletal and nervous systems. Furthermore, vascular and metabolic example, one third of patients with CD develop steroid
dysfunction and cancer can also occur in Crohn’s disease. dependency, with surgery required in one third of these
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patients after initiation of steroid therapy because of evaluation of perianal fistulas and adjacent abscesses123.
a lack of response to treatment107. Various inflamma- Although BUS has some limitations, it has emerged as
tory diseases, such as asthma, bronchitis, pericarditis, a reliable, non-invasive, radiation-free tool for accurate
psoriasis, rheumatoid arthritis and multiple sclerosis, are evaluation of the intestinal wall and extraluminal mani-
associated with CD110. festations117. Detection of bowel wall thickening of more
than 3 mm by BUS results in high sensitivity and speci-
Imaging modalities ficity in diagnosing CD (88–100% when enhancement,
Endoscopic imaging. Ileocolonoscopy remains the gold localization, fistulas and abscesses are considered)121.
standard for the diagnosis of CD and allows the col- Furthermore, BUS also has high sensitivity and speci-
lection of tissue samples for histological evaluation111. ficity for the detection of extraluminal complications,
Endoscopic findings for a diagnosis of CD include a such as fistulizing and stenotic lesions, and abscesses122.
patchy distribution of inflammation and skip lesions.
Macroscopic lesions found in CD are aphthous erosions Histology
(ulcers with diameter less than 5 mm) or ulcers that tend Histological examination of endoscopic biopsy sam-
to be longitudinal (with diameter greater than 5 mm) ples or resection specimens is the gold standard for
with a cobble-stone appearance. Ulcers can be superficial confirming a CD diagnosis and for differential diagno-
or deep, if they erode the muscularis propria; this feature sis (of UC and other non-IBD-related forms of colitis,
is one of the criteria of disease severity. Rectal involve- especially infectious forms). Although there are no his-
ment and circumferential continuous inflammation are tological features that are specific for CD, typical micro-
less common in CD than in UC. scopic features that allow a CD diagnosis include focal
Current guidelines recommend that small-bowel cap- (discontinuous) chronic inflammation, focal crypt irreg-
sule endoscopy (SBCE) should be reserved for patients ularity (discontinuous crypt distortion), granulomas
where there is high suspicion of CD despite previous (not related to crypt injury) and irregular villous archi-
negative ileocolonoscopy and radiological findings97. tecture (in the terminal ileum)114. The pathologist in
SBCE uses a disposable swallowed capsule-shaped tool an IBD multidisciplinary team has an important role
that wirelessly transmits images to a data recorder that in increasing accuracy in the CD diagnosis. Even in
is worn by the patient111, and is a sensitive tool to detect cases of non-specific histological findings, the presence
mucosal abnormalities, such as aphthous erosions or of clinical, endoscopic and imaging findings allows a
ulcers in the small bowel112. The diagnostic yield of SBCE tentative diagnosis of CD to be made.
for suspected or established CD is higher than that for
ileocolonoscopy (47% versus 25%; P = 0.009) and CT Clinical disease activity indexes
enterography (CTE; 68% versus 21%; P < 0.00001), and The Crohn’s Disease Activity Index (CDAI) is a clinical
SBCE had a high negative predictive value113. There is activity index that was developed in 1976 and is used to
a risk of capsule retention when obstructive symptoms quantify the symptoms in patients with CD by assigning
or stenosis are present (13% in patients with established a weighted score for eight clinical or laboratory varia-
CD and 1.6% in patients with suspected CD)114. In bles, including general well-being, loose stool, abdom-
these situations, dedicated small-bowel cross-sectional inal pain, presence of abdominal mass, weight change,
imaging modalities are recommended as the first-line low haematocrit and opiate use for diarrhoea. The CDAI
assessment method115. Device-assisted enteroscopy is an is solely applied in clinical trials to define response to
invasive, time-consuming method that is recommended treatment or disease remission because 50% of patients
only in selected patients for whom histological diagnosis in clinical remission have endoscopic and/or C-reactive
is needed or when endoscopic therapy is indicated116. protein (CRP) evidence of residual, active CD, whereas
Increased costs and the complexity of device-assisted other patients have normal endoscopic findings and
enteroscopy limit its use as a first-line tool in diagnosis CRP levels despite having symptoms124. The Harvey–
of small-bowel CD97. Bradshaw index (HBI) is a simplified Crohn’s disease
activity index that was developed in 1980, and includes
Cross-sectional imaging. Cross-sectional imaging (such only clinical parameters, removing the requirement
as bowel ultrasonography (BUS), CTE and MRI enter- for laboratory analysis. Neither index includes endo-
ography (MRE)) is important for fully assessing disease scopic and radiological assessment and therefore they
extent and the presence of inflammatory complications are solely used to monitor clinical activity. Inclusion of
(such as stenosis, fistulas and abscesses) owing to the inflammatory markers in the HBI or the CDAI in the
transmural nature of CD100. BUS, CTE and MRE have future might add prognostic value to these two indexes.
comparable (and high) accuracy for both CD diagno- Of note, CDAI and HBI scores were positively correlated
sis and detecting complications in patients with CD117. in the PRECiSE 1 and PRECiSE 2 trials124. The HBI may
As CTE requires the use of oral or intravenous contrast be more appropriate than the CDAI in some clinical tri-
agents, exposure to radiation is the major limitation of als and even in routine practice because it is easier to
this method118. CTE has greater than 80% sensitivity and calculate and is less subject to recall bias125.
