; accepted 23 November 2007
ava i l ab l e a t www.sc i enced i r ec t . com
Journal of Crohn's and Colitis (2008) 2, 24–62
Azathioprine;
Infliximab;
Ileal pouch-anal
anastomosis
Contents
5. Medical management of active ulcerative colitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.1. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.1.1. Disease activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.1.2. Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.2. Treatment according to site of disease and disease activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.2.1. Proctitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.2.2. Left sided colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
5.2.3. Extensive ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
5.2.4. Severe ulcerative colitis of any extent. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
5.2.5. Intravenous-steroid resistant ulcerative colitis of any extent . . . . . . . . . . . . . . . . . . . . . . 29
5.2.6. Toxic dilatation and complications of severe ulcerative colitis . . . . . . . . . . . . . . . . . . . . . 31
5.2.7. Refractory proctitis and distal colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Received 23 November 2007
KEYWORDS
Ulcerative colitis;
Acute severe colitis;
Mesalazine;
SPECIAL ARTICLE
European evidence-based Consensus on the
management of ulcerative colitis:
Current management
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. Gassull
for the European Crohn's and Colitis Organisation (ECCO)
⁎ Corresponding authors. Travis is to be contacted at John Radcliffe Hospital, Oxford, OX3 9DU, UK. Tel.: +44 1865 228753; fax: +44 1865
228763. 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: simon.travis@ndm.ox.ac.uk (S.P.L. Travis), Eduard.Stange@rbk.de (E.F. Stange).
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.2007.11.002
25ECCO Consensus on UC: Current management
5.3. Treatment according to the course or behaviour of disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
5.3.1. Treatment of relapse compared to new cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
5.3.2. Early relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
5.3.3. ‘Steroid-dependent’, active ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
5.3.4. Oral steroid-refractory ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
5.3.5. Immunomodulator-refractory ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
5.4. Therapy-specific considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
5.4.1. Aminosalicylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
5.4.2. Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
5.4.3. Infliximab (IFX) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
5.4.4. Other biological therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
5.4.5. Thiopurines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
5.4.6. Methotrexate (MTX) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
5.4.7. Calcineurin inhibitors (ciclosporin (CsA) and tacrolimus) . . . . . . . . . . . . . . . . . . . . . . . . . 38
5.4.8. Alternative therapies whose role remains to be established . . . . . . . . . . . . . . . . . . . . . . . 38
5.5. Preparation for the period after treatment of active disease . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
6. Maintenance of remission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
6.1. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
6.1.1. Maintenance therapy trial design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
6.1.2. Pattern of disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
6.1.3. Risk factors for relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
6.2. Medications for maintenance of remission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
6.2.1. Aminosalicylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
6.2.2. Thiopurines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
6.2.3. Infliximab (IFX) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
6.2.4. Probiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
6.2.5. Other treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
6.3. Duration of maintenance therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
7. Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
7.1. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
7.2. Technical considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
7.2.1. Surgery for acute severe colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
7.2.2. Managing the rectal remnant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
7.2.3. Site of anastomosis for restorative poctocolectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
7.2.4. Anastomostic technique for restorative proctocolectomy . . . . . . . . . . . . . . . . . . . . . . . . 48
7.2.5. Site of anastomosis for neoplasia complicating colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
7.2.6. Role of covering ileostomy for restorative proctocolectomy . . . . . . . . . . . . . . . . . . . . . . . . 49
7.2.7. Number of procedures to maintain competency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
7.2.8. Salvage surgery for pouches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
7.3. Follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
7.3.1. General pouch follow up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
7.3.2. Pouch surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
7.4. Fertility and delivery in patients with a restorative proctocolectomy . . . . . . . . . . . . . . . . . . . . . . 50
7.4.1. Impact of pelvic surgery on fecundity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
