Seminar

Crohn’s disease
Michael Dolinger, Joana Torres, Severine Vermeire

Crohn’s disease is a chronic inflammatory disease of the gastrointestinal tract that might lead to progressive bowel Published Online
damage and disability. The exact cause of Crohn’s disease is unknown, but evidence points towards multifactorial March 1, 2024
https://doi.org/10.1016/
events causing dysregulation of the innate immune system in genetically susceptible people. Commonly affecting the S0140-6736(23)02586-2
terminal ileum and proximal colon, Crohn’s disease inflammation is often discontinuous and patchy, segmental, and
Division of Paediatric
transmural. Identification of characteristic findings on ileocolonoscopy and histology remains the diagnostic gold Gastroenterology, Icahn School
standard, but complete assessment involves laboratory abnormalities, including micronutrient deficiencies, cross- of Medicine at Mount Sinai,
sectional imaging to identify transmural disease extent, severity and complications, and a psychosocial assessment. New York City, NY, USA
(M Dolinger MD); Division of
Treatment strategies for patients with Crohn’s disease now go beyond achieving clinical remission to include deeper Gastroenterology, Hospital da
targets of endoscopic healing and consideration of adjunctive histological and transmural targets to alter disease Luz, Lisbon, Portugal
progression potentially further. The use of early effective advanced therapies and development of therapies targeting (J Torres MD); Hospital Beatriz
alternative novel pathways with improved safety profiles have resulted in a new era of healing in Crohn’s disease Ângelo, Loures, Portugal
(J Torres); Faculdade de
management. Future combination of advanced therapies with diet or other biological drugs and small molecules, Medicina, Universidade de
together with improvements in tight control monitoring tools and predictive biomarkers might continue to improve Lisboa, Lisbon, Portugal
outcomes for patients with Crohn’s disease. (J Torres); Department of
Gastroenterology and
Hepatology, University
Introduction studies on incidence and prevalence from 1990 to 2016 Hospitals Leuven and KU
Crohn’s disease, one of the major entities within the reported a stable or decreasing incidence of adult Crohn’s Leuven, Leuven, Belgium
spectrum of inflammatory bowel diseases (IBDs), is a disease across most high-income countries, but not (Prof S Vermeire MD)
chronic inflammatory disease of the gastrointestinal tract paediatric Crohn’s disease and very-early onset IBD, in Correspondence to:
which might lead to progressive bowel damage and which incidence continues to rise.3 The highest reported Prof Severine Vermeire,
Department of Gastroenterology
disability.1 Crohn’s disease is now global, in part due to incidence rates of adult Crohn’s disease come from and Hepatology, University
rising incidence rates of adult and paediatric disease in Australia (29·3 × 10⁵ person-years), Canada (23·82 × 10⁵ Hospitals Leuven and KU Leuven,
middle-income countries.2,3 Novel insights of cells, cell– person-years), USA (13·9 × 10⁵ person-years), and Europe Leuven 3000, Belgium
cell communication, cytokines, and chemokines (15·4 × 10⁵ person-years). Nonetheless, high incidence severine.vermeire@uzleuven.be

implicated in disease pathogenesis, together with
technological advances, have led to a substantial
expansion of therapeutic options. Alongside the
therapeutic revolution, modalities for non-invasive
monitoring to diagnose and follow-up patients are
rapidly emerging.4,5 Computational analyses of various
omics data using patient-derived blood, stool, and tissue
samples provided new insights and biomarkers, some of
which are detectable before clinical onset of disease,
opening the prospects of early diagnosis and disease
prevention. This Seminar summarises the key advances
of the past decade in each of these domains.
Epidemiology
Crohn’s disease is usually diagnosed between ages 18
years and 35 years; a second smaller peak has been
described between ages 50 years and 60 years.1 European
and North American population-based studies have
reported a lower risk for women to develop Crohn’s
disease during childhood (as compared with ulcerative
colitis), until age 10–14 years, increasing thereafter,
especially after 25–29 years; in contrast to observations in
Asia-Pacific populations, where predominance for Crohn’s
disease in men was observed from adolescence to middle
and late-middle age, potentially highlighting differences
across world regions.6,7 Traditionally regarded as a disease
of high-income countries of North America, Europe, and
Oceania, the 21st century has seen an epidemiological
transition in IBD. Systematic reviews of population-based
areas such as Denmark have reported incidence increasing
from 9·1 person-years (95% CI 8·3–10·0) in 1995 to
17·8 person-years (16·8–19·0) in 2016. Prevalence rates
were highest in Europe (322·0 × 10⁵ person-years) and
Canada (319 × 10⁵ person-years).3 In contrast to plateauing
incidence in high-income countries, areas of the world
with historically low rates, such as Asia or South America,
seem to be witnessing an increase in incidence and
prevalence, possibly due to changes in lifestyle, diet, and
pollution exposure.8 Data from sub-Saharan Africa also
indicate a recent rise in the incidence of ulcerative colitis,
followed by Crohn’s disease.9 Given that Crohn’s disease is
typically diagnosed at a young age, and is associated with
low mortality, prevalence is expected to reach up to 1% of
the population.8,10
Risk factors
The strongest risk factor for developing Crohn’s disease is
having an affected first-degree relative (incidence rate
ratio 7·77, 95 CI 7·05–8·56; high-quality evidence).
However, even in monozygotic twins, concordance for
Crohn’s disease reaches 50%, providing an argument for
the role of environmental factors in Crohn’s disease
pathogenesis.11 Many environmental exposures have been
associated with increased Crohn’s disease risk, with
variable strengths of evidence, such as cigarette smoking
(odds ratio 1·76, 95% CI 1·40–2·20; moderate-quality
evidence) and antibiotic exposure (1·74, 1·35–2·23; low
quality evidence), whereas others such as physical activity