specificity for CD diagnosis119 and high sensitivity
and specificity for diagnosis of fistulas and for detect- Biomarkers
ing CD-related stenosis120. MRE has 89% sensitivity Biomarkers are useful non-invasive tools that give addi-
and 94% specificity for the diagnosis of stenosis121,122. tional information in the management of patients with
Pelvic MRE is the imaging modality of choice for the CD. Data are still lacking regarding their utility in CD
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diagnosis. However, biomarkers might help clinicians especially in monitoring disease activity, relapse, response
in early decisions and interventions characterizing the to therapy and patient-reported outcomes in patients
severity and prognosis of the disease. Moreover, biomark- with CD136. Faecal calprotectin also has a crucial role in
ers might have a role in defining response to treatment a treat-to-target strategy, as in the CALM study, where
and in predicting relapses in the postoperative CD. faecal calprotectin levels were among the treatment fail-
ure criteria used for dose escalations in early CD. To date,
Serological markers. Autoantibodies, such as perinuclear there is no consensus on a specific cut-off value.
antineutrophil cytoplasmic antibodies (pANCAs), and In the STORI trial, patients relapsing after stopping
antimicrobial antibodies, such as anti-Saccharomyces infliximab therapy had increased faecal calprotectin lev-
cerevisiae antibodies (ASCAs), anti-Pseudomonas els 4–6 months in advance of relapse140. Furthermore,
fluorescens-associated sequence I2 antibodies, anti- in an Italian prospective study, a faecal calprotectin
outer membrane porin C antibodies and anti-CBir1 value greater than 200 μg/g within 3 months of surgery
antibodies, are useful biomarkers for CD diagnosis126. showed 63% sensitivity and 75% specificity in predicting
Other circulating antibodies against glycan epitopes of endoscopic disease recurrence at 1 year141.
the bacterial cell wall, such as anti-mannobioside carbo-
hydrate antibodies, anti-laminaribioside carbohydrate Novel potential non-invasive biomarkers
antibodies, anti-chitobioside carbohydrate antibod- As intestinal dysbiosis is implicated in the pathogenesis
ies and anti-laminarin antibodies, are also potentially of CD, several studies have evaluated the role of fae-
beneficial for CD diagnosis127,128. cal and serum microbial markers for diagnosis of CD.
ASCA is the most well-known serological marker in In a multicentre prospective study of an Asian pop-
commercial use for CD diagnosis. The ASCA-positive ulation (95 patients with CD, 81 patients with UC,
rate is 60–70% in CD, 10–15% in UC and less than 5% 65 patients with IBS and 105 healthy volunteers), a com-
in patients with non-IBD colitis126. pANCA is detected in bination of substantially increased abundance of faecal
10–15% of CD cases, 60–70% of UC cases and less than Fusobacterium nucleatum and a decline in F. prausnitzii
5% of non-IBD colitis cases126. Moreover, patients with abundance was a valuable marker for distinguishing
CD who are pANCA-positive usually have a clinical patients with CD from healthy individuals (area under
phenotype resembling that of UC11. Despite the wide- the curve of 0.841 versus 0.811) or patients with IBS (area
spread use of these antibodies, usually to differentiate under the curve of 0.767 versus 0.658)142. In another pro-
between CD and UC, their practical clinical utility in spective multicentre study, a β-diversity analysis showed
general diagnosis of CD is limited and genetic or sero- a clear separation of patients with IBD from healthy indi-
logical testing is currently not recommended for routine viduals and identified Gammaproteobacteria, Entero
diagnosis of CD129. coccus and Enterococcaceae as potential biomarkers for
CRP is a surrogate serological marker of non-specific IBD diagnosis83.
acute inflammation in CD130. CRP is mainly synthe- Although several studies have reported novel emerg-
sized by hepatocytes in response to proinflammatory ing serum and faecal biomarkers involving molecular,
cytokines, such as TNF, IL-1β and IL-6, and is poten- epigenetic, microbial and metabolic pathways associ-
tially helpful to monitor disease activity in patients with ated with gut barrier disruption and implicated in CD
CD97,131. Of note, one third of patients with CD have nor- development and progression, these biomarkers are not
mal CRP levels despite active disease and one third have recommended as a first assessment for the diagnosis of
increased CRP levels despite clinically inactive disease131. the disease143,144.
Furthermore, the value of CRP in predicting clinical
disease course is not well established132–135. Colorectal dysplasia surveillance
To date, colonoscopy is the gold standard for colorec-
Faecal calprotectin. Faecal biomarkers are potential non- tal carcinoma surveillance and chromoendoscopy is
invasive tools to aid in differential diagnosis, especially of recommended in the European Crohn’s and Colitis
inflammatory colitis, or as indicators of CD disease activ- Organisation guidelines123. Improved endoscopic imag-
ity131,136. Calprotectin is a calcium-containing antimicro- ing technology, adherence to surveillance guidelines
bial protein complex that makes up 60% of the cytosolic and endoscopic management of focal dysplasia are key
protein in neutrophils (and lower levels in monocytes and aspects to improve early detection of colitis-associated
macrophages), and is released during acute and chronic cancer in patients with IBD (see Fig. 3 for a proposed
inflammation of the GI tract wall137. Faecal calprotectin algorithm for surveillance for colitis-associated dysplasia
has high sensitivity and specificity in the diagnosis of or cancer in patients with CD).
CD136,138. Faecal calprotectin also has high sensitivity and Other techniques, such as narrow-band imaging,
negative predictive value in differential diagnosis of IBD confocal laser endomicroscopy and full-spectrum
from IBS in patients in whom there is clinical suspicion of endoscopy, may be potentially useful tools to improve
CD, is useful in clinical practice as a screening test indi- detection of colitis-associated dysplasia, but are not
cating the need for further investigation, and reduces the currently widely used in clinical practice119,145. Genetic
requirement for endoscopic diagnosis in adults by 67% analysis of stool samples for colorectal carcinoma sur-
and in children and teenagers by 35%139. Despite the lack veillance in patients with IBD has a detection sensitivity
of validated cut-off values, faecal calprotectin, besides of 100% for carcinoma, 100% for high-grade dysplasia
C‐reactive protein, is considered the standard test for and 67% for low-grade dysplasia (specificity of 89% in
assessing disease activity in CD and showed utility all cases)146.
