European evidence-based Consensus on the management of ulcerative colitis: Current management

5.2.4.1. Investigations on admission 

See Section 7.5.3.

5.2.4.2. Therapeutic approach 

Intravenous corticosteroids remain the mainstay of conventional therapy for acute severe colitis,36 although details (such as the value of antibiotics or parenteral nutrition) are debated by some. As therapeutic options increase (ciclosporin, tacrolimus, or infliximab among others), so too does the opportunity for procrastinating about surgical decisions. The principal clinical dilemmas are how to identify at an early stage those who are likely to need colectomy, and when to start rescue medical therapy in time so that surgery, if it becomes necessary, is not inappropriately delayed. The two are not mutually exclusive and management demands the most taxing clinical judgement. Only one patient in a hundred need die as a result of complications caused by operating too late to negate any benefits of medical therapy. This is why it is recommended that patients should be treated in hospital jointly by a specialist Gastroenterologist and Colorectal surgeon.

5.2.4.3. Conventional therapy 

Treatment with corticosteroids should not be delayed awaiting microbiological results for possible infective causes. Corticosteroids are generally given intravenously using, for example, methylprednisolone 40 mg or hydrocortisone 100 mg four times daily. Higher doses (including 500 mg–1 g methylprednisolone) are no more effective, but lower doses are less effective.4, 37 Bolus injection is as effective as continuous infusion.38 Treatment is usually given for about 5 days, since extending therapy beyond 7 to 10 days carries no benefit.4

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

Other measures are considered appropriate in addition to intravenous steroids:

•Intravenous fluid and electrolyte replacement to correct and prevent dehydration or electrolyte imbalance. Potassium supplementation of at least 60 mmol/day is almost invariably necessary. Hypokalaemia or hypomagnesaemia can promote toxic dilatation.39

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

•Stool cultures and assay for Cl difficile toxin.

•Subcutaneous heparin to reduce the risk of thromboembolism.40

•Nutritional support if the patient is malnourished. Enteral nutrition is most appropriate and associated with significantly fewer complications than parenteral nutrition in acute colitis (9% vs 35%41,). Bowel rest through intravenous nutrition does not alter the outcome,42 but some centres use a food challenge after 5 days in an attempt to discriminate between complete and partial responders to intensive therapy.

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

•Topical therapy (corticosteroids or mesalazine) if tolerated and retained, although there have been no systematic studies in acute severe colitis.36

•Antibiotics only if infection is considered (such as in an acute, first attack of short duration, or after recent admission to hospital), or immediately prior to surgery. Controlled trials of oral or intravenous metronidazole, tobramycin, ciprofloxacin or vancomycin in acute colitis have shown no consistent benefit in addition to conventional therapy.43, 44, 45, 46, 47, 48

•Blood transfusion to maintain a haemoglobin >10 g/dl.

Ciclosporin monotherapy (CsA, 4 mg/kg/day intravenously) is as effective as intravenous methylprednisolone (MeP) 40 mg/day for acute severe colitis. In a randomized trial there was a response in 10/15 CsA patients vs 8/15 MeP patients.49 Furthermore, half of all patients in another study comparing low dose with high dose CsA50 also received CsA monotherapy, without concomitant intravenous steroids. Consequently monotherapy with CsA is a useful option in those patients with severe colitis when steroids are best avoided, such as those susceptible to steroid-psychosis (schizophrenics or previous psychosis), or for some other reason (concomitant osteoporosis, diabetes, or personal preference).

5.2.5.1. Ciclosporin (CsA) 

A placebo-controlled trial in 1994 identified CsA as potential rescue therapy for intravenous steroid-resistant UC (IVSR-UC).61 Nine of 11 patients failing steroids improved on ciclosporin whilst all 9 on placebo failed to improve (RR 0.18, 95%CI 0.05–0.64). However, 3/11 and 4/9 eventually underwent colectomy in the treatment and placebo groups respectively. The narrow therapeutic index of CsA and its side-effect profile has limited acceptability. In 2001, out of the 116 consecutive patients admitted to 29 UK hospitals with severe UC, only 17 (15%) received CsA and only 7 of 33 (21%) who came to colectomy had received CsA.62 In nine studies that used CsA as rescue therapy in the systematic review of severe colitis, only 100/622 (16%) patients treated received CsA.4 The short term response was 51% (95% CI 41–60%) and 29% colectomy (95% CI 25–32), but other case series report 70–80% early response.63, 64, 65 Concerns about early toxicity have been partly addressed by low dose (2 mg/kg) intravenous induction therapy (Section 5.4.7). In the largest randomized study of CsA to date, 73 patients were randomized to either 2 mg/kg or 4 mg/kg of intravenous CsA.50 Response rates at 8 days were similar in both groups (83% and 82% respectively), with 9% coming to colectomy in the 2 mg/kg group and 13% in the 4 mg/kg group. The long-term outcome indicates that a minority avoid colectomy. In two series, 58% of 76 patients64 and 88% of 142 patients65 came to colectomy over 7 years. A Cochrane review66 concluded that numbers in controlled trials were so few (only 5049,61) that there was limited evidence for CsA being more effective than standard treatment alone for severe UC.

5.2.5.2. Tacrolimus 

Tacrolimus is another calcineurin inhibitor, acting through a mechanism similar to CsA (Section 5.4.7). One randomised controlled trial has been performed in ulcerative colitis that included 27/60 patients with acute severe colitis.67 9/16 had a partial response to 0.05 mg/kg/day adjusted to trough levels (up to 15 ng/mL), compared to 2/11 on placebo and the remainder had no response. Results did not reach significance. Case series have shown broadly similar results to ciclosporin after both intravenous (0.01 to 0.02 mg/kg) and oral (0.1 to 0.2 mg/kg) administration (Table 5.2). It carries many of the risks (including nephrotoxicity) of ciclosporin, although tacrolimus is a more effective immunomodulator than ciclosporin in renal or liver transplantation (see Table 5.1).68, 69

Table 5.1. Case series of tacrolimus for steroid-refractory ulcerative colitis, compared to a case series of ciclosporin therapy in similar patients

	Series	n	Response	Colectomy at			Ref
				1–3mo	1 year	2 year
	Ciclosporin (iv 4 mg/kg, then oral)	76	56/76	10/76	16/76	16/76	64
	Tacrolimus iv 0.01/oral 0.2 mg/kg	38	18/38	3/38	12/38	19/38	70
	Tacrolimus iv 0.01 mg/kg	23	22/23		2/23	3/23	71
	Tacrolimus oral 0.15 mg/kg	9	9/9	1/9	–	3/9	72

5.2.5.3. Infliximab 

Infliximab as a single dose (5 mg/kg) may also be effective rescue therapy. A Swedish–Danish study treated 45 patients (24 IFX and 21 placebo with continued intravenous betamethasone).73 7/24 in the IFX group and 14/21 in the placebo group had a colectomy within 3 months (p=0.017; OR 4.9, 95% CI 1.4–17). No patient died. Two different scores were used to identify patients before randomization to IFX or placebo. The Sweden Index54 on day 3 identified sicker patients at an earlier stage than the Seo Index74 calculated on day 5–7. It was the group with less active disease after 5–7 days of intravenous steroids who benefited most from IFX. There have been other small studies of IFX for acute severe colitis refractory to steroids that have not shown a difference in colectomy.75, 76, 77 It should be noted that hospitalized patients with severe colitis represent a very different population to the outpatients in the ACT 1 & 2 studies78 (see Section 5.4.3). A large controlled trial is needed, because case series report 20%, 33%, 57% or 75% ultimately coming to colectomy after IFX for intravenous-steroid resistant ulcerative colitis.79, 80, 81, 82

