Journal of Crohn's and Colitis, 2022, 179–189

https://doi.org/10.1093/ecco-jcc/jjab177
Advance Access publication October 12, 2021
ECCO Guideline/Consensus Paper

ECCO Guideline/Consensus Paper

ECCO Guidelines on Therapeutics in Ulcerative

Colitis: Surgical Treatment
Antonino Spinelli,a Stefanos Bonovas,b, Johan Burisch,c,

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Torsten Kucharzik,d Michel Adamina,e, Vito Annese,f Oliver Bachmann,g,
Dominik Bettenworth,h Maria Chaparro,i, Wladyslawa Czuber-Dochan,j
Piotr Eder,k, Pierre Ellul,l Catarina Fidalgo,m, Gionata Fiorino,n,
Paolo Gionchetti,o Javier P. Gisbert,i Hannah Gordon,p Charlotte Hedin,q,
Stefan Holubar,r, Marietta Iacucci,s Konstantinos Karmiris,t
Konstantinos Katsanos,u Uri Kopylov,v Peter L. Lakatos,w,
Theodore Lytras,x, Ivan Lyutakov,y Nurulamin Noor,z, Gianluca Pellino,aa,
Daniele Piovani,ab Edoardo Savarino,ac, Francesco Selvaggi,ad
Bram Verstockt,ae, Glen Doherty,af Tim Raine,z, Yves Panisag,
a
Department of Biomedical Sciences, Humanitas University, and Division of Colon and Rectal Surgery, IRCCS
Humanitas Research Hospital, Milan, Italy bDepartment of Biomedical Sciences, and IRCCS Humanitas Research
Hospital, Milan, Italy cGastrounit, Medical Division, and Copenhagen Center for Inflammatory Bowel Disease
in Children, Adolescents and Adults, Hvidovre Hospital, University of Copenhagen, Denmark dDepartment of
Gastroenterology, Lüneburg Hospital, University of Hamburg, Lüneburg, Germany eDepartment of Surgery, Clinic of
Visceral and Thoracic Surgery, Cantonal Hospital Winterthur, Zurich, and Department of Biomedical Engineering,
Clinical Research and Artificial Intelligence in Surgery, Faculty of Medicine, University of Basel, Allschwil, Switzerland
f
Department of Gastroenterology, Fakeeh University Hospital, Dubai, UAE gDepartment of Internal Medicine I, Siloah
St. Trudpert Hospital, Pforzheim, and Hannover Medical School, Hannover, Germany hUniversity Hospital Munster,
Department of Medicine B - Gastroenterology and Hepatology, Munster, Germany iGastroenterology Unit, IIS-IP,
Universidad Autónoma de Madrid [UAM], CIBEREHD, Madrid, Spain jKing’s College London, Florence Nightingale
Faculty of Nursing, Midwifery and Palliative Care, London, UK kDepartment of Gastroenterology, Dietetics and
Internal Medicine, Poznań University of Medical Sciences, and Heliodor Święcicki University Hospital, Poznań,
Poland lDepartment of Medicine, Division of Gastroenterology, Mater Dei Hospital, Msida, Malta mGastroenterology
Division, Hospital Beatriz Ângelo, Loures, Portugal nDepartment of Biomedical Sciences, Humanitas University, and
IBD Center, Humanitas Clinical and Research Center, Milan, Italy oIBD Unit, IRCCS Azienda Ospedaliero-Universitaria
di Bologna DIMEC, University of Bologna, Bologna, Italy pDepartment of Gastroenterology, Barts Health NHS Trust,
Royal London Hospital, London, UK qKarolinska Institutet, Department of Medicine Solna, and Karolinska University
Hospital, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden rDepartment
of Colon & Rectal Surgery, Cleveland Clinic, Cleveland, OH, USA sInstitute of Immunology and Immunotherapy,
University of Birmingham, and Division of Gastroenterology, University Hospitals Birmingham NHS Trust,
Birmingham, UK tDepartment of Gastroenterology, Venizeleio General Hospital, Heraklion, Greece uDepartment of
Gastroenterology and Hepatology, Division of Internal Medicine, University and Medical School of Ioannina, Ioannina,
Greece vDepartment of Gastroenterology, Tel-HaShomer Sheba Medical Center, Ramat Gan, and Sackler Medical
School, Tel Aviv, Israel wDivision of Gastroenterology, McGill University Health Centre, Montreal, QC, Canada, and
1st Department of Medicine, Semmelweis University, Budapest, Hungary xSchool of Medicine, European University
Cyprus, Nicosia, Cyprus yDepartment of Gastroenterology, University Hospital ‘Tsaritsa Yoanna - ISUL’, Medical
University Sofia, Sofia, Bulgaria zDepartment of Gastroenterology, Addenbrooke’s Hospital, Cambridge University
Hospitals NHS Trust, Cambridge, UK aaDepartment of Advanced Medical and Surgical Sciences, Universitá degli Studi

© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved.
179
For permissions, please email: [email protected]
180 A. Spinelli et al.

della Campania “Luigi Vanvitelli”, Naples, Italy, and Colorectal Surgery, Vall d’Hebron University Hospital, Barcelona,
Spain abDepartment of Biomedical Sciences, Humanitas University, and IRCCS Humanitas Research Hospital, Milan,
Italy acDepartment of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy adDepartment
of Advanced Medical and Surgical Sciences, Universitá degli Studi della Campania “Luigi Vanvitelli”, Naples,
Italy aeDepartment of Gastroenterology and Hepatology, University Hospitals Leuven, and Department of Chronic
Diseases, Metabolism and Ageing, TARGID - IBD, KU Leuven, Leuven, Belgium afDepartment of Gastroenterology and
Centre for Colorectal Disease, St Vincent’s University Hospital, Dublin, Ireland agDepartment of Colorectal Surgery,
Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Clichy and Université of Paris, France

Corresponding author: Antonino Spinelli, MD, PhD, Director, Division of Colon and Rectal Surgery, IRCCS Humanitas
Research Hospital and Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve
Emanuele, Milan, Italy. Email: [email protected]

Abstract

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This is the second of a series of two articles reporting the European Crohn’s and Colitis Organisation
[ECCO] evidence-based consensus on the management of adult patients with ulcerative colitis
[UC]. The first article is focused on medical management, and the present article addresses
medical treatment of acute severe ulcerative colitis [ASUC] and surgical management of medically
refractory UC patients, including preoperative optimisation, surgical strategies, and technical
issues. The article provides advice for a variety of common clinical and surgical conditions.
Together, the articles represent an update of the evidence-based recommendations of the ECCO
for UC.

Key Words: Ulcerative colitis [UC]; inflammatory bowel disease [IBD]; surgery

Introduction Materials and Methods

Ulcerative colitis [UC] usually presents as a mild condition, but often The present article is part of the ECCO evidence-based consensus on
leads to life-threatening and systemic complications that require ur- the management of UC and covers the medical treatment of ASUC
gent interventions.1–4 Acute severe ulcerative colitis [ASUC] and and the surgical management of medically refractory moderate and
medically refractory UC represent the main indications for surgery severe UC. The current guidelines, together with those on UC med-
in UC patients.5,6 The first-line treatment of ASUC consists of intra- ical management, are intended to update the previous ECCO re-
venous corticosteroid treatment.7,8 However, up to 30% of patients commendations published in 2017.14,15 A  summary of some of the
fail to respond to conservative treatments and require a colectomy.9 key changes from previous ECCO UC guidelines is presented in the
Refractory UC includes steroid dependency and immunomodulator- Supplementary material, available as Supplementary data at ECCO-
or biologic-refractory disease. Refractory UC is often accompanied JCC online.
by deteriorated patient condition and is a recognised risk factor of The current guidelines followed the Oxford methodology. A de-
poor postoperative outcomes10–12; thus a staged procedure is often tailed description of the methodology used to develop the guidelines
preferred, to improve patient status and minimise postoperative is reported in the Supplementary materials.
complications.13
Despite the increasing availability of new pharmacological
General approach to ASUC and surgical
treatments, multiple attempts at conservative management and
consequent therapeutic failures may affect the condition of pa- management of refractory UC
tients with ASUC and refractory UC and considerably influ- ASUC usually presents as acute episodes of a chronic disease with a
ence postoperative outcomes.11,12 Accordingly, multidisciplinary relapsing-remitting pattern. However, ASUC may be the onset fea-
[including gastroenterologists and surgeons] management of UC ture in up of one-third of UC patients.16 ASUC is associated with a
patients is of crucial importance to identify the best therapeutic 30–40% risk of colectomy after one or more severe exacerbations,
pathway. and 10–20% of patients with ASUC need a surgical intervention at
The European Crohn’s and Colitis Organisation [ECCO] aims to their first admission.16–19 The definition and classification of ASUC
develop a practical guide for the medical and surgical management follow the criteria of Truelove and Witts20 and ECCO, which also in-
of adult patients with UC, based on an interdisciplinary, evidence- clude C-reactive protein [CRP] measurement.15 Patients with ASUC
based approach. The present article is focused on the first-line treat- require immediate hospitalisation. The standard initial therapy
ment of adult ASUC patients and on the surgical management of consists of intravenous corticosteroids.15 However, approximately
refractory adult UC patients, including preoperative assessment and 30% of patients fail to respond to conservative treatments.9 Failure
technical aspects. The following statements are complementary to may be predicted using the Travis criterion,13 which combines the
the guidelines on medical treatment of adult UC patients, which are number of stools after 3 days of corticosteroid therapy and the level
presented in a separate article. of serum CRP. In case of failure, different therapeutic strategies may
ECCO Guidelines on Therapeutics in Ulcerative Colitis 181