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Initiation of surveillance for colitis-associated dysplasia imaging, are the only features that are specific for
(8–10 years after onset of symptoms) intestinal tuberculosis.
In addition to infectious disease, ischaemic colitis
should also be considered as a differential diagnosis
Surveillance schedule based on risk factors
for CD, and often presents with mucosal oedema and
erythema, with the rectum remaining intact2.
• Low risk: • Intermediate risk: • High risk: Paediatric IBD

no inflammation, mild inflammation, moderate inflammation,
left-side colitis or CD pseudopolyps or family stricture, PSC or family
First-line investigation in paediatric CD relies on colo-
affecting <50% of colon history of CRC in history history of CRC noscopy with evaluation of the terminal ileum and histo
• Frequency: every 5 years FDRs >50 years of age in FDRs <50 years of age logical confirmation, upper GI tract endoscopy and
• Frequency: every 3 years • Frequency: annually small-bowel assessment153. Serology may have a role in
prognosis153. Paediatric patients with CD who are pos-
itive for ASCA IgA or IgG have a high prevalence of
Recommended surveillance method terminal ileal or ileocaecal disease and are more likely
• Chromoendoscopy with targeted biopsies to need surgery, whereas those who are positive for
• Alternatively, colonoscopy with random biopsies (every 10 cm) and targeted biopsy pANCA are more likely to have pancolitis or left-sided
of any lesion
disease with sparing of the terminal ileum, and ileocaecal
resection is usually not required153,154.
Fig. 3 | Proposed recommendations for surveillance for colitis-associated dysplasia
in patients with CD. Surveillance should begin 8–10 years after a confirmed diagnosis
Management
of Crohn’s disease (CD) at intervals that are determined by risk factors, such as primary
sclerosing cholangitis (PSC), pan-ulcerative colitis (pancolitis), active inflammation,
In the past decade, treatment paradigms have changed,
pseudopolyps or a family history of colorectal carcinoma (CRC). Patients at low risk coinciding with the development of new drugs for CD
(without active inflammation or with restricted colitis) should be endoscopically treatment. Driving these changes is the recognition
assessed (with histopathological analysis of biopsy samples) every 5 years, whereas that some clinical parameters are associated with an
those at intermediate risk (with 3 years of mild inflammation and/or pseudopolyps increased risk of progressive and disabling CD. In addi-
and/or a family history of CRC in first-degree relatives (FDRs) older than 50 years) tion, it is increasingly recognized that mucosal heal-
should be assessed every 3 years. High-risk patients (those with 1 year of moderate ing (defined as restitution of the intestinal lining and
inflammation, stricture, PSC or a family history of CRC in FDRs younger than 50 years) regression or disappearance of endoscopic lesions) is
should be assessed annually. associated with improved short-term outcomes such as
reduced risk of relapse, decreased hospitalization rates,
Differential diagnosis steroid-free remission in follow-up examination and
Differential diagnosis of other conditions, such as UC resection-free intervals1,2. Moreover, in patients with
or intestinal infectious diseases, remains a challenge in CD, mucosal healing decreases the risk of penetrating
some patients, owing to overlapping endoscopic, radio- complications and probability of surgery compared with
graphic and histological features. Segmental disease dis- that in patients with severe ulcerations.
tribution, transmural inflammation and non-caseating Thus, mucosal healing is becoming an important
epithelioid granulomas are ‘hallmarks’ of CD, but some- treatment goal155–157, and most experts generally recom-
times they are not enough for a definitive diagnosis2. mend that management strategies strive for complete
In 10% of patients with CD, the initial diagnosis is of remission, which is defined as both symptomatic and
unclassified colitis147. endoscopic remission157. Moreover, mucosal healing will
Another big challenge, especially in the developing be complemented soon by transmural healing assessed
world, is distinguishing CD from other intestinal dis- by cross-sectional imaging techniques and histology.
eases, such as Behçet’s disease, intestinal lymphoma and However, most randomized controlled trials assess either
intestinal tuberculosis148,149. Behçet’s disease might pres- symptomatic remission or symptomatic response as out-
ent with intestinal inflammation characterized mostly comes, and endoscopic outcomes have been included
by solitary ulcers and EIMs, although these EIMs differ only in contemporary clinical trials, mostly in the past
from those in CD150. However, recurrent oral and gen- decade. In addition, early initiation of highly effective
ital ulcerations increase suspicion of Behçet’s disease, therapies soon after diagnosis can lead to increased rates
and a positive pathergy test result supports a diagno- of clinical remission and to mucosal healing158. When a
sis of Behçet’s disease151. Uveitis and skin involvement therapy is being started, it is important to consider the
are frequent in Behçet’s disease, as with other vasculitic patient’s perspective in regard to adherence with treat-
lesions151. ment and to QOL159,160. Therefore, the cornerstones of
The clinical features of intestinal lymphoma lack management at present are stratifying patients according
specificity, and diagnosis relies on histological confir- to prognostic factors, striving for early disease control by
mation. Patients with intestinal tuberculosis present treating to target and using close monitoring strategies
with fever and night sweats, ulcers of the transverse to maintain complete remission.
colon, patulous (distended) ileocaecal valve and unique
histological features, such as caseating and/or confluent Prognosis
and/or large granulomas152. These features, together At the time of diagnosis or of a flare, assessing the prog-
with a positive smear test result for acid-fast bacillus nosis in individual patients is extremely important, as
and detection of necrotic lymph node by cross-sectional it determines the initial therapeutic approach. Several
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studies have examined prognostic factors (summarized Inflammatory Bowel Diseases using early symptoms
elsewhere160,161); in general, it is important to consider and signs of CD, including persistent perianal lesions,
those factors that are associated with high risk of relapse, family history of CD, weight loss, chronic and post-
increased risk of surgery or the development of com- prandial abdominal pain, nocturnal diarrhoea, fever
plications. Younger age at diagnosis, smoking, longer and absence of rectal urgency107. This scoring system
disease duration, early need for corticosteroids, fistu- showed a high predictive value in diagnosing CD148.