5.2.5.4. Selection 

A recommendation on the best choice between calcineurin inhibitors and IFX in addition to intravenous steroids is not possible until there has been a comparative, randomised controlled trial. Controlled trials comparing CsA and IFX are n progress (2007/08). The individual circumstances of each patient have always to be considered. If a patient has acute severe colitis despite existing treatment with an immunomodulator at an appropriate dose and duration, then there is little that medical therapy can hope to offer since it is unlikely that remission can be maintained. The effect of IFX as maintenance therapy in these circumstances is unclear: such patients are a different to those in the ACT trials and the risks, as well as the potential benefit, of deferring (or even avoiding) colectomy need careful discussion with individual patients. Many gastroenterologists will be more familiar with the adverse-event profile of IFX compared to CsA or tacrolimus. The short half life of CsA, however, is a potential advantage compared to IFX. Consequently if CsA does not work, it is only a matter of hours before it disappears from the circulation, while IFX will circulate for weeks. This may matter if colectomy is performed, since septic complications are the major cause of post-operative morbidity and mortality.82 Although IFX is reported not to increase post-operative sepsis,83 no data are available that relate only to emergency colectomy for sick patients with acute severe UC (Section 7.6.3). In general only a single attempt at rescue therapy with a calcineurin inhibitor or IFX should be considered before colectomy, after careful discussion between the patient, gastroenterologist and colorectal surgeon about the options and potential outcomes. If doubt persists, specialist advice should be sought at an early stage from a referral centre. Use of IFX with CsA has been associated with a particularly high rate of adverse events (see Section 7.6.3).

5.2.6.1. Toxic megacolon 

Toxic dilatation (megacolon) represents the end of a spectrum of severe colitis that has been unrecognized, undertreated, or refractory to appropriate treatment. It is defined as total or segmental non-obstructive dilatation of the colon >6.0 cm associated with systemic toxicity.39, 84 The incidence has never been studied systematically. About 5% of patients with acute, severe colitis admitted to hospital will have toxic dilatation.39 Metabolic disturbance (hypokalaemia or hypomagnesaemia), bowel preparation, or anti-diarrhoeal therapy have been associated with toxic dilatation,39 so these should be corrected or avoided. Earlier diagnosis of severe colitis, more intensive medical management and earlier surgery has reduced the incidence of toxic megacolon complicating ulcerative colitis, but the incidence for infective colitis is rising, reflecting the increasing prevalence and severity of pseudomembranous colitis.85

The key aspects of management are aggressive medical therapy and early surgical decision making. It is no different to conventional therapy for acute severe colitis, except that metronidazole 500 mg three times daily is appropriate on empirical grounds in case of an infective aetiology. The combination of steroids and antibiotics is safe even for infective colitis; steroids reduce inflammation in pseudomembranous colitis.86 Nasogastric suction cannot be expected to decompress the colon and is unnecessary. The classic knee-elbow position may relieve distension,87 but is generally impracticable. A senior surgical opinion is best sought on the day of admission. It should be made clear to all that there is a 24 h window of opportunity for medical treatment to work and that if there is no improvement then early colectomy will be necessary.

5.2.6.2. Perforation, haemorrhage and others 

Perforation is the most serious complication of acute severe colitis, almost invariably associated with colonoscopy or toxic dilatation where colectomy has been inappropriately delayed. It carries a mortality of up to 50%.39 Other complications appear exceptional, including massive haemorrhage (1/66 patients operated on for acute severe colitis in one series88), cerebral sinus thrombosis40 and a poorly recognised panenteritis.89, 90, 91 In a review of 158 middle-aged or older American patients with ulcerative colitis, however, 20/158 had toxic dilatation, perforation or massive haemorrhage and 7/20 died.92

5.2.6.3. Long term outcome of severe colitis 

The long term outcome after admission with acute severe ulcerative colitis is not good. When the outcome of a small, but prospectively-collected cohort of patients who had avoided surgery on the index admission was reexamined after 15 years, 8/22 (36%) complete responders to steroids came to colectomy, compared to 8/10 incomplete responders (stool frequency >3/day, or those with visible blood in the stools at day 7, p=0.082).93 Median time to colectomy was 33.0 months (CI 12.6–67.1) for complete responders vs 6.0 months (95% CI 0.9–17.7) for incomplete responders (p=0.033). The longest period of steroid-free remission was a median 45.0 months (CI 28.2–63.2, range 0–120) for complete, but a median 8.5 months (CI 4.3–22.1, range 1–35) for incomplete responders (p=0.017). Data on the burden of medical and surgical treatment of severe colitis and attendant complications, related to patient-orientated outcomes (hospitalization, time off work, colectomy and mortality) are still required.

5.4.1.1. Efficacy of aminosalicylates 

Much is made of how different delivery systems may influence response, but evidence that it matters in clinical practice is remarkably thin. Delivery systems can be divided into azo-compounds, controlled release, pH-dependent (either pH6 or pH7) and composite (pH-dependent combined with controlled release) (Table 5.3137, 138, 139).

Table 5.3. Delivery systems for 5-ASA137, 138

		Delivery system	Mean peak plasma [5ASA] (μmol/L)	Mean systemic exposure (AUC, μmol/L.h)
	Azo-bond
	Sulfasalazine	Sulfapyridine carrier	0.7–3.5	9.6–27.5
	Olsalazine	5-ASA dimmer	1.2–4.5	–
	Balsalazide	4-amino-benzoyl-β-alanine	2.3–3.5	13.9–22.8
	Controlled release
	Pentasa®	Ethylcellulose coated microgranules	6.5	28.5
	pH7-dependent
	Asacol®	Eudragit-S coating, dissolves at pH7	2.1–10.5	21.5–25.1
	Mesren®	Same	–	–
	Ipocol®	Same	–	–
	pH6-dependent
	Salofalk®	Eudragit-L coating, dissolves at pH6	10.9	38.3
	Mesasal®	Same	5.2 (median)	21.5 (median)
	Claversal®	Same	–
	Composite
	(‘multimatrix’)Mezavant® (EU) Lialda® (US)	Eudragit-S coating of hydrophilic polymer with some 5ASA and lipophilic excipients encapsulating 5ASA	–	no published data

Systematic reviews and meta-analyses concur that aminosalicylates are effective for treating active UC.21, 22, 27 The NNT to induce remission is 10 (95%CI 7–21), although for the lesser target of response or remission the NNT is 4 (95%CI 3–6)22). Available data do not suggest a difference in efficacy between any of the 5-ASA preparations for active UC. Six trials with mesalazine (including two trials on MMX mesalazine) show statistical significance vs placebo.23, 24,140, 141, 142,147 Those with olsalazine143, 144, 145, 146 or balsalazide [unpublished, see ref 27] do not.

Mesalazine is shown to be as effective as sulfasalazine for inducing response or remission (OR 0.83, 95%CI 0.60–1.1321) in the most recent meta-analysis, and is better tolerated. There have been few clinical trials comparing the efficacy of newer aminosalicylates for inducing remission. In 2 of 3 trials of balsalazide vs mesalazine, results for defined primary and secondary endpoints failed to demonstrate statistically significant differences.148, 149, 150 Another study compared Ipocol, a pH7-dependent release mesalazine, with Asacol and found no significant difference in remission rates after 2.4 g/d for 8 weeks.151 Proprietary prescribing of mesalazine is recommended,152 but for active UC the choice of 5ASA cannot be made on the grounds of efficacy alone. The route of delivery, dose frequency, cost and availability are more relevant factors in the choice.

