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ava i l ab l e a t www.sc i enced i rec t . com

Journal of Crohn's and Colitis (2008) 2, 1–23

SPECIAL ARTICLE

European evidence-based Consensus on thediagnosis and management of ulcerative colitis:Definitions and diagnosisE.F. Stange ⁎,1, S.P.L. Travis ⁎,1, S. Vermeire, W. Reinisch, K. Geboes,A. Barakauskiene, R. Feakins, J.F. Fléjou, H. Herfarth, D.W. Hommes,L. Kupcinskas, P.L. Lakatos, G.J. Mantzaris, S. Schreiber,V. Villanacci, B.F. Warrenfor the European Crohn's and Colitis Organisation (ECCO)

Received 23 November 2007; accepted 23 November 2007

KEYWORDSUlcerative colitis;Definitions;Diagnosis;Histopathology;Classification;Activity indices

Contents

1. Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31.2. Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

1.2.1. Distribution of disease (see Section 2.1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.2.2. Active disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.2.3. Remission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51.2.4. Response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51.2.5. Relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51.2.6. Early relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51.2.7. Pattern of relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

⁎ Corresponding authors. Travis is to be contacted at John Radcliffe Hospital, Oxford, OX3 9DU, UK. Tel.: +44 1865 228753; fax: +44 1865228763. Stange, Department of Internal Medicine 1, Robert Bosch Krankenhaus, PO Box 501120, Auerbachstr, 110, 70341 Stuttgart, Germany.Tel.: +49 711 81013404; fax: +49 711 81013793.

E-mail addresses: [email protected] (E.F. Stange), [email protected] (S.P.L. Travis).1 These authors acted as convenors of the Consensus and contributed equally to the work.

1873-9946/$ - see front matter © 2007 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.doi:10.1016/j.crohns.2007.11.001

mailto:[email protected]


http://dx.doi.org/10.1016/j.crohns.2007.11.001

2 E.F. Stange et al.

1.2.8. Steroid-refractory colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51.2.9. Steroid-dependent colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51.2.10. Immunomodulator-refractory colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61.2.11. Refractory distal colitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61.2.12. New patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61.2.13. Alternative therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61.2.14. Complementary therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61.2.15. Expert opinion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

2. Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62.1. Classification according to disease extent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62.2. Classification according to disease severity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

2.2.1. Activity and pattern of disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72.2.2. Choice of index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72.2.3. Clinical and laboratory markers of severity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72.2.4. Remission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

2.3. Classification according to age at onset or concomitant primary sclerosing cholangitis . . . . . . . . . . . . . 82.4. Use of molecular markers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

2.4.1. Serology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82.4.2. Genotyping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

3. Diagnosis and imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83.2. Clinical features and risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

3.2.1. Clinical features of ulcerative colitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83.2.2. Risk factors for ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

3.3. History, examination and diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93.3.1. Medical history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93.3.2. Examination. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93.3.3. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

3.4. Investigation and procedures to establish a diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103.4.1. Initial investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103.4.2. Microbial investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103.4.3. Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113.4.4. Procedures recommended to establish the diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

3.5. Assessment of extent, severity and activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113.5.1. Signs of discontinuous inflammation in ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . 113.5.2. Activity indices in ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123.5.3. Investigations for acute severe colitis on admission . . . . . . . . . . . . . . . . . . . . . . . . . . . 123.5.4. Reassessment of extent and severity of ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

3.6. Endoscopy, ultrasound and colonography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123.6.1. Endoscopic features of ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123.6.2. Abdominal ultrasound and scintigraphy in ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . 133.6.3. Virtual colonography in ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

3.7. Colonic stenosis in ulcerative colitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134. Histopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

4.1. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134.1.1. Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134.1.2. Evaluation of the literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

4.2. Microscopic features — definitions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144.2.1. Crypt architectural abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144.2.2. Epithelial cell abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144.2.3. Inflammatory features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

4.3. Microscopic features — appraisal of the diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154.3.1. Early stage disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154.3.2. Established disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

4.4. Microscopic features — disease activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174.5. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Acknowledgement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

1.2.10. Immunomodulator-refractory colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61.2.11. Refractory distal colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61.2.12. New patient. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61.2.13. Alternative theraphy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61.2.14. Complementary therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61.2.15. Expert opinion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Table 1.1 Levels of evidence and grades of recommendationbased on the Oxford Centre for Evidence Based Medicine (fordetails see http://www.cebm.net/levels_of_evidence.asp#refs)

Level Diagnostic study Therapeutic study

1a Systematic review (SR)with homogeneity of level1 diagnostic studies

Systematic review (SR)with homogeneity ofrandomized controlledtrials (RCTs)

1b Validating cohort studywith good referencestandards

Individual RCT (withnarrow ConfidenceInterval)

1c Specificity is so high that apositive result rules in thediagnosis (“SpPin”) orsensitivity is so high that anegative result rules outthe diagnosis (“SnNout”)

All or none

2a SR with homogeneity oflevel N2 diagnostic studies

SR (with homogeneity )of cohort studies

2b Exploratory cohort studywith good referencestandards

Individual cohort study(including low qualityRCT; e.g., b80%follow up)

2c “Outcomes” research;ecological studies

3a SR with homogeneity of 3band better studies

SR with homogeneity ofcase-control studies

3b Non-consecutive study; orwithout consistentlyapplied referencestandards

Individual case-controlstudy

4 Case-control study, pooror non-independentreference standard

Case-series (and poorquality cohort and case-control studies)

5 Expert opinion withoutexplicit critical appraisal,or based on physiology,bench research or “first

Expert opinion withoutexplicit critical appraisal,or based on physiology,bench research or “first

3ECCO Consensus on UC: Definitions and diagnosis

1. Definitions

1.1. Introduction

Ulcerative colitis is a life long disease arising from aninteraction between genetic and environmental factors, butobserved predominantly in the developed countries of theworld. The precise aetiology is unknownand thereforemedicaltherapy to cure the disease is not yet available. Within Europethere is a North–South gradient, but the incidence appears tohave increased in Southern and developing countries in recentyears.1,2 Patients may live with a considerable symptomburden despite medical treatment (66% describe interferencewith work and 73%with leisure activities3) in the hope that theaetiology of ulcerative colitis will shortly be revealed and acure emerges. Although this is conceivable in the next decade,clinicians have to advise patients on the basis of informationavailable today. Despite randomized trials there will always bemany questions that can only be answered by the exercise ofjudgement and opinion. This leads to differences in practicebetween clinicians, which may be brought into sharp relief bydifferences in emphasis between countries.

The Consensus endeavours to address these differences. TheConsensus is not meant to supersede the guidelines of differentcountries (such as those from theUK,4 or Germany5), which reachbroadly the same conclusions since they are, after all, based onthe sameevidence.Rather, theaimof theConsensus is topromotea European perspective on the management of ulcerative colitis(UC) and its dilemmas. Since the development of guidelines is anexpensive and time-consuming process, it may help to avoidduplication of effort in the future. A European Consensus is alsoconsidered important because an increasing number of thera-peutic trials recruit from Central and Eastern European countrieswhere practice guidelines have yet to be published.

This document sets out the current European Consensus onthe diagnosis andmanagement of UC, reached by the EuropeanCrohn's and Colitis Organisation (ECCO) at a meeting held inBerlin on 20th October 2006. ECCO is a forum for specialists ininflammatory bowel disease from 23 European countries. Likethe initial Consensus on the management of Crohn's disease,6

the current Consensus is grouped into three parts: definitionsand diagnosis; current management; and management ofspecial situations. This first section concerns aims, methodsand definitions of the Consensus, as well as classification,diagnosis, imaging and pathology of UC. The second section oncurrent management includes treatment of active disease,maintenance ofmedically-induced remission and surgery ofUC.The third section on special situations includes pouch disorders,cancer surveillance, pregnancy, paediatrics, psychosomatics,extra-intestinal manifestations and alternative therapy.

The strategy to reach the Consensus involved five steps:
principles” principles”
Grades of recommendationA Consistent level 1 studiesB Consistent level 2 or 3 studies or extrapolations from

level 1 studiesC Level 4 studies or extrapolations from level 2 or 3

studiesD Level 5 evidence or troublingly inconsistent or

inconclusive studies of any level

1. Relevant questions on each of 14 separate topics concern-ing diagnosis and treatment of UC were devised by thechairmen and their working party. The questions werefocused on current practice and areas of controversy in thetask force topic, sent around to the other chairmen to avoidduplication, and then to all 59 participants in the Consensusconference. Participants were asked to answer the ques-tions basedon their experienceaswell as evidence from theliterature (Delphi procedure).7

2. In parallel, the working parties performed a systematicliterature search of their topic with the appropriate keywords using Medline/Pubmed and the Cochrane database,as well as their own files. The evidence level (EL) wasgraded (Table 1.1) according to the Oxford Centre forEvidence Based Medicine.8

3. Provisional guideline statements on their topic were thenwritten by the chairmen, based on answers to the question-naire as well as the literature evidence and were circulated

http://www.cebm.net/levels_of_evidence.asp#refs

http://www.cebm.net/levels_of_evidence.asp#refs

Table 1.3 Disease activity in ulcerative colitis, adaptedfrom Truelove and Witts'13

Mild Moderate ‘inbetweenmild andsevere’

Severe

Bloody stools/day b4 4 or more if ≥6 andPulse b90 bpm ≤90 bpm N90 bpm orTemperature b37.5 °C ≤37.8 °C N37.8 °C orHaemoglobin N11.5 g/dL ≥10.5 g/dL b10.5 g/dL orESR b20 mm/h ≤30 mm/h N30 mm/h oror CRP Normal ≤30 mg/L N30 mg/L

Table 1.4 Mayo score [14,15 and www.gastrojournal.org for


first among the working party and then among theparticipants.

4. The working parties then met in Berlin on the 20 October2006 to agree the statements. Participants gathered underthe Chairmanship of EF Stange and SPL Travis to agree thefinal version of each guideline statement. Technically thiswas donebyprojecting the statements and revising themonscreen until a Consensus was reached. Consensus wasdefined as agreement by N80% of participants, termed aConsensus Statement and numbered for convenience in thedocument. Each recommendation was graded (RG) accord-ing to the Oxford Centre for Evidence Based Medicine,8

based on the level of evidence (Table 1.1).5. The final document on each topic was written by the

chairmen in conjunction with their working party. Con-sensus guideline statements in bold are followed bycomments on the evidence and opinion. Statements areintended to be read in context with qualifying commentsand not read in isolation. The final text was edited forconsistency of style by SPLTravis and EF Stangebeforebeingcirculated and approved by the participants. In some areasthe level of evidence is generally low, which reflects thepaucity of randomized controlled trials. Consequentlyexpert opinion is included where appropriate.

1.2. Definitions

Common agreement has been reached by ECCO aboutfrequently used terms. While the significance of some terms(such as ‘early-’ or ‘pattern of relapse’) is undetermined, suchterms reflect clinical decision-making (such as when to startimmunomodulators) and are considered helpful as a conse-quence. The arbitrariness of some of the definitions isrecognised, but the Consensus considers it useful to agree theterminology.

Ulcerative colitis (UC) is a chronic inflammatory conditioncausing continuous mucosal inflammation of the colon with-out granulomas on biopsy, affecting the rectum and a variableextent of the colon in continuity, which is characterised by arelapsing and remitting course.9

Colitis yet to be classified is the term best suited for theminority of cases where a definitive distinction between UC,Crohn's disease, or other cause of colitis cannot be madeafter the history, endoscopic appearances, histopathology ofmultiple mucosal biopsies and appropriate radiology havebeen taken into account.9,10

Indeterminate colitis is a termpreserved for pathologists todescribe a colectomy specimenwhich has overlapping features

Table 1.2 Distribution of ulcerative colitis (from9)

Term Distribution Description

E1 Proctitis Involvement limited to the rectum (i.e.proximal extent of inflammation is distalto the rectosigmoid junction)

E2 Left-sided Involvement limited to the proportion ofthe colon distal to the splenic flexure(analogous to ‘distal’ colitis)

E3 Extensive Involvement extends proximal to thesplenic flexure, including pancolitis

of ulcerative colitis and Crohn's disease.10,11 It has distinctprognostic factors related to further surgery (Section 7.5.7,first following paper in same issue).

1.2.1. Distribution of disease (see Section 2.1)The Montreal classification (Table 1.29) for defining thedistribution of disease was favoured by 52/59 participants.This is taken to mean the maximal, macroscopic extent ofdisease at colonoscopy, since the long-term prognosis in thepast has used the extent of disease as defined by bariumenema. The implications of more extensive microscopicdisease are not understood. The poor correlation betweenmacroscopic andmicroscopic extent of disease (kappa=0.39) isrecognised.10 So too is the limitation of an extent-basedclassificationwhen theextent varies over time, underlining thedynamic nature of inflammatory bowel disease.12

1.2.2. Active diseaseFor the purposes of this Consensus, clinical disease activity isgrouped into remission, mild, moderate and severe. Precisedefinitions of disease activity are appropriate, since confu-sion arises if the terms are used to refer only to the least,intermediate or most severe third of cases that the physiciancan recall at the time. Among Consensus participants, 31/59considered Truelove and Witts' criteria useful in clinicalpractice (summarized, Table 1.313), in conjunction with sig-moidoscopy to confirm active colitis.

16/59 favoured the Mayo score (Table 1.4),14 with itsmodifications.15 The value of the different indices for thepurpose of clinical trials is beyond the scope of the Consensus,

full details]

Mayoindex

0 1 2 3

Stoolfrequency

Normal 1–2/dayNnormal

3–4/dayNnormal

5/dayNnormal

Rectalbleeding

None Streaks Obvious Mostly blood

Mucosa Normal Mildfriability

Moderatefriability

Spontaneousbleeding

Physician'sglobalassessment

Normal Mild Moderate Severe

http://www.gastrojournal.org


but has recently been reviewed.15 ECCO recognises the needto validate clinical and endoscopic scoring systems.

The Montreal classification (Table 1.5)9,10 is largely basedon Truelove and Witts' criteria, since this reflects clinicalpractice.

Severe colitis (or ‘acute severe colitis’) is preferred to‘fulminant’ colitis, because the term ‘fulminant’ is ill-defined.It was coined in 1950 when it referred to a single attack goingon to death within 1 year,16 which no longer has relevancetoday. Severe colitis defined according to Truelove and Witts'criteria (Table 1.3 and Section 5.1, first following paper insame issue) are easy to apply in outpatients, determine acourse of action (hospital admission for intensive treatment)and anoutcome (only 70% respond to intensive therapy). Thesecriteria are recommended for identifying acute severe colitisby The American College of Gastroenterology (ACG)17 and theAssociation of Coloproctology of Great Britain and Ireland(ACPGBI),18 as well as ECCO.

Moderate colitis has become necessary to distinguish frommildly active disease, because the efficacy of some treatmentsmay differ (Section 5, first following paper in same issue). Thesimplest clinical measure to distinguish moderate from mildlyactive colitis is the presence of mucosal friability (bleeding onlight contact with the rectal mucosa at sigmoidoscopy). Thetechnique of assessing mucosal friability at flexible sigmoido-scopy has yet to be standardised. One approach is to applysufficient pressure on themucosawith closed biopsy forceps tocreate a dimple, maintain the pressure for 3 s and then definefriability if bleeding occurs from the pressure point. This hasyet to be validated.

1.2.3. RemissionRemission is defined as complete resolution of symptoms andendoscopic mucosal healing (Section 2.2.4). Combiningclinical and endoscopy is appropriate for clinical trials,15,19

but remission rates vary by as much as two-fold depending onthe definition of remission used in the trial.20 In clinicalpractice, 33/59 participants agreed that ‘remission’meant astool frequency ≤3/day with no bleeding and no urgency.Remission defined by individual patients has an 86% sensitiv-ity and 76% specificity for a regulatory-defined remission(absence of visible blood and absent mucosal friability),indicating that sigmoidoscopy to confirm mucosal healing isgenerally unnecessary in practice.21

Table 1.5 Montreal classification of disease activity inulcerative colitis9

S0 S1 S2 S3

Remission Mild Moderate Severe

Stools/day Asymptomatic ≤4 N4 ≥6 andBlood May be

presentPresent Present

Pulse Allnormal

Minimal,or nosigns ofsystemictoxicity

N90 bpm orTemperature N37.5 °C orHaemoglobin b10.5 g/dL orESR N30 mm/h

1.2.4. ResponseResponse is defined as clinical and endoscopic improvement,depending (for the purpose of clinical trials) on the activityindex used. In general, this means a decrease in the activityindex of N30%, plus a decrease in the rectal bleeding andendoscopy subscores, but there are many permutations.15

1.2.5. RelapseThe term relapse is used to define a flare of symptoms in apatient with established UC who is in clinical remission, eitherspontaneously or after medical treatment. In the Consensus,47/59 considered rectal bleeding an essential component ofrelapse, and 29/59 believed that a combination of rectalbleeding with an increase in stool frequency and abnormalmucosa at sigmoidoscopy was necessary to define relapse. Inclinical trials, the criteria for relapse should be predefinedwith the score that is being used for an individual study.15

1.2.6. Early relapseAn arbitrary, but clinically relevant period of b3 months afterachieving remission on previous therapy defines earlyrelapse. The therapeutic significance needs to be defined.

1.2.7. Pattern of relapseRelapse may be infrequent (≤1/year), frequent (≥2 relapses/year), or continuous (persistent symptoms of active UCwithouta period of remission).22 Although the terms are arbitrary, theyare considered clinically relevant. An alternative approach thatdefines disease activity over a 5 year period has been proposed(Section 6.1.2, first following paper in same issue), but thisseems more relevant to epidemiological studies, since whatmatters for everyday practice is what is likely to happen in thenext year. The prognostic significance needs to be determined.Nevertheless, care should be taken to distinguish betweenterms that describe disease activity at a point in time and thosethat describe the longitudinal pattern (or ‘behaviour’) of thedisease (Sections 1.2.2 and 2.2.1). The term ‘chronic activedisease’ has been used in the past to define a patient who isdependent on, refractory to, or intolerant of steroids, or whohas diseaseactivity despite immunomodulators. Since this termis ambiguous it is best avoided. Instead, arbitrary, but moreprecise definitions are preferred, including steroid-refractoryor steroid-dependence.

1.2.8. Steroid-refractory colitisPatients who have active disease despite prednisolone up to0.75 mg/kg/day over a period of 4 weeks. This was agreed by45/58 participants, is consistentwith the definition for steroid-refractory Crohn's disease6 and others.15 The definition ishowever likely to evolve, with a reduction in the duration ofsteroid therapy as the threshold for biologic therapy changes.

1.2.9. Steroid-dependent colitisPatients who are either

i) unable to reduce steroids below the equivalent of pre-dnisolone 10 mg/day within 3 months of starting steroids,without recurrent active disease, or

ii) who have a relapse within 3 months of stopping steroids.

This was agreed by 52/58 participants and is consistentwith the definition for steroid-dependent Crohn's disease,6

Table 2.1 Endoscopic scores for ulcerative colitis commonly used in clinical trials

Score 0 1 2 3

Baron et al.156 Normal: matt mucosa,ramifying vascularpattern clearly visible,no spontaneous bleeding,no bleeding tolight touch

Abnormal,but non-haemorrhagic:appearancesbetween 0 and 2

Moderately haemorrhagic:bleeding to light touch,but no spontaneous bleedingseen ahead of the instrumenton initial inspection

Severely haemorrhagic:spontaneous bleedingseen ahead of instrumentat initial inspection andbleeds to light touch

Schroeder etal.158

Normal or inactive disease Mild (erythema,decreasedvascular pattern,mild friability)

Moderate (marked erythema,absent vascular pattern,friability, erosions)

Severe (spontaneousbleeding, ulceration)

Feagan et al.159 Normal, smooth, glisteningmucosa, with vascularpattern visible; not friable

Granular mucosa;vascular patternnot visible; notfriable; hyperaemia

As 1, with a friable mucosa,but not spontaneouslybleeding

As 2, but mucosaspontaneously bleeding


although an alternative definition of relapse within 30 daysof completing a course of steroids, or steroids at a dose of15–25 mg/day for at least 6 months has been proposed.15 Aswith steroid-refractoriness, the definition is likely to evolveas the threshold for biologic therapy changes.

The ECCO definition of steroid-dependence requires thatthe total duration of steroids does not exceed 3months beforea threshold equivalent to prednisolone 10 mg/day is reached.Patients are still considered steroid-dependent if they relapsewithin 3 months of stopping steroids. Although these limits arearbitrary, they serve as guidance for clinical practice and maybe used for uniformity in clinical trials. The aim should be towithdraw steroids completely.

1.2.10. Immunomodulator-refractory colitisPatients who have active disease or relapse in spite ofthiopurines at an appropriate dose for at least 3 months (i.e.azathioprine 2–2.5 mg/kg/day or mercaptopurine 0.75–1mg/kg/day in the absence of leucopenia). The definition isarbitrary, but has increasing clinical relevance when decidingon the place of biological therapy or surgery.

1.2.11. Refractory distal colitisDefined as persistent symptoms due to colonic inflammationconfined to the rectum (proctitis), or left side of the colon (morecommonly the rectosigmoid colon), despite treatment with oraland topical steroids for 6–8 weeks. This represents a commonclinicaldilemma,althoughwhether it isa separateentity isunclear.

1.2.12. New patientA patient with active UC presenting at, or shortly afterdiagnosis, with no previous therapy for UC.

1.2.13. Alternative therapyOne that is used in place of conventional medicine.

1.2.14. Complementary therapiesSimilar treatments used alongside conventional medicine(see section on Alternative therapies for comment).

1.2.15. Expert opinionThe term ‘expert’ is used here to refer to the opinion of thespecialists in inflammatory bowel disease representing multi-

ple disciplines from 23 European countries who contributed tothe ECCO Consensus. In some sections opinions from individualmembers of other expert bodies were obtained, includingindividuals of the European Society of Pathology (ESP) workinggroup on Digestive Diseases, the European Society of Gastro-intestinal and Abdominal Radiology (ESGAR) and the EuropeanSociety of Paediatric Gastroenterology Hepatology and Nutri-tion (ESPGHAN).

2. Classification

2.1. Classification according to disease extent

ECCO Statement 2AThe extent of ulcerative colitis influences the pa-tient's management. Disease extent influences thetreatment modality and determines if oral and/ortopical therapy is initiated [EL1b, RG B]. Diseaseextent influences start and frequency of surveillance[EL2, RG B]. Therefore, a classification according toextent of disease is recommended [EL5, RG D].The preferred classification is an endoscopic classifi-cation as outlined in the Montreal classification intoulcerative proctitis (limited to the rectum), left-sidedcolitis (up to the splenic flexure) andextensive colitis,and by maximal extent upon follow up [EL5, RG D]

There are several reasons why patients with ulcerativecolitis (UC) should be classified according to disease extent.First, the extent of inflammation will influence the patient'smanagement and influence the choice of delivery system for agiven therapy. Indeed, the location and extent of the colitiswill determine if oral and/or topical therapy is initiated. Forinstance, topical therapy in the form of suppositories (forproctitis) or enemas (for left-sided colitis) is often the first linechoice, but oral therapy — often combined with topicaltherapy is appropriate for extensive colitis (beyond the splenicflexure) [EL1b, RG B]. Second, the extent of colitis influencesthe start and the frequency of surveillance [EL2, RG B]. In the


population-based study from Sweden,23 extent of disease wasone of the risk factors for development of colorectal cancer in3117 UC patients followed up from 1 to 60 years after diag-nosis. Whereas no increased relative risk (RR) was attributedto disease confined to the rectum, the RR for left-sided colitisand extensive colitis (previously called pancolitis) were 2.8(95%CI 1.6–4.4) and 14.8 (95%CI 11.4–18.9) respectively.Therefore, patients with left-sided and extensive colitis aregenerally advised to have surveillance colonoscopy from 8 to10 years after symptom onset, but patients with proctitis donot need surveillance (Section 9.2, second following paper insame issue). The contribution of disease extent at diagnosis tothe risk of malignancy has been confirmed more recently bythe EC-IBD study group.24

Once agreed that classification according to diseaseextent is important, the next question is which classificationbest to use? The Consensus group agreed that the preferredclassification is an endoscopic classification into proctitis,left-sided colitis and extensive colitis (beyond the splenicflexure), as defined by the Montreal Working Group on theMolecular classification of IBD9,10 (Section 1.2, Table 1.2). Afourth extent-group of proctosigmoiditis was abandoned,because it lacks any scientific background and does not havedirect therapeutic consequences.

2.2. Classification according to disease severity

ECCO Statement 2BClassification of ulcerative colitis based on diseaseseverity is useful for clinical practice and dictatesthe patient's management [EL1b,RG B]. Disease se-verity influences the treatment modality and deter-mines if no, oral, intravenous or surgical therapy isinitiated. Indices of disease severity have not beenadequately validated. Clinical, laboratory, imagingand endoscopic parameters, including histopathol-ogy assist physicians in patients' management [EL 2,RG B]. There is no fully validated definition of remis-sion. The best way of defining remission is acombination of clinical parameters (i.e. stool fre-quency ≤3/day with no bleeding) and a normalmucosa at endoscopy [EL5, RG D] (majority vote)

2.2.1. Activity and pattern of diseaseIn a population-based study from Copenhagen County,Langholz et al. showed that approximately 50% of patientswill be in clinical remission every year at any time.25 How-ever, the cumulative probability of a relapsing course after25 years of follow up amounted to 90%. The disease activityin the first 2 years after diagnosis indicated (with 70–80%probability) an increased probability of 5 consecutive yearsof active disease and was therefore judged to be a goodparameter to predict the future pattern of disease. This is ahelpful practical point to be used by clinicians when advisingpatients and making management decisions.

A distinction should be made between disease activity at apoint in time (remission, mild, moderate, severe) and theresponse of disease to treatment (using terms such as 5-ASA

or steroid responsive, steroid-refractory, biologic dependentetc.). The two should not be confused by sloppy terminologythat describesmildly active disease that is steroid-dependentas ‘severe’. The consequences (biologic therapy, colectomy)may indeed be considered ‘severe’, but disease activityremains mild. See also Section 3.5.

2.2.2. Choice of indexA classification of UC based on disease activity and severity isimportant because it influences patient's management. Theseverity of the inflammation will be determined if notherapy, oral therapy, intravenous or surgical therapy isinitiated in a given patient. Over the years, many diseaseactivity indices or criteria have been proposed (see Section1.2.2 and Ref. 15 for a review), but none has beenadequately validated. The Consensus recognises the needfor validated clinical and endoscopic indices that relate tooutcome or treatment decisions. Although modifications ofthe original Truelove and Witts' criteria (Section 1.2.1, Table1.3) are used in daily practice, the modified Mayo score(Section 1.2.1, Table 1.4) is used more frequently in currentclinical trials.15 For clinical practice, the Consensus groupjudged that a combination of clinical features, laboratoryfindings, imaging modalities and endoscopic parameters,including histopathology will all assist physicians in theirpatients' management. Endoscopic scoring is illustrated inSection 3.5 and Table 2.1. There is a need for systematicstudy of this area.

2.2.3. Clinical and laboratory markers of severityAmong objective clinical features, bloody stool frequency,body temperature and heart rate are good predictors ofoutcome. Laboratory markers have been studied intensivelywith varying degrees of success. The widely used acute phaseprotein C-reactive protein in this respect is a less goodmarker for assessing disease activity in UC than Crohn'sdisease, except for acute severe colitis, where it hasestablished value in both adults and children.26–28 A raisedCRP N45 mg/L at day 3 following hospital admission forsevere colitis together with more than 8 stools a day is highlypredictive for need for colectomy (Section 5.2.5, firstfollowing paper in same issue). Other positive (erythrocytesedimentation rate, serum procalcitonin29) or negative(albumin) acute phase proteins have been studied, butnone has demonstrated clear superiority (for review seeRef. 30). More recently, faecal markers have demonstratedpromising results. The most studied markers are faecalcalprotectin and lactoferrin, but elastase and the morerecent marker S100A12 have also shown accuracy atdetecting colonic inflammation.31–35 It must be stressedhowever that none of these markers is specific for UC, sincethey merely represent colonic inflammation with an influx ofneutrophils into the gut mucosa, with subsequent sheddingof their granules into the gut lumen.

2.2.4. RemissionAs with the definition of disease activity, there has also notbeen a fully validated definition of remission. The Consensusgroup agreed that the best way of defining remission is acombination of clinical parameters (stool frequency≤3/daywith no bleeding) and normal or quiescent mucosa at endo-scopy (majority vote, Section 1.2.3).20


2.3. Classification according to age at onset orconcomitant primary sclerosing cholangitis

ECCO Statement 2CA classification of UC according to age at onset isnot useful [EL2; RG C]. Classification of UCaccording to the concomitant presence of PSC isimportant because it influences patients' manage-ment (surveillance) [EL2; RG C]

A classification according to age at onset is not usefulbecause it does not affect patient's management. All currentavailable therapies for UC have shown equal efficacy in childrenwith young age at onset compared to adults. The risk of colo-rectal cancer in patients with the onset of UC in childhoodalmost certainly reflects the duration of disease (Section 9.1.2,second following paper in same issue). However, concomitantprimary sclerosing cholangitis (PSC) is an important feature totake into account when giving care to patients with UC given itsincreased associated risk for colorectal cancer.23,36 Thisinfluences decisions on surveillance colonoscopy (Sections9.1.2 and 9.2.4, second following paper in same issue).

2.4. Use of molecular markers

ECCO Statement 2DNo evidence-based recommendation can be madeto implement the routine clinical use of molecularmarkers (genetic, serologic) for the classificationof UC patients [EL2, RG C]

2.4.1. SerologyA number of (auto)antibodies have been described in UCpatients, of which the atypical perinuclear anti-neutrophilcytoplasmatic antibodies (pANCAs) are best known. PositivepANCA serology is found in approximately 50–60% of pa-tients, although large variability exists due to differences inmethodology.37,38 Overall, pANCA has shown good accuracy todifferentiate CD from UC,39–41 but their sensitivity is far fromhigh enough to justify their use in diagnosis. These antibodiesalso lack accuracy in patients with colitis yet to be classified,where these markers would be of greatest clinical value.42 Anumber of other antimicrobial antibodies as ASCA, OmpC, I2,cBir anti-flagellin, ALCA, ACCA, are found mainly in patientswith Crohn's disease.43–46

2.4.2. GenotypingThe very active field of IBD genetics has led to the iden-tification of several genes, most of which are implicated in asusceptibility to Crohn's disease, but some also linked to UC.TheHLA region is without any doubt the regionmost associatedwith UC,47 but the Interleukin-23 Receptor (IL23R) gene onchromosome 1,48 the DLG5 gene on chromosome 10,49 theMultidrug Resistance gene (MDR)-1 and the Toll like Receptor(TLR) genes, have shown associations with UC.50–58 Since UCis a complex multifactorial disease, the disease-associatedmutations in these genes will never be sufficient to cause

disease, nor will the absence of mutations be a guarantee ofremaining free of disease. Therefore, testing for these geneticvariants is not recommended for clinical purposes.

3. Diagnosis and imaging

3.1. Introduction

Ulcerative colitis (UC) primarily presents in late adolescenceand early adulthood, although the diagnosis may be made atany age. A small peak in incidence has been demonstrated insome populations after the fifth decade of life.59 Ulcerativecolitis appears to affect both sexes equally. The inflammationcharacteristically commences in the rectum and extendsproximally in a continuous, confluent and concentric mannerto affect a variable extent of the colon, or its entire mucosalsurface. The definitions and classification of the extent of UCare covered in Sections 1.1 and 2.1 (Table 1.2).9 The proximalextent of inflammation may progress or regress over time, butafter disease regression the distribution of inflammation tendsto match the extent of previous episodes in the event ofrelapse. The view that UC represents continuous colonic in-flammation has, however, been challenged by reports of arectal sparing variant and peri-appendiceal patchy inflamma-tion.60 Symptoms dependon the extent and severity of disease,extra-intestinal manifestations and concurrent therapy.Enteric pathogens may alter the clinical presentation.

3.2. Clinical features and risk factors

3.2.1. Clinical features of ulcerative colitis

ECCO statement 3ASymptoms of ulcerative colitis are dependent uponextent and severity of disease, and most commonlyinclude bloody diarrhoea, rectal bleeding, and/orrectal urgency. Nocturnal defaecation is also oftenreported. Systemic symptoms of malaise, anorexia,or fever are features of a severe attack [EL5, RG D]

The primary presenting symptom of ulcerative colitis isvisible blood in the stools and is reported by more than 90% ofpatients. Associated symptoms generally reflect the en-doscopic severity of the disease as a measure of mucosaldamage and may differ according to disease extent.61–71

Loose stools (or a decrease in stool consistency) formore thansix weeks differentiates UC frommost infectious diarrhoea.72

Patients with extensive active UC present with chronicdiarrhoea almost invariably associated with rectal bleeding,or at least visible blood in the stools. Such patients alsodescribe rectal urgency, tenesmus, passage of mucopurulentexudates, nocturnal defaecation and crampy abdominal pain,or ache over the left iliac fossa prior to and relieved bydefaecation. In contrast, patients with proctitis usuallypresent with rectal bleeding, urgency, tenesmus, andoccasionally severe constipation.64,66 Anal and minor peria-nal lesions may complicate severe diarrhoea, but althoughsimple fistulae may occasionally occur in UC, recurrent orcomplex perianal fistulae should always raise the suspicion ofCrohn's colitis.


The onset of UC is usually insidious and symptoms are oftenpresent for weeks or even months before medical advice issought. The disease may present with intermittent episodesof symptoms or as a severe attack (in about 15%) with sys-temic symptoms includingweight loss, fever and tachycardia,or even nausea and vomiting.73 Extra-intestinal manifesta-tions, especially an axial or peripheral arthropathy, episcler-itis and erythema nodosum may accompany the presentationin about 10% and rarely precede intestinal symptoms.74

Thromboembolism is more frequent in UC than the generalpopulation, but is generally associated with active diseaseand pancolitis.75

3.2.2. Risk factors for ulcerative colitis

ECCO statement 3BSmoking exerts a universal protective effectagainst developing UC and is associated with amilder course of disease [EL2b, RGB]. Appendi-cectomy has been shown to provide some protec-tion against subsequently developing UC and inreducing its severity if performed for ‘true’appendicitis at a younger age [EL2b, RGB].The use of non-selective NSAIDs is probablyassociated with increased risk for exacerbatingUC [EL2b, RGB]. Short-term treatment with COX-2inhibitors is probably safe [EL1b, RGB]. A familyhistory of CD or UC increases the risk fordeveloping UC in another family member [EL2b,RGB]

Active tobacco smoking has a protective effect on thedevelopment and severity of UC.76,77 In contrast, ex-smokershave about a 70% greater risk of developing the disease, whichis often more extensive and refractory than in those who havenever smoked. Rates of hospital admission and colectomyare also higher in ex-smokers than in never-smokers.78,79

Improvements in symptoms and amilder courseof diseasehavebeen reported in ex-smokers who resume smoking,79,80 butthe effect is inconsistent. Smoking may also prevent thedevelopment of primary sclerosing cholangitis (PSC), orpouchitis after colectomy and ileal pouch anal anastomosis,but this too has been challenged.81–83

Cohort studies and meta-analysis have suggested thatappendicectomy performed for true appendicitis at an earlyage may be protective against the onset and subsequentseverity of UC. A 69% risk reduction has been reported forappendicectomy, although a Danish cohort study failed toconfirm this.59,84–88 The protective effect of appendicectomyis additional to that of smoking, but does not appear toprotect against the development of PSC.89 When appendi-cectomy is performed after the onset of ulcerative colitis, theeffect (if any) on the course of the disease is far less clear.

Non-selective non-steroidal anti-inflammatory drugs(NSAIDs) appear to carry a significant risk of exacerbatingulcerative colitis. The magnitude of such risk has never beenadequately determined and it is unclear whether all patientsare affected to the same degree.90–93 In contrast, prelimin-ary evidence from open-label studies and a double-blind

controlled trial suggest that short-term treatment withselective COX-2 inhibitors is safer.93,94 Nonetheless, pro-longed usage is best avoided because of potential adverseeffects on other organ systems.

First-degree relatives of patients with UC have a 10–15-fold risk of developing the disease.95 In a population-basedDanish cohort study, the relative risk for developing UCwas 10amongst relatives with the disease.96 In other terms, the lifetime risk of UC for a first degree relative is around 5%, or a 95%chance of not developing the disease, which may helpreassure a parent with UC concerned about the risk to theirchildren. In familial cases of UC there is a slight female pre-ponderance and younger age of onset compared to sporadiccases.95,97

3.3. History, examination and diagnosis

3.3.1. Medical history

ECCO statement 3CA full medical history should include detailedquestioning about the onset of symptoms, particu-larly recurrent episodes of rectal bleeding or bloodydiarrhoea, urgency, tenesmus, abdominal pain,incontinence, nocturnal diarrhoea, and featuresof extra-intestinal manifestations. Recent travel,food intolerances, contact with enteric infectiousillnesses, medication (including antibiotics andnon-steroidal anti-inflammatory drugs), smokinghabit, sexual practice, family history of IBD andprevious appendicectomy should be explored [EL5,RG D]

The diagnosis of UC is suspected from the clinicalsymptoms (Section 3.2.1). Infectious or drug-inducedforms of colitis should be excluded. The absence of rectalbleeding or symptoms in a current smoker should raisequestions about a diagnosis of UC, since Crohn's colitis wouldbe more likely. Enquiry should be made into the familyhistory and patients asked about possible ocular, oral, jointor skin manifestations.4,98–102

3.3.2. Examination

ECCO statement 3DIn patients with UC physical examination shouldinclude general well-being, pulse rate, body tem-perature, blood pressure, body weight and height,abdominal examination for distention and tender-ness, perineal inspection, digital rectal examina-tion, oral inspection, and check for eye, skin and/orjoint involvement. Physical examination may beunremarkable in patients with mild or evenmoderate disease [EL5, RG D]

Findings on physical examination depend on the extent andseverity of UC. Examination of patients with mild or moderateactivity is usually unremarkable, apart from blood on rectal


examination. Patients with a severe attack exhibit fever,tachycardia, weight loss, colonic tenderness, abdominaldistension, or reduced bowel sounds103 (Section 1.1.2).

3.3.3. Diagnosis

ECCO statement 3EA gold standard for the diagnosis of ulcerativecolitis is not available. The diagnosis should beestablished by a combination of medical history,clinical evaluation, and typical endoscopic andhistological findings. An infective cause should beexcluded. Where there is doubt about the diag-nosis, endoscopic and histological confirmation isnecessary after an interval [EL5, RG D]

The natural history of UC is characterised by episodes ofrelapse and periods of remission, and occasionally by anunremitting, continuous course (about 5%). A single acuteepisode followed by prolonged remission may also occur inabout 5%.25 The frequency of relapse (pattern of disease) isusually defined in the first 3 years, and may be characterisedas frequent (≥2 relapses/year) or infrequent (≤1 relapse/year,22 Sections 1.2.7 and 2.2.1).

It helps patients to establish the diagnosis, extent andseverity of the disease rapidly, because this influences treat-ment options and possibly disease progression.71 Since there isno single pathogenic marker, the diagnosis relies on a combina-tion of medical history, endoscopic findings, histological fea-tures on multiple colonic biopsies and negative stool tests forinfectious agents. It is unreasonable to expect the histopathol-ogist alone to make the diagnosis (Section 4), but normalmucosal biopsies effectively exclude active UC as a cause ofsymptoms. In 10% of patients during the 5 years after initialonset of symptoms, the diagnosis will be changed to Crohn'sdisease or the diagnosis of inflammatory bowel diseasediscounted. Endoscopic and histological confirmation of thediagnosis is considered essential.104 In aminority of patients it isnot possible to characterise the cause of colitis: see Section 1.1for correct usage of the terms ‘colitis-yet-to-be classified’ and‘indeterminate colitis’.9,11

3.4. Investigationandprocedures toestablishadiagnosis

3.4.1. Initial investigations

ECCO statement 3FInitial laboratory investigations should include afull blood count, serum urea, creatinine, electro-lytes, liver enzymes, iron studies, and C-reactiveprotein (CRP) [EL5, RG D]. CRP and erythrocytesedimentation rate (ESR) are useful markers tomonitor the response to treatment in severe colitis[EL2b, RGB]. Microbiological testing for infectiousdiarrhoea including Clostridium difficile toxin isrecommended [EL2b, RG B]. Additional stool testsmay be necessary for patients who report a recenttravel abroad [EL5, RG D]

Every patient with active disease at presentation shouldhave a full blood count, inflammatory markers (CRP or ESR),electrolytes and liver function tests, along with a stool samplefor microbiological testing.103 Laboratory signs of chronicinflammation may be normal in mild or moderate distal UC.The full blood count may reveal thrombocytosis as a result ofthe chronic inflammatory response, anaemia indicatingdisease severity or chronicity and leucocytosis, raising thepossibility of an infectious complication.

For UC excluding proctitis, CRP broadly correlates withclinical activity.105–107 In patients with severe clinicalactivity, an elevated CRP is generally associated with anelevated ESR, anaemia and hypoalbuminaemia. These havebeen used as predictive biomarkers to assess the need forcolectomy in acute severe coliits28,108,109 (Section 5.2.5, firstfollowing paper in same issue). Neither CRP nor ESR is specificenough to differentiate UC from infectious or other causes.