lizing perianal CD161,162, low serum haemoglobin and Early diagnosis of CD (that is, soon after symptom
albumin levels, high serum CRP levels and high faecal onset) combined with early disease control during the
calprotectin levels163–166, the endoscopic presence of deep ‘therapeutic window of opportunity’ (before patients
ulcers167, and overall disease burden and location have develop complications, such as stenosis or penetrating
been associated with increased risk of relapse or a more disease) may be the best way to change the course of
aggressive or complicated disease course (Box 1). Patients the disease, healing the mucosa and thereby decreasing
lacking these factors are generally classified as low risk. hospitalizations, surgical operations, bowel damage and
High-risk patients should be considered for a top-down disability173,174.
treatment strategy, which involves early introduction of
biologic therapy, whereas a step-up treatment strategy Treating to target and close monitoring
(involving conventional therapy comprising corticoster- The therapeutic goals and end points in the management
oids and immunosuppressants) may be considered for of CD continue to evolve4. The Selecting Therapeutic
low-risk patients (Fig. 3). Targets in Inflammatory Bowel Disease (STRIDE) pro-
gramme identified two CD therapeutic targets — clinical
Early disease control and diagnosis and patient-reported outcome remission, which is
Diagnostic delay is common in CD owing to vari- defined as resolution of abdominal pain and diarrhoea
able phenotypes and non-specific clinical findings. or altered bowel habit, and endoscopic remission, which
For example, in Europe, the median diagnostic delay for is defined as endoscopic disappearance of ulcers, or res-
CD ranges from 5 months in France168 to 8 months in olution of inflammation on cross-sectional imaging in
Italy169 and 9 months in Switzerland170, although in other patients who cannot be adequately assessed with ileo-
European countries it can exceed 2 years171. Early CD colonoscopy. Biomarker remission (normal CRP and
has been defined as disease that is diagnosed within faecal calprotectin levels) was considered an adjunctive
18 months of onset of symptoms, with no complications target156.
and no previous treatment with thiopurines, methotrex- Several lines of evidence suggest that mucosal heal-
ate and/or biologic agents. A clear definition of early CD ing is the preferred treatment target. Population-based
is important to study and define the impact of early studies and meta-analyses demonstrated that mucosal
intervention on different long-term outcomes158. Several healing results in improved outcomes, including
studies have shown that treatment of patients with CD decreased risk of requiring surgery, lower relapse rates
should be started promptly (that is, when they have and improved QOL3,175. In the CALM study, tight mon-
early CD) when the disease phenotype is inflammatory to itoring with biomarkers, including serum CRP and fae-
prevent or reduce disease progression172. cal calprotectin, to guide treatment optimization led to
A simple, easy-to-use scoring system, the ‘red flags higher rates of mucosal healing in patients with early
index for suspected Crohn’s disease’, was developed CD who were starting treatment with corticosteroids
by the International Organization for the Study of than in patients receiving conventional therapy176.
This tight monitoring strategy is also associated with
decreased incidence of flares, decreased hospitaliza-
Box 1 | Prognostic factors for aggressive course of Crohn’s disease tion and improved QOL176. This tight control strat-
egy, using currently available biomarkers, is pivotal to
Patient features
Young age at diagnosis (<40 years)161,162 treatment success176. With the adoption of this strategy,
Polymorphisms in NOD2, ATG16L1 and MDR1 (also known as ABCB1)35–37 the concept of step-up versus top-down treatment may
Smoking2,20–23 slowly be replaced as patients requiring biologic ther-
apy are identified earlier in the disease course or when
Disease features
Overall disease burden and location and long duration of disease161 there is a flare. However, mucosal healing as a target
Perianal disease161,162 of the treat-to-target approach and adjustment ther-
Stricturing disease161 apy based on serial endoscopic evaluation does require
Upper gastrointestinal tract Crohn’s disease (oesophagus, stomach, duodenum and more investigation. Indeed, it is unclear whether ther-
jejunum)162 apy should be escalated in patients who have residual
Need for corticosteroids on the first flare-up162 activity on endoscopy but are in clinical remission. Of
Lack of mucosal healing after induction of clinical remission162 note, the SONIC trial showed that symptom assess-
Endoscopic appearance (for example, the presence of deep ulcers)167 ment using the CDAI is not a reliable measure of the
Epithelioid granulomas detected by histological analysis of biopsy specimen2 underlying inflammation, as 50% of patients in clini-
Laboratory markers cal remission have endoscopic and/or CRP evidence of
High serum levels of C-reactive protein, anti-Saccharomyces cerevisiae antibodies, residual, active CD, whereas other patients with symp-
anti-outer membrane porin C antibodies and anti-CBir1 antibodies126,163 toms have normal endoscopic findings and CRP lev-
High faecal calprotectin levels163–166 els177. Therefore, a CDAI below the cut-off might mask
Low serum levels of albumin and haemoglobin163–166
endoscopic activity.
