Outcomes of salvage therapy for steroid-refractory acute severe ulcerative colitis: ciclosporin vs. infliximab

Croft, Anthony; Walsh, Alissa J.; Doecke, James D.; Cooley, Robert N.; Howlett, M.; Radford‐Smith, Graham

doi:10.1111/apt.12375

Cited by 87 publications

(89 citation statements)

References 41 publications

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“…Importantly, post-colectomy quality-of-life scores and interviews with participants who had undergone surgery both suggest that colectomy is not a bad outcome. There is evidence from observational studies that the cumulative rate of colectomy increases over time, not only with ciclosporin, but also with infliximab 18, 19, 20, 21, 22, 23, 24. Hence, we plan to follow the trial and cohort participants for 10 years from recruitment, using routine National Health Service data to monitor readmissions and colectomies, with annual questionnaires to monitor trial patients' quality of life.…”

Section: Discussionmentioning

confidence: 99%

Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial

Williams

Alam

Alrubaiy

et al. 2016

The Lancet Gastroenterology & Hepatology

203

149

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SummaryBackgroundInfliximab and ciclosporin are of similar efficacy in treating acute severe ulcerative colitis, but there has been no comparative evaluation of their relative clinical effectiveness and cost-effectiveness.MethodsIn this mixed methods, open-label, pragmatic randomised trial, we recruited consenting patients aged 18 years or older at 52 district general and teaching hospitals in England, Scotland, and Wales who had been admitted, unscheduled, with severe ulcerative colitis and failed to respond to intravenous hydrocortisone within about 5 days. Patients were randomly allocated (1:1) to receive either infliximab (5 mg/kg intravenous infusion given over 2 h at baseline, and again at 2 weeks and 6 weeks after the first infusion) or ciclosporin (2 mg/kg per day by continuous infusion for up to 7 days, followed by twice-daily tablets delivering 5·5 mg/kg per day for 12 weeks). Randomisation used a web-based password-protected site, with a dynamic algorithm to generate allocations on request, thus protecting against investigator preference or other subversion, while ensuring that each trial group was balanced by centre, which was the only stratification used. Local investigators and participants were aware of the treatment allocated, but the chief investigator and analysts were masked. Analysis was by treatment allocated. The primary outcome was quality-adjusted survival—ie, the area under the curve (AUC) of scores from the Crohn's and Ulcerative Colitis Questionnaire (CUCQ) completed by participants at baseline, 3 months, and 6 months, then every 6 months from 1 year to 3 years. This trial is registered with the ISRCTN Registry, number ISRCTN22663589.FindingsBetween June 17, 2010, and Feb 26, 2013, 270 patients were recruited. 135 patients were allocated to the infliximab group and 135 to the ciclosporin group. 121 (90%) patients in each group were included in the analysis of the primary outcome. There was no significant difference between groups in quality-adjusted survival (mean AUC 564·0 [SD 241·9] in the infliximab group vs 587·0 [226·2] in the ciclosporin group; mean adjusted difference 7·9 [95% CI −22·0 to 37·8]; p=0·603). Likewise, there were no significant differences between groups in the secondary outcomes of CUCQ scores, EQ-5D, or SF-6D scores; frequency of colectomy (55 [41%] of 135 patients in the infliximab group vs 65 [48%] of 135 patients in the ciclosporin group; p=0·223); or mean time to colectomy (811 [95% CI 707–912] days in the infliximab group vs 744 [638–850] days in the ciclosporin group; p=0·251). There were no differences in serious adverse reactions (16 reactions in 14 participants receiving infliximab vs ten in nine patients receiving ciclosporin); serious adverse events (21 in 16 patients vs 25 in 17 patients); or deaths (three in the infliximab group vs none in the ciclosporin group).InterpretationThere was no significant difference between ciclosporin and infliximab in clinical effectiveness.FundingNIHR Health Technology Assessment programme.