The initial diagnosis of UC requires the elimination of in-fectious causes of symptomatic colitis. Stool specimens shouldbe cultured for common pathogens including specific assays forClostridium difficile toxin A and B, Campylobacter spp, andEscherichia coli 0157:H7. Additional tests may be tailored tothe medical history, such as examination of fresh, warm stoolsamples for amoebae or other parasites.

3.4.2. Microbial investigations

ECCO statement 3GIn patients with an established diagnosis of UCmicrobial testing is recommended in cases ofsevere or refractory relapse. This includes testingfor Clostridium difficile and Cytomegalovirusinfection [EL4, RG C]

It is not routinely recommended to screen for pathogenssuch as C. difficile at each flare of the disease, due toinfrequent positive results.110–112 In contrast, microbial stooltests should be performed during refractory or severerelapse, and in those with a history of antibiotic therapywithin an arbitrary 3 months, since C. difficile infection ismore common in these circumstances and associated with apoor clinical outcome.113,114 Flexible sigmoidoscopy may besuperior to stool C. difficile cytotoxin assay in patients withpseudomembranous colitis and is appropriate for patientswith diarrhoea where the stool test is negative.115

Reactivation of Cytomegalovirus (CMV) is commonin ulcerative colitis, particularly (but not invariably) inimmunosuppressed patients with severe colitis.116–118

The clinical relevance of this finding remains uncertain,but CMV infection may cause refractory or severe relapse.The optimal method for detecting clinically relevant CMVinfection in patients with colitis has not yet been es-tablished. Occasional intranuclear inclusion bodies con-sistent with CMV on histopathology do not necessarilyindicate clinically significant infection, but multiple in-tranuclear inclusions are usually significant.119,120 CMVshould be considered in patients with refractory or severecolitis (Section 3.5.3) and if detected, advice takenfrom virologists about the significance and appropriatetherapy.


3.4.3. Biomarkers

ECCO statement 3HAlthough faecal inflammatorymarkers are generallynot considered sufficient to be included routinelyin the diagnostic work up of UC, calprotectin, aneutrophil-derived protein, merits further consid-eration [EL2b, RGB]

The most widely studied serological markers are peri-nuclear anti-neutrophil cytoplasmic antibodies (pANCAs) andanti-Saccharomyces cerevisiae antibodies (ASCA). In mostseries pANCAs are found in up to 65% of patients with UC andin less than 10% of patients with Crohn's disease. It should benoted that the incidence of pANCA in UC may depend uponlocal laboratory expertise and geographical latitude.121,122 Inview of the current limited sensitivity of these markers,their routine use for the diagnosis of ulcerative colitis andfor therapeutic decisions is not clinically justified.123

Of the faecal markers of intestinal inflammation, neu-trophil-derived proteins such as calprotectin, elastase,lysozyme and lactoferin, have been evaluated in IBD.124–126

Faecal calprotectin appears to be the most sensitive, non-invasive biomarker that reflects intestinal inflammationin established IBD.127 However, as with all faecal tests,calprotectin lacks the specificity to discriminate betweentypes of inflammation. Therefore, its use as a diagnostic toolin UC is limited.

3.4.4. Procedures recommended to establish the diagnosis

ECCO statement 3IFor suspected UC, colonoscopy, preferably withileoscopy, and segmental biopsies including therectum are the preferred procedures to establishthe diagnosis and extent of disease [EL5, RGD].Patients with a severe attack should have abdom-inal radiography and active disease confirmed bysigmoidoscopy as a first line procedure [EL5, RGD]

Colonoscopy with intubation of the terminal ileum andsegmental mucosal biopsies are preferred to sigmoidoscopyfor patients with suspected UC. The clinical context andavailability needs to be considered: colonoscopy and bowelpreparation is best avoided in patients with acute severecolitis to avoid procedural delays and a higher risk ofperforation. Colonoscopy establishes the diagnosis anddisease extent in the large majority of cases. It appears tobe more cost-effective than index sigmoidoscopy.60,128

A plain abdominal radiograph is not a diagnostic test forUC, but is valuable in the initial assessment of patientswith suspected severe UC (Section 3.5.3). Oesophagogas-troduodenoscopy and mucosal biopsy are recommended inpatients with upper gastrointestinal symptoms. Wirelesscapsule endoscopy (WCE) represents an advance in bowelimaging, but large prospective studies are needed toconfirm the diagnostic relevance in ulcerative colitis.

WCE is a potentially useful clinical technique for categor-ising those patients with colitis yet to be classified,although a normal WCE does not exclude Crohn'sdisease.129

3.5. Assessment of extent, severity and activity

3.5.1. Signsofdiscontinuous inflammation inulcerativecolitis

ECCO statement 3JWhen there is macroscopic and histological rectalsparing, or the presence of a caecal patch in newlydiagnosed colitis evaluation of the small bowel isindicated [EL 5, RGD]. Involvement of the appen-dix only in left sided or extensive colitis is acommon feature of UC and requires no furtherdiagnostic work up to exclude CD [EL 3a, RGC]

3.5.1.1. Rectal sparing and caecal patch. Macroscopic andmicroscopic rectal sparing have been described in childrenpresenting with UC prior to treatment.130–133 In adults, anormal or patchy inflammation in the rectum is more likely tobe due to topical or systemic therapy for UC.134,135 Patchyinflammation in the caecum is referred to as ‘caecal patch’and is observed in patients with left-sided colitis. The naturalhistory of patients with patchy right colonic inflammationseems to be similar to those with isolated left-sided UC.136,137

Whenever there is a discontinuous pattern of inflammation incolitis, a diagnostic work up of the small bowel is indicated toexclude Crohn's disease.

3.5.1.2. Appendiceal skip lesions. Involvement of theappendix as a skip lesion is reported in up to 75% of patientswith UC.93–95 Appendiceal inflammation has been associatedbothwith amore responsive course of disease and a higher riskof pouchitis after ileal pouch anastomosis.138–141 Both findingsrequire confirmation.

3.5.1.3. Backwash ileitis. Continuous extension of macro-scopic or histological inflammation from the caecum intothe most distal ileum is defined as ‘backwash ileitis’. It isobserved in up to 20% of patients with pancolitis. Rarely, ilealerosions may occur in patients without caecal involvementand this challenges the pathogenic theory that backwashileitis is caused simply by reflux of caecal contents into theileum.142–144 A more refractory course of ulcerative colitishas been suggested in those with backwash ileitis.143

Additional imaging of the small bowel should be consideredin cases of macroscopic backwash ileitis, to differentiate UCfrom Crohn's disease.

3.5.1.4. Small bowel. Small bowel radiology (by enterocly-sis, follow-through, CT enteroclysis, MR enteroclysis, or WCE(reviewed in the ECCO Consensus on diagnosis and imaging inCrohn's disease145) is not routinely recommended. Wherethere is diagnostic difficulty (rectal sparing, atypical symp-toms, macroscopic backwash ileitis) then clinicians shoulddiscuss imaging with an appropriate radiologist and resultsviewed in the context of the clinical history.145


3.5.2. Activity indices in ulcerative colitis

ECCO statement 3KInstruments for measuring clinical and/or endo-scopic disease activity in UC are available, butnone has been subjected to an adequate valida-tion process. In daily routine such indices arebarely used. The incorporation of a simple clinicaland/or endoscopic scoring system is desirable,intended to improve care of UC patients and torealise a standardised IT system for IBD. Immedi-ate admission to hospital is warranted for allpatients fulfilling Truelove & Witts' criteria forsevere colitis to prevent delayed decision-makingwhich may lead to increased perioperative mor-bidity and mortality [EL4, RGD]

Clinical, endoscopic and combined activity indices forulcerative colitis have been reviewed15 (Sections 1.1.2 and2.2.2). At present, disease activity scoring for UC is thepreserve of clinical studies. However, based on the need tostandardise documentation of IBD patients on a Europeanlevel, the incorporation of a simple, valid clinical and/or en-doscopic scoring system in electronic patient files is war-ranted. The original classification of severe UC was proposedby Truelove andWitts in 195513 and has stood the test of time,because it is easy to remember and apply. This classification isstill considered to be the tool of choice to identify readilythose outpatients in need of immediate admission to hospitaland intensive treatment.146

3.5.3. Investigations for acute severe colitis on admissionPatients should have their full blood count, inflammatorymarkers (C-reactive protein, or ESR), electrolytes and liverfunction testsmeasured, alongwith a stool sample for cultureand assay for C. difficile toxin.146

A plain abdominal radiograph should be performed, notonly to exclude colonic dilatation (≥6.0 cm), but also toestimate the extent of disease and look for features thatpredict response to treatment. The proximal extent ofdisease broadly correlates with the distal distribution offaecal residue; in 51 episodes of severe colitis, this guideoverestimated the extent in 18% and underestimated it in8%.108 The presence of mucosal islands (small, circular opaci-ties representing residual mucosa isolated by surroundingulceration), or more than two gas-filled loops of small bowelon the radiograph are associated with a poor response totreatment.147,148

A flexible sigmoidoscopy should confirm the diagnosis ofsevere colitis and help exclude infection, particularly withCytomegalovirus.116,117,149 If it is strongly suspected thatCMV might be responsible for deterioration (such as a patienton immunomodulators in association with a high fever), it isappropriate to request urgent histopathology. An answercan be available within 4 h. Phosphate preparation beforeflexible sigmoidoscopy is considered safe, but is probablybest avoided in patients with a dilated colon. Full colono-scopy in patients with acute severe colitis is not recom-mended. Purgative preparation can provoke dilatation andcolonic perforation is a real hazard of colonoscopy during

active disease. Endoscopic criteria for severe colitis includeextensive mucosal abrasions, deep ulcerations, mucosaldetachment on the edge of these ulcerations and well-likeulceration,150,151 but all of these can be assessed at flexiblesigmoidoscopy.

3.5.4. Reassessmentofextentandseverityofulcerativecolitis

ECCO statement 3LRoutine colonoscopy for patients with UC in remis-sion is unnecessary until the start of a surveillanceprogramme [EL5, RGD]. Endoscopic reassessment isappropriate at a relapse, or for steroid-dependentor -refractory UC or when considering colectomy[EL5, RGD]

Despite the importance of disease location in determiningthe prognosis, the risk of cancer and the choice of therapy,the appropriateness of periodic restaging after index colo-noscopy has never been studied. The value of endoscopicreassessment of disease extent prior to a surveillanceprogramme is much debated. Consequently ECCO statement3L only represents expert opinion. Colonoscopy is more sen-sitive than barium studies for estimating disease extent, butthe risk of malignancy is historically based on contrast studiesand colonoscopy defines a different extent to histopathol-ogy.60,152–154 Chromoendoscopy better correlates with thedisease extent determined by histopathology, but the pro-cedure is time consuming and requires a level of expertise notuniversally available.155 Drug-induced clinical remission maynot be associated with endoscopic or histological remission,but the prognostic implications of endoscopic re-evaluationin quiescent disease have yet to be determined.60 The areacalls for systematic study.

3.6. Endoscopy, ultrasound and colonography

3.6.1. Endoscopic features of ulcerative colitis

ECCO statement 3MNo endoscopic feature is specific for UC. The mostuseful endoscopic features of UC are considered tobe continuous and confluent colonic involvementwith clear demarcation of inflammation and rectalinvolvement. [EL2b, RGB] Endoscopic severity ofUC may be best reflected by the presence ofmucosal friability, spontaneous bleeding and deepulcerations [EL2b, RGB]

Endoscopic changes characteristically commence proximalto the anal verge and extend proximally in a continuous, con-fluent and concentric fashion. The demarcation between in-flamedandnormal areas is usually clear andmay occur abruptlywithin millimetres, especially in distal disease. The endoscopicfeatures of mild inflammation are erythema, vascular con-gestion of the mucosa and loss of visible vascular pattern.Moderately active colitis is characterised by a coarse granular


appearance, mucosal erosions and mucosal friability (bleedingto light touch). Severe colitis is characterised by spontaneousbleeding and ulceration (Table 1.3).60,154,156 The choice ofendoscopic score is complex and has been reviewed.15,157 Incontrast to Crohn's disease, ulcers in severe UC are always em-bedded in inflamed mucosa. The presence of deep ulcerationsis a poor prognostic sign.154 In longstanding disease, mucosalatrophy can result in loss of haustral folds, luminal narrowingand pseudopolyps.

3.6.2. Abdominal ultrasound and scintigraphy inulcerative colitis

ECCO statement 3NTransabdominal and hydrocolonic ultrasound areof secondary value for defining the extent of UC[EL3, RGC]. Doppler ultrasound is a complemen-tary technique for assessing disease activity inexpert hands [EL2b, RGD]

Abdominal ultrasound screens for small bowel or colonicinflammation with a sensitivity of 80–90%. Ultrasound has theadvantage of being low cost and non-invasive, but theaccuracy is very much dependent on the skill of the operatorand there is low specificity for differentiating UC from othercauses of colonic inflammation.160–162 Hydrocolonic ultra-sound (abdominal ultrasonography in conjunction with retro-grade instillation of water in the colon) has a high sensitivityfor identifying active colitis, but the method is too cumber-some for day to day clinical practice.163 Doppler ultrasoundof the superior and inferior mesenteric arteries has beenused to evaluate disease activity and risk of relapse. It shouldnot, however, be considered a standard procedure.164,165 Forthis method to be viable, further prospective, multi-centrestudies are needed.

Leukocyte scintigraphy is safe, non-invasive and poten-tially allows assessment of the presence, extent and activityof inflammation, but the method lacks specificity.166,167 It isunreliable if patients are taking steroids. Novel markers todetect intestinal inflammation which are not associated withexposure to radiation are being developed.

3.6.3. Virtual colonography in ulcerative colitis

ECCO statement 3OVirtual colonography is an evolving technology.The limited data currently available do notdemonstrate a diagnostic value for assessing thedisease extent in patients with suspected orproven UC [EL 4, RGC]

Few studies on a limited number of patients have inves-tigated MR-colonography or CT-colonography in UC. Theresults are conflicting and subtle changes of the mucosa suchas erosions or flat polyps are insufficiently visualized.168–170

Because of these limitations, virtual colonoscopy is noalternative to standard colonoscopy in patients with UC atpresent.

3.7. Colonic stenosis in ulcerative colitis

ECCO statement 3PEach colonic stenosis in UC should raise the sus-picion of colorectal carcinoma. Multiple biopsiesshould be taken and a surgical opinion should besought. When endoscopic intubation of the colon isnot possible, imaging procedures, such as doublecontrast barium enema, CT and/or MRI colonogra-phy may be employed [EL5, RGD]

In longstanding ulcerative colitis, a colonic stricturesignifies an increased risk for colorectal carcinoma andrequires histological and surgical expertise.171 If colonoscopyis incomplete due to stricture, then double or even singlecontrast barium enema is the first choice procedure.172 CTcolonography can reveal the mucosal pattern and colitisproximal to a stricture but may not identify all lesions seen oncolonoscopy.173

4. Histopathology

4.1. General

In ulcerative colitis, histopathology is used for diagnosis, theassessment of disease activity and the identification of intra-epithelial neoplasia (dysplasia). The latter will be addressedseparately.

4.1.1. ConsiderationsSeveral factors have influenced the accuracy of the histo-pathological diagnosis of ulcerative colitis, as it has in Crohn'sdisease. The advent of colonoscopy as the diagnostic proce-dure of choice has had consequences. It has allowed theanalysis of multiple biopsies from different segments of thecolon. More biopsies are obtained, often early in the evolutionof the disease. Furthermore, biopsies can be obtained in youngchildren presenting with bloody diarrhoea. In addition, theintroduction of new therapies inducing mucosal healing hasmade the pathologists aware of the impact of treatment uponthe microscopic features. This has changed the approach tohistopathological diagnosis in the past decade.

4.1.2. Evaluation of the literature

Articles reporting original research into the reproducibility,sensitivity, specificity and predictive value of individualfeatures useful for the histopathological diagnosis of ulcerativecolitis were sought from the literature, using Medline andPubmed. As selection criteria, only those features whichachieved moderate reproducibility judged by the kappastatistic, or findings confirmed by several studies were con-sidered. In addition, we have reviewed studies describing anddefining diagnostic microscopic features.174–193 The literaturecanbedivided into groups, dependingupon thenumber (one, ormultiple) of biopsies examined, or the duration of the disease.In ten studies multiple biopsies were examined (including twocomparing the diagnostic value of both single and multiplebiopsies).184–193


The literature on the duration of the disease can alsobe divided. The first group is composed of studies withbiopsies obtained in patients with an established diagnosisof ulcerative colitis, based on extended clinical follow up.Disease duration varies between 6±3weeks and 12 years.186–189

In these studies patients with doubtful criteria were generallyexcluded.177,178,186 A second group is composed of retrospectivestudies without clear data on the duration of the disease. Thesepapers are retrospective studies and can be pooled with thefirst group, because the diagnosis is again established througha period of follow up. A third group applies to studies on bi-opsies obtained early after onset of the disease, beforetreatment.181,183,190,191,193 For early onset disease, the durationof disease varies between 4 and 14 days (3.69±0.52 days afterthe appearance of rectal bleeding, or 10 days after initialsymptoms).179,181,185 In these studies, the diagnosis was subse-quently confirmed by follow up of the patients and are pro-spective studies. Children aremainly included in the third group.

4.2. Microscopic features — definitions

A large number of microscopic features have been evalu-ated. They can be broadly classified into

• architectural features• epithelial abnormalities, and• inflammatory features.

Architectural features include crypt branching, cryptdistortion, crypt atrophy and surface irregularity. Epithelialcell abnormalities are mucin depletion and Paneth cellmetaplasia. Inflammatory features include increased laminapropria cellularity, basal plasmacytosis, basal lymphoid ag-gregates, lamina propria eosinophils.

4.2.1. Crypt architectural abnormalitiesCrypt branching: two ormore branched (bifurcated) crypts in awell oriented section, whether the branching is in the verticalor horizontal axis.178,181,182,190,194 When applied to a singlecrypt, the feature is less specific.182 The pathogenesis can beaccounted for by regeneration following previous damage ordestruction (cryptolysis).

Mucosal (crypt) distortion: irregularities in crypt size (i.e.variable diameter), spacing, orientation (i.e. loss of paralle-lism), or shape (including branching with a cystic configura-tion).185–187,190, 191,181,182,193,194 In some studies this includesseparation from the underlying muscularis mucosae.181,185

Samples from the anal transition zone or columnar cuff (some-times wrongly termed “low rectal biopsies”) are not suitable forthe assessment of crypt branching or mucosal distortion.

Mucosal (crypt) atrophy and crypt density: a combina-tion of crypt depletion (thinned-out crypts, generallyrecognised by a distance of more than one crypt diameterbetween crypts) and an increase in the distance bet-ween the muscularis mucosae and the base of thecrypts.177,181,194 Some authors emphasise either cryptdepletion185 or an increased distance between themuscularis mucosae and the base of the crypts190 ratherthan both features. An increase in the intercryptal spaceand the crypt–muscularis mucosae distance may benormal in the caecum and distal rectum.194 The distancebetween the muscularis mucosae and the crypt base

should not be evaluated in the vicinity of lymphoidfollicles. The pathogenesis can be explained as a con-sequence of crypt death from disease. If all crypt cellsdie, crypts cannot regenerate and disappear within 48 h inexperimental animals. However, if one or more clonogeniccells survive the insult, rapid proliferation regeneratesthe crypt within 72–96 h in experimental animals. Themucosa subsequently heals by clonal expansion and thenumber of crypts that survive to regenerate following acytotoxic insult correlates with symptom severity inanimal models. A number of growth factors affect cryptregeneration in murine models.195 Nevertheless, itremains unclear what size of (uncrushed) biopsy isadequate for proper evaluation and how many levels ofthe biopsy need to be examined properly to evaluateatrophy.

Surface irregularity: Surface irregularity (synonyms includevillous surface, villiform surface, or villous mucosa)182,185

means wide crypt mouths, giving the mucosal surface a finger-like appearance.181 The impression is due to separation ofcrypts177 and a semantic distinction between “irregularsurface” and “villous surface” has been proposed, accordingto the villous–crypt ratio.186

4.2.2. Epithelial cell abnormalities

Paneth cell metaplasia: Paneth cells are normally extremelyuncommon in the colon distal to the splenic flexure, beingpresent in 0–1.9% of non-IBD controls.196 The presence ofPaneth cells in the distal colon can be termed Paneth cellmetaplasia. The pathogenesis is related to epithelial regen-eration and repair.196

Mucin depletion: defined as a reduction in number ofgoblet cells or depleted mucin within cells.194

4.2.3. Inflammatory features

Basal plasmacytosis: defined either as the presence of plasmacells around (deep 1/5th of the lamina propria) or below thecrypts, alongside or penetrating the muscularis mucosae.Basal plasmacytosis is also referred to as subcryptal plasmacells,185 plasmacytosis with extension in the base of themucosa,193 or accumulation of plasma cells between the baseof the crypts and themuscularis mucosae.190 The abnormalitycan be focal or diffuse and subcryptal location of the cells isnot always present.181,185

Lamina propria cellularity: evaluated according todensity, composition and distribution. An increase in thetotal number of plasma cells, lymphocytes, histiocytes andeosinophils is a feature of all types of colorectalinflammation194 and is of limited discriminant value. Inulcerative colitis the cellular infiltrate is diffuse andtransmucosal.

Increased density has been described as “a subjectivelyabnormal” infiltrate,182, a “prominent” increase (assessedby widening of the intercryptal space by the inflammatoryinfiltrate177 or simple “hypercellularity”.185 The increase isdifficult to quantify. Increased lamina propria cellularitymay also be absent in quiescent disease, following treat-ment, or in the natural course of the disease.178,24 Further-more, increased lamina propria cellularity may persist ininfective colitis197 and is a normal feature of caecalbiopsies.


The composition has been examined to resolve thesedilemmas. Some authors discriminate between anincrease in neutrophils alone and an increase in bothround cells and neutrophils. Neutrophils may be present inthe lamina propria or between epithelial cells, are readilyrecognised and a reproducible feature of inflammation.177

More than three neutrophils in the lamina propria outsidecapillaries may be abnormal,186 but the exact number hasnot been agreed. Neutrophils are a feature of cryptitiswith migration of neutrophils through the crypt epithe-lium, inducing crypt disruption and crypt abscesses, whichmay be responsible for cell surface damage or disruption.The diagnostic value of neutrophils in ulcerative colitis,however, is limited because they are also present ininfective colitis and other forms of colitis.177,185 Incontrast, eosinophils in the lamina propria are highlyvariable. An increase has been noted in ulcerative colitisand a potential diagnostic value has been proposed,but data were obtained from studies of longstandingdisease.178,187

The distribution of the lamina propria cellular inflamma-tory infiltrate has been divided into: focal (normal back-ground cellularity with areas of increased cellularity);patchy (abnormal background cellularity with variableintensity); and diffuse (abnormal background cellularitywith an overall increase in density). These terms arepreferred. Confusion is caused when the term “discontin-uous” is used to describe both focal and patchy changes insome studies,194 or used as a synonym for focal in others.187 Adiffuse increase can be either superficial (confined to thesuperficial and middle thirds of the lamina propria) ortransmucosal (usually maximal in the lower third). Thedistribution can be evaluated in a single sample or betweenmultiple samples from the same site. To avoid diagnosticerror, the criteria of diffuse transmucosal inflammation fordiagnosing ulcerative colitis should be avoided in biopsiesfrom early onset disease in children,193 or after treat-ment and when disease is resolving or quiescent. Inthese circumstances the biopsy may be normal or showfocal changes.189,198,199

Basal lymphoid aggregates: nodular collections of lym-phocytes between the crypt base and muscularis muco-sae,182 without germinal centres.177,182,186,194 At least twoaggregates are needed for this feature to be consideredabnormal.177,186,194

Stromal changes: diffuse thickening of the muscularismucosae or a double muscularis mucosae (which is unusual,but characteristic when present) have been observed inlongstanding active and quiescent ulcerative colitis.200

Backwash ileitis: ileal inflammation in ulcerative colitisis called backwash ileitis, despite the fact that thebackwash or reflux pathogenesis has never been estab-lished. ‘Backwash ileitis’ should be in continuity withcolonic inflammation (see also Section 3.5.1) and thelesions in the caecum should show a similar, or greaterdegree of active inflammation. The ileal lesions in ‘back-wash ileitis’ are characterised by active inflammation inthe villi and lamina propria, together with shortening andblunting of the villi. Focal, isolated ileal erosions, mucousgland metaplasia or patchy oedema with mild ac-tive inflammation are features suggestive of Crohn'sdisease.201,202

ECCO Statement 4AFor a reliable diagnosis of ulcerative colitis multiplebiopsies from five sites around the colon (includingthe rectum) and the ileum should be obtained.Multiple implies a minimum of two samples [EL1b,R GB]

ECCO Statement 4BBiopsies should be accompanied by clinical infor-mation including the age of the patient, durationof disease and duration and type of treatment[EL1b, R GB]. Biopsies from different regionsshould be handled in such a way that the region oforigin can be identified [EL1c RGA]. This can bedone by using different containers, multiwellcassettes, or an acetate strip [EL5, RG D]. Alltissue samples should be fixed immediately byimmersion in buffered formalin or an equivalentsolution prior to transport. It is recommendedthat multiple sections from each sample areexamined [EL5, R G D]

4.3. Microscopic features— appraisal of the diagnosis

4.3.1. Early stage diseaseIt has been proposed that a non-specific increase in theinflammatory infiltrate in the lamina propria in combinationwith absent crypt architectural distortion, indicates a diag-nosis of acute, infective colitis177,185 rather than ulcerativecolitis. This finding, however, is not confirmed in thosestudies of patients with early onset colitis (within 10 days ofsymptoms, Section 4.1.2).179,203

ECCO Statement 4CBasal plasmacytosis at the initial onset has a highpredictive value for the diagnosis of IBD [EL 3, RGC]. Repeat biopsies after an interval may help tosolve differential diagnostic problems and estab-lish a definitive diagnosis especially in adults, byshowing additional features [EL 5, RG D]

Basal plasmacytosis is observed in biopsies obtained at earlyonset in 38–100% of adult patients181,185 and 58% of childrenwith ulcerative colitis.17 It is particularly a feature in youngchildren; in these cases it is notably present in rectal biopsiesand decreases proximally. It is an early feature, sometimes thefirst lesion to appear181,185,190,191,193 and a good predictivemarker.

Glandular abnormalities can be identified with good (83–90%) interobserver agreement.176,186,204 According to moststudies, diffuse crypt architectural irregularity and reducedcrypt numbers or atrophy indicate ulcerative colitis.178,194

Nevertheless, these features may still not be present in


biopsies obtained from patients with colitis at an earlystage.181 Crypt architectural changes were observed inbiopsies obtained between 16 and 30 days after onset,181

but not in earlier biopsies. In another study185 abnormalarchitecture was found in all biopsies obtained within days ofonset, but in this study disease onset was defined by loss ofblood and not by other symptoms. Crypt distortion andmucosal atrophy may return to normal or remain unchangedafter resolution of symptoms.198,199

ECCO Statement 4DIn young children or patients with an aberrant pre-sentation of colitis, UC should always be consideredin the differential diagnosis even if the pathology isnot typical [EL1b RG B]

Reliable diagnostic features may be absent from biopsiesobtained in early onset disease, in acute severe colitis, or inpatients with an atypical immunological response (such asyoung children, or patientswith primary sclerosing cholangitis).The routine use of additional techniques such as immunohis-tochemistry is not recommended at present.

4.3.2. Established disease

ECCO Statement 4EA diagnosis of established ulcerative colitis is basedupon the combination of: basal plasmacytosis(defined as presence of plasma cells around (deeppart of the lamina propria) or below the crypts(subcryptal)), heavy, diffuse transmucosal laminapropria cell increase and widespread mucosal orcrypt architectural distortion [EL 1a, RG A]

The exact number of features needed for diagnosis hasnot been established. A correct diagnosis of ulcerative colitisis reached in approximately 75% of the cases when two orthree of the four features, severe crypt architecturaldistortion, severe decreased crypt density, irregular surfaceand heavy diffuse transmucosal inflammation are present, inthe absence of genuine granulomas.186,191

ECCO Statement 4FWidespread mucosal or crypt architectural distor-tion, mucosal atrophy and a villous or irregularmucosal surface appear later during the evolutionof the disease (4 weeks or more). They suggest adiagnosis of ulcerative colitis in established dis-ease [EL 2, RG B]

In established ulcerative colitis a villous surface is presentin 17–63% of the cases (compared to 0–24% for Crohn's

disease and 0–7% for infective colitis).194 The lesion isobserved in approximately one third of the initial biopsies ofchildren with ulcerative colitis.190 In adults this featurewas present in approximately 23% of the patients presenting16–30 days after the initial symptoms, but not in earlierbiopsies.181

ECCO Statement 4GBasal plasmacytosis is a good diagnostic feature inestablished ulcerative colitis [EL 2, RG B]. A heavy,diffuse transmucosal lamina propria cell increaseis a good diagnostic feature in established activedisease [EL 2, RG B]. Distribution of inflammationalong the colon, with a decreasing gradient ofinflammation from distal to proximal is in favourof a diagnosis of ulcerative colitis in an untreatedpatient [EL5 RG D]

The diagnostic value of basal plasmacytosis is confirmedby studies of biopsies obtained in established disease, beingpresent in up to 63% of cases.186 The feature is rare in non-IBD colitis,182 but it is also common in Crohn's disease.Basal plasmacytosis decreases and can disappear duringtreatment.

A heavy, diffuse, transmucosal, lamina propria cellinfiltrate favours a diagnosis of ulcerative colitis,194 butpatchy inflammation178 can occasionally be seen inulcerative colitis or, when multiple biopsies are examined,a single piece may have evidence of chronic colitis andothers have normal mucosa.190,198,205 The heavy, diffusetransmucosal lamina propria cell increase can be absent inyoung children (b12 years). It can decrease in intensityand become patchy during the natural evolution of thedisease or subsequent to treatment. This feature istherefore mainly useful for the diagnosis in establisheddisease. Its absence does not exclude a diagnosis ofulcerative colitis.

ECCO Statement 4HGeneral or widespread crypt epithelial neutrophils(cryptitis and crypt abscesses) favour ulcerativecolitis. However these lesions may occur ininfections and other types of colitis [EL 2b,RG B]. Lamina propria and intraepithelial neutro-phils are absent in inactive or quiescent disease [EL2b, RG B]

General or widespread crypt epithelial neutrophils favoura diagnosis of ulcerative colitis, but crypt abscesses andcryptitis can also occur in infective colitis, although they areless prominent.18 Neutrophils are absent during inactive orquiescent disease.

Basal lymphoid aggregates favour a diagnosis of estab-lished ulcerative colitis, butmay occur in Crohn's colitis177,182

and are not useful in early onset disease.


ECCO Statement 4IPaneth cell metaplasia distal to the splenic flexureis a non-specific feature. It is suggestive of adiagnosis of ulcerative colitis in established dis-ease [EL 3, RG C]. Severe, widespread mucindepletion is helpful for the diagnosis of ulcerativecolitis in active disease [EL 3, RG C]

Paneth cell metaplasia favours a diagnosis of ulcerativecolitis.187 Thepredictive value is highbut the sensitivity is low.182

It is not seen in biopsies obtained early in the disease177,181 andappears to be related to established disease.196 Mucin depletionalso favours a diagnosis of ulcerative colitis. It correlates withdisease activity, so is a helpful, but not pivotal diagnosticfeature.193 Mucinpreservation inassociationwithactivedisease,however, may favour a diagnosis of Crohn's disease rather thanulcerative colitis.188

4.4. Microscopic features — disease activity

ECCO Statement 4JThe pathology report should give an indication ofthe activity of the disease [EL5 RG D]

Disappearance of mucosal inflammation following treat-ment has been observed,199 so biopsies are also used fordistinguishing between quiescent and active disease, as wellas different grades of activity. Scoring systems have beenintroduced for the assessment of disease activity, particularlyfor therapeutic trials. The potential value of histopathologyfor predicting relapse and evaluating adequate control ofinflammation has implications for therapeutic managementand reducing the risk of neoplasia. Both epithelial damage inassociation with neutrophils and basal plasmacytosis havebeen proposed as markers of disease activity and theprediction of relapse.206–209 The scope of this text does notpermit detailed analysis of these scoring systems.

4.5. Conclusions

The evolution of the microscopic features that are useful for adiagnosis of ulcerative colitis is a time and disease-activitydependent process. This notion is confirmed by experimentalstudies. In early onset disease, few or no characteristic featuresmay be present. In established disease the diagnosis can be basedupon a combination of basal plasmacytosis, crypt architecturalabnormalities, diffuse transmucosa inflammatory infiltrate andepithelial surface irregularity. The natural evolution from active toquiescent disease and treatment also have an impact onmicroscopic features. In quiescent disease, few features maypersist,neutrophils arenotablyabsentandbiopsiesmaybenormal.

It appears important to distinguish between differentsituations for the diagnosis of ulcerative colitis:

• Biopsies obtained during the initial phase of the disease(within two weeks of onset of symptoms, including youngchildren and without treatment)

• Biopsies obtained from patients with established diseasebefore treatment (symptoms for more than 4–6 weeks)

• Biopsies obtained from patients with established dis-ease after treatment (examination of previous biopsies isdesirable).

In every patient, including children, the diagnostic yieldcan be increased when multiple biopsies from differentsegments of the colon are examined, including the rectumand the ileum, although these should be carefully labelledfor proper assessment.191,192,210,211

Contributors

A Barakauskiene, National Centre of Pathology, VilniusUniversity, Vilnius, LithuaniaRM Feakins, Department of Histopathology, The RoyalLondon Hospital, London, United KingdomJF Fléjou, Service d'Anatomie Pathologique, Hôpital SaintAntoine, Paris, FranceK Geboes, Department of Pathology, University HospitalKULeuven, Leuven, BelgiumH Herfarth, Division of Gastroenterology & Hepatology,Department of Medicine, University of North Carolina,Chapel Hill, USADW Hommes, Department of Gastroenterology–Hepatology.Leiden University Medical Centre LUMC, Leiden, TheNetherlandsL Kupcinskas, Department of Gastroenterology, KaunasUniversity of Medicine, Kaunas, LithuaniaPL Lakatos, First Department of Medicine, SemmelweisUniversity, Budapest, HungaryGJ Mantzaris, A' Gastroenterology Clinic, EvangelismosHospital, 45-47 Ypsilantou Street, 10675-Athens, GreeceW Reinisch, Univ.-Klinik Innere Medizin IV, Abt. Gastro-enterol & Hepatol. Waehringer Guertel 18-20, A-1090Vienna, AustriaS Schreiber, Department of General Internal Medicine -University Hospital Schleswig Holstein, Christian-Albrechts-University, Kiel, GermanyEF Stange, Chefarzt, Abteilung für Innere Medizin 1Schwerpunkte Gastroenterologie, Hepatologie und Endokri-nologie, Robert Bosch Krankenhaus, Postfach 501120, Auer-bachstr. 110, 70341 StuttgartSPL Travis, John Radcliffe Hospital, Oxford, UKS Vermeire, Department of Gastroenterology, UniversityHospital Leuven BelgiumV Villanacci, Second Department of Pathology, Spedali Civili,University of Brescia, Brescia, ItalyBF Warren, Department of Cellular Pathology, John RadcliffeHospital, University of Oxford, Oxford, United Kingdom

Acknowledgement

We are particularly grateful to Mrs. Lynn Lane and SophieLane of Oxford for their substantial contribution to coordi-nating and assimilating the Consensus, to the Robert BoschFoundation for an unrestricted educational grant and to allcolleagues who completed the questionnaires and contib-uted to the statements at the Consensus meeting in Berlin,October 2006. The meeting in Berlin was greatly facilitatedby the support of the German competence network on IBD.


The contributors to the Consensus meeting were:Austria Moser, Reinisch, TilgBelgium De Vos, D'Haens, Geboes, Penninckx, VermeireCroatia Kolacek, VucelicCzech Republic LukasDenmark Lebech, Munkholm, WewerFrance Colombel, Cortot, Fléjou, Lémann, Marteau, Panis,Germany Dignass, Herfarth, Hoffman, Jantschek, Kiesslich,Kruis, Kucharzik, Schölmerich, Schreiber, Stange, ZeitzGreece Mantzaris, TsianosHungary LakatosIsrael Chowers, Eliakim,Italy Biancone, Caprilli, Cottone, Gionchetti, Pallone,Prantera, Vecchi, VillanacciLatvia PokrotnieksLithuania Barakauskiene, KupcinskasNetherlands Bemelman, Escher, Hommes, Van der WoudeNorway MoumPortugal FreitasSerbia JojicSlovakia Gregus,Spain Gassull, PanesSweden Øresland, Soderholm, TyskSwitzerland Mitchetti, SeiboldUK Feakins, Forbes, Ghosh, Hamilton, Hawkey, Mitchell,Mortensen, Rhodes, Travis, Warren

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175. Rubio CA, Johansson C, Kock Y. A quantitative method ofestimating inflammation in the rectal mucosa. II. Normal limitsin symptomatic patients. Scand J Gastroenterol 1982;17:1077–81.

176. Rubio CA, Johansson C, Kock Y. A quantitative method ofestimating inflammation in the rectal mucosa. III. Chroniculcerative colitis. Scand J Gastroenterol 1982;17:1083–7.

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178. Schmitz-Moormann P, Himmelmann GW. Does quantitativehistology of rectal biopsy improve the differential diagnosisof Crohn's disease and ulcerative colitis in adults? Pathol ResPract 1988;183:481–8.

179. Therkildsen MH, Jensen BN, Stubbe P, Rasmussen TS. The finaloutcome of patients presenting with their first episode of acutediarrhea and an inflamed mucosa with preserved cryptarchitecture. A clinicopathologic study. Scand J Gastroenterol1989;24:158–64.

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183. Markowitz J, Kahn E, Grancher K, et al. Atypical rectosigmoidhistology in children with newly diagnosed ulcerative colitis.Am J Gastroenterol 1993;88:2034–7.

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187. Theodossi A, Spiegelhalter DJ, Jass J, et al. Observer variationand discriminatory value of biopsy features in inflammatorybowel disease. Gut 1994;35:961–8.

188. Tanaka M, Riddell RH, Saito H, et al. Morphologic criteriaapplicable to biopsy specimens for effective distinction ofinflammatory bowel disease from other forms of colitis and ofCrohn's disease from ulcerative colitis. Scand J Gastroenterol1999;34:55–67.

189. Tanaka M, Saito H, Fukuda S, et al. Simple mucosal biopsycriteria differentiating among Crohn's disease, ulcerativecolitis and other forms of colitis: measurement of validity.Scand J Gastroenterol 2000;35:281–6.

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192. Dejaco C, Osterreicher C, Angelberger S, et al. Diagnosingcolitis: a prospective study on essential parameters forreaching a diagnosis. Endoscopy 2003;35:1004–8.

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194. Jenkins D, Balsitis M, Gallivan S, et al. Guidelines for the initialbiopsy diagnosis of suspected chronic idiopathic inflammatorybowel disease. The British Society of Gastroenterology initia-tive. J Clin Pathol 1997;50:93–105.

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199. Odze R, Antonioli D, Peppercorn M, GoldmanH. Effect of topical5-amino-salicylic acid (5-ASA) therapy on rectal mucosal biopsymorphology in chronic ulcerative colitis. Am J Surg Pathol1993;17:869–75.

200. Soundy V, Davies SE, Warren BF. The double muscularis mucosaein ulcerative colitis: is it all new? Histopathology 1998;32:484–5.

201. Haskell H, Andrews Jr CW, Reddy SJ, et al. Pathologic featuresand clinical significance of “Backwash” ileitis in ulcerativecolitis. Am J Surg Pathol 2005;29:1472–81.

202. Goldstein N, Dulai M. Contemporary morphologic definition ofbackwash ileitis in ulcerative colitis and features thatdistinguish it from Crohn's disease. Am J Clin Pathol2006;126:365–76.

203. Notteghem B, Salomez JL, Gower-Rousseau C, et al. What isthe prognosis in unclassified colitis? Results of a cohort study of104 patients in Northern-Pas-de-Calais region. GastroenterolClin Biol 1993;17:811–5.

204. Cook MG, Dixon MF. An analysis of the reliability of detectionand diagnostic value of various pathological features in Crohn'sdisease and ulcerative colitis. Gut 1973;14:255–62.

205. Glickman JN, Bousvaros A, Farraye FA, et al. Pediatric patientswith untreated ulcerative colitis may present initially withunusual morphologic findings. Am J Surg Pathol 2004;28:190–7.

206. Riley SA, Mani V, Goodman MJ, et al. Microscopic activity inulcerative colitis: what does it mean? Gut 1991;32:174–8.

207. Bitton A, Peppercorn MA, Antonioli DA, et al. Clinical,biological, and histologic parameters as predictors of relapsein ulcerative colitis. Gastroenterology 2001;120:13–20.

208. Nishio Y, Ando T, MaedaO, et al. Predictors of relapse in patientswith quiescent ulcerative colitis. Gut 2006;55:1760–7.

209. Yantiss RK, Sapp HL, Farraye FA, et al. Histologic predictors ofpouchitis in patients with chronic ulcerative colitis. Am J SurgPathol 2004;28:999–1006.

210. Geboes K, Ectors N, D'Haens G, Rutgeerts P. Is ileoscopy withbiopsy worthwhile in patients presenting with symptoms ofIBD. Am J Gastroenterol 1998;93:201–6.