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Drug withdrawal 6 months of a CD diagnosis was no more effective than

Although there is an emerging consensus about the conventional management, such as with corticoster-
importance of initiating treatment soon after diagno- oids, in increasing the duration of clinical remission185.
sis and a treat-to-target strategy in the management However, azathioprine has a role in maintaining remis-
of IBD, debate continues about the risks, benefits and sion in patients with CD who received corticosteroid
timing of stopping treatment when patients are in sta- induction therapy185,186. Moreover, although the primary
ble remission. Moreover, when deciding whether to outcomes were not achieved in the AZTEC and RAPID
discontinue treatment, clinicians should consider the trials, real-life data support the use of thiopurines in
high cost of indefinite maintenance therapy and cumu- reducing the risk of intestinal resection187. Currently,
lative treatment-related toxicity, which increases with the antimetabolite methotrexate is increasingly being
the treatment duration. Relapse rates increase after used in combination with anti-TNF agents to prevent
immunosuppressant monotherapy is stopped following immunogenicity towards these biologic therapies,
a period of remission (30% in CD), whereas there is no although its efficacy in combination therapy requires
increase in relapse rates in patients who discontinue additional investigation188.
immunosuppressant therapy after combination ther- In general, biologic therapies, such as anti-TNF
apy178. In the STORI study, the relapse rate was ~52% at agents, ustekinumab and vedolizumab, are favoured over
2 years after withdrawal of an anti-TNF drug in patients thiopurines in clinical practice, especially in high-risk
receiving combination therapy, indicating that a subset patients. For example, in the SONIC study, disease
of patients in deep remission have a very low risk of remission rates were higher with anti-TNF therapy than
relapse179. with azathioprine189. If thiopurine monotherapy is the
preferred option due to economic and reimbursement
Conventional non-biologic therapies issues, its use should be restricted to selected low-risk
Induction therapy. Corticosteroids, such as budeso- patients189.
nide and prednisone, have been the cornerstone of
CD management for many decades. These agents are Biologic therapies
recommended for the treatment of mild-to-moderate Biologic agents can be used for induction and/or main-
ileal and moderate-to-severe ileocolonic CD. Steroids tenance therapy in the management of CD. The devel-
have a rapid onset of action and are indicated to induce opment of biologic therapies is an important step in
remission in CD but are not indicated for maintenance the treatment of IBD, as these drugs induce remission
of disease remission. The third European evidence- and result in response rates that are not achieved with
based consensus on the diagnosis and management other therapies. Anti-TNF therapies (such as inflix-
of Crohn’s disease from 2016 recommends daily oral imab, adalimumab and certolizumab) have revolu-
administration of budesonide (9 mg) for mild, active, tionized the treatment of CD in the past two decades.
localized ileocaecal CD97. The usual starting dose for With the introduction of infliximab and adalimumab
induction of remission in active CD is 40–60 mg pred- biosimilars, these agents have become increasingly
nisone or equivalent. A higher starting prednisone dose available in many places in the world. Newer biologic
(1 mg/kg) seems to increase the remission rate in the agents, such as ustekinumab and vedolizumab, are also
short term180,181 (weeks to months) but no compara- effective and are approved in the USA and Europe for
tive studies have been performed. Systemic steroids are treating moderate-to-severe CD77,190. The absence of
the first-line therapy for colonic CD97. In mild-to- head-to-head studies, or companion diagnostic testing
moderate cases of CD where steroids are a contrain- to predict response or non-response, results in major
dication, the British Society of Gastroenterology knowledge gaps in the treatment of CD. Physicians often
recommends exclusive enteral nutrition (the use of a make their decisions on the basis of personal experience
completely liquid diet) to induce remission182. with a particular class of drug while considering efficacy,
Mesalazine was approved by the FDA in 1987 for the safety and patient comorbidities. Patients often choose
treatment of CD. However, there is a lack of evidence for therapies on the basis of safety concerns and the most
the efficacy of mesalazine in either induction or main- common routes of administration, mostly preferring oral
tenance therapy in CD. Antibiotics are indicated in the or subcutaneous administration rather than intravenous
case of perianal complications such as abscesses, whereas administration191. Anti-TNF agents are first-line ther-
there is a lack of evidence for the efficacy of antibiotics apy in high-risk patients97, because of decades of clinical
in reducing inflammation in CD. experience, including clinical experience of efficacy and
of low incidence of adverse events, as well as a lack of
Maintenance therapy. Immunosuppressants and bio- robust data on the efficacy of vedolizumab and usteki-
logic agents have shown efficacy in maintenance therapy numab in inducing mucosal healing. Anti-TNF thera-
in CD. The use of thiopurines is limited to the mainte- pies and ustekinumab are favoured over vedolizumab,
nance of CD remission97,182. For example, In the AZTEC which seems to be slightly slower acting, when rapid
study, the early use of azathioprine was no more effec- onset of action is preferred97. However, vedolizumab is
tive than placebo in achieving sustained corticosteroid- the agent of choice in patients with multiple comorbid-
free remission but a post hoc analysis revealed that ities or safety concerns, such as elderly patients, mostly
azathioprine was more effective than placebo in pre- in relation to infection risk because of its intestinal
venting moderate-to-severe relapse183,184. Similarly, in selectivity190. Of interest, the VARSITY trial compared
the RAPID trial, administration of azathioprine within the effectiveness of vedolizumab and adalimumab in
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patients with moderate-to-severe UC; vedolizumab in IBD. Immature TH17 cells differentiate into mature,
seemed to be superior to adalimumab in achieving clin- polarized T H17 cells in response to proinflamma-
ical remission and endoscopic improvement but not tory cytokines, such as IL-12, IL-23, IL-27 and IL-35.
corticosteroid-free clinical remission192. Future trials Blockade of both IL-12 and IL-23 is effective in treat-
might show the same results in CD. Anti-TNF agents ing the chronic intestinal inflammation in both CD
are preferred in patients with severe EIMs, such as and UC. Indeed, TH17-activating proinflammatory
uveitis, ankylosing spondylitis or pyoderma gangreno- cytokines are produced in excess in IBD202, and poly-
sum. Optimization strategies with biologic agents, such morphisms in several TH17-related genes are associated
as dose escalation or frequency, are also an important with IBD202. However, in animal models of experimental
consideration to increase efficacy. Whether immuno- colitis, IL-17A blockade results in exacerbated intestinal
suppressive therapy with methotrexate or a thiopurine inflammation by affecting epithelial tight junction integ-
should be included in induction treatment with a bio- rity, suggesting that IL-17A has a tissue-protective role.
