Journal of Crohn's and Colitis, 2020, 4–22

doi:10.1093/ecco-jcc/jjz180
Advance Access publication November 11, 2019
ECCO Guideline/Consensus Paper

ECCO Guideline/Consensus Paper

ECCO Guidelines on Therapeutics in Crohn's

Disease: Medical Treatment
Joana Torres,a,* Stefanos Bonovas,b,c,*, Glen Doherty,d Torsten Kucharzik,e
Javier P. Gisbert,f Tim Raine,g Michel Adamina,h,i Alessandro Armuzzi,j

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Oliver Bachmann,k, Palle Bager,l Livia Biancone,m Bernd Bokemeyer,n
Peter Bossuyt,o, Johan Burisch,p, Paul Collins,q Alaa El-Hussuna,r
Pierre Ellul,s Cornelia Frei-Lanter,t Federica Furfaro,c Christian Gingert,u
Paolo Gionchetti,v Fernando Gomollon,w Marien González-Lorenzo,b,c
Hannah Gordon,x Tibor Hlavaty,y Pascal Juillerat,z,
Konstantinos Katsanos,aa Uri Kopylov,ab Eduards Krustins,ac
Theodore Lytras,ad, Christian Maaser,ae Fernando Magro,af,
John Kenneth Marshall,ag Pär Myrelid,ah Gianluca Pellino,ai
Isadora Rosa,aj Joao Sabino,ak Edoardo Savarino,al Antonino Spinelli,am
Laurents Stassen,an Mathieu Uzzan,ao Stephan Vavricka,ap
Bram Verstockt,aq, Janindra Warusavitarne,ar Oded Zmora,as
Gionata Fiorinob,c, ; on behalf of the European Crohn’s and Colitis
Organisation [ECCO]
a
Department of Gastroenterology, Hospital Beatriz Ângelo, Loures, Portugal bDepartment of Biomedical Sciences,
Humanitas University, Milan, Italy cIBD Center, Humanitas Clinical and Research Center, Milan, Italy dCentre for
Colorectal Disease, St Vincent’s University Hospital and University College Dublin, Dublin, Ireland eDepartment of
Internal Medicine and Gastroenterology, Hospital Lüneburg, Lüneburg, Germany fGastroenterology Unit, Hospital
Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa [IIS-IP], Universidad Autónoma de Madrid,
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Madrid, Spain
g
Department of Gastroenterology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust,
Cambridge, UK hDepartment of Surgery, Cantonal Hospital Winterthur, Winterthur, Switzerland iUniversity of Basel,
Basel, Switzerland jIBD Unit, Presidio Columbus Fondazione Policlinico Gemelli Universita Cattolica, Rome, Italy
k
Department of Internal Medicine I, Siloah St. Trudpert Hospital, Pforzheim, Germany lDepartment of Hepatology and
Gastroenterology, Aarhus University Hospital, Aarhus, Denmark mDepartment of Systems Medicine, University ‘Tor
Vergata’ of Rome, Rome, Italy nGastroenterology Practice Minden, Minden, Germany oImelda GI Clinical Research
Centre, Imelda General Hospital, Bonheiden, Belgium pGastrounit, Medical Division, Hvidovre Hospital, University of
Copenhagen, Hvidovre, Denmark qDepartment of Gastroenterology, Royal Liverpool University Hospital, Liverpool,
UK rDepartment of Surgery, Aalborg University Hospital, Aalborg, Denmark sDepartment of Medicine, Division of
Gastroenterology, Mater Dei Hospital, Msida, Malta tDepartement of Surgery, Hospital Zollikerberg, Zollikerberg
Zurich, Switzerland uVisceral Surgery, Cantonal Hospital Winterthur, Winterthur, Switzerland; Department of Human
Medicine, University of Witten/Herdecke, Witten, Germany vIBD Unit, DIMEC, University of Bologna, Bologna, Italy
w
IBD UNIT, Hospital Clíico Universitario ‘Lozano Blesa’; IIS Aragón, CIBEREHD, Zaragoza, Spain xDepartment of
Gastroenterology, Barts Health NHS Trust, Royal London Hospital, London, UK yFifth Department of Internal Medicine,
Comenius University Medical School, Bratislava, Slovakia zDivision of Gastroenterology & Hepatology, Inselspital
Bern, Bern, Switzerland aaDepartment of Gastroenterology and Hepatology, University and Medical School of Ioannina,
Ioannina, Greece abDepartment of Gastroenterology, Tel-HaShomer Sheba Medical Center, Ramat Gan, Israel; and

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ECCO Guidelines on Therapeutics in Crohn's Disease: Medical Treatment 5

Sackler Medical School, Tel Aviv, Israel acDepartment of Gastroenterology, Hepatology and Nutrition, Pauls Stradins
Clinical University Hospital, Department of Internal medicine, Riga Stradiņš university, Riga, Latvia adNational Public
Health Organization, Athens, Greece aeOutpatients Department of Gastroenterology, Hospital Lüneburg, Lüneburg,
Germany afDepartment of Pharmacology and Therapeutics; Institute for Molecular and Cell Biology, University of
Porto, Porto, Portugal agDepartment of Medicine [Division of Gastroenterology] and Farncombe Family Digestive
Health Research Institute, McMaster University, Hamilton, ON, Canada ahDepartment of Surgery, and Department
of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden aiDepartment of Advanced Medical
and Surgical Sciences, Universitá degli Studi della Campania ‘Luigi Vanvitelli’, Naples, Italy ajDepartment of
Gastroenterology, IPOLFG, Lisbon, Portugal akDepartment of Gastroenterology and Hepatology, University Hospitals,
KU Leuven, Leuven, Belgium alDepartment of Surgery, Oncology and Gastroenterology, University of Padova,
Padova, Italy amHumanitas Clinical and Research Center, Division of Colon and Rectal Surgery, Humanitas University,
Milan, Italy anDepartment of General Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
ao
Department of Gastroenterology, IBD unit, Beaujon Hospital, APHP, Clichy, France apDivision of Gastroenterology
and Hepatology, University Hospital, Zürich, Switzerland aqDepartment of Gastroenterology and Hepatology,

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University Hospitals Leuven, KU Leuven, Leuven, Belgium; and Department of Chronic Diseases, Metabolism and
Ageing, TARGID-IBD, KU Leuven, Leuven, Belgium arImperial College London, Department of Surgery and Cancer,
St Mark’s Hospital, Department of Gastroenterology, London, UK asDepartment of Surgery, Shamir Medical Center
[Assaf Harofe], Tel Aviv, Israel

* Contributed equally.

Corresponding author: Gionata Fiorino, MD, PhD, Department of Biomedical Sciences, Humanitas University, Via Rita Levi
Montalcini, 20090 Pieve Emanuele, Milan, Italy. Tel.: +39[0]282245555; fax: +39[0]282242591; email: gionataf@gmail.com

1. Introduction do not cover specific situations, such as postoperative management

of adult patients with CD, which was already covered in the latest
Crohn’s disease [CD] is a chronic inflammatory bowel disease [IBD]
ECCO Guidelines on Crohn’s disease.10
that can result in progressive bowel damage and disability.1 CD can
affect individuals of any age, from children to the elderly,2,3 and
may cause significant morbidity and impact on quality of life. Up to 2. Methods
one-third of patients present with complicated behaviour [strictures,
Based on the GRADE workflow, the Guidelines Committee of ECCO
fistula, or abscesses] at diagnosis.4 Most patients over time will de-
[GuiCom] selected a panel of 48 experts supported by a team of
velop a complication, with roughly 50% of patients requiring sur-
methodologists and librarians. Selection was based on IBD expertise,
gery within 10 years of diagnosis.5–7 As the precise aetiology of CD
scientific background, and knowledge of the GRADE methodology.
remains unknown, a curative therapy is not yet available.8 Several
All panellists received adequate training in GRADE before starting
agents are available for the medical treatment of CD. Medical
the process. Additionally, four patients with CD representing the
agents include mesalazine [5-ASA], locally active steroids [such as
European Federation of Crohn’s and Colitis Associations [EFCCA]
budesonide], systemic steroids, thiopurines such as azathioprine
were invited to participate in all face-to-face meetings and to provide
[AZA] and mercaptopurine [MP], methotrexate [MTX], and bio-
their experiences and state their preferences.
logic therapies (such as anti-tumour necrosis factor [TNF], anti-
Three domains for medical treatment of CD were identified:
integrins, and anti-interleukin [IL] 12/23].
The European Crohn’s and Colitis Organisation [ECCO] pro- 1] induction therapy;
duces and regularly updates several guidelines aimed at providing 2] maintenance therapy;
evidence-based guidance on critical aspects of IBD care to all health 3] therapy of fistulising perianal disease.
care professionals who manage patients with IBD. To provide
high-quality evidence-based recommendations on medical treatment All panellists were assigned to one of three working groups coordin-
in CD, ECCO decided to develop these guidelines by adopting the ated by one to two working group leaders under the supervision of
GRADE [Grading of Recommendations Assessment, Development, two Guideline coordinators. The panellists first formulated a series of
and Evaluation] approach.9 GRADE is a systematic process for specific questions using the PICO format [Population, Intervention,
developing guidelines which addresses how to frame the health care Comparator, Outcomes] which were deemed to be clinically im-
questions, summarise the evidence, formulate the recommenda- portant for the medical treatment of CD. The outcomes of all PICO
tions, and grade their strength and the quality of the associated evi- questions were subsequently graded as ‘not important’, ‘important’,
dence. GRADE increases transparency at all levels of this process or ‘critical’ during a face-to-face kick-off meeting in Vienna, using a
and makes explicit the three considerations that lead to a particular Delphi consensus process.
recommendation: the quality of the evidence, the balance of bene- A team of professional librarians performed a comprehensive lit-
fits and harms, and the patients’ values and preferences. Therefore erature search on EMBASE, PubMed/Medline, and Cochrane Central
ECCO reviewed the available high-quality evidence on the medical databases using specific search strings for each PICO question
management of CD and developed evidence-based recommendations [Supplementary Files 1, 2, and 3, available as Supplementary data at
on the medical treatment of adult patients with CD. These guidelines ECCO-JCC online]. Two independent working group members [one
6 J. Torres et al.

assigned to the PICO and another one from the same group as a complications.15,16 Stratifying patients according to their prognostic
second reviewer] assessed the relevance of each abstract to PICO and risk factors and individualising therapy are crucial steps to optimise
included or excluded all the relevant papers for the final data extrac- patient management, although high-quality evidence is not currently
tion and analysis. Subsequently, the working group members assigned available to support this approach. Many factors affect the choice of
to each PICO question systematically reviewed and summarised the medical therapy. These include disease location, disease activity and
evidence on every outcome, to compile a Summary of Findings [SoF] severity, previous response to therapy, and presence of complications
table for each question. The GRADE method follows a hierarchical [i.e., perianal or fistulising disease]. In addition, the individual risk fac-
approach to synthesise evidence; recent high-quality systematic re- tors for progression and complications, the individual patient’s char-
views and meta-analyses of clinical trials were preferentially used to acteristics, and the costs and benefit/risk ratio of each drug should be
create the recommendations. When these were not available, indi- considered. As there is often a disconnect between clinical symptoms
vidual randomised clinical trials [RCTs] followed by observational and underlying inflammation, it is of crucial importance to monitor
studies were reviewed; results of individual studies were pooled using disease and therapy at regular intervals based on objective and meas-
random-effects meta-analysis as appropriate and when needed. To urable markers [endoscopy, C-reactive protein [CRP], calprotectin,
define disease activity and severity [mild-to-moderate and moderate- imaging].17 This approach will provide the clinician with the possi-
to-severe], we accepted the definitions used by the investigators of the bility to adjust therapy if needed, thereby maximising the probability