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ava i l ab l e a t www.sc i enced i r ec t . com


SPECIAL ARTICLE

European evidence-based Consensus on themanagement of ulcerative colitis:Current managementS.P.L. Travis ⁎,1, E.F. Stange ⁎,1, M. Lémann, T. Øresland, W.A. Bemelman,Y. Chowers, J.F. Colombel, G. D'Haens, S. Ghosh, P. Marteau, W. Kruis,N.J.McC. Mortensen, F. Penninckx, M. Gassullfor the European Crohn's and Colitis Organisation (ECCO)

Received 23 November 2007; accepted 23 November 2007

KEYWORDSUlcerative colitis;Acute severe colitis;Mesalazine;Azathioprine;Infliximab;Ileal pouch-analanastomosis

Contents

5. Medical management of active ulcerative colitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265.1. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

5.1.1. Disease activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265.1.2. Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

5.2. Treatment according to site of disease and disease activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265.2.1. Proctitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265.2.2. Left sided colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275.2.3. Extensive ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275.2.4. Severe ulcerative colitis of any extent. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285.2.5. Intravenous-steroid resistant ulcerative colitis of any extent . . . . . . . . . . . . . . . . . . . . . . 295.2.6. Toxic dilatation and complications of severe ulcerative colitis . . . . . . . . . . . . . . . . . . . . . 315.2.7. Refractory proctitis and distal colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

⁎ Corresponding authors. Travis is to be contacted at John Radcliffe Hospital, Oxford, OX3 9DU, UK. Tel.: +44 1865 228753; fax: +44 1865228763. Stange, Department of Internal Medicine 1, Robert Bosch Krankenhaus, PO Box 501120 Auerbachstr, 110, 70341 Stuttgart, Germany.Tel.: +49 711 81013404; fax: +49 711 81013793.

E-mail addresses: [email protected] (S.P.L. Travis), [email protected] (E.F. Stange).1 These authors acted as convenors of the Consensus and contributed equally to the work.





25ECCO Consensus on UC: Current management

5.3. Treatment according to the course or behaviour of disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325.3.1. Treatment of relapse compared to new cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325.3.2. Early relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325.3.3. ‘Steroid-dependent’, active ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325.3.4. Oral steroid-refractory ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325.3.5. Immunomodulator-refractory ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

5.4. Therapy-specific considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355.4.1. Aminosalicylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355.4.2. Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365.4.3. Infliximab (IFX) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365.4.4. Other biological therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375.4.5. Thiopurines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375.4.6. Methotrexate (MTX) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375.4.7. Calcineurin inhibitors (ciclosporin (CsA) and tacrolimus) . . . . . . . . . . . . . . . . . . . . . . . . . 385.4.8. Alternative therapies whose role remains to be established . . . . . . . . . . . . . . . . . . . . . . . 38

5.5. Preparation for the period after treatment of active disease . . . . . . . . . . . . . . . . . . . . . . . . . . . 396. Maintenance of remission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

6.1. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396.1.1. Maintenance therapy trial design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396.1.2. Pattern of disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396.1.3. Risk factors for relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

6.2. Medications for maintenance of remission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406.2.1. Aminosalicylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406.2.2. Thiopurines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436.2.3. Infliximab (IFX) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446.2.4. Probiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456.2.5. Other treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

6.3. Duration of maintenance therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477. Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

7.1. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477.2. Technical considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

7.2.1. Surgery for acute severe colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477.2.2. Managing the rectal remnant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487.2.3. Site of anastomosis for restorative poctocolectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . 487.2.4. Anastomostic technique for restorative proctocolectomy . . . . . . . . . . . . . . . . . . . . . . . . 487.2.5. Site of anastomosis for neoplasia complicating colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . 487.2.6. Role of covering ileostomy for restorative proctocolectomy . . . . . . . . . . . . . . . . . . . . . . . . 497.2.7. Number of procedures to maintain competency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497.2.8. Salvage surgery for pouches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

7.3. Follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497.3.1. General pouch follow up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497.3.2. Pouch surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

7.4. Fertility and delivery in patients with a restorative proctocolectomy . . . . . . . . . . . . . . . . . . . . . . 507.4.1. Impact of pelvic surgery on fecundity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507.4.2. Mode of delivery for patients with restorative proctocolectomy . . . . . . . . . . . . . . . . . . . . 50

7.5. Surgical choices in addition to restorative proctocolectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507.5.1. Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507.5.2. Continent ileostomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507.5.3. Ileorectal anastomosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517.5.4. Cancer surveillance of the rectal remnant after colectomy . . . . . . . . . . . . . . . . . . . . . . . . . 517.5.5. Pouch excision after pouch failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517.5.6. Laparoscopic pouch surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517.5.7. Pouch surgery for indeterminate colitis, or IBD yet-to-be classified . . . . . . . . . . . . . . . . . . 51

7.6. Surgery and medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517.6.1. Perioperative prednisolone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517.6.2. Perioperative azathioprine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527.6.3. Perioperative anti-TNF therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

7.7. Colectomy in practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

ECCO statement 5AMesalazine 1 g suppository daily is the preferredinitial treatment for mild or moderately activeproctitis [EL1b, RG B]. Mesalazine foam enemasare an effective alternative [EL1b]. Suppositoriesmay deliver drug more effectively to the rectumand are better tolerated than enemas [EL3, RG C].Combining topical mesalazine with oral mesala-zine or topical steroid, may bemore effective thaneither alone and should be considered for escala-tion of treatment [EL1b, RG B]. Oral mesalazinealone is less effective [EL1b]

26 S.P.L. Travis et al.

5. Medical management of activeulcerative colitis

5.1. General

The general principles for treating active ulcerative colitisare to consider the activity, distribution (proctitis, left-sided,extensive,1 and pattern of disease (relapse frequency, courseof disease, response to previous medications, side-effectprofile of medication, extra-intestinal manifestation),before treatment decisions are made in conjunction withthe patient.

5.1.1. Disease activityThe principal scoring systems used for clinical trials arecovered in Section 5.1.2 and have been comprehensivelyreviewed.2 Some additional points are clinically relevant.In clinical practice it matters most to distinguish severeulcerative colitis necessitating hospital admission fromthose with mild or moderate disease who can generallybe treated as outpatients. The simplest, best validatedand most widely used index for identifying acute severeUC remains that of Truelove & Wi_tts 3: any patient whohas a bloody stool frequency ≥6/day and a tachycardia(N90 bpm), or temperature N37.8 °C, or anaemia(haemoglobin b10.5 g/dL), or an elevated ESR (N30 mm/h) has severe ulcerative colitis (Table 1.3). This index hasbeen used in 20/32 studies of intensive intravenoustreatment for severe UC.4 Only one additional criterionin addition to the bloody stool frequency ≥6/day isneeded to define a severe attack.5 While these criteriahave the major limitation of being unresponsive andcannot track the course of disease, they do distinguishthe severe from the moderate or mild and have value ineveryday practice because they are easy to use, which noother index achieves. It should be standard practice toconfirm active colitis by sigmoidoscopy or proctoscopybefore starting treatment. Rectal mucosal biopsy helpsexclude unexpected causes of symptoms similar to activedisease (such as cytomegalovirus, amoebic, or otherinfection, rectal mucosal prolapse, Crohn's disease, oreven irritable bowel syndrome and haemorrhoidalbleeding).

5.1.2. ApproachPatients should be encouraged to participate actively intherapeutic decisions. In a systematic review of clinicaltrials, a mean 15% (95%CI 10–21%) of patients enteredremission when receiving placebo.9 Prescribing no treat-ment, however, is rarely an option, because rectalbleeding and urgency are sufficiently concerning to thepatient to justify topical therapy even if no systemictherapy is recommended.

The appropriate choice of medication depends on manyfactors that are best tailored to the individual. Despitegeneral agreement that treatment decisions for active UCshould be based on the distribution, activity and patternof disease, numbers in clinical trials often become toosmall for statistically valid conclusions to be drawn whenpatients are stratified according to the distribution andpattern of disease.7 Different galenic preparations arereleased at different sites and may have local activity

(such as mesalazine preparations, budesonide, or types ofenema). The choice is influenced by the balance betweendrug potency and side-effects; previous response totreatment (especially when considering treatment of arelapse, treatment of steroid-dependent or -refractorydisease, or immunomodulator-refractory disease, Section5.3); and the presence of extraintestinal manifestations(indicating the need for systemic therapy).

5.2. Treatment according to site of disease anddisease activity

5.2.1. Proctitis

Active colitis limited to the rectum should first betreated topically. Suppositories are more appropriate thanenemas, because suppositories target the site of inflam-mation; only 40% of foam enemas and 10% of liquid enemascan be detected in the rectum after 4 hr.10 Topicalmesalazine (5-ASA) induced remission in active proctitisand distal colitis in 31–80% (median 67%) compared to 7–11% given placebo in a meta-analysis of 11 trials in 778patients.11 Topical mesalazine is at least twice as effectiveas topical steroids whether for symptoms (OR 2.42, 95%CI1.72–3.41), endoscopy (OR 1.89, 95%CI 1.29–2.76), orhistology (OR 2.03, 95%CI 1.28–3.20).12 Mesalazine suppo-sitories 1 g daily are highly effective.13 There is no doseresponse to topical therapy above a dose of 1 g mesalazinedaily. Clinical (and endoscopic) remission can occur in up to64% (52%) within 2 weeks.13 Topical steroids should be reservedas second line therapy for patientswho are intolerant of topicalmesalazine.14 Topical mesalazine is more effective than oralmesalazine for proctitis,15 but the combination of oral andtopical mesalazine may be better than either alone for colitisb50 cm from the anal verge.16 There have been no trials oncombination therapy for proctitis alone. Combining topicalmesalazine and steroids also helps: beclomethasone dipropio-nate (3mg) andmesalazine (2 g) enemas produced significantlybetter clinical, endoscopic and histological improvement thaneither agent alone.17 Patients who fail to improve on topicalmesalazine and topical corticosteroids should be treated withadditional oral mesalazine or, alternatively, oral prednisolone,as if the colitis was more extensive or severe (below).Treatment of refractory proctitis is discussed in Section 5.2.7.


5.2.2. Left sided colitis

ECCO statement 5BLeft-sided active ulcerative colitis of mild-moderateseverity should initially be treated with topicalaminosalicylates [EL1b, RG B] combined with oralmesalazineN2 g/day [EL1a, RGA]. Topical steroids ormesalazine alone are also effective, but less effec-tive than combination therapy [EL1b, RG B]. Topicalmesalazine is more effective than topical steroid[EL1a, RG A]. Oral aminosalicylates alone are lesseffective [EL1a, RG A]. Systemic corticosteroids areappropriate if symptoms of active colitis do notrespond rapidly to mesalazine [EL1b, RG C]. Severeleft-sided colitis is usually an indication for hospitaladmission for intensive treatment with systemictherapy [EL1b, RG B]

ECCO statement 5CExtensiveulcerative colitis ofmild-moderate severityshould initially be treated with mesalazine N2 g/day[EL1a, RG A], combined with topical mesalazine[EL1b, RG A]. Oral aminosalicylates alone induceremission only in a minority of patients [EL1a, RG A].Systemic corticosteroids are appropriate if symp-toms of active colitis do not respond rapidly tomesalazine [EL1b, RG C], or who are already takingappropriate maintenance therapy. Severe extensivecolitis is usually an indication for hospital admissionfor intensive treatment [EL1b, RG B]

Combined oral and topical mesalazine therapy is re-commended.14 There has been just one trial on 60 patients ofcombined therapy for distal colitis compared to oral or topicaltherapy alone, showing it toworkmore rapidly andeffectively.16

However, extrapolation from a trial of combination therapy forextensive colitis,18 evidence that topical therapy achieveshigher rectal mucosal 5ASA concentrations than oral therapy19

and is associated with improved clinical outcome,19,20 areconsistent with the recommendation.

Most therapeutic trials of mild or moderate active colitisinclude patients with any disease distribution other thanproctitis, but both oral and topical aminosalicylates (mesala-zine) are effective for left-sided colitis. In a meta-analysis oforal 5-ASA compounds for active colitis,21 mesalazine was morethan twice as effective as placebo (OR 0.40, 95%CI 0.30–0.53),but not significantly better than sulphasalazine (OR 0.83, 95%CI0.60–1.13) for the failure to induce global clinical improvementor remission. Therewas a trend formesalazine to be better thansulfasalazine for endoscopic improvement (OR 0.66, 95%CI0.42–1.04) and mesalazine is better tolerated than sulfasala-zine.21 This is a modest benefit— (NNT to induce remission=10(95% CI 7–21), and NNT=4 to induce response or remission (95%CI 3–6)22). A systematic review of 9 placebo controlled trials oforal aminosalicylates for active ulcerative colitis showed theoverall remission rate to be only 20%.22 Two further placebocontrolled trials of a multimatrix mesalazine formulation formild-moderate UC have been published more recently,23,24 aswell as a combined analysis.25 The first study randomized 280patients to either MMx 4.8 g once daily, MMx 1.2 g twice daily, orplacebo for 8 weeks. The primary endpoint was remission at8 weeks. Once and twice daily dosing produced similar results,with remission rates of 29% and 34% respectively, compared to13% on placebo (pb0.01)23 (see also Section 6.2.1). A furtherplacebo-controlled study compared MMx mesalazine withAsacol® in 346 patients with active, mild-to-moderate UC.24

Clinical and endoscopic remission was achieved in 40.5% givenMMxmesalazine 2.4 g/day once daily and 41.2% given 4.8 g/dayonce daily compared to 22.1% on placebo (p=0.01 and 0.007respectively) and 32.6% given Asacol® (ns).

Meta-analysis of mesalazine for active UC shows a dose-response for improvement from b2.0 g, 2.0–2.9 g and N3.0 g

daily (p=0.002), but not for remission.21 This trend is confirmedby a trial of 4.8 gmesalazine (Asacol®) vs 2.4 gmesalazine dailyin 268 patients with moderately active UC, half of whom haddistal disease. Treatment response was 71.8% in the 4.8 g groupand 59.2% in the 2.4 g group (p=0.036), although remission rateswereonly 20.2% and17.7% respectively (ns).8 Treatmentworkedjust as well for left-sided disease as for extensive colitis, andthere was no increase in side-effects at the higher dose, sohigher doses of mesalazine are recommended for moderatelyactive colitis. A peripheral benefit is a reduction in the mediantime to cessation of rectal bleeding (from 16 days to 9 days(pb0.05)) at the higher dose. This gives a useful timescale fordetermining the speed of response. If rectal bleeding persistsbeyond 10–14days, then the response canbe said to be slowandtherapy augmented, which usually means decisive treatmentwith steroids.

There is something of a transatlantic divide on the thresholdfor using steroids. The practice inmany European countries is tointroduce oral steroids at an early stage, because aminosalicy-lates cannot match the speed of response for patients sufferingmiserable symptoms. The US concern about steroid-inducedside-effects is shared by their patients, but may also be self-fulfilling. Late introduction of steroids selects a more refractorypopulation. Steroids with a colonic release mechanism and lowsystemicbioavailabilty suchasbeclomethasonediproprionateorbudesonide are becoming available. In the largest and mostrecent study of 177 patients with active left-sided or extensivecolitis, beclomethasone diproprionate 5 mg/day had an effectsimilar to that of 2.4 gmesalazine, but without systemic steroidside-effects.26

5.2.3. Extensive ulcerative colitis

The approach is similar to that described for left-sidedcolitis, with the important caveat that there should bea lower threshold for decisive treatment with systemicsteroids. Oral mesalazine is effective,27 but combinationwith topical mesalazine is better. Oral mesalazine(Pentasa®) 4 g/day with a 1 g mesalazine enema in 116patients induced clinical remission by 8 weeks in 64%compared to 43% on oral mesalazine alone (p=0.03).18

This confirms that added benefit of topical mesalazine forextensive colitis. Failure of mild or moderately activedisease to respond within 2 weeks to mesalazine is anindication to consider oral prednisolone. Similarly, if a

ECCO statement 5ESevere active ulcerative colitis with signs of systemictoxicity should be treated in hospital [EL5, RGD]withintravenous steroids (such as methylprednisolone60 mg or hydrocortisone 400 mg daily) [EL1b, RG B].Monotherapy with intravenous ciclosporin (toachieve a minimum therapeutic concentration)[EL1b, RG C] is an option for patients intolerant ofintravenous steroids. Patients are best cared forjointly by a gastroenterologist and colorectal sur-geon [EL5, RG D]


patient already on mesalazine N2 g/day or immunomodulatorsas maintenance therapy has a relapse, decisive treatmentwith steroids is considered appropriate. The reason for thisproactive approach is the risk of complications (includingtoxic dilatation) in patients with extensive disease who areunder-treated.

Treatment with oral and rectal corticosteroids is basedon two early studies on active UC of any extent, includingextensive colitis. Oral prednisolone (starting at 40 mgdaily, with steroid enemas) induced remission in 77% of 118patients with mild to moderate disease within 2 weeks,compared to 48% treated with 8 g/day sulphasalazine andsteroid enemas.28 Similar findings were reported byLennard-Jones,29 who found the combination of oral andrectal steroids to be better than either alone. An ap-propriate regimen for moderately active disease is pre-dnisolone 40 mg/day for 1 week, 30 mg/day for 1 week,then 20 mg/day for 1 month before decreasing by 5 mg/day/week. Many different regimes are used, but it issensible to have a standard approach at any single cen-tre, so that steroid-dependence is recognised at an ear-ly stage and a decision to start immunomodulators isfacilitated. Shorter courses (b3 weeks) are associated withearly relapse and doses of prednisolone b15 mg day areineffective for active disease.30 Oral steroids with lowsystemic bioavailability (budesonide or prednisolone meta-sulphobenzoate, with colonic release mechanisms) areavailable or being developed.31,32

5.2.4. Severe ulcerative colitis of any extentAcute severe ulcerative colitis is a potentially life-threaten-ing condition. The only prevalence data date from 1963: 47/250 (18.8%) first attacks and 109/619 (17.6%) of all patientshave a severe attack as defined by the criteria in Statement5D.33 To grasp the implications of current medical andsurgical therapy requires knowledge of the historicalcontext.

In 1933, 16/21 (75%) died in the first year afteracute presentation with ulcerative colitis in Birmingham34

and in 1950 a mortality of 22% was reported from Oxfordamong 129 cases in the first year after diagnosis.6 In 1955the introduction of steroid therapy reduced mortality ofsevere colitis to 7%, compared to 24% in the placebo group3

and it is now b1% in specialist centres.35 Nevertheless, theresponse to steroids of severe colitis has remained un-changed for 50 years.3,4 In view of this and the 29%colectomy rate (95%CI 28–31%4), the Consensus believesthat patients meeting these criteria are best admitted tohospital for intensive treatment. Management involvesmore than pharmacotherapy.

ECCO statement 5DSevere active ulcerative colitis is best defined byTruelove and Witts' criteria [EL3, RG C]. Patientswith bloody diarrhoea ≥6/day and signs ofsystemic toxicity (tachycardia N90 bpm, feverN37.8 °C, Hb b10.5 g/dL, or an ESR N30 mm/h)should be admitted to hospital for intensivetreatment [EL5, RG D]

5.2.4.1. Investigations on admission. See Section 7.5.3.

5.2.4.2. Therapeutic approach. Intravenous corticoster-oids remain the mainstay of conventional therapy for acutesevere colitis,36 although details (such as the value ofantibiotics or parenteral nutrition) are debated by some. Astherapeutic options increase (ciclosporin, tacrolimus, orinfliximab among others), so too does the opportunity forprocrastinating about surgical decisions. The principal clinicaldilemmas are how to identify at an early stage those who arelikely to need colectomy, and when to start rescue medicaltherapy in time so that surgery, if it becomes necessary, is notinappropriately delayed. The two are not mutually exclusiveand management demands the most taxing clinical judge-ment. Only one patient in a hundred need die as a result ofcomplications caused by operating too late to negate anybenefits ofmedical therapy. This iswhy it is recommended thatpatients should be treated in hospital jointly by a specialistGastroenterologist and Colorectal surgeon.

5.2.4.3. Conventional therapy.

Treatment with corticosteroids should not be delayedawaiting microbiological results for possible infective causes.Corticosteroids are generally given intravenously using, forexample, methylprednisolone 40 mg or hydrocortisone 100 mgfour times daily. Higher doses (including 500 mg–1 g methyl-prednisolone) are no more effective, but lower doses are lesseffective.4,37 Bolus injection is as effective as continuousinfusion.38 Treatment is usually given for about 5 days, sinceextending therapy beyond 7 to 10 days carries no benefit.4

In a systematic review of 32 trials of steroid therapy foracute severe colitis involving 1991 patients from 1974–2006,the overall response to steroids (intravenous hydrocortisone,methylprednisolone, or betamethasone) was 67% (95%CI 65–69%, or 1429/1991).4 Out of the 1991 patients, 565 (29%, 95%CI 28–31%) came to colectomy. Mortality was 1% (22/1991,95% CI 0.7–1.6%) and none of these outcomes changedbetween 1974 and 2006 (R2 =0.07, p=0.8). Because ofsubstantial heterogeneity, it was not possible to discriminatebetween complete and partial responses to steroids. Only aminority (100/1991) received ciclosporin (below).

Other measures are considered appropriate in addition tointravenous steroids:

• Intravenous fluid and electrolyte replacement to correctand prevent dehydration or electrolyte imbalance.

ECCO statement 5FThe response to intravenous steroids is bestassessed objectively (by stool frequency, CRPand abdominal radiography) on or about the thirdday [EL2b, RGB]. Surgical options should beconsidered and discussed at this stage or earlier.Second line therapy with either ciclosporin [EL1b,RG B], or infliximab [EL1b, RG B] or tacrolimus[EL1b, RG B] will often be appropriate. If there isclinical deterioration colectomy is recommended.If there is no improvement within a further 4–7 days, colectomy should usually be recommended[EL5, RG D]. Third line therapy may be consideredat a specialist centre


Potassium supplementation of at least 60 mmol/day isalmost invariably necessary. Hypokalaemia or hypomag-nesaemia can promote toxic dilatation.39

• Sigmoidoscopy or proctosopy and biopsy to confirm thediagnosis and exclude cytomegalovirus infection.

• Stool cultures and assay for Cl difficile toxin.• Subcutaneous heparin to reduce the risk of

thromboembolism.40

• Nutritional support if the patient is malnourished. Enteralnutrition is most appropriate and associated with sig-nificantly fewer complications than parenteral nutritionin acute colitis (9% vs 35%41,). Bowel rest through in-travenous nutrition does not alter the outcome,42 butsome centres use a food challenge after 5 days in anattempt to discriminate between complete and partialresponders to intensive therapy.

• Withdrawal of anticholinergic, antidiarrhoeal agents,NSAID and opioid drugs, which risk precipitating colonicdilatation.39

• Topical therapy (corticosteroids or mesalazine) if toler-ated and retained, although there have been no systema-tic studies in acute severe colitis.36

• Antibiotics only if infection is considered (such as in an acute,first attack of short duration, or after recent admission tohospital), or immediately prior to surgery. Controlled trials oforal or intravenous metronidazole, tobramycin, ciproflox-acin or vancomycin in acute colitis have shown no consistentbenefit in addition to conventional therapy.43–48

• Blood transfusion to maintain a haemoglobin N10 g/dl.

Ciclosporinmonotherapy (CsA,4mg/kg/day intravenously) isas effective as intravenous methylprednisolone (MeP) 40 mg/day for acute severe colitis. In a randomized trial there was aresponse in 10/15 CsA patients vs 8/15 MeP patients.49

Furthermore, half of all patients in another study comparinglow dose with high dose CsA50 also received CsA monotherapy,without concomitant intravenous steroids. Consequently mono-therapy with CsA is a useful option in those patients with severecolitis when steroids are best avoided, such as those susceptibleto steroid-psychosis (schizophrenics or previous psychosis), orfor some other reason (concomitant osteoporosis, diabetes, orpersonal preference).

5.2.5. Intravenous-steroid resistant ulcerative colitis ofany extentThe timing of colectomy for severe colitis remains one of themost difficult decisions that a gastroenterologist has to make.No individual patient wants a colectomy, but it is becomingeasier for physicians to aquiesce with every patient who doesnot want a colectomy as therapeutic options increase. Thequestion is how to do this safely. There are two principaloptions that can be added to intravenous steroids: calcineurininhibitors (ciclosporin or tacrolimus) or infliximab (IFX).

Simple, objective measures are needed to aid decision-making. Factors that predict the need for colectomy in acutesevere colitis can broadly be divided into clinical, biochem-ical and radiological markers. Genetic polymorphisms havethe potential to predict the outcome of disease in anindividual from the time of diagnosis51,52 but they cannot beused for decision-making when colectomy is imminent.

Clinical markers depend on the objective measures ofstool frequency, or temperature. A stool frequency N12/day

on day 2 was associated with 55% colectomy,53 while afrequency N8/day on day 3 of intensive treatment predictedcolectomy in 85% on that admission (‘Oxford index’).5 Thislatter measure has been validated: a frequency N4 and CRPN25 mg/L on day 3 (or when the stool frequency×0.14CRP isN8 on day 3: ‘Sweden index’) predicted colectomy in 75%.54

More recently, CRP and stool frequency on day 3, as well astemperature in children with acute severe colitis predictedthe need for colectomy, in studies that developed a PediatricUC Activity Index55,56 (Section 11.3.3).

Biochemical markers include CRP, albumin and pH. An ESRN75 or a pyrexia N38 °C on admission have been associatedwith a 5–9-fold increase in the need for colectomy in aprospective study of 67 patients.57 In this study, lack ofresponse to steroids was predicted by b40% reduction instool frequency within 5 days. Nevertheless, patients (andtheir doctors) prefer to know an absolute estimate of thelikelihood of colectomy, rather than relative measures. Aretrospective study of 167 patients in whom a high pro-portion (40%) came to colectomy, developed a numericalscore combining mean stool frequency over 3 days, presenceor absence of colonic dilatation and hypoalbuminaemia(b30 g/L) on admission that was associated with the need forcolectomy in up to 85%.58 This needs prospective validation.

Radiological criteria include the presence of colonic di-latation N5.5 cm (associated with a 75% need for colectomy),or mucosal islands on a plain abdominal radiograph (75%colectomy).53 The presence of an ileus (indicated by 3or more small bowel loops of gas) was associated withcolectomy in 73% in a retrospective study,59 but only 50% in aprospective study from the same institution.5 The depth ofcolonic ulceration after gentle air insufflation identified 42/49 patients with deep ulcers that were associated with theneed for colectomy,60 but this is not widely used in clinicalpractice.

Indices exist to be applied, as a threshold for triggeringappropriate action at an early stage. This means surgicalconsultation and assessment by a stomatherapist in additionto augmenting medical treatment. The CRP and stool fre-quency criteria5 are the simplest objective measure, butneither immutable nor always reproduced. Other criteriamay do as well, but must be as straightforward so that adecision to start a calcineurin inhibitor, infliximab, or pro-ceed to colectomy is not inappropriately delayed.


5.2.5.1. Ciclosporin (CsA). A placebo-controlled trial in1994 identified CsA as potential rescue therapy for intrave-nous steroid-resistant UC (IVSR-UC).61 Nine of 11 patientsfailing steroids improved on ciclosporin whilst all 9 onplacebo failed to improve (RR 0.18, 95%CI 0.05–0.64). How-ever, 3/11 and 4/9 eventually underwent colectomy in thetreatment and placebo groups respectively. The narrowtherapeutic index of CsA and its side-effect profile haslimited acceptability. In 2001, out of the 116 consecutivepatients admitted to 29 UK hospitals with severe UC, only 17(15%) received CsA and only 7 of 33 (21%) who came tocolectomy had received CsA.62 In nine studies that used CsAas rescue therapy in the systematic review of severe colitis,only 100/622 (16%) patients treated received CsA.4 The shortterm response was 51% (95% CI 41–60%) and 29% colectomy(95% CI 25–32), but other case series report 70–80% earlyresponse.63–65 Concerns about early toxicity have beenpartly addressed by low dose (2 mg/kg) intravenous induc-tion therapy (Section 5.4.7). In the largest randomized studyof CsA to date, 73 patients were randomized to either 2 mg/kg or 4 mg/kg of intravenous CsA.50 Response rates at 8 dayswere similar in both groups (83% and 82% respectively), with9% coming to colectomy in the 2 mg/kg group and 13% in the4 mg/kg group. The long-term outcome indicates that aminority avoid colectomy. In two series, 58% of 76 patients64

and 88% of 142 patients65 came to colectomy over 7 years. ACochrane review66 concluded that numbers in controlledtrials were so few (only 5049,61) that there was limitedevidence for CsA being more effective than standard treat-ment alone for severe UC.

5.2.5.2. Tacrolimus. Tacrolimus is another calcineurininhibitor, acting through a mechanism similar to CsA (Section5.4.7). One randomised controlled trial has been performedin ulcerative colitis that included 27/60 patients with acutesevere colitis.67 9/16 had a partial response to 0.05 mg/kg/day adjusted to trough levels (up to 15 ng/mL), compared to2/11 on placebo and the remainder had no response. Resultsdid not reach significance. Case series have shown broadlysimilar results to ciclosporin after both intravenous (0.01 to0.02 mg/kg) and oral (0.1 to 0.2 mg/kg) administration(Table 5.2). It carries many of the risks (including nephro-toxicity) of ciclosporin, although tacrolimus is a more ef-fective immunomodulator than ciclosporin in renal or livertransplantation (see Table 5.1).68,69

5.2.5.3. Infliximab. Infliximab as a single dose (5 mg/kg)may also be effective rescue therapy. A Swedish–Danishstudy treated 45 patients (24 IFX and 21 placebo withcontinued intravenous betamethasone).73 7/24 in the IFX

Table 5.1 Case series of tacrolimus for steroid-refractory ulcerasimilar patients

Series n Response

Ciclosporin (iv 4 mg/kg, then oral) 76 56/76Tacrolimus iv 0.01/oral 0.2 mg/kg 38 18/38Tacrolimus iv 0.01 mg/kg 23 22/23Tacrolimus oral 0.15 mg/kg 9 9/9

group and 14/21 in the placebo group had a colectomywithin 3 months (p=0.017; OR 4.9, 95% CI 1.4–17). Nopatient died. Two different scores were used to identifypatients before randomization to IFX or placebo. TheSweden Index54 on day 3 identified sicker patients at anearlier stage than the Seo Index74 calculated on day 5–7. Itwas the group with less active disease after 5–7 days ofintravenous steroids who benefited most from IFX. Therehave been other small studies of IFX for acute severe colitisrefractory to steroids that have not shown a difference incolectomy.75–77 It should be noted that hospitalizedpatients with severe colitis represent a very differentpopulation to the outpatients in the ACT 1 & 2 studies78 (seeSection 5.4.3). A large controlled trial is needed, becausecase series report 20%, 33%, 57% or 75% ultimately coming tocolectomy after IFX for intravenous-steroid resistantulcerative colitis.79–82

5.2.5.4. Selection. A recommendation on the best choicebetween calcineurin inhibitors and IFX in addition tointravenous steroids is not possible until there has been acomparative, randomised controlled trial. Controlled trialscomparing CsA and IFX are n progress (2007/08). The in-dividual circumstances of each patient have always to beconsidered. If a patient has acute severe colitis despite ex-isting treatment with an immunomodulator at an appro-priate dose and duration, then there is little that medicaltherapy can hope to offer since it is unlikely that remissioncan be maintained. The effect of IFX as maintenance therapyin these circumstances is unclear: such patients are adifferent to those in the ACT trials and the risks, as wellas the potential benefit, of deferring (or even avoiding)colectomy need careful discussion with individual patients.Many gastroenterologists will be more familiar with theadverse-event profile of IFX compared to CsA or tacrolimus.The short half life of CsA, however, is a potential advantagecompared to IFX. Consequently if CsA does not work, it is onlya matter of hours before it disappears from the circulation,while IFX will circulate for weeks. This may matter ifcolectomy is performed, since septic complications are themajor cause of post-operative morbidity and mortality.82

Although IFX is reported not to increase post-operativesepsis,83 no data are available that relate only toemergency colectomy for sick patients with acute severeUC (Section 7.6.3). In general only a single attempt atrescue therapy with a calcineurin inhibitor or IFX should beconsidered before colectomy, after careful discussionbetween the patient, gastroenterologist and colorectalsurgeon about the options and potential outcomes. Ifdoubt persists, specialist advice should be sought at an

tive colitis, compared to a case series of ciclosporin therapy in

Colectomy at Ref

1–3mo 1 year 2 year

10/76 16/76 16/76 643/38 12/38 19/38 70

2/23 3/23 711/9 – 3/9 72


early stage from a referral centre. Use of IFX with CsA hasbeen associated with a particularly high rate of adverseevents (see Section 7.6.3).

5.2.6. Toxic dilatation and complications of severeulcerative colitis

5.2.6.1. Toxic megacolon. Toxic dilatation (megacolon)represents the end of a spectrum of severe colitis that hasbeen unrecognized, undertreated, or refractory to appropriatetreatment. It is defined as total or segmental non-obstructivedilatation of the colon N6.0 cm associated with systemictoxicity.39,84 The incidence has never been studied system-atically. About 5% of patients with acute, severe colitisadmitted to hospital will have toxic dilatation.39 Metabolicdisturbance (hypokalaemia or hypomagnesaemia), bowel pre-paration, or anti-diarrhoeal therapy have been associated withtoxic dilatation,39 so these should be corrected or avoided.Earlier diagnosis of severe colitis, more intensive medicalmanagement and earlier surgery has reduced the incidence oftoxic megacolon complicating ulcerative colitis, but theincidence for infective colitis is rising, reflecting the increasingprevalence and severity of pseudomembranous colitis.85

The key aspects of management are aggressive medicaltherapy and early surgical decision making. It is no differentto conventional therapy for acute severe colitis, except thatmetronidazole 500 mg three times daily is appropriate onempirical grounds in case of an infective aetiology. Thecombination of steroids and antibiotics is safe even forinfective colitis; steroids reduce inflammation in pseudo-membranous colitis.86 Nasogastric suction cannot be ex-pected to decompress the colon and is unnecessary. Theclassic knee-elbow position may relieve distension,87 but isgenerally impracticable. A senior surgical opinion is bestsought on the day of admission. It should be made clear to allthat there is a 24 h window of opportunity for medicaltreatment to work and that if there is no improvement thenearly colectomy will be necessary.

5.2.6.2. Perforation, haemorrhage and others. Perforationis themost serious complication of acute severe colitis, almostinvariably associated with colonoscopy or toxic dilatationwhere colectomy has been inappropriately delayed. It carriesa mortality of up to 50%.39 Other complications appearexceptional, including massive haemorrhage (1/66 patientsoperated on for acute severe colitis in one series88), cerebralsinus thrombosis40 and a poorly recognised panenteritis.89–91

In a review of 158 middle-aged or older American patientswith ulcerative colitis, however, 20/158 had toxic dilatation,perforation or massive haemorrhage and 7/20 died.92

5.2.6.3. Long term outcome of severe colitis. The longterm outcome after admission with acute severe ulcerativecolitis is not good. When the outcome of a small, butprospectively-collected cohort of patients who had avoidedsurgery on the index admission was reexamined after15 years, 8/22 (36%) complete responders to steroids cameto colectomy, compared to 8/10 incomplete responders(stool frequency N3/day, or those with visible blood in thestools at day 7, p=0.082).93 Median time to colectomy was33.0 months (CI 12.6–67.1) for complete responders vs6.0 months (95% CI 0.9–17.7) for incomplete responders

(p=0.033). The longest period of steroid-free remission wasa median 45.0 months (CI 28.2–63.2, range 0–120) forcomplete, but a median 8.5 months (CI 4.3–22.1, range 1–35) for incomplete responders (p=0.017). Data on theburden of medical and surgical treatment of severe colitisand attendant complications, related to patient-orientatedoutcomes (hospitalization, time off work, colectomy andmortality) are still required.

5.2.7. Refractory proctitis and distal colitisRefractory proctitis and distal colitis present commonclinical dilemmas.94,95 There are few trials on this specificpopulation, but a coherent therapeutic strategy is needed ifpatients (and their doctors) are not to get frustrated bypersistent symptoms.

Reasons for refractoriness include poor adherence withtherapy, inadequate concentrations of the active drug, thewrong drug, unrecognised complications (such as proximalconstipation or infection) or inappropriate diagnosis (such asco-existent irritable bowel syndrome, unrecognised infec-tion, Crohn's, mucosal prolapse, or very rarely, cancer). Thefirst step is therefore an empathetic review of symptoms andtreatment to date, followed by reassessment of the diagnosisby colonoscopy and serial biopsy. Commonly, a co-existentirritable bowel accounts for more symptoms than activedisease. The next step is to ensure that conventional thera-py (Sections 1.2.1 and 1.2.2) has been vigorously applied.Attention in particular should be paid to topical therapy(topical mesalazine together with topical steroids, afterconsidering suppositories and the type of enema for thedistribution of disease) in conjunction with oral therapy. Thenext step is to treat proximal constipation, since abnormalintestinal motility induces proximal colonic stasis in patientswith distal colitis and this affects drug delivery. In 12 patientswith active left-sided disease, scintigraphy showed that 91%of a labelled, Eudragit-coated resin remained in the proximalcolon, so that only 9% (95%CI 4–15) reached the distal co-lon compared to 31% (95%CI 24–37) in 22 healthy controls(pb0.001).96 Consequently, if sigmoidoscopic inflammationpersists after treatment with topical mesalazine and oralsteroids, a plain abdominal radiograph is appropriate. Ifthere is visible faecal loading in the descending colon, avigorous laxative is appropriate, after explaining the paradoxof proximal constipation despite distal diarrhoea. If symp-toms do not resolve within another 2–4 weeks, distal colitis isbest treated as if it was more extensive or severe.

Refractory distal colitis respondsmore rapidly and better tointensive treatment than oral or topical therapies. In39 patients with distal disease refractory to outpatienttreatment with oral steroids and mesalazine, remission wasachieved by intensive treatment within a week in 90%.97

Should the response be poor, CsA, tacrolimus, or IFX can betried, but only if there is a prospect for maintaining remission.There is a tendency to opt for these treatments beforeadmission for intensive therapy, with a view to continuingtreatment as an outpatient. 56% in the ACT 1&2 studies hadleft-sided or distal colitis. However, the patient must realisethat the steroid-free remission rate after 7 months (30 weeks)on IFX is only 21%78 (see also Section 5.3.3). If disease persistsin spite of these approaches, surgery is likely to be theoutcome, but if the patient is not acutely ill then the decisionshould never be precipitate and a range of topical or anecdotal

ECCO statement 5HPatients with persistently active, steroid-refractorydisease should be treated with azathioprine/mer-captopurine [EL1b, RG B], although surgical optionsshould also be considered and discussed. Intrave-nous steroids, infliximab [EL1b, RG B] or calcineurin


therapies are available (Table 5.2).98–134. The choice dependson local availability and personal preference, since many haveto be made up individually by pharmacy. Clinical judgementand an honest appraisal about the impact of symptoms on thequality of life or employment are necessary.

Up to 10% of patients who have a colectomy for refractoryUC only have distal disease. A total colectomy has to beperformed, usually with ileoanal pouch formation (Section7.2), because segmental resection leaves that part of thecolon most affected and is almost invariably followed byrelapse affecting previously normal bowel. The outcome ofcolectomy and pouch formation for distal colitis is usuallygood. In 263 patients who had a restorative proctocolectomyat one French centre (1986–96), 27 had surgery for distaldisease.135 There was a significant decrease after surgery inmean (SD) diurnal stool frequency (8.2(4) vs 4.7 (2) pb0.05),nocturnal stool frequency and urgency (pb0.001). Previouslyunknown severe dysplasia was identified in 2 patients. All butone patient were satisfied with the results and 25/27 wishedthat they had had surgery sooner.

5.3. Treatment according to the course orbehaviour of disease

Treatment decisions differ between patients at initial pre-sentation and subsequent relapse, depending on the patternof relapse and previous response to therapy. Some patientshave active disease that persists in spite of appropriatetreatment and these are best considered as a separategroup with steroid-refractory disease (see definitions). Ithelps management to recognise other treatment-refractorygroups (immunomodulator-refractory, or anti-TNF-refrac-tory), but precise definitions have not been agreed (Section5.2). They represent an important group of patients whomerit study.

5.3.1. Treatment of relapse compared to new cases

inhibitors [EL3, RG C] should also be considered

ECCO statement 5GPatients who relapse should usually be treatedwith the therapy that was previously effective[EL5, RG D]

The initial treatment of relapse best uses the treatmentthat worked first time, but consideration should be given toother factors and maintenance therapy should be optimised.These include the views of the patient (adverse effects,necessary speed of response, convenience, etc), timing ofrelapse, concurrent therapy (whether a relapse occurredduring treatment with immunomodulators) and adherencewith maintenance therapy.

5.3.2. Early relapseAny patient who has an early (b3 months) relapse is beststarted on azathioprine (AZA) or mercaptopurine (MP),because the treatment strategy should think beyond thecurrent relapse and aim to reduce the risk of a furtherrelapse. Opinion is divided whether to use the same treat-ment to induce remission and taper more slowly, use more

potent induction therapy, or to increase maintenance ther-apy. It is generally unnecessary to re-evaluate the distribu-tion of disease unless this will influence medical or surgicalmanagement. Continued medical therapy that does notachieve steroid-free remission is not recommended.