7.4.2. Mode of delivery for patients with restorative proctocolectomy . . . . . . . . . . . . . . . . . . . . 50
7.5. Surgical choices in addition to restorative proctocolectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
7.5.1. Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
7.5.2. Continent ileostomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
7.5.3. Ileorectal anastomosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
7.5.4. Cancer surveillance of the rectal remnant after colectomy . . . . . . . . . . . . . . . . . . . . . . . . . 51
7.5.5. Pouch excision after pouch failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
7.5.6. Laparoscopic pouch surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
7.5.7. Pouch surgery for indeterminate colitis, or IBD yet-to-be classified . . . . . . . . . . . . . . . . . . 51
7.6. Surgery and medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
7.6.1. Perioperative prednisolone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
7.6.2. Perioperative azathioprine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
7.6.3. Perioperative anti-TNF therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
7.7. Colectomy in practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Active colitis limited to the rectum should first be
treated topically. Suppositories are more appropriate than
enemas, because suppositories target the site of inflam-
mation; only 40% of foam enemas and 10% of liquid enemas
can be detected in the rectum after 4 hr.10 Topical
mesalazine (5-ASA) induced remission in active proctitis
and distal colitis in 31–80% (median 67%) compared to 7–
11% given placebo in a meta-analysis of 11 trials in 778
patients.11 Topical mesalazine is at least twice as effective
as topical steroids whether for symptoms (OR 2.42, 95%CI
1.72–3.41), endoscopy (OR 1.89, 95%CI 1.29–2.76), or
histology (OR 2.03, 95%CI 1.28–3.20).12 Mesalazine suppo-
sitories 1 g daily are highly effective.13 There is no dose
response to topical therapy above a dose of 1 g mesalazine
daily. Clinical (and endoscopic) remission can occur in up to
64% (52%) within 2 weeks.13 Topical steroids should be reserved
26 S.P.L. Travis et al.
5. Medical management of active
ulcerative colitis
5.1. General
The general principles for treating active ulcerative colitis
are to consider the activity, distribution (proctitis, left-sided,
extensive,1 and pattern of disease (relapse frequency, course
of disease, response to previous medications, side-effect
profile of medication, extra-intestinal manifestation),
before treatment decisions are made in conjunction with
the patient.
5.1.1. Disease activity
The principal scoring systems used for clinical trials are
covered in Section 5.1.2 and have been comprehensively
reviewed.2 Some additional points are clinically relevant.
In clinical practice it matters most to distinguish severe
ulcerative colitis necessitating hospital admission from
those with mild or moderate disease who can generally
be treated as outpatients. The simplest, best validated
and most widely used index for identifying acute severe
UC remains that of Truelove & Wi_tts 3: any patient who
has 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 has
been used in 20/32 studies of intensive intravenous
treatment for severe UC.4 Only one additional criterion
in addition to the bloody stool frequency ≥6/day is
needed to define a severe attack.5 While these criteria
have the major limitation of being unresponsive and
cannot track the course of disease, they do distinguish
the severe from the moderate or mild and have value in
everyday practice because they are easy to use, which no
other index achieves. It should be standard practice to
confirm active colitis by sigmoidoscopy or proctoscopy
before starting treatment. Rectal mucosal biopsy helps
exclude unexpected causes of symptoms similar to active
disease (such as cytomegalovirus, amoebic, or other
infection, rectal mucosal prolapse, Crohn's disease, or
even irritable bowel syndrome and haemorrhoidal
bleeding).
5.1.2. Approach
Patients should be encouraged to participate actively in
therapeutic decisions. In a systematic review of clinical
trials, a mean 15% (95%CI 10–21%) of patients entered
remission when receiving placebo.9 Prescribing no treat-
ment, however, is rarely an option, because rectal
bleeding and urgency are sufficiently concerning to the
patient to justify topical therapy even if no systemic
therapy is recommended.
The appropriate choice of medication depends on many
factors that are best tailored to the individual. Despite
general agreement that treatment decisions for active UC
should be based on the distribution, activity and pattern
of disease, numbers in clinical trials often become too
small for statistically valid conclusions to be drawn when
patients are stratified according to the distribution and
pattern of disease.7 Different galenic preparations are
released at different sites and may have local activity
as second line therapy for patientswho are intolerant of topical
mesalazine.14 Topical mesalazine is more effective than oral
mesalazine for proctitis,15 but the combination of oral and
topical mesalazine may be better than either alone for colitis
b50 cm from the anal verge.16 There have been no trials on
combination therapy for proctitis alone. Combining topical
mesalazine and steroids also helps: beclomethasone dipropio-
nate (3mg) andmesalazine (2 g) enemas produced significantly
better clinical, endoscopic and histological improvement than
either agent alone.17 Patients who fail to improve on topical
mesalazine and topical corticosteroids should be treated with
additional 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.