5.4.1.2. Adverse effects of aminosalicylates 

Mesalazine has a topical action on colonic epithelial cells, where it is also metabolised. Systemic exposure is therefore unnecessary. This means that drug efficacy cannot be deduced from pharmacokinetic comparisons, but absorption might conceivably influence adverse events. Despite variable differences in peak serum concentrations, ratio of 5ASA to its metabolite N-acetyl 5ASA, however, the systemic exposure to equimolar doses of all 5-ASA compounds is similar (Table 5.4). Mesalazine intolerance occurs in up to 15%. Diarrhoea (3%), headache (2%), nausea (2%), rash (1%) and thrombocytopenia (<1%) are reported, but a systematic review has confirmed that all new 5-ASA agents are safe, with adverse events that are similar to placebo for mesalazine or olsalazine.153 Acute intolerance in 3% may resemble a flare of colitis since it includes bloody diarrhoea. Recurrence on rechallenge provides the clue. Renal impairment (including interstitial nephritis and nephrotic syndrome) is rare and idiosyncratic. A population-based study found the risk (OR 1.60, CI 1.14–2.26 compared to normal) to be associated with disease severity rather than the dose or type of mesalazine.154

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

		n	Dose, g (n)	Weeks	Remission (unless otherwise stated)	Ref
	Asacol®
	Schroeder 1987	87	4.8 (38), 1.6 (11), 0 (36)	6	24% vs 5% (4.8 vs 0, p=0.047)	140
	Sninsky 1991	158	2.4 (53), 1.6 (53), 0 (52)	6	Response 49% vs 23% (2.4 vs 0, p=0.004)	141
	Balsalazide
	Salix (unpublished)	180	6.75 (72), 4.5 (73), 0 (35)	4	Response 45% vs 45% (6.75 vs 0, ns)	27
	MMx mesalazine
	Lichtenstein 2007	280	4.8 g×1 (94), 1.2 g×2 (93), 0 (93)	8	29% vs 13% (4.8 g×1 vs 0, p=0.009)	23
	Kamm 2007	343	4.8 g×1 (85), 2.4 g×1 (84), 0 (86) Asacol 0.8g×3 (86)	8	41.2% vs 40.5% vs 22.1% vs 32.6% (4.8g×1 vs 0, p=0.007)	24
	Pentasa®
	Hanauer 1993	374	4 (95), 2 (97), 1 (92), 0 (90)	8	29% vs 12% ( 4g vs 0, p=0.0012)	142
	Olsalazine
	Meyers 1987	66	3 (15), 1.5 (16), 0.75 (15), 0 (20)	3	Improvement 50% vs 16% (3 vs 0, p=0.055)	143
	Hetzel 1988	30	2 (15), 0 (15)	8	Improvement 40% vs 11% (p=0.11)	144
	Feurle 1989	105	2 (52), 0 (53)	4	Improvement (ns, no absolute numbers)	145
	Zinberg 1990	15	3 (7), 0 (8)	4	Improvement (4/7 vs 0/8, p<0.05)	146
	Rowasa®
	Sutherland 1990	136	4 (47), 2 (45), 0 (44)	6	Improvement 45% vs 18% (4 vs 0, p<0.05)	147

5.4.1.3. Monitoring 

Patients with pre-existing renal impairment, other potentially nephrotoxic drugs, or co-morbid disease should have renal function monitored during 5-ASA therapy. Many clinicians believe that creatinine and full blood count should be monitored every 3–6 months during aminosalicylate therapy, although there is no evidence favouring one monitoring regime over another.

5.4.2.1. Efficacy of steroids 

There have been only two placebo controlled trials of conventional oral steroids for outpatients with active UC,29, 155 giving an NNT of 2 (95%CI 1.4–5).22 More recently, when 86 (out of a total of 136) newly diagnosed patients with UC were treated with steroids, 51%, 31% and 18% had a complete response, partial or no response respectively at 30 days.156 However, this includes a group of 22/86 who had acute severe colitis needing intravenous treatment. At one year, 55% were in steroid-free remission, 17% were steroid-dependent, 21% had surgery and 7% lost to follow up, but the inclusion of severe colitis makes this difficult to extrapolate to outpatient therapy. Adverse effects and monitoring of steroid therapy are the same as described in the Consensus guidelines on Crohn's disease.157

5.4.3.1. Efficacy of IFX 

A systematic review of the efficacy of IFX for treating patients with moderate to severe UC refractory to corticosteroids and/or immunomodulators, concluded that it was effective for inducing clinical remission, clinical response, promoting mucosal healing, and reducing the need for colectomy in the short term.158 The review took the description of ‘severe’ at face value and failed to discriminate between out-patients and in-patients with acute severe colitis. Nevertheless, in seven RCTs, IFX (three intravenous infusions at 0, 2, and 6 weeks) was more effective than placebo in inducing clinical remission (RR 3.22, 95%CI 2.18–4.76). It was also more effective than placebo at inducing endoscopic remission (RR 1.88, 95%CI 1.54–2.28) and clinical response (RR 1.99, 95% CI 1.65–2.41) at 8 weeks.78, 159, 160, 161, 162 A single infusion of infliximab was also more effective than placebo in reducing the need for colectomy within 90 days after infusion (RR 0.44, 95%CI 0.22–0.87).73 The ACT 1&2 studies are pivotal.78 They are impressively consistent, showing double the remission rate compared to placebo. ACT 1 was a 364 patient study in moderately active UC refractory to oral steroids and/or thiopurines, given IFX 5 mg/kg, 10 mg/kg, or placebo at 0, 2 and 6 weeks, then every 8 weeks for a year. The primary endpoint at week 8 was response (>30% and a 3 point decrease in the Mayo activity index, with virtual cessation of rectal bleeding). This was achieved: 37.2% (placebo), 69.4% (5 mg/kg) and 61.5% (10 mg/kg), p<0.001). So too were pre-defined secondary endpoints of remission (14.9%, 38.8% and 32.0% respectively) and mucosal healing (33.9%, 62.0%, and 59.0%). Duration of effect was maintained through week 30 in all respects (remission in 15.7%, 33.9% and 36.9%, p<0.001). The same goes for ACT 2, an almost identical trial of a further 364 patients, but who could have moderately active UC despite 5-ASA alone (26%) and was 6 months' duration. Response (and remission) rates at week 8 were 29.3% (5.7%, placebo), 64.5% (33.9%, 5 mg/kg) and 69.2% (27.5%, 10 mg/kg, p<0.001). The flat dose-response is comparable to that of IFX for Crohn's disease.157 Unfortunately, a large therapeutic gap persists despite being on 5 mg/kg IFX every 8 weeks, because only 21% (at 7 months) and 26% (at 12 months) achieved steroid-free remission (see Section 5.3.3). This is important because the Consensus stresses the importance of achieving steroid-free remission. Further analysis of the ACT 1 & 2 trial data indicates that there was an associated reduction in colectomy (hazard ratio 0.57, 95% CI 0.37–0.89) during the trial,165 but whether this benefit is maintained remains unclear.The actual role of IFX for UC refractory to conventional therapy for both outpatients and inpatients is discussed in 5.2.5, 5.2.7, 5.3.3, 5.3.4, 5.3.5.

