ECCO Guideline - IBD 2-2017 PDF

Journal of Crohn's and Colitis, 2017, 769–784

doi:10.1093/ecco-jcc/jjx009
Advance Access publication January 28, 2017
ECCO Guideline/Consensus Paper

ECCO Guideline/Consensus Paper

Third European Evidence-based Consensus

on Diagnosis and Management of Ulcerative
Colitis. Part 2: Current Management
Marcus Harbord,a,†,# Rami Eliakim,b,# Dominik Bettenworth,c
Konstantinos Karmiris,d Konstantinos Katsanos,e Uri Kopylov,f
Torsten Kucharzik,g Tamás Molnár,h Tim Raine,i Shaji Sebastian,j
Helena Tavares de Sousa,k Axel Dignass,l,† Franck Carbonnel;m,†
for the European Crohn’s and Colitis Organisation [ECCO]
a
Imperial College London, and Chelsea and Westminster Hospital, London, UK bDepartment of Gastroenterology and
Hepatology, Chaim Sheba Medical Center, Tel Hashomer, Israel cDepartment of Medicine B, University Hospital Münster,
Münster, Germany dDepartment of Gastroenterology, Venizeleio General Hospital, Heraklion, Crete, Greece eDepartment
of Gastroenterology and Hepatology, University and Medical School of Ioannina, Ioannina, Greece fDepartment of
Gastroenterology, Tel-Hashomer Sheba Medical Center, and Sackler School of Medicine, Tel Aviv University, Israel
g
Department of Internal Medicine and Gastroenterology, Hospital Lüneburg, Lüneburg, Germany hFirst Department of
Medicine, University of Szeged, Szeged, Hungary iDepartment of Medicine, University of Cambridge, Cambridge, UK
j
IBD Unit, Hull & East Yorkshire NHS Trust, Hull, UK kGastroenterology Department, Algarve Hospital Center; Biomedical
Sciences & Medicine Department, University of Algarve, Faro, Portugal lDepartment of Medicine I, Agaplesion Markus
Hospital, Frankfurt/Main, Germany mDepartment of Gastroenterology, CHU Bicêtre, Université Paris Sud, Paris, France
†
These authors contributed equally to this paper.
#
These authors acted as convenors of the Consensus.
Corresponding author: Marcus Harbord, BSc, MBBS, PhD, FRCP, Chelsea and Westminster NHS Foundation Trust, 369 Ful-
ham Road, London SW10 9NH, UK. E-mail: [email protected]
Section 11. Medical Management of Active 11.2. Treatment according to site of disease and
Ulcerative Colitis disease activity
11.2.1. Proctitis
11.1. General
The treatment strategy for ulcerative colitis [UC] is mainly based ECCO statement 11A
on the severity, distribution [proctitis, left-sided, extensive]1 and pat-
tern of disease. The latter includes relapse frequency, disease course, A mesalamine 1-g suppository once daily is the preferred
response to previous medications, side effects of medication, and initial treatment for mild or moderately active proctitis
extra-intestinal manifestations. Age at onset, and disease duration [EL1]. Mesalamine foam or enemas are an alternative
are also important factors. It is important to distinguish patients [EL1], but suppositories deliver the drug more effec-
with severe UC necessitating hospital admission from those with tively to the rectum and are better tolerated [EL3]. Topical
mild or moderately active disease who can be managed as outpa- mesalamine is more effective than topical steroids [EL1].
tients. The best validated and most widely used index for identifying Combining topical mesalamine with oral mesalamine or
severe UC remains that of Truelove and Witts.2 Patients with bloody topical steroids is more effective [EL2]
stool frequency ≥ 6/day and a tachycardia [> 90 min−1], or tempera-
ture > 37.8°C, or anaemia [haemoglobin < 10.5 g/dl], or an elevated
ECCO statement 11B
erythrocyte sedimentation rate [ESR] [> 30 mm/h] have severe UC.
Only one additional criterion in addition to the bloody stool fre- Refractory proctitis may require treatment with systemic
quency ≥ 6/day is needed to define a severe attack.3,4 In practice, a steroids, immunosuppressants, and/or biologics [EL4]
C-reactive protein [CRP] of 30 mg/l can be substituted for the ESR.
Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved.
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770 M. Harbord et al.
Topical mesalamine [5-aminosalicylic acid or 5-ASA] is the first-

line therapy for proctitis. A Cochrane systematic review of 38 clini- ECCO statement 11D
cal trials of treatment of proctitis and left-sided colitis confirmed
Systemic corticosteroids are appropriate in patients with
its superiority over placebo for inducing symptomatic, endoscopic,
moderate to severe activity and in those with mild activity
histological response and remission.5 The pooled odds ratio [OR]
who do not respond to mesalamine [EL1]. Oral beclometh-
was: 8.3 for symptomatic remission (8 trials, 95% confidence inter-
asone dipropionate 5 mg/day has similar efficacy and
val [CI] 4.28–16.12; p < 0.00001); 5.3 for endoscopic remission [7
safety profile as oral prednisone in patients with mild
trials, 95% CI 3.15–8.92; p < 0.00001]; and 6.3 for histological
to moderately active ulcerative colitis [EL2]. Budesonide
remission [5 trials, 95% CI 2.74–14.40; p < 0.0001]. Suppositories
MMX 9 mg/day can be considered in patients with mild
are more appropriate than enemas in proctitis as they better target
to moderate disease who are intolerant or refractory to
the site of inflammation and are more acceptable for patients.6 There
aminosalicylates [EL2]. Severe left-sided colitis is an indi-
is no dose response for topical therapy above a dose of 1 g 5-ASA
cation for hospital admission [EL1]
daily.5,7 Once-daily topical therapy is as effective as divided doses.8,9
A meta-analysis found no difference between oral and topical
5-ASA for induction of remission (risk ratio [RR] for no remission Combined oral and topical 5-ASA is the first-line therapy for mild to
with topical 5-ASA: 0.82, 95% CI 0.52–1.28) or time to remis- moderately active left-sided colitis, with an RR of failure to achieve
sion [24.8 vs 25.5 days, respectively], but the trials included in this remission of 0.65 [95% CI = 0.47–0.91] and shorter time to remis-
meta-analysis enrolled patients with UC of any extent, not specifi- sion [11.9 vs 25.5 days; p = 0.002], as compared with oral 5-ASA
cally proctitis.10 In the single trial that included only patients with alone.10 However, either oral or topical 5-ASA alone is more effective
proctitis, rectal 5-ASA was more effective than oral 5-ASA alone.11 than placebo.5,10,19 Topical therapy achieves higher rectal mucosal
However, if oral 5-ASA is used alone, 3.6 g of a pH-dependent 5-ASA concentrations than oral therapy.20 No statistical differences
release preparation appears to be more effective than lower doses were found between foam and liquid enemas regarding induction of
or placebo.12 Moreover in patients with proctosigmoiditis, 5-ASA remission21 or endoscopic healing,7 so either are appropriate treat-
granules rather than tablets are more likely to obtain clinical [78% ments for left-sided UC. Low-volume enemas are not inferior to
vs 55%, p < 0.001] and endoscopic [67% vs 43%, p < 0.001] high-volume enemas and may be better tolerated.22 Although several
remission.13 meta-analyses have confirmed the superiority of rectal 5-ASA over
The combination of oral and topical 5-ASA is more effective than rectal corticosteroids,5,16 a meta-analysis of three trials has suggested
either alone in patients with disease extending < 50 cm from the that rectal beclomethasone diproprionate is equivalent to rectal
anal verge,14 although there is no trial of combination therapy for 5-ASA.2. Evidence exists that 2 g budesonide rectal foam alone is
proctitis alone. Combining topical 5-ASA and topical steroids also able to induce remission at Week 6 for mild to moderate left-sided
helps: beclomethasone dipropionate [3 mg] and 5-ASA [2 g] enemas UC.18 Combination trials with oral and/or rectal 5-ASA and 2 g
produced significantly better clinical, endoscopic, and histological budesonide foam or enemas are needed.
improvement than either agent alone.15 Oral 5-ASA is no more effective than oral sulphasalazine [RR for
Two meta-analyses have shown that topical 5-ASA is more effec- failure to achieve remission 0.90, 95% CI 0.77–1.04] but is better
tive than topical steroids, whether assessing symptomatic, endo- tolerated [RR for an adverse event 0.48, 95% CI 0.36–0.63].24 There
scopic, or histological remission.16 Consequently topical steroids is no difference in efficacy or adherence between once-daily and
should be prescribed to patients who have an inadequate response, divided doses of 5-ASA25,26 nor between the various 5-ASA formula-
or who are intolerant to topical 5-ASA.17 A randomised trial has tions.24,27 It was acknowledged, however, that once-daily dosing is
shown that 2 g budesonide rectal foam alone is more successful than likely to improve compliance outside the clinical trial environment;
placebo in inducing remission at Week 6 in patients with mild to ≥ 2 g/day oral 5-ASA induces remission more effectively than lower
moderate proctosigmoiditis [41.2% vs 24%, p < 0.0001].18 This doses [RR for failure to achieve remission at Weeks 4–8 of 0.91,
drug has not been compared with topical 5-ASA. 95% CI 0.85–0.98].19 Patients with moderate disease may benefit
Compliance and endoscopic activity should be confirmed in those from the higher dose of 4.8 g/day.24
with failure to improve with oral plus topical 5-ASA and/or topical The threshold for the introduction of oral steroids in patients
steroids. Refractory proctitis may require treatment with systemic with mild to moderate left-sided UC depends upon the response
steroids, immunomodulators [IMs], or biologics. The management to and tolerance of 5-ASA, patient’s preference and the physician’s
of refractory proctitis is discussed in section 11.2.7. practice. In the ASCEND II trial, the median time to cessation of
rectal bleeding was 9 days in patients receiving 4.8 g 5-ASA/day
11.2.2. Left-sided ulcerative colitis and 16 days in those receiving 2.4 g/day28; it was 7 days for 4.8 g/
day MMX 5-ASA, although 37–45 days of therapy were required
before sustained complete remission was achieved.29,30 Therefore,
ECCO statement 11C
if a patient’s symptoms deteriorate, rectal bleeding persists beyond
Mild to moderately active left-sided ulcerative colitis 10–14 days, or sustained relief from all symptoms has not been
should initially be treated with an aminosalicylate enema achieved after 40 days of appropriate 5-ASA therapy, additional
≥ 1 g/day [EL1] combined with oral mesalamine ≥ 2.4 therapy with oral systemic steroids should be started. However,
g/day [EL1], which is more effective than oral or topical open-label data suggested that a significant proportion of patients
aminosalicylates, or topical steroids alone [EL1]. Topical who have not responded to 8 weeks’ oral 5-ASA may enter clinical
mesalamine is more effective than topical steroids [EL1]. remission after a further 8 weeks of 4.8 g MMX 5-ASA, irrespective
Once-daily dosing with mesalamine is as effective as of the initial dosing regimen.31
divided doses [EL1] Oral beclomethasone dipropionate is non-inferior, but not
better tolerated, than prednisone after 4 weeks’ treatment.32 Oral