5.3.3. ‘Steroid-dependent’, active ulcerative colitisAzathioprine is significantly more effective than mesalazineat inducing clinical and endoscopic remission inthe treatment of steroid-dependent UC. 72 patients withsteroid-dependent, active UC were randomised to receiveAZA 2 mg/kg/day or oral mesalazine 3.2 g/day, in additionto prednisolone 40 mg/day.136 53% on AZA achieved steroid-free clinical and endoscopic remission after 6 monthscompared to 21% on mesalazine (OR 4.78, 95%CI 1.57–14.5). Infliximab also has a steroid-sparing effect whenadministered every 8 weeks for up to 1 year.78. 408/728(56%) were taking steroids at study entry in the two ACTstudies. After 7 months (30 weeks), 10/139 (7%) on placeboand 28/130 (21%) on 5mg/kg IFX every 8 weeks had achievedsteroid-free remission (p=0.01). After 12 months (ACT 1),the figures were 9% and 26% respectively (p=0.006) (Section5.3.4). AZA should be the first choice of therapy in apparentsteroid dependence. The balance in decision-makingbetween IFX and surgery is addressed above (Sections1.2.3, 1.2.4) and the efficacy of continued AZA or IFX formaintaining remission in Sections 2.2.2 and 2.2.3.

5.3.4. Oral steroid-refractory ulcerative colitis

For active UC that is refractory to steroids, other causesof persistent symptoms including coexistent cytomeg-alovirus, or cancer should be considered. If active UC isconfirmed, immunomodulators should be added and cal-cineurin inhibitors, biological therapy or surgery consid-ered (Section 5.2.5, 5.4.3). Infliximab is indicated if sepsishas been excluded and surgery thought inappropriate atthat stage. The timing of surgery depends on the severityof symptoms, inflammatory burden and other considera-tions (Sections 1.2.4, 1.2.5, 1.4.3). The patient's gender,age, fecundity and extent of disease should be taken intoaccount. The sequence (or hierarchy) of therapy has todepend on the individual circumstances and views of thepatient.

5.3.5. Immunomodulator-refractory ulcerative colitisImmunomodulator-refractory disease is also best reassessedby colonoscopy and biopsy to confirm the diagnosis andexclude complications. A therapeutic strategy that includesconsideration of how steroid-free remission will be achievedand maintained should be discussed with the patient. In the

Table 5.2 Summary of therapies for distal colitis

Agent Proposed mechanism Dose and duration Design n Outcome Ref

Anaesthetic gel Neuroimmune modulation Lignocaine (800 mg) daily. 6–34 weeks Open 100 Remission 10% proctitis, 83% distal colitis.Most had refractory disease; response in6 patients with pancolitis

99

Lignocaine (600 mg) daily. 6 weeks Open 22 12/22 ‘excellent’, 4/22 ‘very good’ response(refractory UC)

100

Ropivacaine (400 mg) daily. 2 weeks Open 12 Clinical and endoscopic improvement(pb0.05)

101

Ropivacaine (200 mg) single dose Random 33 Rectal eicosanoid & neuropeptideconcentrations similar after ropivacainein 19 distal UC compared to 14 controls

102

Appendicectomy Altered Th1/Th2 balance Surgery Cases 16 Remission, with no recurrence for up to3years

103

Arsenic Uncertain Acetarsol (500 mg) vs prednisolone (5 mg)suppositories. 2 weeks

Random 20 9/10 clinical/endoscopic improvement(refractory distal colitis). Potential toxicityin 6/10 (1 week) 2/10 (4 weeks)

104

Bismuth compounds Enhanced mucosal barrier?Reduced bacterial adhesion

Bismuth carbomer (450 mg) enema vs5-ASA (2 g) enema. 4 weeks

Random 63 Bismuth 39% remission, 56% 5-ASA (p=0.16) 105

Bovine colostrum Source of growth factors forepithelial restitution

Colostrum 10% (100 mL enema) vs placebo(albumin) 4 weeks

Random 14 Activity index −2.9 (−0.3 to −5.4) incolostrum group, vs +0.5 (−2.4 to +3.4)in placebo

106

Ciclosporin enemas T-cell immunosuppression Cyclosporin 350 mg vs placebo. 4 weeks Random 40 Cyclosporin 40% improvement vs placebo45%. Open trials in refractory distal UCmore favourable

107

Epidermal growthfactor enemas

Epithelial restitution/repair EGF 5mcg (100 mL enema) vs placebo.12 weeks

Random 24 83% remission at 4 weeks vs 8% on placebo.Rapid and promising; needs repeating.Concern about malignancy

108

Ecabet sodiumenema

Mucosal protection Ecabet sodium 1 g in 20–50 mL. 2 weeks Open 8 Clinical activity index decreased(5.3+1.4 to 0.5+0.8, pb0.05)

109

Immunoglobulin Genemas

Immune response promoter IgG enema Open 7 Ineffective. 1/7 improved. 110

Interleukin-10enemas

? IL-10 deficiency in UC IL-10 100mcg enema for 10 days Open 3 Endoscopic response in refractoryleft-sided colitis

111

Leukocytapheresis ?monocyte adsorption Weekly for 5 weeks Open 30 Clinical remission 21/30 112Nicotine Smoking protective. Transdermal nicotine (15–25 mg) vs

placebo 6 weeksRandom 72 Nicotine 48% remission, placebo 24%

(p=0.03)113

Transdermal nicotine vs placebo. 6 m Random 80 No difference between groups formaintenance therapy

114

Transdermal nicotine (15–25 mg) vsprednisolone (5–15 mg). 6 weeks

Random 61 Nicotine 21% remission vs 47% prednisolone(p=0.035), intention to treat. 11/31nicotine withdrawals (side-effects)

115

(continued on next page) 33EC

CO

Consensus

onUC:Current

managem

ent

Table 5.2 (continued)

Agent Proposed mechanism Dose and duration Design n Outcome Ref

Nicotine Smoking protective. Transdermal nicotine vs placebo. 4weeks Random 64 Nicotine 39% clinical response, placebo9% (p=0.007)

116

Transdermal nicotine (15 mg) with 5ASAenema vs enema+mesalazine2.4 g. 4 weeks

Random 30 Remission 12/15 on nicotine+5ASA enema,5/15 on oral 5ASA+enema (p=0.027)

117

Nicotine tartrate enemas (3–6 mg). 4 weeks Open 10 5/7 improved (previously unresponsive UC).3 withdrawals

118

Nicotine carbomer enemas (6 mg). 4 weeks Open 22 16/17 improved (previously unresponsive).6 withdrawals

119

Propionyl-L-carnitine(PLC) enemas

Epithelial (SCFA) nutrition PLC 6 g (200 mL) twice daily. Open 10 8/10 ‘improved significantly’ 120

Rebamipide Cytoprotective proprionicacid

Enema twice daily, oral steroids continued Open 20 55% remission 9still on steroids) at 3 weeks 121

Short chain fattyacids (variablecomposition)

Epithelial nutrition SCFA mixture vs 5-ASA or steroid enema.6 weeks

Random 45 Most improved in all three groups 122

SCFA mixture vs placebo. 6 weeks Random 40 70% SCFA clinical response, 20% placeboNo change in endoscopic or histology scores

123

SCFA mixture. 6 weeks Open 10 5/10 responded well (refractory distalcolitis)

124

SCFA mixture vs placebo. 6 weeks Random 103 No difference in clinical or histologicalresponse

125

SCFA vs butyrate or placebo. 6 weeks Random 47 No difference between three groups 126Butyrate vs placebo. 6 weeks Random 38 No difference 127

Sucralfate Enhanced mucosal barrier Sucralfate 4 g vs prednisolone meta-sulphobenzoate 20 mg enemas. 4 weeks

Random 44 Predenema 71% cessation of bleeding,sucralfate 28%

128

Sucralfate 10 g vs 5-ASA 2 g vs placebo4 weeks

Random 50 5-ASA superior. Sucralfate no differentfrom placebo

129

Sucralfate 10 g vs hydrocortisone 100 mgenemas. 4 weeks

Random 40 Hydrocortisone 42% remission, sucralfate15%, (pb0.05)

130

Sucralfate 20 g vs methylprednisolone 20 mg(100 mL) twice daily. 4 weeks.

Random 60 No difference between groups 131

Thromboxane A2inhibitor

Inhibition of inflammatorymediator

Ridrogel 300 mg vs prednisolone 30 mg enemas.4 weeks

Random 40 Ridrogel 65% endoscopic remission vs prednisolone75%(no difference)

132

Ridogrel 300 mg (40 mL) Open 11 Decrease in mucosal TxB2, but notother PGs

133

Wheat grass juice Prebiotic and antioxidantTriticum aestivum

WGJ (100 mL) vs placebo Random 21 Decrease in activity index (p=0.031)and rectal bleeding (p=0.025)compared to controls

134

34S.P.L.

Traviset

al.

ECCO statement 5IInfliximab [EL1b, RG B] or surgical options shouldbe considered. Continued medical therapy thatdoes not achieve steroid-free remission is notrecommended [EL5, RG D]


absence of contraindications infliximab should be considered(Section 5.4.3) as well as colectomy, which may be mostappropriate.

5.4. Therapy-specific considerations

The therapeutic goal should be to induce steroid-free clinicalremission, but it is essential to keep in mind how remissionwill be maintained (Section 6). The treatment strategydepends primarily on the activity and distribution of UC(Section 5.2); the current section considers drug-specificaspects of treatment not addressed in that section.

5.4.1. Aminosalicylates

5.4.1.1. Efficacy of aminosalicylates. Much is made ofhow different delivery systems may influence response, butevidence that it matters in clinical practice is remarkablythin. Delivery systems can be divided into azo-compounds,controlled release, pH-dependent (either pH6 or pH7) andcomposite (pH-dependent combined with controlled release)(Table 5.3137–139).

Systematic reviews and meta-analyses concur that amino-salicylates are effective for treating active UC.21,22,27 The NNT

Table 5.3 Delivery systems for 5-ASA137,138

Delivery system

Azo-bondSulfasalazine Sulfapyridine carrierOlsalazine 5-ASA dimmerBalsalazide 4-amino-benzoyl-β-alanine

Controlled releasePentasa® Ethylcellulose coated microg

pH7-dependentAsacol® Eudragit-S coating, dissolvesMesren® SameIpocol® Same

pH6-dependentSalofalk® Eudragit-L coating, dissolvesMesasal® SameClaversal® Same

Composite(‘multimatrix’)Mezavant® (EU)Lialda® (US)

Eudragit-S coating of hydropwith some 5ASA and lipophiliencapsulating 5ASA

to induce remission is 10 (95%CI 7–21), although for the lessertarget of response or remission the NNT is 4 (95%CI 3–6)22).Available data do not suggest a difference in efficacy betweenany of the 5-ASA preparations for active UC. Six trials withmesalazine (including two trials on MMX mesalazine) showstatistical significance vs placebo.23, 24,140–142,147 Those witholsalazine143–146 or balsalazide [unpublished, see ref 27] do not.

Mesalazine is shown to be as effective as sulfasalazine forinducing response or remission (OR 0.83, 95%CI 0.60–1.1321)in the most recent meta-analysis, and is better tolerated.There have been few clinical trials comparing the efficacy ofnewer aminosalicylates for inducing remission. In 2 of 3 trialsof balsalazide vs mesalazine, results for defined primary andsecondary endpoints failed to demonstrate statistically sig-nificant differences.148–150 Another study compared Ipocol, apH7-dependent release mesalazine, with Asacol and foundno significant difference in remission rates after 2.4 g/d for8 weeks.151 Proprietary prescribing of mesalazine is recom-mended,152 but for active UC the choice of 5ASA cannot bemade on the grounds of efficacy alone. The route of delivery,dose frequency, cost and availability are more relevantfactors in the choice.

5.4.1.2. Adverse effects of aminosalicylates. Mesalazinehas a topical action on colonic epithelial cells, where it isalso metabolised. Systemic exposure is therefore unneces-sary. This means that drug efficacy cannot be deduced frompharmacokinetic comparisons, but absorption might con-ceivably influence adverse events. Despite variable differ-ences in peak serum concentrations, ratio of 5ASA to itsmetabolite N-acetyl 5ASA, however, the systemic exposureto equimolar doses of all 5-ASA compounds is similar

Mean peak plasma[5ASA] (μmol/L)

Mean systemicexposure(AUC, μmol/L.h)

0.7–3.5 9.6–27.51.2–4.5 –2.3–3.5 13.9–22.8

ranules 6.5 28.5

at pH7 2.1–10.5 21.5–25.1– –– –

at pH6 10.9 38.35.2 (median) 21.5 (median)–

hilic polymerc excipients

– no published data

Table 5.4 Placebo-controlled trials of newer aminosalicylates for active UC

n Dose, g (n) Weeks Remission (unless otherwise stated) Ref

Asacol®Schroeder 1987 87 4.8 (38), 1.6 (11), 0 (36) 6 24% vs 5% (4.8 vs 0, p=0.047) 140Sninsky 1991 158 2.4 (53), 1.6 (53), 0 (52) 6 Response 49% vs 23% (2.4 vs 0, p=0.004) 141

BalsalazideSalix (unpublished) 180 6.75 (72), 4.5 (73), 0 (35) 4 Response 45% vs 45% (6.75 vs 0, ns) 27

MMx mesalazineLichtenstein 2007 280 4.8 g×1 (94), 1.2 g×2 (93), 0 (93) 8 29% vs 13% (4.8 g×1 vs 0, p=0.009) 23Kamm 2007 343 4.8 g×1 (85), 2.4 g×1 (84), 0 (86)

Asacol 0.8g×3 (86)8 41.2% vs 40.5% vs 22.1% vs 32.6%

(4.8g×1 vs 0, p=0.007)24

Pentasa®Hanauer 1993 374 4 (95), 2 (97), 1 (92), 0 (90) 8 29% vs 12% ( 4g vs 0, p=0.0012) 142

OlsalazineMeyers 1987 66 3 (15), 1.5 (16), 0.75 (15), 0 (20) 3 Improvement 50% vs 16% (3 vs 0, p=0.055) 143Hetzel 1988 30 2 (15), 0 (15) 8 Improvement 40% vs 11% (p=0.11) 144Feurle 1989 105 2 (52), 0 (53) 4 Improvement (ns, no absolute numbers) 145Zinberg 1990 15 3 (7), 0 (8) 4 Improvement (4/7 vs 0/8, pb0.05) 146

Rowasa®Sutherland 1990 136 4 (47), 2 (45), 0 (44) 6 Improvement 45% vs 18% (4 vs 0, pb0.05) 147


(Table 5.4). Mesalazine intolerance occurs in up to 15%.Diarrhoea (3%), headache (2%), nausea (2%), rash (1%) andthrombocytopenia (b1%) are reported, but a systematic reviewhas confirmed that all new 5-ASA agents are safe, with adverseevents that are similar to placebo for mesalazine or olsala-zine.153 Acute intolerance in 3%may resemble a flare of colitissince it includes bloody diarrhoea. Recurrence on rechallengeprovides the clue. Renal impairment (including interstitialnephritis and nephrotic syndrome) is rare and idiosyncratic. Apopulation-based study found the risk (OR 1.60, CI 1.14–2.26compared to normal) to be associated with disease severityrather than the dose or type of mesalazine.154

5.4.1.3. Monitoring. Patients with pre-existing renal im-pairment, other potentially nephrotoxic drugs, or co-morbid disease should have renal function monitoredduring 5-ASA therapy. Many clinicians believe that creati-nine and full blood count should be monitored every 3–6 months during aminosalicylate therapy, although there isno evidence favouring one monitoring regime over another.

5.4.2. Corticosteroids

5.4.2.1. Efficacy of steroids. There have been only twoplacebo controlled trials of conventional oral steroids foroutpatientswith active UC,29,155 giving anNNTof 2 (95%CI 1.4–5).22 More recently, when 86 (out of a total of 136) newlydiagnosed patients with UC were treated with steroids, 51%,31% and 18% had a complete response, partial or no responserespectively at 30 days.156 However, this includes a group of22/86 who had acute severe colitis needing intravenoustreatment. At one year, 55% were in steroid-free remission,17% were steroid-dependent, 21% had surgery and 7% lostto follow up, but the inclusion of severe colitis makes this

difficult to extrapolate to outpatient therapy. Adverse effectsandmonitoring of steroid therapy are the same as described inthe Consensus guidelines on Crohn's disease.157

5.4.3. Infliximab (IFX)

5.4.3.1. Efficacy of IFX. A systematic review of the efficacyof IFX for treating patients with moderate to severe UCrefractory to corticosteroids and/or immunomodulators, con-cluded that it was effective for inducing clinical remission,clinical response, promoting mucosal healing, and reducingthe need for colectomy in the short term.158 The review tookthe description of ‘severe’ at face value and failed to discri-minate between out-patients and in-patients with acutesevere colitis. Nevertheless, in seven RCTs, IFX (threeintravenous infusions at 0, 2, and 6 weeks) was more effectivethan placebo in inducing clinical remission (RR 3.22, 95%CI2.18–4.76). Itwas alsomoreeffective thanplacebo at inducingendoscopic remission (RR 1.88, 95%CI 1.54–2.28) and clinicalresponse (RR 1.99, 95% CI 1.65–2.41) at 8 weeks.78,159–162 Asingle infusion of infliximab was also more effective thanplacebo in reducing the need for colectomy within 90 daysafter infusion (RR 0.44, 95%CI 0.22–0.87).73 The ACT 1&2studies are pivotal.78 They are impressively consistent,showing double the remission rate compared to placebo. ACT1was a 364 patient study inmoderately activeUC refractory tooral steroids and/or thiopurines, given IFX 5 mg/kg, 10 mg/kg,or placebo at 0, 2 and 6 weeks, then every 8 weeks for a year.The primary endpoint at week 8 was response (N30% and a 3point decrease in the Mayo activity index, with virtualcessation of rectal bleeding). This was achieved: 37.2%(placebo), 69.4% (5 mg/kg) and 61.5% (10 mg/kg), pb0.001).So too were pre-defined secondary endpoints of remission(14.9%, 38.8% and 32.0% respectively) and mucosal healing


(33.9%, 62.0%, and 59.0%). Duration of effect was maintainedthrough week 30 in all respects (remission in 15.7%, 33.9% and36.9%, pb0.001). The same goes for ACT 2, an almost identicaltrial of a further 364 patients, but who could have moderatelyactive UC despite 5-ASA alone (26%) and was 6 months'duration. Response (and remission) rates at week 8were 29.3%(5.7%, placebo), 64.5% (33.9%, 5 mg/kg) and 69.2% (27.5%,10 mg/kg, pb0.001). The flat dose-response is comparable tothat of IFX for Crohn's disease.157 Unfortunately, a largetherapeutic gap persists despite being on 5 mg/kg IFX every8weeks, becauseonly21% (at 7months) and26% (at 12months)achieved steroid-free remission (see Section 5.3.3). This isimportant because the Consensus stresses the importance ofachieving steroid-free remission. Further analysis of the ACT 1& 2 trial data indicates that there was an associated reductionin colectomy (hazard ratio 0.57, 95% CI 0.37–0.89) during thetrial,165 but whether this benefit is maintained remainsunclear.The actual role of IFX for UC refractory to conventionaltherapy for both outpatients and inpatients is discussed inSections 1.2.5, 1.2.7, 1.3.3, 1.3.4 and 1.3.5.

5.4.3.2. Adverse effects of IFX. Treatment with IFX isrelatively safe if used for appropriate indications. Adverseevents in the ACTstudies78were nodifferent to those expectedfrom large experience of treating Crohn's disease.163,164

Nevertheless, in common with other biological therapy thereis a risk of serious infection, demyelinating disease andassociated mortality. In the combined analysis of 484 patientswith UC who received IFX in the ACT trials there were 8 whodeveloped pneumonia, 1 tuberculosis and 1 histoplasmosis(who later died) as well as 4 neoplasia (all probably pre-existing, but presenting in the trial period) and 3 neuropathies(2 optic neuritis, 1 multifocal motor), equivalent to 3.5% (17/484). By contrast, in the 244 who received placebo there wasjust 1 basal cell carcinoma. Prolonged medical therapy for apotentially pre-malignant condition with anti-tumor necrosisfactor therapy creates its own anxieties. Tighter surveillanceto detect dysplasia may be necessary, although no evidence-based recommendations can currently be given.

5.4.4. Other biological therapyDespite the proliferation of biological therapies, only few havebeen applied to UC.Adalimumab is an anti-TNF agent similar toIFX, but given subcutaneously with less immunogenicity. Thereare current trials in UC. Visilizumab is an anti-CD3 monoclonalantibody binding to activated T-cells to induce apoptosis. Adose-ranging study in 69 patients with severe, intravenoussteroid-resistant UC showed a 30 day remission rate of 30% (60%response) to 5microg/kg given on two consecutive days.166 APhase III study in intravenous steroid-resistantUC, however,wassuspended in Q307 when interim analysis showed no benefit.Alicaforsen is an anti-sense oligonucleotide to human ICAM1.A complex dose-ranging protocol in 112 patients showed that a240 mg enema every night for 6 weeks was more effective thanplacebo. Remission was only 14% at 6 weeks, but response wasthen maintained for 6 months in 80% compared to 44% onplacebo,167 or a median 146 days compared to 54 days aftermesalamine enemas in another study.168 Another selective anti-adhesionmolecule strategy is also effective for UC. IntravenousMLN-02 (an α4β7 integrin antagonist) was given to 181 patientswithmoderately activeUC.169 Clinical remission rates atweek 6were 33% and 32% for 0.5 mg and 2.0 mg/kg respectively,

compared to 14% on placebo (p=0.03). Although one IL-2receptor (CD25) inhibitor, basiliximab, has shown potential inopen studies for steroid-refractory UC170 another CD25 inhi-bitor, daclizumab, was ineffective in a controlled trial of 159patients with moderately active UC.171 Certolizumab has notyet beenevaluated forUC.172 AnAmerican–European reviewonbiological therapy for UC has been published.173

5.4.5. Thiopurines

5.4.5.1. Efficacy of azathioprine/mercaptopurine. Dataon thiopurines for active UC are few.167 There have been fiveplacebo-controlled trials of AZA for active UC, of between20 and 80 patients each, with differing entry criteria, dose andduration.136,174–178 Data from a recent, well conducted studyon steroid-dependent active UC131 are discussed in Section5.3.3. The main role for thiopurines are as steroid sparingagents (NNT 3). Immunomodulators should be started insteroid-dependent or steroid-refractory patients. For arbitrarybut practical purposes, thiopurines are considered appropriatefor the same indications as for Crohn's disease: patients whohave a severe relapse; thosewho require two ormore corticos-teroid courses within a 12 month period; those whose diseaserelapses as the dose of steroid is reduced below an arbitrary15 mg; and relapse within 3 months of stopping steroids.158

There is some evidence from a retrospectivemulticentre studyof 1176 patients that those on AZA for UC are more likely torelapse if it is discontinued after 4 years than are patients whohave Crohn's disease.179

5.4.5.2. Dose,monitoring andadverse effects of thiopurines.All aspects are considered similar to the use of thiopurines forCrohn's disease.158 More recent work on measuring thiopurinemethyl transferase (TPMT) and ITPA genotypes, TPMT activity,TPMT gene expression and thiopurinemetabolites, is consistentwith previous reports that the development of different typesof toxicity is unpredictable.180 This prospective study on 60patients (27 with UC) study did, however, find that measure-ment of meTIMP early in the steady state phase might identifypatients at risk of developing myelotoxicity. No recommen-dation can be made about routine measurement of TPMTactivity or genotype prior to initiating thiopurine therapy,althoughall agree thatmonitoring of the full blood count beforeand after starting therapy is appropriate.

5.4.6. Methotrexate (MTX)

5.4.6.1. Efficacy of MTX. Studies on MTX for UC aresmall, use varying doses or routes of administration andhave inconsistent outcomes.181–183 The only randomisedplacebo-controlled trial using a dose of 12.5 mg per weekof oral MTX in UC showed no benefit.181 The low dose mayaccount for disappointing efficacy as well as the lack ofside effects. A randomized comparison of oral MTX 15 mg/week (still a relatively low dose) with mercaptopurine (MP)1.5 mg/kg/day and 3 g/day 5-ASA for 72 steroid-dependentpatients (34 UC and 39 Crohn's) showed a remission rate at30 weeks of 79% for MP, 58% for MTX 25% for 5-ASA (pb0.05vs MP, ns vs MTX).182 This is the only published comparisonof MP and MTX. Until more data are available it cannotgenerally be considered an alternative to thiopurines forsteroid-resistant UC (see also Section 6.2.5).


5.4.6.2. Dose and monitoring and adverse effects of MTX.As with thiopurines, all aspects are considered similar toCrohn's disease, for which evidence from controlled trialssupports its use.158,184

5.4.7. Calcineurin inhibitors (ciclosporin (CsA)and tacrolimus)

5.4.7.1. Efficacy of CsA. Details of the role of CsA andtacrolimus for severe UC are given in Sections 1.2.4 and 1.2.5.

5.4.7.2. Dose and monitoring. Low dose CsA (2 mg/kg iv)induction therapy has largely addressed concerns about earlytoxicity. In the largest randomized study of CsA to date, 73patients were randomized to either 2 mg/kg or 4 mg/kg ofintravenous CsA.50 Response rates at 8 days were similar inboth groups (86% and 84% respectively), with 9% coming tocolectomy in the 2 mg/kg group and 13% in the 4 mg/kggroup. The study was too small to show a difference inserious side effects, but there was less hypertension in thelower dose group. The majority of CsA side-effects are dose-dependent. At the 2 mg/kg dose, the mean CsA concentra-tion on day 4 was 246+64 ng/mL, but 345+146 ng/ml withthe 4 mg/kg dose. Suitable target levels to induce remissionare not known, but in responders on oral medication, whole-blood trough levels of 100–200 ng/ml using a monoclonalradioimmunoassay are generally considered satisfactory. Itis said that 2 h post-dose peak levels give the best esti-mate of drug exposure by correlating with the pharmacoki-netic area under the curve185 and an appropriate targetappears to be 700 ng/mL, but this has not been correlatedwith efficacy for UC.

Tacrolimus is more effective when given at a dose thatachieves a trough concentration of 10-15 ng/m.67 The initialoral dose in this randomized trial of 60 steroid-refractorypatients with active UC was 0.05 mg/kg/day, increased ac-cording to the trough level after 24 hr. 13 (68%) achieving thistrough level responded within 2 weeks, compared to 8 (38%)achieving a lower trough level and 2 (10%) in the placebogroup. None had a complete response. Oral dosing may be analternative to intravenous administration but only retro-spective data are available.70

In practice, either calcineurin inhibitor appears able toinduce remission, although whether either alter the long-term pattern of disease is unknown. First principles indicatethat treatment is best continued until immunomodulatortherapy (AZA/MP/MTX) is established. Although this reducesthe short-term colectomy rate, the risk of clinical relapseremains high in the first year after treatment63–65 (seeSection 6.2.2).

5.4.7.3. Adverse effects of calcineurin inhibitors. Hyper-tension, paraesthesiae or tremor and headache are the com-monest adverse events. Hypomagnesaemia, renalimpairment, or gastrointestinal upset affect around half ofpatients.67 Tacrolimus may induce diabetes mellitus. Oppor-tunistic infection is the main concern; 3/86 patients (3.5%)died of opportunistic infections (1 of Pneumocystis jiroveci(carinii) pneumonia and 2 of Aspergillus fumigatus pneumo-nia) in a series from a major specialist centre.186 Opportu-nistic infections and the value of chemoprophylaxis is thetopic of a separate ECCO Consensus.

5.4.8. Alternative therapies whose role remains tobe established

5.4.8.1. Antibiotics. Antibiotics as an adjunct to steroids donot alter the outcome of severe colitis (Section 5.2.4,43–48),but treatment of refractory colitis UC associated with Fuso-bacterium varium has been reported.187 Two weeks' tripletherapy with amoxicillin 500 mg, tetracycline 500 mg andmetronidazole 250 mg all three times daily improved clinical,endoscopic and histological scores in a randomised trial of 20patients.187 More evidence is needed.

5.4.8.2. Helminths. Observations that there is an epide-miological mismatch between UC and helminth infections,together with experimental evidence that several helminthsmoderate immune-mediated models of colitis lead to ther-apeutic trials of Trichuris suis ova. T suis, the pig whipworm,transiently colonises the gut, but is non-pathogenic in man.In a randomised trial of 54 patients with mild-moderatelyactive UC, 3/30 of those treated with 2500 T suis ova every2 weeks for 12 weeks achieved remission compared to 1/24given placebo (ns), with a response in 43% and 17% re-spectively (p=0.04).188 The optimal dose, interval and du-ration of treatment need to be established and the responseconfirmed in a larger study.

5.4.8.3. Heparin. Heparin promotes epithelial restitutionand repair in addition to anticoagulant properties. Out of twosmall controlled trials of unfractionated heparin and threeusing low molecular weight heparin in up to 100 patients,only the smallest trial has shown benefit for active UC.189 Itcannot currently be recommended, although novel deliverysystems are being developed.

5.4.8.4. Interferon-alpha. Interferon alpha induces anti-inflammatory cytokines ((IL-1RA, among others) and downregulates IL-13, giving it a potential role in the treatment ofactive UC. A trial of 60 patients randomised to weeklyinjections of pegylated interferon alpha at 1.0 mcg/kg,0.5 mcg/kg, or placebo for 12 weeks showed no consistentdifferences between the groups.190

5.4.8.5. Leucocytapheresis. Leucocytapheresis involvesextracorporeal removal of leucocytes through an adsorptivesystem of cellulose acetate beads (Adacolumn®, OtsukaPharmaceuticals), or a polyester fibre filter (Cellsorba®,Asahi Medical Company). The former removes 65% ofneutrophils, 55% monocytes, and 2% lymphocytes while thelatter removes up to 100% of neutrophils and monocytes, and20-60% lymphocytes. Sessions last an hour, during whichtime 2–3 l of blood is drawn from one arm, filtered, andinfused into the other arm. A course of treatment is typically5–10 sessions at intervals of 1–2/week. There have been amultiplicity of observational studies, two unusually designedrandomised trials comparing leucocytapheresis with predni-solone191 or a sham column,192 and one large trial comparingit with sham apheresis for active UC that has yet to report. Itappears that leucocytapheresis does something for activeUC, but quite what and how much is difficult to define.193 Ithas wide-spread acceptance in Japan. Expense may limit itsuse, but the outcome of controlled trials will govern itsfuture role in Europe.


5.5. Preparation for the period after treatment ofactive disease

A patient's response to initial therapy should be assessedwithin several weeks. If treatment is effective, the patientshould continue until symptomatic remission is achieved orfurther improvement ceases. An outcome other thansteroid-free remission after treatment of active disease isconsidered unacceptable, whether or not immunomodula-tors or biological therapy is used. Maintenance therapy isrecommended after successful medical treatment of activedisease.

6. Maintenance of remission

6.1. General

6.1.1. Maintenance therapy trial designMost trials of maintenance therapy for UC have enrolledpatients in clinical and endoscopic remission. In such studies,steroids are typically not permitted as concomitant therapy.The endpoint is the absence of relapse (or failure to maintainclinical remission) after 6 or 12 months.2 Clinical relapse isdefined by an increase in stool frequency and recurrence ofrectal bleeding, confirmed by endoscopy (Section 1.1.5). Thisapproach to the evaluation of maintenance therapy is notcast in stone, because in two recent studies, both inductionand subsequent maintenance therapy were assessed in thesame trial of infliximab.78 Using this approach, the clinicalresponse at week 8 was defined as the primary endpoint, andthe efficacy of maintenance therapy evaluated by thesecondary endpoints of clinical response, clinical remissionand mucosal healing at weeks 30 and 54 (Section 6.2.3). Thepivotal endpoint that matters to patients is clinical remissionwith complete corticosteroid discontinuation in those whowere receiving steroids at baseline.

ECCO statement 6AThe goal of maintenance therapy in UC is to main-tain steroid-free remission, clinically [EL1, RG A]and endoscopically defined [EL2, RG B] ECCO statement 6C

Choice of maintenance treatment in UC is deter-mined by disease extent [EL1b, RG B], diseasecourse (frequency of flares) [EL5, RG D], failure ofprevious maintenance treatment [EL5, RG D],severity of the most recent flare [EL5, RG D],treatment used for inducing remission during themost recent flare [EL5, RG D], safety of main-tenance treatment [EL1b, RG B], and cancerprevention [EL2a, RG B]

6.1.2. Pattern of diseaseMore than half of patients with UC have a relapse in the yearfollowing a flare. In clinical trials designed for the main-tenance of remission in patients with clinical remission atbaseline, clinical relapse rates among patients receivingplacebo range from 29% to 43% at 6 months, and from 38% to76% at 12 months.2,9,194 A population-based study carried outin the county of Copenhagen,195 described the outcomein1575 patients in the first 5 years following diagnosis of

ECCO statement 6BMaintenance treatment is recommended for allpatients [EL1a, RG A]. Intermittent therapy isacceptable in a few patients with disease oflimited extent [EL5, RG D]

UC between 1962 and 2005. In the most recent period, thepercentage of patients experiencing an ‘indolent’ course (norelapse during the first 5 years after diagnosis) was 13%, while74% had ‘moderate’ course (two or more relapses within thefirst 5 years, but less than every year), and 13% had an‘aggressive’ course (disease activity at least every yearduring the first 5 years). This highlights using the term‘moderate’ to refer sometimes to the pattern of disease andalso to the activity at a point in time, which can be the sourceof confusion (Sections 5.1.2, 1.1.6, 5.2.1). Furthermore,grouping activity into quintiles seems too long a period foreveryday practice, although highly relevant from an epide-miological perspective. The alternative is to define relapse asinfrequent (b1/yr), frequent (N2 relapses/y), or continuous(persistent symptoms of active UC without a period ofremission)33 (Section 1.1.6).

6.1.3. Risk factors for relapseFew prospective studies have assessed risk factors for relapsein patients with inactive UC.196–200 In one study of 92patients, a shorter duration of current remission and a higherrelapse frequency were predictive of further relapse.196 In asecond study of 64 patients, the frequency of previous re-lapses, extraintestinal manifestations and a low-fibre dietwere independent variables associated with a higher risk ofrelapse.197 In another study of 74 patients including variousbiomarkers and clinical measures, a younger age, multipleprevious relapses (for women), and basal plasmacytosis onrectal biopsy specimens were independent predictors ofrelapse.198 This study did not confirm the two-fold increase inrelapse rate in those with persisting active inflammation(polymorphonuclear leukocytes in the rectal mucosa) ob-served in two earlier histopathology studies.201,202 The im-pact of life events in relapse of UC has been examinedby a number of studies199,200,203 with contradictory results(Section 11.3). Adherence to medical therapy appears to bethe governing factor associated with relapse, since the risk ofrelapse was more than 5-fold higher (OR 5.5, 95%CI 2.3–13.0)among 99 patients who collected b80% of their prescriptionsfor maintenance mesalazine.204

Patients with disease requiring steroids probably havea different outcome to the overall population of patientswith UC. In a population-based study from Olmsted County,Minnesota, the outcome of 183 patients with UC diagnosedbetween 1970 and 1993 was analysed one year after a firstcourse of steroids.205 Among the 63/183 patients treatedwith corticosteroids, 49% had a prolonged response, 22%

ECCO statement 6DOral 5-aminosalicylate (5-ASA) containing com-pounds are the first line maintenance treatmentin patients responding to 5-ASA or steroids (oral orrectal) [EL1a, RG A]. Maintenance with topical 5-ASA is a valuable alternative in proctitis and left-sided colitis [EL1b, RG A]. A combination of oraland rectal 5-ASA can be used as a second linemaintenance treatment [EL1b, RG B]


were steroid dependent and 29% came to colectomy, but only3/183 were treated with AZA/MP (see also Section 5.4.2).

6.2. Medications for maintenance of remission

Details of the action, dosage, side effects and monitoring ofaminosalicylates, steroids, thiopurines, and infliximab are inthe Active Disease section.

6.2.1. Aminosalicylates

6.2.1.1. Oral 5-ASA. The most recent version of theCochrane meta-analysis showed that the Peto odds ratiofor the failure to maintain clinical or endoscopic remission(withdrawals and relapses) for oral 5-ASA vs placebo was 0.47(95% CI, 0.36–0.62), with a number-needed-to-treat (NNT)of 6.206 Randomised controlled trials (RCTs) designed toevaluate the efficacy of oral 5-aminosalicylates (5-ASA) –including sulfasalazine, mesalazine and olsalazine – formaintaining remission are shown in Table 6.1.207–214

6.2.1.2. Rectal 5-ASA. Several RCTs have compared rec-tal mesalazine in various formulations and regimens

Table 6.1 Placebo-controlled trials of oral 5-aminosalicylates fo

Author [ref] Year Number ofpatients

Study drug

Misiewicz207 1965 67 SZPPlacebo

Dissanayake208 1973 64 SZPPlacebo

Riis209 1973 59 SZPPlacebo

Sandberg-Gertzen210 1986 101 OLZPlacebo

Wright211 1993 101 OLZPlacebo

Miner212 1995 205 MSZ2

PlaceboHanauer213 1996 264 MSZ3

MSZPlacebo

Hawkey214 1997 323 MSZ3

Placebo1pb0.05; 2Pentasa; 3Asacol/Claversal; 4pb0.05 for comparison of 5-ASshown) and placebo; (sulfasalazine: SZP; olsalazine: OLZ, and mesalaz

with placebo for maintenance of remission in distal UC(Table 6.2).215,227–237 At 12months, failure tomaintain clinicalor endoscopic remission was 20–48% in the active armscompared to 47–89% in the placebo arms. In all but one ofthe trials, the differences in failure to maintain remissionbetween active and placebo groups were statistically sig-nificant. The only RCT that failed to demonstrate efficacy of 5-ASA suppositories215 followed a three times a week regimen;the difference between the two arms was significant at 3, 6and 9 months but did not reach the significance level at12 months. Other trials have demonstrated efficacy withsimilar intermittent rectal 5-ASA regimens, either alone or incombination with oral 5-ASA. A meta-analysis which includedthe two placebo-controlled trials, showed a superiority ofrectal mesalazine over placebo for remission maintenance at1 year (OR 16.2, 95% CI 4.7–55.9).11

6.2.1.3. Combining oral and topical 5-ASA therapy. Therehave been two RCTs comparing combination treatment withoral mesalazine plus intermittent mesalazine enema to oralmesalazine alone for maintaining remission (Table 6.2).Remission rates were higher in patients receiving the combi-nation. There are also three small RCTs comparing sulfasa-lazine 2 g/day or oral mesalazine 1.6 g/day to intermittentrectal mesalazine, with a trend in favour of the rectaltreatment (Table 6.2).

It is therefore clear that oral or rectal 5-ASA is superior toplacebo in maintaining remission in UC. The data suggestthat rectal 5-ASA has equivalent or slightly superior efficacyto oral mesalazine in distal UC. The combination of oralmesalazine and intermittent rectal 5-ASA appears to providefurther benefit. Although most authors in the studies claimedthat patients found long-term rectal treatment acceptable,a postal survey of the UK patients showed that 80% pre-ferred oral treatment alone.216 However, in another studyin Spain, 5-ASA suppositories were generally well tolerated

r maintaining remission in UC

Dosage (g/day) Duration(months)

Failure tomaintain clinical orendoscopic remission

2 12 29%76%1

2 6 22%55%1

2 6 29%24%

1 6 23%45%1

2 12 63%69%

4 12 43%62%1

0.81.6 6 56%56%71%4

1.6 6 40%59%1

A (both groups) vs placebo; 5comparison of 5-ASA, zileuton (notine: MSZ).

ECCO statement 6EThe minimal effective dose of oral 5-ASA is around1 g per day [EL1a, RG A]. For rectal treatment 3 g/week in divided doses is sufficient to maintainremission. The dose can be tailored individuallyaccording to efficacy and in some cases higher doses±topical 5-ASA may be useful [EL5, RG D]. Althoughsulfasalazine is equally or slightly more effective[EL1a, RG A], other oral 5-ASA preparations arepreferred for toxicity reasons. All the differentavailable preparations of oral 5-ASA are effective[EL1a, RG A]. At the moment, there is no robustevidence to support the choice of any specific 5-ASApreparation for maintenance [EL1a, RG A]


and considered comfortable for treatment of at least oneyear.217 The choice and options should be discussed withpatients. Adding rectal therapy is a treatment option forpatients who have relapsed on oral 5-ASA alone, althoughadherence to prescribed therapy should be addressed.

Table 6.2 Randomized controlled trials of rectal mesalazine comin distal UC


Study drugs Dosag

Sutherland227 1987 29 MSZ enema 2MSZ enema 4

Biddle228 1988 25 MSZ enema 1Placebo -

D'Arienzo229 1990 101 MSZ suppository 0.8Placebo –

D'Albasio230 1990 79 MSZ enema 4 g×7MSZ enemaOral SZP 2g/da

Miner231 1994 92 MSZ enema 4 g/dMSZ enema 4 g/2MSZ enema 4 g/3Placebo –

Andreoli232 1994 31 MSZ enema 4 gx2Oral SZP 2g/da

Mantzaris233 1994 38 MSZ enema 4 g /3Oral MLZ 1.5g/

D'Albasio234 1997 69 MSZ enema+oral 2×4 gOral MSZ alone 1.6g/

D'Albasio235 1998 111 MSZ suppository 0.5×2MSZ suppository 0.5/dPlacebo –

Marteau215 1998 95 MSZ suppository 3×1 gPlacebo –

Hanauer236 2000 65 MSZ suppository 0.5Placebo

Yokoyama237 2007 24 MSZ enema+oral 1 g×2Oral MSZ alone 3g/da

1pb0.05; 2pb0.05 at months 3,6 and 9, but the difference did not reacMSZ: mesalazine; SZP: sulfasalazine.