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studies selected as an evidence basis for our work. of achieving tight control of the disease and inflammation, which is
The quality of evidence was classified into the following four believed to be essential to prevent disease progression.16–18 In add-
categories in accordance with the GRADE approach: ‘high’ [meaning ition to drug therapy, the management of CD should also involve a
that further research is unlikely to change our confidence in the ef- series of general health care maintenance measures. Patients should
fect estimates], ‘moderate’ [further research may change our confi- be encouraged to stop smoking, nutritional deficiencies should be cor-
dence in the effect estimates], ‘low’ [further research likely to change rected, therapy-related side effects [i.e., cancer and infections] should
our confidence in the effect estimates], and ‘very low’ [meaning that be monitored, and appropriate guidance or surveillance for vaccin-
any estimate of effect is very uncertain].9 For each PICO question, ations, osteoporosis, and sun protection should be implemented, as
the quality of evidence was equal to the lowest quality of evidence detailed in previous ECCO guidelines, topical reviews, or both.17,19–23
among those outcomes graded as ‘critical’. The strength of each rec-
ommendation was graded as either ‘strong’ [meaning the desirable 4.  Medical management of Crohn’s disease
effects of an intervention clearly outweigh the undesirable effects,
or vice versa] or as ‘weak’ [meaning the balance is less certain], Section 1 - Induction of Remission
considering also the quality of evidence, values or preferences, and Mild-to-moderate disease
resource use. Whenever the chosen outcomes were not reported in 5-ASA compounds
the clinical trials, this was indicated in the corresponding SoF table.
To support the recommendations, we either extracted summary ef-
Recommendation 1.1. ECCO CD Treatment GL [2019]
fect estimates from the preselected systematic reviews or our group
of methodologists directly performed the comparisons. All recom- We suggest against the use of 5-ASA for induction of
mendations were subject to online voting by the panel members, the remission of Crohn’s disease [weak recommendation,
ECCO National Representatives [two for each country affiliated moderate-quality evidence].
with ECCO], and 13 additional reviewers from a list of ECCO mem-
bers who applied to the open call but were not selected to be part We performed a meta-analysis of seven eligible RCTs that com-
of the Working Groups [see Acknowledgements section]. The final pared the use of oral 5-ASA [five trials]24–28 or sulphasalazine [two
version of all statements/recommendations was discussed among trials]29,30 with placebo in patients with active CD [Supplementary
panel members during a final consensus meeting in Vienna and put Material, SoF Table 1, available as Supplementary data at ECCO-
to a vote; final recommendations were approved if at least 80% of JCC online]. The dosage of 5-ASA administered ranged from 1 g to
the panellists agreed with the statement and its associated strength 3.2  g/day; patients with mild-to-moderate disease with ileal, ileo-
grading. The list of statements, the supporting text and material, and colonic, or colonic disease were included. Overall, there was no sig-
the draft of the manuscript were critically reviewed by two external nificant effect for induction of clinical remission (relative risk [RR]:
Guideline Committee members and by the ECCO Governing Board 1.28; 95% confidence interval [CI]: 0.97–1.69) [Supplementary
members, who also approved the final version of these Guidelines. Figure 1, available as Supplementary data at ECCO-JCC online].
The literature search strategies, the relevant definitions of patient A recent Cochrane review also found no significant overall effect.31
populations and outcomes, a detailed description of the process, and the Both 5-ASA and sulphasalazine appeared to be well tolerated in our
SoF tables summarising the evidence can be found in the Supplementary meta-analysis, as there was no significant increase in withdrawals
Material, available as Supplementary data at ECCO-JCC online. due to adverse effects [AEs] when compared with placebo [RR:
1.13; 95% CI: 0.73–1.84] [Supplementary Figure 2, available as
Supplementary data at ECCO-JCC online].
3.  General approach to the management of Among the five trials of 5-ASA alone there was also no benefit
Crohn’s Disease over placebo for inducing clinical remission [RR: 1.27; 95% CI:
As CD is a lifelong disease, therapy aims to induce remission in the 0.79–2.03] [Supplementary Figure 3, available as Supplementary
short term and maintain remission in the long term. The recognition data at ECCO-JCC online]. No significant increase in withdrawal
that chronic and untreated inflammation [even if asymptomatic] ul- due to AEs was observed in trials that compared 5-ASA alone versus
timately results in poor outcomes11–14 has led to a recent paradigm placebo [RR: 1.0; 95% CI:0.58–1.71] [Supplementary Figure 4,
shift in medical treatment and disease monitoring; it is nowadays rec- available as Supplementary data at ECCO-JCC online]. One pub-
ognised that early intervention and intensive monitoring may prevent lished network meta-analysis noted a small statistically significant
ECCO Guidelines on Therapeutics in Crohn's Disease: Medical Treatment 7

effect on clinical remission among the study arms that evaluated frequently seen in patients receiving budesonide [RR: 1.22; 95% CI:
5-ASA at daily doses of >2.4  g/day.32 However, another network 1.03–1.45] than in patients receiving mesalazine [Supplementary
meta-analysis was unable to confirm any such dose effect.33 A pooled Figure 8, available as Supplementary data at ECCO-JCC online].
analysis of three double-blind placebo-controlled trials of a slow- The safety profile of both compounds was comparable, with similar
release preparation of 5-ASA reported a significantly greater reduc- AE [RR: 0.91; 95% CI: 0.79–1.05] and serious AE [RR: 0.94; 95%
tion in the Crohn’s Disease Activity Index [CDAI] with 5-ASA versus CI: 0.24–3.75] rates in both intervention groups [Supplementary
placebo.34 However, the effect size [an 18-point greater reduction Figures 9 and 10, available as Supplementary data at ECCO-JCC
in CDAI score comparing 5-ASA and placebo] was not clinically online].
significant.
Two older trials compared sulphasalazine with placebo for in- Antibiotics
duction of clinical remission. A  pooled analysis showed a small Numerous studies have studied the efficacy of antibiotic treatment on
effect of borderline statistical significance [RR: 1.38; 95% CI: 1.00– luminal CD. Metronidazole, ciprofloxacin, and anti-mycobacterial
1.89] [Supplementary Figure 5, available as Supplementary data at regimens have been extensively studied. Overall, none has demon-
ECCO-JCC online]. This was not accompanied by any significant strated efficacy to consistently induce clinical remission or mucosal
increase in withdrawals for AEs [RR: 1.88; 95% CI: 0.65–5.47] healing compared with placebo.42–44 In addition, side effects limit the

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[Supplementary Figure 6, available as Supplementary data at ECCO- use of these therapies; recently, the European Medicines Agency has
JCC online]. Subgroup analyses in both trials suggested that the ef- imposed restrictions on the use of ciprofloxacin due to disabling or
ficacy of sulphasalazine was limited to patients with colonic CD.29,30 potentially permanent events [EMA/668915/2018]. Therefore a rec-
The use of topical 5-ASA [enema or suppository] for the treat- ommendation was not made specifically on antibiotics to treat lu-
ment of CD has not been studied in RCTs. minal CD, although they remain indicated for the treatment of septic
complications.
Budesonide
Moderate-to-severe disease
Systemic corticosteroids
Recommendation 1.2. ECCO CD Treatment GL [2019]

We recommend using budesonide for the induction Recommendation 1.3. ECCO CD Treatment GL [2019]
of clinical remission in patients with active mild-to-
moderate Crohn’s disease limited to the ileum and/or In patients with active, moderate-to-severe Crohn’s dis-
ascending colon [strong recommendation, moderate- ease, we suggest the use of systemic corticosteroids for
quality evidence]. the induction of clinical response and remission [weak
recommendation, moderate-quality evidence].
A Cochrane systematic review and meta-analysis35 included
three RCTs36–38 that compared budesonide at a dose of 9  mg/day Two RCTs reported on the efficacy of systemic corticosteroids [oral
with placebo [Supplementary Material, SoF Table 2, available as prednisolone or oral methylprednisolone] compared with placebo for
Supplementary data at ECCO-JCC online]. Two of these trials37,38 the treatment of moderately-to-severely active CD29,30[Supplementary
evaluated clinical response [defined as decrease in CDAI score ≥100 Material, SoF Table 4, available as Supplementary data at ECCO-
or total CDAI score ≤150] at 8 weeks. Clinical remission [CDAI JCC online]. Oral methylprednisolone was administered at a dose of
score ≤150] at 8 weeks was reported in all three RCTs. Budesonide 48 mg/day and reduced on a weekly basis to 32 mg, 24 mg, 20 mg,
was superior to placebo for inducing clinical response [RR: 1.46; 16 mg, and 12 mg.29 Doses of oral prednisolone ranged from 0.50
95% CI: 1.03–2.07] and clinical remission [RR: 1.93; 95% CI: to 0.75 mg/kg with a maximum daily dose of 60 mg.30 Prednisolone
1.37–2.73] in patients with mildly active CD in the small and/or is usually tapered at 5 mg/week over an 8-to 12-week period. Data
large intestine limited to the ascending colon. As compared with from these studies have been synthesised in a Cochrane systematic
conventional steroids [e.g., prednisolone], which are usually asso- review.45
ciated with many systemic side effects, budesonide presented high One trial involving 105 patients reported on induction of clinical
topical anti-inflammatory activity and low systemic absorption and response.29 Clinical response was more common in patients receiving
bioavailability, and therefore had a better safety profile. Budesonide methylprednisolone as compared with placebo [93.6% vs 53.4%;
was shown to be safe [AEs; RR: 0.98; 95% CI: 0.77–1.25] in the RR: 1.75; 95% CI: 1.36–2.25]. Corticosteroids were reported to be
reviewed meta-analysis.35 twice as effective in inducing clinical remission than placebo in the
A Cochrane systematic review and meta-analysis from 2015 re- two studies involving 267 patients [RR: 1.99; 95% CI: 1.51–2.64].45
viewed two RCTs39,40 that compared budesonide at a dose of 9 mg/ Data on the proportion of patients experiencing AEs from the use
day with mesalazine up to 4.5  g/day. More recently, a Japanese of systemic corticosteroids was available from one trial involving
trial41 also evaluated budesonide versus mesalazine in patients 162 patients treated with oral prednisolone.30,46 The frequency of
with active CD [Supplementary Material, SoF Table 3, available as AEs was 5-fold higher in patients receiving corticosteroids compared
Supplementary data at ECCO-JCC online]. All trials evaluated clin- with placebo [31.8% vs 6.5%; RR: 4.89; 95% CI: 1.98–12.07].
ical response [decrease in CDAI  ≥  100 or total CDAI  ≤  150] and Steroid-related AEs included Cushing syndrome, acne, infection [in-
clinical remission [CDAI ≤ 150] at 8 weeks. Budesonide was not su- creased risk of abdominal and pelvic abscesses in patients with CD],
perior to mesalazine for inducing clinical remission [RR: 1.30; 95% ecchymoses, hypertension, diabetes mellitus, osteoporosis, cataracts,
CI: 0.98–1.72] in patients with mildly active CD in the small and/or glaucoma, and growth failure in children. Imprecision was serious
large intestine [Supplementary Figure 7, available as Supplementary for the outcomes considered, due to sparse data, which yielded a
data at ECCO-JCC online]. Nevertheless, clinical response was more moderate quality of evidence overall.
8 J. Torres et al.

