Clinical Medicine 2023 Vol 23, No 6: 549–57 CME SPECIAL: GASTROENTEROLOGY

Crohn’s disease: an update

Authors: Ella Cockburn, A Shahed Kamal,B Andrea Chan, A Vikram Rao,C Tianwei Liu,D Joanna Y HuangE and
Jonathan P SegalF

Crohn’s disease (CD) is a chronic, relapsing and remitting and ocular features.2,3 In all IBD, the prevalence of at least
ABSTRACT

inflammatory bowel disease (IBD) that is increasing in one joint manifestation is 24%, ocular manifestation 27% and
incidence and prevalence globally. Management aims extraintestinal skin manifestation 35%.4 The widely utilised
to achieve endoscopic healing, symptom resolution and Montreal classification system classifies CD phenotype based on
improvement in quality of life. Therapeutic approaches in the age at diagnosis (<16, 17–40, >40 years old), disease location
CD vary depending on disease phenotype. Thiopurines are (ileal, colonic, ileocolonic, isolated upper) and disease behaviour
important in steroid-sparing maintenance therapy, while (non-stricturing/nonpenetrating, stricturing, penetrating,
anti-tumour necrosis factor agents play a fundamental perianal).5 With repeated cycles of intestinal inflammation in
role, especially in fistulising CD. Suboptimal response CD, the disease may evolve to strictures and complications of
to these medications may require escalation to other penetrating disease such as fistulas and abscess formation.6
immunosuppressive and biologic therapies, and surgical The pathogenesis of CD continues to be elucidated and is
intervention is still required in a proportion of patients. thought to involve a complex interplay between environmental
Tailoring treatment to target specific patient phenotypes, factors, immune factors, the gut microbiome and genetic
disease severity and patient wishes is becoming more feasible disposition. Current studies propose that in a genetically
with the growing array of therapeutic options in CD. susceptible individual, environmental exposures can lead to
gut microbiota dysbiosis and intestinal barrier dysfunction,
subsequently resulting in immune dysregulation.7,8 Diagnosis
Introduction
Crohn’s disease (CD) is a chronic, relapsing and remitting Key points
inflammatory bowel disease (IBD) characterised by transmural Crohn’s disease (CD) is common, and its incidence and
inflammation and affecting variable sites along the entire prevalence are increasing.
gastrointestinal tract. The incidence and prevalence of CD varies
across geographic regions, with the highest epidemiological Goals of treatment are to achieve rapid and safe symptom
burden in Europe, Oceania and North America.1 The highest resolution and tissue healing and to improve quality of life.
incidence was reported in Oceania (29.3 per 100 000 person-
years in Australia), and the highest prevalence was reported in Monitoring disease response based on clinical objective
Europe (322 per 100 000 in Germany).1 Additionally, temporal markers, alongside patient-specific disease targets, is
trend analyses demonstrate that newly industrialised countries paramount to optimising management.
in Asia, Africa and South America are facing a rising incidence,
highlighting the global challenge posed by CD.1 Therapeutic options range depending on disease phenotype
CD has a peak incidence between 20–30 years of age, with and patient choice.
common presenting symptoms including diarrhoea, abdominal
Anti-tumour necrosis factor agents remain the mainstay of
pain and systemic symptoms such as fatigue and weight loss.
treatment for fistulising CD, though new drug options are
Other extra-intestinal manifestations include arthropathy,
being explored.
dermatological (pyoderma gangrenosum, erythema nodosum),
Surgical management remains a prominent therapeutic
option for CD, especially in stricturing disease.