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 Seminar

might reduce future risk of disease (relative risk 0·63,
95% CI 0·50–0·79; moderate-quality evidence).12–15
Epidemiological studies have shown some early life
exposures (eg, breastfeeding and exposure to greenspace)
reduce the risk of disease, whereas others (eg, childhood
antibiotic exposure) increase the risk of disease, indicating
a sensitive time-period for microbiome develop­ment and
immune system maturation that could repre­ sent a
window of susceptibility for risk modulation.16,17 Dietary
factors including ultra-processed foods have been
associated with higher risk for developing Crohn’s disease
(hazard ratio 1·82, 95% CI 1·22–2·72 for five or more
servings per day; moderate-high-quality evidence).18
Pathophysiology
The cause of Crohn’s disease is accepted to be
multifactorial with hypotheses that the microbiome and
other environmental factors drive inappropriate activation
of the mucosal immune system in a genetically
susceptible host. Genome-wide association studies and
their meta-analyses have identified more than 260 risk
loci.19 Mutations in NOD2 (CARD15), the first identified
gene conferring Crohn’s disease susceptibility, and other
identified pathways, such as autophagy and endoplasmic
reticulum stress, point to dysregulation of the innate
immune system in response to luminal triggers to be key
in disease onset.20
The intestinal epithelium serves as a barrier between
the intestinal lumen and environment and the mucosal
immune system and protects against harmful bacteria.
An impaired intestinal epithelial barrier is recognised as
a key pathogenic factor, and inflammatory infiltrate is
characterised by the Th1/Th17 response with production
of various proinflammatory cytokines (TNF-α, IFN-γ,
IL-1, IL-6, IL-12, and IL-23) and impaired regulatory T-cell
activity (figure 1).21–25 The luminal gut microbiota in
Crohn’s disease is characterised by decreased diversity
compared with healthy individuals, with a reduction in
Firmicutes and Bacteroides, and an increase in
Actinobacteria and Proteobacteria. Specifically, the
butyrate producers Faecalibacterium prausnitzii and
Roseburia spp are less abundant, whereas adherent-
invasive Escherichia coli are more abundant.26
Clinical features
Crohn’s disease can affect any gastrointestinal tract
segment, most commonly the terminal ileum and
proximal colon in a discontinuous, patchy, segmental,
and transmural manner. Due to the transmural nature of
Crohn’s disease, fistula, abscesses, and strictures
frequently complicate the disease course. Extraintestinal
manifestations, most commonly joint, skin, and eye
manifestations, might be present in up to 50% of patients
(figure 2).27 Presenting symptoms in Crohn’s disease can
be variable, insidious, and dependent on location,
phenotype, and severity, which can result in delays in
diagnosis. Chronic diarrhoea, abdominal pain, weight
loss, and fatigue presenting in a young adult should raise
suspicion.28 Growth retardation or pubertal delay might
be the single sign of Crohn’s disease in children and
adolescents.29 In patients with stricturing disease,
post-prandial abdominal pain, bloating, nausea, or

Healthy state Diseased state

Terminal ileum
luminal environment Paneth cells with mutated genes
Barrier injury or Atg16L1 resulting in impairment in
Harmful
Secretion of breakdown function and decreased barrier
bacteria
antimicrobial (mucosal injury or integrity
invasion
factors inflammation)

Epithelium Paneth cells

NOD2 gene Tissue resident macrophages

expression working towards regeneration
of intestinal epithelial barrier
Cytokines

Immature
Extraluminal environment dentritic cell
(blood vessels, lymphatics, and mesentery) Naive
Monocyte
T cell
Th1, Th17
Plasma cell

Figure 1: Intestinal epithelial barrier in the pathogenesis of Crohn’s disease

The intestinal epithelial barrier is visualised in both a healthy and diseased state, showing barrier injury as a key pathogenic factor in Crohn’s disease. Paneth cells,
an important source of NOD2 expression in the terminal ileum, play a central role in controlling bacterial invasion by secretion of antimicrobial factors. Paneth cell
metaplasia can result in their location outside of the terminal ileum, in the caecum, appendix, and distal colon. Paneth cells rely on autophagy to regulate secretory
capability and capacity. Disruption of this pathway through mutations in genes such as Atg16L1 result in impaired Paneth cell function, dysregulated microbiota, and
decreased barrier integrity. Tissue-resident macrophages are important for the regeneration of intestinal epithelial cells and for maintaining homeostasis in the gut.

2 www.thelancet.com Published online March 1, 2024 https://doi.org/10.1016/S0140-6736(23)02586-2

 Seminar

vomiting might be presenting features. Fistulising

disease symptoms depend on the affected organ:
enterovesical fistulae might present with faecaluria
pneumaturia or recurrent urinary tract infections;
Eyes or ocular
enteroenteric fistulae might be asymptomatic or Uveitis, episcleritis, and
complicate with inflammatory masses, phlegmons, or scleritis
Skin
abscesses; and rectovaginal fistulae might cause Erythema nodosum, pyoderma
dyspareunia or stool discharge from the vagina. gangrenosum, psoriasis, metastatic
Crohn’s disease, and Sweet’s syndrome
Approximately one-fifth of patients present with perianal Oral or mouth
lesions, which can include simple skin tags, anal canal Aphthous stomatitis,
periodontitis, and
lesions (stenosis, fissures, and ulcers), and fistulising orofacial granulomatosis
disease with or without perianal abscesses.30,31
Alternate diagnoses should be excluded through careful
clinical history. Recent gastrointestinal infections, travel, Lungs or respiratory
Granulomatous,
history of contact with tuberculosis, non-steroidal anti- lung disease
inflammatory drugs, and other drug intake should be
sought. Physical examination should evaluate for signs of
anaemia, dehydration, and malnourishment. Patients Liver
might present with a tender mass, most commonly in the Primary sclerosis
right iliac fossa. The perianal area should be carefully cholangitis, and
autoimmune hepatitis Pancreas
inspected for findings indicated above. Acute idiopathic pancreatitis,
and autoimmune pancreatitis

Diagnostic approach
Diagnosis often begins with non-invasive serum and stool
tests to detect inflammation and exclude infection.32
Establishing the diagnosis of Crohn’s disease then
requires a combination of endoscopy to visualise the
mucosa, histological examination, and cross-sectional
imaging, with endoscopy and histopathology remaining
the gold standard.33–35 Diagnostic confirmation is crucial
after physical examination and exclusion of mimicking
pathologies, such as infectious enterocolitis (acute onset,
self-limited, microbial stool evaluation often revealing),
intestinal Bechet (intestinal inflammation and recurrent
oral and genital ulceration), intestinal tuberculosis
(endemic exposure; histology reveals caseating granulo­
mas instead of epithelioid granulomas), and familial
Mediterranean fever enterocolitis (recurrent fever attacks
[Tel-Hashomer criteria]; histology reveals linear ulceration
without epithelioid cell granulomas).36–38 Age of symptom
onset is important, as children 6 years and younger have
increased incidence of monogenic causes and immuno­
deficiencies, such as chronic granulomatous disease,
making genetic testing necessary.39 After diagnosis is
established with endoscopy and histopathology, trans­
mural disease extent, behaviour, and existing compli­
cations should be assessed using cross-sectional imaging.
Diagnostic investigations
Initial laboratory findings might include abnormalities
on the complete blood count, including leucocytosis,
anaemia due to either chronic disease, or micro and
macroscopic blood loss via the gastrointestinal tract, or
both, and thrombocytosis, a surrogate marker of acute
inflammation. Additional inflammatory markers,
C-reactive protein (CRP), and erythrocyte sedimentation
rate might be elevated. A CRP greater than or equal to
Joints or rheumatologic
Peripheral and axial
spondyloarthritis, and
enthesitis
Figure 2: Extraintestinal manifestations of Crohn’s disease
Extraintestinal manifestations of Crohn’s disease might be present in up to 50% of patients, with multiple organs
involved and different manifestations within each organ.
2·7 mg/dL has the highest diagnostic positive predictive
value of 89·6%.40 However, many patients will have a
normal CRP despite active gastrointestinal tract
inflammation.41,42 Use of the stool biomarker faecal
calprotectin less than 40 μg/g in the primary care setting
can exclude diagnosis, with less than 1% of patients later
diagnosed.43 Faecal calprotectin concentrations greater
than or equal to 1000 mg/g result in a maximum
predictive value of 78·7% for Crohn’s disease activity,
and concentrations less than 250 μg/g correlate with
endoscopic remission in Crohn’s disease, whereas two
repeated values greater than 250 μg/g without symptoms
indicate a greater than 50% chance of developing relapse
within 3 months.40,44 Additional serum tests for
hypoalbuminemia and micronutrient deficiencies, such
as iron, vitamin D, B12, B6, folate, selenium, and zinc
can aid in diagnosis.
Although endoscopy is the diagnostic gold standard
required, cross-sectional imaging, particularly intestinal
ultrasound, where available, can be used early in the
diagnostic evaluation to expedite endoscopy. Magnetic
resonance enterography (MRE) or CT enterography

