Journal of Crohn's and Colitis, 2024, 18, 1531–1555

https://doi.org/10.1093/ecco-jcc/jjae091
Advance access publication 15 June 2024
ECCO Guideline/Consensus Paper

ECCO Guidelines on Therapeutics in Crohn’s Disease:

Medical Treatment
Hannah Gordon,a Silvia Minozzi,b Uri Kopylov,c, Bram Verstockt,d,e, María Chaparro,f,

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Christianne Buskens,g, Janindra Warusavitarne,h, Manasi Agrawal,i,j, Mariangela Allocca,k,
Raja Atreya,l, Robert Battat,m, Dominik Bettenworth,n Gabriele Bislenghi,o,
Steven Ross Brown,p Johan Burisch,q, María José Casanova,f, Wladyslawa Czuber-Dochan,r,
Joline de Groof,s Alaa El-Hussuna,t, Pierre Ellul,u Catarina Fidalgo,v,w, Gionata Fiorino,x,
Javier P Gisbert,f, João Guedelha Sabino,d Jurij Hanzel,y,z, Stefan Holubar,aa,
Marietta Iacucci,ab, Nusrat Iqbal,ac, Christina Kapizioni,ad Konstantinos Karmiris,ae,
Taku Kobayashi,af, Paulo Gustavo Kotze,ag, Gaetano Luglio,ah Christian Maaser,ai
Gordon Moran,aj,ak Nurulamin Noor,al, Konstantinos Papamichael,am, Georgios Peros,an
Catherine Reenaers,ao, Giuseppe Sica,ap Rotem Sigall-Boneh,aq,ar, Stephan R. Vavricka,as
Henit Yanai,at, Pär Myrelid,au, Michel Adamina,av, ,Tim Raineaw,
a
Translational Gastroenterology and Liver Unit, University of Oxford, Oxford, UK
b
Department of Epidemiology, Lazio Regional Health Service, Rome, Italy
c
Department of Gastroenterology, Sheba Medical Center, Ramat Gan, Israel
d
Department Gastroenterology & Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
e
Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
f
Gastroenterology Department. Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa [IIS-Princesa], Universidad
Autónoma de Madrid [UAM], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Madrid, Spain
g
Department of Surgery, Amsterdam UMC, Location VUMC, Amsterdam, The Netherlands
h
Department of Colorectal Surgery, St Mark’s Hospital London, United Kingdom
i
Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
j
Center for Molecular Prediction of Inflammatory Bowel Disease [PREDICT], Department of Clinical Medicine, Aalborg University, Copenhagen,
Denmark
k
IRCCS Hospital San Raffaele and University Vita-Salute San Raffaele, Gastroenterology and Endoscopy, Milan, Italy
l
First Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
m
Division of Gastroenterology, Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada
n
CED Schwerpunktpraxis, Münster and Medical Faculty of the University of Münster, Münster, Germany
o
Department of Abdominal Surgery, University Hospitals Leuven, Leuven, Belgium
p
Department of Surgery, Sheffield Teaching Hospitals, Sheffield, UK
q
Gastrounit, Medical Division, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark; Copenhagen Center for Inflammatory
Bowel Disease in Children, Adolescents and Adults; Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark; Department
of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
r
Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King’s College London, London, UK
s
Colorectal Surgery, Royal Surrey NHS Foundation Trust, Guildford, UK
t
Department of Surgery, OpenSourceResearch Organization [OSRC.Network], Aalborg, Denmark
u
Division of Gastroenterology, Mater Dei Hospital, L-Imsida, Malta
v
Division of Gastroenterology, Hospital Beatriz Ângelo, Loures, Portugal
w
Division of Gastroenterology, Hospital da Luz, Lisboa, Portugal
x
IBD Unit, San Camillo-Forlanini Hospital, Rome, Italy
y
Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
z
Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
aa
Department of Colon & Rectal Surgery, Cleveland Clinic, Cleveland, OH, USA
ab
APC Microbiome Ireland, College of Medicine and Health, University College of Cork, Cork, Ireland
ac
Department of Surgery, Worcestershire Acute Hospitals NHS Trust, Worcester, UK
ad
Department of Gastroenterology, Attikon University Hospital, Athens, Greece
ae
Department of Gastroenterology, Venizeleio General Hospital, Heraklion, Greece
af
Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan

© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial
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1532 H. Gordon et al.

ag
Health Sciences Postgraduate Program, Pontificia Universidade Católica do Paraná [PUCPR], Curitiba, Brazil
ah
Department of Public Health, University of Naples Federico II, Naples, Italy
ai
Outpatients Department of Gastroenterology, University Teaching Hospital Lueneburg, Lueneberg, Germany
aj
National Institute of Health Research Nottingham Biomedical Research Centre, University of Nottingham and Nottingham University
Hospitals, Nottingham, UK
ak
Translational Medical Sciences, School of Medicine, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK
al
Department of Medicine, University of Cambridge, School of Clinical Medicine, Cambridge, UK
am
Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School,
Boston, MA, USA
an
Department of Surgery, Cantonal Hospital Winterthur, Winterthur, Switzerland
ao
Gastroenterology Department, Chu Liege, Liege, Belgium

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ap
Department of Surgery, Università Tor Vergata, Roma, Italy
aq
Pediatric Gastroenterology and Nutrition Unit, E. Wolfson Medical Center, Holon, Israel
ar
Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology and Metabolism, University of Amsterdam,
Amsterdam, The Netherlands
as
Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
at
IBD Center, Division of Gastroenterology, Rabin Medical Center, Petah Tikva; Faculty of Medical & Health Sciences, Tel Aviv University, Tel
Aviv, Israel
au
Department of Surgery and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
av
Department of Surgery, Cantonal Hospital of Fribourg & Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
aw
Department of Gastroenterology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
Corresponding author: Hannah Gordon, Translational Gastroenterology and Liver Unit, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3
9DU. Email: hannahgordon@doctors.org.uk

Graphical Abstract
The ECCO GRADE CD We provide practical guidance on choice and
treatment guidelines were optimisation of medical therapy
updated Induction Maintenance Perianal Peripheral Axial Pregnancy Over 65
disease Spondylo- Spondylo- years
CD i i ii arthropathy arthropathy iii
Treatment Systemic iv iv iv iv iv
Medical corticosteroids
Enteral release v v
corticosteroids
GRADE Practice points Enteral Nutrition
Old questions New questions
Thiopurines vi vii
monotherapy
Methotrexate
Update systematic
New systematic
review from 1
review
lnfliximab
April 2018
Adalimumab
Data extraction and summary of evidence Certolizumab

Statement drafting and voting Vedolizumab

Consensus Ustekinumab

Risankizumab vii ix
We recommend a holistic
Upadacitinib
approach to management of x xi xii xiii

CD
Recommended DRUGS SHOULD BE CONSIDERED BY
Can be considered
GRADE statements on medical MERIT, NOT SEQUENCED AS
Not recommended
therapy CONVENTIONAL TO ADVANCED
Insufficient evidence

GRADE statements and practice Drug selection should factor efficacy, safety, patient
points on nutritional therapy characteristics and preferences, disease
characteristics and cost or access to therapies
Practice points on the role of GRADE statements and practice points on therapeutic drug
the multidisciplinary team monitoring, drug sequencing and combination, including ACT

1. Introduction remains unknown and a curative therapy is not yet available.

Contemporary therapy therefore is focused on control of in-
Crohn’s disease [CD] is a chronic inflammatory bowel disease
flammation, using medications along with timely surgical
[IBD] that can result in progressive bowel damage and dis-
interventions to alleviate the symptoms of bowel damage.
ability.1 CD can affect individuals of any age, from children
The European Crohn’s and Colitis Organisation [ECCO]
to the elderly,2,3 and may cause significant morbidity and im-
produces several guidelines aimed at providing evidence-based
pact on quality of life [QoL]. The precise aetiology of CD
ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment 1533

guidance on critical aspects of IBD care. In 2020, ECCO Cochrane Central databases, using specific search strings de-
published new guidelines on the management of CD in two veloped for each PICO question [Supplementary files avail-
manuscripts focused on the medical and surgical management able as Supplementary data at ECCO-JCC online]. For PICO
of disease.4,5 For the 2020 CD guidelines, ECCO adopted the questions retained from the 2020 guidelines, the same search
Grading of Recommendations Assessment, Development, string was used as during the prior literature search, and the
and Evaluation [GRADE] approach, a systematic process for start date of database queries set to the same as the end search
developing guidelines that addresses how to frame the health date for the previous guidelines 1 April 2018. For all new
care questions, summarise the evidence, formulate the recom- PICO questions, the search start date was unlimited. Two in-
mendations, and grade their strength and quality of associ- dependent consensus group members assessed the relevance
ated evidence.6 The present manuscript represents an update of each abstract to the PICO and included or excluded all

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to the 2020 guidelines and is focused specifically on medical the relevant papers for the final data extraction and ana-
management of CD, and a companion manuscript developed lysis. Subsequently, group members systematically reviewed
as part of the same process addresses optimal surgical man- and summarised the evidence on every outcome voted as ‘im-
agement.5 We take a drug-by-drug approach to review the evi- portant’ or ‘critical’, to compile a Summary of Findings [SoF]
dence for various medical and dietary strategies used in the table for each question, or updated the prior SoF tables from
management of CD. 2020 [including revision according to any changes to out-
For this iteration of the guidelines, we have introduced sev- comes deemed critical or important]. We adopted a standard
eral new, clinically relevant questions as chosen by members hierarchical approach, searching for recent, high-quality sys-
of the guidelines group, a systematic approach to reviewing tematic reviews and meta-analyses of clinical trials to use in
and updating previous topics to incorporate any new evi- preference to individual randomised clinical trials [RCTs]
dence, and a reappraisal of all evidence in the context of con- or observational studies. Results of individual studies were
temporary practice. We have also introduced several ‘practice pooled using random-effects meta-analysis as appropriate
points’ to summarise evidence, and expert recommendations and when needed. The quality of evidence was then classi-
in certain key areas of practice where the evidence base is fied and used to inform draft recommendations according to
limited but where clinicians and patients need to make de- the GRADE methodology.6 GRADE evidence levels for safety
cisions nonetheless. Here, where application of the GRADE data tended to be low, due to downgrading for sparsity of
methodology might be impractical, we have used an approach events, reflecting the overall relative safety of the interven-
based on systematic literature review, expert discussion, and tions under consideration. Therefore, whereas the evidence
voting to form consensus recommendations outside the for all ‘important’ and ‘critical’ outcomes was considered in
formal GRADE process. the drafting of a recommendation, we decided to base the
It is important to remember that achieving optimal out- overall assessment of evidence quality used to inform the
comes in CD relies not just on knowledge of the appropriate strength of each recommendation upon the lowest quality of
use of current medical and surgical therapies but also on evidence obtained for the clinical or endoscopic outcomes for
careful attention to wider aspects of management, including each PICO question. Where evidence was not available for
early diagnosis, prompt initial management,7 close moni- an outcome of critical importance, this was reflected in the
toring of treatment response, and psychological and dietary overall assessment of the quality of the evidence. The assess-
support.8 ment of evidence for all individual outcomes was available
to all panel members and is presented in the Supplementary
materials.
2. Methods During initial discussions and based on feedback from pre-
The development of these guidelines followed the GRADE vious ECCO guidelines, we recognised that in certain areas of
workflow, as adopted in previous ECCO guidelines.9 A panel CD management there are limited high-quality sources of evi-
of 46 experts were selected from an open call according to dence available, but that clinicians and patients must make de-
criteria based on IBD expertise, scientific background, know- cisions nonetheless. There are also broad, overarching themes
ledge of GRADE methodology, and prior contribution to relating to approaches to care that cannot be readily formu-
ECCO projects. Additionally, six patients with CD selected by lated into a PICO question. Use of the GRADE approach
the European Federation of Crohn’s and Colitis Associations in these areas can be resource intensive and lead to recom-
[EFFCA] were invited to participate in discussions. The group mendations of limited clinical utility. We therefore decided to
was supported in their work by a team of professional meth- frame a separate series of ‘practice points’ for such common
odologists and librarians. areas of importance. For these, the systematic literature re-
The panellists first agreed on a list of questions using the view and data extraction exercise were followed and the find-
Population, Intervention, Comparator, Outcomes [PICO] ings used to inform drafting of an expert recommendation.
format. PICO questions addressed as part of the 2020 ECCO We recognise that the resulting practice points are based upon
CD guidelines were reviewed and considered for retention a different level of evidence compared with the GRADE re-
with regards to ongoing relevance, and new PICO questions commendations, but hope that they will be of practical use to
were formulated, discussed, and added to the list. The rele- readers nonetheless. These are clearly delineated in the text as
vant outcomes for all PICO questions were graded according distinct from GRADE recommendations.
to importance using a Delphi consensus process. Note that All recommendations and practice points were subject to
for PICO questions retained from 2020, the importance of the two rounds of online voting by the panel members, the ECCO
outcomes was nonetheless revised according to the results of National Representatives [two for each country affiliated with
this new consensus. ECCO], and 37 additional reviewers from a list of ECCO
The professional librarians next performed a comprehen- members who applied to the open call but were not selected
sive literature search on EMBASE, PubMed/Medline, and to be part of the Working Groups [see Acknowledgements
1534 H. Gordon et al.