on 20 February 2018
Consensus on Diagnosis and Management of Ulcerative Colitis 771
non-MMX budesonide does not appear to be efficient in the treat- based solely on faecal calprotectin > 50 mg/kg, in patients in clinical
ment of UC.33,37 Two phase 3 randomised controlled trials (RCTs) remission.43
(Core I and Core II)34,35 have compared oral budesonide MMX Evidence for the superiority of oral corticosteroids over 5-ASA
9 mg/day with placebo in patients with mild to moderate left-sided comes from two early studies in active UC, which included patients
and extensive UC. The 8-week combined clinical and endoscopic with extensive colitis.44,45 An appropriate regimen for moderately
remission rates were 20.3% vs 3.2% (P = 0.0018); and endoscopic active disease is prednisolone 40 mg/day for 1 week, lowering
healing rates were 27.6% vs 17.1% (P = 0.009), for budesonide the daily dose by 5 mg each week, resulting in an 8-week course.
MMX and placebo, respectively.36 In the Core I trial, budesonide Shorter courses [< 3 weeks] are associated with early relapse and
MMX was also compared with oral Asacol at a dose of 2.4 g/ starting doses of prednisolone ≤ 15 mg/day are ineffective for active
day, and no difference was found.34 In the Core II trial, budeso- disease.46
nide MMX was also compared with non-MMX budesonide, and Second-generation corticosteroids [e.g. with a colonic release
no difference was found35─although the study was not adequately mechanism and low systemic bioavailability] are an alternative to
powered to do so. Subgroup analysis of both trials demonstrated conventional preparations. Oral beclomethasone dipropionate [5 mg
that the benefit of budesonide MMX is confined to left-sided dis- daily for 4 weeks, then alternate weekly for a further 4 weeks] is
ease and not extensive colitis.36 A randomised trial has compared non-inferior with a safety profile similar to prednisone [40 mg daily
oral budesonide MMX with placebo in patients with mild to for 2 weeks, then tapered by 10 mg every 2 weeks] in a recent 8-week
moderately active UC inadequately controlled with oral 5-ASA. RCT.32 A study of 177 patients with active left-sided or extensive UC
Budesonide MMX 9 mg/day induced clinical, endoscopic, and reported that oral beclomethasone dipropionate 5 mg/day had an
histological remission at Week 8 more frequently than placebo,38 effect similar to that of 2.4 g 5-ASA,47
providing evidence for an alternative therapy to escalating to The efficacy of oral, non-colonic release budesonide for active UC
conventional steroids. However, there has been no head-to-head was the subject of a previous Cochrane database systematic review
comparative trial between budesonide MMX and conventional of three trials. Budesonide was less likely to induce clinical remis-
steroids.39 sion than oral 5-ASA [RR 0.72, 95% CI 0.57–0.91], with no benefit
over placebo [RR 1.41, 95% CI 0.59–3.39].33 This review has been
11.2.3. Extensive ulcerative colitis updated,48 supporting the use of budesonide MMX predominantly
in left-sided UC, and as adjunctive treatment to 5-ASA; studies with
ECCO statement 11E improved power are needed to assess standard formulation budeso-
Mild to moderately active extensive ulcerative colitis nide in active UC. Two phase 3 induction trials of the novel MMX
should initially be treated with an aminosalicylate enema 9-mg budesonide preparation also failed to demonstrate a benefit
1 g/day [EL1] combined with oral mesalamine ≥ 2.4 g/ over placebo in mild to moderate extensive UC, as opposed to sig-
day [EL1]. Once-daily dosing with mesalamine is as effec- nificant efficacy in left-sided colitis.34–36
tive as divided doses [EL1]. Systemic corticosteroids are There is some evidence for a therapeutic benefit of probiotics
appropriate in patients with moderate to severe activity when added to standard therapy to induce remission,49 particu-
and in those with mild activity who do not respond to larly VSL#3.50 However, two meta-analyses showed significant
mesalamine [EL1]. Severe extensive colitis is an indica- heterogeneity between the nine and three trials evaluated, respec-
tion for hospital admission for intensive treatment [EL1] tively. Earlier meta-analyses failed to demonstrate this beneficial
effect.51,52
Three small RCTs have reported on faecal transplantation [FT]
As the majority of clinical trials in mild to moderate UC include in active UC. More patients reached remission with FT than with
patients with both extensive and left-sided colitis, much of the evi- water enema in one trial.53 In another trial, there was no difference
dence base for this statement is discussed in section 11.2.2. between FT using autologous faeces and that from healthy donors
Oral 5-ASA is clearly more effective than placebo for the induc- administered via nasoduodenal tubes.54 FT modified patients’
tion of remission of mild to moderate extensive UC.19,24 The ben- microbiota, which became more diverse and more similar to those
efit of combining oral and rectal 5-ASA was shown in a trial of of their donors. A third randomised trial has been reported as an
116 patients randomised to oral 5-ASA 4 g/day with a 1-g 5-ASA abstract. A total of 81 patients underwent placebo enemas or FT
enema vs oral 5-ASA with a placebo enema; 64% of the combined from several donors, 5 days a week for 8 weeks; 27% patients
group achieved clinical remission at Week 8 compared with 43% reached steroid-free clinical and endoscopic remission at Week 8
with oral 5-ASA alone [P = 0.03].40 In extensive UC, as in left-sided compared with 8% with placebo [p = 0.02].55 Open-label cross-
UC, oral 5-ASA has similar efficacy to oral sulphasalazine, with a over trials confirmed these findings. These results are encouraging
better safely profile.24 Once-daily 5-ASA is as effective as divided and support the proof of concept for using FT to induce remission
doses,24–26,30,41 irrespective of the 5-ASA formulation24,27 and with no in active UC. Additional studies are warranted in order to define
difference regarding adherence.24 There may be a slight cost advan- the best protocol [e.g. route of administration, preferred donor
tage for once-daily over three-time daily dosing.42 At least 2 g/day characteristics, frequency and duration of treatment] to optimise
oral 5-ASA is more effective than lower doses for inducing remis- efficacy and ensure safety.
sion [RR for failure to achieve remission at Weeks 4–8 of 0.91, 95% There is still insufficient evidence to allow firm conclusions on
CI 0.85–0.98],19 whereas an initial dose of 4.8 g/day for moder- safety and efficacy of helminth therapy in UC.56
ately active UC may be of benefit.24 Failure to respond to 5-ASA is Phosphatidylcholine is a key component of the colonic mucus.
an indication to start oral systemic steroids. Similarly, if a patient Patients with UC have less phosphatidylcholine within their
already receiving 5-ASA ≥ 2 g/day or IMs as maintenance therapy colonic mucus, and therefore a defective mucosal barrier func-
has a relapse, treatment with steroids can be appropriate. Current tion. A randomised trial has evaluated the safety and efficacy of
data are still insufficient to recommend 5-ASA dose escalation LT-02, a pharmaceutical compound that contains at least 94% of

on 20 February 2018
phosphatidylcholine.57 This trial included 175 patients with 5-ASA- A UK-wide audit of severe acute UC has shown that second-line
refractory UC [most of whom had left-sided or extensive colitis], medical therapy with IFX or CsA is not associated with a higher
randomised into four arms: one placebo and three different doses of mortality. In the same study, mortality was significantly higher in
LT-02. Although the differences in remission and endoscopic healing individuals older than 60 and in those with comorbidities.68
rates between placebo and pooled LT-02 arms were not statistically
significant [p = 0.089 and 0.098, respectively], the rates for histologi- 11.2.4.2. Conventional therapy
cal remission were 20% and 40.5%, respectively, [p = 0.016].
Andrographis paniculata is a herbal remedy with inhibitory
ECCO statement 11G
activity against tumour necrosis factor [TNF], interleukin [IL]1β,
and nuclear factor-kappa-B. An RCT58 evaluating safety and effi- Initial recommended treatment for severe active ulcera-
cacy in 224 patients with mild to moderate active UC demonstrated tive colitis is intravenous steroids [EL1]. Monotherapy
improved clinical response and endoscopic healing at Week 8 in with intravenous ciclosporin [EL2] is an alternative espe-
patients who received 1800 mg of Andrographis paniculata as com- cially in cases of serious adverse events due to steroids.
pared with placebo [p = 0.0183 and p = 0.0404, respectively]. All patients should receive adequate volume of intrave-
Another RCT studied the efficacy of intra-rectal oligonucleotide nous fluids, and low-molecular-weight heparin for throm-
TLR-9 agonist in 131 patients with active UC. The primary end- boprophylaxis; electrolyte abnormalities and anaemia
point, remission at Week 12, was obtained in 44.4% and 46.5% should be corrected, if needed [EL5]. Patients are best
of patients randomised to the experimental and placebo groups, cared for jointly by a gastroenterologist and a colorectal
respectively. However, the proportions of patients who reached surgeon [EL5]
symptomatic remission and mucosal and histological healing as well
as remission at Week 4 were significantly higher in patients who Corticosteroids are given intravenously using methylprednisolone
received the TLR-9 agonist.59 60 mg each 24 h or hydrocortisone 100 mg four times daily. Higher
Interferon-γ-inducible protein-10 [IP-10] regulates homing of doses are no more effective, but lower doses are less effective.4,69
immune cells within the inflammed colon, and decreases survival of Bolus injection is as effective as continuous infusion.70 Treatment
gut epithelial cells. IP-10 blockade increases survival of crypt cells and should be given for a defined period, as extending therapy beyond
reduces inflammation in animal models of UC. An RCT has assessed the 7 to 10 days carries no additional benefit.4 A systematic review of
safety and efficacy of eldelumab, a monoclonal antibody against IP-10 32 trials of steroid therapy for acute severe colitis, involving 1991
in 252 UC patients. Remission and response rates were not significantly patients from 1974–2006, reported an overall response to steroids
different between experimental and placebo arms. However, trends [intravenous hydrocortisone, methylprednisolone, or betametha-
towards higher remission and response rates were observed in patients sone] of 67% [95% CI 65–69%].4 Out of the 1991 patients, 565
randomised to eldelumab, particularly in anti TNF-naive patients.60 [29%, 95% CI 28–31%] came to colectomy. Mortality was 1%
It is too early to recommend the use of FT, helminths, LT-02, [22/1991, 95% CI 0.7–1.6%] and none of these outcomes changed
Andrographis paniculata, TLR-9 agonist, or eldelumab in clinical between 1974 and 2006 [R2 = 0.07, p = 0.8]. Because of substantial
practice. Further clinical trials are warranted. heterogeneity, it was not possible to discriminate between complete
and partial responsiveness to steroids.
11.2.4. Severe ulcerative colitis A small RCT demonstrated that 4 mg/kg/day IV CsA monother-
apy was as effective as IV methylprednisolone 40 mg/day for acute
ECCO statement 11F severe UC.71 Half of all patients in another study comparing low-dose
with high-dose CsA72 also received CsA monotherapy, without the
Patients with bloody diarrhoea ≥ 6/day and any signs of need for concomitant IV steroids. Consequently monotherapy with
systemic toxicity (pulse > 90 min–1, temperature > 37.8°C, 2 mg/kg/day CsA [thereafter adjusted based on serum concentration]
haemoglobin < 105 g/l, erythrocyte sedimentation rate is a useful option in those patients with severe UC who should avoid
[ESR] > 30 mm/h, or C-reactive protein [CRP] > 30 mg/l) steroids, such as those susceptible to steroid psychosis, patients with
have severe colitis and should be admitted to hospital for concomitant osteoporosis, or those with poorly controlled diabetes.
intensive treatment [EL4]. Patients with comorbidities or > Other measures that are considered appropriate in addition to
60 years old have a higher risk of mortality [EL3] IV steroids include:
11.2.4.1. Therapeutic approach • IV fluid and electrolyte replacement to correct and prevent dehy-
All patients admitted with severe UC require appropriate investi- dration and electrolyte imbalance. Potassium supplementation
gations to confirm the diagnosis and exclude enteric infection.61 of at least 60 mmol/day is usually necessary. Hypokalaemia or
Intravenous [IV] corticosteroids remain the mainstay of conven- hypomagnesaemia can promote toxic dilatation;73
tional therapy.62 It is essential to ensure that therapeutic alternatives • unprepared flexible sigmoidoscopy and biopsy to confirm the
for the rescue of steroid-refractory disease (ciclosporin [CsA], tac- diagnosis and exclude cytomegalovirus infection74,75 which
rolimus, or infliximab [IFX]) are considered early [on or around Day is associated with a steroid-refractory disease course76,77 and
3 of steroid therapy] and that the decision making process is not requires appropriate treatment;78
delayed. Patients remaining on ineffective medical therapy including • stool cultures and assay for co-existing Clostridium difficile toxin,
corticosteroids suffer a high morbidity associated with delayed sur- which is more prevalent in patients with severe UC and is associ-
gery.63–67 Therefore, it is essential to identify at an early stage patients ated with increased morbidity and mortality.68,79–86 If detected, oral
likely to require colectomy, and to decide when to start rescue medi- vancomycin should be administered87 and faecal microbial trans-
cal therapy. The two are not mutually exclusive and management plant considered.88 Immunosuppressive therapy should be stopped
requires careful clinical judgement. if possible,89 although this may not always be warranted;90