logic agent is still debated. A drawback of currently avail- Conversely, intestinal inflammation is clearly reduced
able biologic agents is their immunogenicity; however, in Il17a-knockout mice. The utility of IL-17A inhibition
the immunogenicity of vedolizumab and ustekinumab for treating patients with CD is also controversial, as the
seems to be lower than that of anti-TNF drugs169. Studies human anti-IL-17A antibody secukinumab showed no
testing the efficacy of combination therapy with these benefit in patients with CD203.
biologic agents and an immunosuppressant compared
with biologic monotherapy are lacking. Pregnancy
Therapeutic drug monitoring (TDM) is crucial when In pregnant women, gut microbial diversity is reduced
a patient stops responding to anti-TNF therapy, as there compared with that in healthy women, although only at
is an association between drug concentrations in the the beginning of pregnancy, and returns to normal in
blood and clinical outcomes193–196. Proactive TDM has middle and late pregnancy, suggesting that pregnancy is
been evaluated, and negative results have been reported safe and beneficial for patients with IBD204.
in multiple studies, although these studies had limitations Overall, pregnancy has been reported to have a ben-
(such as heterogeneous patient populations, rigid thera- eficial effect in CD, as it seems to activate tolerance and
peutic drug level ranges and the lack of using both a TDM suppressive modulation with an increased TH2 or toler-
approach and a biomarker approach)195. Further studies ogenic phenotype. Furthermore, changes in the levels of
are needed to clarify the utility of TDM in this context. pregnancy hormones seem to positively affect the epi-
Furthermore, there is limited evidence for the utility of thelial barrier. For example, the levels of human chori-
TDM in therapy with vedolizumab or ustekinumab196. onic gonadotropin, oestrogen and progesterone increase
There are few or no data on treatment approaches in rapidly during pregnancy and have anti-inflammatory
patients who fail to respond or stop responding to bio- effects in animal models of colitis, including reduced
logic agents. Switching between different non-anti-TNF IL-17 levels and increased IL-10 levels204,205. Of note, gut
biologic drugs or switching to another anti-TNF biologic microbiota changes during pregnancy have not been
drug is an option. In patients who fail to respond to drugs shown to have a beneficial effect in CD. Several fac-
of one mechanism of action, even if the dose is optimized, tors might affect whether pregnancy will be ‘protective’,
it seems logical to switch to drugs that have a different such as ongoing disease activity before conception, gut
mechanism of action197–199. As reported above, reactive microbiota- and hormone- or diet-induced changes, and
TDM is more efficacious than empirical dose escalation underlying genetic risk factors205.
because it is more cost-effective, but proactive TDM is
useful to optimize care in patients with IBD195. Quality of life
Most of the IBD therapies that are commonly used HRQOL is a multidimensional concept that includes
in Western countries, including steroids, antibiotics, thio physical, emotional and social features of health percep-
purines and anti-TNF agents, are also used in Asian tion and health functioning. The chronic and progres-
countries200 (although medical practice differs among sive nature of CD has a debilitating effect on a patient’s
Asian countries). In general, anti-TNF agents are less social, educational, professional and familial activities
frequently used in Asia than in Western countries owing (Fig. 4). The main stressors include abdominal discom-
to cost, lack of health insurance reimbursement, con- fort, bloody stools, diarrhoea, faecal urgency, impaired
cern about opportunistic infections and a lack of cli- appetite and weight loss, a need for long-term use of
nician experience with these drugs200,201. For example, immunosuppressant or immunomodulatory medi-
in a cross-sectional study comparing the management cation, and hospitalization or surgery. Increased per-
of patients with CD in different Asian regions, 40% of ceived stress, decreased social support, higher number
patients in Melbourne, Australia, received an anti-TNF of relapses and, possibly, female sex may be associated
agent compared with only 11% of patients in Hong with worse HRQOL in patients with IBD13.
Kong201. Approaches that are untested or lack evidence Addressing HRQOL in patients with an aggressive
of efficacy, such as alternative and complementary and destructive disease such as CD should be included
medicine, ayurvedic medicine and homeopathy, are in routine clinical practice because it informs clini-
common medical practice for IBD in South Asia and cians about patients’ perception of their health and
Southeast Asia200. the effect of treatments. Measuring QOL involves
TH17 cells and their pathways may have a predomi- assessing domains such as sexual activity, social activ-
nant role in the development of chronic inflammation ity, ability to work or attend school and participate in
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Early diagnosis studies have focused on the development of instru-

• Red flags ments to measure HRQOL for better evaluation of
patient health and therefore better quality of care. In a
review of HRQOL measurements and IBD, the 32-item
Patient stratification
• Comprehensive assessment (serological analysis Inflammatory Bowel Disease Questionnaire (IBDQ-32)
and endoscopic assessment of bowel damage) was the most widely used and had the strongest evi-
• Prognostic factors dence of being reliable, valid and responsive for adult
patients with IBD207.
The 10-item short IBDQ (SIBDQ) and 9-item IBDQ
Low-risk patient High-risk patient (IBDQ-9) are shorter versions of IBDQ-32 that are sim-
• Age >50 years at onset • Age <50 years at onset pler and less time-consuming to complete and have been
• Short disease duration • Smoking translated into different languages, facilitating their use
• Treatment with corticosteroids • Long disease duration worldwide208. In several studies, HRQOL was lower in
not required • Early need for corticosteroids
• Low serum CRP and faecal • Perianal fistula patients with CD than in healthy individuals and disease
calprotectin levels • Low serum haemoglobin and albumin levels activity correlated with poor HRQOL209. In addition, the
• Superficial ulcers • High serum CRP and faecal calprotectin levels presence of EIMs and an increased number of relapses
• Deep ulcers per year are associated with substantially lower HRQOL
scores on the IBDQ-32 scale210. Female sex, tobacco use
and corticosteroid therapy were related to poor HRQOL
Step-up treatment approach Top-down treatment approach
Budesonide (for ileitis and ileocolitis) Biologic agents (with or in a longitudinal, prospective study of 231 patients with
or systemic steroids (for colitis) or steroids without thiopurines) CD, which also found that HRQOL was underestimated
and thiopurines or methotrexate by physicians who were treating patients with CD211.