6.2.1.4. Dose-response effect. A dose-response for main-tenance of remission with mesalazine at doses greaterthan 0.8 g/day has not been established (Tables 6.1–6.3).In an Italian study, no difference was found in relapse rates at1 year on mesalazine 1.2 g compared to 2.4 g/day.218

Patients taking the higher dose were in remission for longerthan those on the lower dose (median time in remission of175 days vs 129 days, pb0.001), but it may be debatedwhether this is clinically significant. For those with extensiveUC, however, the benefit of the higher dose was moremarked (143 days vs 47 days, pb0.005). When the results forpatients in remission at 12 months were analysed afterstratifying for frequently relapsing (N3 relapses per year)vs less frequent relapses, 2.4 g/day was also performedsignificantly better than 1.2 g/day (75% vs 33%, respec-tively). This post hoc analysis must, however, be treatedwith caution.219 Another trial has also reported a trend forbenefit in subjects receiving the higher dose of Pentasa 3 g/day compared with 1.5 g/day (p=0.051).220 As with otherstudies of high doses of 5-ASA, there was no increase in thefrequency of adverse events. It is possible that high doses ofmaintenance oral mesalazine are required in some patients,perhaps in those that required high doses of oral 5-ASA toinduce remission or those with frequently relapsing disease,

pared to placebo or oral formulations for maintaining remission

e (g/day) Duration(months)

Failure to maintain clinicalor endoscopic remission

6 40%46%

12 25%85%1

12 20%80%1

/month 4 g/3days 24 31%28%

y 39%ay 6 19%days 28%days 35%

52%1

/week 12 25%y 40%day 24 26%day 68%1

/week+1.6 g/day 12 39%day 64%1

/day 12 10%ay 32%

47%1

/week 12 48%62%2

24 46%89%1

/week+3 g/day – 18%y 77%

h the significance level at month 12.


but at present, there is no good evidence to support this.221

There are also no data supporting a dose-response relation-ship with rectal 5-ASA for maintaining remission in distal UC(Table 6.2), and no more than 1 g/day is necessary for rectal5-ASA therapy.

6.2.1.5. Comparison of oral 5-ASA formulations. In theCochrane meta-analysis206 the odds ratio for the failure tomaintain clinical or endoscopic remission (withdrawals andrelapses) was calculated for the trials in which sulfasalazineand 5-ASA were compared (Table 6.3).238–250 The odds ratiowas 1.29 (95%CI 1.05–1.57), with a negative NNT, suggestinggreater therapeutic effectiveness for sulfasalazine. Sulfasa-lazine and 5-ASA had similar adverse event profiles (OR 1.16,95% CI 0.62–2.16, and OR 1.31, 95% CI 0.86–1.99 respec-tively). However, the trials that compared 5-ASA and sul-fasalazine are likely to have been biased in favour of

Table 6.3 Trials comparing different oral 5-aminosalicylate form


Study drugs

Azad Khan238 1980 170 SZPSZPSZP

Andreoli239 1987 13 MSZSZP

Ireland240 1988 164 OLZ SZP

Riley241 1988 92 MSZSZP

Mulder242 1988 72 MSZSZP

McIntyre243 1988 79 BLZSZP

Rutgeerts244 1989 273 MSZ1SZP

Kiilerich245 1992 226 OLZSZP

Rijk246 1992 46 OLZSZP

Courtney222 1992 99 OLZMSZ1

Travis247 1994 198 OLZOLZOLZ

Ardizzone248 1995 88 MSZ1

SZPKruis249 1995 160 OLZ

OLZOLZSZP

Nilsson250 1995 OLZSLZ

Fockens220 1995 169 MSZMSZ4

Paoluzi218 2005 156 MSZ1

MSZ1

1Asacol/Claversal; 2pb0.05; 3failure including relapses plus study wfrequent in the 3 g group.

sulfasalazine, because most trials enrolled sulfasalazine-tolerant patients, which would have minimized sulfasala-zine-related adverse events. There is only one, single-blindRCT218,220,222 comparing olsalazine 1 g/day head to headwith oral mesalazine 1.2 g/day as maintenance for UC. At1 year, remission rates were 75% and 54%, respectively(p=0.02). The frequency of adverse events was low in thisstudy, especially the rate of diarrhoea in the olsalazinegroup, perhaps because there was a predominance of pa-tients with distal UC. This study has not been replicated andthe dose inequivalence noted, although this is unlikelyto have mattered (above). No controlled trial has yetbeen published on maintenance of remission with mesalazineMMx.

6.2.1.6. Adherence to 5-ASA treatment. Adherence to 5-ASA appears to be important for improving outcome of

ulations and dosages for maintaining remission in UC

Dosage (g/day) Duration(months)


1 6 33%2 14%4 9%2,6

0.75 12 43%1.5 17%1 6 43%2 26%2

0.82 12 40%46%

1.5 12 45%3 56%2 6 49%2 37%0.75–1.5 12 54%2 42%1 12 54%2 49%1.5–2 12 46%3–4 48%1 12 25%1.2 46%2

0.51 12 52%2 40%

40%3

1 12 38%2 51%0.51.25 6 36%2 49%2 24%

32%

1.5 12 46%3 33%5

1.2 12 74%2.4 70%

ithdrawals; 4Pentasa; 5p=0.057; unacceptable side-effects were


patients with UC. When the adherence rate in 94 outpatientson 5-ASA with clinically quiescent UC for at least 6 monthswas studied, the overall adherence rate was 40% and themedian amount of medication dispensed per patient was 71%(8–130%) of the prescribed regimen.223 Logistic regressionidentified a history of four or more prescriptions and malegender increased the risk of non-adherence. Being married,having extensive disease or having an endoscopy within thepast 24 months reduced non-adherence. The same groupconducted a prospective study to determine the effects ofnon-adherence with 5-ASA among 99 patients with quiescentUC. After 12 months, patients who collected b80% of theirprescriptions had a 5-fold higher OR (5.5, 95% CI 2.3–13.0).204 In a pilot study, patients were randomized toreceive either once-daily or conventional (twice or threetimes daily), mesalazine for maintenance of remission inUC.224 After 6 months, patients in the once-daily armappeared more satisfied with their regimen and consumedmore medication than those in the conventional arm (90%vs 76%; p=0.07). The authors concluded that once-dailyoral formulations of 5-ASA were likely to be a bettertherapeutic option due to their ability to offer compar-able efficacy and improved adherence. This premiseappears correct. An investigator-blinded study of 362patients randomised to receive Pentasa 2 g once daily or1 g twice daily, showed a 12% better remission rate at1 year (73.8% vs 63.6% respectively) in the single dailydose group.225 Patient questionnaires showed significantlygreater compliance (pb0.05) and acceptability (pb0.001)in the once daily group. The study has yet to be reportedin full, but given comparable efficacy between once dailyand divided dosing regimes for the treatment of active UCwith mesalazine MMx (Mezavant®/Lialda®) and Salo-falk®,23-25,226 the effect is likely to be generic ratherthan compound-specific.

6.2.2. Thiopurines

ECCO statement 6FAzathioprine/mercaptopurine is recommendedfor patients who have experienced early orfrequent relapse while taking 5-ASA at optimaldose or who are intolerant to 5-ASA [EL5, RG D],patients that are steroid-dependent [EL1a, RG A]and for patients responding to ciclosporin (ortacrolimus) for induction of remission [EL3, RG C].Azathioprine/6-MP can also be considered in apatient responding to intensive treatment withintravenous steroids for induction of remission[EL5, RG D]. Addition or continuation of oral 5-ASA can be recommended with special attentionto potential myelotoxicity [EL5, RG D]

6.2.2.1. Efficacy of thiopurines for maintenance ofremission. Seven RCTs evaluating the efficacy of thiopurinesazathioprine (AZA) and mercaptopurine (MP) for maintenanceof remission in UC are listed in Table 6.4.136,175,182,251–254 Inthe Cochrane meta-analysis published after the Consensusmeeting,255 six of these studies on 286 patients were

considered. The study quality was judged generallypoor and the evidence for using thiopurines in UC is weakerthan that forCrohn's disease.158AZAwas showntobe superior toplacebo on the basis of four trials (OR for failure to maintainremission 0.41, 95% CI 0.24–0.70). The results were similarwhen analyses were limited to patients who had successfulinduction of remission (data available for two studies). Therewas no clear evidence of a dose-response effect for AZA, or foruse of co-medicationwithmesalazine in these studies. The twoopen label studies that compared MP to mesalazine and AZA tosulfasalazineshowedsignificantheterogeneityandcouldnotbepooled. Adverse effects occurred in 11/127 patients receivingAZA, including acute pancreatitis (3 cases) and bone marrowsuppression (5 cases). Since this meta-analysis, a further RCThasbeenpublishedbyArdizzoneetal.136 72patientswithactivesteroid-dependent UC were randomised (investigator-blind) toAZA 2 mg/kg/day or mesalazine 3.2 g/day for 6-months.Steroid-free, clinical and endoscopic remission was achievedin 53% on AZA, compared to 21% given 5-ASA (intention to treatanalysis: OR 4.78, 95% CI 1.57–14.5). This is the best trial todate.

Evidence in support of the thiopurines for UC also comesfrom observational cohorts in retrospective series.256–262

The best among these is the 30 year cohort from the OxfordIBD clinic between 1968 and 1999.262 In this series, theoverall remission rate in the 346 patients with UC who weretreated with AZA was 58%, but increased to 87% amongpatients on therapy for more than 6 months. The proportionof patients in remission at 5 years was 62% applying a strictdefinition of relapse, or 81% allowing for a brief relapse witha short corticosteroid course. The median time to relapseafter stopping AZA was 18 months.

6.2.2.2. Thiopurines after ciclosporin (or tacrolimus) forinduction of remission. Calcineurin inhibitors are rescuetherapy options for steroid-refractory UC (see Section 5.2.5).Since calcineurin inhibitors are best discontinued within6 months because of nephrotoxicity, these agents aregenerally proposed as induction therapy until slower-actingimmunomodulators such as AZA or MP become effective. AZAor MP are introduced while the patient is still on ciclosporin(CsA) or tacrolimus and steroids are being tapered. Thejustification of thiopurines in this setting, even in patientswho are 5-ASA naive, is the high colectomy rate (36-69% inthe 12 months following introduction of CsA, Section 5.2.563–65). Restrospective series have suggested that thiopurinesreduce the risk of colectomy after the induction periodwith CsA.63,263–265 In 1996, a series of 29 patients success-fully treated with ciclosporin were followed for a median92 weeks, and 22% of patients taking MP required acolectomy, compared to 72% of those not taking MP.263 Inanother series 5/19 patients receiving AZA (26%) underwentcolectomy during the follow-up, compared to 9/11 subjects(81%) who did not receive AZA maintenance (p=0.01).265

Similar results have been reported from Chicago: of 36/42initial responders to CsA, 25 (69%) also received MP or AZA, ofwhom 20% required colectomy vs 45% who did not thiopurinesduring the 5 year follow up.63

After intravenous CsA, a switch to oral therapy occursas soon as a clinical response has been achieved, with aview to acting as a ‘bridge’ until the therapeutic effect ofAZA is achieved. Nevertheless, the usefulness of the oral

ECCO statement 6GIn a patient responding to infliximab, infliximab isrecommended for maintenance treatment [EL1b,RG A]. In azathioprine naïve patients responding toinfliximab induction, azathioprine is an optioninstead of infliximab for maintenance [EL5, RG D]

Table 6.4 Randomized trials of thiopurines compared to placebo or oral 5-aminosalicylates for maintaining remission in UC

Author [ref] Year Numberof patients

Study drugs Dosage Study design Duration(months)


Jewell175 1974 80 Azathioprine 2.5 mg/kg/daythen reduced to1.5–2 mg/kg/dayafter 3 months

Double-blind 121 60%

Placebo – 77%Hawthorne251 1992 672 Azathioprine 100 mg/day Double-blind 12 36%

Placebo – 59%3

Mate-Jimenez182 2000 34 6–mercaptopurine 1 .5 mg/kg/day Open label 181 50%Methotrexate 15 mg/week 85%MSZ 3g/day 93%3

Sood252 2000 50 Azathioprine4 2.mg/kg/day Single (patient)-blind

121 44%

Placebo – 60%3

Sood253 2002 35 Azathioprine4 2.5 mg/kg/day Double-blind 121 23%Placebo – 56%

Sood254 2003 25 Azathioprine+SZP

2 .5 mg/kg/day+6 g/day

Open label 181 77%

SZP 6g/day 44%3

Ardizzone136 2006 72 Azathioprine 2 m g/kg/day Single 6 47%MSZ 3.2g/day (Investigator)-

blind79%3

1Inclusion of patients with active disease who initially received steroids for induction of remission.2All patients included in this study were in remission on azathioprine for at least 6 months (withdrawal design); co-medication with 5-ASAwas permitted and taken by 82% of patients.3pb0.05.4Co-medication with sulfasalazine 6 g/day in all patients.


CsA bridge has been challenged. In a retrospective seriesfrom Barcelona, all responders to iv CsA were treated withAZA, without oral ciclosporin.266 Cumulative probabilitiesof relapse were 42%, 72% and 77% at 1, 3 and 5 years, andcumulative probabilities of colectomy were respectively29%, 35% and 42%. These are similar to or better thanthose reported in the literature, so the authors concludedthat the ‘bridging step’ with oral CsA may not benecessary. This needs more investigation.

Three retrospective studies have assessed the long termoutcome of patients after an attack of UC treated withintravenous CsA.63–65 All describe a high rate of relapse andcolectomy. In 76 patients treated with CsA for intravenoussteroid-refractory UC, 65% relapsed within 1 year, and 90%within 3 years 90%.64 Unusually, a beneficial effect of AZA(given to 35/56 who could tolerate it) could not bedemonstrated either to maintain remission or preventcolectomy (ns). After 5 years 47% in the non-AZA and 40%in the AZA-treated patients came to colectomy, and after7 years the overall colectomy rate was 58%. The Leuvenexperience described 142 patients, 118 (83%) of whom hadan initial response to CsA and avoided colectomy duringinitial hospitalization.65 64/118 (54%) subsequentlyrequired colectomy. The rate of colectomy in those alreadyon AZA compared with those starting AZA concurrently withCsA was 59% vs 31%, respectively (pb0.05). Life-tableanalysis showed that 33% of patients required colectomyat 1 year, but the probability increased to 88% at 7 years ifCsA was used in patients already on AZA. Consequently CsA

has little role for patients who have failed AZA of anappropriate dose and duration.

6.2.3. Infliximab (IFX)

6.2.3.1. Efficacy for maintenance. Details of the ACT 1 & 2studies are given in Section 5.4.3.78. The design of these studieswas different to standard maintenance trials (Section 6.1.1).Patients included in the maintenance phase were not necessa-rily in steroid-free clinical or endoscopic remission. Moreover,non-responders to IFX were taken into account in thecalculation of week 30 and week 54 response or remissionrates. In both studies, a significantly higher proportion ofpatients had a clinical response or remission on IFX at weeks 8and30 (andatweek 54 in theACT1 trial), compared to placebo.In ACT 1, remission rates at week 54 were 35% (5 mg/kg), 34%(10mg/kg) and 17% (placebo). In ACT 2, remission rates atweek30 were 26% (5 mg/kg), 36% (10 mg/kg) and 11% (placebo). Theproportion of patients with a sustained clinical remission at alltime points was 7% (placebo) and 20% (5 mg/kg) after 54 weeks


in ACT 1, and 2% (placebo) and 15% (5 mg/kg) after 30 weeks inACT 2. The steroid-free remission rates in the 74 patientsreceiving corticosteroids at baselinewereverymodest althoughstill statistically significant. In ACT 1, steroid-free remission atweek 54was achieved in 24% (5mg/kg), 19% (10mg/kg) and 10%(placebo). In ACT 2, the corresponding values at week 30(7months) were 18%, 27% and 3%. The rates of clinical responseand remission were similar between the subpopulations ofpatients who were “corticosteroid-refractory” (i.e., thosereceiving corticosteroids at baseline) and those who were“not corticosteroid-refractory”.

6.2.3.2. Combining IFX and immunomodulators.

ECCO statement 6IE. coli Nissle is an effective alternative to 5-ASAfor maintenance [EL1b, RG A]

ECCO statement 6HCombination of infliximab with an immunosup-pressant for at least 6 months, or premedicationwith steroids, is currently recommended in orderto decrease immunogenicity [EL3, RG C]

As with Crohn's disease,158 the combination of IFX and athiopurine analogue or corticosteroids is probably justified todecrease immunogenicity, which is the source of infusionreactions and loss of response.267,268 Since antibodies to IFXoccur early in the treatment, the question of discontinuing theimmunomodulator has been addressed by the Leuven group forCrohn's disease. Results from a single centre open-labelrandomized, withdrawal trial suggest that the immunomodu-lator can be stopped after 6 months with no loss of response toIFX over 2 years.269 These results should still be interpretedwithcaution, because circulating concentrations of IFX declined overtime when the immunomodulator was discontinued. On theother hand, the report of eight cases of a rare form ofhepatosplenic T cell lymphoma occurring in young patientstreated concurrently with IFX and thiopurines must also betaken into account.270 Short-term combination (6 months)appears to offer a good balance between risks and efficacy forthose in whom IFX is continued. If a patient is naïve to AZAwhengiven IFX, a reasonable option is todeterminewhether remission

Table 6.5 Randomized trials of probiotics for maintaining remis

Author [ref] Year Number of patients Study drugs

Kruis274 1997 120 E. coli NissleMesalazine

Rembacken275 1999 116 E. coli NissleMesalazine

Kruis276 2004 327 E. coli NissleMesalazine

Ishikawa277 2000 21 Probiotic mixture1numTreatment2

Zocco278 2006 187 Lactobacillus GGMesalazineCombination

1Bifidobacterium bifidum+Bifidobacterium breve+Lactobacillus acido2Open label study.

will be maintained by AZA alone, without committing thatpatient to maintenance IFX.

Whether IFX acts as a bridge to remission that ismaintained bythiopurines, or whether AZA simply slows the rate of descent toinevitable relapse (the ‘parachute’271), remains debated. Thisstrategyhasnotyetbeen tested inUC,but is anacceptableoptionfor thiopurine-naive patients with steroid-dependent Crohn'sdisease.272 The 2 year follow up of patients who received a singledose of IFX as rescue therapy for intravenous steroid-refractoryUC (Section 5.2.573) presented after the Consensus meeting,showed that 13/16 patientswho receivedAZA avoided colectomy(with orwithout oral 5-ASA) compared to 5/8who received 5-ASAalone (ns).273 Consequently, whether maintenance IFX (with orwithout thiopurines) is better than thiopurines alone to preventrelapse and avoid late colectomy cannot be deduced.

6.2.4. Probiotics

E. coli strain Nissle 1917.Three RCTs have compared the E. coli strain Nissle 1917

(Mutaflor®) to mesalazine for maintenance of remission in UC(Table 6.5). In the first study, 120 outpatients in a multicentre,double-blind, study received 1.5 g/day 5-ASA or 100 mg/day E.coli strain Nissle (corresponding to 25×109 viable E. colibacteria) for 4 days, and then 200 mg/day.274 No concomitantmedications were permitted. After 12 weeks, 11% of patientsreceiving 5-ASA and 16% of those receiving the probioticpatients relapsed. The statistical power was limited by theshort duration of the study, because relatively few patientsrelapsed, but an 11–16% relapse rate within 3 months seemsrather high. Subsequently 116 patients with active UC wererandomized to receive either 5-ASA 2.4 g/day, reducing to1.2 g/day after remission, or 200 mg/day of E. coli strainNissle.275 All patients also received an initial 7 day course of oralgentamicin and either rectal or oral steroids in variable doses.

sion in UC

Dosage Duration (months) Failure to maintainclinical or endoscopicremission

200 mg/day 4 16%1.2g/day 12%200 mg/day 12 73%1.2g/day 73%200 mg/day 12 45%1.5g/day 36%

ber 100 mL 12 27%90%3

18×109 12 15%2.4 g/day 20%

16%

philus.


The remission rate was 75% in the corticosteroid plus 5-ASAgroup, and 68% in the corticosteroid plus E. coli group (ns).During the one year follow up, relapse occurred in 73% of the 5-ASA group and 67% of the E. coli group (ns) after weaning offsteroids. This is a very high relapse rate for reasons that areunclear, but the probiotic was no less effective than 5-ASA.Finally, an equivalence study was conducted.275 327 patientswith UC in remission for no longer than 12months were treatedwith either 5-ASA 1.5 g/day or E. coli Nissle 1917 for 1 year. Therelapse rate was 45% in the E. coli group vs 36% in themesalamine group. The corresponding one-sided upper 95%confidence interval for the difference in treatment was12.8%, which is within the equivalence range of 20% requiredfor acceptance of the non-inferiority hypothesis. It wasconcluded that E. coli strain Nissle 1917 is not inferior to theestablished standard 5-ASA for maintenance of remission inUC, although the relapse rate in this last study was stillhigher than expected.206

6.2.4.1. Other probiotics. No other probiotic has been sub-ject to properly powered RCTs. When 100 ml/day of fermentedmilk containing Bifidobacterium bifidum YIT 4007, B. breve YIT4065, and L. acidophilus YIT 0168 was given to 21 UC patientsover 1 year,277 neither investigators nor patients were blinded,and other treatments could be administered. There were fewerrelapses in the treatment arm (27% in the milk group vs 90% inthe controls), but nodifferences inendoscopic lesions.Anothergroup of 187 patients with UC in remission for less than12monthswere randomised to receive either LactobacillusGG18×109 viable bacteria/day, 5-ASA 2.4 g/day, or the combina-tion.278 There were no differences in sustained clinical orendoscopic remission rates at 6 and 12 months between thethree treatment groups. In a post-hoc analysis, however,treatment with Lactobacillus GG appeared to prolong therelapse-free time compared to 5-ASA. Relapse rates at12 months were 136/10,000 person-months on LactobacillusGG alone and 181/10 000 person-months on 5-ASA (p=0.01).Further studies are needed.

6.2.5. Other treatments

6.2.5.1. Antibiotics. The potential benefit of adding cip-rofloxacin to conventional therapy has been investigated.279 Ina randomized, placebo-controlled, double-blind clinical trial,ciprofloxacin (1–1.5 g/day) or placebo was administered for6 months to 83 patients referred with active UC refractory toconventional treatment. All the patients were initially treatedwith a high but decreasing dose of prednisone and with 5-ASA.Treatment failure was the primary end point, defined as bothsymptomatic and endoscopic failure to respond. The treatmentfailure rate was 21% in the ciprofloxacin-treated group and 44%in the placebo group (p=0.02). The study design was moreappropriate for an induction rather than a maintenance studyand inclusion criteria, definition of clinical response andconcomitant therapies have been criticized.280 Consequentlyciprofloxacin should not be considered effective for maintain-ing remission in UC. In another double-blind, randomized trial,metronidazole (0.6 g/day) and sulfasalazine (2 g/day) werecompared for maintenance of remission in 40 patients with UCin remission for less than 12 months.281 After 1 year,metronidazole was found to be slightly more effective thansulfasalazine. No significant side effects were noted, and in

particular, no paraesthesiae were reported. These dataare regarded as insufficient by the Consensus to recommendantibiotics for maintenance of remission in UC.

6.2.5.2. Methotrexate. Data on methotrexate (MTX) formaintenance of remission in UC are few. The single RCTwasprincipally designed for induction of remission in refractory,active UC and used a dose (12.5 mg/week) that is probablysub-therapeutic (see Section 5.4.6).181 The proportions ofpatients who relapsed after first remission (MTX 64% vsplacebo, 44%) were not significantly different. An open-labelstudy compared MP, MTX and 5-ASA in 72 steroid-dependentIBD patients, including 34 with UC182 (Table 6.4). Patients onprednisone were randomly assigned in a 2:2:1 ratio toreceive oral MP 1 mg/kg, MTX 15 mg/week, or 5-ASA 3 g/day.All patients who achieved remission at week 30 were thenincluded in a maintenance study for 76 weeks. A significantlyhigher proportion of patients achieved remission in the MPgroup (79%) than in the 5-ASA group (25%), with no statisticaldifferences compared to the MTX group (58%). For main-tenance of remission, the higher rate was found in the MPgroup (64%) compared to MTX (14%) and 5-ASA (0%). Too manyquestions were being addressed by this study for conclusionson the relative efficacy of MP and MTX in UC to be drawn.

Several retrospective series have also been publish-ed,183,282–285 to a total of 91 patients. Most had failed orbeen intolerant of AZA and were treated with MTX at variousdoses and routes of administration. The response or remissionrates ranged from 40% to 75%, suggesting that some patientswith UC may respond well to methotrexate. One studydistinguished between patients given MTX for AZA-intoleranceand AZA-failure.285 MTX (median oral dose 20 mg/week) wastolerated by 27/31 (87%) patients who had been unable totolerate AZA. Of those treatedwithMTX after failurewithAZA,5/11 patients had a colectomy vs 5/31 patients who wereintolerant of AZA (pb0.05). The results are heterogeneous andit is possible that the dose of MTX is an important determinantof efficacy, but the Consensus considered that there iscurrently insufficient evidence to recommend MTX for UC.

6.2.5.3. Omega-3 fatty acids (fish oil). Preparationscontaining omega-3 fatty acids and eicosapentaenoïc acid inparticular,may have anti-inflammatory properties by reducingthe production of leucotriene B4286,287 Several studies havebeen conducted in UC with different formulations and dosingof n-3 fatty acids.288–296 Only three randomized controlledtrials were selected for a Cochrane meta-analysis publishedafter the Consensus,297 which included 138 UC patients whowere in remission at the time of recruitment.291,293,294 Thepooled analysis showeda similar relapse rate in the n-3 treatedpatients and controls (RR 1.02, 95%CI 0.51–2.03, p=0.96). Nosignificant adverse events were recorded.

6.2.5.4. Appendicectomy. Studies have focused on the roleof appendicectomy in the UC pathogenesis. A meta-analysisincluded 13 case-control studies and suggested that appendi-cectomy gives a 69% reduction in the risk of developing UC (OR0.31, 95%CI 0.25–0.38;pb0.0001).298 The influence of potentialconfounders such as smoking was excluded. The protectiveeffect of appendicectomy for the development of UC appears tobe limited to patients who undergo appendicectomy before age20 years and is mainly observed for primary appendicectomy

ECCO statement 6 KDue to lack of evidence, no recommendation canbe given for the duration of treatment withazathioprine or infliximab, although prolongeduse of these medications may be considered ifneeded [EL4, RG D]


(surgery for appendicitis) andnot for incidental appendicectomy(removal of the appendix for other reasons).299 The outcome of41 UC patients with an appendicectomy before diagnosis and466 with no previous surgery, who were all prospectively in-cluded in an IBD database, has been compared.300 Previousappendicectomy has a beneficial effect on the course of UC,witha lessmarkedyear-by-year disease activity andadecreasedrisk of colectomy. This protective effect was additive to that ofcurrent smoking. Similar results have been reported from theBrisbane group, who have explored the subject in detail andshown an association between previous appendicetomy for ap-pendicitis andamild course of extensive colitis, but no influenceon the pattern of primary sclerosing cholangitis.301,302 There areonly anecdotal data on the course of UC when appendicectomyis performed after UC diagnosis.103 Consequently, the Consensusconsidered that there is no enough evidence to recommendappendicectomy for preventing relapse in UC.

6.2.5.5. Biological and other therapy. Adalimumab, cer-tolizumab, etanercept, natalizumab, visulizumab, inter-leukin 10, fontolizumab (an anti-interferon γ antibody),basiliximab, daclizumab, alicaforsen (an anti-ICAM1 anti-sense molecule), anti-IL12 and anti-IL6 antibodies have notyet been evaluated for maintenance of remission in UC, andnor have leucocytapheresis, tacrolimus, or cyclophospha-mide in any meaningful way.

6.3. Duration of maintenance therapy

ECCO statement 6JThe general recommendation is to continue 5-ASAmaintenance treatment long-term [EL3b, RG C]since this may reduce the risk of colon cancer[EL4, RG D]

ECCO statement 7AA staged procedure (colectomy first) is recom-mended in the acute case when patients do notrespond to medical therapy [EL 4, RG C], or if apatient has been taking 20 mg or more ofprednisolone for more than 6 weeks [EL 4, RG C]

In 1973, two studies from Sweden and the UK werepublished to assess whether sulfasalzine was still effective atpreventing relapse in UC patients with a long duration ofremission (Table 6.1). In the Swedish study, the authors foundno statistical benefit to maintaining sulfasalazine forpatients who had been symptom-free on sulfasalazine formore than a year.209 However, the number of patients wassmall, the duration of follow-up only 6 months and patientswere selected on clinical symptoms without endoscopic orhistologic criteria. In the UK study, sigmoidoscopy and rectalbiopsy were used at entry.208 The authors found thatmaintenance treatment with sulfasalazine 2 g/day continuedto have a major effect at reducing relapse, even in thesubgroup of patients who had been on sulfasalazine for morethan 3 years. Twenty-six years later, an Italian double-blindwithdrawal RCT included 112 patients with UC in clinical,endoscopic and histological remission who had been onsulfasalazine or 5-ASA for at least 1 year.303 Patients wererandomized to oral Asacol® 1.2 g/day or placebo for 1 year.Despite the small numbers, patients were stratified accord-ing to the length of disease remission prior to randomization.In patients with disease remission for 1–2 years, mesalazineappeared significantly more effective than placebo forpreventing relapse at 12 months (Asacol® 23% and placebo49%, p=0.035). For patients who had been in remission for

more than 2 years however, no statistically significantdifference was observed between relapse rates (5/28 vs 6/23, or 18% vs 26%, respectively), but numbers were verysmall. The results of this study should be regarded withcaution, not only because of the low power, but also becausethe trend was in favour of continuing mesalazine. The debateabout the merits of 5-ASA for chemoprevention of colorectalcancer is covered in Section 9.5.

7. Surgery

7.1. General

Surgery for ulcerative colitis has been refined to offer patientsneeding colectomy a better quality of life. Until the early1980 s, the gold standard for surgery was proctocolectomywith an ileostomy, apart from the sporadic use of ileorectalanastomosis. The Kock continent ileostomy was introduced inthe late 1960 s, but never achieved universal acceptance,although the gain in quality of life compared to proctocolect-omywith a conventional stoma seemed clear enough.304 In thepast 20 years, the new gold standard has become therestorative proctocolectomy with ileal pouch-anal anastomo-sis (IPAA), offering patients an unchanged body image with nostoma and a preserved anal route of defaecation.305 Never-theless, bowel function is not restored to normal and bothfunctional outcomeandquality of life after IPAA have still to becompared to living with an ileostomy.306

This section deals with some aspects on surgery forulcerative colitis. IPAA is probably one of the most frequentlydescribed procedures in colorectal surgery. There have beena vast number of publications (498 papers, 58 reviews), butdespite this good quality evidence in terms of randomisedstudies are scarce (5 on different aspects of pouch surgery),as is so often the case in surgery. The indications and timingof surgery for UC are found in the appropriate sections (acutesevere colitis, Section 5.2.4; refractory colitis, Section5.2.5; dysplasia or cancer, Section 9.4.2).

7.2. Technical considerations

7.2.1. Surgery for acute severe colitis

ECCO statement 7CWhen performing pouch surgery, the maximumlength of anorectal mucosa between the dentateline and the anastomosis should not exceed 2 cm [EL4, RG C]


A staged proctocolectomy (subtotal colectomy first) isconsidered by many surgeons to be a wise first step in thesurgical treatment of ulcerative colitis in acute severecolitis or if patients are saturated with steroids. This isprobably even wiser today when medical therapy foracute severe colitis is prolonged for more than 5 days. Asubtotal colectomy with an ileostomy will cure the patientfrom the burden of the colitis, allowing them to regaingeneral health, normalise nutrition and give the patienttime to consider carefully the option of an IPAA or,perhaps, permanent ileostomy. A preliminary subtotalcolectomy also allows the pathology to be clarified andCrohn's to be excluded. Subtotal colectomy is a relativelysafe procedure even in the critical ill patient.307–309

However it is seldom considered the final solution. Thuspatients have to go through additional surgery whichincurs further risks, additional costs and a prolonged timeunder surgical care.

7.2.2. Managing the rectal remnant

ECCO statement 7EWhen the indication for surgery is cancer ordysplasia and restorative proctocolectomy isperformed, anastomosis at the dentate line isrecommended [EL4, RG C]

ECCO statement 7BWhen performing a colectomy for ulcerativecolitis in emergency circumstances, the wholerectum should be preserved [EL 4, RG C]. Whetherto preserve additional recto-sigmoid colon andhow to deal with bowel closure is left to thesurgeon´s decision [EL 4, RG C]

ECCO statement 7DWhen performing an IPAA it is mandatory that thesurgical team can also perform a mucosectomy anda hand-sewn anastomosis should the stapledanastomosis fail [EL5, RG D]

There are some technical aspects on how to deal withthe rectum when performing an emergency subtotalcolectomy. These might have a bearing on the complica-tion rate and have technical implications when the patientcomes to a later proctectomy. Leaving as little rectum aspossible (i.e., dividing the middle rectum within thepelvis) is not to be recommended, as this will rendersubsequent proctectomy difficult, with a probableincrease in the risk of pelvic nerve injury. The alternativesare to divide the rectum at the level of the promontory(i.e., at the proper rectosigmoid junction) or to leave inaddition the distal part of the sigmoid colon. This allowsthe bowel to be either anchored to the anterior abdominalwall, facilitating subsequent identification and dissection,or to bring the bowel up through the abdominal fasciaeither closed in the subcutaneous fat, or brought forwardas a mucous fistula. The latter option is considered very safe,because no closed bowel is left within the abdomen, but themucous fistula gives the patient another stoma that is not soeasily managed.310 Closing the stump and leaving it within thesubcutaneous fat is as safe, although the skin is probably best beleft to heal through secondary intention in order to avoid woundinfections.311 There are no studies that give information on therisk of subsequent inflammation or bleeding after leavingdiffering lengths of rectum or rectosigmoid colon. When therectum is transsectedwithin the abdominal cavity at the level ofthe promontory, then this warrants transanal rectal drainage forsome days, to prevent blow out of the rectal stump due toretention.

7.2.3. Site of anastomosis for restorative poctocolectomy

The now commonly used stapling technique for performingthe ileo-anal anastomosis usually leaves a remnant ofanorectal mucosa above the dentate line. This can be acause of persistent inflammation (‘cuffitis’), with pouchdysfunction and a risk of dysplasia or (very rarely) cancer.312

On the otherhand, a very short lengthofmucosa (b1 cm) abovethe dentate line would exclude many (or even most) malepatients from the stapling technique, due to technicalproblems achieving a low anastomosis in the narrow malepelvis. Both have to be balanced against the advantage of thestapling technique, which gives patients better nocturnalcontinence.313

7.2.4. Anastomostic technique for restorativeproctocolectomy

Nevertheless, the stapling technique occasionally fails, isimpossible, or inappropriate. There is then seldom room forre-stapling and the only way of avoiding a permanent stomais to hand-sew the anastomosis. Stapling is generallyinappropriate when performing IPAA for dysplasia or cancercomplicating colitis, since the Consensus is to remove allmucosa (Statement 7E, below). All these eventualities meanbeing able to hand-sew the anastomosis.

7.2.5. Site of anastomosis for neoplasia complicating colitis

Since the stapling technique commonly leaves epitheliumwhich may still have malignant potential, the alternative isto perform a mucosectomy from the dentate line. In theory,but not necessarily in practice, this removes all of thepotentially diseased (and pre-malignant) mucosa. Conse-quently if the indication for proctocolectomy is cancercomplicating colitis, this might influence the subsequentrisk of cancer.314 However, the literature reports cancersboth in patients with a stapled anastomosis as well as in


those who have had a mucosectomy, but almost exclusivelyin those who had pre-existing malignancy in the resectedcolon. The number of reported cancers is limited (b30 out oftens of thousands of IPAA performedworld wide) and is not atpresent a matter for alarm.315,316 When there is colonicdysplasia alone rather than cancer, the literature gives noadvice on whether to staple or perform a mucosectomy. Atotal mesorectal excision is, however, mandatory when theindication is dysplasia or cancer.

7.2.6. Role of covering ileostomy for restorativeproctocolectomy

ECCO statement 7FWhen performing a restorative proctocolectomyfor ulcerative colitis a covering loop ileostomy isgenerally recommended, but it can be avoided inselected cases [EL 3b, RG C]

ECCO statement 7IFollow up should be individualised and focus onthose patients with signs of chronic inflammationin their mucosa [EL 5, RG D]

One of the main complications of IPAA surgery, and also thecomplication that might jeopardise the final outcome of theoperation, is a leak in the suture lines of the anastomosis orpouch. Whether the consequences of a leak can be amelio-rated bya covering ileostomyor not is still under debate.317,318

There are some small comparative studies, but no definitiveanswer. However, when performing a coloanal anastomosisafter rectal excision for cancer, it is now established that acovering loop ileostomy reduces the risk of clinical leakage.Nevertheless, in pouch surgery it is sometimes clear at thetime of surgery that themorbidity associatedwith a stomawillnot justify its use, such aswhen there is a thick abdominal walland a short small bowel mesentery, as long as there have beenno problems constructing the anastomosis.319–321

7.2.7. Number of procedures to maintain competency

ECCO statement 7GAn institution performing pouch surgery should domore than ten cases per year [EL 5 RG D]

ECCO statement 7JThere are not enough data to give a recommenda-tion on surveillance of pouches with respect tomalignant changes. However, patients operated

When performing complex surgical procedures that alsodemand sophisticated perioperative care, it has been shownthat institutions performing larger numbers of operationshave better outcomes than those who only operate on suchcases occasionally.322 There are no details pertaining to IPAA,but it seems reasonable to assume that this holds for pouchsurgery and the figure of ten per year for the unit is arbitrary,but considered reasonable by surgical members of ECCO.

7.2.8. Salvage surgery for pouches

ECCO statement 7HSalvage surgery for complications of IPAA shouldonly be done in special centres with adequatelyskilled staff and a reasonable number of proce-dures performed per annum [EL5, RG D]

From the perspective of a lifetime, failure rates for IPAAwill probably be in the region of 15%. Failure implies that thepatient has an ileostomy for an indefinite period, with orwithout pouch excision. Failures are usually due to septiccomplications or persistent pouch dysfunction, but some-times the reason is a missed diagnosis of Crohn's disease withfistulation, or refractory pouchitis. Before deciding that apouch has failed, the option of salvage surgery either as acorrective procedure or a complete “redo” has to be consid-ered. Thepatientwill invariably havea viewon this and it shouldonlybeundertakenbycolorectal surgeonswith special expertisein this area. Reported series of pouch rescue surgery describe asalvage rate above 50% and a still acceptable functionaloutcome.323–327 If pouch surgery is sufficiently complex torecommend a minimum case-load each year for a unit, it seemsappropriate that salvage surgerywhich is evenmore challengingshould only be performed in unitswith a substantial case volumeload and expertise, although it is impossible to quantify a‘reasonable number’.

7.3. Follow-up

7.3.1. General pouch follow up

General follow-up of people with an IPAA is a matter ofdebate. There are no data to suggest that lack of follow-upincurs any risk for the patient, disregarding the debate onthe risk of cancer. A proportion of patients (perhaps 20–30%)will develop pouchitis (Section 8.1), which may be recurrentor persisting. These patients will need continuing specialistcare, because primary care physicians or generalists will nothave the expertise necessary for management. The stapledIPAA where there is a varying length of mucosa below theanastomosis (see statement 7C, above), poses an additionalproblem compared to the hand-sewn IPAA, since thesepatients in principle have not had a curative procedure.However the remaining mucosa represents a very minutefraction compared to the original colon, which does notrepresent a risk or clinical problem for most patients.316

7.3.2. Pouch surveillance

on for cancer or dysplasia should be followed longterm [EL5, RG D]

The risk of malignant changes arising from the pouchmucosa as a result of colonic metaplasia in the pouch hasgenerated much debate. Fewer than 30 pouch cancers havebeen reported (2007), almost all in patients operated with


dysplasia or cancer already present in the specimen atprimary surgery. Many of the cancers originate fromanorectal mucosal remnant, which is the basis of therecommendation for mucosectomy (statement 7E,above).314,315 The frequency of small bowel cancers in thebackground population is very low and the risk of developinga pouch cancer de novo is likely to be as uncommon, butremains undefined.328

7.4. Fertility and delivery in patients with arestorative proctocolectomy

7.4.1. Impact of pelvic surgery on fecundity

ECCO statement 7 MNo defined age limit for performing an IPAA can berecommended [EL 5, RG D]

ECCO statement 7NThe continent ileostomy is still a viable optionthat can be used when there is no possibility ofperforming an ileal pouch anal anastomosis, orwhen the IPAA fails for other reasons thanpouchitis, or when the patient specifically re-

ECCO statement 7KIn a fertile female patient the option of an ileorectalanastomosis should always be considered, because

It has been convincingly demonstrated in three cohortstudies that female fecundity or fertility is reduced afterIPAA.329–332 The reason for this is most probably adhesionsaffecting the fallopian tubes.333 The magnitude of thisproblem is under debate, with one study showing N70%reduction and the others demonstrating around 30% reducedfecundity. There is however good evidence from a study onpatients with familial adenomatous polyposis, comparingwomen with an ileo-rectal anastomosis (IRA) with those withan IPAA, showing that there is no reduction in fecundityassociated with an IRA.334,335 This appears to be because anIRA does not induce pelvic fibrosis to nearly the same extentas an IPAA. This has lead to a modification in practice at somecentres, offering fertile female patients an IRA, provided therectum is not grossly inflamed, with a view to later pouchsurgery when the family is complete. Not every woman is acandidate for this approach. Symptoms are less when therehas been a colectomy, since the inflamed colon has beenremoved, but the rectum can be expected to remain in-flamed. The persisting risk of rectal malignancy is discussedin Section 7.5.3. On the other hand, IRA does not disturbsphincter function, unlike IPAA, does not impair fecundityand can be discussed as a temporising option.