on 20 February 2018
• subcutaneous prophylactic low-molecular-weight heparin to mandate surgical consultation and assessment by a stoma therapist
reduce the risk of thromboembolism, which is increased in if this has not already occurred. Genetic polymorphisms have limited
patients with inflammatory bowel disease [IBD], especially dur- potential to predict disease outcomes, and cannot be used for deci-
ing a disease flare; and is not related to other thromboembolic sion making when colectomy is imminent.107 Criteria are as follows.
risk factors;91–94
• Clinical markers. A stool frequency > 12/day on Day 2 of IV
• nutritional support if the patient is malnourished. Enteral nutri-
corticosteroids was associated with a colectomy rate of 55%,108
tion is most appropriate and associated with fewer complications
whereas a frequency > eight/day, or between three and eight
than parenteral nutrition in acute colitis [9% vs 35%].95 Bowel
together with a CRP > 45 mg/l on Day 3, predicted colectomy in
rest through IV nutrition does not alter outcomes;96
85% during that admission: known as the Oxford Criteria.3 This
• withdrawal of anticholinergic, anti-diarrhoeal, non-steroidal
index is more widely used than the Sweden Index.109 UK IBD
anti-inflammatory, and opioid drugs, which may risk precipitat-
audit data suggest that colectomy may not be so common, occur-
ing colonic dilatation;97–101
ring in only one-third of those with high scores using the Oxford
• topical therapy [corticosteroids or 5-ASA] if tolerated and
criteria.110
retained, although there have been no systematic studies in acute
• Biochemical markers. An ESR > 75 mm/h or a body temperature
severe colitis;62
> 38°C on admission was associated with a 5 to 9-fold increase
• antibiotics, only if infection is considered [such as in a first
in the need for colectomy in a prospective study of 67 patients.111
attack of short duration; after recent admission to hospital; or
In this study, lack of response to steroids was predicted by < 40%
after travel to an area where amoebiasis is endemic], or imme-
reduction in stool frequency within 5 days. Nevertheless, patients
diately prior to surgery. Controlled trials of oral or IV metroni-
[and their doctors] prefer to know an absolute estimate of the
dazole, tobramycin, ciprofloxacin, or vancomycin in acute UC
likelihood of colectomy, rather than relative measures.
have shown no consistent benefit in addition to conventional
• Radiological/endoscopic criteria. These include the presence
therapy;102–104
of colonic dilatation > 5.5 cm or mucosal islands on a plain
• blood transfusion to maintain a haemoglobin above 8–10 g/dl;105
abdominal radiograph [both associated with colectomy in
• an essential multidisciplinary approach between gastroenterolo-
75%].108 A retrospective study reported that the presence of an
gists and colorectal surgeons.
ileus [indicated by three or more small bowel loops of gas] was
associated with colectomy in 73% of patients.112 The depth of
11.2.5. Intravenous steroid-refractory ulcerative colitis of any extent colonic ulceration after gentle air insufflation identified 42/49
patients with deep ulcers that were associated with the need
ECCO statement 11H for colectomy,113 but this is not widely used in clinical prac-
tice. Several studies have shown that endoscopic appearance at
The response to intravenous steroids should be best admission may also predict the need for colectomy.114,115 In a
assessed by the third day [EL3]; in non-responders, study from Oxford, 13/14 patients with acute severe UC and
treatment options including ciclosporin [EL1], infliximab an ulcerative colitis endoscopic index of severity score of 7 or 8
[EL1], tacrolimus [EL2], or surgery should be considered. needed rescue therapy with IFX or CsA, colectomy, or readmis-
Colectomy is recommended if there is no improvement sion.116 Deep ulcerations, the most severe endoscopic lesions, are
following 4–7 days of salvage therapy [EL4] located in the distal part of the colon and can be detected by a
sigmoidoscopy.115 Therefore, complete colonoscopy is not neces-
Over the recent past, clinical trials of different salvage therapies sary, and carries an increased risk of perforation in patients with
for patients with severe UC refractory to IV steroids have been severe UC.
published. However, it is important that physicians do not acqui- • Combined clinical, biochemical, and radiological/endoscopic
esce with the patient’s understandable desire to delay surgery with criteria. A retrospective study of 85 patients, including 30
inappropriate or unduly prolonged courses of therapy, as this will patients who came to colectomy, showed that patients with deep
increase the morbidity and mortality associated with subsequent sur- ulceration on sigmoidoscopy and Truelove and Witts’ criteria had
gery.63,64 Therefore, the important issues that must be considered and a steroid failure rate of 85%.117 Another retrospective study of
discussed with the patient include the following. 167 patients, in whom 40% came to colectomy, enabled develop-
ment of a numerical score combining mean stool frequency over
• Can one predict who will fail to respond to IV corticosteroids 3 days, presence or absence of colonic dilatation, and hypoalbu-
early, so that appropriate salvage therapy can be started in a minaemia [< 30 g/l] on admission, which was associated with the
timely fashion? need for colectomy in up to 85%.117
• Are the available salvage therapies [calcineurin inhibitors or IFX]
equally effective? Are there subgroups of patients in whom one 11.2.5.1. Ciclosporin
strategy is preferred over another? Two RCTs have confirmed the efficacy of CsA in the treatment of
• When should the response to salvage therapy be assessed, and if severe UC.71,118 The study by Lichtiger only included patients who
a patient fails to respond to one salvage therapy should a second had failed IV corticosteroids.118 Nine of 11 patients failing steroids
therapy be commenced? improved on 4 mg/kg/day IV CsA, whereas all nine on placebo
failed to improve [RR 0.18, 95% CI 0.05–0.64]. In a further trial,
Simple, objective measures are needed to aid decision making. 73 patients were randomised to either 2 mg/kg or 4 mg/kg of IV
Factors that predict steroid failure in acute severe colitis can broadly CsA,72 with subsequent dose adjustment based on serum concentra-
be divided into clinical, biochemical, and radiological. Scoring sys- tion. Response rates at Day 8 were similar in both groups [83%
tems in clinical practice use a combination of clinical and biochemi- and 82%, respectively], with 9% coming to colectomy in the 2-mg/
cal markers3 [for a review, see106]. These predictive indices should kg group and 13% in the 4-mg/kg group. Although not all patients

on 20 February 2018
were failing IV corticosteroids at entry, a starting dose of 2 mg/kg/ severe disease randomised at Day 3. An earlier pilot study and a ret-
day has become the standard dose used in clinical practice. Pooling rospective review of IFX for acute severe colitis refractory to steroids
results from controlled and non-controlled clinical trials, between have shown variable results.132,133 Long-term follow-up of patients in
76% and 85% of patients will respond to IV CsA and avoid colec- the RCT revealed a colectomy rate at 3 years of 12/24 [50%] patients
tomy in the short term.71,72,118–120 Of 135 steroid-refractory patients given IFX and 16/21 [76%] given placebo [without maintenance
started on CsA at 2 mg/kg in the randomised controlled Comparison IFX being provided] [p = 0.012], although use of thiopurine therapy
Of iNfliximab and CsA in STeroid Resistant Ulcerative Colitis was not controlled and differed between groups.134 A retrospective
[CONSTRUCT] trial, colectomy rates were 25% in hospital, 30% multicentre study of 211 steroid-refractory patients receiving IFX
by 3 months, and 45% by 12 months.121 These suggest a median therapy reported colectomy rates of 36%, 41%, and 47% after 1, 3,
time to response of 4 days, which allows timely colectomy in non- and 5 years, respectively, from therapy initiation.135 Of 135 steroid-
responders.72 However, the narrow therapeutic index of CsA and refractory patients started on IFX in the recent CONSTRUCT study,
its side effect profile [including mortality rates of 3–4%] has lim- colectomy rates were 21% in hospital, 29% by 3 months, and 35%
ited acceptability, such that in the 2008 UK National IBD audit only by 12 months.121 Case series report 20% to 75% colectomy rates
24% of patients admitted with steroid-refractory severe UC received after IFX for IV steroid-refractory UC.133,136–141
CsA. A Cochrane review122 concluded that numbers in controlled tri- Several studies have assessed predictors of response to IFX in
als were so few that there was limited evidence for CsA being more patients with severe and/or corticosteroid-refractory disease. At
effective than standard treatment alone for severe UC. admission, high CRP level, low serum albumin, perinuclear anti-neu-
In two series, 58% of 76 patients123 and 88% of 142 patients120 trophil cytoplasmic antibody seropositivity, and severe endoscopic
who had received CsA, came to colectomy over 7 years. A single- lesions are associated with subsequent colectomy or relapse.141,142
centre review of the long-term outcome of 71 patients treated with Short-term [i.e. Weeks 10 to 14] complete clinical response, endo-
IV CsA for severe colitis reported that successful transition to an oral scopic healing, and serum IFX level above 2.5 ug/ml at Week 14,
thiopurine was a significant factor in preventing future colectomy predict colectomy-free and relapse-free survival.88 Low serum IFX
[OR 0.01, 95% CI 0.001–0.09; p < 0.0001].124 Successful transition concentrations [median 2.9 ug/ml] at Week 6 has been associated
to thiopurine therapy and being thiopurine-naïve at baseline have with primary non-response.143 A study found that IFX is lost in stools
been confirmed as factors that reduce the risk of long-term colec- of patients with UC and that high faecal concentration of IFX in the
tomy in this patient group.120,125,126 Patients who have UC refractory first days after therapy initiation is associated with primary non-
to adequate thiopurine therapy may therefore be less suitable candi- response.144 Serum IFX levels at 2 weeks are lower in acute severe
dates for CsA rescue therapy. compared with moderately severe UC, although it is not known
whether intensified induction is associated with better outcomes.145
11.2.5.2. Tacrolimus The therapeutic regimen also appears to influence the response
Tacrolimus is a calcineurin inhibitor that acts via a mechanism simi- to IFX. A retrospective study of 83 patients suggests that patients
lar to CsA. One RCT of two tacrolimus dosing strategies has shown receiving a single infusion are more likely to require colectomy at
significant benefit over placebo in patients with UC.127 This included 2 months than those who receive two or more infusions [9/26 com-
27/60 patients with severe colitis. No patient entered complete pared with 3/57; p = 0.001, OR = 9.53].146 A multi-centre study con-
remission in any group. A partial response was seen in: 67% [4/6] of cluded that a three-dose induction regimen is the treatment of choice
patients on tacrolimus adjusted to trough levels 10–15 ng/ml; 50% for preventing early colectomy in severe steroid-refractory UC.142
[5/10] of patients on tacrolimus adjusted to trough levels 5–10 ng/ A small retrospective study has reported that an accelerated IFX
ml; and 18% [2/11] of patients on placebo (p = nonsignificant [ns]). induction strategy [median period of 24 days] was associated with a
This study was underpowered to detect a difference in patients with reduction in the need for early colectomy in 50 hospitalised patients
severe colitis. In a 2-week RCT conducted in 62 patients, oral admin- with acute severe UC.147 Finally, thiopurine-naïve status was protec-
istation of tacrolimus was significantly more effective than placebo tive from colectomy in a cohort of steroid-dependent UC patients
to induce remission and endoscopic healing in patients with steroid- treated with IFX plus azathioprine.148
refractory UC.128 A recent systematic review and meta-analysis has
combined the data of these two trials and those of observational 11.2.5.4. Selection between calcineurin inhibitors and infliximab
studies; it demonstrated that clinical response at 2 weeks was signifi- The open-label CYSIF trial randomised 111 thiopurine-naive patients
cantly higher with tacrolimus than with placebo [RR = 4.61, 95% with severe colitis [Lichtiger score > 10] despite 5 days of IV steroids,
CI = 2.09–10.17; p = 0.15 × 10−3]. Colectomy-free rates at 1, 3, 6, to IV CsA 2 mg/kg/d for 8 days [levels 150–250 ng/ml] followed
and 12 months were 0.86, 0.84, 0.78, and 0.69, respectively.129 The by 4 mg/kg/day oral therapy, or IFX 5 mg/kg at Weeks 0, 2, and
long-term cumulative colectomy-free survival in patients with UC 6.149 All responders at Day 7 received oral azathioprine and tapered
treated with tacrolimus has been reported to be 57% at 44 months, steroids from Day 8. The trial was initially powered to demonstrate
although this included a very heterogeneous population.130 less treatment failure with CsA than IFX between Days 7 and 98
[lack of response at Day 7, relapse between Days 7 and 98 defined
11.2.5.3. Infliximab as lack of steroid-free remission at Day 98, colectomy, or treatment
Infliximab as a single dose [5 mg/kg] is an effective salvage therapy interruption before Day 98]. Approximately 85% patients in both
in patients with severe UC refractory to IV steroids. A pivotal RCT groups responded to treatment by Day 7. Treatment failure at Day
included 45 patients [24 receiving IFX and 21 receiving placebo] 98 [the primary endpoint] was reported in 60% patients in the CsA
who were all initially treated with IV betamethasone.131 Colectomy arm compared with 54% patients in the IFX arm [treatment differ-
rates at 3 months were significantly lower in patients receiving IFX ence 6.4%, 95% CI 12–24.8%; p = 0.49]. The colectomy rate by
compared with placebo [7/24 vs 14/21: p = 0.017; OR 4.9, 95% Day 98 in the CsA vs the IFX group was 18% vs 21% [p = 0.66].149
CI 1.4–17]. Patients with less active disease who were randomised Serious adverse events were not significantly different between IFX
after 5–7 days of IV steroids benefited more than patients with more and CsA [17/56 on IFX vs 9/55 on CsA]. The CONSTRUCT trial