section]. The pre-final versions of all recommendations and exist on the impact of higher dose [> 2.4 g/day] mesalazine
practice points were discussed among panel members during therapy on clinical remission.18,19 To assess for impact of de-
a series of final virtual consensus meetings before being put to livery mechanism, pooled data from three trials for a slow-
a vote; final versions were approved only if at least 80% of the release preparation of mesalazine reported a significantly
panellists agreed with the statement. The resulting statements greater reduction in the absolute value of the Crohn’s Disease
and draft of this manuscript were critically reviewed by two Activity Index [CDAI] compared with placebo [weighted
external Guideline Committee members and by the ECCO mean difference of 18 points]. However, the clinical signifi-
Governing Board members, who also approved the final ver- cance of this difference is not meaningful.20
sion of these guidelines. Statements and practice points are Data comparing sulphasalazine with placebo as induc-
ordered by drug, with statements concerning induction and tion therapy in CD are derived from RCTs performed prior

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maintenance therapy presented together where relevant. All to 1985. Pooled data showed borderline significantly higher
statements should be read in the context of the supporting clinical remission rates favouring sulphasalazine [RR: 1.38;
text that follows. A brief summary of the statements and text 95% CI: 1.00–1.89] and similar AE-related treatment with-
is presented at the start of each section of supporting text. drawal rates between sulphasalazine and placebo [RR: 1.88;
The literature search strategies, the relevant definitions of 95% CI: 0.65–5.47]. Importantly, analysis stratified by disease
patient populations and outcomes, a detailed description of location showed sulphasalazine benefited only patients with
the process, and the SoF tables on the evidence can be found colonic disease, whereas those with small-bowel involvement
in the Supplementary material, available as Supplementary did not have higher clinical remission rates compared with
data at ECCO-JCC online. placebo.15,16 There are no RCT data on the use of topical
5-ASA [enema or suppository] as induction therapy in CD.
Oral 5-ASA has been extensively studied for the mainten-
3. Medical Management of CD ance of medically induced remission in patients with CD.
3.1. 5-Aminosalicylates in the treatment of CD Overall, 11 placebo-controlled clinical trials assessed doses
3.1.1. 5-Aminosalicylates for the induction of remission in between 1 and 4 g per day.21 Treatment durations varied be-
CD tween 4 and 36 months, with a 12-month evaluation most
commonly assessed. No statistically significant benefit has
been demonstrated for clinical outcomes with oral 5-ASA
Statement 1.1. We recommend against the use of
[risk ratio for relapse 0.98; 95% CI: 0.91–1.07]. No statis-
5-aminosalicylic acid for induction of remission of CD
tically significant benefit was demonstrated based on disease
[strong recommendation, moderate-quality evidence].
location, such as for patients with colonic-only involvement
[Consensus: 100%]
or with proctitis. However, given the relatively small nature
of all the studies conducted in CD, none of the 11 placebo-
3.1.2. 5-Aminosalicylates for the maintenance of remission controlled trials were adequately powered to assess efficacy
in CD in different sub-phenotypes. No significant differences were
reported in AEs [RR: 1.05; 95% CI: 0.95-1.17] or serious
adverse events [SAEs] [RR: 1.43; 95% CI: 0.24–8.44] be-
Statement 1.2. We recommend against the use of oral tween 5-ASA and placebo. However, no definitive statements
5-aminosalicylic acid as maintenance therapy in CD [strong about safety can be made, given the limited available safety
recommendation, low-quality evidence]. [Consensus: data in CD [10 AEs in 1814 patients, and three SAEs in 576
100%] patients].21

5-aminosalicylic acid has no role in contemporary manage- 3.2. Steroids in the treatment of CD
ment of CD, regardless of disease location, based on a con- 3.2.1. Locally acting steroids in the treatment of CD
sistent lack of evidence of efficacy.
3.2.1.1. Budesonide for the induction of remission in CD
There have been no new studies on 5-aminosalicylic acid
[5-ASA] in induction of remission published since the previ-
ously published ECCO guidelines on therapeutics in CD.4 A Statement 2.1. We recommend budesonide for the induc-
meta-analysis was performed by the ECCO working group tion of clinical remission in patients with active, mild-to-
on seven RCTs that compared induction therapy with oral moderate CD limited to the ileum and/or ascending colon
mesalazine10–14 or sulphasalazine15,16 with placebo in patients [strong recommendation, moderate-quality evidence].
with active CD. 5-ASA doses of 1–3.2 g/day were for mild- [Consensus: 100%]
to-moderate ileal, ileo-colonic, or colonic CD. There, clinical
remission rates between 5-ASA therapy and placebo were Locally acting oral steroids are effective in induction of re-
similar (relative risk [RR]: 1.28; 95% confidence interval mission in CD and have a more favourable side-effect profile
[CI]: 0.97–1.69) and these data are consistent with other than systemic steroids. They have a role in induction of remis-
meta-analyses.17 Adverse event [AE]-related treatment with- sion of mild-to-moderate CD but have no role as maintenance
drawals were similar between treatment and placebo groups therapy.
[RR: 1.13; 95% CI: 0.73–1.84]. A 2015 systematic review and meta-analysis22 compared
When excluding sulphasalazine trials, similar conclusions the efficacy and safety of induction therapy with budesonide
were reached for lack of benefit compared with placebo for with placebo. This analysis included three RCTs of patients
induction of clinical remission [RR: 1.27; 95% CI: 0.79–2.03] with mild CD with disease location in the small intestine, as-
and similar AE-related treatment withdrawal [RR: 1.0; 95% cending colon, or both.23–25 Budesonide 9 mg was superior to
CI: 0.58–1.71]. Contradictory network meta-analysis data placebo for inducing clinical remission [CDAI ≤ 150] at Week
ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment 1535

8 [RR: 1.93; 95% CI: 1.37–2.73]. In addition, withdrawals acne, hirsutism, infection, ecchymoses, hypertension, dia-
due to AEs [RR: 1.14; 95% CI: 0.46–2.79] and corticosteroid- betes mellitus, osteoporosis, cataracts, and glaucoma. A non-
related AEs [RR: 0.97; 95% CI: 0.76–1.23] were similar negligible proportion of patients experienced corticosteroid
between budesonide 9 mg and placebo.22 An updated meta- dependency or excessive exposure to these drugs, which is
analysis in 2018 contained no new induction RCTs.26 preventable.33 In addition to the aforementioned AEs, there is
Meta-analyses from 2015 and 2018 reviewed two RCTs27,28 substantial evidence on the association of corticosteroid use
comparing budesonide 9 mg daily with mesalazine < 4.5 g with increased incidence of infection34 and death.35,36
daily for mild-to-moderate CD. Another RCT in 2018 also Imprecision associated with a low number of events for
compared budesonide 9 mg daily with mesalazine 1 g three all efficacy and safety outcomes led to the downgrading of
times daily in patients with mild CD and disease location in evidence to moderate quality. The availability of induction

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the small intestine, ascending colon, or both.29 Budesonide agents with a more favourable risk-benefit profile led to the
had similar clinical remission [CDAI ≤ 150] rates at Week 8 recommendation being classed as ‘weak’. Clinicians should
[RR: 1.30; 95% CI: 0.98–1.72] as compared with mesalazine. seek to minimise steroid usage in their practice. In instances
However, clinical response [decrease in CDAI ≥ 100 or total where steroids are used, the need for more than a single course
CDAI ≤ 150] rates were higher among budesonide-treated pa- of corticosteroids in 1 year or the presence of corticosteroid
tients [RR: 1.22; 95% CI: 1.03–1.45]. Further data are needed dependency [the inability to taper and stop steroids without
regarding the impact of budesonide on mucosal healing. a clinical flare or relapse] should warrant a steroid-sparing
AE [RR: 0.91; 95% CI: 0.79–1.05] and SAE [RR: 0.94; strategy.
95% CI: 0.24–3.75] rates were similar between budesonide
and mesalazine-treated patients. Budesonide does not appear 3.3. Immunomodulators in the treatment of CD
to be more effective than placebo for the maintenance of re- 3.3.1. Thiopurines in the treatment of CD
mission in CD.30 3.3.1.1. Thiopurines for the induction of remission in CD

3.2.2. Systemic corticosteroids in the treatment of CD Statement 3.1. We recommend against the use of thiopurine
3.2.2.1. Systemic corticosteroids for the induction of monotherapy as induction therapy for CD [strong recom-
remission in CD mendation, very low-quality evidence]. [Consensus: 100%]

Statement 2.2. We suggest systemic corticosteroids can

be used as induction therapy in patients with active, 3.3.1.2. Thiopurines for the maintenance of remission in CD
moderate-to-severe CD [weak recommendation, moderate-
quality evidence]. [Consensus 100%] Statement 3.2. We suggest thiopurine monotherapy can be
used as maintenance therapy in CD [weak recommenda-
Although systemic steroids are effective in induction of remis- tion, low-quality evidence]. [Consensus: 95%]
sion in CD, they are associated with significant morbidity and
mortality. Therefore, they should only be used as induction Thiopurines may be effective in maintenance of remission in
therapy when there is no alternative agent available for timely CD after induction has been achieved by other means, but
administration. Steroids should never be used as maintenance clinicians should consider their side-effect profile and the
therapy. availability of other therapies.
The efficacy of systemic corticosteroids [oral Several studies have evaluated thiopurines compared with
methylprednisolone or oral prednisolone] compared with placebo for induction of remission and response in CD16,37–43;
placebo for the treatment of moderately-to-severely active the data have been synthesied in a Cochrane systematic re-
CD was assessed in two RCTs.15,16 Data from these studies view.44 Five trials evaluated thiopurines for induction of clin-
were synthesised in a Cochrane systematic review.15 Oral ical remission [12–17 weeks] in comparison with placebo;
methylprednisolone was administered at a dose of 48 mg/ four used azathioprine16,37,38,41 and one mercaptopurine.40 The
day and tapered on a weekly basis to 32 mg, 24 mg, and trials differed in the definition of remission and the time of
4 mg weekly thereafter to 12 mg, resulting in a 6-week in- endpoint assessment, and most allowed concomitant cortico-
duction period.15 Doses of oral prednisolone ranged from steroids [except for Summers et al.16]. There was no significant
0.50 to 0.75 mg/kg with a maximum daily dose of 60 mg, difference in clinical remission compared with placebo (48%
dependent on baseline CDAI. Induction lasted for 17 weeks, [95/197] vs 37% [68/183], RR: 1.23; 95% CI: 0.97–1.55).
with tapering to a dose of 0.25 mg/kg based on the CDAI.16 Three trials reported clinical response using non-
One trial involving 105 patients reported on induction of standardised disease activity measures based on physician as-
clinical response.15 Clinical response was more common in sessment.39,42,43 There was no significant difference compared
patients receiving methylprednisolone compared with pla- with placebo (42.9% [12/28] vs 26.9% [7/26], RR: 1.87;
cebo [93.6% vs 53.4%, RR: 1.75; 95% CI: 1.36–2.25]. 95% CI: 0.44–7.96]). Heterogeneity and sparse data led to
Corticosteroids were twice as effective in inducing clinical downgrading the quality of evidence to very low.
remission than placebo in the two studies15,16 involving 267 A single trial reported on AEs during induction41 with no
patients [RR: 1.99; 95% CI: 1.51–2.64].31 significant difference between thiopurines and placebo (69%
Data on AEs were available from one trial involving 162 [36/52] vs 86% [24/28], RR: 0.81; 95% CI: 0.64–1.02]).
patients treated with oral prednisolone.16,32 The frequency of SAEs were reported in two trials16,41; 13.5% of those receiving
AEs was 5-fold higher in patients receiving corticosteroids azathioprine [AZA] versus 3.8% of those receiving placebo
compared with placebo [31.8% vs 6.5%, RR: 4.89; 95% CI: developed SAEs [pooled RR: 2.57; 95% CI: 0.92–7.13]. The
1.98–12.07]. Steroid-related AEs included Cushing syndrome, quality of evidence was deemed low due to a very low number
1536 H. Gordon et al.

of events [n = 19] and wide confidence intervals. In conjunc- 3.3.2.2. Methotrexate for the maintenance of remission in
tion with ample data supporting the delayed onset of action CD
of thiopurines,45 a strong recommendation against thiopurine
use as induction therapy was made despite the very low Statement 4.2. We suggest parenteral methotrexate mono-
quality of evidence. therapy can be used as maintenance therapy in moderate-
When considering thiopurines as maintenance therapy, to-severe CD [weak recommendation, low-quality
one meta-analysis consisting of six studies [489 partici- evidence]. [Consensus: 97%]
pants] reported the efficacy and safety in patients with
steroid-dependent CD [and thus was judged to provide in- Parenteral methotrexate may be effective in the treatment of
direct evidence in patients without steroid dependency]. 46 CD, whereas studies of oral methotrexate have failed to dem-