Immunosuppressants Methotrexate
Thiopurines Only one relevant placebo-controlled RCT was retrieved. In this
study,55 141 steroid-dependent patients with active CD were ran-
Recommendation 1.4. ECCO CD Treatment GL [2019] domised to either 25 mg/week of intramuscular MTX or placebo for
16 weeks, with a concomitant daily dose of prednisolone [20 mg at
We suggest against the use of thiopurines as mono- initiation] that was reduced over a 3-month period [Supplementary
therapy for the induction of remission of moderate-to- Material, SoF Table 6, available as Supplementary data at ECCO-
severe luminal Crohn’s disease [weak recommendation, JCC online]. After 16 weeks, a significantly larger proportion of
very low-quality evidence]. patients treated with MTX were in clinical remission than placebo
[RR: 2.06; 95% CI: 1.09–3.89]. The rate of treatment discontinu-
Several studies have reported on the use of thiopurines compared ation for AEs [mainly liver enzyme elevations and nausea] was sig-
with placebo for induction of remission and response in CD30,47–53 nificantly higher in comparison with placebo [RR: 8.00; 95% CI:
[Supplementary Material, SoF Table 5, available as Supplementary 1.09–58.51]. However, this study is strongly limited by imprecision
data at ECCO-JCC online]. Five trials evaluated the use of and some confounding factors, such as the concomitant use of ster-
thiopurines for induction of clinical remission [12–17 weeks] in oids. No studies were found that compared MTX monotherapy

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comparison with placebo30,47,48,51 [using CDAI or Harvey-Bradshaw versus placebo for the induction of remission of moderate-to-severe
index]. Overall, 380 patients were analysed. The active comparator CD. No agreement was achieved in the Consensus regarding the use
was AZA in four of these trials,30,47,51 and the active drug was MP of MTX for inducing CD remission, and therefore the Consensus
in the remaining trial.54 The trials were heterogeneous in terms of decided to make no recommendation.
study design, follow-up time, definition of active disease, and def- Three small and heterogeneous studies compared the efficacy
inition of remission. Except for Summers et al.,30 most of the trials of MTX and thiopurines for induction of remission in CD56–60
allowed for the use of concomitant steroids. The pooled analysis [Supplementary Material, SoF Table 7, available as Supplementary
was performed on an intention-to-treat basis and revealed no dif- data at ECCO-JCC online]. These studies used different dosages and
ferences for induction of remission between thiopurines and pla- routes of administration. Two studies used oral MTX at doses of
cebo; 48% [95/197] in the active intervention compared with 37% 16  mg/week59 and 12.5  mg/week,56 and one used intravenous [IV]
[68/183] in the placebo group achieved remission [RR: 1.23; 95% MTX at 25 mg/week.60 All patients were steroid-dependent and re-
CI: 0.97–1.55]. ceived systemic steroids at inclusion. None of the individual studies
Three trials reported on clinical response, albeit not with stand- or the pooled analysis demonstrated a significant difference in the
ardised measures of disease activity.49,52,53 In these trials, different likelihood to achieve remission [RR: 0.87; 95% CI: 0.70–1.09]
types of physician global assessment of disease improvement [clin- [Supplementary Figure 12, available as Supplementary data at
ical response] were used.49,52,53 Overall, 42.8% of the patients re- ECCO-JCC online]. Although the risk of AEs is higher with MTX,
ceiving thiopurines, as compared with 26.9% of those receiving the data are very sparse and the quality of evidence is very low for
placebo, showed clinical improvement. The RR of obtaining clinical both outcomes. Accordingly, no recommendation can be made.
response was 1.87 [95% CI: 0.44–7.96]. Heterogeneity was serious Based on the current evidence, agreement on a recommendation
[I2 = 69%] and imprecision very serious due to sparse data and wide for the use of MTX for inducing clinical remission in patients with
confidence intervals; thus the quality of evidence was very low for CD could not be reached. However, MTX may be considered as an
this outcome [Supplementary Figure 11, available as Supplementary option for steroid-dependent patients with moderate-to-severe dis-
data at ECCO-JCC online]. ease when alternative options [including surgery] cannot be used.
Only one trial reported on AEs during induction.51 The pooled The need to stop therapy in patients planning a pregnancy must be
RR of any AEs was not significantly different between placebo and considered.61
thiopurines [86% vs 69%; RR: 0.81; 95% CI: 0.64–1.02]. Serious
AEs were reported in two trials30,51 including 125 patients; 13.5% Monoclonal antibodies
of those receiving AZA versus 3.8% of those receiving placebo de-
veloped serious AEs [pooled RR: 2.57; 95% CI: 0.92–7.13]. The Recommendation 1.5. ECCO CD Treatment GL [2019]
quality of evidence was deemed low due to a very low number of
events [n = 19] and wide confidence intervals. We recommend the use of TNF inhibitors [infliximab,
One study reported on a validated quality of life measure adalimumab, and certolizumab pegol] to induce remis-
[Inflammatory Bowel Disease Questionnaire: IBDQ].51 The greatest sion in patients with moderate-to-severe Crohn’s disease
difference between groups was observed at Week 4 [43% for AZA who have not responded to conventional therapy [strong
and 30% for placebo]. Regarding biochemical improvement, only recommendation, moderate-quality evidence].
some of the trials reported on changes at the end of the induction
period; no dichotomous data were available that allowed for a Monoclonal antibodies directed against TNF-α are fast-acting
pooled analysis calculation. Overall, most trials reported no differ- and potent anti-inflammatory agents. Anti-TNF therapies ap-
ences in biomarkers of inflammation such as erythrocyte sedimenta- proved for the treatment of CD include infliximab, adalimumab,
tion rate [ESR], CRP, or orosomucoid in those receiving thiopurines and certolizumab pegol [the latter is not approved in the European
as compared with placebo.48,52–54 Reinisch et al.51 reported a similar Union for CD, but is commercially available in Switzerland and
proportion of elevated faecal calprotectin at baseline and at Weeks Russia]. Infliximab is a chimeric mouse-human immunoglobulin [Ig]
4 and 12 for the thiopurines and placebo groups. Candy et al.47 re- G1 monoclonal antibody administered intravenously at a dose of
ported a slight increase of ESR in the group receiving placebo and 5 mg/kg at 0, 2, and 6 weeks during induction and every 8 weeks
prednisolone versus a statistically significant decrease in ESR in thereafter. Adalimumab is a fully humanised IgG1 monoclonal
those receiving AZA and prednisone. antibody given subcutaneously [SC] at a dose of 160 mg, and then
ECCO Guidelines on Therapeutics in Crohn's Disease: Medical Treatment 9

80 mg 2 weeks after induction, followed by 40 mg SC every 2 weeks.

Certolizumab pegol is a PEGylated Fab fragment against TNF-α, Recommendation 1.7. ECCO CD Treatment GL [2019]
self-administered SC at a dose of 400 mg at Weeks 0, 2, and 4, fol-
We recommend combination therapy with a thiopurine
lowed by 400 mg every 4 weeks thereafter.
when starting infliximab to induce remission in patients
Data on anti-TNF agents versus placebo [infliximab,
with moderate-to-severe Crohn’s disease, who have had
adalimumab, and certolizumab pegol] from several meta-analyses of an inadequate response to conventional therapy [strong
RCTs62–64 support their efficacy for induction of clinical remission recommendation, moderate-quality evidence].
[RR: 1.6; 95% CI: 1.17–2.36] and clinical response [RR: 1.43; 95%
CI: 1.17–1.73] [Supplementary Material, SoF Table 8, available as
The SONIC [Study Of Biologic and Immunomodulator Naive
Supplementary data at ECCO-JCC online] in patients who did not
Patients In Crohn’s Disease] RCT70 compared the efficacy of
achieve adequate response or were intolerant to corticosteroids and/
infliximab combined with AZA over infliximab monotherapy in
or immunosuppressants. Limited endoscopic data were available for
patients naïve to both therapies, who failed to respond to steroids
the induction period; two studies showed a non-significant trend to-
or 5-ASA [Supplementary Material, SoF Table 10, available as
wards enhanced mucosal healing [RR: 3.25; 95% CI: 0.53–19.8].65,66
Supplementary data at ECCO-JCC online]. Combination therapy