5.4.3.2. Adverse effects of IFX 

Treatment with IFX is relatively safe if used for appropriate indications. Adverse events in the ACT studies78 were no different to those expected from large experience of treating Crohn's disease.163, 164 Nevertheless, in common with other biological therapy there is a risk of serious infection, demyelinating disease and associated mortality. In the combined analysis of 484 patients with UC who received IFX in the ACT trials there were 8 who developed pneumonia, 1 tuberculosis and 1 histoplasmosis (who later died) as well as 4 neoplasia (all probably pre-existing, but presenting in the trial period) and 3 neuropathies (2 optic neuritis, 1 multifocal motor), equivalent to 3.5% (17/484). By contrast, in the 244 who received placebo there was just 1 basal cell carcinoma. Prolonged medical therapy for a potentially pre-malignant condition with anti-tumor necrosis factor therapy creates its own anxieties. Tighter surveillance to detect dysplasia may be necessary, although no evidence-based recommendations can currently be given.

5.4.5.1. Efficacy of azathioprine/mercaptopurine 

Data on thiopurines for active UC are few.167 There have been five placebo-controlled trials of AZA for active UC, of between 20 and 80 patients each, with differing entry criteria, dose and duration.136, 174, 175, 176, 177, 178 Data from a recent, well conducted study on steroid-dependent active UC131 are discussed in Section 5.3.3. The main role for thiopurines are as steroid sparing agents (NNT 3). Immunomodulators should be started in steroid-dependent or steroid-refractory patients. For arbitrary but practical purposes, thiopurines are considered appropriate for the same indications as for Crohn's disease: patients who have a severe relapse; those who require two or more corticosteroid courses within a 12 month period; those whose disease relapses as the dose of steroid is reduced below an arbitrary 15 mg; and relapse within 3 months of stopping steroids.158 There is some evidence from a retrospective multicentre study of 1176 patients that those on AZA for UC are more likely to relapse if it is discontinued after 4 years than are patients who have Crohn's disease.179

5.4.5.2. Dose, monitoring and adverse effects of thiopurines 

All aspects are considered similar to the use of thiopurines for Crohn's disease.158 More recent work on measuring thiopurine methyl transferase (TPMT) and ITPA genotypes, TPMT activity, TPMT gene expression and thiopurine metabolites, is consistent with previous reports that the development of different types of toxicity is unpredictable.180 This prospective study on 60 patients (27 with UC) study did, however, find that measurement of meTIMP early in the steady state phase might identify patients at risk of developing myelotoxicity. No recommendation can be made about routine measurement of TPMT activity or genotype prior to initiating thiopurine therapy, although all agree that monitoring of the full blood count before and after starting therapy is appropriate.

5.4.6.1. Efficacy of MTX 

Studies on MTX for UC are small, use varying doses or routes of administration and have inconsistent outcomes.181, 182, 183 The only randomised placebo-controlled trial using a dose of 12.5 mg per week of oral MTX in UC showed no benefit.181 The low dose may account for disappointing efficacy as well as the lack of side effects. A randomized comparison of oral MTX 15 mg/week (still a relatively low dose) with mercaptopurine (MP) 1.5 mg/kg/day and 3 g/day 5-ASA for 72 steroid-dependent patients (34 UC and 39 Crohn's) showed a remission rate at 30 weeks of 79% for MP, 58% for MTX 25% for 5-ASA (p<0.05 vs MP, ns vs MTX).182 This is the only published comparison of MP and MTX. Until more data are available it cannot generally be considered an alternative to thiopurines for steroid-resistant UC (see also Section 6.2.5).

5.4.6.2. Dose and monitoring and adverse effects of MTX 

As with thiopurines, all aspects are considered similar to Crohn's disease, for which evidence from controlled trials supports its use.158, 184

5.4.7.1. Efficacy of CsA 

Details of the role of CsA and tacrolimus for severe UC are given in 5.2.4, 5.2.5.

5.4.7.2. Dose and monitoring 

Low dose CsA (2 mg/kg iv) induction therapy has largely addressed concerns about early toxicity. In the largest randomized study of CsA to date, 73 patients were randomized to either 2 mg/kg or 4 mg/kg of intravenous CsA.50 Response rates at 8 days were similar in both groups (86% and 84% respectively), with 9% coming to colectomy in the 2 mg/kg group and 13% in the 4 mg/kg group. The study was too small to show a difference in serious side effects, but there was less hypertension in the lower dose group. The majority of CsA side-effects are dose-dependent. At the 2 mg/kg dose, the mean CsA concentration on day 4 was 246+64 ng/mL, but 345+146 ng/ml with the 4 mg/kg dose. Suitable target levels to induce remission are not known, but in responders on oral medication, whole-blood trough levels of 100–200 ng/ml using a monoclonal radioimmunoassay are generally considered satisfactory. It is said that 2 h post-dose peak levels give the best estimate of drug exposure by correlating with the pharmacokinetic area under the curve185 and an appropriate target appears to be 700 ng/mL, but this has not been correlated with efficacy for UC.

Tacrolimus is more effective when given at a dose that achieves a trough concentration of 10-15 ng/m.67 The initial oral dose in this randomized trial of 60 steroid-refractory patients with active UC was 0.05 mg/kg/day, increased according to the trough level after 24 hr. 13 (68%) achieving this trough level responded within 2 weeks, compared to 8 (38%) achieving a lower trough level and 2 (10%) in the placebo group. None had a complete response. Oral dosing may be an alternative to intravenous administration but only retrospective data are available.70

In practice, either calcineurin inhibitor appears able to induce remission, although whether either alter the long-term pattern of disease is unknown. First principles indicate that treatment is best continued until immunomodulator therapy (AZA/MP/MTX) is established. Although this reduces the short-term colectomy rate, the risk of clinical relapse remains high in the first year after treatment63, 64, 65 (see Section 6.2.2).

5.4.7.3. Adverse effects of calcineurin inhibitors 

Hypertension, paraesthesiae or tremor and headache are the commonest adverse events. Hypomagnesaemia, renal impairment, or gastrointestinal upset affect around half of patients.67 Tacrolimus may induce diabetes mellitus. Opportunistic infection is the main concern; 3/86 patients (3.5%) died of opportunistic infections (1 of Pneumocystis jiroveci (carinii) pneumonia and 2 of Aspergillus fumigatus pneumonia) in a series from a major specialist centre.186 Opportunistic infections and the value of chemoprophylaxis is the topic of a separate ECCO Consensus.

5.4.8.1. Antibiotics 

Antibiotics as an adjunct to steroids do not alter the outcome of severe colitis (Section 5.2.4,43, 44, 45, 46, 47, 48), but treatment of refractory colitis UC associated with Fusobacterium varium has been reported.187 Two weeks' triple therapy with amoxicillin 500 mg, tetracycline 500 mg and metronidazole 250 mg all three times daily improved clinical, endoscopic and histological scores in a randomised trial of 20 patients.187 More evidence is needed.

5.4.8.2. Helminths 

Observations that there is an epidemiological mismatch between UC and helminth infections, together with experimental evidence that several helminths moderate immune-mediated models of colitis lead to therapeutic trials of Trichuris suis ova. T suis, the pig whipworm, transiently colonises the gut, but is non-pathogenic in man. In a randomised trial of 54 patients with mild-moderately active UC, 3/30 of those treated with 2500 T suis ova every 2 weeks for 12 weeks achieved remission compared to 1/24 given placebo (ns), with a response in 43% and 17% respectively (p=0.04).188 The optimal dose, interval and duration of treatment need to be established and the response confirmed in a larger study.

5.4.8.3. Heparin 

Heparin promotes epithelial restitution and repair in addition to anticoagulant properties. Out of two small controlled trials of unfractionated heparin and three using low molecular weight heparin in up to 100 patients, only the smallest trial has shown benefit for active UC.189 It cannot currently be recommended, although novel delivery systems are being developed.