7.4.2. Mode of delivery for patients with restorativeproctocolectomy

fecundity is at risk after IPAA [EL3b, RG B]

ECCO statement 7LWith regard to bowel function a caesarean route ofdelivery in a female with an IPAA is recommended[EL 5, RG D]

quests this solution [EL 4, RG C]

Vaginal delivery has a 0.5–3.5% risk of inflicting seriousmaternal sphincter tears.336,337 The risk is highest at thefirst delivery. On the other hand, multiple deliveries havebeen shown to prolong pudendal nerve terminal motorlatency.338,339 People with an IPAA have a very limitedmargin for maintaining faecal continence compared to the

general population. This is because many factors con-sidered important for normal continence, such as solidstools, rectal sensation, recto-anal nervous interplaythrough a recto-anal inhibitory reflex, are absent inpeople with an IPAA. Consequently they rely heavily ontheir sphincter for maintaining continence. Principally onthese grounds many surgeons recommend that theirpatient have a caesarian section rather than a vaginaldelivery. Nevertheless, in a cohort where caesariansection was recommended only for obstetric reasons,this group experienced very little or no difference in earlypostoperative continence and bowel function.340 Althoughit suggests that vaginal delivery is safe in selected cases,it remains contrary to two other papers that support therecommendation for caesarian delivery both in Europe andthe US.341,342

7.5. Surgical choices in addition to restorativeproctocolectomy

7.5.1. Age

Faecal continence in both men and women deteriorateswith increasing age. Females that have given birth carry ahigher risk of poor continence, probably because sub-clinicalinjuries add to age-related changes in nerve function,collagen elasticity and muscle strength. Consequently it isreasonable to consider whether an upper age limit for IPAAshould apply. It has however been demonstrated that IPAAwill function reasonably well in people 70 years of age andolder in carefully selected cases.343–345

7.5.2. Continent ileostomy

The continent ileostomy (‘Kock pouch’) was the fore-runner to the IPAA. It is a complex procedure with a highpotential for complications affecting the valve mechanismthat provides continence. However, with a functioningcontinent ileostomy patients report excellent quality of lifewith a next-to-normal body image.346–348 Furthermore afailed pelvic pouch can still be converted to a continentileostomy, providing an alternative in those patients thatabsolutely cannot accept a conventional stoma.325,349 Amajor problem is that this operation is still performed at onlya few centres in Europe.


7.5.3. Ileorectal anastomosis

ECCO statement 7OAn ileorectal anastomosis should be considered onlyin special cases (such as for reasons of fertility) [EL4,RG C] ECCO statement 7R

Laparoscopic restorative proctocolectomy with anIPAA is a feasible operation; it gives shorter scarsbut there is no evidence for additional benefit tothe patient [EL 2a, RG B]

An ileorectal anastomosis is historically burdened. It is notonly non-curative, but also leaves patients with the likelihoodof persistent symptoms from refractory rectal inflammationand a risk of later cancer. Even so, recent series show a betterthan expected durability, with half of the patients still livingwith an IRA after 10 years.350,351 Its role in the management ofwomen facing surgery before they have completed their familyis discussed above (Section 7.4.1). It can be assumed that thecancer risk with medical therapy and surveillance is at leastless than in those who have not had surgery.

7.5.4. Cancer surveillance of the rectal remnant aftercolectomy

ECCO statement 7PFor patients who have a colectomy and ileostomy,surveillance of the retained rectum is appropriate,although it can be left in situ if the patient sowishes [EL5, RG D]

ECCO statement 7SIn indeterminate colitis or colonic IBD yet-to-beclassified, an IPAA can be offered with theinformation that there is an increased risk ofcomplications and pouch failure [EL4, RG C]

The literature gives no direct guidance in this matter.Some patients that come to colectomy with an ileostomy as afirst operation get accustomed to livingwith a stoma and havevery fewproblems from their retained rectum. If a patient hasno wish for further surgery, the question arises whether thereis any reason for rectal excision. The balance is between therisk of a cancer in the disconnected bowel and the incon-venience and risks of a proctectomy. Taking out the rectum isamajor operation with a considerable surgical morbidity withwound healing problems and risk of sexual dysfunction both inwomen and men.352,353 Options of proctectomy or surveil-lance of the retained rectal remnant should be discussed withthe patient.

7.5.5. Pouch excision after pouch failure

ECCO statement 7QIn a patient where the pouch has failed and there isno hope of re-establishing the anal route of defeca-tion, there are not enough data to make anyrecommendationonwhether or not thepouch shouldbe removed [EL5, RG D]

ECCO statement 7TPrednisolone 20 mg daily or equivalent for morefor more than six weeks is a risk factor for surgicalcomplications [EL3b, RG C]. Therefore, corticos-teroids should be weaned if possible

The dilemma is similar in the patient with a failed,disconnected pelvic pouch. Some of these patients do nothave any further pouch-related problems. There is as yet noevidence that the risk of malignant change is increased in thedisconnected pouch. The morbidity of pouch excision isprobably no less than for proctectomy.324 For individuals who

have had severe septic complications, it is reasonable toassume that the risk of pelvic nerve injury is increased.

7.5.6. Laparoscopic pouch surgery

Minimally invasive surgery is gradually being incorporatedinto colorectal practice and is a feasible alternative for manypatients, provided that surgeons are adequately trained inthis technique. No randomised studies have yet shown anymajor differences from open surgery.354,355

7.5.7. Pouch surgery for indeterminate colitis, or IBD yet-to-be classified

About 10% of patients with colitis will not have a definitivediagnosis that discriminates between Crohn's and ulcerativecolitis. Terminology is discussed in Section 5. There are reportsof less favourable outcomes when performing pouch surgery forpatients with indeterminate colitis, although others find nosignificant differences.356,357 Inmost series that report outcomeafter pouch surgery, those with a secondary diagnosis of Crohn'sdisease are burdened with very high complication and failurerates. Although one group has reported outcomes equivalent tothose with UC for patients with a pre-operative Crohn'sdiagnosis, none had pre-operative small bowel or perianaldisease.358 Pouch surgery for patients with a definitive diagnosisof Crohn's disease cannot be recommended. For those inwhom itis considered an option, very careful discussion with the patientabout increased risks of sepsis and pouch failure is appropriate.

7.6. Surgery and medication

7.6.1. Perioperative prednisolone

Uncontrolled or retrospective series indicate that patientstakingN20mgprednisolone forN6weeks havean increased riskof surgical complications.359,360 The rate of steroid reductionafter colectomy for acute severe colitis depends on the dose


and duration of steroids prior to surgery. Any recommendationsof the rate are arbitrary, but the aim is to avoid acute steroidwithdrawal (‘Addisonian’) crisis, characterised by hypoten-sion, hyponatraemia and hypoglycaemia in its most severeform. Milder symptoms may be disguised as a ‘slower thannormal’ recovery from surgery. There is little science to steroidwithdrawal. As a general guide, if patients have been oncorticosteroids for b1 month, steroids can usually be stoppedabruptly after surgery without ill effect. For those on steroidsfor 1–3months, a reduction from20mg/dayafter colectomy of5 mg/day each week is generally appropriate. For patients onsteroids for 3–6 months, a reduction of 2.5 mg/d each week isprobablymore appropriate, while for the occasional patient onsteroids for longer than 6 months, then a dose reduction of1 mg/week (or even more slowly) is advisable.

7.6.2. Perioperative azathioprine

ECCO statement 7UPre-operative azathioprine does not increase the riskof postoperative complications [EL3b, RG C]. Co-lectomy for ulcerative colitis immediately followingor in the medium term after the use of ciclosporinappears to have no higher rate of postoperativecomplications [EL2b, RG D], while there are nosufficient data yet available for infliximab

Azathioprine does not appear to increase the risk ofsurgical complications although debate continues.360–363

7.6.3. Perioperative anti-TNF therapyTNFα is a key player in the immune response. Inhibition ofTNF by infliximab (IFX) or other agents could potentially leadto serious post-operative complications. There is particularconcern that emergency colectomy within a few weeks ofinfliximab may be associated with more septic complica-tions. Even if IFX does not increase the risk of sepsis, it is stilllikely that should a septic complication occur, then it will bemore severe in the presence of circulating anti-TNF antibody.Whilst it is generally accepted that elective surgery forCrohn's disease in the presence of IFX is not associatedwith higher rates of sepsis,83,364 the same may not apply toemergency colectomy for acute severe colitis (Section5.2.5). In a Scottish survey 13/39 patients came to colectomyafter IFX treatment for acute severe colitis. One patient whoinitially responded to infliximab died of septic shock frombronchopneumonia 3 weeks after treatment, and anotherhad severe post-operative sepsis resistant to anti-bacterialtherapy and only responding to intensive antifungal treat-ment.82 There has also been a worrying report of 20 patientsreceiving ciclosporin (for a mean 3.8 months, range 0.5–12.2) before IFX, or IFX (mean 2 infusions, range 1–3) beforeciclosporin for severe steroid-refractory colitis.365 One pa-tient died from E. coli septicaemia, another becamejaundiced and another developed herpetic oesophagitis.Such therapy in combination in an endeavour to avoidcolectomy carries high risks and cannot be recommended.Similar concerns have been raised from the Mayo clinicrelating to IPAA after IFX.366 Between 2002 and 2005, 47patients received IFX before IPAA, and 254 patients received

none. IFX patients were younger than non-IFX patients (meanage 28.1 to 39.3 years, pb0.001), probably reflectingconcern that all medical options were explored before sur-gery. Overall surgical morbidity was similar (61.7% and48.8%, IFX and non-IFX respectively, p=0.10), with nomortality. Anastomotic leaks (p=0.02), pouch-specific(p=0.01) and infectious (pb0.01) complications were morecommon in IFX patients. Multivariate analysis revealed IFX asthe only factor independently associated with infectiouscomplications (OR 3.5; 95%CI 1.6–7.5). When age, corticos-teroid dose, azathioprine, and severity of colitis werefactored into the analysis, IFX remained significantly as-sociated with infectious complications (OR 2.7; 95% CI, 1.1–6.7). This illustrates the need for caution when using IFX inthe perioperative period of severe colitis.

7.7. Colectomy in practice

The rate of colectomy varies according to the patientcohort, duration of follow up and geographical location.Studies published in the early 1990 s reported an overallcolectomy rates of 23%, 28% and 34% after 10 years of followup, with rates as high as 35% at 5 years and 42% and 54% at10 years for extensive colitis.367–369 It is unclear whetherthe overall rate is changing, even in areas with excellentpopulation-based data such as Copenhagen, where therehas traditionally been a high rate of colectomy. Whenpatients diagnosed with UC in Copenhagen during 2003–2005 were followed prospectively only 6% of patientsunderwent surgery during the year of diagnosis, signifi-cantly less than earlier reported.370 This might reflect anincreasing prevalence of proctitis and milder initial coursediagnosed in the 1990s, but when 3 consecutive population-based IBD cohorts from Copenhagen (1962–2005), wereassessed the cumulative surgery rate in 1575 patients withulcerative colitis did not decrease significantly.195 Never-theless, in a 781 patient European inception cohort (1991-93) from 7 countries, the overall 10 year cumulative risk ofcolectomy was only 8.7%.371 Colectomy rates for extensivecolitis at diagnosis in Denmark, Norway and the Netherlandswere 22.1% compared to 8.5% for Greece, Italy, Spain andIsrael. The extent of disease did not differ betweennorthern and southern centres, but the prevalence ofproctitis or distal colitis was remarkably high (75%, or557/745 patients). This is as likely to explain the low overallcolectomy rate as are cultural differences or acceptance ofsymptoms between countries. The 10 year colectomy ratewas 2% for proctitis/distal disease, 18% for extensivedisease at diagnosis, and 39% for the 11% (62/557) patientswith proctitis progressing to extensive colitis during followup.

Contributors

Willem Bemelman, Minimal Invasive and Colorectal Surgery,Department of Surgery, Academic Medical Center, PO Box22700, 1100 DE AmsterdamYehuda Chowers, Dept. Gastroenterology Chaim ShebaMedical Center, Tel Hashomer 52621, IsraelJean Frédéric Colombel, Dept of HepatoGastroenterology,Hospital Huriez, Rue Michel Polonovski, 59037 Lille, France


Geert D'Haens, GI Clinical Research Centre, Imelda Hospital,2820 Bonheiden, BelgiumMiquel Gassull, Head of Dept of Gastroenterology andHepatology, Hospital Universitari Germans, Trias i Pujol,Carretera del Canyet, s/n 08916, Barcelona, SpainSubrata Ghosh, Gastroenterology Section, Imperial CollegeLondon, Hammersmith Campus, Du Cane Road, London W120NNWolfgang Kruis, Dept of Internal Medicine, EvangelischesKrankenhaus Kalk HGmbh, Buchforststrasse 2, 51103 Cologne,GermanyMarc Lémann, Service de Gastroentérologie, Hospital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, FrancePhilippe Marteau, AP-HP, Medico-surgical Department ofDigestive Diseases, Laribosière Hospital, 2 rue AmbroiseParé, 75010 & Paris 7 Univerity, Paris, FranceNeil Mortensen, Professor of Colorectal Surgery and Fellow ofGreen College, University of Oxford and Consultant GeneralSurgeon, Oxford Radcliffe Hospitals NHS Trust, Oxford, UKTomØresland, Dept of Surgery, AkerhusUniversity Hospital, N-1478 Lørenskog, NorwayFreddy Penninckx, Professor and Chairman, Department ofAbdominal Surgery, University Clinics Gasthuisberg, CatholicUniversity Leuven, Herestraat 49, 3000 Leuven, Belgium.Eduard Stange, Chefarzt, Abteilung für Innere Medizin 1Schwerpunkte Gastroenterologie, Hepatologie und Endokri-nologie, Robert Bosch Krankenhaus, Postfach 501120, Auer-bachstr. 110, 70341 StuttgartSimon Travis, John Radcliffe Hospital, Oxford, UK

Acknowledgements

Weare particularly grateful toMrs Lynn Lane and Sophie Lane ofOxford for their substantial contribution to coordinating andassimilating the Consensus, to the Robert Bosch Foundation foran unrestricted educational grant and to all colleagues whocompleted the questionnaires and contributed to the state-ments at the Consensus meeting in Berlin, October 2006. Themeeting in Berlin was greatly facilitated by the support of theGerman competence network on IBD.

The contributors to the Consensus meeting were:Austria Moser, Reinisch, TilgBelgium De Vos, D'Haens, Geboes, Penninckx, VermeireCroatia Kolacek, VucelicCzech Republic LukasDenmark Lebech, Munkholm, WewerFrance Colombel, Cortot, Fléjou, Lémann, Marteau, PanisGermany Dignass, Herfarth, Hoffmann, Jantschek, Kiesslich,Kruis, Kucharzik, Schölmerich, Schreiber, Stange, ZeitzGreece Mantzaris, TsianosHungary LakatosIsrael Chowers, EliakimItaly Biancone, Caprilli, Cottone, Gionchetti, Pallone,Prantera, Vecchi, VillanacciLatvia PokrotnieksLithuania Barakauskiene, Kupcinskas,Netherlands Bemelman, Escher, Hommes, Van der WoudeNorway MoumPortugal FreitasSerbia Jojic

Slovakia GregusSpain Gassull, PanesSweden Øresland, Soderholm, TyskSwitzerland Mitchetti, SeiboldUK Feakins, Forbes, Ghosh, Hamilton, Hawkey, Mitchell,Mortensen, Rhodes, Travis, Warren

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SPECIAL ARTICLE

European evidence-based Consensus on themanagement of ulcerative colitis:Special situationsLivia Biancone, Pierre Michetti, Simon Travis⁎,1, Johanna C. Escher,Gabriele Moser, Alastair Forbes, Jörg C Hoffmann, Axel Dignass,Paolo Gionchetti, Günter Jantschek, Ralf Kiesslich, Sanja Kolacek,Rod Mitchell, Julian Panes, Johan Soderholm, Boris Vucelic, Eduard Stange⁎,1

for the European Crohn's and Colitis Organisation (ECCO)

Received 30 December 2007; accepted 30 December 2007

KEYWORDSUlcerative colitis;Pouchitis;Colorectal cancersurveillance;Adolescence;Psychosomatic

Contents

8. Pouchitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 658.1. General. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

8.1.1. Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 658.1.2. Endoscopy (‘pouchoscopy’) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 658.1.3. Histopathology of pouchitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668.1.4. Differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668.1.5. Risk factors for pouchitis and pouch dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

8.2. Pattern of pouchitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668.2.1. Acute and chronic pouchitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668.2.2. Scoring of pouchitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668.2.3. Recurrent pouchitis and complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

⁎ Corresponding authors. Travis is to be contacted at John Radcliffe Hospital, Oxford, OX3 9DU, UK. Tel.: +44 1865 228753; fax: +44 1865228763. Stange, Department of Internal Medicine 1, Robert Bosch Krankenhaus, PO Box 501120, Auerbachstr, 110, 70341 Stuttgart, Germany.Tel.: +49 711 81013404; fax: +49 711 81013793.

E-mail addresses: [email protected] (S. Travis), [email protected] (E. Stange).1 These authors acted as convenors of the Consensus and contributed equally to the work.

1873-9946/$ - see front matter © 2008 European CrohnTs and Colitis Organisation. Published by Elsevier B.V. All rights reserved.doi:10.1016/j.crohns.2007.12.001

64 L. Biancone et al.

8.3. Medical treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678.3.1. Acute pouchitis: antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678.3.2. Chronic pouchitis: combination antibiotic therapy or budesonide. . . . . . . . . . . . . . . . . . . 678.3.3. Acute and chronic refractory pouchitis: other agents . . . . . . . . . . . . . . . . . . . . . . . . . 678.3.4. Maintenance of remission: probiotics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688.3.5. Prevention of pouchitis: probiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

8.4. Cuffitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689. Surveillance for colorectal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

9.1. Risk of cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689.1.1. Estimation of risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689.1.2. Risk factors for cancer development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

9.2. Surveillance colonoscopy programmes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699.2.1. Screening and surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699.2.2. Effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699.2.3. Initial screening colonoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 709.2.4. Surveillance schedules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

9.3. Colonoscopic procedures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 709.3.1. Number and site of biopsies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 709.3.2. Chromoendoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

9.4. Dysplasia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 719.4.1. Risk of progression to cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 719.4.2. Dysplasia and colectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 719.4.3. Dysplasia and raised lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

9.5. Chemoprevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 729.6. Prognosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

10. Children and adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7210.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7210.2. Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

10.2.1. Diagnostic threshold. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7310.2.2. Documentation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7310.2.3. Diagnostic procedures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

10.3. Induction therapy in children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7310.3.1. Distal colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7310.3.2. Extensive colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7410.3.3. Severe colitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

10.4. Maintenance therapy in children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7510.4.1. Aminosalicylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7510.4.2. Thiopurines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

10.5. Surgery in children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7510.5.1. Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7510.5.2. Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

10.6. Nutritional support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7510.7. Psychosocial support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7510.8. Transition of care to adult services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

11. Pregnancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7612. Psychosomatics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

12.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7612.2. Influence of psychological factors on disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

12.2.1. Aetiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7612.2.2. Pattern of disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

12.3. Psychological disturbances in ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7612.4. Approach to psychological disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

12.4.1. Communication with patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7712.4.2. Psychological support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7712.4.3. Therapeutic intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7712.4.4. Therapeutic choice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

13. Extraintestinal manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7813.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7813.2. Arthropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

13.2.1. Pauciarticular peripheral arthropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7813.2.2. Polyarticular peripheral arthropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

65ECCO Consensus on UC: Special situations

13.2.3. Axial arthropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7913.2.4. Therapy of arthropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

13.3. Cutaneous manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7913.3.1. Erythema nodosum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7913.3.2. Pyoderma gangrenosum (PG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8013.3.3. Sweet's syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

13.4. Ocular manifestations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8013.4.1. Episcleritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8013.4.2. Uveitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8013.4.3. Cataracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

13.5. Hepatobiliary disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8013.5.1. Primary sclerosing cholangitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

13.6. Metabolic bone disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8113.6.1. Diagnosis and fracture risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8113.6.2. Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

13.7. Other systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8213.8. Organisation of services for EIMs associated with ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . 82

14. Complementary and alternative medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8214.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8214.2. Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8214.3. Use of CAM. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

8. Pouchitis

8.1. General

Proctocolectomy with ileal pouch-anal anastomosis (IPAA)is the procedure of choice for most patients with ulcerativecolitis (UC) requiring colectomy.1 Pouchitis is a non-specificinflammation of the ileal reservoir and the most commoncomplication of IPAA in patients with UC.2–7 Its frequency isrelated to the duration of the follow-up, occurring in up to50% of patients 10 years after IPAA in large series frommajor referral centres.1–9 The cumulative incidence ofpouchitis in patients with an IPAA for familial adenomatouspolyposis is much lower, ranging from 0 to 10%.10–12

Reasons for the higher frequency of pouchitis in UC remainunknown. Whether the pouchitis more commonly developswithin the first years after IPAA or whether the riskcontinues to increase with longer follow-up remainsundefined.

ECCO Statement 8AThe diagnosis of pouchitis requires the presence ofsymptoms, together with characteristic endoscopic andhistological abnormalities [EL3a, RGB]. Extensive colitis,extraintestinal manifestations (eg primary sclerosing cho-langitis), being a non-smoker, p-ANCA positive serology, andnon-steroidal anti-inflammatory drug use are possible riskfactors for pouchitis [EL3b, RG D ]

8.1.1. SymptomsAfter total proctocolectomy with IPAA, median stoolfrequency is 4 to 8 bowel movements1–4,13,14 with 700 mL

of semiformed/liquid stool per day2,13,14. Symptoms relatedto pouchitis include increased stool frequency and liquidity,abdominal cramping, urgency, tenesmus and pelvic dis-comfort (2, 15). Rectal bleeding, fever, or extraintestinalmanifestations may occur. Rectal bleeding is more oftenrelated to inflammation of the rectal cuff (“cuffitis”),16

than to pouchitis. Poor faecal incontinence may occur in theabsence of pouchitis after IPAA, but is more common inpatients with pouchitis. Symptoms of pouch dysfunction inpatients with IPAA may be caused by conditions other thanpouchitis, including Crohn's disease of the pouch,17–19

cuffitis,16 and an irritable pouch.20 This is why the diagnosisdepends on endoscopy and biopsy in conjunction withsymptoms.

8.1.2. Endoscopy (‘pouchoscopy’)Pouchoscopy and pouch mucosal biopsy should be per-formed in patients with symptoms compatible withpouchitis, in order to confirm the diagnosis.15 Patientswith an ileoanal pouch occasionally have a stricture at thepouch-anal anastomosis, so a gastroscope rather than acolonoscope may better be necessary for pouchoscopy.Endoscopic findings compatible with pouchitis includediffuse erythema caused by inflammation of the ilealpouch, which may be patchy, unlike that observed in UC.Characteristic endoscopic findings include oedema, gran-ularity, friability, spontaneous or contact bleeding, loss ofvascular pattern, mucous exudates, haemorrhage, erosionsand ulceration.17 Erosions and/or ulcers along the stapleline do not necessarily indicate pouchitis. Characteristi-cally, these findings are non-specific and lesions may bediscontinuous, unlike the colorectal lesions in UC.18,21,22

Biopsies should be taken from the pouch mucosa and fromthe afferent limb above the pouch, but not along thestaple line.


8.1.3. Histopathology of pouchitisHistological findings of pouchitis are also non-specific,including acute inflammation with polymorphonuclearleukocyte infiltration, crypt abscesses and ulceration, inassociation with a chronic inflammatory infiltrate.21,22

There may be discrepancy between endoscopic andhistologic findings in pouchitis, possibly related to sam-pling error.23,24 Morphological changes of the epitheliumlining the ileal pouch normally develop in the 12–18 monthsafter ileostomy closure, characterised by flattening and areduced number, or disappearance of the villi, leading tovillous atrophy (“colonic metaplasia”).22–24 Although theaetiology of pouchitis remains unknown, it can be inferredfrom the predeliction for patients with UC and theresponse to antibiotic therapy that the bacterial floraand whatever predisposes to UC itself are involved in thepathogenesis of tissue damage in the ileoanal pouch.25,26

Pouchitis tends to occur only after colonic metaplasia hasdeveloped in the pouch, although a causal association isunproven.

ECCO Statement 8BThe most frequent symptoms of pouchitis are increasednumber of liquid stools, urgency, abdominal crampingand pelvic discomfort. Fever and bleeding are rare [EL1c,RG B]. Routine pouchoscopy after clinical remission is notrequired [EL5, RG D]

8.1.4. Differential diagnosisThe clinical history and biopsies help discriminate betweenpouchitis, ischaemia, Crohn's disease (CD) and other rareforms of pouch dysfunction such as collagenous pouchitis,Clostridium difficile or cytomegalovirus pouchitis.27–29

Secondary pouchitis, caused by pelvic sepsis, usually causesfocal inflammation and should be considered. Biopsies takenfrom the ileum above the pouch may reveal pre-pouch ileitisas a cause of pouch dysfunction, although this usually causesvisible ulceration that may be confused with Crohn'sdisease.30 The possibility of non-specific ileitis caused byNSAIDs should be considered.31

8.1.5. Risk factors for pouchitis and pouch dysfunctionReported risk factors for pouchitis include extensive UC,1,32

backwash ileitis,32 extraintestinal manifestations (especiallyprimary sclerosing cholangitis),5,19,33 being a non-smoker34

and regular use of NSAIDs.31,35 Interleukin-1 receptor antago-nist gene polymorphisms36 and the presence of perinuclearneutrophil cytoplasmic antibodies37 are also associated withpouchitis. Not surprisingly studies are discordant with regardto the role of each risk factor. Some of the best data on riskfactors come from the Cleveland Clinic.38 240 consecutivepatients were classified as having healthy pouches (n=49),pouchitis (n=61), Crohn's disease (n=39), cuffitis (n=41), orirritable pouch syndrome (n=50). The risk of developingpouchitis was increased 3–5 fold when the indication for IPAAwas dysplasia (OR 3.89; 95% CI 1.69–8.98), or when the patienthad never smoked (OR 5.09; 95% CI 1.01–25.69), or usedNSAIDs (OR 3.24; 95% CI 1.71–6.13), or (perhaps surprisingly)had never used anxiolytics (OR 5.19; 95% CI 1.45–18.59). Therisk of turning out to have Crohn's disease of the pouch wasgreatly increased by being a current smoker (OR 4.77; 95% CI,

1.39–16–25), and modestly associated by having a pouch oflong duration (OR 1.20; 95% CI 1.12.–1.30). Cuffitis wasassociated with symptoms of arthralgia (OR 4.13; 95% CI 1.91–8.94) and a younger age (OR 1.16; 95% CI 1.01–1.33). Irritablepouch syndrome is probably under-recognised, although is acommon cause of pouch dysfunction when other causes(including a small volume pouch, incomplete evacuation andpouch volvulus) have been excluded and investigations arenormal. The principal risk factor is the use of antidepressants(OR 4.17; 95% CI 1.95–8.92) or anxiolytics (OR 3.21; 95% CI1.34–7.47), which suggests that these people may have hadirritable bowel syndrome contributing to symptoms of colitisbefore pouch surgery.38

These risk factors should not preclude proctocolectomy ifsurgery is appropriate, but should inform pre-operativediscussions with the patient and family. In particular thepossibility that IBS may be contributing to symptoms ofrefractory UC should be considered and objective evidenceof treatment refractory colitis obtained before surgery. Ifthere is a disparity between preoperative and endoscopicappearance, or if the patient is on antidepressants, then therisk of pouch dysfunction after IPAA needs particularlycareful consideration. Similarly, if a patient has primarysclerosing cholangitis, then it is appropriate to discuss thehigher risk of pouchitis. This is appropriate management ofexpectations rather than a contraindication to appropriatesurgery.

8.2. Pattern of pouchitis

8.2.1. Acute and chronic pouchitisOn the basis of symptoms and endoscopy, pouchitis can bedivided into remission (normal pouch frequency) or activepouchitis (increased frequency with endoscopic appear-ances and histology consistent with pouchitis).15,39 Activepouchitis may then be divided into acute or chronic,depending on the symptom duration. The threshold forchronicity is a symptom duration of N4 weeks. Up to 10% ofpatients develop chronic pouchitis requiring long-termtreatment, and a small subgroup has pouchitis refractoryto medical treatment.3

8.2.2. Scoring of pouchitisThe Pouchitis Disease Activity Index (PDAI) has beendeveloped to standardize diagnostic criteria and assess theseverity of pouchitis.15,39,40 The PDAI is a composite scorethat evaluates symptoms, endoscopy and histology. Eachcomponent score has a maximum of 6 points. Patients with atotal PDAI score ≥7 are classified as having pouchitis, so apatient has to have both symptoms and endoscopic orhistological evidence of pouchitis and, ideally, all three.The problem is that about a quarter of patients with a highsymptom score suggestive of pouchitis may not fulfil criteriafor the diagnosis of pouchitis, as assessed by the PDAI, sinceendoscopic or histological criteria may be absent. Conse-quently a relatively large number of patients may beunnecessarily treated for puchitis when symptoms are dueto other conditions. Other scoring systems have beendevised, including that by Moskowitz21 and an index fromHeidelberg. Comparisons with the PDAI41,42 show that theyare not interchangeable, but this affects clinical trials ratherthan clinical practice.


8.2.3. Recurrent pouchitis and complicationsPouchitis recurs in more than 50%.3,15,39 Patients withrecurrent pouchitis can broadly be grouped into threecategories: infrequent episodes (b1/yr), a relapsing course(1–3 episodes/yr) or a continuous course. Pouchitis mayfurther be termed treatment responsive or refractory, basedon response to single-antibiotic therapy (see 8.3.2).7,9

Although these distinctions are largely arbitrary, they helpboth patients and their physicians when considering manage-ment options to alter the pattern of pouchitis. Complicationsof pouchitis include abscesses, fistulae, stenosis of thepouch-anal anastomosis and adenocarcinoma of thepouch.7,27,39 This latter complication is exceptional andalmost only occurs when there is pre-exiting dysplasia orcarcinoma in the original colectomy specimen.

8.3. Medical treatment

8.3.1. Acute pouchitis: antibiotics

ECCO Statement 8CThe majority of patients respond to metronidazole orciprofloxacin, although the optimum modality of treat-ment is not clearly defined [EL1b, RG B]. Side-effects areless frequent using ciprofloxacin [EL1c, RG B]. Antidiar-rhoeal drugs may reduce the number of daily liquid stoolsin patients, independent of pouchitis [EL5, RGD]

Treatment of pouchitis is largely empirical and only smallplacebo-controlled trials have been conducted. Antibiotics arethe mainstay of treatment, and metronidazole and ciproflox-acin are the most common initial approaches, often with arapid response. The odds ratio of inducing a response using oralmetronidazole compared with placebo in active chronicpouchitis was 26.67 (95% CI 2.31–308.01, NNT=2).43 Therandomised trials of bothmetronidazole and ciprofloxacin are,however, small.44–46 The two have been compared in anothersmall randomised trial.47 Seven patients received ciproflox-acin 1 g/day and nine patients metronidazole 20 mg/kg/dayfor a period of 2 weeks. Ciprofloxacin lowered the PDAI scorefrom10.1±2.3 to 3.3±1.7 (p=0.0001),whereasmetronidazolereduced the PDAI score from 9.7±2.3 to 5.8±1.7 (p=0.0002).Therewas a significantly greater reduction in the ciprofloxacincompared to metronidazole in terms of the total PDAI(p=0.002), symptom score (p=0.03) and endoscopic score(p=0.03), as well as fewer adverse events (33% of metronida-zole-treated patients reported side-effects, but none onciprofloxacin). Combination antibiotic therapy is an optionfor persistent symptoms (below).

8.3.2. Chronic pouchitis: combination antibiotic therapyor budesonide

ECCO Statement 8DIn chronic pouchitis, combined antibiotic treatment iseffective [EL1b, RG B]

For patients who have persistent symptoms, alternativediagnoses should be considered, including undiagnosedCrohn's disease, pouch-anal or ileal-pouch stricture, infec-

tion with CMV or Cl difficile, collagenous pouchitis, cuffitis,anatomical disorders, or irritable pouch syndrome. Approxi-mately 10–15% of patients with acute pouchitis developchronic pouchitis, which may be “treatment responsive” or“treatment refractory” to single-antibiotic therapy.39

Patients with chronic, refractory pouchitis do not respondto conventional therapy and often continue to suffersymptoms, which is a common cause of pouch failure.Combination antibiotic therapy or oral budesonide maywork. 16 consecutive patients with chronic, refractorypouchitis (disease N4 weeks and failure to respond toN4 weeks of single-antibiotic therapy) were treated withciprofloxacin 1 g/day and tinidazole 15 mg/kg/day for4 weeks.47 A historic cohort of ten consecutive patients withchronic refractory pouchitis treatedwith 5–8 g oral and topicalmesalazine daily was used as a comparator. These refractorypatients had a significant reduction in the total PDAI score anda significant improvement in quality-of-life score (pb0.002)when taking ciprofloxacin and tinidazole, compared to base-line. The rate of clinical remission in the antibiotic group was87.5% and for the mesalazine group was 50%.

In another study, 18 patients non-responders to metroni-dazole, ciprofloxacin or amoxycillin/clavulanic acid for4 weeks were treated orally with rifaximin 2 g/day (anonabsorbable, broad spectrum antibiotic) and ciprofloxacin1 g/day for 15 days. Sixteen out of 18 patients (88.8%) eitherimproved (n=10) or went into remission (n=6).48 MedianPDAI scores before and after therapy were 11 (range 9–17)and 4 (range 0–16), respectively (pb0.002). A British groupobserved similar benefit in just 8 patients.49 In anothercombination study, 44 patients with refractory pouchitisreceived metronidazole 800 mg–1 g/day and ciprofloxacin1 g/day for 28 days.50 36 patients (82%) went into remissionandmedian PDAI scores before and after therapy were 12 and3 respectively (pb0.0001). The alternative is oral budeso-nide CIR 9 mg daily for 8 weeks, which achieved remission in15/20 (75%) patients not responding after 1 month ofciprofloxacin or metronidazole.51 The message is simpleenough, even if the trials are underpowered: if ciprofloxacindoes not work, then try it in combination with an imidazoleantibiotic or rifaximin, or try oral budesonide.

8.3.3. Acute and chronic refractory pouchitis: otheragentsThe variety of approaches illustrates the challenges of tryingto find treatment that works for a new disorder. These arelargely of historic interest. Budesonide enemas were aseffective as metronidazole for acute pouchitis in a rando-mised controlled trial.52 Ciclosporin enemas were successfulfor chronic pouchitis in a pilot study53 and oral azathioprinemay help if patients relapse become budesonide-dependent.Uncontrolled studies of short-chain fatty acid enemas54,55

showed little value. Glutamine and butyrate suppositorieshave been compared for chronic pouchitis.56 Of more recentinterest, infliximab has been tried in patients with chronic,(very) refractory pouchitis not responding either to metro-nidazole or ciprofloxacin 1 g/day for 4 weeks or oralbudesonide CIR 9 mg/day for 8 weeks. 10/12 (83.3%) suchpatients treated with infliximab 5 mg/kg at 0, 2 and 6 weekswent into remission.57 The median PDAI score before therapywas 13 (range 8–18) and 2 (range 0–9) after infliximab(pb0.001) and the IBDQ also significantly improved from 96


(range 74– 184) to 196 (92– 230) ( p b 0.001). 57 Infliximab hasbeen used when the cause of pouch dysfunction is Crohn'sdisease, or fistulation. 58 Benefit been also been reportedfrom alicaforsen enemas (an inhibitor of intercellularadhesion molecule (ICAM)-1) in an open-label trial.59

8.3.4. Maintenance of remission: probiotics

ECCO Statement 8EVSL#3 (18 × 10 11 of 8 bacterial strains for 9 or 12 months)has shown efficacy for maintaining antibiotic-inducedremission [EL1b, RG B]. VSL#3 (9 ×1011 bacteria) has also

ECCO Statement 8ERectal cuff inflammation (cuffitis) may induce symptomssimilar to pouchitis or irritable pouch syndrome, althoughbleeding is more frequent [EL2a, RG B]. Topical 5-ASA has

ECCO Statement 9APatients with longstanding ulcerative colitis appear to havean increased risk of colorectal cancer (CRC) as compared to

In chronic pouchitis, once remission has been obtained,treatment with the highly concentrated probiotic mixtureVSL#3 is able to maintain remission. Two double-blind,placebo-controlled studies have shown the efficacy ofVSL#3 (450 billion bacteria of 8 different strains/g) tomaintain remission in patients with chronic pouchitis. In thefirst study, 40 patients who achieved clinical and endo-scopic remission after one month of combined antibiotictreatment (rifaximin 2 g/day+ciprofloxacin 1 g/day), wererandomised to receive either VSL#3, 6 g/day (18×1011

bac teri a/ day), or placebo for 9 mo nths.60 All 20 patient swho received placebo relapsed, while 17 of the 20 patients(85%) treated with VSL#3 remained in clinical and endo-scopic remission at the end of the study. Interestingly, all 17patients relapsed within four months after stoppingVSL#3.60 In the second study, 36 patients with chronic,refractory pouchitis who achieved remission (PDAI =0)after 1 month of combined antibiotic treatment (metroni-dazole+ciprofloxacin) received 6 g/once a day of VSL#3 orplacebo for 1 year. Remission rates at one year were 85% inthe VSL#3 group and 6% in the placebo group (pb0.001).61

8.3.5. Prevention of pouchitis: probioticsThe same probiotic preparation (VSL#3) has been shown toprevent pouchitis within the first year after surgery, in arandomised, double-blind, placebo-controlled study. Fortyconsecutive patients undergoing IPAA for UC were rando-mised within a week after ileostomy closure, to VSL#3 3 g(9 × 10 11 ) per day or placebo for 12 months. Patients wereassessed clinically, endoscopically and histologically at 1, 3,6, 9 and 12 months. Patients treated with VSL#3 had asi gni fi can tly l ower i nc ide n ce o f a cu te pou chi ti s ( 10 %)compared with those treated with placebo (40%) ( p b 0.05),and experienced a significant improvement of quality oflife.62 The mechanism by which therapy with probioticsworks remains elusive, but has been investigated.63 Mucosa-associated pouch microbiota before and after therapy withVSL#3 shows that patients who develop pouchitis whiletreated with placebo have low bacterial and high fungaldiversity. Bacterial diversity was increased and fungaldiversity was reduced in patients in remission maintainedwith VSL#3 (p=0.001). Real time PCR experiments demon-strated that VSL#3 increased the total number of bacterialcells (p=0.002) and modified the spectrum of bacteriatowards anaerobic species. Taxa-specific clone librariesshowed that the spectrum of Lactobacillus sp. and Bifido-bacter sp. was altered on probiotic therapy. The diversity ofthe fungal flora was repressed. Restoration of the integrity of

shown efficacy for preventing pouchitis [EL2b, RG C]

a “protective” intestinal mucosa related microbiota couldtherefore be a potential mechanism of probiotic bacteria ininflammatory barrier diseases of the lower gastrointestinaltract.

8.4. Cuffitis

Cuffitis, especially after double-stapled IPAA (see Section7, preceding paper same issue) can cause pouch dysfunctionwith symptoms that mimic pouchitis or irritable pouchsyndrome (IPS). Unlike IPS (which may coexist) bleeding isa characteristic feature of cuffitis. Endoscopy by an informedendoscopist is diagnostic, but care has to be taken toexamine the cuff of columnar epithelium between thedentate line and pouch-anal anastomosis (Section 7.2.3,preceding paper same issue).64 In an open-label trial, 14consecutive patients with cuffitis were treated with mesa-lamine suppositories 500 mg twice daily.16 Mesalazinesuppositories significantly reduced the total Cuffitis ActivityIndex (derived from the PDAI) from 11.9±3.17 to 6.21±3.19(pb0.001). Symptom subscore (from 3.24±1.28 to 1.79±1.31), endoscopy subscore (from 3.14±1.29 to 1.00±1.52)and histology subscore (4.93±1.77 to 3.57±1.39) were allsignificantly reduced. 92% of patients with bloody bowelmovements and 70% with arthralgia (a characteristic clinicalfeature of cuffitis, Section 8.1.5) improved on therapy. Nosystemic or topical adverse effects were reported.