on 20 February 2018
found no significant difference regarding quality of life, colectomy, 11.2.6.2. Perforation, haemorrhage and thromboembolism
mortality rates, or the occurence of serious infections in 270 patients Perforation is the most serious complication of acute severe colitis
with acute severe steroid-resistant UC treated with CsA or IFX.121 and can be associated with inappropriate total colonoscopy or toxic
A meta-analysis of six retrospective studies also found comparable dilatation where colectomy has been inappropriately delayed. It car-
remission rates in patients with acute severe steroid-refractory UC ries a mortality of up to 50%.97 Other complications include mas-
receiving CsA or IFX.150 Finally, length of hospital stay and in-hospi- sive haemorrhage, and thromboembolism including cerebral sinus
tal costs have been reduced, but total treatment cost increased since thrombosis.91,92
the introduction of IFX as rescue therapy compared with CsA.151
Therefore, the choice between options for salvage therapy should 11.2.6.3. Long-term outcome of severe colitis
be individualised. Intravenous CsA should be avoided in patients There is evidence that achieving complete clinical remission dur-
with a low cholesterol or magnesium in view of the increased inci- ing the index hospital admission improves long-term outcome and
dence of neurological side effects in this patient group. If a patient delays the need for colectomy.163 Patients needing CsA for acute
has acute severe colitis despite existing treatment with an IM at an severe colitis, who are naïve to IM therapy and successfully tran-
appropriate dose and duration, it is important to consider whether sition to thiopurine maintenance therapy, are less likely to require
current therapies maintaining long-term remission are suitably effec- colectomy during long-term follow-up.120,124,125 Unsurprisingly, irre-
tive, recognising that new therapies may become available during the spective of whether CsA or IFX is used as salvage therapy, patients
next few years.152 Prolonged use of corticosteroids is an important with clinical, biochemical, or endoscopic evidence of more severe
risk factor for postoperative complications after colectomy.153 One disease at presentation are more likely to require colectomy.164
small series reported that CsA did not increase the risk of compli-
cations after colectomy.154 In contrast, there is ongoing debate as 11.2.7. Refractory proctitis and distal colitis
to whether IFX increases the risk of surgical complications,153,155–159 It is important to identify the aetiology of refractory disease. One
although one report of 108 patients found no association between explanation is that the disease is refractory to medication being pre-
rescue therapy and postoperative complications.160 scribed. However, alternative explanations include:
1] poor adherence to prescribed therapy;

11.2.5.5. Third-line medical therapy 2] delivery of an inadequate concentration of the active drug to the
In general, only a single attempt at rescue therapy with a calcineurin inflamed mucosa;
inhibitor or IFX should be considered before referral for colectomy. 3] unrecognised complications [such as proximal constipation or
Sequential rescue therapy has been assessed by a systematic literature infection];
review that included 10 studies and 314 participants.161 Short-term 4] inappropriate diagnosis [e.g. irritable bowel syndrome, Crohn’s
response and remission rates were 62.4% and 38.9%, respectively. disease [CD], mucosal prolapse, cancer].
Colectomy rates were 28.3% at 3 months and 42.3% at 12 months.
Adverse events occurred in 23% of patients, including serious infec- Therefore, the initial step is to review current symptoms, treatment
tions in 6.7% and mortality in 1%. These results may suggest that history, and adherence to medical therapy. This should be followed
the risk of sequential therapy in steroid-refractory UC is acceptable. by reassessment of the diagnosis by stool culture, endoscopy, and
However, the evidence is poor. No recommendation for [or against] biopsy. The next step is to ensure that conventional therapy [sections
the use of sequential rescue therapy can be made on the basis of 11.2.1 and 11.2.2] has been used appropriately. Attention should
the available data. Third-line medical therapy can be considered in focus on the formulation of topical therapy and whether it was used
specialist referral centres in highly selected cases, after careful discus- in conjunction with an adequate dose of oral therapy. An abdominal
sion between the patient, gastroenterologist, and colorectal surgeon. X-ray can be useful to diagnose proximal constipation, since abnor-
Additional antibiotic therapy has been assessed in an open-label mal intestinal motility induces proximal colonic stasis in patients
study based upon 30 UC patients. Treatment with amoxicillin, tet- with distal colitis, which may affect drug delivery.165 If there is visible
racycline, and metronidazole for 2 weeks appeared to be effective faecal loading, a laxative should be considered.
in steroid-refractory UC162; however, an earlier, blinded RCT in 39 Patients with endoscopically documented active distal colitis or
patients with acute severe colitis demonstrated no benefit from met- proctitis, who fail oral corticosteroids combined with oral and rectal
ronidazole and tobramycin.103 5-ASA therapy, have refractory disease. Therapeutic options include
admission for IV steroid therapy, which has been reported to induce
11.2.6. Toxic dilatation and complications of severe ulcerative remission in a high proportion of patients.166 Alternatively, there is
colitis open-label evidence, often from retrospective case reviews, support-
11.2.6.1. Toxic megacolon ing the use of salvage medical therapies such as oral or rectal CsA,
Toxic megacolon is defined as total or segmental non-obstructive oral or rectal tacrolimus, or IFX.167–171
dilatation of the colon ≥ 5.5 cm, associated with systemic toxicity.97 If disease persists, surgery is likely to be the outcome. RCTs have
Risk factors include hypokalaemia, hypomagnesaemia, bowel prep- suggested a benefit of short-chain fatty acid enemas,172,173 although
aration, and the use of anti-diarrhoeal therapy.97 Earlier diagnosis difficulties with production and availability limit their use. Small
of severe colitis, more intensive medical management, and earlier open-label trials have suggested benefit from alternative topical
surgery have reduced the incidence and mortality of toxic megaco- therapies such as lidocaine enemas, arsenic suppositories, epider-
lon complicating UC. In addition to IV hydrocortisone, empirical mal growth factor enemas, alicaforsen enemas, and transdermal
treatment with oral vancomycin should be considered until stool is nicotine patches.174–178 Retrospective cohort studies have suggested
confirmed negative for C. difficile toxin. An opinion from an experi- that appendicectomy may improve patients with refractory procti-
enced colorectal surgeon is required on the day of admission. There tis.179–182 Up to 10% of patients who have a colectomy for refractory
is a limited window of opportunity for medical treatment to work UC only have distal colitis. The outcome of colectomy and pouch
and, without rapid improvement, early colectomy will be necessary. formation for distal UC is usually good.183

on 20 February 2018
11.3. Treatment according to the course or behaviour at Week 6 were then re-randomised to receive maintenance treat-
of disease ment with either placebo or golimumab; 51.5% of patients entered
11.3.1. Steroid-dependent active ulcerative colitis PURSUIT-M on corticosteroids, including 36% on ≥ 20 mg/day
prednisolone. Specifically for those patients entering PURSUIT-M
ECCO statement 11I receiving corticosteroids, 34.4% of those treated with golimumab
and 20.7% who received placebo achieved steroid-free remission by
Patients with steroid-dependent disease should be treated Week 54 [p = 0.024].189
with a thiopurine [EL2], anti-TNF [EL1] [preferably com- Taken together, all these anti-TNF agents are more effective
bined with thiopurines, at least for infliximab [EL2]], than placebo in obtaining and maintaining steroid-free remission in
vedolizumab [EL2], or methotrexate [EL2]. In case of treat- those receiving corticosteroids at baseline. An important considera-
ment failure, second-line medical therapy with an alterna- tion is the utility of combination therapy with anti-TNF and IM.
tive anti-TNF [EL4], vedolizumab [EL2], or colectomy [EL5] The UC-SUCCESS trial suggests that a combination of IFX plus
should be considered azathioprine is more effective than using IFX alone.191 This was a
16-week, randomised, double-blind, controlled trial in biologic-
Azathioprine is significantly more effective than 5-ASA at achieving naïve patients with moderate to severe UC, who were largely naïve
clinical and endoscopic remission in steroid-dependent UC. In an to IM. Corticosteroid-free remission at Week 16 was achieved by
open-label trial, 72 patients were randomised to receive azathioprine 39.7% [31 of 78] patients receiving IFX/azathioprine, compared
2 mg/kg/day or oral 5-ASA 3.2 g/day, in addition to prednisolone with 22.1% [17 of 77] receiving IFX alone [p = 0.017] and 23.7%
40 mg/day;184 53% of patients receiving azathioprine achieved ster- [18 of 76] receiving azathioprine alone [p = 0.032]. Combination
oid-free clinical and endoscopic remission after 6 months compared therapy within RCTs has not been assessed for adalimumab or goli-
with 21% with 5-ASA [OR 4.78, 95% CI 1.57–14.5]. In addition, mumab or in IM-exposed patients [see section 11.3.3].
an open label observational cohort study in 42 steroid-dependent Another important question is the efficacy of a second anti-TNF
patients reported steroid-free remission with azathioprine at 12, 24, after the failure of a first one. In ULTRA-2, the co-primary endpoint
and 36 months of 55%, 52%, and 45%, respectively.185 These stud- of clinical remission at Week 8 was not met in the TNF-failure popu-
ies suggest that thiopurines are efficacious in patients who flare when lation. The other co-primary endpoint of clinical remission at Week
steroids are withdrawn. 52 was achieved in this population [10.2% on adalimumab vs 3.0%
Steroid-free remission was a secondary endpoint of the pivotal on placebo, p = 0.039], although the difference from placebo for this,
trials of anti-TNF in UC. For IFX, the ACT-1 and ACT-2 trials each as well as several other secondary endpoints, was smaller in the TNF-
included 364 patients with endoscopically confirmed moderate/ failure population than in the TNF-naïve population. The secondary
severely active colitis despite treatment with corticosteroids and/ endpoint of corticosteroid-free remission at Week 52 in those patients
or thiopurines [ACT-1], or with corticosteroids and/or thiopurine receiving steroids at baseline was not met in the TNF-failure popula-
and/or 5-ASA [ACT-2]. Participants were all anti-TNF naïve, and tion. A recent meta-analysis has addressed the clinical success rate of
randomised to receive placebo or IFX; 56% of patients entered the a second anti-TNF after the failure of a first one, in patients exposed
combined studies on steroids, including 38% who were taking the [or not] to steroids. Eight UC studies were included, all of them
equivalent of ≥ 20 mg/day prednisolone. For those participants who switched IFX to adalimumab. The response rate ranged from 23%
were receiving corticosteroids at baseline, 21.5% of those receiv- to 92%, whereas the remission rates varied between 0% and 50%.192
ing IFX reached steroid-free remission by Week 30, compared with However, due to heterogeneity in study design, it was not possible to
7.2% of those receiving placebo [p = 0.007].186 Cohort but not estimate the pooling efficacy through a formal meta-analysis.
RCTs have reported on the effectiveness of IFX in steroid-dependent Steroid-free remission was also a secondary endpoint of the
patients.148,187 pivotal trial of vedolizumab in endoscopically confirmed moder-
In ULTRA 2, the pivotal RCT of adalimumab in patients with ate/severely active UC, GEMINI-1.193 Similar to the PURSUIT tri-
moderate to severe UC, 494 adult patients with endoscopically con- als already discussed, GEMINI-1 included an induction trial of 374
firmed moderate/severely active colitis despite treatment with corti- patients, with Week 6 responders then re-randomised to vedoli-
costeroids and/or thiopurines, were randomised to receive 160 mg zumab or placebo during a maintenance phase. Additional induc-
adalimumab at Week 0, 80 mg at Week 2, and then 40 mg every tion responders for the randomised maintenance phase were drawn
other week from Week 4.188 A total of 59% of participants entered from a second cohort who had received open-label vedolizumab
the study receiving corticosteroids and 40% of participants had a induction therapy.193 Participants were refractory to steroids and/or
history of previous anti-TNF failure. In all, 31% of participants who thiopurines and/or anti-TNF therapy. A total of 53.7% of patients
received adalimumab were steroid-free at Week 16 compared with in the GEMINI 1 trial were receiving glucocorticoids at study base-
16% allocated to placebo [p < 0.05]. At Week 52, 13.3% of partici- line and 48% had failed previous anti-TNF therapy. In those who
pants in the adalimumab group, who had been receiving corticoster- were receiving corticosteroids at baseline, and who responded to
oids at baseline, were in steroid-free remission compared with 5.7% induction therapy and were re-randomised to vedolizumab, 38.5%
in the placebo group [p = 0.035]. achieved steroid-free remission at Week 52, compared with 13.9%
The efficacy of golimumab in patients with endoscopically re-randomised to placebo [p < 0.001]. Neither concurrent treatment
confirmed moderate/severely active UC refractory to steroids and/ with corticosteroids, IMs, nor previous treatment with TNF antago-
or 5-ASA and/or thiopurines was established in the PURSUIT tri- nists affected the efficacy of vedolizumab in the induction or mainte-
als.189,190 Participants were all anti-TNF naïve. In these studies, nance phases, suggesting that patients with steroid-dependent disease
assessment of induction and maintenance were uncoupled, with or previous anti-TNF failure have a comparable outcome. A German
a placebo-controlled randomised series of induction trials across cohort study reported that 25% of UC and CD patients were in
different golimumab dosing regimens. In the PURSUIT-M trial, clinical remission by 14 weeks.194 Data on the use of anti-TNF after
464 patients showing evidence of response to induction therapy primary failure of vedolizumab are currently not available.