Authors: Agastroenterology resident, Royal Melbourne Hospital, The future of CD will see a range of new medical treatments
Melbourne, Australia; Bmedical registrar, Northern Health, targeting immunomodulation and microbiome manipulation
Melbourne, Australia; Cmedical registrar, Western Health, to try and facilitate personalised treatment approach.
Melbourne, Australia; Dgastroenterology intern, Royal Melbourne
Hospital, Melbourne, Australia; Egastroenterology registrar, KEYWORDS: Crohn’s disease, inflammatory bowel disease,
Royal Melbourne Hospital, Melbourne, Australia; Fconsultant biologics
gastroenterologist, Royal Melbourne Hospital and University of
DOI: 10.7861/clinmed.2023-0493
Melbourne, Melbourne, Australia

© Royal College of Physicians 2023. All rights reserved. 549

Ella Cockburn, Shahed Kamal, Andrea Chan et al

involves a combination of clinical, biochemical, cross-sectional (PRO2), was prioritised as the immediate treatment target.12
imaging, endoscopic, and histological investigations (Table 1).9–11 Clinical remission (ie PRO2 abdominal pain ≤1 and stool frequency
≤3), and normalisation of C-reactive protein (CRP) and faecal
Treatment targets calprotectin, were considered intermediate treatment targets.12
Endoscopic healing (assessed by sigmoidoscopy, colonoscopy,
Identifying evidence-based and clinically relevant treatment capsule endoscopy, or balloon enteroscopy) and normalised health
targets is essential for guiding management strategies for related QoL were described as long-term targets.12 Histological
patients with IBD. In 2021, the International Organization remission and transmural healing were not included as treatment
for the Study of IBD (IOIBD) published an update on targets.
their proposed treatment targets for IBD in the Selecting
Therapeutic Targets in Inflammatory Bowel Disease II (STRIDE-
Severity of disease presentation
II) Initiative.12 STRIDE-II recommendations for treating-to-
target were classified into clinical, endoscopic and transmural Methods of monitoring severity of inflammation are important to
assessment, biomarkers, and quality of life and disability. assess medication efficacy, rule out complications, and prevent
Targets were categorised as either immediate, intermediate or progression.13 Monitoring tools include symptom-based scoring
long-term. systems, biochemical markers, endoscopy, enteroscopy, and cross-
Clinical response, defined as a decrease of at least 50% in sectional imaging. The benefits and weaknesses of these methods
abdominal pain and stool frequency on patient-reported outcome are described in Table 2.

Table 1. Investigations for Crohn’s disease8–10

Investigation Type of investigation Common findings in Crohn’s Notes
disease
Blood tests Full blood count Anaemia, thrombocytosis, Raised inflammatory markers such as
C-reactive protein elevated inflammatory markers, C-reactive protein broadly correlates
hypoalbuminaemia with clinical severity
Urea and electrolytes
Hypoalbuminaemia can reflect severe
Liver biochemistry
inflammation and malnutrition
Albumin
Haematinics
Stool studies Faecal calprotectin Faecal calprotectin is elevated due Faecal calprotectin can aid in
to intestinal inflammation in IBD differentiating between IBD and
functional intestinal diseases such as
irritable bowel syndrome (IBS)
C difficile toxin assay Stool specimens should rule out Can have co-occurrence of CD and
Stool MCS/OCP depending on infectious aetiology infection
clinical history
Endoscopy Flexible sigmoidoscopy often Skip lesions, aphthous ulcers, linear Rectal sparing is suggestive of CD
performed in cases of acute ulceration, cobblestone pattern, fat Endoscopic scoring systems include
severe colitis wrapping, strictures, fistula Crohn’s Disease Endoscopic Index of
Ileocolonoscopy to further Severity (CDEIS) and the Simplified
delineate bowel involvement Endoscopic activity Score for Crohn’s
disease (SES-CD)
Small bowel capsule endoscopy As above May be used where there is a
high suspicion of disease despite
inconclusive ileocolonoscopy/imaging
Risk of capsule retention when
obstructive symptoms or stenosis is
present
Histology Biopsies obtained from Findings suggestive of CD include Granulomas is suggestive of CD over
endoscopy focal (discontinuous) inflammation, ulcerative colitis
focal crypt irregularity, granulomas
Imaging CT enterography Mural hyperenhancement, wall MRE and intestinal ultrasound often
MR enterography thickening, strictures, fistulas, preferred over CT due to reduced
abscesses radiation exposure
Intestinal ultrasound
CD = Crohn’s disease; IBD = Inflammatory bowel disease; MCS = microscopy, culture and sensitivity; OCP = ova, cysts, parasites; MRE = MR enterography

550 © Royal College of Physicians 2023. All rights reserved.