Furthermore, CD has a substantially negative effect on
family life and professional performance212.
Follow-up and close monitoring Treatment is an additional important stressor that
TDM, QOL, mucosal healing, bowel damage assessment affects HRQOL in patients with CD. In a study of
169 patients with CD, HRQOL was lower in patients
Inflammation? treated with corticosteroids or azathioprine than in
patients receiving no treatment213. Furthermore, sur-
Yes No gery and the potential need for an ostomy are additional
Remission
stressors for patients with CD. Of note, there was no
Therapy optimization
• Dose optimization • Switch out substantial difference in HRQOL in patients achieving
• Addition of of class for remission after surgery compared with patients in remis-
immunosuppressants primary anti-TNF sion without surgery214. Fatigue in chronic diseases such
• Switch within class for non-response as CD has been increasingly recognized as impairing
secondary anti-TNF (e.g. vedolizumab
loss of response or ustekinumab) QOL, even in patients with IBD who are in remission215.
In both CD and UC, fatigue has been shown to affect
HRQOL independently of disease activity or anaemia215.
Fig. 4 | Treatment approaches in Crohn’s disease. The treatment approach in Crohn’s
disease should be based on patient stratification at diagnosis into those at low risk and
Most patients with CD are affected by the disease
those at high risk of disease progression. Early diagnosis (that is, soon after symptom in the most productive years of their lives — during
onset) may be facilitated by the use of the red flags system (symptoms or signs suggestive their working or reproductive years. The symptom that
of Crohn’s disease). Stratification is achieved by extensive assessment of disease activity patients with CD refer to as the most difficult is pain.
(by serological and faecal analysis and endoscopic assessment of bowel damage) and Indeed, in 90% of patients, mainly abdominal pain is
prognostic factors, such as disease duration, age, smoking, early need for corticosteroids, significantly associated with diminished QOL216. Disease
complications, and ulcers. Patients at low risk of disease progression are treated by a activity is another stressor associated with decreased
step-up approach, involving induction therapy with corticosteroids, either intestinally QOL211. Social support is generally understood to have
targeted (using budesonide) or systemic (prednisone), or steroids in combination with a positive influence on outcomes such as QOL. The QOL
thiopurines or methotrexate. Patients at high risk of disease progression are treated by a
of patients with IBD is positively influenced by spousal
top-down approach, involving induction therapy comprising biologic agents (such as
anti-tumour necrosis factor (anti-TNF) therapies, the anti-integrin antibody vedolizumab
support210. Therapeutic strategies have been modified
and the anti-cytokine antibody ustekinumab), with or without thiopurines. Close to reduce the important stressors and thereby improve
monitoring is useful during follow-up to measure mucosal healing and assess quality of QOL, for example by inducing and maintaining remis-
life (QOL), and involves therapeutic drug monitoring (TDM), serum and faecal tests and sion and avoiding complications182. In clinical practice,
endoscopic evaluation of bowel damage. If no inflammation is detected at follow-up measuring HRQOL can have a direct impact on the
(that is, remission), disease activity is closely monitored in patients. However, if improvement of patient outcomes217 (Fig. 5).
inflammation is detected, then a number of steps are undertaken to identify alternative
treatments, such as those with a different mechanism of action or in a different Outlook
therapeutic class. CRP, C-reactive protein. CD is a chronic, systemic, progressive and destructive
inflammatory disorder that is increasing in incidence
sports and recreation, and body image206. In addition, worldwide. In the past two decades, the concept of pro-
HRQOL can be measured using either general instru- gressive disease has emerged with a definition of CD as
ments that are applicable to various chronic diseases or a destructive disease involving accumulating damage
disease-specific instruments. In the past 10 years, many that leads to disabling complications, such as strictures,
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abscesses and fistulas. In the past few years, therapeutic such as the Lémann score or CD severity indices, in
strategies have been directed towards achieving mucosal clinical practice and clinical trials might allow early
healing, which has resulted in disease severity and bowel treatment that could change the natural history of CD.
damage being redefined218,219. Various patient charac-
teristics and disease features assessed at diagnosis have Pathogenesis
recently been reported as prognostic factors (Box 1) for Studies of dysfunction in other organs might represent
an aggressive disease course in patients with CD219. a reservoir for knowledge transfer to illuminate patho-
genetic mechanisms in the intestines. For example, more
Disease progression than one third of patients with CD develop a distinct
Approximately 50% of patients with CD show dis- fibrostenosing phenotype, which is characterized by
ease progression in the 10 years after diagnosis. progressive narrowing of the intestinal lumen that can
Consequently, new tools have been developed to assess lead to bowel obstruction222,223, and there is currently no
bowel damage, defined as cumulative structural dam- approved or effective treatment for intestinal fibrosis in
age to the digestive system, and to stratify patients and IBD. Studies in the liver introduced the new concept of
prevent complications, such as hospitalization and sur- reversibility of fibrosis, the extent of which is depend-
gery. The Lémann score is the first tool that measures ent on the stage of fibrosis. Soon, new antifibrotic drugs
the cumulative structural damage to the bowel in CD, by developed from these studies of liver fibrosis will be
endoscopic assessment of the presence of strictures and combined with biologic therapies, and early stratifica-
penetrating lesions (that is, fistulas and abscesses), tion of individual patients with CD who are at risk of
and the requirement for surgical resection. The score a stricturing disease course should provide the ideal
facilitates the identification of patients who are at high patient population for these treatments.