be considered. However, after 7  days without significant improve- surgery, perioperative optimisation, surgical approaches, and related
ments, a surgical intervention is highly recommended to avoid the technical strategies.
perioperative complications usually associated with emergent pro-
cedures.21–23 In case of semi-elective surgery, a staged procedure is 1.  Medical Management of ASUC
preferred, including subtotal colectomy with ileostomy during the
first operation, followed by ileal pouch-anal anastomosis [IPAA]
construction, and then a final operation with ileostomy closure.24
1.1.Statement 1.1.
This standard ‘three-step’ approach can be replaced by a modi-
fied two-step approach, starting also with subtotal colectomy but Intravenous corticosteroids as the initial standard treat-
followed by pouch construction, without temporary stoma, thus ment for adult patients with ASUC are recommended,
avoiding the third operation. A detailed flowchart of the staged pro- as this treatment induces clinical remission and reduces
cedures is shown in Figure 1. Since early colectomy in ASUC patients mortality [EL3]
is associated with significant improvements in perioperative out-
comes and is now widely accepted,25,26 we will restrict the focus of
the ASUC guidelines to the medical therapeutic options for treating

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The only randomised controlled trial [RCT] including placebo in the
ASUC and address surgical management exclusively for medically setting of ASUC is the paramount work by Truelove and Witts, who
refractory UC. observed that steroids induced clinical remission and decreased mor-
The surgical management of moderate-to-severe refractory UC tality without increasing serious adverse events.20,31 Risk of bias led
is more varied compared with that of ASUC and there is currently to downgrading of the evidence level from 2 to 3.  No conclusions
less consensus. Since refractory UC is usually managed in an elective could be drawn about the need for surgery, as the authors included
setting, the focus has progressively shifted from sole resolution of derivative ostomies and colectomies without distinguishing the type
symptoms to parallel improvement in functions. Up to 25% of UC of surgery in the report. Since the results of this pivotal study, placebo-
patients require a surgical intervention in their lifetime.27,28 Although controlled trials to clarify these and other aspects would be unethical.
total proctocolectomy may provide a definitive resolution of UC
symptoms, complete removal of the colon and the associated loss
of function may be socially and psychologically unacceptable for 1.2.Statement 1.2.
the patient.29 Successful surgical management may provide the reso-
lution of ongoing symptoms and eliminate the need for continuous Either infliximab or cyclosporine should be used in adult
medical care [including hospitalisations and recurrent transfusions] patients with steroid-refractory ASUC. When choosing be-
and immunosuppressive therapies, while protecting the patient from tween these strategies, centre experience and a plan for
malignancy risk. At the same time, the ideal surgical strategy should maintenance therapy after cyclosporine should be con-
ensure acceptable long-term functional outcomes and minimise peri- sidered [EL3]
operative complications.30 In recent decades, the surgical options for
the treatment of refractory UC have evolved, combining technical ad-
vancements with a more comprehensive management of periopera- RCTs and meta-analyses indicate that infliximab is as effective as
tive pathways. In addition to the medical management of ASUC, cyclosporine in inducing clinical response in adult patients with
the following guidelines also focus on several aspects of the surgical steroid-refractory ASUC (OR [odds ratio]: 1.08; 95% CI [confi-
management of medically refractory UC, including indication for dence interval]: 0.73–1.60], with no significant differences regarding

Single-stage 2-stage Modified-2-stage 3-stage

Restorative procedure

Restorative Restorative Total colectomy Total colectomy

proctocolectomy proctocolectomy
without ileostomy with ileostomy Restorative Restorative
proctectomy proctectomy with
Ileostomy closure without ileostomy ileostomy

Ileostomy closure

Non-restorative Total colectomy

Non-restorative procedure

proctocolectomy
with end ileostomy Non-restorative
proctectomy with
end ileostomy

Figure 1.  A detailed flowchart of the staged procedures for proctocolectomy. Published with permission from Prof. Antonino Spinelli.!
182 A. Spinelli et al.

serious adverse events [OR: 1.78; 95% CI: 0.97–3.27], rate of col-
ectomy at 12  months [OR: 0.76; 95% CI: 0.51–1.14], or in im- 1.4.Statement 1.4.
provement of quality of life [QoL] or mortality [OR: 1.37; 95%
Third-line sequential rescue therapies with calcineurin in-
CI 0.31–6.10].32–34 Colectomy-free survival appeared to be similar
hibitors [cyclosporine or tacrolimus] in ASUC refractory
and also at long-term follow-up [5 years].35 Length of hospital stay
to corticosteroid therapy may delay the need for colec-
appeared to be shorter with infliximab, although this was only ob-
tomy but are associated with high rates of adverse events
served in one post-hoc analysis.36 Quality of evidence was down-
and should only be administered in specialised centres
graded due to imprecision and publication bias.
[EL2a]