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However, the evidence was downgraded due to imprecision. Data on
resulted in higher rates of clinical remission at Week 26 as com-
clinical remission were highly heterogeneous [I2  =  63%], and data
pared with infliximab monotherapy [RR: 1.64; 95% CI: 1.07–2.53].
on endoscopic improvement were affected by high imprecision due
Combination therapy was also more likely to result in mucosal
to the low number of patients included in the meta-analysis [n = 35].
healing at this timepoint [RR: 1.82; 95% CI: 1.01–3.26]. There was
Data on patient-reported outcomes [PRO] response and remission,
no difference in AEs for those receiving combination therapy. Rather,
biochemical and radiological improvement, and quality of life are in-
there were significantly lower rates of serious AEs in those receiving
sufficient. There was no difference in terms of AEs [RR: 0.99; 95% combination therapy [RR: 0.56; 95% CI: 0.32–0.97].
CI: 0.90–1.08]. A commonly encountered scenario in clinical practice is patients
The choice of anti-TNF agent depends on patient preference, who have failed or have had an inadequate response to thiopurines
availability, cost, and accessibility. However, in a 2015 network and in whom anti-TNF therapy is planned. No RCT has directly
meta-analysis, pairwise comparison revealed that infliximab with compared whether in such cases thiopurine maintenance in combin-
AZA [OR: 3.1; 95% CI: 1.4–7.7] and adalimumab monotherapy ation with the anti-TNF would carry additional benefits in terms of
[OR: 2.1; 95% CI: 1–4.6] were superior to certolizumab pegol for efficacy. A post-hoc analysis of RCTs has shown no added benefit of
induction of remission.67 the continued use of immunomodulator therapy after starting anti-
The timing of introduction of biologic agents is a matter of TNF therapy in this setting.74 However, immunogenicity should be
debate. It has been suggested that patients presenting with poor considered and, in the absence of direct evidence, an individualised
prognostic factors [e.g. fistulising perianal disease, extensive dis- approach should be considered.74
ease, deep ulcerations, complicated phenotype] would benefit from
the early introduction of anti-TNF to achieve a reduced risk of Recommendation 1.8. ECCO CD Treatment GL [2019]
surgery, hospitalisation, or development of disease-related compli-
cations.15 Furthermore, anti-TNF agents might be more effective We recommend ustekinumab for induction of remission
if introduced earlier [in the first 2 years] in disease course,68–72 al- in patients with moderate-to-severe Crohn’s disease with
though these results are based on post-hoc analyses from clinical inadequate response to conventional therapy and/or to
trials. anti-TNF therapy [strong recommendation, high-quality
evidence].
Recommendation 1.6. ECCO CD Treatment GL [2019]
Ustekinumab is an IgG1 monoclonal antibody that binds to the p40
We suggest against the combination of adalimumab and subunit shared by the pro-inflammatory interleukins 12 and 23.75
thiopurines over adalimumab alone to achieve clinical re- In CD, induction should be given IV using a weight-based regimen
mission and response [weak recommendation, moderate- of approximately 6  mg/kg.75,76 One systematic review and meta-
quality evidence]. analysis pooled the results from RCTs in which ustekinumab was
compared with placebo for induction of remission in patients with
Only one RCT [the DIAMOND trial]73 studied the use of combin- moderate-to-severe active luminal CD77[Supplementary Material,
ation therapy of adalimumab with thiopurine as compared with SoF Table 11, available as Supplementary data at ECCO-JCC on-
adalimumab monotherapy for the induction of clinical remission line]. Four trials76,78–80 involving 1947 patients treated with different
in patients naïve to both therapies [Supplementary Material, ustekinumab intravenous doses or equivalent placebo reported in-
SoF Table 9, available as Supplementary data at ECCO-JCC duction of clinical response and induction of clinical remission at
online]. In this trial, combination therapy was not superior to Week 6.  Data were extracted and a meta-analysis was performed,
adalimumab monotherapy for inducing clinical remission [RR: yielding an RR of obtaining clinical response of 1.56 [95% CI:
0.95; 95% CI: 0.78–1.15]. However, combination therapy was 1.38–1.77] versus placebo [Supplementary Figure 13, available as
associated with endoscopic improvement at Week 26 [RR: 1.32; Supplementary data at ECCO-JCC online]. The quality of evidence
95% CI: 1.06–1.65], although this benefit was lost at the end was high. The RR of obtaining clinical remission was 1.76 [95% CI:
of 1  year. There was no increase in AEs leading to discontinu- 1.40–2.22] [Supplementary Figure 14, available as Supplementary
ation associated with combination therapy [RR: 1.03; 95% CI: data at ECCO-JCC online]. The quality of evidence was high. An
0.60–1.78]. Of note, the dose of AZA used in this trial was lower endoscopic substudy involving 252 CD patients revealed that 47.7%
than the usual dose used in CD patients [25–100 mg/day instead of patients receiving ustekinumab achieved endoscopic improvement
of 2–2.5 mg/kg/day]. at 8 weeks as compared with 29.9% of those receiving placebo [RR:
10 J. Torres et al.

1.60; 95% CI: 1.13–2.26]. The quality of evidence was moderate. and clinical remission [Supplementary Material, SoF Table 13, avail-
Four trials76,78–80 reported on AEs [2024 patients] or serious AEs able as Supplementary data at ECCO-JCC online]. The pooled RR of
[1947 patients] after induction. The pooled RR of any AEs was not clinical response [35.8% vs 33.1%; RR:1.14; 95% CI: 0.65–1.99] and
significantly different between ustekinumab and placebo [62.0% vs clinical remission [16.3% vs. 13.3%; RR: 1.16; 95% CI: 0.54–2.48]
63.9%; RR: 0.96; 95% CI: 0.90–1.03] [Supplementary Figure 15, were not significantly different between ustekinumab and vedolizumab,
available as Supplementary data at ECCO-JCC online]. Similarly, but the quality of evidence was very low for both outcomes.
the pooled RR of any serious AEs was not significantly different be- Four trials76,79,82,85 involving a total of 1541 patients treated with
tween ustekinumab and placebo [5.2% vs 6.4%; RR: 0.79; 95% CI: ustekinumab or vedolizumab reported on AEs or serious AEs after
0.54–1.15] [Supplementary Figure 16, available as Supplementary induction. The pooled RR of any AEs was not significantly dif-
data at ECCO-JCC online]; the quality of evidence was high. The ferent between ustekinumab and vedolizumab [64.2% vs 56.2%;
rate of antibody drug formation seems to be low [under 5%].81 RR: 1.00; 95% CI: 0.82–1.23]. Finally, the pooled RR of any ser-
ious AEs was not significantly different between ustekinumab and
vedolizumab [7.1% vs 7.7%; RR: 0.95; 95% CI: 0.43–2.12]; the
Recommendation 1.9. ECCO CD Treatment GL [2019]
quality of evidence was very low. However, surgery should always
be considered as an option in refractory patients.

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We recommend vedolizumab for induction of response
and remission in patients with moderate-to-severe
Crohn’s disease with inadequate response to conven-
tional therapy and/or to anti-TNF therapy [strong recom- Key Points for Clinical Practice
mendation, moderate-quality evidence]. Budesonide is effective for the induction of remission in patients with
mild-to-moderate CD, defined as a CDAI between 150 and 220, and/
or presence of mild lesions at endoscopy, or a Simple Endoscopic
Vedolizumab is a monoclonal IgG1 antibody that acts by blocking
Score-CD [SES-CD] ≤6, or a Crohn’s Disease Endoscopic Index of
the α4β7 integrin resulting in gut-selective anti-inflammatory ac-
Severity [CDEIS] ≤8 with ileal and/or right colon involvement; 5-ASA
tivity.82 It is administered intravenously at a fixed dose of 300  mg
compounds and sulphasalazine have no therapeutic effect. There is a
at 0, 2, and 6 weeks for induction, and every 8 weeks thereafter.
knowledge gap on how to treat mild-to-moderate CD localised in dif-
Patients who do not achieve response at Week 6 can benefit from
ferent parts of the gastrointestinal tract other than the ileum and right
an additional administration at Week 10.83 Three randomised trials
colon, or in patients with extensive disease. Therefore the decision is
involving 969 patients treated with vedolizumab or placebo re-
left to the clinician, who should consider the patient’s individual char-
ported on induction of clinical response, induction of clinical re-
acteristics, prognostic factors, and cost/benefit ratios of therapies.
mission, and serious AEs in adult patients with moderate-to-severe
Although systemic steroids are effective in inducing remission in
active CD82,84,85[Supplementary Material, SoF Table 12, available as
moderate-to-severe CD, they are limited by important side effects.
Supplementary data at ECCO-JCC online]. Patients in these studies
Additionally, long-term use of corticosteroids does not prevent dis-
were followed up for 6 to 10 weeks. Clinical remission was more
ease relapse.30,87 Therefore we suggest that the presence of cortico-
common in patients receiving vedolizumab compared with placebo
steroid dependency or excess [the inability to wean steroids below
[RR: 2.01; 95% CI: 1.50–2.71] [Supplementary Figure 17, available
the equivalent of prednisolone 10 mg/day or budesonide 3 mg/day
as Supplementary data at ECCO-JCC online]. Likewise, clinical re-
within 3 months of starting steroids, a relapse within 3 months of
sponse was also more common in patients receiving vedolizumab
stopping steroids, or the need for more than a single course of cor-
compared with placebo [40.8% vs 25.7%; RR: 1.55; 95% CI:
ticosteroids in 1 year] should all warrant a steroid-sparing strategy.
1.14–2.11] [Supplementary Figure 18, available as Supplementary
Thiopurines alone are not effective in inducing remission. However,
data at ECCO-JCC online]. The quality of evidence for these out-
since thiopurines have a slow onset of action [8–12 weeks]43 and are
comes was high. Rates of serious AEs with vedolizumab were not
effective for maintaining remission in steroid-dependent CD patients
significantly different with placebo [RR: 0.94; 95% CI: 0.61–1.45]
[see Maintenance, 6.2.1., Recommendation 2.2.], they are frequently
[Supplementary Figure 19, available as Supplementary data at
combined with steroids at the commencement of therapy. In patients
ECCO-JCC online]. The quality of evidence for this outcome was
with steroid dependency, a combination of steroids and MTX has
moderate due to serious imprecision arising from sparse data.
limited efficacy in inducing remission at Week 16 and is associated
with a high risk of AEs. Therefore, this option may be considered
Recommendation 1.10. ECCO CD Treatment GL [2019] only where other medical treatments and surgery are not indicated
or are associated with some increased individual risks.88
We equally suggest the use of either ustekinumab or
For patients with moderate-to-severe CD [usually defined as a
vedolizumab for the treatment of moderate-to-severe
CDAI  >220 and/or CDEIS  >8 or SES-CD  >6] with inadequate re-
active luminal Crohn’s disease in patients who have pre-
sponse or intolerance to conventional therapy [steroids and/or
viously failed anti-TNF therapy [weak recommendation,
thiopurines], we recommend the use of monoclonal antibodies.
very low-quality evidence].
These include anti-TNF agents [such as infliximab, adalimumab, and
certolizumab pegol], ustekinumab, or vedolizumab. All these agents
One systematic review and meta-analysis performed an indirect are effective both in biologic-naïve and -experienced CD populations.
comparison of ustekinumab and vedolizumab for induction of re- The choice depends on patient characteristics and preferences, costs,
mission in patients with moderate-to-severe active luminal CD who and local availability.8 For the induction of remission, in treatment-
were non-responsive or intolerant to previous anti-TNF agents.86 naïve patients, the combination of infliximab with thiopurines is
Four trials76,79,82,85 involving a total of 1249 patients treated with more effective than infliximab alone for achieving steroid-free re-
ustekinumab or vedolizumab reported on induction of clinical response mission.70 For adalimumab, no benefit of combination therapy over
ECCO Guidelines on Therapeutics in Crohn's Disease: Medical Treatment 11

adalimumab alone was observed in the only RCT performed to date.73 Oral 5-ASA compounds have been extensively studied for the main-
The SONIC trial70 demonstrated the superiority of either infliximab tenance of medically induced remission of CD [Supplementary
alone or the combination of infliximab and AZA over AZA mono- Material, SoF Table 14, available as Supplementary data at ECCO-
therapy or even in combination with steroids; this option should be JCC online]. No statistically significant benefit has been demonstrated
considered and even preferred in steroid-dependent patients. The [RR: 1.03; 95% CI: 0.92–1.16] [Supplementary Figure 20, available
REACT [Early Combined Immunosuppression for the Management as Supplementary data at ECCO-JCC online]. Overall, 11 placebo-
of Crohn’s Disease] trial showed that the early use of monoclonal controlled trials that assessed doses between 1 and 4  g/day were
antibodies [adalimumab] combined with immunosuppressants in pa- identified. Treatment durations ranged from 4 months to 36 months,
tients at high risk of complications, as compared with a more conven- with most trials evaluating a 12-month duration of therapy.94 There
tional stepwise management, was associated with significantly lower were no significant differences in the proportion of patients experi-
rates of complications and need for hospitalisation and/or surgery in encing an AE, or withdrawing due to AEs or serious AEs [RR: 1.93;
patients with early CD.15 A  prospective cohort study demonstrated 95% CI: 0.18–21.1]. The safety data were very sparse [three events]
that concomitant immunomodulator use is associated with lower im- and considerably limited this conclusion [Supplementary Figure 21,
munogenicity to anti-TNF.89 In clinical practice, the potential added available as Supplementary data at ECCO-JCC online].
efficacy benefit and lower immunogenicity of combination therapy