 Crohn’s disease

Table 2. Severity of Crohn’s Disease

Strengths Weaknesses
Symptom-based scoring systems Correlates closely with symptoms Subjective interpretation, clinical symptoms
Crohn’s Disease Activity Index Useful to assess efficacy in clinical trials poorly correlate with severity of endoscopic
(CDAI) lesions
Harvey Bradshaw Index (HBI)
Perianal Disease Activity Index
(specific to fistulising disease)
Biomarkers (C-reactive protein, C-reactive protein has short half-life, useful for May have normal C-reactive Protein levels in
calprotectin) detecting and following up Crohn’s disease active disease
activity
Calprotectin levels correlate with endoscopic and
histological scores
Endoscopic Gold standard for assessing mucosal activity Invasive
Mucosal sampling Bowel preparation
Validated scores of severities (CDEIS/SES-CD) Cannot visualise small intestine proximal to
terminal ileum
No transmural evaluation
Enteroscopy (including capsule Visualisation of small bowel Bowel preparation
endoscopy, push enteroscopy and Less invasive than endoscopy Costs
balloon-assisted endoscopy)
No transmural evaluation
Cannot biopsy with capsule endoscopy
Not widely available
Magnetic resonance imaging Evaluate small and large bowel Involves bowel distension, intravenous contrast
Examine transmural and extra-intestinal activity Tolerated poorly by claustrophobic patients
Perianal evaluation
Radiation-free
CT Evaluate small and large bowel Radiation exposure
Examine transmural and extra-intestinal activity Involves bowel distention and intravenous
Widely available contrast

Intestinal ultrasound Evaluate terminal ileum and colon Limited assessment of proximal ileum,
Examine transmural and extra-intestinal activity jejunum, transverse colon, rectum
Radiation-free Limited by large body habitus
Option to use doppler and contrast enhanced
techniques

Medical therapy has minimal side effects given its first pass liver metabolism and
rapid elimination.16,17 However, in cases of severe ileocaecal CD
Medical therapies for CD vary according to the disease phenotype or colonic CD, prednisolone has been shown to be superior to
and for different phases of the illness. budesonide, as evidenced by Rutgeert et al reducing mean CDAI
from 279 to 136, compared to 275 to 175 (p=0.001), at the cost of
Corticosteroids increased corticosteroid-associated side effects in 48 versus 29 of
the total 176 patients (p=0.003).16
Steroids such as prednisolone, methylprednisolone and
hydrocortisone are effective as an induction agent in CD; however,
Thiopurines
they are ineffective at maintaining remission or reducing flare
frequency and disease recurrence.14 Prolonged corticosteroid Unlike in ulcerative colitis (UC), 5-amino-salicylic acid (5-ASA) is
therapy is associated with increased morbidity and causes deemed to be ineffective in CD.18 Instead, immunomodulation
numerous well-known multisystem side effects.15 Alternatively, and antimetabolite activity with thiopurines is the mainstay of
in mild-to-moderate CD, enteric-coated budesonide is equally steroid-sparing maintenance therapy. However, thiopurines, such
efficacious compared to prednisolone in inducing remission and as azathioprine and 6-mercaptopurine, only become effective

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Ella Cockburn, Shahed Kamal, Andrea Chan et al