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 Seminar
(CTE) should be performed at diagnosis to evaluate the
entirety of the bowel. MRE, where available, should be
considered first line over CTE in favour of limiting
radiation exposure. Intestinal ultrasound can then
complement MRE and CTE, having similar sensitivity to
MRE for detecting disease presence in the terminal
ileum (92% vs 97%).45 Intestinal ultrasound scores
moderately correlate with the Simple Endoscopic Score
for Crohn’s Disease (SES-CD; p=0·55–0·80), showing
high sensitivity (83–95%) and moderate specificity
(70–85%) to detect endoscopic inflammation.46,47
Endoscopic evaluation with histopathology for
confirmation of Crohn’s disease diagnosis and exclusion
of mimicking pathologies is essential. The most common
findings are longitudinal ulcerations, often with
erythema, oedema, and a nodular or cobblestone
appearance of the mucosa.35 Scoring systems such as the
SES-CD and Crohn’s disease Endoscopic Index of Severity
are used to grade severity of endoscopic inflammation.48,49
See Online for appendix The hallmark histological feature of Crohn’s disease is
the epithelioid granuloma; however, this is seen in fewer
than 20% of biopsies. Additional histological features
include focal patchy inflammatory infiltrate, lymphoid
aggregates, and pyloric gland metaplasia.34 When
diagnosis is uncertain and suspicion remains, evaluation
of the entire small bowel mucosa using wireless capsule
endoscopy can be useful, especially in children with
growth retardation.50
Classifying disease activity and severity
Using the above diagnostic approach, characterising
clinical features, serum and stool biomarkers, endoscopy
with histopathology, and cross-sectional imaging allows
for the classification of Crohn’s disease on the basis of
location, phenotype, and severity (Montreal or Paris
Classification).51,52 Classification can aid in risk stratification
for the development of complications or surgery.
Management
Management of Crohn’s disease has changed considerably
in parallel with newly available therapies and therapeutic
strategy evolution. Previously, Crohn’s disease was
Previous
Trials
Targan S CLASSIC-1 PRECISE-1
1997 2006 2007
Clinical response or remission
Endpoints
CDAI-70 Clinical remission CDAI-100 response,
response, (CDAI <150), week 6; response at
week 4 week 4 both weeks 6 and
26 in patients with
CRP >10 mg/L
Figure 3: Evolution of treatment goals in Crohn’s disease trials with steroid-free remission and endoscopic response
APS=abdominal pain score. CDAI=Crohn’s disease activity index. CDAI-70=70-point decrease in Crohn’s disease activity index. CDAI-100=100-point decrease in
Crohn’s disease activity index. CRP=C-reactive protein. SF=stool frequency score.
4 www.thelancet.com Published online March 1, 2024 https://doi.org/10.1016/S0140-6736(23)02586-2
managed with 5-aminosalicylates, repeated corticosteroid
courses, and immunomodulators, the only available
options at the time. High intestinal resection rates and
complications from long-term corticosteroid exposure
often left patients with clinical significant morbidities and
productivity loss. The approval of the first biological drug,
infliximab, in 1998, revolutionised Crohn’s disease
treatment. The introduction of anti-TNF therapies led to
major shifts in the therapeutic framework, from
symptomatic clinical remission towards sustained deep
remission. Treatment strategies shifted in parallel with
the evolution of therapeutic goals. Central to these
strategies are the early introduction of effective therapy,
allied with a tight and frequent control of inflammatory
activity, and adjustment of therapy on the basis of that
assessment (treat-to-target strategy).53,54
Evolution of endpoints and therapeutic goals
Therapeutic expansion has contributed to more stringent
endpoints in clinical trials (figure 3; appendix). The
STRIDE II consensus incorporated both short (clinical
response [≤50% in patient reported-outcomes of abdominal
pain and stool frequency]), intermediate (clinical remission
[abdominal pain score ≤1 and a stool frequency score ≤3, or
Harvey Bradshaw Index <5] and normalisation of
biomarkers [CRP and faecal calprotectin <150–200 mg/g]),
and long-term treatment goals (endoscopic healing
[SES-CD <3], normalised quality of life, absence of
disability, and restoration of growth for children).55
Although histological and transmural healing are not yet
formal treatment goals, they are considered useful
adjunctive tools.
Early intervention
Post-hoc data have revealed that biological therapy is
more effective if introduced earlier in the disease course,
preparing for the concept of early intervention and
opportunity. A systematic review and individual-patient
data meta-analysis of all placebo-controlled trials of
biologics approved for Crohn’s disease showed that
higher remission rates were observed during induction
in patients with shorter disease duration (≤18 months) in
Current Future
GEMINI2 UNITI 1&2 ADVANCE MOTIVATE
2013 2016 2022 2022
Clinical remission CDAI-100
(CDAI <150) and response, Endoscopic response
CDAI-100 week 6
response, CDAI <150 (USA), SF <2·8,
week 6 APS <1, week 12
Disease
modification