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Azathioprine [1.0–2.5 mg/kg/day] was significantly su- onstrate efficacy.
perior to placebo for maintaining clinical remission over In the single eligible, placebo-controlled, RCT,54 141 steroid-
a 6–18 month period [73% vs 62%, RR: 1.19; 95% CI: dependent patients with active CD were randomised to either
1.05–1.34]. 46 This meta-analysis also demonstrated that 25 mg/week of intramuscular methotrexate or placebo for 16
a significantly higher proportion of azathioprine-treated weeks, with a concomitant daily dose of prednisone [20 mg
patients [9%] withdrew due to AEs compared with pla- at initiation] that was tapered over 10 weeks. At Week 16, a
cebo [2%, RR: 3.12; 95% CI: 1.59–6.09] and experienced significantly larger proportion of patients treated with metho-
more SAEs [azathioprine 9% vs placebo 3%, RR: 2.45; trexate were in clinical remission than those reveiving placebo
95% CI: 1.22–4.90]. The most prevalent AEs included (39% [37/94] vs 19% [9/47], RR: 2.06; 95% CI: 1.09–3.89]).
pancreatitis, leukopenia, nausea, allergic reactions, and The rate of treatment discontinuation for AEs [mainly ele-
infections.46 The frequent dose-limiting haematopoietic vated liver enzymes and nausea] was significantly higher when
toxicity that is seen in thiopurine-treated patients can compared with placebo (17% [16/94] versus 2% [1/47], RR:
be decreased by thiopurine methyltransferase analysis 8.00; 95% CI: 1.09–58.51). The effect size estimates for re-
[enzymatic activity or genotype] prior to commencing mission are imprecise and the results may be confounded by
thiopurine therapy. Loss-of-function variants of the nu- the concomitant use of corticosteroids. There were no studies
cleoside diphosphate linked moiety X [Nudix]-type motif comparing methotrexate without concurrent steroid use with
15 [NUDT15] genotype, common in Asian populations, placebo, for the induction of remission, resulting in indirect-
also predispose to myelosuppression and can also be ness of evidence when considering patients without steroid
analysed prior to treatment initiation. 47,48 Large cohort dependency.
studies have also suggested limited efficacy as mainten- Two further studies evaluated the efficacy of oral metho-
ance therapy in CD. 49 trexate at lower doses [12.5 mg weekly or 15 mg weekly]55,56
A nationwide French cohort study confirmed an increased compared with placebo in steroid-dependent patients with
adjusted hazard ratio [HR] for serious infections [HR: 1.32; CD, and found no significant difference for induction of clin-
95% CI: 1.23–1.42] in thiopurine-treated patients when ical remission.
compared with unexposed patients.50 Patients on thiopurines Methotrexate may be considered as an option for steroid-
are at increased risk for lymphoproliferative disorders and dependent patients when alternative options [including
myeloproliferative disorders, with older patients and those surgery] cannot be used. The teratogenicity of the drug
without a previous Epstein–Barr virus infection at highest must be considered and patients counselled appropriately.9
risk.51 A systematic review and meta-analysis [four studies] Retrospective data suggest that methotrexate has some effi-
on the risk of lymphoma in patients exposed to thiopurine cacy in peripheral arthritis in IBD.57
monotherapy versus patients unexposed to anti-tumour ne- Evidence on the use of parenterally administered metho-
crosis factor [TNF] agents or thiopurines demonstrated that trexate as maintenance therapy is derived from a single,
the pooled incidence rate [IRR] of lymphoma was 2.23 [95% double-blind, placebo-controlled RCT where patients with
CI: 1.79–2.79].52 Patients on thiopurine monotherapy are also steroid-dependent CD were administered weekly intramus-
at an increased risk of non-melanoma skin cancer [NMSC] cular injections of 15 mg methotrexate or placebo for 40
and may have an increased risk of cervical high-grade dys- weeks. Patients with previously active CD, who had entered
plasia and cancer.51 remission after 16–24 weeks of treatment with 25 mg metho-
The SONIC trial showed thiopurine monotherapy to be in- trexate given intramuscularly once weekly, were randomly
ferior to infliximab monotherapy or combination therapy.53 assigned to receive either methotrexate 15 mg intramuscu-
Along with the lack of efficacy in induction and the adverse larly once weekly or placebo for 40 weeks. No other treat-
safety profile, this limits the use of thiopurines as maintenance ments for CD were permitted. After 40 weeks, the proportion
therapy and is reflected in the weak recommendation given by of patients who remained in clinical remission was higher
the consensus group. in the methotrexate group [65% vs 39%, RR: 1.67; 95%
CI: 1.05–2.67].58 No differences in SAEs were observed, al-
3.3.2. Methotrexate in the treatment of CD though nausea and vomiting occurred numerically more fre-
3.3.2.1. Methotrexate for the induction of remission in CD quently among patients in the methotrexate group [40% vs
25%]. Patients treated with methotrexate may be at increased
Statement 4.1. We suggest parenteral methotrexate can be risk of NMSC, as demonstrated in a single, nested, case-
used as induction therapy in moderate-to-severe CD [weak control study (odds ratio [OR]: 8.55; 95%: CI 2.55–31.8).59
recommendation, moderate-quality evidence]. [Consensus: However, other studies exploring NMSC in patients with
94%] IBD failed to demonstrate such an association.51,60,61 Low-
dose oral methotrexate [12.5–15 mg/week] as monotherapy
ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment 1537

does not appear to be effective for maintenance of remission 2, and 6 weeks during induction and every 8 weeks thereafter
in CD.62 when continued IV. The efficacy of infliximab monotherapy
for induction therapy in patients with active CD was evalu-
3.4. TNFα antagonists in treatment of CD ated in one small [n = 108], randomised, placebo-controlled
3.4.1. Infliximab in the treatment of CD trial comparing a single infusion of infliximab 5 mg/kg
3.4.1.1. Infliximab monotherapy for the induction of [n = 27], 10 mg/kg [n = 28], or 20 mg/kg [n = 28] with placebo
remission in CD [n = 25]. In this trial, standard dosing of infliximab [5 mg/
kg] was superior to placebo for inducing clinical response
at Week 12 [RR: 4.01; 95% CI: 1.29–12.44]. Superiority of
Statement 5.1. We recommend infliximab as induction
infliximab was not observed for clinical remission at Week 12
therapy with moderate-to-severe active CD [strong recom-

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[RR: 3.70; 95% CI: 0.87–15.80]. Endoscopic endpoints were
mendation, moderate-quality evidence]. [Consensus: 100%]
not reported. Although safety was evaluated in this study, AEs
were pooled for all dosing schemes of infliximab, precluding
any conclusion on the safety profile of standard dosing of
3.4.1.2. Infliximab monotherapy for the maintenance of
infliximab, with the level of certainty further affected by
remission in CD
sparse data.63 Following the pivotal trial of Targan et al., the
ACCENT I trial established the induction dosing time points
Statement 5.2. We recommend infliximab as maintenance of Week 0 followed by Week 2 and Week 6.64
therapy in moderate-to-severe CD [strong recommenda- No separate meta-analysis has focused primarily on the
tion, low-quality evidence]. [Consensus: 100%] outcomes of infliximab maintenance therapy in patients with
CD. Two landmark RCTs were published more than 20 years
ago, and were pooled for the purpose of this guideline.64,65
3.4.1.3. Infliximab combination therapy for the induction of In total, 408 patients who clinically responded to one dose
remission in CD of infliximab [CDAI decrease ≥ 70] were included. After 44
weeks, the overall likelihood of achieving clinical remission
Statement 5.3. We recommend combination therapy with a with infliximab [5 or 10 mg/kg every 8 weeks] over placebo
thiopurine when starting infliximab as induction therapy in was 2.15 [95% CI: 1.52–3.05]. Mucosal healing [defined as
patients with moderate-to-severe CD [strong recommenda- absence of mucosal ulceration] was assessed at 54 weeks in
tion, moderate-quality evidence]. [Consensus: 100%] one RCT,66 showing superiority of infliximab over placebo
[RR: 7.00; 95% CI: 1.02–48.10]. However, patients in the
placebo group received episodic doses of infliximab.
3.4.1.4. Infliximab combination therapy for the maintenance In the pivotal trials, AEs [RR: 0.97; 95% CI: 0.88–1.07], SAEs
of remission in CD [RR: 0.86; 95% CI: 0.65–1.14], and serious infections [RR: 0.85;
95% CI: 0.36–2.00] were not different between infliximab and
placebo.64,65 In a network analysis performed in the framework
Statement 5.4. We recommend combination therapy with
of a Cochrane collaboration, the dose-adjusted OR for severe
infliximab and thiopurines for a minimum of 6–12 months
AEs for infliximab was 1.13 [95% CI: 0.79–1.62].67 Evidence
when using infliximab as maintenance therapy in patients
for clinical and endoscopic outcomes for infliximab main-
with CD [strong recommendation, moderate-quality evi-
tenance therapy was downgraded due to imprecision [sparse
dence]. [Consensus: 100%]
events] and indirectness [since the 10 mg/kg dose is higher than
the standard maintenance dose of 5 mg/kg] in the two pivotal
RCTs. This led to an overall assessment of the level of evidence
3.4.1.5. Withdrawal of immunomodulator in patients with as low. Nevertheless, consensus participants decided to make a
long-term remission when using infliximab to treat CD strong recommendation for use in maintenance therapy based
on extensive real-world experience relating to efficacy and safety
Statement 5.5. In patients with CD who have achieved of standard dosing, and the widespread availability of infliximab
long-term remission with the combination of anti-TNF and as biosimilars with relatively low acquisition costs.
thiopurines, we suggest de-escalation to anti-TNF mono- The SONIC RCT53 compared the efficacy of infliximab
therapy and withdrawal of thiopurines [weak recommenda- combined with azathioprine over infliximab monotherapy
tion, moderate-quality evidence]. [Consensus: 100%] in patients naïve to both therapies, who failed to respond to
steroids or 5-ASA. Combination therapy resulted in higher
Infliximab is effective for the induction and maintenance of rates of clinical remission at Week 26 when compared with
remission in CD. Combination therapy used during induc- infliximab monotherapy [RR: 1.64; 95% CI: 1.07–2.53].
tion and for the first 6–12 months can improve efficacy and Combination therapy was also more likely to result in mu-
reduce immunogenicity; data to support this practice are cosal healing at this time point [RR: 1.82; 95% CI: 1.01–
largely derived from studies evaluating combination with a 3.26]. There were significantly lower rates of SAEs in those
thiopurine. Once long-term remission has been established, receiving combination therapy [RR: 0.56; 95% CI: 0.32–
the immunomodulator can be withdrawn in most patients, 0.97],53 with no difference in total AEs. In addition, several
although caution may be exercised in patients with prior im- prospective68 and retrospective observational studies69–71
munogenicity to an anti-TNF. and a network meta-analysis have also suggested the benefit
Infliximab is monoclonal antibody targeting TNFα, which of combination therapy with azathioprine over infliximab
is administered intravenously [IV] at a dose of 5 mg/kg at 0, monotherapy.72 Combination therapy with azathioprine
1538 H. Gordon et al.

appears to improve efficacy by enhancing pharmacokinetic be discussed individually with the patient, and risk factors
features of infliximab.73 for disease progression and residual disease activity should
For patients who achieved clinical remission after in- be considered. Finally, in patients with immunogenic failure
duction with combination therapy with infliximab and towards a first anti-TNF agent, the addition of thiopurines
immunomodulator, two RCTs provide data on combination during switch to a second anti-TNF agent increases efficacy
therapy versus monotherapy within the maintenance period; and reduces immunogenicity.81 In these patients, evaluation of
these are the SONIC trial53 for combination of infliximab thiopurine discontinuation should be done with special cau-
with azathioprine, and the COMMIT trial74 for combination tion, with de-escalation considered predominantly in patients
of infliximab with methotrexate. Meta-analysis of these data without prior immunogenicity.
revealed higher rates of mucosal healing [RR: 1.46; 95% CI:
3.4.2. Adalimumab in the treatment of CD