9. Surveillance for colorectal cancer

9.1. Risk of cancer

9.1.1. Estimation of risk

shown efficacy [EL4, RGD]

Patients with long standing UC have a higher risk ofdeveloping colorectal carcinoma (CRC) than the averagepopulation. The magnitude of this risk, however, is still thesubject of a debate. Indeed, while older reports included intwo meta-analyses65,66 confirmed a rapid increase of the riskafter ten years of disease, the magnitude of the risk in recentpopulation-based studies appears much smaller.67,68 In fact,although Eaden and colleagues computed a cumulative CRCrisk of 18% in UC patients after 30 years of disease, risks ofonly 7.5% and 2.1% respectively were observed in two studiespublished since 2004.67,68 Furthermore, in the largest reportof surveillance colonoscopy in at-risk population of patientswith extensive UC to date (600 patients over a 30 yearperiod), the cumulative incidence of CRC by colitis duration

the general population [EL2]


was 2.5% at 20 years, 7.6% at 30 years, and 10.8% at40 years.69 In this study from St Mark's, only 30/600 patients(5%) developed CRC. The reasons for such an improvement inthe risk of CRC are still unclear but may include improvedcontrol of mucosal inflammation, more extensive use of 5-ASA compounds, the implementation of surveillance pro-grammes and timely colectomy.70 Taken together thesestudies suggest that the CRC risk in UC patients should bekept under scrutiny. Nevertheless, the best evidence, asprovided by concordant meta-analyses, indicates that therisk of CRC development is increased in UC [EL2]. The ECCOConsensus working party, through their answers to ques-tionnaires, supported this evaluation of the data.

9.1.2. Risk factors for cancer development

ECCO Statement 9BRisk is highest in patients with extensive colitis,intermediate in patients with left-sided colitis, and notincreased in proctitis [EL2].

ECCO Statement 9DSurveillance colonoscopy may permit earlier detection ofCRC, with a corresponding improved prognosis [EL3, RGB]. Unequivocal evidence that surveillance colonoscopyprolongs survival in patients with UC is lacking [EL3, RG B]

Several independent factors affect the magnitude of therisk of malignant transformation. The duration of disease andextent of mucosal inflammation are the most prominent.There is no uniform definition of the duration of disease,although onset of symptoms has generally been used in thestudies that have identified this parameter as a risk factor. Ina review of 19 practice and population-based studies, Eadenconfirmed that the CRC risk appears to increase 8–10 yearsafter the onset of UC related symptoms65 and subsequentlyincreases in later decades of the disease [EL2].

ECCO Statement 9CPatientswith early onset of disease (ageb20 years at onset ofdisease) and patients with UC-associated primary sclerosingcholangitis (PSC)mayhaveaparticularly increased risk [EL2].Persistent inflammation and family history of CRC maycontribute to the risk of CRC in patients with UC [EL3]

The extent of mucosal inflammation (including backwashileitis) has been correlated with the risk of CRC in severalstudies, as well as in a systematic review [EL2].66,67,71–75

Other factors have also been associatedwith a high CRC risk inall or part of these studies. These include young age at onsetof the disease (less than 20 years of age at the time ofdiagnosis)65 and an association with primary sclerosingcholangitis (PSC) [EL2].76 However, there was no differencein median age at onset of colitis for those with or without CRCin the 600-patient study from St Mark's (p=0.8, Mann–Whitney) years.69 The persistence of mucosal inflamma-tion72,73 or a family history of CRC77 may also contribute to anincreased risk, but the association has been less consistentacross the studies [EL3]. In a nested case-control study fromtwowell-defined, population-based IBD cohorts (CopenhagenCounty, Denmark and Olmsted County, Minnesota) 43 cases ofIBD-associated CRC were matched on six criteria to 1–3controls (n=102). Significant associations were foundbetween PSC (OR 6.9, 95% CI 1.2–40.0), the percentage oftime with clinically active disease (OR per 5% increase 1.2,

95% CI 1.0–1.4), and≥12months of continuous symptoms (OR3.2 95% CI 1.2–8.6).78 The presence of pseudopolyps, whichcan be considered amarker of severity of inflammation, havebeen associated with double the risk of CRC (OR 2.5; 95% CI:1.4–4.6),73,79 which is a useful practice point for clinicians.

9.2. Surveillance colonoscopy programmes

9.2.1. Screening and surveillanceSince dysplastic changes in colonic mucosa are associatedwith an increased risk of CRC in UC, surveillance colonoscopyprogrammes have been developed with the aim of reducingmorbidity and mortality due to CRC, while avoidingunnecessary prophylactic colectomy. Surveillance for CRCin patients with UC amounts to more than just performingrepeated colonoscopies, but includes reviewing patientsymptoms, medication use and laboratory values as well asupdating personal and familial medical history. At the onsetof these programmes, an initial screening colonoscopy isperformed, with the goal of reassessing disease extent andconfirming the absence of dysplastic lesions. Thereaftersurveillance colonoscopies are regularly performed atdefined intervals (below).

9.2.2. Effectiveness

The effectiveness of these programmes has been eval-uated in some prospective studies, systematically reviewedby the Cochrane collaboration.66 An American consensusconference, held under the auspices of the Crohn's andColitis Foundation of America, also reviewed the usefulnessof screening and surveillance colonoscopies in 2005.80 TheCochrane collaboration used death related to CRC as theprimary endpoint for the evaluation of surveillance pro-grammes in UC, limiting their analysis to prospectiverandomised studies that included a control group. Theauthors were unable to demonstrate a benefit of surveillanceprogrammes for preventing CRC-related death in UC by thesestrict parameters, but included only two studies in their finalanalysis.81,82 An earlier meta-analysis included a third studyyet to be published in full, but concluded that there was animproved 5-year survival in patients undergoing surveillance,compared to UC patients outside surveillance programmes.83

Furthermore, in the largest and most meticulous screeningprogramme reported to date, involving 600 patients, 2627colonoscopies, 5932 patient-years of follow-up and a caecalintubation rate of 98.7%, with no significant complications,16/30 cancers were interval cancers.69

Unequivocal evidence for the benefit of these programmesis therefore lacking and the apparent benefit could still belinked to lead-time bias. Patients in surveillance programmesmay have an earlier diagnosis of CRC even if CRC is detectedindependently of surveillance colonoscopy. Diagnosis of CRC inpatients outside such programmes may arise from later,

ECCO Statement 9GIf primary sclerosing cholangitis (PSC) is associated toUC, surveillance should be performed annually from thetime of PSC diagnosis [EL3, RG B]


symptom-driven investigation [EL3]. These issues are bestdiscussed with patients before entry into a surveillanceprogramme.

The Consensus had divided opinions regarding the abilityof surveillance colonoscopy programmes to improve survivalin UC patients, in keeping with the contrasting results of themeta-analyses. Only one third of the voting expertsconsidered that the procedure could achieve this goal,while two-thirds remained unconvinced or attributed anybenefit to potential lead-time bias. Nevertheless, it shouldbe noted that any benefit estimated in years of life savedmay be much greater in UC patients than for generalpopulation screening. This is because UC-related CRC tendsto occur earlier in life and with a higher frequency than in thegeneral population. Mathematical models have evaluatedthat the duration of life saved per case screened ranges from1.2 to 5 years in UC patients, compared to 1.2 to 4 months ingeneral population screening,66,84 depending on the para-meters included in the calculation.

9.2.3. Initial screening colonoscopy

ECCO Statement 9EScreening colonoscopy should be offered 8–10 years afterthe onset of UC symptoms to all patients to reassess disease

As duration of disease is a major risk factor for thedevelopment of CRC in UC patients, it is rational to propose ascreening colonoscopy when the risk starts to increase, i.e.after 8–10 years from the onset of disease [EL2]. This initialcolonoscopy also aims to reassess the extent of disease, sincethis parameter also impacts on the risk of CRC. Nevertheless,the appropriateness of screening colonoscopy as a way ofreassessing disease extent and potential risk has not beenformally established. It has been proposed in reviews and aprior consensus report,80 as well as being agreed during thepresent Consensus conference by the participating experts[EL5].

9.2.4. Surveillance schedules

extent [EL5, RG D]

ECCO Statement 9FIn extensive colitis, surveillance should start afterscreening colonoscopy and be performed every other yearup to year 20 of disease, then annually [EL2, RG B].Surveillance should start 15 years after onset of disease inleft-sided or distal UC. Proctitis does not require furthersurveillance [EL2, RG B]

The surveillance schedule is also arbitrary, but because CRChas been observed within 2 years of surveillance colono-scopy,85,86 intervals between repeat investigations should notexceed this and should be shorter in patients with particularlyhigh risks such as those with longstanding disease or PSC.

Furthermore, although disease extent is central to CRCrisk assessment, this parameter may be difficult to define,implying that surveillance may be offered to large groups ofpatients. Considerable differences between extent assessedby colonoscopy and histology have been reported,87 as well

as variations in extent over time.88 Neoplasia has beenreported in areas of microscopic involvement withoutendoscopically visible inflammation. Thus, disease extentshould be defined not only by the outcome of screeningcolonoscopy, but also by the results of previous procedures.In contrast, there is good evidence that the CRC risk is lowerin patients with limited disease71,75 as defined by colono-scopy or barium enema, so a reasonable compromise is todefer surveillance until later time points in patients withlimited macroscopic disease [EL2]. This all assumes that adecision has been made with the patient that surveillance isappropriate. If the risk of CRC complicating colitis is thoughtto be no higher than the general population, surveillancemay be considered unnecessary.

In other situations, such as patients with UC-associatedPSC, the risk of developing a CRC is not only particularly high,but has been reported to occur early (median 2.9 years) inthe course of the disease.89 These patients should enter in amore intensive surveillance programme once the diagnosis ofPSC has been established.

The recommendations by ECCO (Statements 9E–9G) arecontingent on a perceived increased risk of CRC in UC(Statements 9A–9C) and widespread acceptance in severalEuropean countries that screening for CRC in the generalpopulation is appropriate. If the latter applies, it is difficultto justify failure to screen a group of patients with higher riskof CRC more closely. The recommendation grades areappropriate to the strength of the evidence.

9.3. Colonoscopic procedures

9.3.1. Number and site of biopsiesEvidence for procedural techniques during surveillancecolonoscopy is better documented than the benefit of theprogramme itself. At least 33 biopsies should be obtainedfrom the various segments of the colon to achieve 90–95%sensitivity for the detection of dysplasia.90–93 A reasonableapproach would therefore to perform 4 random biopsiesevery 10 cm around the colon. Extra biopsies should beobtained from strictured or raised areas and from otherabnormal areas in the colon. Full colonoscopy is necessarybecause about a third of UC-associated CRC develop in theproximal colon.85 This strategy is further supported by theobservation that most dysplastic lesions are visible duringcareful colonoscopy. In a study performed on 525 patientswho underwent 2204 surveillance colonoscopies, Rutterdetected 110 neoplastic areas in 56 patients.94 Eighty-five(77.3%) were macroscopically visible at colonoscopy and 25(22.7%) were macroscopically invisible. Fifty patients(89.3%) had macroscopically detectable neoplasia, whileonly 6 (10.7%) had macroscopically invisible lesions. Thevalue of random biopsies, however, is limited compared tooptical techniques that enhance detection of dysplasticepithelium.


9.3.2. Chromoendoscopy

ECCO Statement 9HRandom biopsies (4 every 10 cm) and targeted biopsies ofany visible lesion should be performed during surveillancecolonoscopy [EL2b, RGB]. Methylene blue or indigo carminechromoendoscopy is an alternative to random biopsies forappropriately trained endoscopists and is superior torandom biopsies in the detection rate of neoplastic lesions[EL1b, RG B]

ECCO Statement 9JHigh grade dysplasia in flat mucosa and adenocarcinomaare indications for proctocolectomy [EL2, RG B]. A patientwith low-grade dysplasia in flat mucosa should be offeredproctocolectomy or repeat surveillance biopsies within 3–6 months [EL2b, RG B]

ECCO Statement 9KA raised lesion with dysplasia should be completely resected.In the absence of dysplasia in the flat surrounding mucosa,meticulous endoscopic surveillance should be proposed

The yield of surveillance colonoscopy can be improved byspraying dyes (such as methylene blue or indigo carmine) thathighlight subtle changes in the architecture of the colonicmucosa.95–101 All studies have confirmed an improved diag-nostic yield for dysplasia detection using chromoendoscopy.With this method, random biopsies of apparently normalmucosa is of no additional value compared to targeted biopsiesobtained after dye staining of the mucosa.101 Comparablediagnostic yields from chromoendoscopy have been obtainedwith both methylene blue and indigo carmine.97,98 Despitethese good results, a single from experienced investigatorsfound that nodysplasiawasmissedevenwithout dye spraying.94

However, trained endoscopists in chromoendoscopy may evenfurther distinguish neoplastic from non-neoplastic changes,based on surface crypt architecture based on pit patternrecognition with a sensitivity of 93% and 97%, respectively.Colonoscopy with dye staining did not take significantly longerthan conventional colonoscopy.98 This endoscopic approachmay not only improve the yield of screening and surveillancecolonoscopies, but also decrease the workload of pathologistsbecause fewer biopsies are needed per procedure.

9.4. Dysplasia

The ultimate goal of surveillance colonoscopy is to identifywhether the colonic mucosa has already undergone the earlysteps of malignant transformation (i.e. to detect dysplasia),which identifies UC patients at the highest risk of CRCdevelopment.102,103 Dysplasia in UC is stratified as low grade,high grade or indefinite for dysplasia, according to thepresence or absence of specific histological changes in theepithelium. If biopsies are indefinite for dysplasia and this isconfirmed by an experienced pathologist, then follow-upsurveillance colonoscopy within 3 to 6 months is recom-mended, with intensification of UC therapy in the meantime.

9.4.1. Risk of progression to cancer

ECCO Statement 9IA finding of dysplasia should be confirmed by an independentpathologist [EL2b, RG B]

[EL2b, RG B]. If endoscopic resection is not possible or ifdysplasia is found in the surrounding flat mucosa,proctocolectomy should be recommended [EL2b, RG B]

The grade of dysplasia is important because it impacts onthe sensitivity and specificity of the presence or futuredevelopment of CRC. Dysplasia of any grade has beenreported to have a 74% sensitivity and 74% sensitivity forCRC development, while in the same series from the Mayo

Clinic, high grade dysplasia had lower sensitivity (34%) but98% specificity for CRC detection.104 In the most recentmeta-analysis, low-grade dysplasia was found to be asso-ciated with a 9-fold increased risk of developing CRC and a12-fold risk of developing advanced neoplasia.105 Therefore,the finding of low-grade dysplasia carries a substantial risk:such a finding has important prognostic implications. For thisreason, dysplasia should be confirmed by an experiencedpathologist, because interobserver variation for the detec-tion of dysplasia is high.106–108 Furthermore, individualstudies that do not show an increased risk of malignanttransformation in low-grade dysplasia109 need to be placed inthe context of the meta-analysis.

9.4.2. Dysplasia and colectomy

Once dysplasia is found, the rationale of such a surveil-lance programme demands that colectomy is performed,because the risk of CRC is appreciably increased.105 If highgrade dysplasia is present, the decision is easier, because therisk of concomitant CRC may be as high as 32%,106 assumingthat the biopsies were indeed obtained from flat mucosa andnot from an adenoma. If low-grade dysplasia is detected, the9-fold increased risk of developing CRC reported in the mostrecent meta-analysis105 could reasonably be viewed asjustification for colectomy as well, and this option shouldbe discussed with the patient.110 However, because somefollow-up studies of patients with \low-grade dysplasia haveshown a low rate of CRC development,86,111 it seems areasonable compromise to continue surveillance with exten-sive biopsy sampling at shorter (perhaps 3–6 month) intervalsin those who will adhere strictly to the surveillance program.This remains controversial in the literature and was discussedduring the conference as well.66,112

9.4.3. Dysplasia and raised lesions

Raised lesions on a background of UC have been tradition-ally referred to as “Dysplasia Associated Lesion or Mass” orDALM. Until recently this finding has been considered anabsolute indication for colectomy. It is increasingly recognised,however, that some of these raised lesions may resemblesporadic adenomas and that they may be amenable tocomplete endoscopic resection.97,113–115 If the polypectomyis confirmed complete by histology and if biopsies obtained

ECCO Statement LChemoprevention with 5-ASA compounds may reduce theincidence of colorectal cancer in UC patients and shouldbe considered for all UC patients [EL2, RG B]. Colorectalcancer chemoprevention with ursodeoxycholic acidshould be given to patients with PSC [EL1b, RG B]


from the flat mucosa immediately adjacent to the polypect-omy site show no dysplasia and if, in addition, no dysplasia isfound elsewhere in the colon, then colectomy may be safelydeferred. Careful follow-up, preferably with surveillancecolonoscopy at 3 months and then 6 monthly, is needed ifthis strategy is followed, because at least half of such patientsin the four studies quoted developed further raised lesions. Ifthe lesion does not resemble typical adenoma, is notrespectable, or is associated with dysplasia in the adjacentmucosa, then colectomy is indicated due to the high risk ofconcomitant CRC.90,113

9.5. Chemoprevention

The risk of developing CRC has been shown to be higher inpatients with persistent mucosal inflammation,73 and thusappropriate therapy may reduce the risk of CRC associatedwith chronic UC. Several studies suggest that sulfasalazine ormesalazine may lead to a risk reduction, referred to as achemoprotection. Velayos et al. performed a meta-analysisthat included 334 cases of CRC, 140 cases of dysplasia and atotal of 1932 subjects extracted from 3 cohort studies and 6case-control studies.79 This suggested that in a populationmatched for extent and duration of UC, aminosalicylatesmay reduce the risk of colorectal cancer. The risk reductionwas significant for CRC development (OR 0.51, 95% CI 0.37–0.69), but not for dysplasia (OR 1.18, 95% CI 0.41–3.43). Inview of the low toxicity of mesalazine and considering thatthe number of patients needed to treat (NNT) to prevent oneCRCmay be as low as 7 in patients with 30 years of disease,116

the Consensus felt that such a therapy should be consideredand potentially offered to all UC patients in the absence ofcontraindications. The limitations of the data are, however,recognised and some large studies have shown no benefit.78

When 76 cases of CRC and UC in a cohort of 18,969 patients inthe UK General Practice Research Database were comparedto six matched control cases, regular users of 5ASA (definedas six or more prescriptions in the preceding 12 months) hada trend towards a lower risk of CRC compared with irregularuses (unadjusted OR 0.7, 95% CI 0.44–1.03). For mesalazine,but not sulfasalazine, the effect was significant dependingon the total number of prescriptions: OR 1.13 (0.49–2.59) for6–12 prescriptions, OR 0.30 (0.11–0.83) for 13–30 prescrip-tions and OR 0.31 (0.11–0.84) for N30 prescriptions.117

Patients with UC-associated PSC appear to be at particu-larly high risk of developing CRC.75 In follow-up to arandomised trial evaluating the benefit of ursodeoxycholicacid in these patients, patients assigned to active medicationfor their biliary disease had a lower incidence of dysplasiaand CRC development compared to patients assigned toplacebo.118 This study confirmed prior data from a cross-sectional study119 in the setting of a prospective randomisedtrial. The Consensus considered these data sufficientevidence to recommend this therapy in all patients with UCand PSC, considering the potential benefit of the drug onboth conditions and low toxicity. Nevertheless, the limita-tions of the data are again recognised, since not all studieshave identified an association between PSC and CRC inpatients with UC.79 Interestingly, when the same groupexamined population-based as opposed to hospital-basedcohorts, a significant association between PSC and CRC wasidentified (OR 6.9, 95% CI 1.2–40), although a protective

effect of aminosailcylates could not be discerned (cumula-tive dose of sulfasalazine (OR per kg 1.1, 95% CI 1.0–1.3) andmesalazine (OR per kg 1.3, 95% CI 0.9–1.9).78

9.6. Prognosis

The prognosis of CRC complicating UC has generally beenconsidered worse than for sporadic CRC. This may not bevalid. In a report from the Mayo Clinic, 290 patients with IBD-associated CRC (241 with chronic ulcerative colitis and 49with Crohn's disease) were matched with an equal number ofage- and sex-matched sporadic CRC patients between 1976and 1996. 55% of IBD-related tumours were distal to thesplenic flexure compared to 78% of sporadic CRC, but duringa median follow-up period of 5 years, 163 IBD-associated CRCpatients died (56%), compared with 164 sporadic CRCpatients (57%). The 5-year survival rates were 54% in theIBD-CRC subgroup vs. 53% in the sporadic CRC subgroup(p=0.94).120 This is not that dissimilar to experience from StMark's Hospital. In the largest experience of surveillancecolonoscopy in 600 patients during 5932 patient–years offollow-up, 30 patients (5%) developed CRC, with a 5-yearsurvival rate of 73.3%.69

The prognosis of colorectal dysplasia in IBD is also debated(Section 9.4.1). In a population-based study from Minnesota,29/725 (4%) IBD patients developed flat dysplasia (n=8), aDysplasia Associated Lesion or Mass (DALM, n=1), or anadenoma-associated lesion or mass (ALM n=18) in an area ofIBD, or an ALM outside the area of IBD (n=2). Among 6patients with flat low-grade dysplasia (fLGD) who did notundergo colectomy, none progressed during a median of 17.8(range 6–21) years of observation with a median of 3 (range0–12) surveillance colonoscopies. Four (22%) patients withALMs in areas of IBD who did not undergo surgery developedlow-grade dysplasia or DALMs. Dysplasia located proximal tothe splenic flexure was significantly associated with a risk ofrecurrence or progression of dysplasia. This population-based cohort did not confirm an increased risk of cancerrelated to flat low-grade dysplasia,78 which is at odds withthe meta-analysis.105

10. Children and adolescents

10.1. Introduction

About 10–15% of patients with inflammatory bowel diseaseare diagnosed before the age of 18 years.121 During pubertythe incidence is 7 per 100 000 per year and increases furtherduring adolescence to about 12 per 100 000 at age 20–29,consistent with a peak around the age of 30 years.122 Inchildren most cohort studies show a lower incidence ofulcerative colitis (UC) compared to Crohn's disease (CD),123

but the incidence of CD has clearly increased over the past

ECCO Statement 10CIleocolonoscopy and biopsies should be performed in allchildren or adolescents with a suspicion of inflammatorybowel disease (IBD). Upper gastrointestinal endoscopy isrecommended when ileocolonoscopy does not confirm adiagnosis of ulcerative colitis [EL2a, RG B]


decade. In contrast, the incidence of UC is stable in somestudies,124–126 but increasing in other cohorts.127–129 Themedian age of onset of symptoms in UC is 12 years in mostpaediatric studies,122,130,131 but the diagnostic delay isconsiderably shorter than for CD. In contrast to adults, theclinical presentation of UC is often more severe in children,which may be explained by the predominance of pancolitis(70–80% of children) at the time of diagnosis.131,132

10.2. Diagnosis

10.2.1. Diagnostic threshold

ECCO Statement 10AUlcerative colitis should be suspected in a childwith chronic(≥4 weeks) or recurrent (≥2 episodes in 6 months) bloodydiarrhoea, after exclusion of infective or other causes. Thisapplies particularly when there is growth failure and/orpubertal delay, a family history of IBD, increasedmarkers ofinflammation, or if anaemia is present [EL2b, RG B]

ECCO Statement 10DIn children and adolescents (up to 16–18 years of age),endoscopy should be performed by a specialist withexperience in paediatric gastroenterology, preferably by apaediatric gastroenterologist [EL 5, RG D], in a setting thatis suitable for diagnosing and treating children with IBD(paediatric hospital, with access to general anaesthesia)

In contrast to paediatric CD and its diverse symptomatol-ogy, the clinical manifestation of UC is almost uniformlybloody diarrhoea (84–94% of children), accompanied bytenesmus.132 Although an infective aetiology should beexcluded, its presence does not exclude a diagnosis of UCor CD. The combination of rectal bleeding, anaemia andincreased ESR identified 86% of patients with IBD prior to anendoscopic procedure.133 Other retrospective case serieshave confirmed the diagnostic value of increased inflamma-tory markers and anaemia for IBD.134,135

A shorter interval from symptoms to diagnosis of UCprobably explains why growth failure is half as commoncompared to CD. As with adults, the greatest risk factor fordeveloping UC in childhood is to have a family member withulcerative colitis (relative risk 7–17).137,138 The risk for CD ina family member with Crohn's disease is a relative risk of 15–35. The stronger the family history, the earlier the onset ofsymptoms. For patients with early-onset UC (b5 years' age),26%–44% have a family history of UC, compared to olderpatients or children with CD.139,140 Genetic factors are likelyto have a stronger influence in paediatric IBD, especially inearly-onset acute severe UC, compared to older children oradults.141,142 Nevertheless, most children with IBD have nofamily history and are considered sporadic.

10.2.2. Documentation

ECCO Statement 10BIn all childrenwithUC, the height,weight (andpre-diagnosisgrowth curve) and pubertal stage, should be recorded atdiagnosis, and regularly during follow-up [EL3b, RG B]

ECCO Statement 10EOral [EL2b,RGB] aminosalicylates and/or topicalaminosalicylates (suppositories in proctitis, enemas inleft-sided colitis) [EL5, RGD] are appropriate initialinduction therapy for mild to moderate distal colitis inchildren or adolescents

Growth failure is a unique complication of paediatric IBD,caused by a combination of inadequate calorie intake, increasedlosses and active inflammation. Efficacy of medical treatmentand concomitant mucosal remission is characterised by normallinear growth and pubertal development. In contrast, whencatch-up growth does not occur after growth failure at

diagnosis, or when height velocity decreases during mainte-nance treatment, it is highly likely that there is persistentdisease activity, so therapy should be more aggressive and anadequate calorie intake ensured.136,143,144

10.2.3. Diagnostic procedures

The IBD working group of the European Society of PaediatricGastroenterology Hepatology and Nutrition (ESPGHAN) hasreached a consensus on the diagnosis of IBD in children, whichhas been summarised in the ‘Porto Criteria’.145 This group feelsit essential to establish a diagnosis of the type of disease, aswellas to determine severity, localisation, andextent of thedisease,before treatment is started. Paediatric patients with UC havemore extensive disease and rectal sparing in up to 30%,146 so acomplete diagnostic work-up is warranted in children withbloody diarrhoea. Evidence supporting colonoscopy with ilealintubation and multiple biopsies, rather than sigmoidoscopyalone, is provided by retrospective cohort studies.146–148 Incases with extensive colitis that cannot be classified, gastro-duodenoscopy may allow definitive diagnosis.149

The ECCO Consensus agrees that a paediatric gastroenter-ologist, rather than a specialist in adult endoscopy, should bestperform endoscopy in children suspected of IBD. The mostimportant argument is quality of care, particularly becauseendoscopy in children is preferably done under generalanaesthesia: this is preferred for reasons of comfort and careand has been shown to be safe.150–155 Moreover, the treatmentand follow-up of children and adolescentswith IBD should be inthe hands of a paediatric gastroenterologist who is aware ofage-related differences in disease presentation and treat-ment. Such specialists are experienced in handling problemssuch as linear growth retardation and pubertal delay.156

10.3. Induction therapy in children

10.3.1. Distal colitis

ECCO Statement 10GFor severe pancolitis in children, corticosteroids are firstline therapy [EL4, RG D]. If the response is insufficient,intravenous ciclosporin [EL4, RG C] or infliximab [EL4, RGC], or colectomy are appropriate options


No studies have been performed in children with distalcolitis. A questionnaire sent to members of the IBD workinggroup of ESPGHAN, however, revealed great variation of carein the treatment of distal colitis. The first choice was eitheroral treatment alone (mesalazine 21%, sulfasalazine 36%), orin combination with topical treatment (mesalazine 36%,corticosteroids 7%). Considering the rarity of proctitis inchildren, no standard treatment protocols exist.

10.3.2. Extensive colitis

ECCO Statement 10FFor mild to moderate pancolitis in children, oralmesalazine/sulfasalazine is recommended as first linetherapy [EL2b, RG B]. Oral steroids are appropriate if theresponse is insufficient [EL4, RG D]

Only one prospective study has confirmed the efficacy oforal aminosalicylates in children with active ulcerativecolitis.157 In this trial, a clinical response at 8 weeks wasseen in 79% of patients receiving sulfasalazine (60 mg/kg/day) and 50% of patients on olsalazine (30 mg/kg/day).Retrospective studies have also shown that oral aminosali-cylates effectively induce clinical remission.158–162

Although sulfasalazine may cause more gastrointestinalside-effects, it is the preferred aminosalicylate treatment inyoung children who cannot swallow tablets, because it isavailable as a suspension. Alternatively, mesalazine can begiven as an enteric-coated granule formulation. Based onexpert opinion and extrapolation from pharmacokineticstudies,159,161,163 the advised dose (oral and rectal mesalazinecombined) in children aged 12 years or older of mesalazine, is50–75 mg/kg/day with a maximum of 4 g/day. For sulfasala-zine it is 100 mg/kg/day with a maximum of 6 g/day.

Concerning oral corticosteroids, no studies have beenperformed in children with UC. Nevertheless, prospectivelycollected data from the US Pediatric Inflammatory BowelDisease Collaborative Research Group Registry databaseprovides a useful insight.164 In 97 children (age b16 yr) withnewly diagnosed UC between 2002 and 2005, with a minimumof 1 year of follow-up, 79% received corticosteroids, most(62/77) within 30 days of diagnosis. For those treated within30 days, disease activity at 3months was inactive in 60%,mildin 27%, and moderate or severe in 11%. At 12 months, 31 of 62(50%) of the early corticosteroid-treated patients wereconsidered corticosteroid responsive and 28 (45%) werecorticosteroid-dependent. A total of 4 patients receivingcorticosteroids required colectomy in the first year. Immu-nomodulators were used in 61% of all corticosteroid-treatedpatients. This is similar to adults: early response is excellent,but dependence is common, even with immunomodulators.Evaluation among the IBD working group of ESPGHANdemonstrated that 46% favoured addition of corticosteroidsif response to aminosalicylates was found to be insufficient.Oral prednisolone is given as a once daily dose of 1–2 mg/kg/day, with a maximum dose of 40 mg, for 2–4 weeks (untilclinical remission), then tapered to zero in 6–8 weeks.Although not supported by clinical evidence from randomisedclinical trials, calcium and vitamin D are usually supplemen-ted during a course of steroid treatment.

10.3.3. Severe colitis

Although no randomised clinical studies have been per-formed in childrenwith acute severeUC, all respondents to theESPGHAN questionnaire agreed that corticosteroids are thefirst line therapy in severe pancolitis. In a meta-regression ofresponse to steroids in 32 studies involving 1991 patients(1974–2006), only 43 children were included.165 To evaluatethe outcome in children, a retrospective study of 74 admissionsin 63 children (57% males, age at diagnosis 10.9±4 yr, 79%extensive colitis) treated at Toronto SickKids Hospital 1995–99was performed.166 41% failed intravenous steroids by dischargeand 23 (37%) came to colectomy on that admission. By oneyear, 54% and by 5 yr 59% had come to colectomy. There was noclear consensus from ESPGHAN as to whether corticosteroidsshould be given as the only treatment (25% of respondents), orin combination with oral mesalazine (25%), or intravenouslywith adjunctive parenteral nutrition (50%). Given the similar-ity in the response of children to steroids compared to adults(Section 5.2.4, preceding paper same issue), it seems unlikelythat mesalazine is necessary. Although nutritional support isparticularly appropriate in children, TPN in adults has not beenshown to offer any advantage when managing acute severecolitis (Section 5.2.4, preceding paper same issue).

When 3–5 days of intravenous corticosteroids are inef-fective, rescue therapy with ciclosporin, tacrolimus, orinfliximab are the only two options to avoid or postponecolectomy. An objective assessment of the response tosteroids facilitates management as it does in adults (seeSection 5.2.5, preceding paper same issue). A paediatricindex of severity as been developed166 and when calculatedon day 3, strongly predicts failure of intravenous steroids.167

As with adults, stool frequency (p=0.001) and CRP (p=0.045)on day 3 (but not day 1) predict failure, along withtemperature (p=0.001). Case studies with intravenousciclosporin in children with severe, steroid-refractory colitiswho are candidates for surgery, have shown remission of thedisease in up to 80% of cases.168–172 In many children,however, tapering of oral ciclosporin resulted in a relapseand was followed by colectomy within a year of cessation oftreatment. In occasional patients, short term ciclosporintreatment can effectively induce remission while waiting forazathioprine maintenance treatment to take effect.170

Infliximab has not been studied prospectively, but smallretrospective studies in new-onset steroid-refractory patientsshow complete remission in 75–88% of patients.173–175 Withthe small numbers of patients studied and limited follow-up, itis currently unknownwhether infliximab therapy is effective inavoiding colectomy, or whether it simply defers it. TheConsensus view is that rescue therapy with either ciclosporin,tacrolimus, or infliximab should only be initiated in a specialistcentre where a paediatric and/or colorectal surgeon areavailable and involved in the treatment of these severely sickchildren.


10.4. Maintenance therapy in children

ECCO Statement 10HOral mesalazine or sulfasalazine are recommendedmaintenance treatment in the same dose as for inductiontherapy [EL5, RG D]. For difficult patients with extendedand/or relapsing disease, who are steroid-refractory orsteroid-dependent, azathioprine/mercaptopurine isrecommended [EL4, RG C]. Long-term steroids arecontraindicated and ciclosporin is inappropriate ECCO Statement 10J

Colectomy should be performed by an experiencedpaediatric surgeon, ideally with the assistance of acolorectal surgeon with paediatric experience; ileo-pouch-anal anastomosis (IPAA) should only be performedin a highly specialised centre [EL 4, RG C]

ECCO Statement 10KEnteral or parenteral nutritional therapy is inappropriateprimary treatment. However, a nutritional evaluation isessential and nutritional support should be provided whenrequired [EL5, RG D]

ECCO Statement 10L

10.4.1. AminosalicylatesThe efficacy of mesalazine or sulfasalazine maintenancetreatment has not been studied in children with UC. From theIBD working group of ESPGHAN questionnaire respondents,57% advised continuing the same mesalazine dose as used forinduction, while 43% advised a lower dose. The Consensusview is based on results from adult studies that indicate thathigh dose 5-ASA is effective maintenance treatment. Long-term corticosteroids are absolutely contraindicated, becausethey do not maintain remission and have a negative effect onlinear growth and bone mineralisation. Ciclosporin main-tenance treatment is ineffective and inappropriate, becauseserious, sometimes irreversible, side-effects may occur.

10.4.2. ThiopurinesRetrospective cohort studies have demonstrated that main-tenance with azathioprine/mercaptopurine is effective, whileachieving a steroid-sparing effect.176–179 This steroid-sparingeffect is more evident when azathioprine treatment is startedearly in the course of disease, within 2 years after diagnosis.179

The advised dose for azathioprine in children is 2–3mg/kg/dayand that for mercaptopurine is 1–1.5 mg/kg/day.

10.5. Surgery in children

ECCO Statement 10IColectomy is indicated for severe colitis with acutecomplications not responding to medical therapy;persistently active disease with failure or toxicity ofmedical treatment; failure to taper corticosteroidtreatment despite immunosupressant use; growthretardation or pubertal delay despite medicaltreatment [EL 4, RG C]

There is no indication for a “special diet” for ulcerativecolitis, because none are effective and there is a risk ofnutritional deficiencies [EL5, RG D]

ECCO Statement 10MPsychosocial support is important adjunctive treatment,because depressive symptoms are frequent andpsychosocial support may be associated with a betteroutcome and a better quality of life [EL3b, RG B]

10.5.1. IndicationsIn acute severe colitis, the decision to perform colectomyshould be evaluated on a day-to-day basis by both the medicaland surgical team. If the disease is not responding to 7–10 daysof either calcineurin inhibitors (ciclosporin, tacrolimus) orinfliximab, colectomy is indicated.

Colectomy is also indicated for persistently active disease,when corticosteroid dependency exists despite concomitanttherapy with azathioprine/mercaptopurine, or when immu-nosuppressive treatment has side-effects. Growth failuredespite apparently adequate maintenance therapy is also anindication for colectomy, even when clinical symptoms appear

mild.180–184 Preliminary (and anecdotal) experience withinfliximab in children suggests that it may be more effectivein acutely ill patients, compared to patients with chronicrefractory disease.173,175,185 It rarely achieves steroid-freeremission. Therefore, infliximab cannot be recommendedfor chronic steroid-dependent disease in children.

10.5.2. Procedures

Depending on the local circumstances, a child needingcolectomy should be referred for expert care at a specialistcentre. Case series of IPAA in children show good results interms of quality of life, continence and incidence ofpouchitis.181,182,186–189 However, in very young children(b10 years), pouchitis is reported in 75% of the patients.190

Because IPAA decreases female fecundity,191,192 colectomywith ileorectal anastomosis until later IPAA may be a betteroption in girls.193 Expert advice should be sought.

10.6. Nutritional support

It has not been shown that enteral nutrition has a primarytherapeutic role in ulcerative colitis. There are many theoriesthat suggest that diet may be implicated in the aetiology ofinflammatory bowel disease. However, there is, as yet, nodietary approach proven to reduce the risk of developing IBD.Children with IBD have increased calorie and protein require-ments, so intake should be at least 120% of recommended dailyallowances (RDA). If oral intake is poor due to anorexia during aperiod of disease activity, high-calorie supplements may beindicated and specialist dietetic advice is appropriate.

10.7. Psychosocial support


Children and adolescents with IBD are at greater risk ofdeveloping behavioural difficulties or emotional dysfunctionand depression in particular (in almost 25% of patients), aswell as anxiety, social dysfunction and low self-esteemcompared to healthy children.194–197 The quality of life inadolescents with IBD is generally lower than healthycontrols.198–201 Two large randomised studies have demon-strated that psychosocial support by a patient-orientatedself-management approach can have a beneficial influenceon the course of disease.202,203 Therefore, appropriatemedical information and mental health support are recom-mended, because this may influence disease activity.195

10.8. Transition of care to adult services

ECCO Statement 10NTransitional clinics represent optimal care and are highlyrecommended [EL5, RG D]

ECCO Statement 12AA speculated association between psychological factors andthe aetiology of ulcerative colitis cannot be proven. Thereis, however, an influence of psychological distress andmooddisorders on the course of the disease [EL1b, RG B]

ECCO Statement 12BThere is evidence of an interaction between psychologicalfactors and IBD activity. Depression and perceived chronicdistress represent risk factors for relapse of the disease. Itremains controversial whether acute life events triggerrelapses [EL 1b, RG B]. Most patients consider stress tohave an influence on their illness [EL 4, RG C]

ECCO Statement 12CPsychological disturbances seem to be a consequence of theillness rather than thecauseof, or specific toulcerative colitis.The degree of psychological distress and disturbancescorrelates with the disease severity, predicts health-related

A careful transition of patients from the paediatric service toadult gastroenterologists is vital, because it may reinforcetreatment adherence and improve quality of life.204 There aremany differences between paediatric and adult care. In thepaediatric service, children and adolescents with IBD are usuallyseen together with their parents and often receive moreattention, because the disease is uncommon in childrencompared to adults. A paediatric specialist nurse may be onhand to advise and be a point of contact for the child or parents.Endoscopy is performed under general anaesthesia, whereas thisis exceptional in adults. On the other hand, the paediatricgastroenterologist rarely discusses long-term issues, such ascancer risk or surveillance. Close collaboration between thepaediatric and adult services will overcome these differences.The ideal setting for this is a transitional clinic where adolescentpatients are seen by both specialists.205 The alternative is toestablish a parallel clinic, where paediatric and adult IBD clinicsrun independently but at the same time, so that when a suitablepatient is seen, it is then a simple matter for the paediatric oradult gastroenterologist to go down the corridor to contact theiropposite number so that the young person can be introduced orseen together. A trained IBD nurse specialist can play animportant role coordinating care between the service, thepatient and the family during the transitional period.

11. Pregnancy

The section on pregnancy and ulcerative colitis will bepublished subsequently. Theprinciples ofmanaging pregnancy,delivery, breast-feeding and Crohn's disease also apply toulcerative colitis.206 See also Cornish J, Tan E, Teare J, et al. Ameta-analysis on the influence of inflammatory bowel diseaseon pregnancy. Gut 2007;56:830–7.

12. Psychosomatics

12.1. Introduction

While psychosocial factors are generally considered important inulcerative colitis, controversy still exists about their role. Thisleads to potential inconsistencies in clinical practice. Abiopsychosocial model207,208 represents an advantage over a

biomedical model, because it embodies the complex biologicaland psychosocial interactions that explain human illness or itseffects. Attention to psychosocial factors associated withulcerative colitis may have consequences not only on psychoso-cial well-being and quality of life, but also on the activity of thedisease itself. The key words used in the systematic literaturereview of Medline and Embase for this review were ulcerativecolitis as well as inflammatory bowel disease and irritable bowelsyndrome— psychology; psychosocial; psychotherapy; quality oflife; doctor patient relationship; and psychopharmaceuticals.

12.2. Influence of psychological factors on disease

12.2.1. Aetiology

Studies about the influence of psychological factors on thedevelopment of ulcerative colitis are very limited. There are a fewstudies with hypothetical interpretations about the influence ofpsychosocial factors on the aetiology of the disease.209–212 Manystudiesonpsychosocial factors relateto inflammatoryboweldisease(IBD) rather than ulcerative colitis or Crohn's disease in particular.