5.4.8.4. Interferon-alpha 

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

5.4.8.5. Leucocytapheresis 

Leucocytapheresis involves extracorporeal removal of leucocytes through an adsorptive system of cellulose acetate beads (Adacolumn®, Otsuka Pharmaceuticals), or a polyester fibre filter (Cellsorba®, Asahi Medical Company). The former removes 65% of neutrophils, 55% monocytes, and 2% lymphocytes while the latter removes up to 100% of neutrophils and monocytes, and 20-60% lymphocytes. Sessions last an hour, during which time 2–3 l of blood is drawn from one arm, filtered, and infused into the other arm. A course of treatment is typically 5–10 sessions at intervals of 1–2/week. There have been a multiplicity of observational studies, two unusually designed randomised trials comparing leucocytapheresis with prednisolone191 or a sham column,192 and one large trial comparing it with sham apheresis for active UC that has yet to report. It appears that leucocytapheresis does something for active UC, but quite what and how much is difficult to define.193 It has wide-spread acceptance in Japan. Expense may limit its use, but the outcome of controlled trials will govern its future role in Europe.

6.2.1.1. Oral 5-ASA 

The most recent version of the Cochrane meta-analysis showed that the Peto odds ratio for the failure to maintain clinical or endoscopic remission (withdrawals and relapses) for oral 5-ASA vs placebo was 0.47 (95% CI, 0.36–0.62), with a number-needed-to-treat (NNT) of 6.206 Randomised controlled trials (RCTs) designed to evaluate the efficacy of oral 5-aminosalicylates (5-ASA) – including sulfasalazine, mesalazine and olsalazine – for maintaining remission are shown in Table 6.1.207, 208, 209, 210, 211, 212, 213, 214

Table 6.1. Placebo-controlled trials of oral 5-aminosalicylates for maintaining remission in UC

	Author [ref]	Year	Number of patients	Study drug	Dosage (g/day)	Duration (months)	Failure to maintain clinical or endoscopic remission
	Misiewicz207	1965	67	SZP	2	12	29%
				Placebo			76%1
	Dissanayake208	1973	64	SZP	2	6	22%
				Placebo			55%1
	Riis209	1973	59	SZP	2	6	29%
				Placebo			24%
	Sandberg-Gertzen210	1986	101	OLZ	1	6	23%
				Placebo			45%1
	Wright211	1993	101	OLZ	2	12	63%
				Placebo			69%
	Miner212	1995	205	MSZ2	4	12	43%
				Placebo			62%1
	Hanauer213	1996	264	MSZ3	0.81.6	6	56%
				MSZ			56%
				Placebo			71%4
	Hawkey214	1997	323	MSZ3	1.6	6	40%
				Placebo			59%1

1p<0.05; 2Pentasa; 3Asacol/Claversal; 4p<0.05 for comparison of 5-ASA (both groups) vs placebo; 5comparison of 5-ASA, zileuton (not shown) and placebo; (sulfasalazine: SZP; olsalazine: OLZ, and mesalazine: MSZ).

6.2.1.2. Rectal 5-ASA 

Several RCTs have compared rectal mesalazine in various formulations and regimens with placebo for maintenance of remission in distal UC (Table 6.2).215, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237 At 12 months, failure to maintain clinical or endoscopic remission was 20–48% in the active arms compared to 47–89% in the placebo arms. In all but one of the trials, the differences in failure to maintain remission between active and placebo groups were statistically significant. The only RCT that failed to demonstrate efficacy of 5-ASA suppositories215 followed a three times a week regimen; the difference between the two arms was significant at 3, 6 and 9 months but did not reach the significance level at 12 months. Other trials have demonstrated efficacy with similar intermittent rectal 5-ASA regimens, either alone or in combination with oral 5-ASA. A meta-analysis which included the two placebo-controlled trials, showed a superiority of rectal mesalazine over placebo for remission maintenance at 1 year (OR 16.2, 95% CI 4.7–55.9).11

Table 6.2. Randomized controlled trials of rectal mesalazine compared to placebo or oral formulations for maintaining remission in distal UC

	Author [ref]	Year	Number of patients	Study drugs	Dosage (g/day)	Duration (months)	Failure to maintain clinical or endoscopic remission
	Sutherland227	1987	29	MSZ enema	2	6	40%
				MSZ enema	4		46%
	Biddle228	1988	25	MSZ enema	1	12	25%
				Placebo	-		85%1
	D'Arienzo229	1990	101	MSZ suppository	0.8	12	20%
				Placebo	–		80%1
	D'Albasio230	1990	79	MSZ enema	4 g×7/month 4 g/3days	24	31%
				MSZ enema			28%
				Oral SZP	2g/day		39%
	Miner231	1994	92	MSZ enema	4 g/day	6	19%
				MSZ enema	4 g/2 days		28%
				MSZ enema	4 g/3 days		35%
				Placebo	–		52%1
	Andreoli232	1994	31	MSZ enema	4 gx2/week	12	25%
				Oral SZP	2g/day		40%
	Mantzaris233	1994	38	MSZ enema	4 g /3 day	24	26%
				Oral MLZ	1.5g/day		68%1
	D'Albasio234	1997	69	MSZ enema+oral	2×4 g/week+1.6 g/day	12	39%
				Oral MSZ alone	1.6g/day		64%1
	D'Albasio235	1998	111	MSZ suppository	0.5×2/day	12	10%
				MSZ suppository	0.5/day		32%
				Placebo	–		47%1
	Marteau215	1998	95	MSZ suppository	3×1 g/week	12	48%
				Placebo	–		62%2
	Hanauer236	2000	65	MSZ suppository	0.5	24	46%
				Placebo			89%1
	Yokoyama237	2007	24	MSZ enema+oral	1 g×2/week+3 g/day	–	18%
				Oral MSZ alone	3g/day		77%

1p<0.05; 2p<0.05 at months 3,6 and 9, but the difference did not reach the significance level at month 12. MSZ: mesalazine; SZP: sulfasalazine.

6.2.1.3. Combining oral and topical 5-ASA therapy 

There have been two RCTs comparing combination treatment with oral mesalazine plus intermittent mesalazine enema to oral mesalazine alone for maintaining remission (Table 6.2). Remission rates were higher in patients receiving the combination. There are also three small RCTs comparing sulfasalazine 2 g/day or oral mesalazine 1.6 g/day to intermittent rectal mesalazine, with a trend in favour of the rectal treatment (Table 6.2).

It is therefore clear that oral or rectal 5-ASA is superior to placebo in maintaining remission in UC. The data suggest that rectal 5-ASA has equivalent or slightly superior efficacy to oral mesalazine in distal UC. The combination of oral mesalazine and intermittent rectal 5-ASA appears to provide further benefit. Although most authors in the studies claimed that patients found long-term rectal treatment acceptable, a postal survey of the UK patients showed that 80% preferred oral treatment alone.216 However, in another study in Spain, 5-ASA suppositories were generally well tolerated and considered comfortable for treatment of at least one year.217 The choice and options should be discussed with patients. Adding rectal therapy is a treatment option for patients who have relapsed on oral 5-ASA alone, although adherence to prescribed therapy should be addressed.