risk of rapid disease progression, thereby informing
decisions to modify therapy220. Bowel damage and the Treatment
Lémann score have been demonstrated to be independ- Personalized medicine is emerging in the treatment of
ent prognostic factors for the requirement of intestinal CD, and represents a shift from controlling the symp-
surgery and CD-related hospitalization during patient toms of the disease to preventing disability in the long
follow-up4,103. term224. Personalized medicine has been defined as cus-
The International Organization for the Study of tomized health care informed by an individual’s unique
Inflammatory Bowel Diseases selected the most impor- genomic, clinical and environmental information225. In
tant attributes of IBD to create an index to define overall CD, stratifying patients on the basis of severity indices
disease severity. For CD, the presence of mucosal lesions represents the future approach in the era of personalize
(15.8%), a history of a fistula (10.9%), a history of an medicine160. Models to predict disease outcomes are in
abscess (9.7%) and a history of intestinal resection (74%) development, such as a validated Web-based predictive
explained the overall disease severity221. tool that requires the inclusion of clinical, serologi-
Preventing disease progression is an achievement cal, genetic, endoscopic and imaging information226.
that is sorely needed in the management of CD. Thus, Soon, personalized medicine will involve incorporating
the focus of future research should be to identify pre- not only symptoms, serological markers and endoscopic
dictive biomarkers, and the introduction of toolkits to and histological assessment into our patient evaluations
define and measure disease severity and progression, but also genetic and molecular phenotypes, added to
our existing knowledge of clinical and demographic
Physical status and functional abilities factors.
• Pain (e.g. joint and abdominal pain) Current available treatments for CD have limitations,
• Defecation (e.g. diarrhoea, bloody stool and faecal urgency) and new options are needed. Although targeted biologic
• Sleep therapies have been a significant advance, parenteral
• Energy levels (e.g. fatigue)
administration and the potential for immunogenicity
are major drawbacks of these therapies. A host of orally
Economic and/or administered small molecules are emerging as potential
Psychological status therapies in CD, including selective Janus kinase (JAK)
vocational status
and well-being
• Body image
• Education (e.g. ability inhibitors (for example, filgotinib and upadacitinib)197
QOL to attend school and and sphingosine-1-phosphate receptor 1 (S1PR1) ago-
• Emotional status
participate in sports
(e.g. depression,
and recreation
nists (for example, ozanimod and etrasimod)198. In addi-
anxiety and anger)
• Work (e.g. ability to work) tion, selective IL-23 inhibition (for example, the anti-p19
antibodies risankizumab and brazikumab) has shown
promise199. Although the antibiotic regimens that have
Social and interpersonal interactions
been studied to date have not consistently demonstrated
• Relationships (e.g. ability to attend social events)
• Sexual functions (e.g. frequency of intercourse, efficacy, non-absorbable antibiotics, such as rifaximin,
receptivity and initiative, pleasure and orgasm) warrant further study in CD. In addition, manipulating
the microbiota through the diet or other means, includ-
Fig. 5 | Factors that affect QOL domains in Crohn’s disease. The quality of life (QOL) ing faecal microbiota transplantation, may prove to be
of patients is assessed in physical, psychological, social and economic domains. Quality of beneficial and is also being investigated.
life in patients with Crohn’s disease is affected by disease symptoms, complications and
extraintestinal manifestations as well as the therapies that are used to treat the disease. Published online 02 April 2020
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mucosal healing predicts favorable clinical outcomes in Author contributions and Takeda, has served as a scientific advisory board member
inflammatory bowel disease: a meta-analysis. Inflamm. Introduction (G.R., L.P.-B. and S.D.); Epidemiology (S.C.N.); for AbbVie, Ferring and Takeda and has received research
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directions. Clin. Gastroenterol. Hepatol. 14, and S.D.). Peer review information
348–354.e17 (2016). Nature Reviews Disease Primers thanks B.D. Ye, A. Forbes, J.
220. Pariente, B. et al. Development of the Crohn’s disease Competing interests Gisbert, G. Monteleone, A. Regueiro and the other, anony-
digestive damage score, the Lémann score. Inflamm. S.D. has served as a speaker, consultant and advisory board mous, reviewer(s) for their contribution to the peer review of
Bowel Dis. 17, 1415–1422 (2011). member for Schering-Plough, AbbVie, Merck Sharp & Dohme, this work.
221. Siegel, C. A. et al. Development of an index to define UCB Pharma, Ferring, Cellerix, Takeda Pharmaceutical
overall disease severity in IBD. Gut 67, 244–254 Company, Nycomed, Pharmacosmos, Actelion, Alpha Publisher’s note
(2018). Wasserman, Genentech, Grünenthal, Pfizer, AstraZeneca, Novo Springer Nature remains neutral with regard to jurisdictional
This study discusses the development of severity Nordisk, Cosmo Pharmaceuticals, Vifor, Johnson & Johnson claims in published maps and institutional affiliations.
indices to allow assessment of disease severity and Nikkiso Europe GmbH. L.P.-B. has received consulting fees
and bowel damage progression in the future. from AbbVie, Amgen, Biogaran, Boehringer Ingelheim, © Springer Nature Limited 2020
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PRIMER

NATURE REvIEwS | DisEAsE PRimERs | Article citation ID: (2020) 6:22 1

Author addresses The rapid changes in CD epidemiology are a global

2 | Article citation ID: (2020) 6:22 www.nature.com/nrdp

Epithelial cell Insight into geographical variations, especially related

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4 | Article citation ID: (2020) 6:22 www.nature.com/nrdp

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Microbial dysbiosis Diagnosis, screening and prevention

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• Low risk: • Intermediate risk: • High risk: Paediatric IBD

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Drug withdrawal 6 months of a CD diagnosis was no more effective than

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Early diagnosis studies have focused on the development of instru-

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