on 20 February 2018
Methotrexate has been studied in a multicentre trial includ- 2 weeks was significantly higher with tacrolimus than with placebo
ing 111 patients with steroid-dependent UC.195 The primary end- [RR 4.61, 95% CI 2.09–10.17; p = 0.15 × 10–3]. Colectomy-free
point, steroid-free remission at Week 16 [defined as a Mayo score rates at 1, 3, 6, and 12 months were 0.86, 0.84, 0.78, and 0.69,
≤ 2 with no sub-score > 1 and complete withdrawal of steroids], respectively.129 An open study of 100 patients with moderate to
was achieved in 31.7% patients assigned to methotrexate [MTX] severe UC compared tacrolimus and anti-TNF, with similar efficacy
and 19.6% patients who received placebo [p = 0.15]. The rate of and safety outcomes.198
steroid-free clinical remission at Week 16 [defined as a Mayo score Two phase 3 trials have studied the efficacy of oral tofacitinib
≤ 2 with no sub-score > 1] was 41.7% for MTX and 23.5% for [a janus kinase inhibitor, 10 mg twice daily] as induction therapy
placebo [Pp = 0.04]. This trial failed to show that parenteral MTX in 1139 patients with active, moderate to severe UC.199 Included
is beneficial for induction of steroid-free remission in UC. However, patients had failed corticosteroids, azathioprine, or anti-TNF [53–
MTX induced clinical remission without steroids at Week 16 more 58% of patients were previously exposed]. Remission at Week 8 was
frequently than placebo, and was associated with better control of achieved in 18.5% and 16.6% in the tofacitinib arms vs 8.2% and
disease-related symptoms. 3.6% in the placebo arms; both differences were statistically sig-
nificant. Increased serum levels of cholesterol and creatine kinase
11.3.2. Oral steroid-refractory active ulcerative colitis were observed with tofacitinib. It has not yet been licensed for use
in Europe.
ECCO statement 11J Another recent randomised phase 2 trial using ozanimod [a mod-
ulator of the sphingosine-1-phosphate receptor subtypes 1 and 5]
Moderate disease refractory to oral steroids should be showed that 16% of patients who received ozanimod 1 mg/day, and
treated either with intravenous steroids [EL4] or anti-TNF 6% of patients who received placebo, reached clinical remission at
[EL1] preferably combined with thiopurines, at least for Week 8 [p = 0.048].200 Larger studies are needed to study the efficacy
infliximab [EL2], vedolizumab [EL2], or tacrolimus [EL2]. and safety of ozanimod in moderate to severe UC.
Second-line medical therapy with a different anti TNF
[EL4] or vedolizumab [EL2] may be an option; colectomy
11.3.3. Immunomodulator-refractory ulcerative colitis
should also be considered
ECCO statement 11K
In patients with active steroid-refractory UC, other causes of per-
sistent symptoms such as coexistent cytomegalovirus, C. difficile- Patients with moderate colitis refractory to thiopurines
associated disease, or cancer, should be considered. Intravenous should be treated with anti-TNF [EL1], preferably com-
steroids are still an option in patients with confirmed, active steroid- bined with thiopurines, at least for infliximab [EL2], or
refractory UC, even though patients with moderately active UC are vedolizumab [EL2]. In case of treatment failure, a differ-
preferably not treated in hospital. Intravenous steroids have been ent anti-TNF [EL4] or vedolizumab [EL2] should be con-
suggested to be more efficient in a retrospective study involving 110 sidered, and colectomy recommended if further medical
episodes of disease refractory to oral steroids.109,196 However, almost therapy does not achieve a clear clinical benefit [EL5]
half of the patients developed early steroid-dependency in this study.
As already discussed, anti-TNF therapy and vedolizumab have IM-refractory disease is best assessed by endoscopy and biopsy to
shown clear evidence of benefit in patients with corticosteroid confirm the diagnosis and exclude complications. For active UC
dependency, through achievement of corticosteroid-free remission in that is refractory to thiopurines, other causes of persistent symp-
patients receiving steroids at baseline.186,188–190,193,197 All the pivotal toms include coexistent cytomegalovirus or C. difficile-associated
trials included corticosteroid-refractory disease as a potential inclu- disease. A therapeutic strategy to induce and maintain steroid-free
sion criterion and demonstrated efficacy of biologic therapy across a remission should be discussed with the patient. In the absence of
range of endpoints. However, although rates of corticosteroid usage contraindications, biologic therapy should be considered. Infliximab,
at baseline and some dose thresholds were reported, steroid doses adalimumab, golimumab, and vedolizumab have all been evaluated
used before inclusion may have been suboptimal, and it is not always for use in UC refractory to thiopurines. Tofacitinib has also been
possible to differentiate all steroid-dependent or steroid-refractory shown to be effective in this patient population.199,201
patients and assess trial outcomes separately for these groups across The ACT 1 and ACT 2 trials included 334/728 [46%] patients
all trials. with active disease despite concomitant IM therapy.186 Infliximab
Tacrolimus has been studied in two randomised double-blind at either dose [5 or 10 mg/kg] achieved clinical remission in a sig-
controlled trials. In the first trial, 60 corticosteroid-refractory UC nificantly greater proportion of patients at Week 8 than placebo,
patients were randomly assigned to receive oral tacrolimus at high although the response for the subgroup of IM-refractory patients
serum trough [10–15 ng/ml; n = 19] or low serum trough [5–10 ng/ was not reported. A Cochrane database systematic review, of seven
ml; n = 21] levels, or placebo [n = 20].127 Two weeks after treatment, trials of IFX for treating patients with moderate to severe UC
the clinical response rates were 68.4% and 38.1% in the high-trough refractory to corticosteroids and/or IMs, concluded that IFX [three
and low-trough groups, respectively, and 10.0% in the placebo intravenous infusions at 0, 2, and 6 weeks] was more effective than
group. An RCT that included 62 patients with corticosteroid-refrac- placebo at inducing clinical remission at Week 8 [RR 3.22, 95% CI
tory, moderate to severe UC128 assessed oral tacrolimus, with serum 2.18–4.76].202 This review did not report the benefit in the patient
trough levels fixed at 10–15 ng/ml; a similar result to the first study subgroup refractory to IM therapy.
was obtained, with clinical response rates of 50.0% in the tacrolimus In the ULTRA-1 trial demonstrating superiority of adalimumab
group and 13.3% in the placebo group at Week 2 [p = 0.003]. Several over placebo for the induction of remission of UC [see statements
retrospective cohort studies have been reported.171 A recent system- 11G and 11H], 154 of the 390 [39%] patients were receiving con-
atic review and meta-analysis has reported that clinical response at comitant immunosuppression at baseline.203,204 In patients receiving

on 20 February 2018
concomitant IM without corticosteroids, adalimumab induced clini- There is case series evidence to support the use of tacroli-
cal remission at Week 8 in 8/53 [15.1%] patients, compared with mus,209,210 but no controlled clinical trial has included this patient
0/18 patients receiving placebo [0%]; for those receiving concomi- group. Careful discussion with the patients is required as to the
tant IM with corticosteroids, Week 8 remission rates were 6/49 relative risks and benefits of immunosuppressive therapy compared
[12.2%] for adalimumab compared with 2/34 [5.9%] for placebo. with colectomy, which may be a more appropriate option for some
In the ULTRA-2 trial, 173 of 494 patients [35%] were on concomi- patients.
tant immunosuppression.188 A separate subgroup analysis for these
patients was not reported. 11.4. Biosimilars
Adalimumab 160 mg/80 mg/40 mg alternate weekly induced clini- The currently available infliximab biosimilars have molecular struc-
cal remission at Week 8 in 8/53 [15.1%] patients compared with 2/52 tures very close to that of the reference product. Both biosimilars
patients receiving placebo [3.8%]. A prospective cohort study of 53 and the reference product [IFX] have similar physical and chemi-
patients receiving either IFX or adalimumab for moderately active UC cal properties, biological activity, pharmacokinetics, and animal and
reported short-term clinical response in 88.7% patients with no sig- healthy volunteers’ toxicity. Two phase 3 trials have shown that the
nificant difference in the response rates between drugs.205 All patients IFX biosimilars and IFX have similar efficacy, toxicity, and immu-
recruited had failed or were intolerant to IM therapy, although only nogenicity in rheumatoid arthritis and ankylosing spondyloarthri-
5/25 patients treated with adalimumab and 15/28 patients treated tis.211,212 Open-label studies suggest that IFX biosimilars are efficient
with IFX were taking concomitant IM therapy at baseline. in UC.213–217 Comparative phase 3 trials are progressing. Based on
The PURSUIT trial of golimumab included 31.2% of patients preclinical and clinical data, the European Medicines Agency has
with moderate to highly active disease, taking thiopurines.189 allowed the IFX biosimilars to be marketed in rheumatoid arthritis,
Concurrent treatment with IMs did not affect efficacy. spondyloarthritis, UC, and CD. The ECCO position statement on
A common question is whether to continue an IM when start- biosimilars has recently been updated.218
ing anti-TNF therapy in patients with IM-refractory colitis. The
UC-SUCCESS trial191 only included patients with steroid-refractory
disease, and patients were required to be either IM naïve [the case in Section 12. Maintenance of Remission
90%] or last exposed to IM > 3 months preceding inclusion. Hence
12.1.1. Goal of maintenance therapy
the cohort represented a largely IM-naïve population, from which it
may not be possible to draw direct extrapolation to guide therapy in
ECCO statement 12A
IM-refractory patients. The recommendation given for the combined
use of IFX and thiopurines in IM-refractory patients is therefore The goal of maintenance therapy in ulcerative colitis is
based on indirect data showing that concomitant immunosuppres- to maintain steroid-free remission, defined clinically [EL1]
sion might reduce antibody production and/or increase trough levels and endoscopically [EL2]
of IFX and efficacy of treatment.206,207 Neither subgroup analysis of
clinical trials nor retrospective analysis of pharmacokinetic samples
The endpoint that matters most to patients is steroid-free clinical
would appear to support a similar conclusion for adalimumab or
remission. Clinical relapse, defined by an increase in stool frequency
golimumab.189,208
and recurrence of rectal bleeding, and confirmed by endoscopy, is
The GEMINI 1 trial included 17.8% of patients taking IMs and
not the only approach to the evaluation of maintenance therapy, and
16.6% of patients taking glucocorticoids and IMs.193 Subgroup anal-
several pivotal trials have addressed other endpoints. In particular,
ysis for response to induction therapy did not report the total cohort
recent trial designs have tended to assess both induction and subse-
of previous -IM failures, but only those with previous IM failure with
quent maintenance in the same study. Using this approach, clinical
no history of anti-TNF failure, in whom a trend towards benefit for
response to induction therapy has been defined as a primary end-
vedolizumab compared with placebo was observed but did not reach
point, with the efficacy of maintenance therapy evaluated as a sec-
statistical significance [49% vs 34.5%; p = 0.08]. Subgroup analysis
ondary endpoint,186 or as a co-primary endpoint,219 or as an endpoint
in the maintenance study, using this same definition of previous IM
for evaluation solely in those who have responded to and undergone
failure without a history of anti-TNF failure, showed a significantly
re-randomisation at the end of induction therapy.189,193 Additionally,
higher remission rate at 1 year for those induction responders who
the definition of remission has varied, complicating efforts to make
were re-randomised to vedolizumab maintenance therapy [44.6%
meaningful comparisons between different trials.220,221
for those dosed with vedolizumab every 8 weeks [p = 0.001 vs pla-
cebo]; 50% for those dosed every 4 weeks [p < 0.001 vs placebo];
18% for those on placebo]. Ongoing concomitant treatment with 12.1.2. Impact of remission on long-term outcome
IMs did not substantially affect the efficacy of vedolizumab.
As described in section 11.3.1, data on second-line therapy with ECCO statement 12B
a second anti-TNF after failure of an initial anti-TNF are limited
Long-term maintenance treatment is recommended for
[see statement 11G]. For vedolizumab, GEMINI-1 included 48% of
almost all patients [EL1]. Intermittent therapy is accept-
patients with a history of previous anti-TNF therapy; in exploratory
able insome patients with proctitis [EL3]
subanalyses, outcomes were not significantly different in this group
of patients, suggesting that patients with a history of anti-TNF fail-
ure may have a comparable outcome to anti-TNF naïve patients. Long-term prognostic studies show low rates of remission [< 50%
The OCTAVE 1 and 2 trials of tofacitinib199 included patients of patients]. Ongoing treatment with 5-ASA, thiopurines, or biologic
who had failed azathioprine. Therefore, tofacitinib may be an option therapy increases long-term remission rates.19,222,223 A stringent end-
in patients with moderate to severe UC refractory to thiopurines, point for remission [clinical plus endoscopic remission] is related to
once it has been approved by the European Medicines Agency. longer duration of remission. For example, an endoscopic score of 0