6.2.1.4. Dose-response effect 

A dose-response for maintenance of remission with mesalazine at doses greater than 0.8 g/day has not been established (Table 6.1, Table 6.2, Table 6.3). In an Italian study, no difference was found in relapse rates at 1 year on mesalazine 1.2 g compared to 2.4 g/day.218 Patients taking the higher dose were in remission for longer than those on the lower dose (median time in remission of 175 days vs 129 days, p<0.001), but it may be debated whether this is clinically significant. For those with extensive UC, however, the benefit of the higher dose was more marked (143 days vs 47 days, p<0.005). When the results for patients in remission at 12 months were analysed after stratifying for frequently relapsing (>3 relapses per year) vs less frequent relapses, 2.4 g/day was also performed significantly better than 1.2 g/day (75% vs 33%, respectively). This post hoc analysis must, however, be treated with caution.219 Another trial has also reported a trend for benefit in subjects receiving the higher dose of Pentasa 3 g/day compared with 1.5 g/day (p=0.051).220 As with other studies of high doses of 5-ASA, there was no increase in the frequency of adverse events. It is possible that high doses of maintenance oral mesalazine are required in some patients, perhaps in those that required high doses of oral 5-ASA to induce remission or those with frequently relapsing disease, but at present, there is no good evidence to support this.221 There are also no data supporting a dose-response relationship with rectal 5-ASA for maintaining remission in distal UC (Table 6.2), and no more than 1 g/day is necessary for rectal 5-ASA therapy.

Table 6.3. Trials comparing different oral 5-aminosalicylate formulations and dosages for maintaining remission in UC

	Author [ref]	Year	Number of patients	Study drugs	Dosage (g/day)	Duration (months)	Failure to maintain clinical or endoscopic remission
	Azad Khan238	1980	170	SZP	1	6	33%
				SZP	2		14%
				SZP	4		9%2,6
	Andreoli239	1987	13	MSZ	0.75	12	43%
				SZP	1.5		17%
	Ireland240	1988	164	OLZ SZP	1	6	43%
					2		26%2
	Riley241	1988	92	MSZSZP	0.82	12	40%
							46%
	Mulder242	1988	72	MSZSZP	1.5	12	45%
					3		56%
	McIntyre243	1988	79	BLZ	2	6	49%
				SZP	2		37%
	Rutgeerts244	1989	273	MSZ1SZP	0.75–1.5	12	54%
					2		42%
	Kiilerich245	1992	226	OLZ	1	12	54%
				SZP	2		49%
	Rijk246	1992	46	OLZ	1.5–2	12	46%
				SZP	3–4		48%
	Courtney222	1992	99	OLZ	1	12	25%
				MSZ1	1.2		46%2
	Travis247	1994	198	OLZ	0.51	12	52%
				OLZ	2		40%
				OLZ			40%3
	Ardizzone248	1995	88	MSZ1	1	12	38%
				SZP	2		51%
	Kruis249	1995	160	OLZ	0.51.25	6	36%
				OLZ	2		49%
				OLZ	2		24%
				SZP			32%
	Nilsson250	1995		OLZ
				SLZ
	Fockens220	1995	169	MSZ	1.5	12	46%
				MSZ4	3		33%5
	Paoluzi218	2005	156	MSZ1	1.2	12	74%
				MSZ1	2.4		70%

1Asacol/Claversal; 2p<0.05; 3failure including relapses plus study withdrawals; 4Pentasa; 5p=0.057; unacceptable side-effects were frequent in the 3 g group.

6.2.1.5. Comparison of oral 5-ASA formulations 

In the Cochrane meta-analysis206 the odds ratio for the failure to maintain clinical or endoscopic remission (withdrawals and relapses) was calculated for the trials in which sulfasalazine and 5-ASA were compared (Table 6.3).218, 220, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250 The odds ratio was 1.29 (95%CI 1.05–1.57), with a negative NNT, suggesting greater therapeutic effectiveness for sulfasalazine. Sulfasalazine and 5-ASA had similar adverse event profiles (OR 1.16, 95% CI 0.62–2.16, and OR 1.31, 95% CI 0.86–1.99 respectively). However, the trials that compared 5-ASA and sulfasalazine are likely to have been biased in favour of sulfasalazine, because most trials enrolled sulfasalazine-tolerant patients, which would have minimized sulfasalazine-related adverse events. There is only one, single-blind RCT218,220,222 comparing olsalazine 1 g/day head to head with oral mesalazine 1.2 g/day as maintenance for UC. At 1 year, remission rates were 75% and 54%, respectively (p=0.02). The frequency of adverse events was low in this study, especially the rate of diarrhoea in the olsalazine group, perhaps because there was a predominance of patients with distal UC. This study has not been replicated and the dose inequivalence noted, although this is unlikely to have mattered (above). No controlled trial has yet been published on maintenance of remission with mesalazine MMx.

6.2.1.6. Adherence to 5-ASA treatment 

Adherence to 5-ASA appears to be important for improving outcome of patients with UC. When the adherence rate in 94 outpatients on 5-ASA with clinically quiescent UC for at least 6 months was studied, the overall adherence rate was 40% and the median amount of medication dispensed per patient was 71% (8–130%) of the prescribed regimen.223 Logistic regression identified a history of four or more prescriptions and male gender increased the risk of non-adherence. Being married, having extensive disease or having an endoscopy within the past 24 months reduced non-adherence. The same group conducted a prospective study to determine the effects of non-adherence with 5-ASA among 99 patients with quiescent UC. After 12 months, patients who collected <80% of their prescriptions had a 5-fold higher OR (5.5, 95% CI 2.3–13.0).204 In a pilot study, patients were randomized to receive either once-daily or conventional (twice or three times daily), mesalazine for maintenance of remission in UC.224 After 6 months, patients in the once-daily arm appeared more satisfied with their regimen and consumed more medication than those in the conventional arm (90% vs 76%; p=0.07). The authors concluded that once-daily oral formulations of 5-ASA were likely to be a better therapeutic option due to their ability to offer comparable efficacy and improved adherence. This premise appears correct. An investigator-blinded study of 362 patients randomised to receive Pentasa 2 g once daily or 1 g twice daily, showed a 12% better remission rate at 1 year (73.8% vs 63.6% respectively) in the single daily dose group.225 Patient questionnaires showed significantly greater compliance (p<0.05) and acceptability (p<0.001) in the once daily group. The study has yet to be reported in full, but given comparable efficacy between once daily and divided dosing regimes for the treatment of active UC with mesalazine MMx (Mezavant®/Lialda®) and Salofalk®,23, 24, 25, 226 the effect is likely to be generic rather than compound-specific.

6.2.2.1. Efficacy of thiopurines for maintenance of remission 

Seven RCTs evaluating the efficacy of thiopurines azathioprine (AZA) and mercaptopurine (MP) for maintenance of remission in UC are listed in Table 6.4.136, 175, 182, 251, 252, 253, 254 In the Cochrane meta-analysis published after the Consensus meeting,255 six of these studies on 286 patients were considered. The study quality was judged generally poor and the evidence for using thiopurines in UC is weaker than that for Crohn's disease.158 AZA was shown to be superior to placebo on the basis of four trials (OR for failure to maintain remission 0.41, 95% CI 0.24–0.70). The results were similar when analyses were limited to patients who had successful induction of remission (data available for two studies). There was no clear evidence of a dose-response effect for AZA, or for use of co-medication with mesalazine in these studies. The two open label studies that compared MP to mesalazine and AZA to sulfasalazine showed significant heterogeneity and could not be pooled. Adverse effects occurred in 11/127 patients receiving AZA, including acute pancreatitis (3 cases) and bone marrow suppression (5 cases). Since this meta-analysis, a further RCT has been published by Ardizzone et al.136 72 patients with active steroid-dependent UC were randomised (investigator-blind) to AZA 2 mg/kg/day or mesalazine 3.2 g/day for 6-months. Steroid-free, clinical and endoscopic remission was achieved in 53% on AZA, compared to 21% given 5-ASA (intention to treat analysis: OR 4.78, 95% CI 1.57–14.5). This is the best trial to date.