after 8–12 weeks, with the slower onset time rendering these Infliximab is the first studied anti-TNF deemed to be safe and
medications ineffective as induction agents.18 Thiopurines are well-tolerated in achieving and maintaining clinical remission
useful in maintaining remission and facilitating weaning of and enabling steroid weaning.18,20 Concurrent use of infliximab
induction corticosteroid therapy. Prior to commencing thiopurines, with other immunomodulatory therapies, such as azathioprine,
thiopurine methyltransferase (TPMT) polymorphisms should be is thought to have synergistic efficacy.21 This was demonstrated
checked to help guide optimal dosing. TPMT is a key enzyme in the SONIC trial, and dual agents resulted in reduction in the
in thiopurine metabolism, and different polymorphisms may formation of anti-drug antibodies (ADAs) to infliximab.21 ADAs
predispose individuals to profound myelosuppression.18 Similarly, can occur with immunologic agents such as infliximab, occurring
nudix hydrolase 15 (NUDT15) deficiency also predisposes to in 7-10% of patients receiving regular infliximab, and have been
thiopurine-induced cytotoxicities and can be tested for.18 In those shown to increase rates of infusion reactions, loss of efficacy of
that cannot tolerate thiopurines, low-dose methotrexate is an therapy and delayed hypersensitivity reactions.18
alternative option. It has been shown to induce remission in 65% Adalimumab has been shown to effectively induce and maintain
of patients compared with 39% of placebo recipients (p=0.04), long-term clinical remission in moderate to severe CD, based
and reduces prednisolone requirement during relapse in 28 on improvement of Crohn’s Disease Activity Index (CDAI) and
percent of patients compared to 58 percent of placebo recipients Inflammatory Bowel Disease Questionnaire (IBDQ) scores, and
(p=0.01).19 endoscopically with findings or early and sustained mucosal
healing in moderate-to-severe ileocolonic CD.18 Adalimumab
has similar effects on complete closure of fistulas compared to
Biologics
infliximab and in those who have lost response to Infliximab,
Biologic agents have facilitated landmark changes in the Adalimumab has been shown to be effective as per the CLASSIC II
management of CD. The anti-tumour necrosis factor (anti- trial.22
TNF) agents, namely infliximab, adalimumab, golimumab and Certolizumab pegol is a pegylated Fab’ fragment of the anti-TNF
certolizumab, work to inhibit the endotoxin-mediated shock monoclonal antibody (mAb) that has a high affinity for TNF-alpha.
promoted by TNF release in the mucosa and lamina propria of Delivered subcutaneously, certolizumab has had mixed outcomes
Crohn’s patients (See Fig 1).18 from the PRECiSE-1 and 2 trial, being shown to be lacking in efficacy

Fig 1. Mechanism of action for biologics and small molecules used in Crohn’s disease. TNF = tumour necrosis factor; JAK = Janus kinase; STAT =
signal transducer and activator of transcription; IL = interleukin; CXCL = chemokine.

552 © Royal College of Physicians 2023. All rights reserved.