Efficacy
5-aminosalicylate (oral)
57
5-aminosalycilates Not effective for induction or maintenance
and sulphasalazine
Budesonide57 (oral)
budesonide Effective in inducing clinical remission in
mildly active ileal or ileocecal Crohn’s disease
compared with placebo; three RCTs
compared with mesalamine (no statistical
significant differences were observed for
clinical remission, response, or adverse
events)
Systemic corticosteroids57 (oral and intravenous)
Prednisone, Effective in inducing clinical remission and
prednisolone, response in moderate to severe Crohn’s
methylprednisolone disease; oral methylprednisolone 48 mg/day
and reduced on a weekly basis to 32 mg,
24 mg, 20 mg, 16 mg, and 12 mg;58 oral
prednisolone ranged from 0·50 mg/kg to
0·75 mg/kg, with a maximum daily dose of
60 mg;59 prednisolone is usually tapered at
5 mg/week over an 8–12-week period, but
can be tapered at a quicker rate depending
on the efficacy of the advanced therapy
initiated
Thiopurines57 (oral)
6-mercaptopurine Not effective for induction of clinical
and azathioprine remission or response; recommend
Induction of performing thiopurine methyltransferase
remission before initiation; consideration of NUDT15
polymorphisms depending on local
guidelines to reduce potential adverse
events by starting at a lower dose or adding
allopurinol in the setting of
hypermethylation
6-mercaptopurine More effective than placebo based on a
and azathioprine pooled analysis in maintaining remission in
Maintenance of steroid-dependent Crohn’s disease patients
remission
Methotrexate57 (oral and subcutaneous)
Induction of Effective for inducing clinical remission in
remission steroid-dependent patients over a 16-week
period (25 mg/week of intramuscular
methotrexate combined with steroids);
folate supplementation can be used to
reduce potential side-effects
Maintenance of More effective than placebo in a single RCT
remission in maintaining remission in patients with
steroid-dependent Crohn’s disease
(methotrexate 15 mg/week intramuscularly)
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Quality of the data Key adverse effects
Low to moderate Well tolerated; key adverse events include renal
toxicity (interstitial nephritis and nephrotic
syndrome), rare pulmonary toxicities (interstitial
lung disease and pulmonary granulomatosis),
pericarditis, and Stevens-Johnson syndrome
Moderate Well tolerated; not to be used as a maintenance
strategy; key adverse events include yeast
infections (oral and genitourinary in females),
urinary tract infections, and mild Cushing
syndrome
Moderate Adverse events five times more frequent
compared with placebo; key adverse events
include Cushing syndrome, infection (increased
risk of abdominal and pelvic abscesses in patients
with Crohn’s disease), and growth failure in
children; additional adverse events include
musculoskeletal (osteoporosis, osteonecrosis,
and myopathy), acne, psychiatric (psychosis,
suicidal ideation), metabolic (hypothalamic
pituitary axis suppression, hypertension,
diabetes, and cataracts), ecchymoses, and
glaucoma
Very low In a pooled analysis of five RCTs, no statistical
significant difference with placebo for adverse
events; higher, albeit non-significant rates of
serious adverse events; key adverse events
include allergic reactions and pancreatitis
Moderate Adverse events and serious adverse events
during maintenance treatment were significantly
higher than with placebo; key adverse events
include poor gastrointestinal tolerance,
myelosuppression, leukopenia, and potential
increased risk of malignancies (lymphoma, non-
melanoma skin cancer, myeloid disorders, and
urinary tract cancers); cautious use encouraged in
boys, adolescents, and young men and older
people who are at increased risk of developing
malignancy; other serious adverse events include
allergic reaction and infection
Low Key adverse events resulting in treatment
discontinuation were liver enzyme elevation and
nausea, which were significantly higher than
placebo
Moderate Key adverse events are nausea and vomiting,
which occurred more frequently among patients
compared with placebo
Seminar
Limitations of data
Little data available on clinical
response, PRO response and
remission, biochemical and
endoscopic improvement, and
serious adverse events
One RCT comparing budesonide to
5-aminosalicylate with serious
inconsistency; overall no clinical
significant risk of bias; no high-
quality data on biomarker or
endoscopic response or remission
Serious imprecision due to sparse
adverse events in RCTs, lowering
the quality of evidence
Heterogenous trials (study design,
follow-up time, definition of active
disease, and definition of
remission); most trials allowed for
concomitant use of steroids; the
quality of evidence for estimating
adverse events or serious adverse
events low due to reduced number
of events and wide confidence
intervals
No data
No studies looking at methotrexate
monotherapy; the single RCT
available is limited by serious or
very serious imprecision due to the
confounding effect of concomitant
use of steroids
Serious imprecision due to sparse
data; no data on biomarker
remission, PRO remission, and
serious adverse events
(Table 1 continues on next page)
5
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Efficacy
(Continued from previous page)
Anti-TNF57 (intravenous and subcutaneous)
Infliximab, Effective for induction and maintenance of
adalimumab, and clinical remission and response, and for
certolizumab pegol endoscopic improvement and remission in
moderate to severe Crohn’s disease;
combination therapy with
immunomodulators might be used to
reduce development of anti-drug antibodies
Anti-Integrin57 (intravenous and subcutaneous)
Vedolizumab Effective for induction and maintenance of
clinical remission and response, for
maintenance of steroid-free clinical
remission, and for endoscopic improvement
and remission in moderate to severe Crohn’s
disease; effective for inducing endoscopic,
radiological, and histological healing
Anti-IL-12 or IL-2357 (intravenous and subcutaneous)
Ustekinumab Effective for induction and maintenance of
clinical remission and response, for
maintenance of steroid-free clinical
remission, and for endoscopic improvement
and remission in moderate to severe Crohn’s
disease
Anti-IL-2360 (intravenous and subcutaneous)
Risankizumab Effective for induction and maintenance of
clinical remission and response, and for
endoscopic remission
JAK inhibitors61 (oral)
Tofacitinib Not effective for inducing clinical remission
or endoscopic remission
Filgotinib Effective for inducing clinical remission
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Quality of the data Key adverse effects Limitations of data
Moderate Key serious adverse event include higher risk of Pooled analysis from RCTs limited
serious infections and higher risk of lymphoma to assess steroid-free clinical
when combined with thiopurines, particularly in remission, PRO remission,
older people; additional adverse events include radiological and biochemical
psoriasiform eczematous reactions of the skin remission, quality of life, and
serious adverse events
Moderate No statistical significant difference in adverse Limited quality of evidence, serious
events or serious adverse events compared with (imprecision) to assess serious
placebo in RCTs; no safety signals from long- adverse events due to sparse data;
term follow-up studies to date; key adverse data on endoscopic, radiological,
events include Crohn’s disease exacerbation, and histological healing are not
arthralgia, headache, and nausea; rarely, infusion placebo controlled; limited data on
reactions (most often without the need for biomarker normalisation
discontinuation), enteric and sinopulmonary
infections, and diffuse severe musculoskeletal
pain occur
Moderate to high No statistical significant difference in adverse Little data on biomarker and
events or serious adverse events compared with endoscopic remission
placebo in RCTs; no safety signals from long-
term follow-up studies to date; key adverse
events include upper respiratory tract infection,
nasopharyngitis, infusion, and injection site
reactions; rare adverse events and serious
adverse events include serious infections,
arthralgias, rash, headache, and elevated
transaminases
High Lower risk of serious adverse events during Little real-world data available;
induction and maintenance with risankizumab long-term safety profile unknown
was seen; key adverse events include in the setting of Crohn’s disease
hypersensitivity and injection site reactions and
hepatotoxicity; the most frequent adverse events
are headache, arthralgia, and nasopharyngitis
Moderate to high Key serious adverse events include herpes zoster, High placebo rates, inclusion of
although not frequently encountered in Crohn’s patients with mild disease, and lack
disease RCTs; EMA PRAC assessment of requirement for centrally read
recommends caution to use on patients older confirmation of endoscopic
than 65 years with risk factors or history of inflammation or elevated CRP or
smoking due to potential risk for MACE and faecal calprotectin at enrolment
malignancy; other adverse events include
leukopenia, elevated transaminases,
hypercholesterolemia, and development or
worsening of acne
Moderate to high Key serious adverse events include herpes zoster, Failed to get regulatory approval
although not frequently encountered in Crohn’s due to failure to meet the co-
disease RCTs; EMA PRAC assessment primary endpoint of clinical
recommends caution to use on patients older remission and endoscopic response
than 65 years with risk factors or history of at week 10
smoking due to potential risk for MACE and
malignancy; other adverse events include
leukopenia, elevated transaminases,
hypercholesterolemia, and development or
worsening of acne
(Table 1 continues on next page)