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

	Author [ref]	Year	Number of patients	Study drugs	Dosage	Study design	Duration (months)	Failure to maintain clinical or endoscopic remission
	Jewell175	1974	80	Azathioprine	2.5 mg/kg/day then reduced to 1.5–2 mg/kg/day after 3 months	Double-blind	121	60%
				Placebo	–			77%
	Hawthorne251	1992	672	Azathioprine	100 mg/day	Double-blind	12	36%
				Placebo	–			59%3
	Mate-Jimenez182	2000	34	6–mercaptopurine	1 .5 mg/kg/day	Open label	181	50%
				Methotrexate	15 mg/week			85%
				MSZ	3g/day			93%3
	Sood252	2000	50	Azathioprine4	2.mg/kg/day	Single (patient)-blind	121	44%
				Placebo	–			60%3
	Sood253	2002	35	Azathioprine4	2.5 mg/kg/day	Double-blind	121	23%
				Placebo	–			56%
	Sood254	2003	25	Azathioprine+SZP	2 .5 mg/kg/day+6 g/day	Open label	181	77%
				SZP	6g/day			44%3
	Ardizzone136	2006	72	Azathioprine	2 m g/kg/day	Single	6	47%
				MSZ	3.2g/day	(Investigator)-blind		79%3

1Inclusion of patients with active disease who initially received steroids for induction of remission. 2All patients included in this study were in remission on azathioprine for at least 6 months (withdrawal design); co-medication with 5-ASA was permitted and taken by 82% of patients. 3p<0.05. 4Co-medication with sulfasalazine 6 g/day in all patients.

Evidence in support of the thiopurines for UC also comes from observational cohorts in retrospective series.256, 257, 258, 259, 260, 261, 262 The best among these is the 30 year cohort from the Oxford IBD clinic between 1968 and 1999.262 In this series, the overall remission rate in the 346 patients with UC who were treated with AZA was 58%, but increased to 87% among patients on therapy for more than 6 months. The proportion of patients in remission at 5 years was 62% applying a strict definition of relapse, or 81% allowing for a brief relapse with a short corticosteroid course. The median time to relapse after stopping AZA was 18 months.

6.2.2.2. Thiopurines after ciclosporin (or tacrolimus) for induction of remission 

Calcineurin inhibitors are rescue therapy options for steroid-refractory UC (see Section 5.2.5). Since calcineurin inhibitors are best discontinued within 6 months because of nephrotoxicity, these agents are generally proposed as induction therapy until slower-acting immunomodulators such as AZA or MP become effective. AZA or MP are introduced while the patient is still on ciclosporin (CsA) or tacrolimus and steroids are being tapered. The justification of thiopurines in this setting, even in patients who are 5-ASA naive, is the high colectomy rate (36-69% in the 12 months following introduction of CsA, Section 5.2.5 63, 64, 65). Restrospective series have suggested that thiopurines reduce the risk of colectomy after the induction period with CsA.63, 263, 264, 265 In 1996, a series of 29 patients successfully treated with ciclosporin were followed for a median 92 weeks, and 22% of patients taking MP required a colectomy, compared to 72% of those not taking MP.263 In another series 5/19 patients receiving AZA (26%) underwent colectomy during the follow-up, compared to 9/11 subjects (81%) who did not receive AZA maintenance (p=0.01).265 Similar results have been reported from Chicago: of 36/42 initial responders to CsA, 25 (69%) also received MP or AZA, of whom 20% required colectomy vs 45% who did not thiopurines during the 5 year follow up.63

After intravenous CsA, a switch to oral therapy occurs as soon as a clinical response has been achieved, with a view to acting as a ‘bridge’ until the therapeutic effect of AZA is achieved. Nevertheless, the usefulness of the oral CsA bridge has been challenged. In a retrospective series from Barcelona, all responders to iv CsA were treated with AZA, without oral ciclosporin.266 Cumulative probabilities of relapse were 42%, 72% and 77% at 1, 3 and 5 years, and cumulative probabilities of colectomy were respectively 29%, 35% and 42%. These are similar to or better than those reported in the literature, so the authors concluded that the ‘bridging step’ with oral CsA may not be necessary. This needs more investigation.

Three retrospective studies have assessed the long term outcome of patients after an attack of UC treated with intravenous CsA.63, 64, 65 All describe a high rate of relapse and colectomy. In 76 patients treated with CsA for intravenous steroid-refractory UC, 65% relapsed within 1 year, and 90% within 3 years 90%.64 Unusually, a beneficial effect of AZA (given to 35/56 who could tolerate it) could not be demonstrated either to maintain remission or prevent colectomy (ns). After 5 years 47% in the non-AZA and 40% in the AZA-treated patients came to colectomy, and after 7 years the overall colectomy rate was 58%. The Leuven experience described 142 patients, 118 (83%) of whom had an initial response to CsA and avoided colectomy during initial hospitalization.65 64/118 (54%) subsequently required colectomy. The rate of colectomy in those already on AZA compared with those starting AZA concurrently with CsA was 59% vs 31%, respectively (p<0.05). Life-table analysis showed that 33% of patients required colectomy at 1 year, but the probability increased to 88% at 7 years if CsA was used in patients already on AZA. Consequently CsA has little role for patients who have failed AZA of an appropriate dose and duration.

6.2.3.1. Efficacy for maintenance 

Details of the ACT 1 & 2 studies are given in Section 5.4.3.78. The design of these studies was different to standard maintenance trials (Section 6.1.1). Patients included in the maintenance phase were not necessarily in steroid-free clinical or endoscopic remission. Moreover, non-responders to IFX were taken into account in the calculation of week 30 and week 54 response or remission rates. In both studies, a significantly higher proportion of patients had a clinical response or remission on IFX at weeks 8 and 30 (and at week 54 in the ACT 1 trial), compared to placebo. In ACT 1, remission rates at week 54 were 35% (5 mg/kg), 34% (10 mg/kg) and 17% (placebo). In ACT 2, remission rates at week 30 were 26% (5 mg/kg), 36% (10 mg/kg) and 11% (placebo). The proportion of patients with a sustained clinical remission at all time points was 7% (placebo) and 20% (5 mg/kg) after 54 weeks in ACT 1, and 2% (placebo) and 15% (5 mg/kg) after 30 weeks in ACT 2. The steroid-free remission rates in the 74 patients receiving corticosteroids at baseline were very modest although still statistically significant. In ACT 1, steroid-free remission at week 54 was achieved in 24% (5 mg/kg), 19% (10 mg/kg) and 10% (placebo). In ACT 2, the corresponding values at week 30 (7 months) were 18%, 27% and 3%. The rates of clinical response and remission were similar between the subpopulations of patients who were “corticosteroid-refractory” (i.e., those receiving corticosteroids at baseline) and those who were “not corticosteroid-refractory”.

6.2.3.2. Combining IFX and immunomodulators 

As with Crohn's disease,158 the combination of IFX and a thiopurine analogue or corticosteroids is probably justified to decrease immunogenicity, which is the source of infusion reactions and loss of response.267, 268 Since antibodies to IFX occur early in the treatment, the question of discontinuing the immunomodulator has been addressed by the Leuven group for Crohn's disease. Results from a single centre open-label randomized, withdrawal trial suggest that the immunomodulator can be stopped after 6 months with no loss of response to IFX over 2 years.269 These results should still be interpreted with caution, because circulating concentrations of IFX declined over time when the immunomodulator was discontinued. On the other hand, the report of eight cases of a rare form of hepatosplenic T cell lymphoma occurring in young patients treated concurrently with IFX and thiopurines must also be taken into account.270 Short-term combination (6 months) appears to offer a good balance between risks and efficacy for those in whom IFX is continued. If a patient is naïve to AZA when given IFX, a reasonable option is to determine whether remission will be maintained by AZA alone, without committing that patient to maintenance IFX.