(such as mesalazine preparations, budesonide, or types of
enema). The choice is influenced by the balance between
drug potency and side-effects; previous response to
treatment (especially when considering treatment of a
relapse, treatment of steroid-dependent or -refractory
disease, or immunomodulator-refractory disease, Section
5.3); and the presence of extraintestinal manifestations
(indicating the need for systemic therapy).
5.2. Treatment according to site of disease and
disease activity
5.2.1. Proctitis
ECCO statement 5A
Mesalazine 1 g suppository daily is the preferred
initial treatment for mild or moderately active
proctitis [EL1b, RG B]. Mesalazine foam enemas
are an effective alternative [EL1b]. Suppositories
may deliver drug more effectively to the rectum
and are better tolerated than enemas [EL3, RG C].
Combining topical mesalazine with oral mesala-
zine or topical steroid, may bemore effective than
either alone and should be considered for escala-
tion of treatment [EL1b, RG B]. Oral mesalazine
alone is less effective [EL1b]
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 of
oral aminosalicylates for active ulcerative colitis showed the
overall remission rate to be only 20%.22 Two further placebo
controlled trials of a multimatrix mesalazine formulation for
mild-moderate UC have been published more recently,23,24 as
well as a combined analysis.25 The first study randomized 280
patients to either MMx 4.8 g once daily, MMx 1.2 g twice daily, or
placebo for 8 weeks. The primary endpoint was remission at
8 weeks. Once and twice daily dosing produced similar results,
with remission rates of 29% and 34% respectively, compared to
13% on placebo (pb0.01)23 (see also Section 6.2.1). A further
placebo-controlled study compared MMx mesalazine with
Asacol® in 346 patients with active, mild-to-moderate UC.24
Clinical and endoscopic remission was achieved in 40.5% given
MMxmesalazine 2.4 g/day once daily and 41.2% given 4.8 g/day
once daily compared to 22.1% on placebo (p=0.01 and 0.007
respectively) and 32.6% given Asacol® (ns).
determining the speed of response. If rectal bleeding persists
beyond 10–14days, then the response canbe said to be slowand
therapy augmented, which usually means decisive treatment
with steroids.
There is something of a transatlantic divide on the threshold
for using steroids. The practice inmany European countries is to
introduce oral steroids at an early stage, because aminosalicy-
lates cannot match the speed of response for patients suffering
miserable symptoms. The US concern about steroid-induced
side-effects is shared by their patients, but may also be self-
fulfilling. Late introduction of steroids selects a more refractory
population. Steroids with a colonic release mechanism and low
systemicbioavailabilty suchasbeclomethasonediproprionateor
budesonide are becoming available. In the largest and most
recent study of 177 patients with active left-sided or extensive
colitis, beclomethasone diproprionate 5 mg/day had an effect
27ECCO Consensus on UC: Current management
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
5.2.2. Left sided colitis
Combined oral and topical mesalazine therapy is re-
commended.14 There has been just one trial on 60 patients of
combined therapy for distal colitis compared to oral or topical
therapy alone, showing it toworkmore rapidly andeffectively.16
However, extrapolation from a trial of combination therapy for
extensive colitis,18 evidence that topical therapy achieves
higher rectal mucosal 5ASA concentrations than oral therapy19
and is associated with improved clinical outcome,19,20 are
consistent with the recommendation.
Most therapeutic trials of mild or moderate active colitis
include patients with any disease distribution other than
proctitis, but both oral and topical aminosalicylates (mesala-
zine) are effective for left-sided colitis. In a meta-analysis of
oral 5-ASA compounds for active colitis,21 mesalazine was more
than twice as effective as placebo (OR 0.40, 95%CI 0.30–0.53),
but not significantly better than sulphasalazine (OR 0.83, 95%CI
0.60–1.13) for the failure to induce global clinical improvement
or remission. Therewas a trend formesalazine to be better than
sulfasalazine for endoscopic improvement (OR 0.66, 95%CI
0.42–1.04) and mesalazine is better tolerated than sulfasala-
ECCO statement 5B
Left-sided active ulcerative colitis of mild-moderate
severity should initially be treated with topical
aminosalicylates [EL1b, RG B] combined with oral
mesalazineN2 g/day [EL1a, RGA]. Topical steroids or
mesalazine alone are also effective, but less effec-
tive than combination therapy [EL1b, RG B]. Topical
mesalazine is more effective than topical steroid
[EL1a, RG A].