 Crohn’s disease

at reducing CDAI in the former, and superior to placebo in this would be beneficial to determine the role for upadacitinib in these
regard in the latter.18 Owing to mixed outcomes its uptake is varied patients.29
internationally in CD.
Golimumab is another anti-TNF alpha agent and in some Faecal transplant
observational studies has shown to be efficacious in CD refractory
to other anti-TNF therapies, though further exploration of its In the era of progressive understanding of the gut microbiome as
clinical utility in CD is required.23 a key antigenic driver in IBD, the use of multiple faecal microbiota
Notably, 30–50% of patients are primary non-responders to transplants (FMT) has been explored and requires further
anti-TNFs, with subsequent loss of response being a significant research.32
issue.24 Primary non-response due to immunogenicity to infliximab
or adalimumab may be predicted by low drug concentrations Follow-up and surveillance
at week 14.18 Consequently, the development of newer biologic
Follow-up and surveillance play an important role in the
agents is a key area of immunosuppressive advancement.
management of patients with CD, which includes the use of
T-lymphocytes have been shown to play a pivotal immunological
patient-reported outcome measures (PROMs), endoscopic
role in CD pathogenesis. Vedolizumab inhibits the α4β7 integrin
evaluation and non-invasive monitoring modalities such as
found on lymphocytes, preventing their migration into the gut
Intestinal Ultrasound (IUS).
wall via the mucosal addressin cell adhesion molecule-1, which is
PROMs are questionnaires completed by patients to assess their
upregulated in intestinal vasculature in IBD.18 Vedolizumab has
symptoms and overall well-being, offering valuable information on
been found to successfully induce remission compared to placebo
the impact of CD on patients’ lives.12 However, there is discordance
at 6 weeks in the GEMINI-II study, with significantly higher rates
between clinical symptoms and mucosal inflammation in CD, and
of remission by 52 weeks achieved in those who remitted on
treatment decisions focused solely on PROMs may result in over- or
induction.25 They also achieved improvement in CR100 (decrease
under-treatment.33
in CDAI by 100 points) response and glucocorticoid remission
Objective markers of disease severity to monitor were mentioned
when given 4 or 8 times weekly.25 Vedolizumab as per the
previously, including endoscopy, faecal calprotectin and
GEMINI-3 study is unlikely to be of benefit in induction, but may
monitoring of blood tests such as C-reactive protein (CRP) and
be a useful maintenance therapy, when bridged with co-induction
erythrocyte sedimentation rate (ESR).12
agents of corticosteroids for those with moderate to severe CD
Non-invasive monitoring modalities such as IUS have gained
who have failed previous conventional therapies.26
relevance, adding clinical value in assessing transmural disease
Ustekinumab is a monoclonal antibody against the p40 subunit
activity in CD.33 Kucharzik et al proposed a monitoring algorithm
of IL12 and IL-23 (See Fig 1), found in the UNITI-1, UNITI-2
for CD to guide treatment decisions and assess disease activity.33
and IM-UNITI trials to be superior to placebo in inducing and
The algorithm involves an early IUS assessment in conjunction
maintaining remission in patients with moderate-to-severe CD.27
with PROMs and CRP measurement at 4–6 weeks after treatment
Patients administered 6 mg/kg or 130 mg ustekinumab had higher
initiation, particularly in patients with highly active disease. This
remission rates by 6 weeks, and on 8 to 12 weekly maintenance
approach not only detects treatment response but also excludes
doses were more likely to be in remission regardless of previous
any possible complications. Furthermore, follow-up IUS and
treatment response to an anti-TNF agent.27 Ustekinumab has
measurement of both CRP and calprotectin are recommended at
been approved for use for CD following previous therapy failures
3 months after treatment initiation. At 6 months, these modalities
and is efficacious in treating perianal disease and fistula healing.28
are repeated, with the addition of endoscopy. Lastly, follow-up
after 12 months with the possible incorporation of magnetic
Janus kinase (JAK) inhibitors resonance enterography (MRE).33 While this proposed monitoring
In inflamed tissue in CD, especially in patients with disease algorithm presents great potential, further studies are needed to
refractory to anti-TNF therapy, the JAK–STAT genes and the establish its efficacy and feasibility.
STAT3 pathway are upregulated (Fig 1).29 Upadacitinib, a small Importantly, CD patients are at increased risk of colorectal
molecular inhibitor selective for JAK1, has been shown through cancer (CRC) and need routine screening with endoscopy. The risk
the U-EXCEL, U-EXCEED and U-ENDURE studies to be effective of CD patients developing CRC is estimated to be 2% after 10
in achieving clinical remission, endoscopic response, and quality years, 8% after 20 years and 18% after 30 years of disease.34 This
of life outcomes in the induction and maintenance treatment of elevated risk has been theorised to arise from dysplasia, hence
moderate-to-severe CD.29 Surprisingly, however, tofacitinib, a pan- surveillance colonoscopy to detect dysplasia is recommended
JAK inhibitor, has been found to be beneficial in UC management for patients 8 years after onset of symptoms.35 The intervals of
but not in CD.29,30 surveillance vary based on the level of risk for CRC and the society
issuing the guidelines, ranging from 1–5 years.36 Research efforts
Fistulising disease are ongoing to explore new technologies to improve dysplasia
detection in IBD surveillance, including the use of panoramic views
Prior to biologics, fistulising CD was notoriously difficult to manage. during colonoscopy, use of virtual chromoendoscopy with narrow
ACCENT-II demonstrated that infliximab is effective in inducing band imaging and high definition iSCAN technology.
closing of rectovaginal fistulas and increases duration of sustained
fistula closure by 3 months compared to placebo when given as
Surgical management
induction and maintenance therapy.31 Adalimumab has also
been shown to be effective in complete closure of fistulas.22 Given Typically, medical treatment is the first line of intervention for CD,
JAK1 polymorphisms have been identified in fistulising disease, it however surgery becomes necessary when medical therapies fail,