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1.00–2.13] and improved patient-reported outcomes, meas-
ured as change in Inflammatory Bowel Disease Questionnaire 3.4.2.1. Adalimumab monotherapy for the induction of
[IBDQ] score from baseline (mean difference [MD]: 4.8; 95% remission in CD
CI: 2.23–11.83]) Although resulting in numerically higher ef-
ficacy rates, combination therapy was not superior in clinical Statement 6.1. We recommend adalimumab as induction
response [RR: 1.21; 95% CI: 0.96–1.53], clinical remission therapy in patients with moderate-to-severe CD [strong
[RR: 1.25; 95% CI: 0.97–1.61], or steroid-free clinical remis- recommendation, moderate-quality evidence]. [Consensus:
sion [RR: 1.15; 95% CI: 0.85–1.55]. SAEs were less frequent 100%]
with combination therapy [RR: 0.66; 95% CI: 0.41–0.98],
whereas total AEs [RR: 1.01; 95% CI: 0.94–1.09] were
similar between groups. 3.4.2.2. Adalimumab monotherapy for the maintenance of
More recently, infliximab has been licensed for subcuta- remission in CD
neous [SC] maintenance administration after intravenous
[IV] induction dosing. This decision was based on pharma-
Statement 6.2. We recommend adalimumab monotherapy
cokinetic and safety data comparing maintenance SC dosing
as maintenance therapy in moderate-to-severe CD [strong
every 2 weeks with IV dosing.75 Subsequent RCT data have
recommendation, moderate-quality evidence]. [Consensus:
demonstrated the superiority of maintenance SC infliximab
100%]
versus placebo for clinical and endoscopic endpoints among
responders to IV infliximab induction therapy, demonstrating
that this formulation is an effective option for responders
3.4.2.3. Adalimumab combination therapy for the induction
to IV induction.76 Multiple cohort studies have reported the
of remission in CD
effectiveness and safety of switching patients already estab-
lished on standard doses of IV maintenance infliximab to SC
maintenance dosing.77 Future recommendations on infliximab Statement 6.3. We suggest adalimumab monotherapy
combination therapy may change with emerging evidence on should be used over combination therapy with thiopurines
the efficacy, pharmacokinetics, and immunogenicity of SC as induction therapy in patients with moderate-to-severe
infliximab.78 CD naïve to biologics [weak recommendation, moderate-
The combination of anti-TNF therapy with a thiopurine is quality evidence]. [Consensus: 100%]
associated with adverse long-term safety signals in terms of
risk of both serious infection and malignancy.50,51 This raises
questions regarding potential de-escalation of treatment for 3.4.2.4. Adalimumab combination therapy for the
patients in stable remission. The recent SPARE trial investi- maintenance of remission in CD
gated clinical relapse in CD patients in steroid-free clinical re-
mission for a minimum 8 months under combined infliximab Statement 6.4. We suggest adalimumab monotherapy
and immunomodulator therapy, who either continued com- should be used over combination with an immunomodulator
bination therapy or stopped infliximab or immunosup- as maintenance therapy in patients with moderate-to-
pressive therapy.79 In this study with 211 randomised CD severe CD naïve to biologics [weak recommendation, low-
patients, clinical remission was significantly more often quality evidence]. [Consensus: 98%]
maintained over 2 years of follow-up when combination
therapy was de-escalated to infliximab monotherapy [63/69; Adalimumab is effective for the induction and maintenance of
91%] when compared with immunomodulator monotherapy remission in CD. Available evidence does not support combin-
[46/71; 65%] [RR: 1.41; 95% CI: 1.17-1.7]. There were no ation with an immunomodulator in biologic-naïve patients,
significant differences in clinical relapse rates, endoscopic although combination therapy may be considered in patients
outcomes, or pharmacokinetic outcomes between the group with prior immunogenicity to an alternative anti-TNF.
continuing combination therapy and those discontinuing Adalimumab is a fully humanised IgG1 monoclonal anti-
immunomodulator therapy. AEs occurred at a similar fre- body directed against TNFα, approved for the treatment of
quency across treatment groups. moderate-to-severe CD. Adalimumab is administered SC at a
In general, a higher risk of lymphoma exists when anti- dose of 160 mg and then 80 mg 2 weeks after induction, fol-
TNF agents are combined with conventional immunosup- lowed by 40 mg SC every 2 weeks. A meta-analysis of pooled
pression, although the absolute rates remain very low and are data on adalimumab versus placebo from three RCTs82–84
estimated at 1.9 per 10 000 patient-years in a meta-analysis involving 680 patients with moderate-to-severe CD, who did
consisting of almost 9000 patients included in the SEER data- not achieve adequate response or were intolerant to cortico-
base.80 In clinical practice, the decision to de-escalate should steroids and/or immunosuppressants, demonstrated efficacy
ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment 1539

for induction of clinical remission [RR: 3.58; 95% CI: 2.42– 0.01–5.00], or any AE [RR: 0.81; 95% CI: 0.47–1.38].90,91
5.29] and clinical response [RR: 1.98; 95% CI: 1.47–2.67] Likewise, a meta-analysis that included retrospective studies
within 4 weeks of therapy initiation. Limited endoscopic data also revealed that combination therapy was not superior to
were available for the induction period only in one study; the monotherapy for maintenance of remission [OR: 1.08; 95%
data showed a significant trend towards enhanced mucosal CI: 0.79–1.48, p = 0.48].93 More recently, post-hoc analysis of
healing [RR: 30.51; 95% CI: 1.87–498.81]. However, this six RCTs [CLASSIC-I, GAIN, CHARM, EXTEND, ULTRA
evidence was downgraded due to high imprecision arising 1, and ULTRA 2] demonstrated no efficacy benefits with
from sparse data.85 There was no difference in AEs between immunomodulator and adalimumab combination therapy
those receiving adalimumab or placebo during the induc- when compared with adalimumab monotherapy in CD pa-
tion period [RR: 0.91; 95% CI: 0.75–1.11].82–84 Rates of tients with inadequate disease control on immunomodulatory

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SAEs with adalimumab were also not significantly different therapy.94
from placebo [RR: 0.29; 95% CI: 0.09–0.96], but evidence The DIAMOND study included patients naïve to
was downgraded due to imprecision from sparse data.82–84 adalimumab. In the case of immune-mediated loss of re-
Data revealed improved QoL based on the IBDQ within 4 sponse to a first anti-TNF, RCT evidence suggests that com-
weeks of therapy initiation[RR: 0.91; 95% CI: 0.75–1.11]. bination therapy is of benefit with the second anti-TNF.81
A Cochrane review based on three RCTs revealed similar re- Additionally, the observational PANTS study demonstrated
sults for clinical remission, response, improvement in QoL, a significant reduction in anti-adalimumab antibody devel-
and AEs during the first 4 weeks of therapy.86 opment with adalimumab combination therapy in anti-TNF-
Data from three RCTs in individuals with moderate- naïve patients [HR: 0.44; 95% CI: 0.31–0.61],68 suggesting
to-severe CD, who responded to induction therapy that some patients may benefit from combination therapy
[CHARM, EXTEND 1, CLASSIC-II], demonstrated effi- with adalimumab and a thiopurine, depending on genetic
cacy of adalimumab 40 mg SC every 2 weeks over placebo predisposition.95 Therefore, combining adalimumab with an
for maintenance of clinical remission [RR: 2.70; 95% CI: immunomodulator should be considered in high-risk groups,
1.75–4.19] at 52–56 weeks of follow-up.85,87,88 Outcomes including those with prior immunogenic failure to other
of clinical response [RR: 2.01; 95% CI: 1.14–3.55], but not anti-TNFs.
corticosteroid-free remission [RR: 2.32; 95% CI: 0.62-8.63],
were also improved with adalimumab.87,88 RCT data on 3.4.3. Certolizumab in the treatment of CD
endoscopic outcomes are more limited, but suggest efficacy 3.4.2.1. Certolizumab for the induction of remission in CD
of adalimumab relative to placebo in endoscopic remission
[RR: 9.14; 95% CI 2.21–37.80], endoscopic response [RR: Statement 7.1. We suggest certolizumab can be used as
14.22; 95% CI: 1.93–104.98], and mucosal healing [RR: induction therapy in patients with moderate-to-severe
31.00; 95% CI: 1.90–506.95].85 Based on a post-hoc analysis CD [weak recommendation, moderate-quality evidence].
of a single, placebo-controlled trial, QoL improvement was [Consensus: 97%]
greater with adalimumab [RR: 1.32; 95% CI: 1.11–1.62].89
Regarding safety during the maintenance period, pooled
clinical trial data indicated that adalimumab was associ-
ated with fewer SAEs than placebo [RR: 0.57; 95% CI: 3.4.3.2. Certolizumab for the maintenance of remission in
0.39–0.83], and associations with any AE [RR: 1.00; 95% CD
CI: 0.86–1.15] and serious infections were comparable [RR:
0.79; 95% CI: 0.34–1.79].85,87,88 In a network analysis per- Statement 7.2. We suggest certolizumab can be used as
formed in the framework of a Cochrane collaboration, the maintenance therapy in moderate-to-severe CD [weak rec-
dose-adjusted OR for SAEs for adalimumab was 1.01 [95% ommendation, moderate-quality evidence]. [Consensus:
CI: 0.64–1.59].67 100%]
Only one open-label RCT [the DIAMOND trial]90 studied
the use of combination therapy of adalimumab with a Certolizumab may be an effective treatment for the induction
thiopurine when compared with adalimumab monotherapy and maintenance of remission in CD. Availability varies be-
for the induction of clinical remission in patients naïve to tween regions; it is not approved by the European Medicines
both therapies. In this trial, combination therapy was not Agency.
superior to adalimumab monotherapy for inducing clinical Certolizumab pegol [herein termed certolizumab] is a hu-
remission at Week 26 [primary endpoint] [RR: 0.95; 95% manised polyethylene glycol [PEG]ylated F[ab] fragment of
CI: 0.78–1.15]. However, combination therapy was associ- a monoclonal antibody directed against TNFα. Although
ated with endoscopic improvement at Week 26 [RR: 1.32; certolizumab is not approved by the European Medicines
95% CI: 1.06–1.65], although this benefit was lost by Week Agency [EU] for the treatment of CD, it is commercially
52. There was no increase in AEs leading to discontinuation available elsewhere, including in Switzerland and Russia. The
associated with combination therapy [RR: 1.03; 95% CI: efficacy and safety of certolizumab for induction therapy in
0.60–1.78]. patients with moderately to severely active CD was evaluated
The Week 52 maintenance outcomes of the DIAMOND in four randomised, placebo-controlled trials including a total
trial demonstrated no clinical benefit of combination therapy of 1485 patients.96–98 A Cochrane review from 2019 evaluated
in clinical remission [RR: 1.07; 95% CI: 0.91–1.25], clinical the efficacy and safety of certolizumab as induction therapy
response [RR: 0.95; 95% CI: 0.78–1.15],90,91 steroid-free clin- for CD.99 Certolizumab was superior to placebo for induction
ical remission [RR: 0.97; 95% CI: 0.85–1.12],91 endoscopic of clinical response [RR: 1.29; 95% CI: 1.09–1.53] and clin-
response [RR: 1.20; 95% CI: 0.89–1.62],92 mucosal healing ical remission [RR: 1.36; 95% CI: 1.11–1.66]. Endoscopic
[RR: 1.77; 95% CI: 0.82–3.82],92 SAEs [RR: 0.25; 95% CI: outcomes were not reported. The rates of any SAEs [RR: 1.35;
1540 H. Gordon et al.

95% CI: 0.93–1.97] were not different between certolizumab higher rates of favourable therapeutic outcomes in pa-
and placebo. tients with CD.101 Low drug concentrations are also asso-
Two RCTs assessed the efficacy and safety of certolizumab ciated with primary non-response [PNR], loss of response
as maintenance therapy [400 mg every 4 weeks] in patients [LOR], and development of anti-drug antibodies.68 A key
with moderate-to-severe CD [PRECISE I and II].97,100 A total question is whether dose optimisation in clinical practice,
of 1088 patients [30% had previous infliximab failure] were based on prospective measurement of drug levels [pro-
included and followed for only 26 weeks. Compared with pla- active therapeutic drug monitoring, or TDM] can confer
cebo, certolizumab maintained a higher clinical response rate clinical benefit.
[reduction ≥ 100 points from baseline CDAI, OR: 1.64; 95% Pooled data from RCTs showed no statistically significant
CI: 1.38–1.95] and resulted in greater rates of clinical remis- difference between proactive TDM and standard-of-care anti-