1.3.Statement 1.3.
A meta-analysis performed in 2015 found that after sequential
There is currently insufficient evidence to determine the treatment with infliximab followed by calcineurin inhibitors [cyclo-
optimal regimen of infliximab rescue therapy in patients sporine or tacrolimus], 62% [95% CI: 57–68%] and 39% [95% CI:
with ASUC refractory to corticosteroid therapy [EL4] 33–44%] of patients achieved short-term treatment response and re-

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mission, respectively. Colectomy rates were 28% [95% CI: 22–34%]
at 3  months and 42% [95% CI: 36–49%] at 12  months. Adverse
A meta-analysis including five RCTs and 30 retrospective and six events were experienced by 23% [95% CI: 18–28%] of patients,
prospective observational cohort studies reported the colectomy-free including serious infections in 7% [95% CI: 4–10%]. Mortality
survival of ASUC patients after different infliximab induction strat- was observed in 1% [95% CI: 0–2%]. However, this meta-analysis
egies. Overall, colectomy-free survival following infliximab rescue was based on low-quality evidence and thus any definite conclusion
therapy was 79% [95% CI: 75–84%] at 3 months and 70% [95% on appropriate sequence of therapies was not possible.44 Moreover,
CI: 66–74%] at 12 months.37 We did not find RCTs that compared sequential third-line therapy is associated with significant adverse
different induction dosing strategy regimens. A  single pilot RCT events and death.45 Recent preliminary studies have focused on
[that was prematurely terminated] explored the outcomes of dif- tofacitinib in ASUC patients refractory to corticosteroid treatment
ferent infliximab doses.38 Colectomy-free survival at 3 months was and have shown promising results and a good safety profile, but
higher with 5 mg/kg multiple-dose induction compared with 5 mg/ further investigations are needed to confirm its efficacy.46,47 In con-
kg single dose [OR: 4.24; 95% CI: 2.44–7.36; p <0.001], suggesting clusion, third-line therapies with infliximab and calcineurin inhibi-
that initial treatment with multiple 5 mg/kg infliximab doses may be tors may delay, but not prevent, colectomies and should be carefully
superior to single-dose salvage.38,39 balanced with the higher risks of adverse outcomes. Sequential
A retrospective cohort study did not reveal differences in rescue therapy should only be administered at specialised referral
short-term [30 days] or long-term [12 months] colectomy rates be- centres familiar with the use of calcineurin inhibition.
tween ASUC patients treated with accelerated- or standard-dose Venous thromboembolism [VTE]– particularly deep vein throm-
infliximab.40 bosis [DVT] and pulmonary embolism [PE] –is common in UC pa-
Patients with ASUC have a high inflammatory burden, with ac- tients due to multifactorial and disease-related causes,48–53and may
celerated clearance and faecal loss of infliximab that may lead to low lead to significant morbidity and mortality.54–56 The incidence of VTE
concentrations and immunogenicity. Infliximab concentration is also correlates with disease activity49,53,57 and increases in hospitalised
affected by low albumin levels, which are common among ASUC subjects,49 making ASUC patients at a high risk of developing VTE
patients due to malnutrition and protein loss. These considerations among the IBD population. Although several consensus guidelines
may make it reasonable to initiate treatment with intensive dosing support the use of anticoagulation prophylaxis in hospitalised UC
regimens of infliximab. However, it is still unclear whether dose in- patients with active disease,8,58–61 there is still a substantial incon-
tensification will improve clinical outcomes in these circumstances.41 sistency in VTE prophylaxis administration.62 Prophylaxis with low
Eight observational studies including 736 patients] [9–14] re- molecular weight heparin and fondaparinux significantly reduces
ported that 3-month colectomy rates were comparable between the the risk of VTE in hospitalised IBD patients, with minimal side ef-
dose-intensification group [either high-dose or accelerated induc- fects.61,63,64 However, robust evidence and well-designed clinical trials
tion] and the standard induction group [OR: 0.70; 95% CI: 0.39– are lacking on the actual effectiveness of VTE prophylaxis and on
1.27; p = 0.24], although patients in the dose-intensification group the optimal dose regimen for ASUC patients.
had higher mean CRP and lower albumin levels. However, a recent
retrospective propensity score matched cohort study revealed re-
duced short-term, but not long-term, colectomy rates in patients re- 2.  Medical Versus Surgical Management of
ceiving accelerated infliximab dosing.42 Recently, the British Society Refractory Moderate-to-severe UC
of Gastroenterology guidelines recommended accelerated dosing
in patients who have not responded to the standard dose [5  mg/
kg] after 3–5  days.43 Therefore, there is no consensus whether in-
2.1.Statement 2.1.
tensive or standard infliximab dosing regimens are recommended.
Furthermore, most of the studies were low-quality, uncontrolled, Reconstructive surgery may be offered to refractory and
observational cohorts confounded by patient selection bias, hetero- corticosteroid-dependent patients and improves quality
geneity, and imprecision. Thus, the optimal regimen for infliximab of life despite the risk of early and late complications
salvage therapy for ASUC remains unclear. Future RCTs are needed [EL2b]. Proctocolectomy with end-ileostomy is an alterna-
to fill these knowledge gaps and to investigate the role of early thera- tive for some patients and has lower morbidity and com-
peutic drug monitoring in IBD patients treated with infliximab and parable quality of life [EL3a]
dose optimisation.
ECCO Guidelines on Therapeutics in Ulcerative Colitis 183