on 20 February 2018
[defined as complete mucosal healing] applied to a post-hoc analysis diagnosis was associated with a lower colectomy rate [2% vs 8%
of the ACT 1 and 2 trials, revealed that patients with healing at Week without mucosal healing, p = 0.02].237 Meta-analysis of clinical
8 had a 4-fold increased likelihood of remission at Week 30 of IFX predictors of colectomy in patients with UC identified male gender,
treatment.224,225 Whereas mucosal healing correlates with improved extensive disease, need for corticosteroids, non-smoking status, and
clinical outcomes,225,226 it has not been demonstrated that treatment hospitalisation for UC as significantly associated with colectomy
approaches specifically targeting mucosal healing as an endpoint risk.238 Recent systematic review confirms an association between
are themselves associated with improved clinical outcomes, and it mucosal healing and colectomy avoidance, steroid-free remission,
is possible that patients achieving mucosal healing in such studies and clinical remission.225
represent a subgroup with less aggressive disease.
12.2. Medications for Maintenance of Remission

12.1.3. Risk factors for relapse
ECCO statement 12C ECCO statement 12D
Choice of maintenance treatment is determined by dis- Options for a stepwise escalation of maintenance therapy
ease extent [EL1], disease course [frequency and inten- include dose escalation of oral/rectal aminosalicylates
sity of flares] [EL5], failure and adverse events of previous [EL1], the addition of thiopurines [EL2], and anti-TNF ther-
maintenance treatment [EL5], severity of the most recent apy or vedolizumab [EL1]
flare [EL5], treatment used for inducing remission during
the most recent flare [EL5], safety of maintenance treat-
ment [EL1], and cancer prevention [EL2] 12.2.1. Aminosalicylates
Few prospective studies have assessed risk factors for relapse in ECCO statement 12E
patients with inactive UC.227–231 In one study of 92 patients, a shorter
duration of current remission and a higher relapse frequency were Mesalamine compounds are the first-line maintenance
predictive of further relapse.227 In a study of 64 patients, the fre- treatment in patients responding to mesalamine or ster-
quency of previous relapses, extra-intestinal manifestations, and a oids [oral or rectal] [EL1]. Rectal mesalamine is first-line
low-fibre diet were independent variables associated with a higher maintenance in proctitis and an alternative in left-sided
risk of relapse.228 In a study of 74 patients including various bio- colitis [EL1]. A combination of oral and rectal mesalamine
markers and clinical measures, younger age, multiple previous may be used as second-line maintenance treatment [EL1]
relapses [for women], and basal plasmacytosis on rectal biopsy
specimens, were independent predictors of relapse.229 This study did 12.2.1.1. Oral 5-ASA
not confirm the 2-fold increase in relapse rate in those with per- A Cochrane meta-analysis showed that the relative risk of failure
sisting active inflammation [polymorphonuclear leukocytes in the to maintain clinical or endoscopic remission [defined by with-
rectal mucosa] observed in two earlier histopathology studies.232,233 drawal or relapse] for oral 5-ASA vs placebo was 0.69 [95% CI
Histology grade has recently been reported as having the strong- 0.62–0.77].24 Numerous RCTs designed to evaluate the efficacy of
est association with the risk of clinical relapse in patients with UC oral 5-ASA, including sulphasalazine, various 5-ASA formulations,
who are in clinical remission.234 Adherence to medical therapy still olsalazine, and balsalazide, for maintaining remission have been
appears to be a governing factor associated with relapse, since the conducted.239–248
risk of relapse was more than 5-fold higher [OR 5.5, 95% CI 2.3–
13.0] among 99 patients who collected < 80% of their prescriptions 12.2.1.2. Rectal 5-ASA
for maintenance 5-ASA.235 Several RCTs have compared rectal 5-ASA in various formulations
Patients with disease requiring steroids probably have a differ- and regimens with placebo for maintenance of remission in distal
ent outcome compared with the overall population of patients with UC.249–255 At 12 months, failure to maintain clinical or endoscopic
UC. In a population-based study, the outcome of 183 patients with remission was 20–48% in the active arms compared with 47–89%
UC diagnosed between 1970 and 1993 was analysed 1 year after a in the placebo arms. In all but one of the trials, the differences in
first course of steroids.236 Among the 63/183 patients treated with failure to maintain remission between active and placebo groups
corticosteroids, 49% had a prolonged response, 22% were steroid were statistically significant. A meta-analysis, that included four
dependent, and 29% came to colectomy, but only 3/183 were treated placebo-controlled trials, showed a superiority of rectal 5-ASA over
with thiopurines. placebo for maintenance of remission at 1 year [RR 2.22, 95% CI
Both mucosal healing and a previous episode of acute severe 1.26–3.90].256
colitis impact on the key outcome of colectomy. In a population-
based study from south east Norway, 423/519 patients with UC 12.2.1.3. Combining oral and topical 5-ASA therapy
were available for analysis at 10 years [53 had died and 43 were There have been two RCTs comparing combination treatment with
lost to follow-up].237 The cumulative colectomy rate after 10 years oral 5-ASA plus intermittent 5-ASA enema with oral 5-ASA alone,
was 9.8% [95% CI 7.4–12.4%]. Initial presentation with extensive for maintaining remission. Remission rates were higher in patients
colitis or acute severe colitis tripled the risk of subsequent colectomy receiving the combination.252,257
[HR 3.57, 95% CI 1.60–7.96], whereas age ≥ 50 years at diagnosis Oral or rectal 5-ASA is superior to placebo in maintaining remis-
reduced the risk by 3-fold [HR 0.28, 95% CI 0.12–0.65]. Relapsing sion in UC. Rectal 5-ASA has equivalent or slightly superior effi-
disease occurred in 83%, but half [48%] of the patients were relapse cacy to oral 5-ASA in distal UC. The combination of oral 5-ASA
free during the last 5 years. Mucosal healing by 12 months from and intermittent rectal 5-ASA appears to provide further benefit.

on 20 February 2018
Although the long-term tolerance and acceptability of rectal treat- suggesting greater therapeutic effectiveness for sulphasalazine,
ment is variable, 258 adding rectal therapy is a treatment option for although not when restricting analysis to those studies reporting
patients who have relapsed on oral 5-ASA alone, although adherence endpoints at 12 months [RR 1.10, 95% CI 0.98–1.23]; nor when
to prescribed therapy should be addressed. A valid alternative is the excluding olsalazine [RR 1.08, 95% CI 0.92–1.26], a drug limited
use of formulations that have been demonstrated to provide signifi- by adverse events. Overall, adverse events of 5-ASA are no differ-
cant levels of 5-ASA in the distal colon. This has been demonstrated ent to sulphasalazine [RR 1.07, 95% CI 0.82–1.40]. However, most
with good efficacy for newer 5-ASA granule formulations and trials enrolled sulphasalazine-tolerant patients, which would have
MMX-mesalamine that are superior to conventional ileal-release minimised sulphasalazine-related adverse events. No significant
5-ASA in distal UC.13,246,259 differences in efficacy or adverse event rates were found analysing
pooled studies comparing different 5-ASA formulations.
ECCO statement 12F 12.2.1.6. Adherence to 5-ASA treatment

The effective dose of oral mesalamine to maintain remis- Adherence to 5-ASA therapy improves outcome in patients with UC.
sion is 2 g/day [EL1]. For rectal treatment, 3 g/week in The adherence rate in 94 outpatients taking 5-ASA with clinically
divided doses may be sufficient. Once-daily administra- quiescent UC for at least 6 months was 40% and the median amount
tion of mesalamine is the preferred dosing regimen [EL2]. of medication dispensed per patient was 71% [8–130%] of that pre-
Although sulphasalazine is equally or slightly more effec- scribe.d265 Logistic regression found that a history of four or more
tive [EL1], oral mesalamine preparations are preferred to prescriptions or male gender increased the risk of non-adherence. In
reduce toxicity. All preparations of oral mesalamine are a pilot study, patients were randomised to receive either once-daily
effective [EL1] or conventional [two or three times daily] 5-ASA for maintenance
of remission in UC.266 After 6 months, patients in the once-daily
arm appeared more satisfied with their regimen and consumed
12.2.1.4. Dose-response effect more medication than those in the conventional arm [90% vs 76%;
A clear dose-response for maintenance of remission with 5-ASA has p = 0.07]. The authors concluded that once-daily oral formulations
not been established. No difference was found in relapse rates at 1 year of 5-ASA were likely to be a better therapeutic option with com-
with 5-ASA 1.2 g/day compared with 2.4 g/day.260 Patients taking the parable efficacy and improved adherence. An investigator-blinded
higher dose were in remission for longer than those on the lower dose study of 362 patients randomised to receive ethylcellulose-coated
[median time in remission of 175 days vs 129 days, p < 0.001]. For 5-ASA, 2 g once daily or 1 g twice daily, showed a 12% better remis-
those with extensive UC, however, the benefit of the higher dose was sion rate at 1 year [73.8% vs 63.6%, respectively] in the once-daily
more prolonged [143 days vs 47 days, p < 0.005]. When the results dose group.241 Patient questionnaires showed significantly greater
for patients in remission at 12 months were analysed after stratifying compliance [p < 0.05] and acceptability [p < 0.001] in the once-
for frequently relapsing disease [> 3 relapses per year] vs less frequent daily group. Given the comparable efficacy between once-daily and
relapses, 2.4 g/day also performed significantly better than 1.2 g/day divided dosing regimens for the treatment of active UC with other
[75% vs 33%, respectively]. Systematic review of seven RCTs19 has 5-ASA formulations, this effect is likely to be generic rather than
confirmed greater benefit for doses of at least 2 g/day [studies included compound-specific.241,242,246,264
mesalamine, olsalazine, sulphasalazine, and balsalazide] as compared
with lower doses. Higher doses [≥ 2 g/day] are not associated with
12.2.2. Thiopurines
more adverse events.261 Recent Canadian guidelines recommend 2 g/
day 5-ASA as maintenance therapy for UC patients in remission.262 It
ECCO statement 12G
is possible that patients who required higher doses of oral 5-ASA to
induce remission or those with frequently relapsing disease require Thiopurines are recommended for: patients with mild to
higher maintenance doses as well, but at present there is no robust moderate disease activity who have experienced early
evidence to support this.263 There are also no data supporting a dose- or frequent relapse while taking mesalamine at optimal
response relationship with rectal 5-ASA for maintaining remission in dose or who are intolerant of mesalamine [EL5]; patients
distal UC, and no more than 1 g/day is required. who are steroid-dependent [EL2]; and patients respond-
Several studies25,241,242,246,264 have compared different dosing regi- ing to ciclosporin or tacrolimus [EL3]
mens for various 5-ASA formulations. Without exception, they have all
concluded that once-daily administration is at least as effective as twice 12.2.2.1. Efficacy of thiopurines for maintenance of remission
or three times daily administration. The comparable efficacy between Several RCTs evaluating the efficacy of thiopurines (azathioprine
once-daily and divided dosing regimens in the maintenance treatment and mercaptopurine [MP]) for maintenance of remission in UC
of UC, obtained with different 5-ASA formulations, suggests that this have been performed.184,267–272 In a Cochrane meta-analysis, seven of
effect is generic to 5-ASA rather than compound-specific. Interestingly, these studies on 302 patients were considered.222 The study qual-
once-daily administration of 5-ASA has not been found to be associated ity was judged as generally poor and the evidence for using thio-
with an increased rate of side effects in any of these studies. In conjunc- purines in UC was weaker than for CD. Azathioprine was superior
tion with the likely improvement in patient convenience and adherence to placebo on the basis of four trials [RR for failure to maintain
to treatment, this makes once-daily administration of 5ASA compounds remission 0.68, 95% CI 0.54–0.86]. The results were similar when
the first choice in maintenance therapy in patients with UC. limited to patients with successful induction of remission [data avail-
able for two studies]. There was no clear evidence of a dose-response
12.2.1.5. Comparison of oral 5-ASA formulations effect for co-medication with 5-ASA in these studies. Adverse effects
A Cochrane meta-analysis24 compared sulphasalazine and different occurred in 9/115 patients receiving azathioprine, including acute
5-ASA formulations. The odds ratio was 1.14 [95% CI 1.03–1.27] pancreatitis [three cases] and bone marrow suppression [five cases].