Whether IFX acts as a bridge to remission that is maintained by thiopurines, or whether AZA simply slows the rate of descent to inevitable relapse (the ‘parachute’271), remains debated. This strategy has not yet been tested in UC, but is an acceptable option for thiopurine-naive patients with steroid-dependent Crohn's disease.272 The 2 year follow up of patients who received a single dose of IFX as rescue therapy for intravenous steroid-refractory UC (Section 5.2.573) presented after the Consensus meeting, showed that 13/16 patients who received AZA avoided colectomy (with or without oral 5-ASA) compared to 5/8 who received 5-ASA alone (ns).273 Consequently, whether maintenance IFX (with or without thiopurines) is better than thiopurines alone to prevent relapse and avoid late colectomy cannot be deduced.

6.2.4.1. Other probiotics 

No other probiotic has been subject to properly powered RCTs. When 100 ml/day of fermented milk containing Bifidobacterium bifidum YIT 4007, B. breve YIT 4065, and L. acidophilus YIT 0168 was given to 21 UC patients over 1 year,277 neither investigators nor patients were blinded, and other treatments could be administered. There were fewer relapses in the treatment arm (27% in the milk group vs 90% in the controls), but no differences in endoscopic lesions. Another group of 187 patients with UC in remission for less than 12 months were randomised to receive either Lactobacillus GG 18×109 viable bacteria/day, 5-ASA 2.4 g/day, or the combination.278 There were no differences in sustained clinical or endoscopic remission rates at 6 and 12 months between the three treatment groups. In a post-hoc analysis, however, treatment with Lactobacillus GG appeared to prolong the relapse-free time compared to 5-ASA. Relapse rates at 12 months were 136/10,000 person-months on Lactobacillus GG alone and 181/10 000 person-months on 5-ASA (p=0.01). Further studies are needed.

6.2.5.1. Antibiotics 

The potential benefit of adding ciprofloxacin to conventional therapy has been investigated.279 In a randomized, placebo-controlled, double-blind clinical trial, ciprofloxacin (1–1.5 g/day) or placebo was administered for 6 months to 83 patients referred with active UC refractory to conventional treatment. All the patients were initially treated with a high but decreasing dose of prednisone and with 5-ASA. Treatment failure was the primary end point, defined as both symptomatic and endoscopic failure to respond. The treatment failure rate was 21% in the ciprofloxacin-treated group and 44% in the placebo group (p=0.02). The study design was more appropriate for an induction rather than a maintenance study and inclusion criteria, definition of clinical response and concomitant therapies have been criticized.280 Consequently ciprofloxacin should not be considered effective for maintaining remission in UC. In another double-blind, randomized trial, metronidazole (0.6 g/day) and sulfasalazine (2 g/day) were compared for maintenance of remission in 40 patients with UC in remission for less than 12 months.281 After 1 year, metronidazole was found to be slightly more effective than sulfasalazine. No significant side effects were noted, and in particular, no paraesthesiae were reported. These data are regarded as insufficient by the Consensus to recommend antibiotics for maintenance of remission in UC.

6.2.5.2. Methotrexate 

Data on methotrexate (MTX) for maintenance of remission in UC are few. The single RCT was principally designed for induction of remission in refractory, active UC and used a dose (12.5 mg/week) that is probably sub-therapeutic (see Section 5.4.6).181 The proportions of patients who relapsed after first remission (MTX 64% vs placebo, 44%) were not significantly different. An open-label study compared MP, MTX and 5-ASA in 72 steroid-dependent IBD patients, including 34 with UC182 (Table 6.4). Patients on prednisone were randomly assigned in a 2:2:1 ratio to receive oral MP 1 mg/kg, MTX 15 mg/week, or 5-ASA 3 g/day. All patients who achieved remission at week 30 were then included in a maintenance study for 76 weeks. A significantly higher proportion of patients achieved remission in the MP group (79%) than in the 5-ASA group (25%), with no statistical differences compared to the MTX group (58%). For maintenance of remission, the higher rate was found in the MP group (64%) compared to MTX (14%) and 5-ASA (0%). Too many questions were being addressed by this study for conclusions on the relative efficacy of MP and MTX in UC to be drawn.

Several retrospective series have also been published,183, 282, 283, 284, 285 to a total of 91 patients. Most had failed or been intolerant of AZA and were treated with MTX at various doses and routes of administration. The response or remission rates ranged from 40% to 75%, suggesting that some patients with UC may respond well to methotrexate. One study distinguished between patients given MTX for AZA-intolerance and AZA-failure.285 MTX (median oral dose 20 mg/week) was tolerated by 27/31 (87%) patients who had been unable to tolerate AZA. Of those treated with MTX after failure with AZA, 5/11 patients had a colectomy vs 5/31 patients who were intolerant of AZA (p<0.05). The results are heterogeneous and it is possible that the dose of MTX is an important determinant of efficacy, but the Consensus considered that there is currently insufficient evidence to recommend MTX for UC.

6.2.5.3. Omega-3 fatty acids (fish oil) 

Preparations containing omega-3 fatty acids and eicosapentaenoïc acid in particular, may have anti-inflammatory properties by reducing the production of leucotriene B4286, 287 Several studies have been conducted in UC with different formulations and dosing of n-3 fatty acids.288, 289, 290, 291, 292, 293, 294, 295, 296 Only three randomized controlled trials were selected for a Cochrane meta-analysis published after the Consensus,297 which included 138 UC patients who were in remission at the time of recruitment.291, 293, 294 The pooled analysis showed a similar relapse rate in the n-3 treated patients and controls (RR 1.02, 95%CI 0.51–2.03, p=0.96). No significant adverse events were recorded.

6.2.5.4. Appendicectomy 

Studies have focused on the role of appendicectomy in the UC pathogenesis. A meta-analysis included 13 case-control studies and suggested that appendicectomy gives a 69% reduction in the risk of developing UC (OR 0.31, 95%CI 0.25–0.38; p<0.0001).298 The influence of potential confounders such as smoking was excluded. The protective effect of appendicectomy for the development of UC appears to be limited to patients who undergo appendicectomy before age 20 years and is mainly observed for primary appendicectomy (surgery for appendicitis) and not for incidental appendicectomy (removal of the appendix for other reasons).299 The outcome of 41 UC patients with an appendicectomy before diagnosis and 466 with no previous surgery, who were all prospectively included in an IBD database, has been compared.300 Previous appendicectomy has a beneficial effect on the course of UC, with a less marked year-by-year disease activity and a decreased risk of colectomy. This protective effect was additive to that of current smoking. Similar results have been reported from the Brisbane group, who have explored the subject in detail and shown an association between previous appendicetomy for appendicitis and a mild course of extensive colitis, but no influence on the pattern of primary sclerosing cholangitis.301, 302 There are only anecdotal data on the course of UC when appendicectomy is performed after UC diagnosis.103 Consequently, the Consensus considered that there is no enough evidence to recommend appendicectomy for preventing relapse in UC.

6.2.5.5. Biological and other therapy 

Adalimumab, certolizumab, etanercept, natalizumab, visulizumab, interleukin 10, fontolizumab (an anti-interferon γ antibody), basiliximab, daclizumab, alicaforsen (an anti-ICAM1 antisense molecule), anti-IL12 and anti-IL6 antibodies have not yet been evaluated for maintenance of remission in UC, and nor have leucocytapheresis, tacrolimus, or cyclophosphamide in any meaningful way.