Efficacy
(Continued from previous page)
Upadacitinib Effective for inducing and maintaining
clinical response and remission, and
endoscopic improvement and remission
Anti-TNF=anti-tumour necrosis factor. CRP=C-reactive protein. EMA=European Medicines Agency. MACE=major adverse cardiovascular events. PRAC=Pharmacovigilance Risk Assessment Committee.
PRO=patient reported outcome. RCT=randomised controlled trial.
Table 1: Efficacy and safety of Crohn’s disease pharmacotherapy
both active and placebo treatment groups, compared
with remission rates in patients with longer disease
duration (>18 months).56 However, absence of validated
objective biomarkers for prediction of disease course
makes it difficult to appropriately select patients that
benefit the most from early intensive treatment.
Medical management
Recent therapeutic expansion with new biologics and
small molecules, either recently introduced or soon to
arrive in practice, has complicated treatment choice.
Treatment selection should actively involve the patient in
the decision-making process and be individually guided by
disease activity, location, phenotype, patient (comorbidities,
lifestyle, wish for pregnancy, etc) and drug-related factors
(safety, cost, speed of onset, administration, etc). Patient
education on therapeutic goals and monitoring strategy
should be provided before treatment, in conjunction with
treatment selection counselling. Table 1 summarises the
efficacy and safety of pharmacotherapy discussed below.
Aminosalicylates
Aminosalicylates are not effective in treating Crohn’s
disease and have low efficacy to prevent postoperative
recurrence and, therefore, should not be used during
induction or maintenance.
Antibiotics
Antibiotics are indicated to treat Crohn’s disease-related
perianal and intra-abdominal abscesses, not for treatment
of luminal Crohn’s disease nor as monotherapy for
complex fistulising disease.57 One study suggests that
ciprofloxacin combined with anti-TNF therapy could
impact anti-TNF efficacy for perianal fistula closure in
the short term, but not long term, after antibiotic therapy
discontinuation.62
Corticosteroids
For patients with mild localised ileal or ileocecal disease,
budesonide, a locally acting glucocorticosteroid with
fewer side-effects compared with prednisone, is
www.thelancet.com Published online March 1, 2024 https://doi.org/10.1016/S0140-6736(23)02586-2
Seminar
Quality of the data Key adverse effects Limitations of data
Moderate to high Key serious adverse events include herpes zoster, No data
although not frequently encountered in Crohn’s
disease RCTs; EMA PRAC assessment recommends
caution to use on patients older than 65 years
with risk factors or history of smoking due to
potential risk for MACE and malignancy; other
adverse events include leukopenia, elevated
transaminases, hypercholesterolemia, and
development or worsening of acne
recommended for induction of remission.57 Systemic
corticosteroids are effective in inducing remission in
moderate-to-severe Crohn’s disease and other disease
locations, but have no proven efficacy as maintenance
treatment. Steroid-free remission is a major treatment
goal, and repeated systemic corticosteroid courses should
be avoided given the well known toxicity associated with
prolonged exposure (table 1).
Immunomodulators
Thiopurines (azathioprine and mercaptopurine) and
methotrexate might be used as monotherapy for
maintenance or remission in steroid-dependent Crohn’s
disease and have an important role in preventing
antidrug–antibody development (immunogenicity) to
anti-TNF.57 Efficacy of thiopurines to achieve endoscopic
healing is substantially lower compared with anti-TNF.63
Two controlled trials in early Crohn’s disease did not
show azathioprine monotherapy efficacy for disease modi­
fication.64,65 In the prospective PANTS study, immuno­
modulator addition to anti-TNF mitigated the risk of
immunogenicity.66 Besides limited efficacy, thiopurines
are frequently poorly tolerated (gastrointestinal intolerance
in ~15% of patients), can cause myelosup­ pression,
idiosyncratic pancreatitis, and have potential for increased
risk of malignancies (lymphoma, non-mela­ noma skin
cancers, myeloid disorders, and urinary tract cancers).
Therefore, thiopurines should be used with caution in
young men and older patients who are at increased risk of
developing malig­nancy.
Anti-TNF therapy
Anti-TNF agents are among the most effective therapies
to induce and maintain remission in Crohn’s disease.
Although three agents (infliximab, adalimumab, and
certoliziumab pegol) are approved, only infliximab and
adalimumab are used globally; use of certolizumab is
limited to fewer countries. Infliximab is the only
advanced therapy with a dedicated randomised controlled
trial to show efficacy for the treatment of perianal disease,
whereas adalimumab has shown efficacy, compared to
7
 Seminar
For more on Janus kinase
inhibitors see https://www.ema.
europa.eu/en/medicines/human/
referrals/janus-kinase-inhibitors-
jaki
8 www.thelancet.com Published online March 1, 2024 https://doi.org/10.1016/S0140-6736(23)02586-2
placebo, for fistula healing in the CHARM trial as a
secondary endpoint.67,68 Additional advantages of anti-
TNF include their efficacy in treating extraintestinal
manifestations, such as pyoderma, uveitis, psoriasis, and
axial spondyloarthropathy, and specific situations such as
stricture (CREOLE study) disease, postoperative
prophylaxis (PREVENT study), and pregnancy (PIANO
study).69–71 Due to immunogenicity potential, anti-TNF
efficacy is improved when combined with an immuno­
modulator.66
Biosimilars, which are similar in efficacy and safety to
the originators while representing potential cost-savings
and greater access worldwide, have been approved since
September, 2013 in Europe and April, 2016 in the USA.
Although anti-TNFs provided an important therapeutic
advancement, and for patients with perianal fistulising
disease remain the most effective option, response to
treatment is not observed in 15–20% of patients, and
30% of patients will lose response over time.66 Side-
effects of anti-TNFs, including serious infections and
psoriasiform eczematous reactions of the skin, paved the
way for newer, safer agents.72,73 The risks and benefits of
combination therapy with an immunomodulator need to
be considered, especially in older people, given the
higher risk for infections and lymphomas.74,75
Therapies targeting alternative pathways to anti-TNF
Vedolizumab and ustekinumab are IgG1 biologics with
different mechanisms of action, the approval of which
followed anti-TNF for treatment of moderate-to-severe
Crohn’s disease. Both classes appear to have few serious
side effects (table 1) and reduced immunogenicity
without the need for combination therapy with an
immunomodulator, although long-term safety data are
still limited. First-line use is limited in many countries
due to reimbursement policies that require previous
anti-TNF failure.
Vedolizumab is an anti-α4β7 integrin monoclonal
antibody with gut selectivity, administered intravenously
every 8 weeks during maintenance, following an
induction period (weeks 0, 2, and 6).76 Although gut
selectivity of vedolizumab is responsible for its favourable
safety profile, it limits the use in treatment of Crohn’s
disease with extraintestinal manifestations. Within the
class of lymphocyte trafficking agents, other molecules
such as etrolizumab and ontamalimab have not met
efficacy endpoints in randomised controlled trials.77,78
Ustekinumab, an anti-IL-12 and IL-23 p40 antibody, is
given by subcutaneous injection every 8 weeks following
weight-based dosage intravenous induction.79
Ustekinumab is also approved for plaque psoriasis and
psoriatic arthritis. Within the class of IL-12 and IL-23
signalling, promising antibodies targeting the p19
subunit are expected to provide better efficacy over
ustekinumab, and phase 3 data are available for
risankizumab, whereas phase 2 data have been published
for mirikizumab and guselkumab.80–83
There has been a shift towards new convenient oral
agents in recent years that lack immunogenicity, have a
short half-life, and fast onset of action janus kinase (JAK)
inhibitors interfere with STAT signalling and have broad
and potent anti-inflammatory effects. Tofacitinib has not
shown efficacy in phase 2 studies and stopped further
development in Crohn’s disease. Upadacitinib and
filgotinib, JAK-1 selective agents, completed phase 3.84,85
The randomised phase 3 upadacitinib induction studies,
U-EXCEL and U-EXCEED, and the maintenance
U-ENDURE study, met primary endpoints of inducing
and maintaining clinical remission and endoscopic
response in patients with moderate to severe Crohn’s
disease.86 JAK inhibitors have advantages of targeting
multiple extraintestinal mani­ festations but should be
used with caution in patients with risk factors for
thromboembolic events. Furthermore, this class of agents
should only be used if no alternative treatment options
are available in patients 65 years or older, or at increased
risk of cancer or major cardiovascular events (table 1).
Positioning of therapies
With newer therapies arriving to clinical practice, there is
great debate on how to position and sequence advanced
therapies. The SEAVUE head-to-head trial comparing
ustekinumab and adalimumab as induction and
maintenance therapy in moderate-to-severe biological
naive Crohn’s disease showed similar rates of clinical
and endoscopic remission after 1 year.87 A recent network
meta-analysis looking at efficacy of therapies in moderate-
to-severe Crohn’s disease reported that infliximab
5 mg/kg ranked first for induction of clinical remission,
but risankizumab 600 mg ranked first in patients who
were biologically exposed. Upadacitinib 30 mg once per
day ranked first for maintenance of remission.88 Although
network meta-analyses might be useful to estimate
comparative efficacy and safety outcomes, they reflect
indirect comparisons and cannot replace head-to-head
trials. Additionally, there is increasing acknowledgement
that features such as disease location and disease
duration can affect efficacy outcomes—aspects that are
usually not considered in randomised controlled trials.
Although the quest for molecular markers that might
guide therapy selection (precision medicine) continues,
therapy positioning in clinical practice is often driven by
disease activity and desired safety profile, in addition to
other factors such as reimbursement policies, drug-
related factors (cost or mode of administration), and
patient-related factors (comorbidities or wish for
pregnancy; table 1). In table 2, we describe some of the
scenarios frequently encountered in clinical practice, and
how those might affect positioning for currently approved
therapies for moderate-to-severe Crohn’s disease.
Surgery
Surgical indications can be divided into abdominal
Crohn’s disease and perianal Crohn’s disease, with
 Seminar