12.2.2. Pattern of disease

Psychological factors are considered to have an influence onthe course of the disease, which is consistent with evidence inthe recent literature about the influence of subjectiveperceived psychological distress on disease activity of ulcerativecolitis.213–217 Studies about the influence ofmajor life events onthe biological disease activity have yielded contradictoryresults.218–220 Patients themselves and themajority of Europeanexperts at the Consensus conference consider psychosocialdistress as influencing the risk of relapse.221,222 One study showsa heightened response to stressors and the greater epithelialdamage in IBD patients, which suggests that stress-inducedactivation of the brain-gut axis and ofmucosalmast cellsmay beimportant in the initiation and/or flare up of IBD.223

12.3. Psychological disturbances in ulcerative colitis

qualityof lifeand influences thecourseofdisease [EL1b,RGB]

ECCO Statement 12DClinicians should particularly assess depression among theirpatients with active disease and those with abdominal painin remission [EL 2b, RG B]

ECCO Statement 12FPhysicians should assess the patient's psychosocial status,quality of life and demand for additional psychological careand recommend psychotherapy if indicated. Integratedpsychosomatic and gastroenterology care should beavailable [EL 2b, RG B]. Patients should be informed of theexistence of patient associations [EL 5, RG D]


Patients with ulcerative colitis seem to have no more, oronly slightly more, psychological disturbances compared topatients with other chronic diseases.211,224–229 A consistentassociation between psychological factors and the preva-lence of IBS-like symptoms in patients in remission has beenreported.229–232 There is also evidence that children andadolescents with IBD comprise a population at high risk ofdeveloping a psychiatric disorder.233,234 A recent study with alarge IBD population has shown that IBD patients experiencea rate of depression that is triple that of the generalpopulation (16.3% vs. 5.6%).235 In this study 17% of depressedpatients had considered suicide in the past 12 months and anadditional 30% had considered suicide at an earlier time. Inindividuals who were currently depressed, female patientswere more likely than males ever to have considered suicide(50% vs. 31%). Depressive coping strategies are positivelyassociated and predict health-related quality of life.236

Furthermore, the psychosocial consequences of the illnessbecome more significant with increasing severity of thedisease and quality of life is related to disease activity,symptoms 218,224,237–243 and female gender.237,244,245

12.4. Approach to psychological disorders

12.4.1. Communication with patients

ECCO Statement 12EThe psychosocial consequences and health-related qualityof life of patients should be taken into account in clinicalpractice at regular visits. Individual information andexplanation about the disease should be provided througha personal interview. The course of the disease can beimproved by combining self-management and patient-centred consultations [EL 1b and 3b, RG B]

ECCO Statement 12GPsychotherapeutic interventions are indicated forpsychological disorders associated with ulcerative colitis[EL 1b, RG B]

Health perceptions impact on the experience of theillness.226 Increasing physician awareness of the fact thatpsychologically distressed patients have difficulty in proces-sing clinically relevant information 246 may lead to improveddoctor–patient communication.247 It is important thatpatients are informed about their condition through anindividual interview, in conjunction with emotional support.This is because a lower level of information is associated withgreater concern,248 despite the impression of some doctorsthat more information increases the level of anxiety.Psychosocial factors are strongly correlated with healthcare utilization.249 Self-management guidebooks togetherwith patient-centred consultations improve patients' diseasecontrol.250,251 It should however be recognised that educa-tional booklets on their own do not seem to be helpful andmay even worsen the health-related quality of life ofpatients attending tertiary centres.252 In addition, patienteducation programmes seem to have very limited or even noinfluence on the course of their illness, their health-relatedquality of life, or their psychological affect.253–255 Almost all

experts at the Consensus (91%) are convinced that a gooddoctor–patient relationship is helpful psychologically andtake psychosocial factors into account for both diagnosis andtherapy. Most experts at tertiary centres have the opportu-nity for integrated somatic and psychological care ofpatients. However, patients describe deficiencies in thecare of family members, insufficient information andinadequate access to healthcare resources.256

12.4.2. Psychological support

For assessment of quality of life, two validated IBD-specificquestionnaires have been shown to be sensitive, reproducibleand responsive for use in clinical trials: the InflammatoryBowel Disease Questionnaire (IBDQ)257 and the Rating Form ofInflammatory Bowel Disease Patient Concerns (RFIPC).258

Detection and treatment of psychological distress has thepotential to improve health-related quality of life.259 Thepresence of psychological disorders contributes to poor qualityof life and the number of doctor visits, regardless of theseverity of the condition.249 This is the common experience ofdoctors caring for patients with IBD, even if the potential orneed to treat this aspect of the illness is perceived.

To assess the demand for psychological care in chronicdiseases, a validated questionnaire is available, developedand based on inflammatory bowel disease.260 Most experts(80%) feel themselves able to recommend psychotherapyduring a discussion with patients. There is no study on theircompetence at doing this, but this is consistent with theexperience of participants in the European Consensus on themanagement of Crohn's disease,206 the German Consensus onCrohn's disease,56 and that on ulcerative colitis.261,262 Sincestrategies aimed at improving social support can have afavourable impact on psychological distress,263 training ofgastroenterologists to integrate psychosocial factors inclinical practice should be taken into consideration.

12.4.3. Therapeutic intervention

Psychotherapy and relaxation methods have a positiveinfluence on IBD, mainly affecting the psychological dimen-sions of the illness such as psychological well-being, copingstrategies and psychological distress,264–268 as well asperception of pain.269 This underpins the recommendation(Statement 12G). The diagnosis of ulcerative colitis isinsufficient alone to recommend psychotherapy, sincestudies of psychotherapy on patients without psychological


disturbance show little or no benefit.270 One study thatcombined patients with Crohn's disease and ulcerative colitisreported an influence of psychotherapy on disease activity,but there was inhomogeneity in randomisation of thetreatment and control groups, so the results are not includedin the evidence-based recommendation.

12.4.4. Therapeutic choice

ECCO Statement 12GThe choice of psychotherapeutic method depends on thepsychological disturbance and should best be made byspecialists (Psychotherapist, Specialist for PsychosomaticMedicine, Psychiatrist). Psychopharmaceuticals should beprescribed for defined indications [EL 5, RG D]

ECCO Statement 13ADiagnosis of non-axial arthritis and arthropathy associatedwith UC ismade on clinical grounds based on characteristicfeatures and exclusion of other specific forms of arthritis[EL3b, RG C]. Type I is pauciarticular and affects large jointsacutely at times of UC activity. Type II is polyarticular,affecting a larger number of peripheral joints independentlyof UC activity [EL 2b, RG B] Axial arthritis, including sacro-iliitis and ankylosing spondylitis, is diagnosedon conventionalrheumatological grounds, and is supported by characteristicradiological changes, magnetic resonance imaging being themost sensitive [EL2b, RG B]. Although HLA B-27 is over-represented in axial arthritis related to UC this is not ofdiagnostic value [EL2b, RG B]

There is no evidence that one psychotherapeutic methodshould be preferred over another. Relaxation exercises areuseful, since they are easy to learn and perform. Expertopinion believes that there is an advantage if the psy-chotherapist has experience in the treatment of patientswith chronic inflammatory bowel diseases and works closelywith the patient's gastroenterologist. There are no specificstudies on the use of individual psychopharmaceuticals inulcerative colitis.271 In spite of this, almost all expertsbelieve that there are clinical situations in which antide-pressants should be recommended for treatment of psycho-logical distress associated with ulcerative colitis.

13. Extraintestinal manifestations

13.1. Introduction

Extra-intestinal manifestations (EIMs) occur in up to 30% ofpatients affectedbyulcerative colitis or Crohn's disease,272–274

although it is probable that studies from referral centres haveover-estimated the prevalence and community studies suggestthat their prevalencemay bemuch lower.What is interesting isthat the occurrence of one EIM appears to predispose toothers. This suggests an underlying generic susceptibility insome patients that is largely genetically determined, althoughmay yet be prone to environmental influence. Female patientswith colitis (either ulcerative or Crohn's colitis) appear to beparticularly susceptible.275

Scoring systems such as the Crohn's disease activity index(CDAI) include EIMs in the assessment. This is a weakness,although not widely recognised, since only some EIMs arerelated to disease activity and a genetic susceptibility in aminority of patients introduces bias. Those EIMs broadlyrelated to the activity of colitis include oligoarticularperipheral arthritis, erythema nodosum, oral aphthous ulcersand episcleritis.274 Polyarticular peripheral arthritis, pyo-derma gangrenosum [PG], uveitis and spondylarthropathytend to pursue a course independent of disease activity, whileprimary sclerosing cholangitis [PSC] is most prevalent inpatients with colitis that follows an apparently mild course.

For those EIMs closely related to ulcerative colitis activity,treatment can parallel that of the underlying disease.Treatment otherwise is mainly on a case-by-case basis asrandomised controlled trials are mostly lacking. Specific

therapy for EIMs is strongly influenced by current IBDtreatment, and may include increasing dosage of existingdrugs or the addition of new agents.

Consensus review indicates that gastroenterologists willbe comfortable diagnosing and treating the more commonextraintestinal manifestations, unless they prove resistant,with the exception of eye involvement for which the adviceof an ophthalmologist is selected in a great majority of cases(93%). It is noted however that the frequency with whichroutine dermatological (46%) and rheumatological (31%)advice would be sought has increased since the reviewpanel was interrogated on their approach to EIMs of Crohn'sdisease in 2004.206 This section concentrates on the morefrequently encountered EIMs, for which at least somequantifiable data exist. Thrombotic complications of colitisand their prevention are considered in the section on acutemanagement of colitis. Anaemia in colitis (as in Crohn'sdisease) is too frequently neglected: authorative guidelineshave been published separately.276

13.2. Arthropathies

The diagnosis of non-axial arthritis and arthropathyassociated with inflammatory bowel disease (IBD) is madeon clinical grounds and t types have been defined by theOxford group. The distinction is supported by differences ingenetic susceptibility.277 Type I is a large joint pauciarticulararthropathy that occurs at times of IBD activity, while type IIis a polyarticular small joint arthropathy, whose activity islargely independent of IBD activity. Axial arthritis includessacroiliitis and ankylosing spondylitis which are diagnosedclinically, supported by characteristic radiological changes.Magnetic resonance imaging is the diagnostic tool of choice.

13.2.1. Pauciarticular peripheral arthropathyType I arthropathy277 predominantly affects weight-bearingjoints, including the ankles, knees, hips, wrists, elbows andshoulders. Pauciarticular means that fewer than five jointsare affected. The arthritis is usually acute, self-limiting,resolves within weeks as disease activity decreases, andleaves no permanent joint damage. Clinical examinationreveals painful, tender, swollen joints. Aspiration is unne-cessary unless an alternative diagnosis is suspected. Thedifferential diagnosis includes osteoarthritis, septic arthritis,pyrophosphate arthropathy, coincidental rheumatoid

ECCO Statement 13CDiagnosis of the cutaneous manifestations of UC is madeon clinical grounds, based on their characteristic featuresand (to some extent) the exclusion of other specific skindisorders; biopsy is rarely appropriate or necessary [EL3b,RG C]


arthritis, or occasionally, gout. If just one hip joint is affectedthen steroid-induced osteonecrosis should be considered.279

13.2.2. Polyarticular peripheral arthropathyType II arthritis predominantly affects the small joints ofboth hands as a symmetrical arthropathy. Pain is commonlydisproportionate to the signs of arthritis. It usually persistsfor months or years and follows a course independent of IBDactivity. It may persist after colectomy or start after ileo-pouch-anal anastomosis. The differential diagnosis includesosteoarthritis, but also includes treatment side-effects suchas steroid-induced pseudorheumatism (which is commonafter withdrawal of long-term steroids) and mesalazine- orazathioprine-induced arthropathy.278

13.2.3. Axial arthropathyAsymptomatic sacroiliitis is common, with up to 50% of colitispatients having abnormal radiography.279 Symptomaticsacroiliitis is characterised by pain in the buttocks afterrest, which then improves with movement. The clinical signof discomfort in the sacroiliac joints during bilateral pressureon the pelvic brim is indicative. The principal symptom ofankylosing spondylitis is persistent low back pain, usuallybeginning before the age of 30. Clinical examination revealsloss of the lumbar lordosis and limited spinal flexion.Conventional radiographs of the back are usually normal inthe early stages of disease. Spinal CT scans and radionuclidebone scans are more sensitive than plain radiographs, but thegold standard is now magnetic resonance imaging(MRI).280,281 There is however an impression that minorabnormalities of little or no clinical consequence may beseen on MRI; this remains to be determined by longer-termfollow-up. In advanced cases there may be squaring of thevertebral bodies, marginal syndesmophytes and bony pro-liferation, with ankylosis producing the classical “bamboospine”. HLA B-27 associations is found in a majority (up to75%) of patients with axial arthritis, but is less common thanin patients with ankylosing spondylitis not associated withIBD. It is unrelated to sacroiliitis and HLA typing has no role inthe management of individual patient.282,283

13.2.4. Therapy of arthropathies

ECCO Statement 13BTreatment of arthritis and arthropathy associated with UCis based almost entirely on extrapolation from that forother forms of arthritis. There is some support for use ofsulfasalazine, simple analgesics, non-steroidal anti-inflammatory agents, local steroid injections, andphysiotherapy [EL4, RG D]. In Type I peripheral arthritisthe emphasis should be on that of the underlying colitis[EL2c, RG C]. In axial arthritis the arguments in favour ofintensive physiotherapy [EL2a, RG B], sulfasalazine [EL2a,RG C], methotrexate [EL3b, RG C], and infliximab [EL2a,RG C], are somewhat stronger

Treatment of arthritis and arthropathy associated withIBD is largely empirical. This includes the use of simpleanalgesics, sulfasalazine, local steroid injections and phy-siotherapy, but whether or not to use non-steroidal anti-

inflammatory agents is a continuing dilemma, even thoughshort term use appears not to exacerbate colitis.284

For Type I peripheral arthritis the emphasis should be onthe treatment of active disease, including steroids, immu-nomodulation, and anti-TNF therapy as appropriate. Resolu-tion of the arthropathy can be expected. The joint-specificdrug of first choice for all forms of IBD-related arthritisappears to be sulfasalazine, but convincing evidence tosupport this is lacking. Nevertheless, it was favoured by thegreatest minority of panel members (41%). Symptomaticrelief may be obtained from simple analgesics, rest andphysiotherapy.279,284,285,286 Although there is concern thatnon-steroidal anti-inflammatory agents (conventional andCOX II inhibitors) may aggravate the underlying colitis,287,288

they have been used by many gastroenterologists to goodeffect with limited risk of exacerbating colitis. A previoushistory of flare related to NSAID intake seems to be the bestindicator of individual risk. A randomised study of the safetyof celecoxib in colitis283 indicated that short-term use(b2 weeks) did not exacerbate colitis. Local steroid injectioninto the worst-affected joints often provides rapid, buttemporary relief. Type II arthritis generally resolves witheffective treatment of the colitis.289

Treatment of axial arthritis should include intensivephysiotherapy, together with disease modifying drugs suchas sulfasalazine, andmethotrexate.279,285,289 The safety andefficacy of infliximab in ankylosing spondylitis is estab-lished, but is best reserved for intractable or severelydebilitating symptoms.290,291 This is because of the 15%prevalence of immunogenicity and the small, but definablerisk of notable adverse events such as sepsis, tuberculosis, ordemyelination.

13.3. Cutaneous manifestations

13.3.1. Erythema nodosumErythema nodosum is usually readily recognised. It ischaracterised by raised, tender, red or violet subcutaneousnodules of 1 to 5 cm in diameter. It commonly affects theextensor surfaces of the extremities, particularly theanterior tibial area, and usually occurs at times of activityof the colitis. A firm clinical diagnosis can normally be made,and biopsy is not normally appropriate. If performed, thehistology reveals a non-specific focal panniculitis.292,293

Because erythema nodosum is closely related to diseaseactivity, despite a genetic link,294 treatment is based on thatof the underlying colitis. Systemic steroids are usuallyrequired (76% Consensus view). In resistant cases or whenthere are frequent relapses, immunomodulation withazathioprine and/or infliximab may be added, but it isexceptional to need such measures just because of erythemanodosum. Oral potassium iodide has been used successfully inrefractory cases.295


13.3.2. Pyoderma gangrenosum (PG)Lesions are often preceded by trauma at the site (which mayhave beenmany years earlier) through a phenomenon knownas pathergy. PG can occur anywhere on the body, includingthe genitalia, but the commonest sites are the shins andadjacent to stomas. Initially they take the form of single ormultiple erythematous papules or pustules, but subsequentnecrosis of the dermis leads to the development of deepexcavating ulcerations that contain purulentmaterial that issterile on culture unless secondary infection has occurred.

Treatment of pyoderma gangrenosum has relied ontopical and systemic steroids. Steroids were consideredthe most effective treatment for pyoderma gangrenosum(54% Consensus view), with intravenous ciclosporin ortacrolimus reserved for refractory cases.296–298 There are,however, no reliable trials to support the use of high dosesteroids or calcineurin inhibitors and these drugs haveappreciable potential side-effects. Infliximab has changedthe management of PG. In the first controlled trial inpyoderma (which also included patients without IBD)infliximab 5 mg/kg or placebo was given at week 0.299 Atweek 2 (the primary end point), significantly more patientsin the infliximab group had improved (46% (6/13)) comparedwith the placebo group (6% (1/17), p=0.025). Overall, 29patients received infliximab with 69% (20/29) demonstrat-ing a beneficial clinical response. Remission at week 6 was21% (6/29). There was no response in 31% (9/29) of patients.Infliximab is still reserved for more troublesome cases, but ishighly effective.

13.3.3. Sweet's syndromeSweet's syndrome is characterised by tender, red inflamma-tory nodules or papules, usually affecting the upper limbs,face or neck. It has only been recognised as an extraintestinalmanifestation of IBD relatively recently.300,301 It is part of thegroup of acute neutrophilic dermatoses that includespyoderma gangrenosum, but can be distinguished by itsappearance, distribution and histological features. There is astrong predilection for women (87%), patients with colonicdisease (100%) and those with other extraintestinal features(77%). The rash is associated with active disease in 67–80%,but may precede the onset of intestinal symptoms in 21% andhas been reported 3 months after proctocolectomy forulcerative colitis.

13.4. Ocular manifestations

Uveitis and episcleritis are probably the most commonextraintestinal manifestations of IBD.273,302

ECCO Statement 13DA confident diagnosis of simple episcleritis may notrequire specific treatment, but if necessary will usuallyrespond to topical steroids [EL4, RG D]. When diagnosis isuncertain referral to an ophthalmologist for expertopinion and slit-lamp examination is recommended [EL4,RG D]. Uveitis is treated with steroids, and it may benecessary to use both topical and systemic routes [EL3b,RG C]. Immunomodulatory therapy has been thoughthelpful in resistant cases [EL4, RG D]

13.4.1. EpiscleritisEpiscleritis may be painless, presenting simply withhyperaemic sclera and conjunctiva, but itching andburning sensations may also occur.303 Diagnosis of simpleepiscleritis depends on the exclusion of the more sinisterfeatures of uveitis. When this is not possible referral to anophthalmologist for an expert opinion and slit-lampexamination is essential. Episcleritis usually does notrequire specific treatment other than for underlyingdisease activity. It will respond to topical steroids ifsymptoms are troublesome — but take care that infection(including herpetic), ulceration, and uveitis are notoverlooked.

13.4.2. UveitisUveitis is less common, but has potentially severeconsequences. When related to ulcerative colitis it isfrequently bilateral, insidious in onset and long-lasting.304

Patients complain of eye pain, blurred vision, photophobiaand headaches. Potential progression to loss of visionshould prompt urgent referral to an ophthalmologist. Slit-lamp examination will confirm the diagnosis and differ-entiates between anterior and posterior uveitis. Uveitis istreated with steroids, and it may be necessary to use bothtopical and systemic routes. Infliximab is rapidly effec-tive,304 but treatment should be guided by specialists.

13.4.3. CataractsChronic corticosteroid use for treatment of UC is associatedwith numerous complications and may result in posteriorsubcapsular cataracts develop in a significant proportion(25%) of patients receiving 15 mg or more of prednisone for1 year.305 Although steroids do not prevent relapse and haveno place in the long-termmanagement of UC, any patient onlong-term steroids should undergo routine (probably annual)slit lamp examination.

13.5. Hepatobiliary disease

Hepatobiliary disease is relatively common in IBD andmagnetic resonance cholangiography (MRC) indicates thatit may be more prevalent than currently estimated inulcerative colitis.306 Primary sclerosing cholangitis (PSC)constitutes the most important condition relatively specificto the underlying IBD. Other conditions associated with IBDmore commonly than in the general population includepericholangitis, steatosis, chronic hepatitis, cirrhosis, andgallstone formation. Hepatotoxicity from some drugs usedfor colitis should always be considered, although usuallypresents within 3 weeks of starting medication and not atlater stages.

The finding of abnormal liver function tests, rather thansymptoms or signs of liver disease, is the most commonpresentation. Diagnosis of hepatobiliary disorders thenfollows the standard investigatory pathways for abnormalliver function tests, with ultrasound scanning, serology toidentify specific auto-immune or infective causes, andliver biopsy. Predominantly cholestasis or the biliary-typepain will prompt ultrasonographic assessment, which mayreveal gall stones, steatosis, be consistent with cirrhosis,or (less often) show an abnormal duct pattern suggestive ofPSC.

ECCO Statement 13EPSC appears to respond to ursodeoxycholic acid, whichimproves abnormal liver function tests [EL1b, RG B] andmay, at 20 mg/kg, improve liver histology and prognosis[EL2a, RG C]. It is possible that ursodeoxycholic acid alsoreduces the risk of colonic cancer in PSC patients [EL2a,RG C]. ERCP may be used to treat dominant strictures bydilatation and/or stenting [EL4, RG C]. Advanced liverdisease may necessitate transplantation [EL2a, RG B]


13.5.1. Primary sclerosing cholangitisFor patients with cholestasis the probability of PSC isappreciably increased if the ultrasound scan is normal, if drugside-effects are thought unlikely, and if serological tests forprimary liver disease are negative. Magnetic resonance cholan-giography (MRC) is now established as the first-line diagnostictest for PSC.307 The characteristic pattern shows irregular bileducts, with zones of both narrowing and dilatation. If MRC isnormal and PSC still suspected (such as otherwise unexplainedcholestasis in a patient with IBD), then it is safer and probablymore effective to do a liver biopsy rather than diagnostic ERCP,since this will detect predominant small duct disease. PSCsubstantially increases the risk of both cholangiocarcinoma andcolorectal carcinoma (Section 9.1.2, 9.5).

PSC appears to respond to ursodeoxycholic acid (ursodiol),which improves abnormal liver function tests308 and may, at20 mg/kg, possibly improve prognosis. It is possible that it alsoreduces the risk of colonic cancer in these patients118 (Section9.5). Tacrolimus has yielded a rapid decrease in liver enzymes,but no histological improvement.309 ERCP may be used to treatdominant strictures by dilatation and/or stenting. Advancedliver diseasemay necessitate transplantation, but recurrence ofPSC in the transplanted liver occurs in approximately 20% ofpatients.308,310 Specialist advice is appropriatewhenmanagingapatientwithPSCand IBD. Becauseof thehigher risk of colorectalcancer, it is generally considered appropriate to perform annualscreening colonoscopy from the time of diagnosis.

13.6. Metabolic bone disease

ECCO Statement 13EDiagnosis of osteoporosis in adults is best made from a Tscore of less than −2.5 on radiographic bone densitometry[EL1a, RG A], all other diagnostic methods having currentlimitations [EL2b, RG B]. The presence of osteoporosisidentifies patients at above average risk for fracture andwho should receive treatment [EL2b, RG B]

ECCO Statement 13GWeight-bearing exercise [EL2b, RG B], stopping smoking[EL3b, RG C], avoiding alcohol excess [EL4, RG D], andmaintaining adequate dietary calcium (N1 g/day) [EL2b,RG B] are beneficial. In post-menopausal women withosteoporosis, regular use of bisphosphonates, calcitoninand its derivatives, and raloxifene reduce or preventfurther bone loss [EL2b, RG C]. Data in males withosteoporosis are less secure but bisphosphonates areprobably of value [EL3b, RG C]. Newer data also supportthe use of strontium salts [EL2a, RG B]

ECCO Statement 13FOsteopenia may be a prognostic marker for futureosteoporosis, but presents little direct risk [EL2b, RG C].However if the T score is less than −1.5, treatment withcalcium, vitamin D and a bisphosphonate should beconsidered [EL4, RG C]. Pre-existing history of fracture isof substantial adverse prognostic significance and suchpatients should be treated for osteoporosis even if the Tscore is normal [EL4, RG C]

13.6.1. Diagnosis and fracture riskOsteoporosis and osteopenia are common in patients withIBD (20–50%), but the actual number of fractures in IBD isonly slightly increased to the general population.311,312 In astudy using the general practice research database, therelative risk of hip fracture was 1.62 (95% CI 1.24–2.11) forall IBD, 1.49 (1.04–2.15) for ulcerative colitis and 2.08(1.36–3.18) for Crohn's disease.312 Contributing factorsinclude age, steroid treatment, smoking, low physical activ-ity (including that from hospitalisation), inflammatorycytokines, and probably also resection with pouch formation.

Diagnosis is conventionally based on bone densitometry(DEXA scanning), osteoporosis being defined as a T score ofless than −2.5. Ultrasound has been suggested as method ofscreening, but is not yet reliable. The presence of osteo-porosis increases the risk of fracture of long bones and of thespine, although probably a great deal less in young patientsthan was once thought. It is conventional to use a radiologicaldiagnosis of osteoporosis as an indication for specific therapy.

Osteopenia (T score less than −1.0) is thought by some tobe an important risk factor for fracture in its own right, butthis is increasingly questioned.313 It is, however, probablethat it is a marker of increased risk of later osteoporosis evenif the risk is not absolute. Therapeutic intervention isprobably not justified on present knowledge, but continuedsurveillance for bone loss is appropriate. It is important toput risks into perspective when discussing with patients.

The risks of osteoporosis (and the potential risks fromosteopenia) should be explained. The recommended dietarycalcium intake should be1000–1500mg/day,which oftenmeanssupplementation even in patients not taking corticosteroids. Itshould be noted that recommendations for the treatment ofosteoporosisapplyonlytoadultsovertheageof25years,andthatevidence for treating oestopenia is circumstantial. Thediagnosisof osteoporosis in children and long-term consequences oftreatmentwith bisphosphonates are unknown.

13.6.2. Management

The risks of osteoporosis (and the potential risks fromosteopenia) should be explained. The treatment of osteoporosisis based on studies that are not specific to IBD.314 Weight-bearing, isometric exercise, stopping smoking, avoiding alcoholexcess and maintaining adequate dietary calcium (N1 g/day)are beneficial, but such advice is often overlooked. Hormonereplacement treatment is no longer generally advised in post-menopausal women with osteoporosis, because studies havedemonstrated a slightly increased risk of breast cancer and of

ECCO Statement 13AAlternative medicines for ulcerative colitis (UC) excludethe possibility of using conventional therapy at the sametime [EL5, RG D]. Complementary medicines for UC allowconcomitant conventional therapy [EL5, RG D]


cardiovascular events.315 Regular use of bisphosphonates,calcitonin and its derivatives, and raloxifene (a selectiveoestrogen receptor modulator) may reduce or prevent furtherbone loss. Data in males with osteoporosis are few, butbisphosphonates are probably of value and an importantpractice point is that testosterone should be measured. Thosewith low testosterone may benefit from supplementation.Routine administration of vitamin D is not warranted. Patientson corticosteroids for short periods do not merit routine use ofbone protection with bisphosphonates, assuming a normalcalcium intake and all other risk factors being equal.315

13.7. Other systems

Other systems are found to be abnormal in UC more often thanwould be expected by chance and these associations maytherefore be considered to be extra-intestinal manifestations.Examples include respiratory complaints (especially asthma),cardiac and pericarditic conditions, nephrological disease (bothnephritis and amyloidosis), neurological conditions (especiallymultiple sclerosis) and urinary tract stones.274,302 Their diag-nosis and management is not considered in further detail,because the routes to diagnosis are no different from those ingeneral medical practice and because their management isfundamentally independent of that of the colitis. The issue ofinterstitial nephritis associated with 5-ASA therapy316 isconsidered in the section on colitis therapy (Section 5.4.1,preceding paper same issue.)289 Anaemia and ulcerative colitisdeserves greater proactive management by gastroenterologiststhan it generally receives, because it is associated withsubstantial impairment of the quality of life. Reasons for nottreating anaemia effectively often dwell on intolerance to oraliron therapy and difficulty in delivering or risks associated withparenteral iron, but this is no longer tenable and expectations ofboth patients and physicians should be raised.276

13.8. Organisation of services for EIMs associatedwith ulcerative colitis

ECCO Statement 13 GOrganisation of services to facilitate expert managementof extra-intestinal manifestation may include combinedor parallel specialist clinics conducted with clinicians

ECCO Statement 13BAlternative medicine for UC as defined above is stronglydiscouraged [EL5, RG D]

Themorecommonextra-intestinalmanifestations affectingjoints and skin may be profitably managed by a close workingrelationship between the gastroenterologist and rheumatolo-gist or dermatologist respectively. It is easier to ensure thatinter-disciplinary knowledge is used to best advantage for thepatient by the existence of periodic clinics for rheumatology,dermatology and other specialties held in parallel, and in somecases by joint consultations. Awareness of atypical presenta-tions and of new exploratory therapies is therefore enhanced.

14. Complementary and alternative medicines

14.1. Introduction

The use of complementary and alternative medicine amongUC patients is common, and physicians are frequently

from the other relevant disciplines [EL4, RG D]

confronted with questions about their use. Reasons forusing such therapies are worries about conventional treat-ment, including perceived lack of effectiveness and fearabout side-effects, in addition to subjective benefit fromcomplementary or alternative therapies. However, evidencefor the efficacy and safety of CAMs is often lacking, becausethere are very few controlled trials that assessed thesetherapies in UC and even these are underpowered for whatthey aim to establish. Consequently, because of the lack ofpower and other methodological problems in the reportedstudies, it is difficult for physicians to inform their patientsadequately. Nevertheless, complementary and alternativetreatments warrant further evaluation from public interestalone. Although complementary medicine appears to begenerally safe and non-toxic, this cannot be assumed andpotential side-effects should be considered for each sub-stance, particularly when microorganisms are used inconjunction with conventional immunomodulators.

14.2. Definitions

Complementary and alternative medicines represent adiverse group of medical and non-medical products andtherapeutic approaches that are not presently considered partof conventional therapy. Products that have established efficacyin UC, such as specific probiotics (E. coli Nissle 1917, forexample), are not considered complementary or alternativemedicines and are described elsewhere (Section 6.2.4, preced-ing paper same issue). On the other, hand remedies fromdifferent, often non-Western, cultures are included in this groupof therapies, as well as those that are unproven. An importantdistinction between alternative and complementarymedicine isits relation to conventional therapy. Alternative medicineexplicitly excludes concomitant conventional therapy, butcomplementary medicine allows the complementary approachin conjunctionwith conventional therapy. It is helpful if patientsare aware of this distinction, not least because alternativemedicine for a serious, potentially life-threatening conditionsuch as acute severe colitis would be dangerous.

14.3. Use of CAM

Since alternative medicine by definition does not allowconventional therapy, even when necessary, this type of UCtherapy can lead to severe complications from the underlyingcondition. In contrast, complementary medicine is usually safeand is possible if patientswant touse it. Fromapractical point ofview, if patients discuss complementary therapy in the contextof conventional medical consultation, it is usually an indicator


that the patient or their family want to know more about theircondition, the conventional medicine that is being prescribes,and the therapeutic strategy. It should alert practitioners tounmet need, if only for more detailed explanation.

ECCO Sttatement 13CUC patients should be asked about the use of alternativeand complementary medicines [EL5, RG D]

Complementary and alternative medicines are commonlyused by UC patients.317–321 Although the use of complemen-tary medicine is considered largely safe, there are publishedcase reports on systemic fungal infection in immunocompro-mised patients.321 In addition, herbal medicine such as StJohn's Wort, can interact with immunosuppressive agentsand need to be checked for potential interactions.322,323 It istherefore appropriate to enquire about the use of alternativeand complementary medicine.

ECCO Statement 13DThere is insufficient evidence for the use of Trichuris suisova, Saccharomyces boulardii, or Bifidobacteria in thetreatment of UC [EL5, RG D]

Although some probiotics and one helminth have beeninvestigated in clinical studies, these publications areconsidered of insufficient power to take a view on whetherto recommend their use. Their design was single centre andsample size too small.324–329

ECCO Statement 13EThere is insufficient evidence for the use of acupuncture,Boswellia serrata gum, germinated barley, aloe vera geland other herbal medicines in the treatment of UC [EL5,RG D]

Other complementarymedicines have been studied in smallstudies or in countries where randomised, double-blind,placebo-controlled trials are not the practice norm for judgingthe merits of therapy. Because of sample size, study design,concomitant therapies and questionable transferability, thefollowing agents cannot currently be recommended fortreating UC, either active disease or as maintenance:acupuncture,330–332 Boswellia serrata gum,333 prebiotic ger-minated barley foodstuff,334–336 aloe vera gel337 and otherherbal medicines.338 A report on curcuminmaintenance thera-py (2 g daily, added to aminosalicylates for 6 months) showed asignal for benefit in a double-blind, placebo-controlled trial of89 patients.339 This both needs confirmation and illustrates theneed to explore complementarymedicines subject to the samerigorous proof of benefit as conventional therapy.340

Contributors

Livia Biancone, Cattedra di Gastroenterologia, Diparti-mento di Medicina Interna, Università Tor Vergata, ViaMontpellier, 1 00133 Rome, Italy

Axel Dignass, Head Department of Medicine I, Markus-HospitalAcademic Teaching Hospital, Johann-Wolfgang-Geothe Univer-sity, Wilhelm-Epstein-Str. 2; D-60431 Frankfurt/Main, GermanyJohanna C. Escher, Erasmus MC-Sophia Children's Hospital,Rotterdam, the NetherlandsAlastair Forbes, Dept. Gastroenterology, Maple House,University College Hospital, 235 Euston Road, LondonNWI 2BUPaolo Gionchetti, Dept. of Internal Medicine and Gastro-enterology, Policlinico S. Orsola, University of Bologna, ItalyJörgC.Hoffmann,MedizinischeKlinik I, St.Marienkrankenhaus,Salzburgerstrasse 15, D67067 Ludwigshafen, GermanyGünter Jantchek, Klinik für Psychosomatik und Psychother-apie, Universitätsklinikum Schleswig-Holstein, CampusLübeck, Ratzeburger Allee 160, 23538 Lübeck, GermanyRalf Kiesslich, I. Med. Clinic, Johannes Guttenberg Uni-versity of Mainz, GermanySanja Kolacek, Children's Hospital Zagreb, Klaiceva 16,10000 Zagreb, CroatiaPierre Michetti, Division of Gastroenterology and Hepatol-ogy, Centre Hospitalier Universaire Vaudois, Lausanne,SwitzerlandRod Mitchell, European Federation of Crohn's & UlcerativeColitis Associations, 39 Crusader Road, Bearwood, Bourne-mouth, Dorset BH11 9TY, UKGabriele Moser, Dept. Internal Medicine IV, UniversityHospital of Vienna, Waehringer Guertel 18-20, 1090 Vienna,AustriaJulian Panes, Inflammatory bowel disease Unit, HospitalClinic, Villaroel 170, 08036 Barcelona, SpainJohan Soderholm, Department of Surgery, UniversityHospital, SE-581 85 Linköping, SwedenEduard Stange, Chefarzt, Abteilung für Innere Medizin 1Schwerpunkte Gastroenterologie, Hepatologie und Endokri-nologie, Robert Bosch Krankenhaus, Postfach 501120,Auerbachstr. 110, 70341 Stuttgart, GermanySimon Travis, John Radcliffe Hospital, Oxford OX3 9DU, UKBoris Vucelic, University Hospital Rebro, Division ofGastroenterology & Hepatology, Kispaticeva 12, 10000Zagreb, Croatia

Acknowledgements

We are particularly grateful to Mrs Lynn Lane and Sophie Laneof Oxford for their substantial contribution to coordinatingand assimilating the Consensus, to the Robert Bosch Founda-tion for an unrestricted educational grant and to all colleagueswho completed the questionnaires and contributed to thestatements at the Consensus meeting in Berlin, October 2006.

The contributors to the Consensus meeting wereAustria Moser, Reinisch, TilgBelgium De Vos, D'Haens, Geboes, Penninckx, VermeireCroatia Kolacek, VucelicCzech Republic LukasDenmark Lebend, Munkholm, Wewer

Germany Dignass, Herfarth, Hoffmann, Jantschek, Kiesslich,Kruis, Kucharzik, Schölmerich, Schreiber, Stange, ZeitzGreece Mantzaris, TsianosHungary Lakatos

é ééFrance Colombel, Cortot, Fl jou, L émann, Marteau, Panis


Israel Chowers, Eliakim,Italy Biancone, Caprilli, Cottone, Gionchetti, Pallone,Prantera, Vecchi, VillanacciLatvia PokrotnieksLithuania Barakauskiene, KupcinskasNetherlands Bemelman, Escher, Hommes, Van der WoudeNorway MoumPortugal FreitasSerbia JojicSlovakia Gregus,Spain Gassull, PanesSweden Øresland, Soderholm, TyskSwitzerland Mitchetti, SeiboldUK Feakins, Forbes, Ghosh, Hamilton, Hawkey, Mitchell,Mortensen, Rhodes, Travis, Warren

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Journal of Crohn's and Colitis (2008) 2, 190

CORRIGENDUM

Corrigendum to “European-evidence-based consensuson the management of ulcerative colitis:Current management”[J Crohns & Colitis 2 (2008) 24–62]S.P.L. Travis ⁎,1, E.F. Stange ⁎,1, M. Lémann, T. Øresland, W.A. Bemelman,Y. Chowers, J.F. Colombel, G. D'Haens, S. Ghosh, P. Marteau, W. Kruis,N.J.McC. Mortensen, F. Penninckx, M. Gassullfor the European Crohn's and Colitis Organisation (ECCO)

The Publisher and Authors regret and apologise that Table 6.5 on page 45 was incorrectly printed. The corrected table is:

Table 6.5 Randomized trials of probiotics for maintaining remission in UC


Study drugs Dosage Duration(months)

Failure to maintain clinicalor endoscopic remission

Kruis274 1997 120 E. coli Nissle 200 mg/day 3 16%Mesalazine 1.5 g/day 11%

Rembacken275 1999 116 E. coli Nissle 200 mg/day 12 67%Mesalazine 1.2 g/day 73%

Kruis276 2004 327 E. coli Nissle 200 mg/day 12 45%Mesalazine 1.5 g/day 37%

Ishikawa277 2000 21 Probiotic mixture a number 100 mL 12 27%Treatment b 90%

Zocco278 2006 187 Lactobacillus GG 18×109 12 15%Mesalazine 2.4 g/day 20%Combination 16%

a Bifidobacterium bifidum+Bifidobacterium breve+Lactobacillus acidophilus.b Open label study.

DOI of original article: 10.1016/j.crohns.2007.11.002.⁎ Corresponding authors. S.P.L. Travis is to be contacted at tel.: +44 1865 228753; fax: +44 1865 228763. E.F. Stange, tel.: +49 0711 81013404;

fax: +49 0711 81013793.E-mail address: [email protected] (S.P.L. Travis).

1 These authors acted as convenors of the Consensus and contributed equally to the work.




ava i l ab l e a t www.sc i enced i rec t . com

Journal of Crohn's and Colitis (2008) 2, 191

CORRIGENDUM

Corrigendumto “Europeanevidence-basedconsensusonthe management of ulcerative colitis:Special situations”[J Crohns & Colitis 2 (2008) 63–92]Livia Biancone, Pierre Michetti, Simon Travis⁎, Johanna C. Escher,Gabriele Moser, Alastair Forbes, Jörg C. Hoffmann, Axel Dignass,Paolo Gionchetti, Günter Jantschek, Raplh Kiesslich, Sanja Kolacek,Rod Mitchell, Julian Panes, Johan Soderblom, Boris Vucelic, Eduard Stange⁎for the European Crohn's & Colitis Organisation (ECCO)

The Publisher and Authors regret the omission of the author (Janneke van der Woude) from the above list. The corrected fulllist of authors is:

Livia Biancone, Pierre Michetti, Simon Travis⁎, 1, Johanna C. Escher,Gabriele Moser, Alastair Forbes, Jörg C. Hoffmann, Axel Dignass,Paolo Gionchetti, Günter Jantschek, Raplh Kiesslich, Sanja Kolacek,Janneke van der Woude, Rod Mitchell, Julian Panes, Johan Soderblom,Boris Vucelic, Eduard Stange⁎, 1

for the European Crohn's & Colitis Organisation (ECCO)

DOI of original article: 10.1016/j.crohns.2007.12.001.⁎ Corresponding authors. S. Travis is to be contacted at tel.: +44 1865 228753; fax: +44 1865 228763. E. Stange, Department of Internal

Medicine 1, Robert Bosch Krankenhaus, PO Box 501120, Auerbachstr. 110, 70341 Stuttgart, Germany. Tel.: +49 0711 81013404; fax: +49 071181013793

1873-9946/$ - see front matter © 2008 European Crohn’s and Colitis Organisation. Published by Elsevier B.V. All rights reserved.doi:10.1016/j.crohns.2008.03.007



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