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Ella Cockburn, Shahed Kamal, Andrea Chan et al

with some series reporting up to 75% of CD patients undergoing and healing rates, since it alone results in significant reintervention
surgery during the course of their lives.37 Recent studies have rates.48 One disadvantage on the use of setons is that the fistula
shown a decreasing trend in the need for surgery among tract cannot close while it is still there; currently there is no consensus
CD patients, attributed to changes in clinical practices, early on the optimal timing for seton removal. In a small prospective trial,
disease detection, implementation of practice guidelines and setons were maintained for the duration of infliximab induction which
advancements in biological therapies.38 Surgery is indicated for resulted in an overall new abscess rate of 0%.49 Hence, this study
patients with stricturing CD with partial or complete obstructive recommended to keep the seton in place at least until the induction
symptoms, fistulising or perianal CD with infectious complications, of the anti-TNF treatment period has been completed. After its
failure of medical therapy, steroid dependence, high grade removal, the fistula can close.
dysplasia and cancer.39,40
One of the common complications in CD that may require
The future
surgery is the development of strictures, which can occur within
the first 10 years after diagnosis.41 Strictures result from fibrosis of Several novel therapeutic targets are being explored as
the intestines and may involve any segment of the gastrointestinal treatment options for CD. These include monoclonal antibodies
tract. There are two types of strictures: de novo strictures, (risankizumab and mirikizumab) as well as sphingosine-1-
typically found in the terminal ileum and ileocolonic region, phosphate receptor modulators (such as etrasimod). Furthermore,
and anastomotic strictures, which can develop after intestinal several phase I/II trials are exploring the use of mesenchymal
resection.41 The management of CD strictures involves various stem cells as therapy for severe CD. These up-and-coming
approaches, including medical therapy, endoscopic interventions treatments present an exciting alternative for clinicians to consider
(such as balloon dilatation), and surgical procedures.42 Up to 66% in patients who have progressed on standard therapies.
of CD patients with strictures fail medical therapy and 40% fail Inflammatory cytokines play an important role in the initiation
endoscopic dilation, thus needing surgery.43 and propagation of CD. IL-23 has been identified as a key player in
A study by Bossuyt et al in 201814 developed a risk stratification the maintenance of a chronic inflammatory state in the intestines.
model called the BACARDI risk model to guide treatment strategy Specifically, it induces the differentiation of naïve T-helper cells,
selection for patients with stricturing ileal CD. This model assigns which then go on to release further pro-inflammatory molecules.
points based on factors, including Montreal classification, anti- Risankizumab is a monoclonal antibody targeting IL-23 that
TNF exposure, CARD15/NOD2 mutation, and high CRP levels. has been explored as a treatment option in 3 phase III trials.
Patients are categorised into low (0–1 points), medium (2–3 The ADVANCE, MOTIVATE, and FORTIFY studies compared
points), high (4–5 points) and all risk (6 points) groups. They risankizumab with placebo in participants with moderate to
found that for patients with all risk factors, surgery-free survival severe CD. In all three trials, risankizumab was associated with
rate is 0% after 5 years and 19% for those in the high-risk group. clinical remission and endoscopic improvement after 12 weeks of
These patients most likely will benefit from early surgery after therapy.50 Similarly, mirikizumab is an IgG4 monoclonal antibody
diagnosis of stricture instead of medical or endoscopic therapies. that binds to the p19 subunit of IL-23, inhibiting its binding to the
For medium risk group, surgery-free survival rate is 38% after 5 IL-23 receptor. A recent phase II trial showed that CD patients
years, hence these patients may benefit from optimising medical receiving induction mirikizumab had improved endoscopic
therapies, performing endoscopic dilation when necessary and response, compared to placebo, at 12 weeks and this effect
re-assessment of the stricture every 12 months. Lastly, the low- was preserved when continued as maintenance therapy.51 Both
risk group have a surgery-free survival rate of 77% after 5 years, risankizumab and mirikizumab require ongoing study in phase
therefore the best clinical approach for this group is to continue IV and head-to-head trials to compare their effectiveness with
medical treatment and/or endoscopic therapy if needed. This current treatment options in CD.
model has great potential to guide in determining the most Sphingosine-1-phosphate (S1P) receptor modulators have
appropriate therapeutic approach for CD-associated strictures.44 recently been explored as an oral treatment option in CD.
Fistulising perianal CD (CD-PAF) affects about 30–50% of CD These receptors are involved in the trafficking of lymphocytes
patients during the course of their disease and about 80% of those from lymph nodes into the blood stream and are commonly
fistulas are classified as complex.45 Medical therapy is recommended known as an established treatment target for conditions such
as a first line treatment however despite advances in current available as multiple sclerosis. Early phase II data from the CULTIVATE
therapies about two-thirds of patients with CD-PAF require perianal study, demonstrated a modest effect in terms of endoscopic and
surgery and approximately 7% require major abdominal surgery.46 clinical improvement when etrasimod was taken by patients for
The choice of surgical procedure is based on the complexity and 14 weeks.52 These early results, although based on a small sample
location of the fistula, with minimising the risk for sphincter injury size, do demonstrate the potential for the use of etrasimod in the
in mind. About 80% of fistulas have been associated with perianal treatment of severe CD.
abscess, for which incision and drainage is the most common Mesenchymal stem cell (MSC) therapy is also currently being
intervention.46 Adequate drainage is important since fistulas are studied as an option to treat severe or refractory CD. These cells,
potential sources of pelvic sepsis.47 In addition, non-cutting setons derived from bone marrow, are known to inhibit T-cell reactivity
are typically used to decrease the incidence of recurrent abscess as well as promote healing, and have thus been explored as a
formation and the development of new fistulous tracts. Cutting potential treatment for several autoimmune conditions. With
setons carry a high risk of anal incontinence due to scarring of the regards to CD, most studies have looked at the use of MSC in the
anal canal; hence, loose setons are preferred since it can preserve the treatment of peri-anal fistulising disease. MSCs are theorised to
integrity of external anal sphincter.47 Surgery using setons is carried downregulate immune activity and promote healing at the site
out with concomitant dual therapy with biologics to improve efficacy of perinal fistula and reduce the need for subsequent surgery.