emergent and non-emergent considerations. Emergent

Initial therapy consideration Selection reasoning
abdominal Crohn’s disease surgery indications include
acute bowel obstruction with vomiting, absence of Age ≥60–65 years or other risk Vedolizumab or ustekinumab Lower risk of serious infections
factors for serious infections74,60 compared with anti-TNF or JAK
passage of stool or flatus per rectum, and intestinal
Perianal disease67,68 Infliximab (adalimumab as RCT data for infliximab; post-hoc
perforation, whereas non-emergent indications include second-line therapy if secondary data available for adalimumab
medically refractory disease and complications not LOR to infliximab)
amenable to medical therapy. For perianal Crohn’s Prevention of postoperative Anti-TNF or vedolizumab RCT data available
disease surgery, complex fistulae and perianal abscesses recurrence70
are common indications, with pelvic sepsis being an High inflammatory burden (deep Anti-TNF or upadacitinib Fast onset of action
ulcerations, high CRP,
emergent indication. Surgical management should be
hypoalbuminemia, or severe
multidisciplinary, including nutritional optimisation, disease activity)
steroid tapering, thromboembolic event prevention, Psoriasis or psoriatic arthritis Anti-TNF or ustekinumab Both target bowel and skin
laboratory abnormality correction, smoking cessation inflammation
counselling, and post-surgical monitoring and pro­ Axial spa Anti-TNF or JAKs Both target bowel and axial
phylactic therapy discussions.89 The positioning of inflammation
surgery early in Crohn’s disease has been supported by Preconception and pregnancy71 Anti-TNF (greatest experience), Established safety and do not
vedolizumab, or ustekinumab cross placenta during the first
the L!RIC trial,90 in which patients with uncomplicated trimester of pregnancy
terminal ileitis less than 40 cm, for whom conventional Thiopurine contraindicated Vedolizumab, ustekinumab, or Less or no immunogenicity; no
therapy did not elicit a response, were randomly assigned (intolerance or history of upadacitinib evident benefit of using
to early laparoscopic resection or infliximab initiation. pancreatitis) combination therapy to increase
The primary endpoint, quality of life (measured by the efficacy