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sion [CDAI score ≤ 150 points, OR: 1.55; 95% CI: 1.23–1.95]. TNF therapy in clinical remission [three studies, RR: 1.12;
Furthermore, QoL as assessed by a minimum 16-point increase 95% CI: 0.90–1.39], steroid-free clinical remission [three
in the IBDQ from baseline showed a significant improvement studies, RR: 1.00; 95% CI: 0.77–1.31], endoscopic remission
in patients treated with certolizumab, with a relative effect of [two studies, RR: 0.96; 95% CI: 0.72–1.27], biochemical re-
1.35 [95% CI: 1.17–1.55]. Endoscopic outcomes were not mission [two studies, RR: 1.08; 95% CI: 0.87–1.33], SAEs
measured. The incidence of SAEs did not differ significantly [two studies, RR: 1.27; 95% CI: 0.76–2.14], or serious in-
between patients treated with certolizumab and those who re- fections [two studies, RR: 1.47; 95% CI: 0.10–21.20].102–106
ceived placebo, with a relative effect of 1.19 [95% CI: 0.70– However, these RCTs had some important methodological
2.02]. In a network analysis performed in the framework of a issues regarding study design, including a rather low cut-off
Cochrane collaboration, the dose-adjusted OR for severe AEs drug concentration for dose escalation, heterogeneity of study
for certolizumab was 1.57 [95% CI: 0.96–2.57].67 populations, and the fact that proactive TDM did not start
The reporting of all maintenance endpoints at the early early during induction.
time points of Week 26 resulted in downgrading the evidence In a recent systematic review and meta-analysis, there
quality of clinical maintenance endpoints. When combined was no significant difference in the risk of failing to main-
with the absence of endoscopic endpoints, the consensus group tain clinical remission in patients who underwent proactive
decided that the strength of recommendation should be weak. TDM versus clinically driven dose adjustments in patients
Consistent with the weak recommendation for certolizumab with CD treated with anti-TNF therapy [RR: 0.87; 95% CI:
as a maintenance therapy, and the widespread availability and 0.66-1.15].107 Similarly, another meta-analysis showed no
suitability of other anti-TNF therapies, including biosimilar superiority of proactive TDM compared with conventional
options, the consensus group agreed that the recommenda- management in maintaining clinical remission with anti-TNF
tion for use of certolizumab as induction therapy should also agents [RR: 1.16; 95% CI: 0.98–1.37].108 On this basis, there
be weak. was insufficient evidence to recommend the use of proactive
therapeutic monitoring for patients with CD undergoing
treatment with anti-TNF therapy.
3.4.4. Drug monitoring when using anti-TNF therapy
However, the consensus group noted that there was evi-
3.4.4.1. Proactive and reactive drug monitoring compared dence for additional important outcomes outside the remit
with standard of care of our voted GRADE outcomes, which may confer benefit
to the patient. A meta-analysis including both retrospective
Statement 8.1. There is insufficient evidence to recommend studies and RCTs found that proactive TDM of anti-TNF
the use of proactive therapeutic drug monitoring. compared therapy was associated with a significantly decreased risk of
with reactive therapeutic drug monitoring or standard of treatment failure compared with either standard of care [RR:
care. when using anti-TNF agents [weak recommendation, 0.64; 95% CI: 0.48–0.85] or reactive TDM [RR: 0.46; 95%
very low-quality evidence]. [Consensus: 100%] CI: 0.21–0.98]. Moreover, proactive TDM was associated
with a significant reduction in hospitalisation [RR: 0.33; 95%
CI: 0.21–0.54].109 These findings were replicated in another
Practice Point 1: Therapeutic drug monitoring may be used meta-analysis that also highlighted potential cost efficiency of
when optimising dose in patients with CD treated with proactive TDM.108
anti-TNF therapy. [Consensus: 94%] Proactive TDM may also be useful in other clinical
scenarios, such as anti-TNF therapy de-escalation,110 re-
The use of therapeutic drug monitoring for anti-TNF therapy starting infliximab following a pause in scheduled drug ad-
was evaluated with both a GRADE evaluation and develop- ministration, and optimising infliximab monotherapy when
ment of a practice point. GRADE evaluation of trial data combination therapy with an immunomodulator is not pos-
did not demonstrate superiority of proactive drug moni- sible due to patient preference or high risk of SAEs.111 Recent
toring compared with reactive monitoring or no drug moni- data from two studies, including mainly patients with CD,
toring, when considering our predefined GRADE outcomes. suggest that proactive TDM can also mitigate risk of im-
However, further assessment of the literature during develop- munogenicity to anti-TNF therapy and treatment cessation in
ment of the practice point highlighted several ways in which patients with a positive HLA-DQA1*05 genotype, previously
therapeutic drug monitoring can be useful when optimising found to predispose to development of anti-drug antibodies
dose of anti-TNF therapy, which is reflected in widespread against infliximab and adalimumab.95,112,113
use in clinical practice as discussed in the text. Data from paediatric studies were not included in the
Numerous prospective studies and post-hoc analysis GRADE analysis. However, cumulative evidence from RCTs
of RCTs have shown that higher anti-TNF drug concen- suggests that proactive TDM of anti-TNF therapy is asso-
trations during maintenance therapy are associated with ciated with better outcomes compared with clinically based
ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment 1541

dosing or reactive TDM in CD in paediatric populations.114,115 efficacy in clinical response [RR: 1.56; 95% CI: 1.38–1.57]
In particular, the PAILOT RCT, including children with CD and clinical remission [RR: 1.76; 95% CI: 1.40–2.22]. Two
naïve to biological therapy who responded to adalimumab substudies125,127 involving 252 patients revealed that more pa-
induction therapy, showed that sustained corticosteroid-free tients receiving ustekinumab achieved endoscopic improve-
clinical remission was significantly higher in the proactive ment compared with placebo [47.7% vs 29.9%, RR: 1.60;
compared with the reactive TDM arm [82% vs 48%, respect- 95% CI: 1.13–2.26] and a reduction in the mean global hist-
ively, p = 0.002].114 Moreover, a recent RCT on a biologic- ology activity scores [from 10.4 ± 7.0 to 7.1 ± 5.9; p < 0.001]
naïve paediatric population with CD, who responded to at 8 weeks. A more recent RCT128 investigating the efficacy
infliximab induction therapy, showed that proactive TDM and safety of guselkumab in CD, in which ustekinumab was
compared with clinically based dosing was superior regarding administered in a reference arm [63 patients], reported similar

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sustained corticosteroid-free clinical remission [89.5% vs results at 12 weeks. Two studies129,130 reported on the effect of
70.9%, p = 0.025] and endoscopic healing [85% vs 57.1%, ustekinumab on health-related QoL. The RR was 2.42 [95%
p = 0.025].115 CI: 1.27–4.61] for achieving PRO-2 remission, 2.14 [95%
Reactive TDM, defined as the evaluation of drug concen- CI: 1.27–3.62] for IBDQ remission, and 1.86 [95% CI: 1.33–
trations and antidrug antibody titres when PNR or LOR 2.59] for IBDQ response at 12 weeks.128 Similarly, signifi-
occur, may help identify the mechanisms underlying these un- cantly greater proportions of patients receiving ustekinumab
desirable outcomes, which in turn may shape future drug se- had clinically meaningful IBDQ and SF-36 score improve-
lection.116 Observational study data suggest that this may be ment at 8 weeks compared with placebo in a pooled ana-
a cost-effective strategy associated with potential for better lysis of two pivotal RCTs. One study reported pooled safety
therapeutic outcomes.117–119 results of phase 2/3 RCTs on any AEs or SAEs after induc-
Consequently, while recognising the problems with the evi- tion [1653 patients].129 The pooled RR of any AEs was not
dence base reflected in the GRADE statement, the consensus significantly different between ustekinumab and placebo
group recognises a place for TDM in clinical care, when avail- [53.8% vs 56.1%, RR: 0.96; 95% CI: 0.89–1.03]. Similarly,
able. Nonetheless, several problems concerning TDM for the pooled RR of any SAEs and of any serious infection were
anti-TNF therapy remain, including identification of optimal not significantly different between ustekinumab and placebo
drug concentration targets, assay variability, and feasibility [4.5% vs 6.2%, RR: 0.72; 95% CI: 0.51–1.02; and 1.1%
of timely dosing interventions. Importantly, although there is vs 1.2%, RR: 0.95; 95% CI: 0.45–2.01, respectively]. The
some evidence of dose-response relationships for non-anti- rate of antidrug antibody formation was < 5%.131 Finally, a
TNF biologics in CD, there is much less evidence to suggest meta-analysis132 of 63 observational studies [8529 patients]
a potential benefit for TDM-guided dosing, and use of TDM reported that 60% [95% CI: 54–67%, I2 = 93%] of patients
in the routine care of patients treated with non-anti-TNF who received ustekinumab achieved clinical response, 37%
biologics is not supported.120,121 [95% CI: 28–46%, I2 = 97%] achieved clinical remission, and
33% [95% CI: 27–40%, I2 = 86%] achieved corticosteroid-
3.5. IL-12/IL-23 inhibitors in the treatment of CD free clinical remission at 8–14 weeks, replicating the results of
3.5.1. Ustekinumab in the treatment of CD RCTs in a real-world setting of refractory patients with CD.
3.5.1.1. Ustekinumab for the induction of remission in CD Maintenance outcomes were also evaluated. One RCT in-
cluded patients with moderate-to-severe CD who responded to
ustekinumab induction therapy. Patients were re-randomised
Statement 9.1. We recommend ustekinumab as induction
to receive ustekinumab 90 mg [either every 8 weeks or every
therapy in moderate-to-severe CD [strong recommenda-
12 weeks] or placebo. More patients receiving ustekinumab
tion, moderate-quality evidence]. [Consensus: 100%]
when compared with those receiving placebo were in clin-
ical remission over a 44-week follow-up [51% vs 35.9%,
RR: 1.42; 95% CI: 1.10–1.84],124 and at Week 56 [50.2%
3.5.1.2. Ustekinumab for the maintenance of remission in
vs 27.7%; RR: 1.83; 95% CI: 1.35–2.47].131,133 The same
CD
study showed that more patients receiving ustekinumab were
also in corticosteroid-free clinical remission over a 44-week
Statement 9.2. We recommend ustekinumab as mainten- follow-up [44.7% vs 29.8%, RR: 1.50; 95% CI: 1.12–2.02]
ance therapy in moderate-to-severe CD [strong recommen- and after 56 weeks of treatment [44.7% vs 22.1%; RR: 2.02;
dation, moderate-quality evidence]. [Consensus: 100%] 95% CI: 1.43–2.86].124,131,133 Similar results were shown for
clinical response. There are limited placebo-controlled trial
Ustekinumab is effective for the induction and maintenance data from a subgroup analysis on endoscopic remission [total
of remission in CD. SES-CD score ≤ 2] and mucosal healing [complete absence of
Ustekinumab is an IgG1 monoclonal antibody that binds to any mucosal ulcerations among patients who presented with
the p40 subunit shared by the pro-inflammatory interleukins ulceration in at least one ileocolonic segment at induction].
12 and 23. In CD, induction is given IV using a weight-based There was no statistically significant difference in mucosal
regimen of approximately 6 mg/kg. One systematic review healing [RR: 3.13; 95% CI: 0.40–24.53] or endoscopic remis-
and meta-analysis pooled the results from RCTs in which sion [RR: 2.61; 95% CI: 0.32–21.08] between ustekinumab
ustekinumab was compared with placebo for induction of and placebo.125 Nevertheless, outcome data from a large
remission in adult patients with moderately to severely ac- randomised trial comparing treatment with ustekinumab
tive luminal CD.122 Four trials123–126 involving 1947 patients every 8 weeks with adalimumab every 2 weeks showed
treated with different ustekinumab IV doses or equivalent pla- similar endoscopic outcomes between the two groups.134 In
cebo reported on induction outcomes at 6 weeks. Data were addition, post-hoc analyses showed that ustekinumab im-
extracted and a meta-analysis was performed, demonstrating proved health-related QoL compared with placebo.129 A
1542 H. Gordon et al.

pooled safety analysis from phase 2/3 studies showed that [ustekinumab 29% vs adalimumab 31%, RR: 0.93, 95% CI:
there was no statistically significant difference between 0.67–1.28] at Week 52.134
placebo- or ustekinumab-treated patients for SAEs [RR: 1.03; Overall, the safety profile was similar between groups for
95% CI: 0.85–1.26] and serious infections [RR: 1.57; 95% AEs [RR: 1.03, 95% CI 0.93–1.14] and SAEs [RR: 0.82,
CI: 0.98–2.51] for a mean follow-up of 48 weeks.130 95% CI 0.22–3.00]. However, the numerical proportions of
patients in the ustekinumab group [34%] who experienced
3.5.2. Ustekinumab compared with adalimumab for infections was lower than in the adalimumab group [41%],
induction of remission in CD although rates of serious infections were similar.134
Overall, the consensus group noted that data from this
Statement 10.1. We suggest adalimumab or ustekinumab single RCT suggested similar efficacy and safety outcomes,

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are equally as effective as induction therapy in biologic- with moderate evidence quality. Nonetheless, the study
naïve patients with moderate-to-severe CD [weak recom- used doses of drugs that did not entirely align with licensed
mendation, moderate-quality evidence]. [Consensus: 100%] doses within Europe, and dose escalation was not permitted.
The findings may not apply to patients with previous bio-
logic therapy failure or longer disease history. Furthermore,
3.5.2.1. Ustekinumab compared with adalimumab for longer-term follow-up beyond 1 year would be required to
maintenance of remission in CD determine if efficacy and safety are sustained similarly with
each drug. Overall, this led to a decision to make a weak
recommendation, reflecting the strength of the evidence and
Statement 10.2. We suggest adalimumab and ustekinumab
these additional concerns.
are equally as effective as maintenance therapy in biologic-
naïve patients with moderate-to-severe CD [weak recom- 3.5.3. Risankizumab in the treatment of CD
mendation, moderate-quality evidence]. [Consensus: 100%]
3.5.3.1. Risankizumab for the induction of remission in CD