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Section: Discussionmentioning

confidence: 99%

Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial

Williams

Alam

Alrubaiy

et al. 2016

The Lancet Gastroenterology & Hepatology

203

149

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“…We used the electronic search strategies checklist of the Cochrane Collaboration. 31 We identified nine observational studies and one RCT [32][33][34][35][36][37][38][39][40][41] that compared the efficacy and safety of ciclosporin with those of infliximab ( Table 1). Although both ciclosporin and infliximab were effective in steroid-resistant UC, results did not agree which drug was better.…”

Section: Review Of Literaturementioning

confidence: 99%

“…[32][33][34][35] One small retrospective study 34 of 38 patients with acute UC resistant to steroids showed a higher rate of colectomy in patients who received ciclosporin (63% and 68% at 3 and 12 months, respectively) than in those who received infliximab (21% and 37% at 3 and 12 months, respectively); there was no significant difference between groups in adverse events (AEs) or steroid dependence. A prospective study 36 found the colectomy-free rate at discharge, and at 3 and 12 months from admission, was significantly higher in patients who had infliximab as a rescue therapy (n = 45) compared with those who had ciclosporin (n = 38). A minute retrospective study 35 of two cohorts of patients (15 on ciclosporin and six on infliximab) showed a higher rate of colectomy and opportunistic infection in patients who received ciclosporin compared with those who received infliximab.…”

Section: Review Of Literaturementioning

confidence: 99%

Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: pragmatic randomised Trial and economic evaluation (CONSTRUCT)

Williams

Alam

Alrubaiy

et al. 2016

Health Technol Assess

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BackgroundThe efficacy of infliximab and ciclosporin in treating severe ulcerative colitis (UC) is proven, but there has been no comparative evaluation of effectiveness.ObjectiveTo compare the clinical effectiveness and cost-effectiveness of infliximab and ciclosporin in treating steroid-resistant acute severe UC.MethodBetween May 2010 and February 2013 we recruited 270 participants from 52 hospitals in England, Scotland and Wales to an open-label parallel-group, pragmatic randomised trial. Consented patients admitted with severe colitis completed baseline quality-of-life questionnaires before receiving intravenous hydrocortisone. If they failed to respond within about 5 days, and met other inclusion criteria, we invited them to participate and used a web-based adaptive randomisation algorithm to allocate them in equal proportions between 5 mg/kg of intravenous infliximab at 0, 2 and 6 weeks or 2 mg/kg/day of intravenous ciclosporin for 7 days followed by 5.5 mg/kg/day of oral ciclosporin until 12 weeks from randomisation. Further treatment was at the discretion of physicians responsible for clinical management. The primary outcome was quality-adjusted survival (QAS): the area under the curve (AUC) of scores derived from Crohn’s and Ulcerative Colitis Questionnaires completed by participants at 3 and 6 months, and then 6-monthly over 1–3 years, more frequently after surgery. Secondary outcomes collected simultaneously included European Quality of Life-5 Dimensions (EQ-5D) scores and NHS resource use to estimate cost-effectiveness. Blinding was possible only for data analysts. We interviewed 20 trial participants and 23 participating professionals. Funded data collection finished in March 2014. Most participants consented to complete annual questionnaires and for us to analyse their routinely collected health data over 10 years.ResultsThe 135 participants in each group were well matched at baseline. In 121 participants analysed in each group, we found no significant difference between infliximab and ciclosporin in QAS [mean difference in AUC/day 0.0297 favouring ciclosporin, 95% confidence interval (CI) –0.0088 to 0.0682;p = 0.129]; EQ-5D scores (quality-adjusted life-year mean difference 0.021 favouring ciclosporin, 95% CI –0.032 to 0.096;p = 0.350); Short Form questionnaire-6 Dimensions scores (mean difference 0.0051 favouring ciclosporin, 95% CI –0.0250 to 0.0353;p = 0.737). There was no statistically significant difference in colectomy rates [odds ratio (OR) 1.350 favouring infliximab, 95% CI 0.832 to 2.188;p = 0.223]; numbers of serious adverse reactions (event ratio = 0.938 favouring ciclosporin, 95% CI 0.590 to 1.493;p = 0.788); participants with serious adverse reactions (OR 0.660 favouring ciclosporin, 95% CI 0.282 to 1.546;p = 0.338); numbers of serious adverse events (event ratio 1.075 favouring infliximab, 95% CI 0.603 to 1.917;p = 0.807); participants with serious adverse events (OR 0.999 favouring infliximab, 95% CI 0.473 to 2.114;p = 0.998); deaths (all three who died received infliximab;p = 0.247) or concomitant use of immunosuppressants. The lower cost of ciclosporin led to lower total NHS costs (mean difference –£5632, 95% CI –£8305 to –£2773;p < 0.001). Interviews highlighted the debilitating effect of UC; participants were more positive about infliximab than ciclosporin. Professionals reported advantages and disadvantages with both drugs, but nurses disliked the intravenous ciclosporin.ConclusionsTotal cost to the NHS was considerably higher for infliximab than ciclosporin. Nevertheless, there was no significant difference between the two drugs in clinical effectiveness, colectomy rates, incidence of SAEs or reactions, or mortality, when measured 1–3 years post treatment. To assess long-term outcome participants will be followed up for 10 years post randomisation, using questionnaires and routinely collected data. Further studies will be needed to evaluate the efficacy and effectiveness of new anti-tumour necrosis factor drugs and formulations of ciclosporin.Trial registrationCurrent Controlled Trials ISRCTN22663589.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 44. See the NIHR Journals Library website for further project information.