Inflammatory Bowel Disease Question­naire) was similar
in both groups.90 When comparing adverse events, clinical
significant surgical intervention-related complications
occurred in four of 73 patients in the resection group,
and treatment related serious adverse events occurred in
two of 70 patients in the infliximab group. At 5-year
follow-up, although none of the surgical patients required
re-resection, approximately one-quarter of patients
required a biologic, whereas in the anti-TNF group half of
the patients needed surgery.91 As Crohn’s disease is
lifelong, and post-surgical recurrence occurs frequently,
balloon dilation or novel stent placement in patients
with obstructive Crohn’s disease should be
considered.92 Resection of the mesentery, and the Kono-S
anastomosis (antimesenteric, functional, end-to-end,
hand-sewn ileocolic anastomosis) are recently proposed
surgical techniques that might decrease the chance of
postoperative recurrence when surgery is performed.93,94
During surgical resection, emphasis should be placed on
small bowel preservation and maintenance of continence
for perianal surgery.
Treatment and surgical management of perianal
Crohn’s disease remains challenging. In a
multidisciplinary team approach with an experienced
colorectal surgeon and gastroenterologist, treatment
might require examination under anaesthesia, incision,
and drainage of abscesses, with placement of non-cutting
setons to facilitate drainage of fistula tracts and prevent
ongoing infection and sepsis, and optimisation of
medical therapies, simultaneously. Ultimately, many
patients require stoma creation to divert stool from the
perianal area to aid healing. However, once a stoma is
created, there is a high chance of permanence. Review of
potential stoma complications, such as leaking of stool
contents, peristomal complications such as pyoderma
gangrenosum, and surgical complications such as
Loss of response to a first anti-TNF Alternative anti-TNF in Higher chances of developing
due to immunogenicity combination with antibodies to a second anti-TNF
immunomodulators, agent compared with first anti-
vedolizumab, ustekinumab, and TNF
upadacitinib
Possible clinical scenarios that might drive therapeutic decision and positioning of different advanced therapies.
CRP=C-reactive protein. LOR=loss of response. RCT=randomised controlled trial. *The therapeutic options listed reflect
the authors’ own clinical opinion.
Table 2: Positioning of Crohn’s disease therapies in different clinical scenarios*
prolapse or obstruction should be discussed with the
patient before creation.
Mental health and the burden of living with Crohn’s disease
Crohn’s disease has a significant psychological impact, with
anxiety and depressive symptoms in 35% and 22% of
patients, respectively.95 Psychosocial comorbidities are often
exacerbated by unpredictable flares and symptoms, causing
coping difficulties and substantial distress; however, for
many people, the severity of psychological distress is
independent of gastrointestinal activity.96 During periods of
clinical remission, not only during flares, fatigue and
persistence of food-related issues can be reported in up to
50% of patients, including loss of appetite and independent
use of diet to control symptoms, which affect patient lives
and require addressing during clinical visits.97,98 Symptoms
of anxiety and depression in patients with IBD are often
driven by specific areas of concern; disease impact,
treatment, intimacy, and stigma can contribute to work
impairment and low self-esteem.99 Cognitive behavioural
therapy is an effective option to improve symptoms of
anxiety or depression and quality of life in patients with
Crohn’s disease, but is limited by availability at few expert
centres.100
Psychosocial effects of Crohn’s disease can lead to high
rates of disability. In a 10-year follow-up study of a Danish

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 Seminar
unselected population-based inception cohort, Crohn’s
disease patients presented substantial direct costs, but
also indirect costs of lost income, paid sick leave, leaves
of absence, or unemployment benefits.101
Monitoring strategies and tools
Tight monitoring
Central to disease control is activity monitoring in specific
intervals based on objective biomarkers (tight
monitoring). The CALM study was a randomised, two-
arm, multicentre, open-label study, in which therapy was
escalated based on symptoms (conventional group) or
objective biomarkers of inflammation, CRP or faecal
calprotectin, or both (tight control group).102 This study
showed that biomarker dominant tight control was
associated with better clinical and endoscopic outcomes
compared with symptom-driven control alone.102
Treat-to-target
STARDUST was the first treat-to-target trial in Crohn’s
disease in which therapy was adjusted on the basis of
endoscopic response. The primary endpoint of endoscopic
response (SES-CD decrease of 50%) at week 52 was not
met, possibly due to high efficacy in the standard of care
group and a primarily bio-naive population.103 The cluster
randomisation REACT-2 trial in Crohn’s disease will
assess whether treating to endoscopic healing will reduce
disease progression and complications (NCT01698307).
After random assignment of 525 patients with Crohn’s
disease to early combination therapy and therapy
intensification to target absence of ulcers (>5 mm in size;
enhanced care) and 569 patients to standard of care and
treatment intensification to target clinical remission
(Harvey-Bradshaw Index <4), the primary endpoint
(Crohn’s disease-related complications) was achieved in
40·9% and 43·1% of patients (adjusted risk difference
[ARD] −1·5%; 95% CI −10·2 to 7·2; p=0·73). Although
complete analysis is needed, a high proportion of patients
in remission at study entry might be the reason for the
apparent lack of significant difference in endpoints
between groups. In post-hoc analysis based on active
disease, defined by CRP greater than 5 mg/L and presence
of baseline ulcerations, the ARD was −15·1% (−27·8 to
−2·4) and −21·6% (−34·3% to 8·9; p<0·001) for enhanced
care versus standard-of-care, respectively.104
Cross-sectional imaging in the treat-to-target strategy
STRIDE-II considered transmural healing as an adjunctive
goal, but since publication, increased use of transmural
disease activity monitoring and healing as a treatment
target have become increasingly recognised.55 MRE
indices have shown capability for monitoring treatment
responsiveness, but multiple barriers to implementation,
such as cost, availability, real-world specificity, and
tolerability have reduced its use in tight control.105,106 For
serial transmural tight monitoring assessment, intestinal
ultrasound is emerging as a patient-centric modality. The
10 www.thelancet.com Published online March 1, 2024 https://doi.org/10.1016/S0140-6736(23)02586-2
ability to monitor transmural disease activity using
intestinal ultrasound for rapid response assessment and
decision making and response has begun to shift cross-
sectional imaging from a static to dynamic tool.
Incorporation of early intestinal ultrasound assessment,
benchmarked to gold standard endoscopy and MRE to
monitor responsiveness is likely to enhance our ability for
accurate tight monitoring. In centres where intestinal
ultrasound is available for short interval tight monitoring,
MRE can be used in a similar treat-to-target manner as
endoscopy to assess for transmural healing.
Intestinal ultrasound as a monitor of treatment response
Two multicentre studies have shown that monitoring
treatment response to biological therapies with intestinal
ultrasound is possible.107,108 A decrease in bowel wall
thickness can occur within 12 weeks of treatment
initiation. In children with Crohn’s disease, changes in
bowel wall thickness can be seen as early as 2 weeks
after anti-TNF initiation; in adults, change in bowel wall
thickness at 4 weeks could predict endoscopic
response.108,109
Future direction
Predicting disease onset and the prospect of disease prevention
Data support the concept that Crohn’s disease is present
before clinical symptoms.110 Preclinical studies could lead
to a better understanding of disease initiation events and
potentially uncover biomarkers that aid in disease
prediction and prognostication before symptoms.
Antimicrobial markers and up to 51 proteins have been
shown to be predictive of Crohn’s disease future
diagnosis.111,112 Antimicrobial antibodies in first-degree
relatives have also shown to increase risk of developing
future Crohn’s disease.113 Increased intestinal permeability
was also associated with future development of Crohn’s
disease.114
Predicting disease course
To better predict disease at diagnosis, the RISK cohort of
newly diagnosed, treatment-naive paediatric patients
with Crohn’s disease identified an extracellular matrix
signature associated with risk of stricture within 3 years.115
A CD8+ T-cell transcriptional signature that has been
shown to predict disease course is currently being
explored in the biomarker-stratified PROFILE trial.116,117
Monitoring disease progression
The SPIRIT initiative proposed goals to achieve in disease-
modification trials for preventing disease progression.118
The Lemann Index, an objective reproducible measure of
Crohn’s disease progression and structural bowel damage,
has been proposed as one outcome of such trials.119,120
Combination of advanced therapies and new approaches
Despite five distinct classes of advanced therapies soon
to be available in the clinic, remission rates for all agents