RCT evidence suggests that ustekinumab and adalimumab

may be equally effective for the induction and maintenance of Statement 11.1. We recommend risankizumab as induction
remission in CD in patients without prior biologic exposure. therapy in moderate-to-severe CD [strong recommenda-
The SEAVUE trial [phase 3b]134 was an active com- tion, high-quality evidence]. [Consensus: 100%]
parator randomised trial that used a ‘treat-through’ design
to compare the effectiveness and safety of ustekinumab
and adalimumab monotherapy in biologic-naïve adult pa- 3.5.3.2. Risankizumab for the maintenance of remission in
tients with moderately to severely active CD. Of note, the CD
threshold of endoscopic disease required for trial inclusion
was lower compared with several other studies [requiring Statement 11.2. We recommend risankizumab as mainten-
at least one, single ulcer of any size]. The primary endpoint ance therapy in moderate-to-severe CD [strong recommen-
was the proportion of patients in clinical remission [CDAI dation; high-quality evidence]. [Consensus: 100%]
score < 150] at Week 52. A total of 386 patients were en-
rolled and randomly assigned to receive ustekinumab Risankizumab is effective for the induction and maintenance
[n = 191] or adalimumab [n = 195]. Ustekinumab induction of remission in CD.
was approximately 6 mg/kg IV on Day 0, followed by main- Risankizumab is a humanised, monoclonal IgG1 class anti-
tenance of 90 mg SC at Week 8, and then 90 mg SC once body that binds to the p19 subunit of IL-23. Two placebo-
every 8 weeks. Adalimumab induction was 160 mg SC on controlled RCTs were identified.135 The two studies included
Day 0, 80 mg SC at Week 2, followed by maintenance of a total of 889 patients with moderately to severely active CD,
40 mg SC at Week 4, and then once every 2 weeks. Study with evaluable outcome data after exposure to either three IV
treatments were administered as monotherapy and without doses of 600 mg risankizumab [Weeks 0, 4, and 8] or placebo,
dose modifications. Both monotherapies were effective for with primary outcome measures captured at Week 12. Clinical
induction of remission at Week 16 [ustekinumab 57% vs response and clinical remission were achieved more often in
adalimumab 60%, difference -3%, 95% CI: -13 to 7; nom- patients receiving risankizumab compared with placebo [RR:
inal p = 0.55] and demonstrated comparative efficacy [RR: 1.79, 95% CI: 1.47–2.17 and RR: 1.95, 95% CI:1.57–2.43,
0.95, 95% CI: 0.80–1.13]. Response rates at 16 weeks were respectively]. Endoscopic response and endoscopic remission
similar between agents [72% vs 73%, respectively], with were achieved with risankizumab more often than placebo
moderate-quality evidence. Safety outcomes for both groups [RR: 2.96, 95% CI: 2.17–4.05 and RR: 3.22, 95% CI: 1.93–
did not show significant differences. 5.38, respectively]. Rates of any AEs in patients treated with
When considering maintenance outcomes at Week 52, risankizumab occurred statistically less often than in patients
64.9% [124/191] of patients receiving ustekinumab every receiving placebo [RR: 0.85, 95% CI: 0.62–1.17]. SAEs and
8 weeks versus 61.0% [119/195] of patients receiving serious infections occurred less often in risankizumab-treated
adalimumab every 2 weeks were in clinical remission [RR: patients [RR: 0.45, 95% CI: 0.3–0.67 and RR: 0.21, 95% CI:
1.06, 95% CI: 0.91–1.24].134 Similarly, corticosteroid-free 0.07–0.65, respectively].
clinical remission was achieved in 61% of the ustekinumab Clinical responders to risankizumab from the two phase 3
group and 57% of the adalimumab group [RR: 1.06, 95% induction trials were re-randomised in a single maintenance
CI: 0.90–1.25]. Both treatment groups showed similar endo- therapy trial. A total of 141 evaluable participants received
scopic response [ustekinumab 42% vs adalimumab 37%, RR: 360 mg risankizumab SC every 8 weeks, and 164 partici-
1.14, 95% CI: 0.88–1.47] and endoscopic remission rates pants received SC placebo.136 Compared with placebo, more
ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment 1543

patients treated with risankizumab achieved clinical remis- 1.55, 95% CI: 1.25–1.91], with 44.7% [197/441] of pa-
sion [51.8% vs 39.6%, RR: 1.31, 95% CI: 1.02–1.67] or tients receiving vedolizumab in clinical remission when
endoscopic response [46.8% vs 22.0%, RR: 2.13, 95% CI: compared with 27.1% [81/299] of patients receiving pla-
1.52–2.99] at Week 52.136,137 A higher proportion of patients cebo. Moreover, vedolizumab was effective at maintaining
on risankizumab maintenance also achieved clinical response, steroid-free clinical remission [RR: 2.23, 95% CI: 1.44–
endoscopic remission, and ulcer-free endoscopy after 1 year 3.44]; this endpoint was achieved in 39.0% [71/182] of
of therapy. The overall incidence of any SAEs or serious infec- patients receiving vedolizumab compared with 16.3%
tions were similar across study groups. [21/129] of patients receiving placebo. Again, no endo-
scopic data were generated during the registrational trials,
3.6. Anti-integrin therapies in the treatment of CD although endoscopic outcomes have been collected during

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3.6.1. Vedolizumab in the treatment of CD open-label clinical trials and cohort studies.145 Vedolizumab
3.6.1.1. Vedolizumab for the induction of remission in CD showed a similar incidence of AEs [RR: 0.96, 95% CI:
0.86–1.08], SAEs [RR: 0.98, 95% CI: 0.67–1.44], and ser-
ious infections [RR: 0.32, 95% CI: 0.09–1.13] compared
Statement 12.1. We recommend vedolizumab as induction
with placebo through Week 52–60. Similar safety signals
therapy in moderate-to-severe CD [strong recommenda-
were observed in the GEMINI long‐term safety study that
tion, moderate-quality evidence]. [Consensus: 100%]
followed CD patients exposed to IV vedolizumab every 4
weeks for a median of 32 months [range 0.03–100.3].146
3.6.1.2. Vedolizumab for the maintenance of remission in 3.7. Janus kinase inhibitors in the treatment of CD
CD
3.7.1. Upadacitinib in the treatment of CD
3.7.1.1. Upadacitinib for the induction of remission in CD
Statement 12.2. We recommend vedolizumab as mainten-
ance therapy in moderate-to-severe CD [strong recommen-
dation, moderate-quality evidence]. [Consensus: 100%] Statement 13.1. We recommend upadacitinib as induction
therapy in moderate-to-severe CD [strong recommenda-
Vedolizumab is effective for the induction and maintenance tion; high-quality evidence]. [Consensus: 100%]
of remission in CD.
Vedolizumab is a monoclonal IgG1 antibody that acts by
blocking the α4β7 integrin, resulting in disruption of lympho- 3.7.1.2. Upadacitinib for the maintenance of remission in
cyte trafficking and anti-inflammatory activity. It is adminis- CD
tered IV at a fixed dose of 300 mg at 0, 2, and 6 weeks for
induction. Patients who do not achieve response at Week 6 can Statement 13.2. We recommend upadacitinib as mainten-
benefit from an additional administration at Week 10.138 Four ance therapy in moderate-to-severe CD [strong recommen-
RCTs involving 1126 patients treated with vedolizumab or dation; moderate-quality evidence]. [Consensus: 100%]
placebo reported on clinical and safety outcomes in adult pa-
tients with moderately to severely active luminal CD at 6–10 Upadacitinib is the only JAK inhibitor recommended for the
weeks.139–142 Data were extracted and a meta-analysis was per- induction and maintenance of remission in CD.
formed. Vedolizumab was superior to placebo in induction of Upadacitinib is an oral Janus kinase [JAK] inhibitor with
clinical response [RR: 1.59, 95% CI: 1.32–1.91] and clinical relatively increased selectivity for JAK-1. Two RCTs147 re-
remission [RR: 2.00, 95% CI: 1.51–2.66]. Endoscopic out- ported outcomes for a total 1021 patients who were random-
come data were not assessed. The pooled RR of any AEs was ised in a 2:1 ratio to receive either 45 mg/day of upadacitinib
not significantly different between vedolizumab and placebo or placebo for 12 weeks. We meta-analysed outcomes from
[62% vs 53.8%, RR: 1.15, 95% CI: 0.88–1.51]. Similarly, the these trials. A significantly higher percentage of patients re-
pooled RR of SAEs was not significantly different between ceiving upadacitinib achieved clinical remission than those
vedolizumab and placebo [9.0% vs 9.2%, RR: 0.99, 95% CI: who received placebo [44.4% vs 25.1%, p < 0.001] and endo-
0.68–1.44]. scopic response [40.2% vs 8.4%, p < 0.001]. Significantly
A meta-analysis143 of 74 observational studies [13 663 higher proportions of patients on upadacitinib achieved
patients] reported that 56% [95% CI: 51–61%, I2 = 89%] clinical response, steroid-free remission, and endoscopic re-
of the patients who received vedolizumab exhibited clinical mission when compared with placebo. The overall incidence
response, 36% [95% CI: 32–40%, I2 = 85%] achieved clin- of safety outcomes was similar between patients exposed to
ical remission, 30% [95% CI: 25–34%, I2 = 87%] achieved upadacitinib and placebo.
corticosteroid-free clinical remission, and 29% [95% CI: Clinical responders from the induction RCTs were
19–42%, I2 = 58%] achieved mucosal healing at 6–16 weeks, re-randomised to receive daily upadacitinib 15 mg
replicating the results of RCTs in a real-world setting of re- [n = 169], upadacitinib 30 mg [n = 168], or placebo
fractory patients with CD. [n = 165].148 When compared with placebo, maintenance
Maintenance therapy with vedolizumab was investigated therapy with upadacitinib, 15 mg once daily and 30 mg
in three RCTs in patients with moderate-to-severe CD who once daily by Week 52, resulted in significantly higher rates
had responded to induction therapy. Vedolizumab was ad- of clinical remission [37.3% and 47.6% vs 15.1%, respect-
ministered IV at 300 mg every 8 weeks in two studies139,142 ively, p < 0.001 for both comparisons], endoscopic response
and SC at 108 mg every 2 weeks in one study.144 Following [35.5% and 40.1% vs 7.3%, respectively, p < 0.001 for
52–60 weeks of maintenance therapy, vedolizumab was both], and remission [19.1% and 28.6% vs 5.5%, respect-
superior to placebo in achieving clinical remission [RR: ively, p < 0.001 for both].
1544 H. Gordon et al.

A higher proportion of patients on upadacitinib main- and polymeric] and fat composition or method of administra-
tenance achieved clinical response and steroid-free clinical tion [nasogastric or oral].150 Using EEN effectively requires a
remission with improved QoL. Efficacy outcomes were all multidisciplinary team [MDT], with dietitian support playing
numerically higher in the group receiving higher doses of a pivotal role.153
maintenance therapy, although this should be viewed against
safety and cost considerations. The overall incidence of any 3.8.2. Dietary therapies in the management of CD
SAEs or serious infections were similar across study groups. 3.8.2.1. Dietary therapy for the induction of remission in
Herpes zoster infection was reported in 4.0% of patients re- CD
ceiving maintenance treatment with 15 mg upadacitinib and
7.2% of patients receiving 30 mg upadacitinib, compared Practice Point 2A. There is emerging evidence that dietary

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with 4.7% in the placebo group. No adjudicated cardiovas- therapies may be beneficial in reducing the inflammatory
cular events were reported. One case of hepatic vein throm- burden in CD. However, currently no universally applicable
bosis concurrent with exacerbation of CD was reported in a diet will benefit all patients with CD. Dietary intervention
patient receiving 30 mg upadacitinib. should primarily be considered based on disease activity,
the patient’s motivation, the current evidence, and the
3.8. Nutritional therapy in the treatment of CD availability of dietetic support. All patients with CD should
3.8.1. Exclusive enteral nutrition for the induction of have access to dietary services, especially during disease
remission in CD flare. [Consensus: 97%]