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needs to be balanced against a potential increase in AEs in the long Immunosuppressants
term.90,91 Combination therapy does not seem to be associated with Thiopurines
safety concerns, at least in the short term. However, a large nation-
wide cohort study showed that combination therapy is associated
with higher risk for lymphoma and serious infection, as compared Recommendation 2.2. ECCO CD Treatment GL [2019]
with anti-TNF monotherapy. 90,91 Therefore the decision is left to the
Thiopurines are recommended for the maintenance of
clinician, who should consider patient characteristics, costs, risks, and
remission in patients with steroid-dependent Crohn’s
local regulations. Importantly, risk needs to be individualised as spe-
disease [strong recommendation, moderate-quality
cific patient groups, such as the elderly, maybe at higher risk for infec-
evidence].
tions or lymphoma and young males maybe at higher risk for specific
complications, such as hepatosplenic T cell lymphoma.92,93
In patients who fail anti-TNF therapy, ustekinumab or vedolizumab The effect of maintenance treatment with AZA or MP administered
are indicated. There is currently no direct evidence on the comparison to patients with CD who are steroid-dependent has been investi-
between vedolizumab versus anti-TNF and ustekinumab versus anti- gated in one meta-analysis95 [Supplementary Material, SoF Table
TNF in patients treated either with vedolizumab or ustekinumab as 15, available as Supplementary data at ECCO-JCC online]. This
a first biologic. No RCTS have specifically assessed the efficacy and meta-analysis included data from six trials published between 1971
safety of these agents when used in combination therapy as compared and 2013.30,47,53,96–99 A total of 489 patients treated with AZA [1.0
with monotherapy; however, overall immunogenicity rates seem to be to 2.5 mg/kg/day] were included and followed for 6 to 18 months.
low. Besides, in the originator trials, no difference in efficacy was ob- Clinical remission was defined according to different criteria [CDAI
served in those patients treated concomitantly with immunomodulator. in three, disease activity score [DAS] two, in others one]. AZA was
However, in patients with moderate-to-severe CD with limited dis- superior to placebo for the maintenance of remission in steroid-
ease extent or refractory to at least one monoclonal antibody, surgery dependent patients [RR: 1.19; 95% CI: 1.05–1.34].
should always be considered as an alternative option. Safety outcomes were reported in four trials published between
While RCTs evaluate the efficacy of a drug for induction of remission 1978 and 2013,30,96–98 including a total of 556 patients followed for 6
and thereafter for maintaining remission using validated indices of clinical to 18 months. The overall risk of inducing serious AEs during main-
activity, the clinician usually bases his or her choice of first-line therapy tenance treatment with thiopurines was significantly higher than
not only on symptoms but also on the perceived disease severity [the im- with placebo [RR: 2.45; 95% CI: 1.22–4.90]. The rate of serious
pact of disease in the individual patient, the cumulative complications AEs reported in patients treated with thiopurines versus placebo
and surgical resections, risk factors for complications, the inflammatory was 9.0% [22/245] versus 2.9% [9/311]. Pancreatitis, leukopenia,
burden of disease, and disease course].1 Therefore, appropriate studies nausea, allergic reaction, and infections were the most frequent ser-
that address the early use of biologics over a stepwise approach, focusing ious AEs.
on the prevention of complications and disease-modification outcomes,
and that validate risk factors for disease progression [age, extensive dis-
Recommendation 2.3. ECCO CD Treatment GL [2019]
ease, upper tract involvement] should be performed. Such studies were
identified by this Consensus as very important research gaps. We recommend against the early introduction of
thiopurine therapy in patients with newly diagnosed
Section 2 - Maintenance of Remission Crohn’s disease for maintaining remission [weak recom-
mendation, low-quality evidence]
5-ASA compounds

It has been hypothesised that the early introduction of

Recommendation 2.1. ECCO CD Treatment GL [2019]
thiopurines could modify disease course. Two studies have evaluated
We recommend against the use of oral 5-aminosalicylic the efficacy of early use of thiopurines: the AZTEC [AZathioprine
acid for maintenance of medically induced remission in for Treatment of Early Crohn’s disease in adults]98 and the RAPID
patients with Crohn’s disease [strong recommendation, [Résultat de l’Adjonction Précoce d’ImmunoDépresseurs]100 trials
low-quality evidence]. [Supplementary Material, SoF Table 16, available as Supplementary
data at ECCO-JCC online]. The latter has been excluded from our
12 J. Torres et al.

SoF table because it was not conducted against placebo or no treat- administered to patients with CD who had achieved disease remission
ment. In the AZTEC study, adult patients with a recent [<8 weeks] with the same anti-TNF drug62,63 [Supplementary Material, SoF Table
diagnosis of uncomplicated CD were randomised to receive either 18, available as Supplementary data at ECCO-JCC online]. Five land-
AZA or placebo up to Week 76. Only corticosteroids were allowed mark trials published between 2002 and 200771,101–104 were pooled in
to treat active disease in this study population. The results were not the meta-analysis from Stidham et al.62; one study was on infliximab,
statistically significant for any of the critical outcomes evaluated. two on adalimumab, and two on certolizumab pegol. A total of 1771
After 76 weeks of treatment, clinical remission did not differ be- patients were included and followed for 24 to 30 weeks. Four of
tween the two groups [RR: 1.27; 95% CI: 0.94–1.72]; 30 patients the five studies included primary responders only, and one study in-
treated with AZA [44.1%] and 23 given placebo [36.5%] were in cluded all subjects. Clinical remission was defined as a CDAI score
sustained corticosteroid-free remission [RR: 1.21; 95% CI: 0.79– <150. The overall likelihood of maintaining remission with anti-
1.84]. The rates of relapse [defined as CDAI score >175] and cor- TNFs versus placebo was 1.78 [95% CI: 1.51–2.09]. The following
ticosteroid requirements were similar between groups. Serious AEs values were achieved with infliximab: 1.86 [95% CI: 1.21–2.86];
occurred in 14 patients [20.6%] in the AZA group and 7 [11.1%] in with adalimumab: 2.06 [95% CI: 1.59–2.82]; and with certolizumab
the placebo group [RR: 1.85; 95% CI: 0.8–4.29]. pegol: 1.62 [95% CI: 1.30–2.02]. A network meta-analysis62 found no
statistically significant differences between the three agents.

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There are no pooled data available on serious AEs of all anti-
Methotrexate
TNFs as against placebo. In a network analysis performed in the
framework of a Cochrane collaboration,105 the dose-adjusted odds
Recommendation 2.4. ECCO CD Treatment GL [2019] ratios [Ors] [95% CI] for SAEs for adalimumab, infliximab, and
We recommend methotrexate administered parenterally certolizumab pegol were 1.01 [0.64–1.59], 1.13 [0.79–1.62], and
for the maintenance of remission in patients with steroid- 1.57 [0.96–2.57], respectively. Thus monotherapy with anti-TNFs is
dependent Crohn’s disease [weak recommendation, considered safe as compared with placebo for the maintenance of
moderate-quality evidence]. remission in CD patients, although the relatively small sample size
and short follow-up of RCTs do not allow the detection of AEs that
Data on the use of parenterally administered MTX are derived from may appear in larger and longer observational studies.
one double-blind, placebo-controlled RCT55 where patients were ad-
ministered weekly intramuscular injections of 15 mg MTX, or pla- Recommendation 2.6. ECCO CD Treatment GL [2019]
cebo of identical appearance, for 40 weeks [Supplementary Material, We recommend vedolizumab for maintaining clinical re-
SoF Table 17, available as Supplementary data at ECCO-JCC on- mission in patients with moderate-to-severe Crohn’s dis-
line]. Patients with previously active CD, who had entered remission ease who achieved remission with vedolizumab [strong
after 16 to 24 weeks of treatment with 25 mg MTX given intramus- recommendation, moderate-quality evidence].
cularly once weekly, were randomly assigned to receive either MTX
at a dose of 15 mg intramuscularly once weekly or placebo, for 40
weeks. No other treatments for CD were permitted. After 40 weeks, Vedolizumab monotherapy, given IV at 300 mg every 8 weeks, was
the proportion of patients who remained in remission was higher in superior to placebo in maintaining clinical remission in patients with
the MTX group than in the placebo group [65% vs 39 %; RR: 1.67; moderate-to-severe CD who achieved remission with vedolizumab
95% CI: 1.05–2.67]. Fewer than 50% of the patients in the MTX [RR: 1.81; 95% CI: 1.26–2.59] [Supplementary Material, SoF Table
group had relapsed by the end of the study. 19, available as Supplementary data at ECCO-JCC online]. At Week
There were no differences in severe AEs in the MTX group 52, 60/154 patients [39.0%] receiving vedolizumab every 8 weeks
[n  =  40] as compared with the placebo group [n  =  36] over the and 56/154 patients [36.4%] receiving vedolizumab every 4 weeks
40-week observational period [one patient had cervical dysplasia were in clinical remission as compared with 33/153 patients [21.6%]
and the other had a viral respiratory tract infection]. Nausea and receiving placebo [p <0.001 and p = 0.004, respectively]. Moreover,
vomiting occurred more frequently among patients in the MTX vedolizumab was effective at maintaining steroid-free clinical remis-
group [40% vs 25% in the placebo group]. Although none of the sion [RR: 2.00; 95% CI: 1.11–3.61] and showed a similar incidence
symptoms was severe, one patient discontinued treatment because of AEs compared with placebo through week 54 [RR: 1.21; 95%
of these symptoms. No patient had leukopenia of sufficient severity CI: 0.73–2.00].82 Longer-term data beyond 52 weeks are required to
to require withholding treatment or withdrawal from the study. The correctly evaluate the safety profile.
overall incidence of AEs was similar in both groups.
Recommendation 2.7. ECCO CD Treatment GL [2019]