Five systematic reviews were performed to define the risk of early No data support routine perioperative administration of enteral or
and late complications after restorative proctocolectomy with parenteral nutrition.73 Delaying surgery by 7–14  days should be
IPAA. Early complications [within 30 days after surgery] occurred considered in patients with malnutrition.74 High-quality evidence
in 9–65% of patients, and late complications occurred in 3–55% suggests that iron supplementation is recommended when iron de-
of patients.65,66 Systematic reviews indicate that the most frequent ficiency is present, with the goal of normalising haemoglobin [Hb]
complications were pouchitis [2–50%],30,65–67 wound infection levels and iron stores.15,74
[7–45%],30,65,66 bowel obstruction [2–33%],65,66 ileus [14–30%],66
sepsis [0–20%],30,65–67 anastomotic leak [0.5–10%],30,66 and fis-
tula [0–6%].66 The most common late complications were ileus 3.2.Statement 3.2.
[3–25%],66 faecal incontinence [21–22%],66 pouch loss [0–17%],30,66
Patients taking >20  mg prednisolone for >6 weeks are
chronic pouchitis [10–16%],30,67 Crohn’s-like disease of the pouch
at increased risk of early complications and pouch-
[13%],67 and fistula [0–8%].66 The overall mortality rate after sur-
specific complications. Steroids should be weaned be-
gery was 0.1%.66
fore restorative proctectomy or proctocolectomy, and if
Despite the rates of early and late complications, most patients
this is not possible, surgery should be postponed [EL4].
were satisfied with the surgical outcomes and more than 50% of pa-

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Preoperative thiopurines or cyclosporine do not increase
tients would have preferred an earlier operation.68 Delayed surgery
the risk of postoperative complications [EL3]. Patients on
may increase morbidity, length of stay, and hospital costs.69 A recent
biologics might be at increased risk of developing early
meta-analysis focused on third-line therapies in severe chronic UC
and late pouch-specific complications; three-stage or
showed that, despite short-term improvements, third-line therapies
two-stage modified approaches with deferred pouch con-
only delay the need for colectomy and result in higher rates of com-
struction could be considered under these circumstances
plications.68 Moreover, the overall rate of surgery for patients with
[EL4]. Single-stage restorative proctocolectomy should
UC is approximately 30%30,65,67,68,70 but increases to 53% in steroid-
be avoided in patients receiving biologics [EL5]
refractory UC patients. The most common reasons to perform sur-
gery are persistent malaise,68 poor drug compliance,68 dysplasia or
cancer,30,68 consuming symptoms,30 and willingness to discontinue
constant medical care [e.g., hospitalisations, recurrent transfusions] Low-quality studies reported that patients who have received
or immunosuppressive therapy.30 Three systematic reviews reported >20  mg prednisolone for >6 weeks are at 5-fold increased risk of
that over 90% of patients who had colectomy had a good QoL,68 infectious and short-term pouch-specific complications.15 Steroids
with a happiness score of 10/1030 and a Cleveland global QoL of should be weaned before surgery; if this is not possible, pouch con-
9/10.30 Patients had five to six bowel motions per day68 and one at struction should be postponed.15 Thiopurines or cyclosporine do not
night,30 with a continence over 90%30,68 and full continence of stool increase the risk of postoperative complications.15
and gas up to 80% at 10  years.30 Up to 93.3% of patients had a Patients on biologics are at increased risk of early and post-
functioning pouch at 30 years, with stable QoL scores.71 ileostomy closure pouch-related complications [OR: 4.12; 95% CI:
The studies that compared ileostomy with IPAA were all retro- 2.37–7.15], but study quality is low.75 Given the conflicting evidence,
spective and revealed similar results, using a different QoL score. it would be prudent to avoid single-stage proctocolectomy with ileal
Occasionally the scores obtained in specific domains of health- pouch construction in patients on anti-tumour necrosis factor [TNF]
related QoL differed significantly between the surgical techniques therapies.15
[including body image, travelling, and sexual activity]. Removing
the diseased colon offers a good QoL when compared with medical
treatment in UC patients, with a morbidity ranging between 20% 3.3.Statement 3.3.
and 25%.72 Prophylactic anticoagulation therapy in adult patients
with active UC during hospitalisation is recommended,
3.  Preoperative Optimisation of Refractory considering the high risk of venous thromboembolism
Moderate-to-severe UC [VTE] during UC flares [EL4]