are plateauing at approximately 30%.121 Combining
biologics has so far not provided answers. Other solutions
include improved patient stratification with companion
biomarkers to enrich study populations.
Predicting response to therapies
To date, no validated markers are available, as oncostatin
M and TREM-1 have provided conflicting results to
predict anti-TNF non-response.122,123 Carrying HLA-
DQA1*05 polymorphisms was associated with an
increased risk of development of antibodies against anti-
TNF agents.124
Diet modification to treat Crohn’s disease
In addition to potential effects on intestinal inflammation
and symptoms, dietary therapies also enhance the
nutritional status of patients with Crohn’s disease. The
benefit of dietary therapies is evident in the preoperative
setting, in which treatment with exclusive enteral
nutrition (EEN) shortens duration of surgery and reduces
postoperative complications.125 EEN is used globally as an
alternative to steroids, especially in children, where it has
a benefit over corticosteroids in improving mucosal
inflammation.126 Although complying with a strict EEN
diet is challenging, partial enteral nutrition (PEN) might
only be needed. When used in combination with the
Crohn’s disease exclusion diet (CDED; a whole foods diet
administered in phases attempting to limit foods that
alter the microbiome or intestinal barrier), PEN plus
CDED was superior to EEN alone in inducing clinical
remission and normalising CRP compared with EEN
alone after 12 weeks.127 CDED alone has been shown to
have no differences in sustained or endoscopic remission
24 weeks after initiation combined to CDED with PEN in
an open-label, pilot, randomised trial of adults.128 The
evidence for the simple carbohydrate and Mediterranean
diets remains less clear.129
Search strategy and selection criteria
We searched for relevant manuscripts using PubMed,
MEDLINE, and the Cochrane Library, from database inception
until Sept 1, 2022. The search combined the MeSH terms
“Crohn’s disease” and “inflammatory bowel disease” with
subheadings “biomarkers”, “complications”, “diagnosis”,
“endoscopy”, “epidemiology”, “genetics”, “imaging”,
“monitoring”, “pathophysiology”, “precision”, “prediction”,
“prevention”, “surveillance”, “target”, and “therapy”.
We searched bibliographies of the included articles for
additional references and critically reviewed all manuscripts
considered. We then prioritised manuscripts published since
the last version of this Seminar over the past 5 years. Where
possible, priority was given to randomised, placebo-
controlled trials, and meta-analyses. Relevant abstracts from
major meetings were also considered before publication of
associated manuscripts.
www.thelancet.com Published online March 1, 2024 https://doi.org/10.1016/S0140-6736(23)02586-2
Seminar
Targeting transmural healing to improve long-term outcomes
Transmural healing confers additional benefits over
mucosal healing for decreasing the risk of Crohn’s disease
progression.130–134 Postoperative patients with Crohn’s
disease who have transmural inflammation but mucosal
healing have increased risk of endoscopic and surgical
recurrence.135 Patients with Crohn’s disease with evidence
of transmural healing have reduced medication escalation,
corticosteroid use, hospitalisation, and surgery.136 It has
become clear that achievement of transmural healing is
more readily possible today, but rates of transmural
healing in Crohn’s disease still remain low overall, at
25–42%, 1–2 years after biological therapy initiation.137–139
Contributors
All authors contributed to the manuscript concept and design, and
drafted, revised, and approved the final version of the manuscript.
Declaration of interests
MD is a consultant for Neurologica, a subsidiary of Samsung Electronics,
and Pfizer. He has received grant funding from the Helmsley Charitable
Trust. JT has received grant support from AbbVie and Janssen; payments
or honoraria from AbbVie, Janssen, and Pfizer; advisory board fees from
for AbbVie, Pfizer, and Janssen; and support for meetings or travel, or
both, from AbbVie. SV has received research support from AbbVie,
Johnson & Johnson, Pfizer, Galapagos, and Takeda; lecture fees from
AbbVie, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Bristol Myers
Squibb, Ferring, Galapagos, Genentech-Roche, Gilead, Janssen, Johnson
& Johnson, Lilly, Materia Prima, Merck Sharp & Dohme, Pfizer, Takeda,
Tillotts Pharma, and Zealand Pharma; and consulting fees from AbbVie,
AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals,
AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera,
Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK,
Hospira, Imidomics, Janssen, Johnson & Johnson, Lilly, Materia Prima,
MiroBio, Morphic, MrMHealth, Mundipharma Merck, Pfizer, Prodigest,
Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire,
Surrozen, Takeda, Theravance, Tillots Pharma, and Zealand Pharma.
Acknowledgments
We would thank academic medical illustrator Jill Gregory for her help
with the original figure design.
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