Monoclonal antibodies We recommend the use of ustekinumab to maintain

clinical remission in patients with Crohn’s disease who
achieved remission with ustekinumab [strong recommen-
Recommendation 2.5. ECCO CD Treatment GL [2019] dation, moderate-quality evidence].
In patients with Crohn’s disease who achieved remission
One RCT reported outcomes for the maintenance of remission
with anti-TNF agents, maintenance treatment using the
with ustekinumab in CD patients [Supplementary Material, SoF
same treatment is recommended [strong recommenda-
Table 20, available as Supplementary data at ECCO-JCC online].79
tion, moderate-quality evidence].
Patients responding to ustekinumab in the induction period were
re-randomised to receive ustekinumab every 8 or 12 weeks or pla-
Two systematic reviews analysed the effect of maintenance treatment cebo. Over a 44-week period, 51% of the patients receiving SC
with anti-TNFs [infliximab, adalimumab, and certolizumab pegol] ustekinumab were in clinical remission as compared with 35.9%
ECCO Guidelines on Therapeutics in Crohn's Disease: Medical Treatment 13

of those receiving placebo [RR: 1.42; 95% CI: 1.10–1.84]. A sub- Table 21, available as Supplementary data at ECCO-JCC online].
group analysis demonstrated that at Week 44, clinical remission was These two RCTs showed no advantage of therapeutic drug moni-
achieved by 53.1% of patients receiving ustekinumab every 8 weeks toring [TDM] over clinically based anti-TNF dosing for any of our
and by 48.8% of patients receiving ustekinumab every 12 weeks, critical outcomes, namely clinical remission [one study; 62.6% vs
as compared with 35.9% in the placebo group. The difference be- 54.9%; RR: 1.14; 95% CI: 0.89–1.47], steroid-free clinical remis-
tween treatment every 8 weeks and placebo was 17.2% [95% CI: sion [one study; 30.5% vs 40.0%; RR: 0.76; 95% CI: 0.46–1.26],
5.3–29.2] and was 13% between treatment every 12 weeks and endoscopic remission [one study; 51.2% vs 52.5%; RR: 0.98; 95%
placebo [95% CI: 1.1–24.9]. Therefore there was no difference be- CI: 0.68–1.40], biochemical remission [one study; 62.6% vs 54.9%;
tween ustekinumab administered every 8 or 12 weeks. At 44 weeks, RR: 1.14; 95% CI: 0.89–1.47], or serious AEs [one study; 34.1% vs
corticosteroid-free remission was achieved in 29.8% of patients 27.5%; RR: 1.24; 95% CI: 0.68–2.23].107,108
receiving placebo versus 44.7% of patients receiving ustekinumab In the TAXIT trial, a total of 273 IBD patients with stable re-
[RR: 1.50; 95% CI: 1.12–2.02]. The pooled RR of any AEs was not sponse to maintenance infliximab therapy were randomised either
significantly different between patients who were given placebo and to concentration- or clinically-based infliximab dosing. Both groups
those administered ustekinumab [15.0% vs 11.0%; RR: 0.73; 95% were dose-optimised or dose-reduced to achieve a baseline trough
CI: 0.43–1.25]. level between 3 and 7 μg/mL. This dose-optimisation phase of the

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There are limited data on endoscopic remission, as this was study showed that in patients in clinical remission, a trough level
assessed in a subgroup analysis of 70 patients [46 receiving <3 μg/mL or >7 μg/mL was observed in 29% and 27% of patients,
ustekinumab vs 24 receiving placebo] at 44 weeks. There was no respectively. No differences in clinical or biochemical remission at
statistically significant difference in endoscopic remission between 1 year were observed between clinically- [66%] and proactive TDM-
patients in the placebo group as compared with patients in the treat- [69%] based groups.107 Nevertheless, the group who received pro-
ment arm [RR: 2.61; 95% CI: 0.32–21.08]. active monitoring had fewer relapses during follow-up [7% vs 17%;
There were no deaths during the 44 weeks of maintenance. p = 0.018].
Common AEs were headache, nausea, and arthralgia, with no sig- In the TAILORIX trial, 122 biologically naïve patients with
nificant difference in occurrence between the ustekinumab and pla- CD, treated with an induction combination therapy with infliximab
cebo groups. There was an identical occurrence of non-melanoma and immunosuppressant, were randomised after 14 weeks to the
skin cancers in the maintenance groups [n  =  4 patients in placebo following three groups: dose intensification based on clinical fea-
and ustekinumab groups]. Longer-term data beyond 52 weeks are tures, biomarkers, and trough levels of infliximab, with optimisation
required to correctly evaluate the safety profile. steps of 2.5  mg/kg [TDM1]; or of 5  mg/kg [TDM2]; or dose in-
There are no randomised head-to-head trials comparing tensification based on clinical features alone [control group].108 The
vedolizumab or ustekinumab with anti-TNF agents for the main- infliximab dose was adapted to maintain a trough level >3 μg/mL.
tenance of clinical remission in patients with moderate-to-severe There was no difference in sustained steroid-free clinical remission
CD who have achieved response or remission with the same agent. with mucosal healing [CDAI <150 from Weeks 22 to 54] in the three
A  network meta-analysis106 included nine RCTs [all trials used the randomisation arms [33% in TDM1; 27% in TDM2; 40% in con-
CDAI to define clinical remission] with varying follow-up times. trol; p = 0.50].
The certolizumab pegol trial had a follow-up time of only 26 weeks. Both studies have important limitations in their study de-
All comparisons were indirect [through the placebo, the ‘common signs,107,108 which collectively have lowered the strength of our
comparator’]. Therefore, the quality of evidence was very low. No recommendation. The outcomes in both studies were clinical remis-
specific agent was safer than the others in the maintenance phase. sion but other important issues, such as costs and immunogenicity,
Based on efficacy data, there is no evidence to support switching to also need to be considered. The prospective cohort study PANTS
vedolizumab or ustekinumab in patients who responded to induc- [Personalised Anti-TNF Therapy in Crohn’s Disease Study] showed
tion treatment with any anti-TNF, or vice versa. There is a clear need that anti-TNF failure is highly dependent on low drug concentra-
to identify biomarkers that could guide therapeutic choices, and to tions and immunogenicity, and that dose intensification, especially
conduct appropriately sized head-to-head trials that could allow for during the induction period, may improve outcomes and treatment
the identification of patient subgroups who would benefit from a success.89 Therefore, the Consensus believes that large, well-powered
given biologic over the other. prospective RCTs with adequate stratification of patients are still
required.

Maintenance strategies
Recommendation 2.9. ECCO CD Treatment GL [2019]

In Crohn’s disease patients who have lost response to an

Recommendation 2.8. ECCO CD Treatment GL [2019]
anti-TNF agent, there is currently insufficient evidence to
In Crohn’s disease patients in clinical remission under recommend for or against the use of reactive therapeutic
anti-TNF treatment, there is currently insufficient evi- drug monitoring to improve clinical outcomes [weak rec-
dence to recommend for or against the use of proactive ommendation, low-quality evidence].
therapeutic drug monitoring to improve clinical outcomes
as compared to routine care [weak recommendation,
Reactive TDM refers to the practice of measuring anti-TNF trough
moderate-quality evidence].
level drug concentration and/or antidrug antibodies [ADA] in pa-
tients on anti-TNF therapy with active disease, to elucidate the
Data from two RCTs with a total of 395 patients with CD were mechanism of loss of response [LOR] and to guide clinical deci-
used to support this recommendation [Supplementary Material, SoF sion making. Reactive TDM was compared with empirical IFX
14 J. Torres et al.

optimisation [based on clinical judgment alone] in only one ran- ECCO-JCC online]. However, regular assessment for the long-term
domised, controlled, single-blind, multicentre study in a cohort of 69 risks/benefits should be performed considering the long-term safety
patients with CD with secondary IFX failure.109 Patients were ran- data from the population base. To summarise, the evidence for the
domised to IFX dose intensification [5 mg/kg every 4 weeks; n = 36] prevention of clinical relapse is in favour of continuation of treat-
or interventions based on serum IFX and IFX ADA levels using the ment, as significantly more relapses occurred when the treatment
proposed algorithm [n = 33]. There was no difference in regaining was discontinued; the risk of SAEs was not different between AZA
clinical response between the TDM-based group [19/33, 57.6%] and and placebo/no treatment. Data from studies that compared pa-
the symptom-based group [19/36, 52.8%] [RR: 1.09; 95% CI: 0.71– tients receiving AZA versus placebo/no treatment for more than
1.67; p = 0.81] [Supplementary Material, SoF Table 22, available as 18  months are lacking, and this represents an important research
Supplementary data at ECCO-JCC online]. gap. Data from observational population studies suggest caution
However, numerous studies have shown a positive association and regular monitoring, especially for the risk of non-melanoma skin
between adequate drug concentration and various clinical outcomes cancer and lymphoma in patients exposed to long-term treatment
from clinical response to mucosal healing. Based on these obser- with thiopurines.20 The limited follow-up time and the number of
vational data, recent clinical practice guidelines and a group of 25 patients included in the studies of the meta-analysis are unable to
international experts supported the use of reactive TDM, despite capture AEs and serious AEs that may occur in the long term.

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recognising the very low quality of evidence.110,111 Supporting evi- We also reviewed the literature to compare the approach of using
dence comes from case-control observational studies.112,113 In a retro- long-term, low-dose thiopurines versus drug discontinuation. After
spective study of 312 patients with endoscopically active IBD treated an exhaustive literature search, we did not find evidence comparing
with IFX who underwent dose escalation, TDM-based [n = 149] and the two treatment strategies. Only one trial was identified where
clinical decision-based [n = 163] cohorts were compared for endo- dose reduction of thiopurines was compared with discontinuing
scopic remission and CRP at a median of 6 months after adjustment. thiopurines in the setting of combination therapy in patients with
Post-adjustment, endoscopic remission was observed in 63% of pa- IBD. The information was incomplete as it was not possible to sep-
tients in the TDM cohort as compared with 48% in the non-TDM arate data from ulcerative colitis and CD patients.118 Therefore, no
cohort [p  =  0.05]; clinical response was observed in 69% versus specific recommendation was made.
57% [p = 0.01], and there fewer hospitalisations in the TDM group
[22% TDM vs 35% non-TDM; p  =  0.025].112 In another study, a
Recommendation 2.11. ECCO CD Treatment GL [2019]
modified version of the Steenholdt optimisation algorithm,113 using
a cut-off of 3  μg/ml, was applied to a prospective cohort. Clinical In patients with Crohn’s disease who have achieved
response at 12 weeks was compared between this group and a long-term remission with the combination of infliximab
retrospective control group in which dosing decisions were made and immunosuppressants, we suggest monotherapy
independently of TDM results. There was no significant difference with infliximab [weak recommendation, very low-quality
in clinical outcomes,113 but the TDM approach was significantly evidence].
more cost-effective [>10% decrease in costs]. Therefore, the existing
limited evidence does not support an association between a reactive
TDM strategy and superior clinical outcomes but does suggest a cost A Cochrane review117 based on two RCTs118,119 revealed the same
savings benefit even after considering biosimilar use.114 relapse rate among patients who continued combination therapy
with AZA [27/56; 48%] or infliximab monotherapy [27/55; 49%]
[RR: 1.02; 95% CI: 0.68–1.52] [Supplementary Material, SoF
Recommendation 2.10. ECCO CD Treatment GL [2019] Table 24, available as Supplementary data at ECCO-JCC online].
The same meta-analysis117 analysed the rates of AEs for infliximab
We suggest continuation of thiopurines in Crohn’s dis-
versus combination therapy [RR:1.11; 95% CI: 0.44–2.81; very
ease patients in long-term remission on thiopurine main-
low-quality evidence] or serious AEs [RR: 1.00; 95% CI: 0.21–4.66;
tenance therapy, as the risk of relapse is higher when the
very low-quality evidence]. These results are rather uncertain due to
treatment is discontinued [weak recommendation, low-
an unclear risk of bias. Common AEs in the combination therapy
quality evidence].
studies included infections, elevated liver values, arthralgia, and in-
fusion reactions. For some infrequent AEs, longer follow-up studies
We conducted our own meta-analysis to compare the two strat- [>12 months] are necessary to correctly evaluate the safety profile.
egies [i.e., cessation vs continuation of treatment] in 215 CD A higher risk of lymphoma exists when anti-TNF agents are com-
patients in long-term remission on thiopurine maintenance bined with conventional immunosuppression. However, the absolute
therapy [Supplementary Material, SoF Table 23, available as rates remain very low [3.23; 95% CI 1.5–6.9] and were estimated
Supplementary data at ECCO-JCC online]. Data from four trials as 1.9 per 10  000 patient-years in one meta-analysis consisting of
were included.96,97,115–117 Patients included received AZA from 6 to almost 9000 patients included in the SEER database.120
42 months before being randomised to continue or stop AZA115 or to
continue AZA or placebo.96,97,116 All studies had a follow-up time of
Recommendation 2.12. ECCO CD Treatment GL [2019]
12 to 18 months. Our results revealed that the RR of clinical relapse
is 2.39 [95% CI: 1.38–4.13] [Supplementary Figure 22, available as In patients with Crohn’s disease who have achieved
Supplementary data at ECCO-JCC online]. Our meta-analysis effect long-term remission with the combination of adalimumab
estimate for serious AEs was RR 0.32 [95% CI: 0.04–2.92]. Although and immunosuppressants, we suggest monotherapy
the data showed a trend towards fewer serious AEs occurring with with adalimumab [weak recommendation, low-quality
discontinuation of treatment, the results were not statistically signifi- evidence].
cant [Supplementary Figure 23, available as Supplementary data at
ECCO Guidelines on Therapeutics in Crohn's Disease: Medical Treatment 15