3.1.Statement 3.1. One of the extraintestinal manifestations of UC is venous thrombo-

embolism [VTE], which is higher among UC patients who underwent
Correction of altered body composition and nutrition im- an emergency or elective colectomy [OR: 5.28; 95% CI: 1.93–4.45
balances is advised preoperatively, despite limited evi- and OR: 3.69; 95% CI: 1.30–10.44, respectively] compared with
dence [EL5].There is no evidence to support routine enteral medically responsive UC patients.76
or parenteral nutrition to improve the surgical outcomes Patients with IBD have a 2- to 3-fold increased risk for VTE com-
of patients with UC [EL5]. Iron supplementation is recom- pared with healthy controls and an up to 8-fold increased risk during
mended when iron-deficiency anaemia is present [EL1] a disease flare or hospitalisation.77,78 An observational study with
439 UC patients revealed a thrombosis prevalence of 5%, and half
of the patients developed thrombosis during a UC flare [11% vs.
Nutritional alterations predict poor postoperative outcomes and 1%; OR: 8.0].79
mortality and affect QoL.73,74 Routine perioperative assessment by Among 7078 IBD patients, only 0.6% received post-discharge
a nutritionist should be considered in IBD patients in remission, as anticoagulation prophylaxis and 235 patients [3%] developed
part of multidisciplinary management.74 Even if current evidence is thromboembolic complications. The strongest predictors of VTE
limited, it is advisable to correct undernutrition or overnutrition.73,74 were stoma creation [OR: 1.95; 95% CI: 1.34–2.84] and J-pouch
184 A. Spinelli et al.

reconstruction [OR: 2.66; 95% CI: 1.65–4.29].80 Among 837 IBD Although advanced age is a major consideration in procedure se-
patients, 14 VTE events were reported, of which 79% received lection for patients who are candidates for either procedure, a shared
prophylaxis, but only 36% within 24 h of admission.81 decision-making approach should be used to tailor procedure selec-
A study with 2788 IBD patients reported that pharmacological tion according to the patient’s preference.93
thromboprophylaxis during IBD-related hospitalisation is associated
with reduced risk of post-hospitalisation VTE [hazard ratio: 0.46;
95%CI: 0.22–0.97].82 Patients who received VTE pharmacological 4.2.Statement 4.2.
prophylaxis were more likely to be on the surgical service [75% vs.
IPAA may be performed as a two or three stage pro-
13%; p <0.001].63,83
cedure. Modified two-stage IPAA may be associated with
Several studies suggested that pharmacological prophylaxis does
fewer complications and shorter length of stay than three-
not lead to increased incidence of gastrointestinal bleeding events in
stage or two-stage IPAA in patients with medically refrac-
UC patients.63,84–86 A meta-analysis suggested that heparin adminis-
tory UC operated in expert centres, but more evidence is
tration in patients with UC is safe, with no major bleeding events
needed [EL3]
(the average reported dose was Enoxaparin/100 Anti-Xa IU/kg/day
subcutaneously [s.c.] for 12 weeks).87 The Toronto consensus for