on 20 February 2018
Evidence to support the use of thiopurines for UC also comes [and at Week 54 in the ACT 1 trial], compared with placebo. In ACT
from retrospective series.273–278 In the Oxford series, the overall 1, remission rates at Week 54 were 35% [5 mg/kg], 34% [10 mg/
remission rate in 346 patients with UC who were treated with aza- kg], and 17% [placebo]. In ACT 2, remission rates at Week 30 were
thioprine was 58%, but increased to 87% among patients receiv- 26% [5 mg/kg], 36% [10 mg/kg], and 11% [placebo]. The propor-
ing therapy for more than 6 months. The proportion of patients in tion of patients with a sustained clinical remission at all time points
remission at 5 years was 62% when applying a strict definition of was 7% [placebo] and 20% [5 mg/kg] after 54 weeks in ACT 1, and
relapse, or 81% allowing for a brief relapse with a short corticoster- 2% [placebo] and 15% [5 mg/kg] after 30 weeks in ACT 2. The ster-
oid course. The median time to relapse after stopping azathioprine oid-free remission rates in the 74 patients receiving corticosteroids
was 18 months.279 A recent retrospective study reported relapse at baseline were very modest, although still statistically significant.
rates of 36% by 3 years following stopping thiopurines in patients In ACT 1, steroid-free remission at Week 54 was achieved in 24%
in sustained remission, particularly in patients with extensive UC, [5 mg/kg], 19% [10 mg/kg], and 10% [placebo]. In ACT 2, the cor-
evidence of biological disease activity at the time of cessation, or a responding values at Week 30 [7 months] were 18%, 27%, and 3%.
short duration of thiopurine treatment.280 The rates of clinical response and remission were similar between the
subpopulations of patients who were ‘corticosteroid-refractory’ [i.e.
12.2.2.2. Thiopurines after calcineurin inhibitors for induction those receiving corticosteroids at baseline] and those who were ‘not
of remission corticosteroid-refractory’.
Calcineurin inhibitors [CsA, tacrolimus] are rescue therapy options In long-term follow-up, 121 outpatients with refractory UC
for steroid-refractory UC. Since they are best discontinued within treated with IFX were analysed for colectomy-free survival.
6 months because of side effects, these agents are generally pro- Secondary measures were sustained clinical response and serious
posed as induction therapy until slower-acting IMs become effec- adverse events. From the 81 patients [67%] with an initial clinical
tive. Azathioprine or mercaptopurine [MP] are introduced while response to IFX, 68% had a sustained clinical response. No inde-
the patient is still receiving CsA or tacrolimus, and steroids are pendent predictors of sustained clinical response could be identi-
being tapered. The justification for thiopurines in this setting, even fied. Over a median [interquartile range] [IQR] follow-up period
in patients who are 5-ASA naive, is the high colectomy rate [36– of 33.0 [17.0–49.8] months, 21 patients [17%] came to colectomy.
69% in the 12 months following introduction of CsA119,120,281,282]. Independent predictors of colectomy were absence of short-term
Retrospective series have suggested that thiopurines reduce the risk clinical response [hazard ratio 10.8, 95% CI 3.5–32.8; p < 0.001], a
of colectomy after induction with CsA.119,120,283 baseline CRP level ≥ 5 mg/l [HR 14.5, 95% CI 2.0–108.6; p = 0.006],
After IV CsA, a switch to oral therapy occurs as soon as a clinical and previous IV treatment with corticosteroids and/or CsA [HR
response has been achieved, with a view to acting as a ‘bridge’ until 2.4, 95% CI 1.1–5.9; p = 0.033].284 Complete mucosal healing has
the therapeutic effects of thiopurines are achieved. independently been shown to be associated with a lower colectomy
rate [95% colectomy-free at Week 54, compared with 80% with an
endoscopic Mayo Clinic sub-score of 3; p = 0.0004].224
12.2.3. Anti-TNF and anti-adhesion therapy
In ULTRA 2, significantly more adalimumab-treated than pla-
cebo-treated patients achieved clinical remission at Week 8 [16.5%
ECCO statement 12H
vs 9.3%; p = 0.019], Week 52 [17.3% vs 8.5%; p = 0.004], and
In patients responding to anti-TNF, maintaining remission both Weeks 8 and 52 [8.5% vs 4.1%; p = 0.047]. Similar signifi-
by continuing anti-TNF therapy with or without thiopu- cant results were observed at all time points for clinical response and
rines [EL1] is appropriate. The use of thiopurine mainte- mucosal healing. As already discussed [section 11.3.1], in contrast
nance is an alternative option [EL3] to the ACT and PURSUIT studies, patients were allowed previous
anti-TNF therapy [this group comprised 40% of the final study pop-
ulation]. Importantly, treatment benefits were greatest in anti-TNF
ECCO statement 12I naïve patients, since among patients who had previously received
anti-TNF, rates of remission at Week 8 were no better than placebo
Anti-TNF or vedolizumab may be used as first-line biological and rates at Week 52 were just 10.2% [vs placebo 3%, p = 0.039].
therapy. Vedolizumab is effective in patients failing anti-TNF This study remains the only RCT to test the efficacy of alterna-
[EL2]. In patients responding to vedolizumab, maintenance tive anti-TNF therapy in previous treatment failures. Nonetheless,
therapy with vedolizumab is appropriate [EL2] reported rates of maintenance of remission at 1 year, in case series
following switching IFX treatment failures to adalimumab in UC,
range from 10% to 50%.192
ECCO statement 12J The risk of all-cause [0.18 vs 0.26; p = 0.03], UC-related [0.12
vs 0.22; p = 0.02], and UC- or drug-related [0.14 vs 0.24; p = 0.005]
In thiopurine-naïve patients with severe colitis respond- hospitalisations by Week 52 were significantly lower in patients
ing to steroids, ciclosporin or tacrolimus, thiopurines receiving adalimumab in comparison with placebo in the combined
are appropriate to maintain remission [EL2]. Patients patient cohort of the ULTRA 1 and 2 trials.285 Fou-year follow-up
responding to infliximab should continue infliximab with data from ULTRA 1 and 2, along with the long-term extension study
or without thiopurines [EL2]; thiopurine maintenance is ULTRA 3, have been reported.286 For the 199 patients followed to
an alternative option [EL4] Week 208, the remission rate was 24.7%.
The efficacy of subcutaneous golimumab for maintenance of
12.2.3.1. Anti-TNF for maintenance of remission remission in moderate to severe UC was evaluated in the PURSUIT-M
In the ACT studies,186 a significantly higher proportion of patients trial.189 Anti-TNF naïve patients who responded in the induction
had a clinical response or remission with IFX at Weeks 8 and 30 studies [n = 464] were re-randomised to placebo or injections of

on 20 February 2018
50 mg or 100 mg golimumab every 4 weeks through Week 52. no sub-score > 1], as compared with 15.9% of patients who
Among the subset of patients who had achieved a response by Week switched to placebo [p < 0.001 for both groups vs placebo]. Rates
6 in the induction studies, clinical response was maintained through of durable clinical response [defined as response at both Weeks 6
Week 54 in 47.0% of patients receiving 50 mg golimumab, 49.7% of and 52], durable clinical remission [remission at both Weeks 6
patients receiving 100 mg golimumab, and 31.2% of patients receiv- and 52], mucosal healing, and glucocorticoid-free remission,
ing placebo [p = 0.010 and p < 0.001, respectively]. At Weeks 30 were all significantly higher among patients assigned to vedoli-
and 54, a higher percentage of patients who received 100 mg goli- zumab. No clear differences in efficacy were observed between the
mumab were in clinical remission and had mucosal healing [27.8% two vedolizumab regimens, although treatment intensification to
and 42.4%, respectively,] than patients given placebo [15.6% and 4-weekly dosing has been reported to recapture clinical response
26.6%; p = 0.004 and p = 0.002, respectively].189 Sustained clinical in patients losing response to 8-weekly dosing.297 Concurrent
benefit up to 2 years has been published.287 treatment with glucocorticoids or IMs did not substantively
affect the efficacy of vedolizumab and, importantly, the benefit
12.2.3.2. Therapeutic drug monitoring over placebo appeared to be consistent regardless of previous
A dose-response relationship has been reported for all anti-TNF anti-TNF failure.298 The frequency of adverse events was similar
agents between serum drug levels and clinical outcomes.186,190,288 in the vedolizumab and placebo groups. A long-term, open-label
Therapeutic drug monitoring is being increasingly adopted to try to extension of the GEMINI-1 study has shown sustained benefit to
optimise outcomes, particularly during maintenance treatment.289,290 3 years for a significant number of initial responders.297 As for
The TAXIT trial randomised 263 adults with IBD [85 with UC] to anti-TNF agents, vedolizumab shows a dose-response relation-
drug level-based optimisation of IFX dosing during maintenance ship to clinical outcomes,299 providing interest in dose-adjustment
treatment or to dose titration based upon clinical judgement. Clinical based upon drug-level testing.
remission did not differ between the two groups, but significantly Currently, there is no reliable evidence to guide the choice of
fewer relapses were observed in the concentration-based dosing arm biologic agent for maintenance treatment in UC. No head-to head,
over 1 year; pharmaco-economic evaluation showed small overall prospective trials are available. In a recent network meta-analysis,
cost savings using concentration-based dosing.291 A retrospective IFX, adalimumab, golimumab, and vedolizumab were all superior to
review of 247 patients [42 with UC] suggested that trough levels or placebo for maintenance of remission and response; however, supe-
anti-drug antibodies to IFX or adalimumab guide therapeutic deci- riority of one agent over another could not be clearly established221
sions in more than two-thirds of patients.292 A recent meta-analysis and further studies are needed.
of 13 studies on the use of anti-drug antibodies and IFX trough lev-
els indicated that the presence of anti-drug antibodies was associated 12.2.4. Probiotics
with more loss of clinical response in IBD patients, although this was Three RCTs have compared E.coli Nissle [EcN] to 5-ASA for main-
not significant in UC patients.293 tenance of remission in UC. In a multicentre, double-blind study,
120 outpatients received 1.5 g/day 5-ASA or 100 mg/day EcN
12.2.3.3. Combining anti-TNF and immunomodulators [corresponding to 25 x 109 viable E. coli bacteria] for 4 days, and
As discussed above [sections 11.3.1 and 11.3.3], the superior efficacy then 200 mg/day.300 Concomitant medications were not permit-
of IFX in combination with azathioprine has been demonstrated in ted. After 12 weeks, 11% of patients receiving 5-ASA and 16% of
the UC-SUCCESS study for biologic- and IM-naïve patients with those receiving the probiotic relapsed. Subsequently 116 patients
steroid-refractory disease.191 Although similar data are lacking for with active UC were randomised to receive either 5-ASA 2.4 g/day,
patients refractory to IM therapy, as with CD,294 the combination reducing to 1.2 g/day after remission, or 200 mg/day of EcN.301 All
of IFX and a thiopurine analogue is probably justified to decrease patients also received an initial 7-day course of oral gentamicin and
immunogenicity, which is the source of infusion reactions and loss either rectal or oral steroids in variable doses. The remission rate
of response.206,207,295 In a retrospective Italian study, combination was 75% in the corticosteroid plus 5-ASA group, and 68% in the
therapy of IFX with thiopurines was an independent predictor for corticosteroid plus EcN group [p = ns]. During 1-year follow-up,
sustained clinical response [p < 0.0001; hazard ratio 3.98, 95% CI relapse occurred in 73% of the 5-ASA group and 67% of the EcN
1.73–9.14].148 It is not known whether subsequent IM discontinua- group [p = ns], after weaning off steroids. Finally, an equivalence
tion is deleterious in UC, although indirect evidence in CD from a study was conducted in 327 patients with UC in remission for no
single centre, open-label, randomised withdrawal trial showed that longer than 12 months, who were treated with either 5-ASA 1.5 g/
IMs can be stopped after 6 months with no loss of response to IFX day or EcN for 1 year.302 The relapse rate was 45% in the EcN
over 2 years.296 group vs 36% in the 5-ASA group [p = ns]. It was concluded that
Although RCT data are currently lacking, neither subgroup anal- EcN is not inferior to the established standard 5-ASA for mainte-
ysis of clinical trials, nor retrospective analysis of pharmacokinetic nance of remission in UC.
samples, would appear to support a similar conclusion regarding IM In addition to these RCTs, an open-label pilot study investi-
co-prescription for adalimumab or golimumab.189,208 gated the clinical benefit of EcN for maintenance therapy in young
patients with UC. A total of 34 patients with UC in remission, aged
12.2.3.4. Vedolizumab for maintenance of remission between 11 and 18 years, were allocated either to EcN [two capsules
The efficacy of vedolizumab for maintenance of clinical remis- daily, n = 24] or 5-ASA [median 1.5 g/day, n = 10], observed over
sion in patients responding to induction therapy was evaluated 1 year. This small study was underpowered to show any difference
in the GEMINI 1 study.193 At Week 52, 41.8% of initial respond- or equivalence, but the relapse rate was 6/24 in the EcN group and
ers who continued to receive vedolizumab every 8 weeks and 3/10 in the 5-ASA group. Data on the patients’ global health and
44.8% of patients who continued to receive vedolizumab every development were favourable and no serious adverse events were
4 weeks were in clinical remission [Mayo Clinic score ≤ 2 and reported.303 The utility of EcN is limited by its limited availability.