On the basis of a meta-analysis of nine studies on adalimumab by In conclusion, observational studies report that up to half of
Chalhoub et al.,121 the data included were re-analysed because the patients will experience a relapse within the following 12  months
intervention and control groups had to be reversed to match the rele- after withdrawal. However, in the absence of controlled studies, the
vant PICO question. The result of this recalculation did not reveal evidence surrounding withdrawal of anti-TNF therapy in patients
any differences in maintenance of clinical remission [RR: 1.01; 95% with long-term remission remains scarce and inconclusive. Hence,
CI: 0.91–1.13] between combination therapy and monotherapy no recommendation regarding anti-TNF therapy can be made. The
[Supplementary Material, SoF Table 25 and Supplementary Figure management decision therefore lies with the clinician, who should
24, available as Supplementary data at ECCO-JCC online]. Whereas carefully consider the patient’s profile, values, and preferences, and
this meta-analysis was limited to 1 year of follow-up [Week 56] in any resource implications.135
the sensitivity analysis, studies with a longer follow-up [>52 weeks]
showed similar results. There are no quality data available for Key Points for Clinical Practice
steroid-free clinical remission. However in the ADHERE cohort,
which is an open-label extension study that prospectively follows up Immunosuppressants and biologic agents are the most effective ther-
the cohort of patients originally enrolled in the CHARM study on apies to maintain medically-induced remission in moderate-to-severe
adalimumab,71 the rates of steroid-free remission were similar in pa- CD patients. Aminosalicylates and steroids are not recommended

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tients with or without concomitant immunosuppression at baseline in this setting due to lack of efficacy and long-term risk of serious
after 3 years of follow-up.122 The meta-analysis by Chalhoub et al.121 AEs [steroids]. For patients with mild disease, no data are avail-
which was re-calculated did not show any differences in serious AEs able which suggest any specific treatment strategy; no therapy and
between monotherapy with adalimumab and combination therapy tight monitoring may be considered in this patient population in the
[RR: 0.88; 95% CI: 0.62–1.26] [Supplementary Figure 25, available maintenance phase.
as Supplementary data at ECCO-JCC online]. Our literature search and data analysis showed that immuno-
suppressants, such as thiopurines and MTX, are recommended to
maintain remission in steroid-dependent patients. As discussed in
Recommendation 2.13. ECCO CD Treatment GL [2019] the previous section, the role of adding MTX or thiopurines to
steroids for the induction of remission is limited. However, after
There is insufficient evidence to recommend either con-
steroids are stopped, maintenance with thiopurines or MTX [ad-
tinuation or withdrawal of anti-TNF therapy in Crohn’s
ministered parenterally] can be an appropriate strategy. The choice
disease patients after achieving long-term remission.
between the two drug classes depends on careful consideration of
Therefore, the decision to continue anti-TNF therapy
patient’s individual characteristics and preferences, safety profile,
should be individualised and potential consequences
and drug availability. There is low-quality evidence supporting the
[risks and benefits] should always be discussed with the
continuation of thiopurines for long-term remission, as studies
patient.
that directly compared long-term treatment with AZA, versus no
treatment or placebo, did not have follow-up times >18  months.
Currently, no randomised controlled study data regarding the with- Clinicians should balance the increased risk of relapse of thiopurine
drawal of anti-TNF therapy in CD patients with inactive disease discontinuation with the increased risk of AEs. Many observational
are available.123 This is true for anti-TNF therapy as monotherapy studies have now reported an increased risk of lymphoma and skin
or when used in a combination therapy regimen. Several observa- cancer for patients treated with thiopurines.136,137 Therefore, regular
tional studies investigated disease course in CD patients following monitoring should be provided to patients continuing thiopurines
withdrawal of anti-TNF therapy. A prospective study followed 115 in the long term. Given the increased risk of AEs due to thiopurines,
patients with CD on combination therapy for at least 1 year, who monoclonal antibodies can also be considered in this particular
discontinued anti-TNF after being in steroid-free clinical remission group of patients.
for at least 6 months. The relapse rates at 12 and 24 months were For CD patients where medically-induced remission has been
43.9% ± 5.0% and 52.2% ± 5.2%, respectively.70 A systematic re- achieved by a biologic agent-based strategy, the use of the same agent
view and meta-analysis included 23 observational cohort studies of is recommended to maintain remission. There is high-quality evi-
920 CD patients and found an overall relapse rate of 44% [95% dence in favour of this approach for anti-TNF agents, vedolizumab,
CI: 36–51%; follow-up range: 6–125 months].124 Furthermore, the and ustekinumab. There is no evidence to support switching to a
relapse rate was 38% [95% CI: 13–63%; 126 patients] at 6 months different monoclonal antibody after treatment induction with a
after discontinuation, 40% [95% CI: 33–48%; 813 patients] at monoclonal antibody that was successful. Longer-term data be-
12  months, and 49% [95% CI: 31–68%; 228 patients; range of yond 52 weeks are required to correctly evaluate the safety profile
follow-up 28–125  months] at >25  months. The meta-analysis in- of monoclonal antibodies, as the relatively small sample size and
cluded studies in children and patients with perianal disease. short follow-up of RCTs does not allow for detection of some AEs,
Following the aforementioned meta-analysis, 10 observational particularly very rare AEs, which may appear in larger and longer
cohort studies reported relapse rates in accordance with the findings observational studies.
of the meta-analysis.125–134 Two of these studies represent extensions The combination of an anti-TNF agent and thiopurines is ef-
of studies included in the meta-analysis.131,132 One study investigated fective and safe both for induction and for maintenance. The risk
the risk of relapse in patients treated with a combination of anti- of lymphoma with infliximab and thiopurines remains very low,
TNF and an immunomodulator, who discontinued either of the two but should be considered19 and adequately addressed with the same
drugs.134 The study found no difference in relapse rates with regards screening and prevention and regular monitoring recommended for
to the withdrawn drug; that is, 17/55 patients [30.9%] on biologic thiopurine therapy.19 Therefore, when remission is achieved with
therapy withdrawal relapsed compared with 4/20 patients [20%] in combination therapy with anti-TNF agents, maintenance with the
which the immunomodulator was withdrawn [p = 0.401]. same biologic agent in monotherapy can be suggested.
16 J. Torres et al.

Routine strategies to monitor and optimise biologic therapy in CD

by a TDM approach are not supported by the available controlled evi- Recommendation 3.2. ECCO CD Treatment GL [2019]
dence, although we recognise the limitations. There is no clear clinical
We suggest adalimumab may be used for induction and
benefit in favour of a proactive or reactive TDM approach, from the
maintenance of remission in complex perianal fistulae in
current data. However, some recent data suggest that a reactive TDM
Crohn’s disease [weak recommendation, very low-quality
approach can result in cost savings also in the era of biosimilars,114
evidence].
potentially justifying the use of such an approach where TDM is avail-
able. TDM can at least be used to guide dose optimisation.
Fistula healing in the subgroup of patients with enterocutaneous and/
There is currently no evidence to give any recommendation re-
or perianal fistulae at baseline [n = 117] was a secondary endpoint of
garding dose reduction of thiopurines during maintenance and there
the CHARM double-blind, placebo-controlled, randomised trial.147
is no evidence on the benefits of withdrawing or continuing biologic
A subsequent post-hoc analysis that focused specifically on the effi-
agents in patients with stable long-term remission, due to the lack of
cacy of adalimumab over time in this subgroup confirmed the super-
controlled studies. As stated in our Consensus, the decision is left to
iority of adalimumab over placebo [RR: 2.57; 95% CI: 1.13–5.84]
the clinicians and should be individualised and discussed with the
for fistula healing after 56 weeks147 [Supplementary Material, SoF
patient, carefully considering the risk of relapse, disease progression

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Table 27, available as Supplementary data at ECCO-JCC online].
and development of complications, and the risks of potential side
Data from CHARM combined with data from the open-label ex-
effects. The long-term management of patients in remission is there-
tension study ADHERE showed that there was no significant in-
fore an important research gap.
crease in serious AEs for patients treated with adalimumab [RR:
1.21; 95% CI: 0.43–3.38].71,148 Evidence was also sought for main-
tenance of fistula healing beyond 56 weeks, resolution of perianal
Section 3 - Perianal Fistulising Disease
sepsis, stoma-free survival, and quality of life; however, data were
Therapeutic management of complex perianal insufficient. Although we strongly recommend infliximab as first-line
fistulising disease biologic therapy in complex perianal CD [Recommendation 3.1],
adalimumab may have a role in patients with previous infliximab
Recommendation 3.1. ECCO CD Treatment GL [2019] failure due to immunogenicity [either primary non-responders or
secondary loss-of-responders]. The open-label CHOICE trial in-
We recommend infliximab for the induction and main- deed demonstrated that complete fistula healing [mainly perianal
tenance of remission in complex perianal fistulae in fistula] could be achieved in 39% of patients [34/88] who initiated
Crohn’s disease [strong recommendation; low quality of adalimumab after infliximab failure.149 This finding has also been
evidence]. reported in a limited case series.150