Statement 14.1. We suggest exclusive enteral nutrition

can be used as induction therapy in patients with mild- 3.8.2.2. Dietary therapy for the maintenance of remission in
to-moderate CD who are motivated to adhere to dietary CD
therapy, have access to dietetic support, and prefer to avoid
corticosteroids. [Weak recommendation, very low-quality Practice Point 2B. Partial enteral nutrition might be con-
evidence.] [Consensus: 100%] sidered as a strategy for maintaining remission, with or
without additional medication, in a subset of patients who
Exclusive enteral nutrition [EEN] is suggested for induction are willing and able to tolerate the formula with routine
of remission in CD. A meta-analysis of available data for adult monitoring. [Consensus: 100%]
patients demonstrated inferiority to steroids in intention-to-
treat analysis; however, similar rates of induction of remission Recently, food-based diets have gained attention as a po-
were found when restricting analysis to patients who were tential adjunct or monotherapy for reducing inflammation in
able to adhere to therapy. As steroid use is associated with active CD, offering a more palatable alternative to EEN.154
high morbidity, we suggest EEN as an alternative to steroids The Crohn’s Disease Exclusion Diet [CDED] is currently the
in motivated patients with appropriate dietetic support. most studied approach with accumulating supportive data
EEN is a therapeutic approach involving the consumption for its use in adult patients with CD.155–157 A recent pilot
of a liquid medical formula as the sole food source, usually RCT, involving adult patients with active mild-to-moderate
for 6–8 weeks. In children with luminal mildly to moderately disease, showed that CDED, either alone or in combination
active CD, EEN is the first-line therapy for inducing clinical with partial enteral nutrition [PEN] as monotherapy, resulted
remission according to ECCO-ESPGHAN guidelines, with in a 62% remission rate at Week 6, with 50% of patients
data showing superiority over corticosteroids in achieving maintaining remission up to Week 24 and 35% achieving
mucosal healing.149 In adults, several studies show that in pa- endoscopic remission.157 Based on the currently available
tients who are able to tolerate the diet, EEN can be effective evidence, the recent ESPEN guidelines recommended consid-
for induction of remission,150 even in complicated diseases,151 ering using CDED as an alternative to EEN in adults with
and as preoperative optimisation therapy.152 An age subgroup mild-to-moderate CD.158
analysis [> 18] conducted in the most recent Cochrane re- Another noteworthy study investigated the Specific
view, including six trials with very low-quality evidence, indi- Carbohydrate Diet [SCD] alongside the Mediterranean diet
cated that 45% [87/194] of EEN patients achieved remission as an adjunct to licensed medical therapy. Both diets exhib-
compared with 73% [116/158] of patients treated with cor- ited approximately 40% symptomatic remission rates, with
ticosteroids [RR: 0.65, 95% CI: 0.52–0.82].150 However, a no significant difference observed. Consequently, the au-
per-protocol analysis did not reveal a significant difference thors concluded that the Mediterranean diet, given its ease
in inducing remission between EEN and corticosteroids. This of adherence, should be preferred over SCD.159 An additional
suggests that the disparity in the success of EEN between diet derivative from the SCD is the IBD anti-inflammatory
children and adults is primarily attributed to compliance. AE diet, with one case series in IBD showing an improvement in
rates did not significantly differ between EEN and cortico- Harvey–Bradshaw Index [HBI] and potential as an adjunct
steroids during the trial period, although milder AEs were re- dietary therapy with ongoing studies.160–162
ported with EEN. Additional interventions, such as CD-TREAT, aim to rep-
Consequently, where clinicians and patients wish to attempt licate EEN’s nutritional composition and effects on the in-
use of EEN as a therapeutic alternative to corticosteroids for testinal microbiota, with ongoing studies in adults exploring
induction of remission in CD, it is important to focus on strat- efficacy with promising preliminary data.163 Last, the low
egies to enhance compliance and improve palatability. The ef- fermentable oligosaccharides, disaccharides, monosacchar-
fectiveness of EEN does not appear to be influenced by the ides, and polyols [FODMAP] diet has shown promise in al-
type of formula, including protein [elemental, semi-elemental, leviating intestinal symptoms without significant impact on
ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment 1545

inflammation. Therefore, the low FODMAP diet is recom- indirect comparisons based on network meta-analyses.169–171
mended primarily for patients with quiescent CD experien- However, it is important to note that these are sensitive to
cing functional symptoms.164 differences between trial populations, definitions and timing
Numerous studies, particularly within the Japanese popu- of outcome measures, and design of maintenance studies.
lation, suggest that Partial Enteral Nutrition (PEN) may be Cohort studies can provide complementary evidence on real-
effective as a long-term strategy to maintain remission. In a world populations, often including groups that might other-
meta-analysis including eight studies, patients receiving PEN wise be excluded from clinical trials, with use of statistical
[420–1800 kcal/d] had a significantly lower clinical relapse methodologies to correct for baseline differences in measured
rate [RR: 0.67, 95% CI: 0.54–0.82, p < 0.01] over 0.5 to 2 confounders.71 These studies should be considered alongside
years compared with those not receiving nutritional therapy. assessment of potential sources of bias, unmeasured con-

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The authors concluded that PEN may be more effective than founding factors, and difficulties inherent in the lack of ran-
the absence of enteral nutrition therapy for the maintenance domisation. Additionally, understanding of safety data may
of remission in CD, with a good safety profile.165 Another be improved with analysis of similar data that may be avail-
meta-analysis showed that adding PEN to infliximab led able for patients exposed to a drug for a different licensed
to 74.5% remission at 1 year compared with 49.2% using indication, although again, clinicians should consider to what
infliximab alone [OR: 2.93, p < 0.01].166 The use of PEN for extent the risk profile of the external population matches the
maintenance of remission was suggested as a treatment option patient under consideration.
to prolong remission, by the paediatric ECCO-ESPGHAN Ultimately, whereas it is not appropriate to form firm con-
guidelines in the case of low-risk patients.149 clusions from indirect methodologies such as network meta-
analyses or large cohort studies, taken in isolation, these can
3.9. Sequencing and combination of therapies in provide valuable insight. Where alternative sources of indirect
CD evidence are discrepant, it is not possible to form clear pre-
3.9.1. Sequencing of advanced therapies in CD dictions of relative drug performance. When the findings are
congruent, this may provide some confidence in the applica-
Practice Point 3. There is currently insufficient evidence to tion of the results to clinical practice.
direct how advanced therapies should be positioned in a Given the potential for uncertainty in many of these com-
therapeutic algorithm for luminal CD. Decisions should parisons, it is also important to understand the factors im-
consider efficacy, safety, patient preferences and character- portant in decision making for an individual patient. Different
istics, disease characteristics, and cost or access to ther- patients may apply different priority to, for example, efficacy,
apies. [Consensus: 97%] safety, or other aspects of the therapeutic profile. Clinicians
should also consider disease-related factors [such as perianal
Positioning of therapies in CD is one of the main challenges disease and extraintestinal manifestations57] and patient-
in daily clinical practice. This is particularly true of agents related factors [such as comorbidity, including concurrent
commonly termed advanced therapies: biologic therapies and immune-mediated disorders, age, desire to become pregnant,
targeted small molecules. All approved drugs can be effective and susceptibility to infection], all of which may have implica-
for patients with CD, but data enabling direct comparison tions for the risk-benefit profile of any given therapy. Finally,
between drugs are largely absent. Limited, head-to-head short-term, long-term, direct, and indirect costs should be
RCT data exist, such as the SEAVUE trial, which compared considered in the decision process, which may differ from re-
adalimumab and ustekinumab in CD134 and the SEQUENCE gion to region. We have summarised the situations in which
trial, which compared risankizumab and ustekinumab.167 specific therapies may be beneficial in CD [Figure 1].
Even with these large and well-conducted RCTs, it is im-
3.9.2. Advanced combination therapies in treatment of CD
portant to consider that they apply to specific comparisons
made in specific populations. For example, in SEAVUE, the
finding of broadly comparable efficacy between ustekinumab Practice Point 4. Advanced combination therapy may be
and adalimumab relates to the treatment of patients without necessary when there are uncontrolled extraintestinal
prior biologic exposure and without the option of dose es- manifestations or symptomatic immune-mediated dis-
calation. Likewise, the SEQUENCE trial, presented in ab- orders needing more than one agent to achieve remission.
stract form only during the preparation of these guidelines, Advanced combination therapy may also be an option for
showed significantly higher rates of response and remission refractory CD. There is currently no evidence to support ad-
for clinical and endoscopic outcomes in patients treated in vanced combination therapy in patients naïve to advanced
an open-label manner with risankizumab over those treated therapies, even in high-risk patients. [Consensus: 100%]
with ustekinumab, specifically among a population of pa-
tients with failure of prior anti-TNF therapy.167,168 Despite important progress in therapy for CD, up to 60%
Even with other head-to-head RCTs in progress, there will of patients fail to achieve long-term remission.179 Advanced
still be insufficient direct evidence to address many questions combination therapy [ACT] refers to the combination of
that arise in routine clinical practice. In this context, clin- biologic agents, targeted small molecules, or both, and can
icians can and should try to make treatment recommenda- be considered for the following three different settings: un-
tions based upon understanding of the available evidence. controlled extraintestinal manifestations, patients with
This includes the consideration as to what extent evidence concomitant immune-mediated diseases, and patients with
from populations that differ slightly from the patient under a refractory IBD phenotype where no surgical options are
consideration may be used to inform decision making for feasible.180 When considering refractory disease, it is rea-
the individual patient. Clinicians may also wish to consider sonable to combine agents that have resulted at least in a
1546 H. Gordon et al.

Induction Maintenance Perianal Peripheral Axial Pregnancy Over 65

disease Spondylo- Spondylo- years
arthropathy arthropathy
i i ii
Systemic iv iv iv iv iv
corticosteroids
Enteral release v v
corticosteroids

Enteral Nutrition

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Thiopurines vi vii
monotherapy
Methotrexate

lnfliximab

Adalimumab

Certolizumab

Vedolizumab

Ustekinumab

Risankizumab viii ix

Upadacitinib x xi xii xiii

Recommended

Can be considered

Not recommended

Insufficient evidence

Figure 1. Medical therapy in the management of CD. i. This figure summarises a complex area with limitations to much of the available data,
it is not intended to replace individualised decision making. Please see the main text of these guidelines for discussion of the evidence base;
recommendations and considerations are derived from GRADE recommendations and suggestions, respectively, for induction and maintenance
outcomes. ii. Recommendations on the medical management of perianal disease are adapted from the CD Treatment Guideline surgical manuscript5.
iii. Recommendations on the safe medical management of CD during pregnancy are taken from the ECCO guidelines on sexuality, fertility, pregnancy
and lactation,9 with strength of recommendation aligned to the GRADE recommendations of this guideline. iv. Systemic corticosteroids should only
be used if there are no available alternatives, particularly in patients over the age of 65, or as a bridge to the initiation of an effective maintenance
therapy. v. Enterally acting corticosteroids can only be considered as induction agents in pregnancy and in the over-65s, and are not recommended for
maintenance of remission. vi. Thiopurines can be continued as maintenance therapy in pregnancy, but should not be newly started as monotherapy
nor used as induction agents.9 vii. Can be considered case by case if there are no available alternatives. viii. Inferred from positive trial data in psoriatic
arthritis.172–174 ix. Inferred from negative trial data in axial spondyloarthritis.175 x. Upadacitinib may represent a therapeutic alternative in patients with prior
anti-tumour necrosis factor [TNF] failure, intolerance, or contraindications. This is based upon post-hoc analysis of randomised controlled trial [RCT] data
showing a significant benefit over placebo across a range of relevant fistula endpoints176. xi. Inferred from positive trial data in psoriatic arthritis.177 xii.
Inferred from positive trial data in axial spondyloarthritis.178 xiii. EMA recommend reserving for when no alternatives are available in patients over the
age of 65.

partial response before, without adverse side effects. When patients judged to be at high risk of disease progression or
ACT is aimed at controlling extraintestinal manifestations complications.
or immune-medicated diseases, the preferred combination Evidence on ACT in IBD is mostly retrospective with
should be based on the specific clinical setting, including any limited quality, and has recently been gathered in two system-
prior evidence of partial response to a particular agent, avail- atic reviews with meta-analyses that include studies reporting
ability of evidence suggesting potential efficacy from other on outcomes in both UC and CD.179,181 Table 1 summarises
relevant indications, and safety considerations. Whereas the single RCT and the cohorts that have reported outcomes
targeting more than one mechanistic pathway in patients with ACT specifically for CD patients. The use of ACT for
naïve to advanced therapies may make sense, particu- CD was the focus of the phase 4 single-arm EXPLORER
larly if the underlying biology is better characterised, there trial [NCT02764762], which was designed to investigate
is currently no evidence to support ACT upfront, even in the safety and efficacy of the combination of vedolizumab,
Table 1 Available evidence for advanced combined therapy in CD.

