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A severe attack is seen in approximately 15% of patients with ulcerative colitis (UC).1 Corticosteroids remain a mainstay in the management. However, about 30% of the patients are unresponsive and will require colectomy short-term,2, 3 and long-term studies report even higher colectomy frequencies.4 Therefore, new therapeutic alternatives are searched for. Ciclosporin was the first successful rescue therapy.5, 6 The short-term success rate was high with remission rates of 74–88%, but the long-term efficacy has been disappointing. In retrospective analyses from Oxford and Leuven, colectomy rates after 7–8 years have reached 58–88%.7, 8 Severe side effects including mortality have also limited its use. Infliximab treatment was subsequently introduced in unresponsive acute UC with conflicting results at first.9, 10 In a controlled Swedish-Danish trial using infliximab as rescue therapy, colectomy rates after 3 months were lower in infliximab-treated patients (29%) compared with placebo-treated patients (67%).11 However, the long-term prognosis after rescue therapy with infliximab remains largely unknown.12
We present a 3-year follow-up study of patients who participated in the Swedish-Danish infliximab/placebo trial conducted between July 2001 and January 2004. The primary objective was to determine the number of patients escaping a colectomy at follow-up. Secondary objectives were to determine the number of patients in clinical and endoscopic remission and to assess health-related quality of life.
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The aim with rescue therapy in UC is to induce clinical and endoscopic remission and to reduce colectomy frequency without increasing morbidity and mortality. This study emphasizes the value of infliximab as rescue therapy in acute severe steroid-refractory UC, as the short-term response remained in a long-term perspective. In our original trial, colectomy frequency after 3 months was significantly reduced in patients treated with infliximab compared with placebo.11 Our short-term results are supported by uncontrolled studies, reporting colectomy frequencies between 15% and 33% during the first few months.19–21 However, higher figures of up to 75–80% have been reported elsewhere.22, 23
The present study, which has the longest follow-up period, shows that a difference remains after 3 years in favour of infliximab, with a colectomy frequency of 50% compared with 76% in the placebo group. Most colectomies were performed during the first 3 months and only few during the subsequent follow-up period. Retrospective long-term follow-up data from other centres support our long-term results. In the largest series, Kohn et al. reported colectomy-free survival in 58/83 (70%) patients treated with infliximab for steroid-refractory severe UC during a median follow-up period of 23 months.20 In a Scottish study, 13/39 patients underwent early colectomy after infliximab rescue therapy, and another two patients were operated later during a median follow-up of 203 days reaching a total colectomy frequency of 38%.21 Jacobovits et al. reported that of a subgroup of 14 patients, treated as in-patients with infliximab owing to severe, steroid-refractory UC, eight (57%) patients had a colectomy during a follow-up for 274 days.19 Others reported that 8 (38%) of 21 infliximab-treated patients were operated during a median follow-up of 155 days,24 and in another small series, 2 (18%) of 11 patients had a colectomy.25
The comparison of these studies is impeded by differences regarding inclusion criteria, definition of steroid failure, treatment regime including number and time of infliximab infusions, subsequent maintenance therapy, duration of follow-up period and the retrospective uncontrolled study design. In our original trial, only hospitalized patients with an acute, steroid-refractory, moderate-to-severe attack of UC were included. We used one single infusion of infliximab 5 mg/kg as our original study was designed prior to the results of Active Ulcerative Colitis Trial (ACT)-1 and ACT-2 trials.26 In these studies, patients with chronic steroid-dependant UC were included, whereas patients who had received intravenous corticosteroids within 2 weeks or were judged likely to require colectomy within 12 weeks were excluded.27 Patients were randomized to receive infliximab infusions, 5 or 10 mg/kg, at weeks 0, 2 and 6 and then every 8 weeks or placebo. The cumulative colectomy frequencies through 54 weeks were low and reached 10% for patients given infliximab and 17% for those given placebo.27 The low colectomy frequency in the placebo group illustrates that patients included in these trials had less severe UC compared with patients in our study and a comparison of outcome is therefore not justified.
In other studies,24, 25 rescue therapy with a standard schedule of three infusions on weeks 0, 2 and 6 was given, whereas other authors gave a various number of infusions.19, 20 Kohn et al. concluded that two or more infusions seemed more effective than one single infusion.20 There is thus a need for prospective randomized trials to define the optimal dosing regime of infliximab as rescue therapy in UC.
The benefit of rescue therapy with infliximab obviously was achieved during the first 3 months (Figure 1), and during the subsequent follow-up period, the proportion of colectomies was similar in the two groups: infliximab group 5/17 (29%) and placebo group 2/7 (29%). Mucosal healing is an important therapeutic goal in UC and has been shown to be a predictor of future disease course and long-term prognosis. It is associated with improved quality of life and with a lower risk of relapse, colectomy and colorectal cancer.28 In this study, presence of mucosal healing at 3 months predicted the future risk of colectomy. None of eight patients achieving endoscopic remission (Mayo endoscopic subscore = 0) underwent surgery during the 3-year follow-up compared with 7/14 patients without endoscopic remission. Likewise, in a population-based Norwegian cohort, a lower colectomy frequency was seen in UC patients with mucosal healing compared with those with inflammatory activity.29
The importance of optimal maintenance therapy after successful rescue therapy is emphasized by studies showing lower colectomy frequencies in patients who received thiopurines after ciclosporin rescue therapy compared with those not given immunomodulators.8, 30, 31 It is reasonable to assume that the 3-year colectomy rate is more dependent on the maintenance therapy than on a single infusion of infliximab as rescue therapy. However, there is currently no evidence that thiopurine therapy reduces the colectomy risk after rescue therapy with infliximab in a severe attack of UC.19–21 Our original study design did not define treatment beyond 3 months, and the distribution of subsequent maintenance therapy thus differed between the two groups. In the infliximab-treated group, 12/16 patients received azathioprine compared with 4/7 in the placebo group. Colectomy frequencies did not differ in patients receiving azathioprine after infliximab compared with those not given thiopurines (3/12 vs. 2/4, P = 0.55) (Table 1). Furthermore, some patients received additional therapy with anti-TNF or leucocytapheresis probably reflecting a more aggressive disease course. The use of maintenance therapy differed also in other studies using 5-ASA only, azathioprine or mercaptopurine alone or in combination with 5-ASA or with scheduled infliximab.19, 21, 24, 25 Accordingly, the best maintenance treatment after successful rescue therapy with infliximab needs further study. Azathioprine is superior to 5-ASA in corticosteroid-dependant UC32 and may be recommended as maintenance therapy in azathioprine-naïve patients responding to infliximab induction. Scheduled infliximab infusions are an alternative in a patient who, during immunosuppressive therapy, develops a severe attack and responds to infliximab induction.33 The evidence, however, for such a recommendation in a patient successfully treated with rescue therapy in severe UC is limited at present.
Adverse events were benign in the present series and did not differ between the two treatment groups. They occurred, as expected, during the first 3 months after the infliximab infusion.11 During this follow-up period, adverse events, such as small intestinal obstruction or high ileostomy output, were related to previous colectomy and not to infliximab therapy.
In conclusion, this study supports the use of infliximab in acute severe steroid refractory UC, and the favourable short-term response remains in a long-term perspective. Mucosal healing at 3 months after rescue therapy influenced subsequent colectomy frequency. The optimal dosing of infliximab and best possible maintenance therapy after successful rescue therapy need to be defined. Infliximab treatment was safe, but serious complications may occur.20, 21 All these aspects must be taken into account and carefully discussed with the patient in the choice between rescue therapy and colectomy in a severe attack of UC.