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the management of IBD in pregnancy recommended anticoagulant
thromboprophylaxis during hospitalisation over no prophylaxis.88 A modified two-stage IPAA comprises first a total colectomy with
In conclusion, it is essential to emphasise that there are no estab- end-ileostomy, leaving the rectum in situ, followed by a proctectomy
lished RCTs that have evaluated the efficacy of thromboprophylaxis and ileal pouch-anal reconstruction with ileostomy take-down.
in patients with IBD, due to the incidence of VTE. However, our Patients often undergo total colectomy at a late stage of their dis-
ECCO consensus group determined that given the higher risk of ease and present in an exhausted, catabolic state while being heavily
thrombosis in UC patients with disease flare, VTE prophylaxis medically treated, including with steroids. Hence, the second step is
should be considered over no prophylaxis. typically performed a few weeks to months after colectomy, allowing
time for the patient to recover and for medications to be tapered.
Proctectomy and IPAA construction can then be performed together
4.  Surgical Strategy of Refractory as a modified two-stage approach, thus avoiding a diverting ileos-
Moderate-to-severe UC tomy which requires a third operative step for reversal and is asso-
ciated with additional morbidity.94,95 The modified two-stage IPAA
is may become a standard of care, replacing one-stage, two-stage,
4.1.Statement 4.1. and three-stage IPAA.96–99 Clinical results in adults favour a modi-
fied two-stage approach, with better anastomotic leak rates,99,100
After total proctocolectomy for medically refractory UC, fewer postoperative septic complications, and less small-bowel ob-
IPAA is the procedure of choice, but permanent end- struction101 when compared with two-stage and three-stage IPAA.
ileostomy is also a reasonable option for some patients. A modified two-stage IPAA is also associated with less resource con-
A  shared decision-making approach should be used to sumption and decreased length of hospital stay.98,99 The IPAA leak
tailor procedure selection to the patient’s preference [EL3] rate is approximately 10% with a modified two-stage approach in
expert centres. Functional results of IPAA are affected by the oc-
currence of an anastomotic leak, in particular without a diverting
Although IPAA is the procedure of choice for medically refractory stoma.102 It is therefore crucial to ensure a diligent postoperative
UC patients requiring surgery, both IPAA and total proctocolectomy follow-up, including serial CRP measurements and early investiga-
with end-ileostomy are reasonable options. Total proctocolectomy tion of any suspicion of leak. Indeed, when detected and addressed
with end-ileostomy may be offered to patients with contraindica- early, most leaking IPAAs can be salvaged and long-term pouch
tions to IPAA. These operations result in similar overall short- and function can be preserved.103
long-term complication rates, QoL, and costs. IPAA is associated Pouch-related complications include pouchitis, Crohn’s disease
with a high risk of pouch-related complications and costs. Total of the pouch, cuffitis, and irritable pouch. Among these, pouchitis
proctocolectomy with end-ileostomy is associated with a high risk is the most common complication, occurring in up to 80% of pa-
for ileostomy-related complications and costs. tients after 30 years from the pouch construction.71,104–106 Pouchitis
Overall, the short-term risks of these procedures appear equiva- is commonly diagnosed by endoscopy and histological characterisa-
lent and occur in approximately 30% in each group; IPAA is asso- tion. According to the duration and type of symptoms, pouchitis can
ciated with risk of short-term anastomotic leak, fistula, or stricture, be classified into acute [symptoms resolving within 4 weeks], chronic
and total proctocolectomy is associated with risk of a non-healing [symptoms last >4 weeks], or relapsing [three or more episodes of
perineal wound. The long-term complication profiles for these two pouchitis occur in a year]. Treatment for acute pouchitis includes anti-
procedures are different due to differences in anatomy. IPAA pa- biotic administration, mainly consisting of ciprofloxacin and metro-
tients are at risk for faecal incontinence, pouchitis, fistula formation, nidazole.107–109 However, the evidence of efficacy is low, including
and pouch failure, and total proctocolectomy patients are at risk only one small RCT demonstrating the superiority of ciprofloxacin
for parastomal hernia and ileostomy prolapse.66,89–92 QoL also ap- over metronidazole in terms of symptoms reduction and endoscopic
pears equivalent; in a systematic review of 13 observational studies response.64 An RCT of rifaximin failed to demonstrate a superiority
with 783 IPAA and 820 total proctocolectomy patients, the two pro- compared with placebo,110 and budesonide enemas and metronida-
cedures were comparable in overall health-related QoL.72,92 Patients zole were equally effective for inducing remission.111 Patients with
who undergo total proctocolectomy with end-ileostomy have ile- chronic pouchitis can develop antibiotic-refractory symptoms. Due
ostomy supply-related costs, and patients who undergo IPAA have to persistent and debilitating symptoms they may ultimately develop
costs related to endoscopic surveillance of the pouch.91,92 pouch failure requiring pouch defunctioning and definitive stoma
ECCO Guidelines on Therapeutics in Ulcerative Colitis 185

construction. Several medications have been investigated to induce large, with several meta-analyses in UC reporting benefits in terms of
remission in chronic antibiotic-refractory pouchitis, including bio- short- and long-term morbidity, functional outcomes, cosmesis, and
logic therapy, probiotics, and immunodulators, although the overall QoL.120–125 There is a single RCT including long-term results,126,127 but
quality of evidence is low.112 nationwide data support minimally invasive approaches,120 which
have long been endorsed by expert centres worldwide. Laparoscopy
should be offered for elective and emergent segmental and total col-
5.  Technical Aspects of Surgical Approaches ectomy and for reconstructive surgery. Although desirable, lapar-
for Refractory Moderate-to-severe UC oscopy is not always possible. Patients with previous abdominal
surgery and extensive adhesions or cardiopulmonary instability may
require an open procedure. Lack of surgical expertise may also limit
5.1.Statement 5.1. access to laparoscopy, particularly in the emergent setting or in re-
mote locations. Operative time tends to be greater when a minim-
IPAA may be constructed using either a stapled or a ally invasive approach is chosen, and resource consumption may be
handsewn technique, with comparable functional out- increased.123 It is important to note that a previous open procedure
comes. Thus, the type of anastomosis should be left to does not mandate a second open procedure. For example, a patient