Infliximab was the first agent shown to be effective in an RCT for Recommendation 3.3. ECCO CD Treatment GL [2019]
inducing closure of perianal fistulae and for maintaining this re-
sponse over 1 year. Complete response [defined as the absence of any In patients with Crohn’s disease and complex perianal
draining fistulae at two consecutive visits at least 4 weeks apart] was fistula there is insufficient evidence regarding the ef-
observed in 4/31 placebo patients [12.9%] versus 29/63 infliximab fect of adding immunomodulators to anti-TNF on fis-
patients [46%] [RR: 3.57; 95% CI: 1.38–9.25138] [Supplementary tula healing [weak recommendation, very low-quality
Material, SoF Table 26, available as Supplementary data at ECCO- evidence].
JCC online]. Subsequently, the ACCENT II trial evaluated the effi-
cacy of infliximab [5 mg/kg every 8 weeks] in a maintenance trial in We identified a single study74 [a pooled analysis of individual
195 patients who had a response [defined as a reduction of 50% of data from the intervention arms only of studies] that com-
draining fistulae in two visits at least 4 weeks apart] at Week 14 after pared anti-TNF versus placebo. Only a pooled effect estimate
open-label induction treatment with infliximab. A complete response was provided [i.e., OR of complete fistula closure in those on
was maintained until Week 54 in 19 of 99 placebo patients [19.2%] immunomodulators vs those not on immunomodulators was 1.10;
versus 33 of 96 infliximab patients [34.4%] [RR: 1.79; 95% CI: 1.10– 95% CI: 0.68–1.78] without further information on numbers of
2.92].139 A meta-analysis of the existing data revealed that infliximab patients by compared group. Therefore, event rates and absolute
was found to be effective in inducing fistula healing [RR: 3.57; 95% risk differences could not be calculated. Furthermore, a retro-
CI:1.38–9.25] and in maintaining clinical fistula healing [RR: 1.79; spective study revealed a hazard ratio of 2.58 [95% CI: 1.16–5.6]
95% CI:1.10–2.92] with no significant risk of serious AEs as com- for fistula healing in favour of the intervention arm [combination
pared with placebo [RR: 1.31; 95% CI: 0.11–15.25] [Supplementary infliximab and immunomodulator] in patients with CD naïve to
Figure 26, available as Supplementary data at ECCO-JCC online]. immunosuppressive therapy.151 There is thus insufficient evidence
A combined evaluation of both RCTs for safety revealed a risk of ser- to support a decision for or against the use of immunomodulators
ious AEs of 18.9% [33/175 patients] in placebo groups versus 11.9% in this context. Further research is necessary to reduce uncertainty
[24/201] in infliximab patients. These data from RCTs have been con- and may be warranted, considering the anticipated costs and side
firmed in several uncontrolled studies.140 effects of combination therapy. In particular, we note the evidence
In clinical practice, infliximab is often used in combination with in luminal CD, where addition of immunomodulators reduces im-
immunosuppressants, antibiotics, and surgical treatment.141–144 Some munogenicity of long-term anti-TNF therapy. We therefore rec-
retrospective data suggest that fistula healing is more likely in pa- ommend further research that should focus on the additional
tients with higher infliximab trough levels, which suggests the need treatment effect of combination therapy and the impact on im-
for personalised dosing in this setting.145,146 munogenicity to anti-TNF agents.
ECCO Guidelines on Therapeutics in Crohn's Disease: Medical Treatment 17

perianal fistulae [Supplementary Material, SoF Table 30, available as

Recommendation 3.4. ECCO CD Treatment GL [2019] Supplementary data at ECCO-JCC online]. Remission at Week 10
was observed in 1/8 [12.5%] placebo patients versus 3/17 [17.6%]
In patients with Crohn’s disease and complex perianal fis-
patients treated with antibiotics [RR: 1.41; 95% CI: 0.17–11.54].156
tula there is insufficient evidence to recommend the use
Complete healing was observed in 3/10 [30%] patients treated
of ustekinumab for fistula healing [weak recommenda-
with ciprofloxacin and 0/8 patients treated with metronidazole.
tion, moderate-quality evidence].
Uncontrolled data or data from studies on combination therapy with
anti-TNF suggest that ciprofloxacin can improve the efficacy of anti-
No randomised trial has directly assessed the role of ustekinumab
TNF in the short term with good safety. However, this combination
in fistula healing. A post-hoc analysis of 238 patients who entered
does not impact on longer-term healing rates.42,157 Despite the lack
the phase 2 CERTIFI and phase 3 UNITI 1/2 studies with fistulae at
of evidence to support their role as monotherapy in closing perianal
baseline has been reported152 [Supplementary Material, SoF Table
fistulae, antibiotics remain indicated and recommended to treat and
28, available as Supplementary data at ECCO-JCC online]. This
control perianal sepsis.
study included only patients with perianal fistulae and did not dif-
ferentiate between simple and complex fistulae. The analysis showed

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a measurable but statistically insignificant effect of ustekinumab for Recommendation 3.7. ECCO CD Treatment GL [2019]
induction of remission [RR: 1.77; 95% CI:0.93–3.37] but no differ-
We suggest against using thiopurine monotherapy
ence in comparison with placebo was found for maintenance of re-
[azathioprine, mercaptopurine] for fistula closure in pa-
mission.153 We also sought evidence for the effect of ustekinumab on
tients with Crohn’s disease and complex perianal fistulae
longer-term maintenance of fistula remission, serious AEs, resolution
[weak recommendation, very low-quality evidence].
of perianal sepsis, stoma-free survival, and quality of life; however,
data were insufficient. Further research is therefore warranted to de-
termine if ustekinumab is beneficial to patients with perianal fistulae. The effect of AZA on fistula healing in complex perianal CD has
been numerically reported in RCTs in 18 patients only.49,52,53,158
A  meta-analysis on this limited group of patients demonstrated
Recommendation 3.5. ECCO CD Treatment GL [2019]
that AZA is not superior to placebo for fistula healing [RR: 2.00;
In patients with Crohn’s disease and complex perianal fis- 95% CI: 0.67–5.93].95 A  fourth study50 reported complete fistula
tula there is insufficient evidence to recommend the use closure in 9/29 [31%] fistulae during MP therapy, in contrast to
of vedolizumab for fistula healing [weak recommenda- 1/17 [6%] in placebo-treated fistulae [Supplementary Material, SoF
tion, low-quality evidence]. Table 31, available as Supplementary data at ECCO-JCC online].
Nevertheless, these data could not be incorporated in the pooled
analysis, as data were reported as number of fistulae closing rather
A post-hoc analysis of 45 patients, who entered the GEMINI 2 study
than number of patients who had complete fistulae closing. With the
with complex perianal fistulae at baseline, demonstrated a trend in
availability of effective anti-TNF agents, the group felt that it would
favour of vedolizumab compared with placebo for fistula healing
be inappropriate to recommend any further randomised, placebo-
[RR: 2.23; 95% CI: 0.57–8.72] although this result was not stat-
controlled, double-blind trial studying the efficacy of AZA in com-
istically significant153,154 [Supplementary Material, SoF Table 29,
plex perianal fistulae.
available as Supplementary data at ECCO-JCC online]. The inter-
pretation of this study was limited by sparse data [only 13 patients
met the endpoint across treatment arms] and specification of fistulae
Key Points for Clinical Practice
type [perianal in only 74% of patients]. Evidence was sought also
for long-term maintenance of clinical fistula healing, serious AEs, This section contains recommendations on the medical treatment of
quality of life, resolution of perianal sepsis, and stoma-free survival; perianal disease. However, the management of complex perianal dis-
however, data were insufficient. The only RCT [NCT02630966]155 ease should be considered together with the concomitant treatment
that compared two different induction schedules of vedolizumab of luminal disease.
[300 mg at Weeks 0, 2, 6, 10, and 14 vs 300 mg at Weeks 0, 2, 6, For the medical treatment of perianal fistulae, no evidence sup-
and 14] was prematurely stopped due to slow recruitment and there- ports the use of monotherapy with antibiotics or thiopurines. The
fore is inconclusive. However, significant differences were observed highest-quality evidence supports the use of infliximab as first choice.
between the two study groups. The efficacy of vedolizumab for fis- In patients refractory or intolerant to infliximab, there is low-quality
tula healing remains an important research gap. evidence to support the use of adalimumab. The current evidence
is too limited to support the use of ustekinumab and vedolizumab
in clinical practice. However, ustekinumab or vedolizumab may be
Recommendation 3.6. ECCO CD Treatment GL [2019] considered in patients where anti-TNFs are ineffective or contra-
indicated and there are no treatment options, especially when con-
We suggest against using antibiotics alone for fistula
comitant luminal disease is present. There is insufficient evidence on
closure in patients with Crohn’s disease and complex
the use of combination therapy [specifically infliximab] combined
perianal fistulae [weak recommendation, low-quality
with thiopurines. However, this can be considered when chosen as a
evidence].
therapy for concomitant luminal disease or for anti-immunogenicity
purposes.
Antibiotics are widely used in the treatment of perianal CD, but Although there is no randomised study that compared the com-
most published studies are uncontrolled.141 To our knowledge, bination of surgical treatment and infliximab with infliximab alone,
there is only one RCT that compared placebo with antibiotics in joint management and approach by IBD clinicians and surgeons is
18 J. Torres et al.

considered the standard of care for treatment of complex perianal Viennot, and Signe Wildt. We would also like to thank the additional reviewers
disease. This is important, since control of sepsis and prevention of of these Guidelines: Giorgos Bamias, Yago Gonzalez Lama, Marietta Iacucci,
perianal infections is necessary before starting any treatment that Anna Valeryevna Kagramanova, Jost Langhorst, Gaetano Luglio, Annick
Moens, Nurulamin Noor, Iago Rodríguez-Lago, Gerhard Rogler, Simone
affects the immune system response. Any immunosuppressive treat-
Saibeni, Carsten Schmidt, Tony Tham, and Andres Yarur.
ment must be stopped in case of onset of septic complications in
patients with IBD.
Author Contributions
5. Conclusion JT, GF, MA, OZ coordinated the project; SB, TL, and MG-L advised on
GRADE methodology, trained the working group members, and performed
These recommendations summarise the current evidence on the med- the analysis of data; GD, TK, JG, TR, AS, and JW coordinated the working
ical management of patients with CD. Several research gaps have groups; all the authors listed contributed to the identification of relevant data
been identified during the revision and analysis of data, which should and data interpretation, and drafted and discussed the final recommendations;
be addressed by further research. Where evidence is lacking or is very all the authors participated in the final Consensus; GF, JT, SB, GD, TK, JG,
weak and evidence-based recommendations cannot be given, ECCO and TR drafted this manuscript; all authors, the ECCO Guideline Committee
provides alternative tools, such as Topical Reviews21,92,135,159–161 or [GuiCom], and the ECCO Governing Board approved the final version of the

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Position Papers.162 We state that Guidelines aim to guide the clin- manuscript.
icians’ decisions with the best evidence available, but it is up to every
clinician to adapt these Guidelines to local regulations and to the
Supplementary Data
patient’s individual characteristics and needs. ECCO will also aim
to disseminate these guidelines by educational activities [i.e., edu- Supplementary data are available at ECCO-JCC online.
cational platforms, ECCO Workshop, e-learning, and e-Guide] and
to support any initiative to integrate ECCO Guidelines into clinical
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