Author Study design Population Outcomes Combination [n exposed] Safety Efficacy Notes
[year]

Sands Randomised 79 adult patients with active Safety, tolerability Infliximab + natalizumab [52] AEs reported in CDAI decrease [38 vs Steroids, anti-
[2007]182 controlled CD despite infliximab clinical remission, quality Infliximab + placebo [27] 48/52 vs 17/27 3.5 points; p = 0.085] biotics, and
trial of life; CRP SAEs reported in immunomodulators
1/52 vs 1/27 allowed
Yang Retro- 22 adult patients with refrac- Endoscopic improvement Vedolizumab + ustekinumab [8] AEs in 3/24 trials Endoscopic improve- Assessment at 32
[2020]183 spective tory CD [with total of 24 Endoscopic remission, Vedolizumab + anti-TNF [13] [13%] ment [43%] weeks
cohort different ACT exposures] clinical response, clinical Ustekinumab + anti-TNF [3] Endoscopic remission
remission, CRP [26%]
Clinical response [50%]
Clinical remission
[41%]
Steroid-free clinical re-
mission [36%]
Significant CRP decline
[17 to 9 mg/dL,
p = 0.02]
ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment

Lee Retro- 19 adult patients with CD Clinical response Tofacitinib + ustekinumab [11/19] 0/19 SAEs 8/19 clinical response 3/19 patients added
[2020]184 spective Clinical remission Tofacitinib + vedolizumab [7/19] 7/19 AEs 6/19 clinical remission the second treat-
cohort Endoscopic response Tofacitinib + certolizumab [1/19] 2/19 endoscopic re- ment for pyoderma
Endoscopic remission sponse gangrenosum
Biochemical remission 2/19 endoscopic remis- 16/19 added the
AEs sion second treatment
SAEs 3/19 biochemical remis- for CD
sion Assessment between
Weeks 30 and 36
Steroids and metho-
trexate allowed
Colombel Open-label 55 biologic-naïve adult pa- Endoscopic remission Vedolizumab + adalimumab + metho- 48/55 AEs 19/55 endoscopic re- Assessment at Week
[2022]185 clinical tients with moderate-to- se- Clinical remission trexate 6/55 SAEs mission 26
trial vere newly diagnosed CD AEs 34/55 clinical remission
Interim ana- [prior 24 months] at high SAEs
lysis risk of complications

CDAI, Crohn’s disease activity index; CRP, C-reactive protein; SAE, severe adverse event.
1547

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1548 H. Gordon et al.

adalimumab, and methotrexate in patients newly diagnosed outpatient visits.190 In the UK, care of CD patients in a centre
with CD with the presence of features predictive of an in- with an active MDT was associated with reduced excess ex-
creased risk of disease complications. There was no com- posure to corticosteroids.191
parator arm, although post-hoc Bayesian analysis suggested In recent years, dietitians have assumed a prominent role
a high degree of probability that the combination treat- in the treatment of patients with CD, specifically in guiding
ment was more effective than benchmark estimates for the the implementation of therapeutic diets, such as EEN, con-
efficacy of adalimumab or vedolizumab monotherapy.185 ducting assessments of nutritional status, and enhancing
Ongoing RCTs of ACT, including a trial of guselkumab with overall quality of care.153 A real-world prospective study from
golimumab [NCT05242471], may improve understanding of Israel reported favourable outcomes among a cohort of newly
potential efficacy and safety. Cost-effectiveness analyses will diagnosed CD patients [n = 76] treated by MDT, including

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be important prior to any more widespread adoption of these dietitian input.192 Other innovations in care delivery include
approaches. increased use of remote monitoring and telemedicine. Two
studies in paediatric populations193,194 revealed that tele-
3.10. Optimisation of the delivery of care in the medicine can support improved access to IBD services and
treatment of CD improved attendance at follow-up appointments. An RCT of
3.10.1. The role of the MDT and governance around 909 patients in The Netherlands found that use of telemedi-
decision making in the treatment of CD cine to support patient self-management improved outcomes
for patients with IBD compared with standard care, including
Practice Point 5. We recommend involvement of an MDT reductions in the number of outpatient visits and number of
in clinical management and joint decision making in hospital admissions.195 In a similar manner, a retrospective
managing care of patients with CD. [Consensus: 97%] multicentre cohort study revealed increased treatment suc-
cess among 69 patients managed through a virtual clinic
Health care organisations and clinicians should be continu- while undergoing dose optimisation of anti-TNF therapy for
ously improving and safeguarding the quality of care. Shared CD, when compared with 80 patients receiving standard out-
decision making [SDM] practised by MDT members is fun- patient care.196
damental to attaining this goal and delivering patient-centred It is recognised that not all centres have health care profes-
care. Data from two systematic reviews [62 and 28 manu- sionals across all the different MDT specialties. Nonetheless,
scripts, respectively, number of patients not stated] suggested efforts should be made to build an MDT with the widest range
that using an integrated care model and MDT consisting of of specialties available. More research is needed on the role of
health care professionals across specialties [eg, gastroenterol- different MDT members and different care delivery models to
ogists, IBD nurses, colorectal surgeons, psychologists or coun- understand long-term value for patients. In particular, better
sellors, dietitians, radiologists, pathologists, pharmacists] understanding of cost-effectiveness may help manage funding
achieved the most effective management of IBD. This was for implementation.
reflected in reduced hospital admissions and IBD-related sur-
gery and comorbidities, with associated reductions in direct 3.10.2. The role of ‘treat-to-target’ and early treatment in
and indirect costs of care compared with a more traditional the management of CD
patient-physician model.186,187 A cross-sectional survey con-
ducted in the USA, with 306 patients with autoimmune con- Practice Point 6. We recommend a tight control and treat-
ditions including 102 with IBD, examined the impact of SDM to-target approach for management of patients with CD.
for biologic treatment selection and treatment outcomes.188 [Consensus: 97%]
Among the SDM participants, the mean number of treatments
discussed with the physician was significantly higher than for ‘Treat-to-target’ describes an approach where a treatment
the non-SDM group [2.8 vs 2.2, p < 0.05], more SDM parti- goal is set and agreed upon following discussions between
cipants reported thinking about the impact of a medication individual patients and treating clinicians, with one or more
on the future than non-SDM participants [83.2% vs 72.6%, targets specified to measure progress towards that goal.197
p < 0.05], and more SDM patients self-reported a likelihood Following initiation of any therapy, these targets are then as-
of adherence to treatment compared with patients managed sessed, with modification of treatment considered if a target is
without SDM [p = 0.001]. missed.198 Significant improvement in medium- and long-term
Measuring the impact of changes in systems of care delivery outcomes has been reported for patients when targeting more
can be challenging, and data are largely limited to observa- objective£ measures of inflammation (such as normalisation
tional studies. A Norwegian cross-sectional survey examined of faecal calprotectin or serum C-reactive protein [CRP])
health-related QoL outcomes among patients living with IBD when compared with subjective measures [such as clinical
who received solely physician-delivered care [n = 164], com- symptoms alone].199,200 Moreover, early combined immuno-
pared with those receiving care delivered by a team including suppression followed by a treat-to-target approach is asso-
physicians and IBD nurses [n = 140]. QoL outcomes were sig- ciated with reduced occurrence of surgery, reduced hospital
nificantly better in the group receiving MDT care, although admissions, and lower risk of serious disease-related com-
the magnitude of difference fell short of an a priori-defined plications.201 Notably, the majority of evidence to date for
threshold of clinical significance.189 A Belgian study [n = 1313 a treat-to-target approach has been with anti-TNF therapy.
patients] reported that IBD nurse involvement in starting im- Indeed, a treat-to-target strategy trial to guide ustekinumab
munosuppressive therapy, follow-up care, flare management, dose escalation failed to show a benefit of more aggressive
and providing disease information and psychosocial support dose escalation driven by early endoscopy and more fre-
to patients, systematically increased contact with patients, quent clinical monitoring, although arguably the intensity of
resulting in avoidance of emergency room and unscheduled clinical monitoring was not substantially different between
ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment 1549

treatment arms.202 There is still debate about what should be Funding

the optimal treatment target[s] in CD. There is also a lack of
This project was initiated, funded, and supported by ECCO.
evidence to reassure patients and clinicians contemplating a
change in treatment in the event of a partial response that
falls short of meeting a target and where dose optimisation Conflict of Interest
has already occurred. Unlike in clinical trials, treatment tar- ECCO has diligently maintained a disclosure policy of poten-
gets should be individualised where possible and should be tial conflicts of interests [CoI]. The conflict-of-interest declar-
agreed upon as part of a SDM process between clinicians and ation is based on a form used by the International Committee
patients. In addition, targets and goals of treatment should be of Medical Journal Editors [ICMJE]. The CoI disclosures are
regarded as dynamic and a decision can be made to change not only stored at the ECCO Office and the editorial office of

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treatment targets over time. JCC, but are also open to public scrutiny on the ECCO web-
Regardless of the monitoring strategy chosen, it is in- site [https://www.ecco-ibd.eu/about-ecco/ecco-disclosures.
creasingly clear that early effective treatment should be a html], providing a comprehensive overview of potential con-
focus of management in CD, with emphasis on avoidance of flicts of interest of the authors.
diagnostic delays and any delays in initiation of treatment.
Chronic, untreated inflammation, even if asymptomatic, ul-
timately results in poor outcomes, whiereas early control of Acknowledgements
inflammatory burden reduces the risk of long-term compli- We would like to thank and acknowledge the ECCO Office for
cations of disease.199,203 Typically, effectiveness of the drugs logistical and coordination support: Dr Fadi Ifram for project
discussed in these guidelines appears to be greater when used management, Dr Paul Freudenberger for the literature search,
earlier in disease course.204 Consequently, clinicians should and Torsten Karge for support with informatics and the online
work to ensure rapid access for patients with suspected CD Guidelines platform. We gratefully thank the EFCCA patient
to appropriate diagnostic tests and clinical expertise, with representatives who proactively collaborated in the devel-
urgent consideration of early treatment. Previous trials opment of these Guidelines: Bastien Corsat, Xavier Donnet,
have hinted at the effectiveness of such an approach,134,205 Evelyn Gross, Janek Kapper, Lucie Lastikova, and Antonio
and the recently reported UK PROFILE trial provides im- Valdivia. We would also like to thank Ibrahim Ethem Gecim
portant evidence in favour of early aggressive treatment of for his work in the abstract screening process. We would like to
CD. PROFILE enrolled patients with moderate-to-severe thank and acknowledge the ECCO National Representatives
CD at a median of just 12 days after diagnosis.7 Patients and additional reviewers, who acted as external reviewers and
received initial corticosteroid therapy and were randomised. provided suggestions on the recommendations and supporting
A total of 193 patients received ‘accelerated step-up’ care, text to this document: Pascal Juillerat, Allesandra Soriano,
with steroid taper alongside protocol-defined follow-up, Mark Samaan, Tiago Cúrdia Gonçalves, Edoardo Savarino,
further corticosteroids and initiation of immunomodulator Federica Furfaro, Davide Giuseppe Ribaldone, Gulustan
therapy in the event of a flare, and then anti-TNF therapy Babayeva-Sadiqova, Aurelien Amiot, Gianmichele Meucci,
in the event of a further flare. In the other arm, 193 pa- Iago Rodríguez Lago, Mathieu Uzzan, Gerassimos Mantzaris,
tients received ‘top-down’ combination therapy with IV Beatriz Gros Alcalde, Vito Annese, Eduard Brunet Mas,
infliximab and immunomodulator therapy and could taper Maria Jose Garcia, Eirini Zach, John Marshall, Carla Felice,
the initial corticosteroid course more rapidly. The primary Maha Maher, Paul Pollack, Andreas Blesl, Negreanu Lucian,
endpoint of sustained steroid- and surgery-free remission Ferdinando D’Amico, Dimitrios Karagiannis, Patrick Allen,
to Week 48 was more frequent in the ‘top-down’ than in Oliver Bachmann, Imerio Angriman, Anna Kagramanova,
the ‘accelerated step-up’ arm [79% vs 15%, p < 0.001]. Dahham Alsoud, Natália Queiroz, Usha Chauhan, Petra
Endoscopic remission was more frequent in the ‘top-down’ Golovics, Chen Sarbagili, Lorenzo Bertani, Ulf Helwig, Clas-
arm [67% vs 44%, p < 0.001], with similarly positive data Göran af Björkesten, Ante Bogut, Anthony Buisson, Ignacio
for QoL endpoints, avoidance of admissions, and reduction Catalan-Serra, Aslı Çifcibaşı Örmeci, Marco Daperno, Mihai
in CD-related surgery. Mircea Diculescu, Dana Duricová, Piotr Eder, Magdalena
When patients are started on any treatment, clear defin- Gawron-Kiszka, Ayal Hirsch, Ondrej Hradsky, Hendrik Laja,
itions should be set as to how and when treatment success will Sara Onali, Samuel Raimundo Fernandes, Christian Philipp
be defined and assessed, with a focus on prompt actions in the Selinger, Helena Tavares de Sousa, Svetlana Turcan, Sophie
event of treatment non-response. Notably, for these guidelines Vieujean, and Yamile Zabana.
the consensus group chose to remove from all recommenda-
tions a need for patients to have ‘failed’, proven intolerant
to, or have contraindications to ‘conventional’ therapy. This Disclaimer
decision reflects a growing unease with the term ‘conventional The ECCO Guidelines are targeted at health care professionals
therapy’, as many of the treatments discussed in these guide- only and are based on an international consensus process. This
lines can now be regarded as forming an established part of process includes intensive literature research as explained in
the ‘conventional’ management of CD. Therefore, whereas the methodology section, and may not reflect subsequent sci-
these guidelines have appraised the available evidence for a entific developments, if any, until the next Guidelines update
range of treatments used in the management of CD, it remains is prepared. Readers of the Guidelines acknowledge that re-
for local payers to consider the health economic impacts, the search about medical and health issues is constantly evolving
disease burden, and the impact on long-term outcomes, of and diagnoses, treatments, and dose schedules for medications
mandating treatment cycles with treatments receiving only a are being revised continually. Therefore, the European Crohn´s
weak recommendation in these guidelines. and Colitis Organisation [ECCO] encourages all readers to
1550 H. Gordon et al.

also consult the most up-to-date published product informa- 11. Rasmussen S, Lauritsen K, Tage-Jensen U, et al. 5-aminosalicylic
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Organisation [ECCO] and/or any of its staff members and/ randomized, double-blind, placebo-controlled trial of the oral
or any consensus contributor may not be held liable for any mesalamine [5-ASA] preparation, Asacol, in the treatment of
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express or implied, as to the accuracy or completeness of the 14. Ferring Pharmaceuticals. PEACE Study: A Study with Pentasa in
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and expressly disclaims, responsibility for any liability, loss, or gov/study/NCT00862121 Accessed November 2023.
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