554 © Royal College of Physicians 2023. All rights reserved.

 Crohn’s disease

a Acve Crohn’s disease b Treatment targets

Treatment
according to risk Immediate targets Intermediate targets Long-term targets Consider, but not formal targets
G ut m
e nt a l icro
nm bi Clinical outcome Clinical remission Endoscopic healing Transmural healing
iro o Decrease abdominal – Abdominal pain <1
v

m
En

pain and stool – Stool frequency <3

e
frequency by 50%
mune fa ct ors

Normalisa on of

disposition
Genetic
laboratory tests
– CRP
Normalisaon of
– Faecal
quality of life
Im

calprotein

Targets not reached

c Monitoring d Treatment op ons e Future therapies

For failed medical therapy; Sphingosine-1-phosphate

Clinical Biomarkers Surgery complicaons such as stricturing CD receptor modulators

An-TNF primary treatment

Colon cancer Biologics for fistulising CD
screening Monoclonal anbodies
Symptom-based CRP Faecal
scoring system calprotein Surveillance colonoscopy
8 years a€er onset Immunomodulators For maintaining remission
Endoscopy Mesenchymal stem
Enteroscopy of symptoms
cell treatment
CT scan For maintaining remission
MRI Cor costeroids and reducing flare
Intesnal ultrasound
Imaging/procedures

Fig 2. Crohn’s disease treatment landscape. a) Risk factors leading to Crohn’s Disease. b) Treatment Targets for Crohn’s Disease as per STRIDE II
recommendations. c) Tools to monitor severity of disease and risk for colon cancer. d) Current treatment options for CD. e) Future therapies for CD.

Several phase I-III trials have studied the effect of MSC injection accurately to treatment. While promising, the implementation
at perianal site on disease progression. Results have shown of this approach on a large scale is currently limited by both
improved clinical as well as radiological remission at both 25 weeks financial and logistical challenges. Nevertheless further study
and 1 year.53 Further studies with larger sample size are required is already underway, heralding a promising future for the use of
to further evaluate the efficacy as well as safety of MSC as a personalised medicine in CD treatment.
treatment option. Fig 2 summarises the key points from this article. ■
The current classification system for CD is based on a
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