on 20 February 2018
No evidence has yet been reported that any other probiotic is 12.3. Duration of maintenance therapy
effective for maintaining remission in patients with UC;304–306 see
Supplementary material for details (available at ECCO-JCC online). ECCO statement 12K
12.2.5. Other treatments Mesalamine maintenance treatment should be contin-

12.2.5.1. Antibiotics ued long-term [EL3]; this may reduce the risk of colon
Ciprofloxacin [1–1.5 g/day] or placebo was administered for cancer [EL3]
6 months to 83 patients referred with active UC refractory to con-
ventional treatment, in an RCT. All the patients were initially treated 12.3.1. Aminosalicylates
with high but decreasing doses of prednisone, and 5-ASA. The treat- Studies have been published to assess whether sulphasalazine
ment failure rate was 21% in the ciprofloxacin-treated group and is effective at preventing relapse in patients with UC after a long
44% in the placebo group [p = 0.02]. However the study design duration of remission. In one study, the authors found no statisti-
can be criticised, including the inclusion criteria, lack of standard- cal benefit for patients who had been symptom-free on sulphasala-
ised definition of response, confounding effects of concomitant zine for more than a year.313 However, the number of patients was
therapies, suboptimal baseline treatment, and unbalancing between small, the duration of follow-up only 6 months, and patients were
groups.307 Consequently, ciprofloxacin should not be considered selected using clinical symptoms without endoscopic or histologi-
effective for maintaining remission in UC until further trials are sup- cal criteria. In another study, sigmoidoscopy and rectal biopsy were
portive. In another double-blind, randomised trial, metronidazole used at entry.244 The authors found that maintenance treatment with
[0.6 g/day] and sulphasalazine [2 g/day] were compared for mainte- sulphasalazine 2g/day reduced relapse rates, even in the subgroup
nance of remission in 40 patients with UC in remission for less than of patients who had been on sulphasalazine for more than 3 years.
12 months.308 After 1 year, metronidazole was found to be slightly A double-blind withdrawal RCT 26 years later included 112 patients
more effective than sulphasalazine. These data were regarded as with UC in clinical, endoscopic and histological remission, who had
insufficient by the Consensus to recommend antibiotics for mainte- been on sulphasalazine or 5-ASA for at least 1 year.314 Patients were
nance of remission in UC. randomised to oral 5-ASA 1.2 g/day or placebo for 1 year. Despite
the small numbers, patients were stratified according to the dura-
12.2.5.2. Methotrexate tion of disease remission preceding randomisation. In patients with
Data on MTX for maintenance of remission in UC are few. The disease remission for 1–2 years, 5-ASA appeared more effective
single placebo-controlled RCT was principally designed for induc- than placebo for preventing relapse at 12 months [5-ASA 23% and
tion of remission in refractory, active UC and used an oral dose of placebo 49%; p = 0.035]. For patients who had been in remission
12.5 mg/week, which is probably sub-therapeutic.309 The proportion for more than 2 years however, no statistically significant difference
of patients who relapsed after first remission [MTX 64% vs pla- was observed between relapse rates [5/28 vs 6/23, or 18% vs 26%,
cebo 44%] or who maintained remission at 9 months [MTX 36% respectively], but patient numbers were very small. The results of this
vs placebo 54%] were not significantly different. An open-label study should be regarded with caution, not only because of the low
study compared MP, MTX, and 5-ASA in 72 steroid-dependent IBD power, but also because the maintenance dose was lower than that
patients, including 34 with UC.271 Patients were randomly assigned now recommended [see section 12.2.1].
in a 2:2:1 ratio to receive MP 1 mg/kg, MTX 15 mg/week orally, or
5-ASA 3g/day. All patients who achieved remission at Week 30 were ECCO statement 12L
then included in a maintenance study for 76 weeks. A significantly In view of limited evidence, no recommendation can be
higher proportion of patients achieved remission in the MP group given for the duration of treatment with azathioprine,
[79%] than in the 5-ASA group [25%], with no statistical differences anti-TNF, or vedolizumab, although prolonged use of
compared with the MTX group [58%]. For maintenance of remis- these medications may be needed [EL4]
sion, the highest rate was found in the MP group [64%] compared
with MTX [14%] and 5-ASA [0%].
12.3.2. Thiopurines
Several retrospective series have been published.310,311 Most of the
There are few data on factors predicting response to azathioprine,
patients included had failed or were intolerant of azathioprine and
and there is uncertainty regarding the optimal duration of treatment.
were treated with MTX at various doses and routes of administra-
In a retrospective analysis with 622 patients with either CD or UC,
tion. The response or remission rates ranged from 30% to 80%,
the remission rates at 6 months were 64% and 87%, respectively.
when the drug was given by parenteral route in doses between 20 mg
The proportion of patients thereafter remaining in remission at 1,
and 25 mg, suggesting that some patients with UC may respond
3, and 5 years was 0.95, 0.69, and 0.55, respectively. There was no
to MTX. MTX [median oral dose 20 mg/week] was tolerated by
difference in relapse rates between CD and UC. After stopping aza-
27/31 [87%] patients who had been unable to tolerate azathioprine.
thioprine, the proportion of patients remaining in remission at 1, 3,
Of those treated with MTX after failure with azathioprine, 5/11
and 5 years was 0.63, 0.44, and 0.35 [of 222 patients] respectively.
patients had a colectomy, compared with 5/31 patients intolerant of
The duration of azathioprine treatment did not affect the relapse rate
azathioprine.311 In another study, MTX induced a response in 65%
after stopping treatment [p = 0.68].279 A recent systematic review sup-
[15/23] of those who were either previously intolerant and in 78%
ports continuing maintenance thiopurines in patients in remission.315
[7/9] of those who had previously failed thiopurine therapy.310 The
results are heterogeneous and it is possible that the dose of MTX is
a determinant of efficacy, but the Consensus considered that there is 12.3.3. Anti-TNF and vedolizumab therapy
currently insufficient evidence to recommend MTX for maintenance Several studies, most of them neither prospective nor randomised,
of remission in UC. A Cochrane systematic review reached the same have reported long-term efficacy data in UC [reviewed in316].
conclusion.312 Extension studies of clinical trials support sustained benefit for initial

on 20 February 2018
responders to IFX, adalimumab, golimumab, and vedolizumab, but gastroenterologists. This area has been addressed by an ECCO
the interpretation of results is complicated by differences in trial Topical Review.320
design and thus direct comparisons between studies are not possi-
ble.286,287,297,317 No withdrawal study of anti-TNF therapy has been
Conflict of Interest
reported in UC, although a multinational, retrospective cohort study
reported an association between IFX discontinuation and increased ECCO has diligently maintained a disclosure policy of potential conflicts of
interests [CoI]. The conflict of interest declaration is based on a form used by
risk of relapse; following IFX re-initiation, response was attained in
the International Committee of Medical Journal Editors [ICMJE]. The CoI
77% and remission in 51%.318 This has been addressed recently by
statement is not only stored at the ECCO Office and the editorial office of
systematic review319 reporting that 28% of UC patients relapse at
JCC, but is also open to public scrutiny on the ECCO website [https://www.
12 months after anti-TNF withdrawal. ecco-ibd.eu/about-ecco/ecco-disclosures.html] providing a comprehensive
overview of potential conflicts of interest of authors.
12.4. Maintenance of remission and transition

from paediatric to adult care Disclaimer
The ECCO Consensus Guidelines are based on an international consensus
process. Any treatment decisions are a matter for the individual clinician
ECCO statement 12M and should not be based exclusively on the content of the ECCO Consensus
Guidelines. The European Crohn´s and Colitis Organisation and/or any of its
Transition to adult services should be coordinated by pae-
staff members and/or any consensus contributor may not be held liable for
diatric and adult teams. It usually commences in mid ado-
any information published in good faith in the ECCO Consensus Guidelines.
lescence, depending on the development of the patient
and the availability of paediatric and adult gastroenterolo-
gists [EL5] Acknowledgments
Working groups [lead author shown first]: WG1: Fernando Magro, Johan
Burisch, Jimmy Limdi, Sandro Ardizzone, Cord Langner; WG2: Franck
ECCO statement 12N Carbonnel, Dominik Bettenworth, Konstantinos Karmiris, Torsten Kucharzik,
Shaji Sebastian, Helen Tavares de Sousa; WG3: Axel Dignass, Tim Raine, Uri
Transition is successful when the patient has acquired Kopylov, Konstantinos Katsanos, Tamas Molnar; WG4: Paolo Gionchetti,
the self-management skills to visit and talk to the doctor Peter Hindryckx, Ailsa Hart, Manuel Barriero de Acosta, Henriette Vind
alone, understands disease management including risks Thaysen; WG5: Florian Rieder, Kristina Gecse, Gianluca Pellino, Edyta
and benefits, and is adherent to treatment [EL4] Zagórowicz, Alessandro Armuzzi. Reviewers, on behalf of GuiCom: Glen
Doherty [Ireland] and Gionata Fiorino [Italy]; and on behalf of the Governing
Board: Julian Panes [Spain] and Gerassimos Mantzaris [Greece].
The optimal timing of transition from paediatric to adult manage-
ment of UC has to be decided on an individual basis by a joint team
of paediatric and adult gastroenterologists. The transition period References
usually starts from the age of 16–18 years, depending on patient References for this paper are available as supplementary data at ECCO-JCC
development and availability of qualified paediatric and adult online.

on 20 February 2018

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Journal of Crohn's and Colitis, 2017, 769–784

ECCO Guideline/Consensus Paper

Third European Evidence-based Consensus

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Topical mesalamine [5-aminosalicylic acid or 5-ASA] is the first-

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1] poor adherence to prescribed therapy;

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12.2. Medications for Maintenance of Remission

ECCO statement 12C ECCO statement 12D

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ECCO statement 12F 12.2.1.6. Adherence to 5-ASA treatment

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12.2.5. Other treatments Mesalamine maintenance treatment should be contin-

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12.4. Maintenance of remission and transition

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