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the surgeon’s discretion [EL2] who had an open colectomy and end-ileostomy for fulminant colitis
should attempt laparoscopic proctectomy and IPAA reconstruction.
Beyond functional outcomes, minimally invasive approaches are also
Overall, stapled and handsewn IPAAs seem to result in compar- associated with better fecundity and pregnancy outcomes.128–130
able complication rates, functional outcomes, and QoL. In a meta-
analysis of four randomised controlled trials including 184 patients
[53% stapled, 43% handsewn], no significant differences were ob- 5.3.Statement 5.3.
served in terms of functional outcomes, sphincter resting pressure,
Although associated with an increased risk of rectal dys-
or squeeze pressures.113 Based on low-quality evidence, the stapled
plasia, cancer, and dysplasia or cancer recurrence, pa-
technique may be more likely to achieve perfect continence [90% vs.
tients with UC and a minimally affected rectum can be
67%; p <0.0001] compared with the handsewn approach.114 Despite
offered the option of an ileo-rectal anastomosis [IRA]
slightly better functional outcomes after stapled anastomosis, overall
[EL4]
QoL appears equivalent between the two groups.114,115
Although handsewn IPAA is more commonly performed in pa-
tients with dysplasia or cancer, the approach does not reduce the
probability of recurrence.115 In a systematic review of observational IRA is associated with better functional outcomes [number of bowel
studies with 43 rectal cancer patients, most of the cases [70%; movements and nocturnal frequency] compared with IPAA.131–134
30 patients] occurred after mucosectomy with handsewn anasto- Failure rates are similar between IRA and IPAA.135,136 IRA failure
mosis, and 30% [13 patients] occurred after stapled anastomosis. rates were estimated at 27.0% [95% CI: 22–32] and 40.0% [95%
Of 28 reported cases of dysplasia, 27 [96%] cases occurred after CI: 33–47] at 10 and 20 years, respectively, and may be decreased
mucosectomy with handsewn anastomosis, and one [4%] occurred with a two-stage procedure approach [OR: 0.10; 95% CI: 0.03–
after stapled anastomosis. The median time to dysplasia or cancer 0.41].137 Two-thirds of secondary proctectomies were performed for
was 10 years.116 In a systematic review of 23 observational studies refractory proctitis, and 20% for rectal neoplasia. Acute proctitis
with 2040 patients, the pooled prevalence rate of neoplasia after occurred in 70% of patients; 76% experienced chronic proctitis.138
IPAA was 1.1% and was equally distributed in the pouch, rectal cuff, IRA may be associated with an increased risk of rectal cancer devel-
and anal transition zones. Previous colorectal dysplasia or cancer, opment,135,139 but this was based on limited and low-quality data.
but not pouchitis or duration of follow-up, were predictive of rectal
cancer or dysplasia,117 indicating that mucosectomy with handsewn Conclusion
anastomosis does not eliminate the risk of subsequent dysplasia
or cancer. The variability in symptoms and clinical manifestations of UC makes it
Due to a paucity of high-quality data, no recommendations difficult to establish a unique and predefined therapeutic pathway; the
can be made with regards to sexual function, strictures, and septic lack of specific protocols may restrict the management of these patients
complications between stapled and handsewn techniques, although to highly specialised centres, thus limiting accessibility to medical care.
stapled IPAA is likely associated with a higher rate of cuffitis.118,119 In addition to continuous updates on novel therapeutic strategies
and technical trainings, the key to successful management of UC pa-
tients is to promote a multidisciplinary approach with close commu-
5.2.Statement 5.2. nication between different IBD specialists, who should remember the
relevant social and economic burden of UC.
Laparoscopic surgery is the preferred approach to patients These guidelines were developed using the Oxford methodology,
with medically refractory UC, as it is associated with lower which combines a robust methodological strategy with a multidiscip-
intra- and postoperative morbidity, faster recovery, fewer linary approach. Whereas each statement was drafted by an expert
adhesions and incisional hernias, shorter hospital length of on the topic, identification of the critical questions and discussion on
stay, improved female fecundity, and better cosmesis [EL2] the retrieved evidence involved all members of the committee, which
allowed for the identification of aspects that may otherwise have
been overlooked.
Laparoscopy is the preferred approach to bowel resection for ex- In addition to the clinical questions addressed in these guidelines,
perienced surgeons. Evidence in favour of this recommendation is we recognise that many other topics would have been worthy of
186 A. Spinelli et al.

discussion. These include early postoperative management of UC provided suggestions on the recommendations and statements: Mariangela
patients and the possibility of implementing an enhanced recovery Allocca [Italy], Michele Carvello [Italy], Gabriele Dragoni [Belgium], Daniela
pathway [with related challenges and advantages] and management Gilardi [Italy], Jost Langhorst [Germany], Lieven Pouillon [Belgium], Iago
Rodríguez-Lago [Spain], Simone Saibeni [Italy], Beatriz Sicilia [Spain].
of pouch-related complications, which are addressed in previous
guidelines.14,15 However, the clinical questions were selected with the
aim of providing relevant updates on neglected topics.
The peculiarity of the clinical questions in these guidelines, par-
Supplementary Data
ticularly in the surgical field, often made it difficult to provide specific Supplementary data are available at ECCO-JCC online.
recommendations. However, the drafting process identified critical
needs and revealed gaps in knowledge, thus laying the groundwork References
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