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“…If there is no substantial improvement in disease intensity over a period of 72 h by conservative intensive care and drug treatment with high-dose steroids, surgery should be considered and interdisciplinarily discussed as an alternative to a further increase in drug therapy with calcineurin inhibitors or anti-TNFα antagonists [11,19]. Of note, a further increase in drug therapy using calcineurin inhibitors or anti-TNFα antibodies can postpone surgery for another year in approximately 42-65% of patients [20,21]. Furthermore, independent analyses showed that delayed surgery in severe acute colitis results in significantly more major complications and higher mortality rates [22,23].…”

Section: Duration and Escalation Of Conservative Treatment Versus Surmentioning

confidence: 99%

Impact of Modern Drug Therapy on Surgery: Ulcerative Colitis

Kuehn

Hodin

2018

Visc Med

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Background: The primary treatment of ulcerative colitis (UC) is conservative, and substantial therapeutic progress has been made in the past few decades. Meanwhile, biologicals have become a mainstay in the treatment for steroid-refractory UC. Despite further development of drug therapy and an increased time span to operation, a significant proportion of patients with UC require surgical intervention. Surgical intervention needs to be carried out in medically refractory cases, imminent or malignant transformation, or complications. This article discusses the impact of modern drug therapy on surgery for UC. Methods: A selective literature search of PubMed was conducted, taking into account current studies, reviews, meta-analyses, and guidelines. Selected articles were then reviewed in detail and recommendations were drafted based on data and conclusions of the articles. Results: In recent years, modern drug therapy has changed the timing, approach, and outcomes of surgery for UC. Most of the studies showed a decrease in surgery rates over time while the rate of emergency colectomies remains unchanged. So far, no convincing surgery-sparing effect of newer medications has been established, and it remains debatable if surgery rates have decreased because of improved management for UC in general or due to the introduction of biologicals. The intensified conservative therapy with increasing use of biologics has been accompanied by a trend towards performing a three-step procedure in the last decade. There is a subset of patients with complex refractory disease who most likely benefit from elective surgery as an alternative to prolonged conservative therapies after failure of first-line treatment. The majority of patients after ileal pouch-anal anastomosis can avoid hospitalizations and colitis-related medications with their associated potential adverse effects. In addition, the procedure substantially reduces UC-related symptoms and the risk for dysplasia or cancer. There is a long-term pouch success rate of >90% after 10 and 20 years of follow-up. Conclusion: Conservative medical therapy in the treatment of UC will continue to develop and the number of approved therapeutics will grow. Surgery should not be considered as the negative endpoint of treatment modalities but as a good alternative to a prolonged conservative therapy for some patients. In conclusion, a close cooperation between the various disciplines in the pre- and postoperative management is essential in order to optimize the timing and outcome of patients with UC.

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Outcomes of salvage therapy for steroid-refractory acute severe ulcerative colitis: ciclosporin vs. infliximab

Abstract: SUMMARY BackgroundUp to 40% of patients who present with acute severe ulcerative colitis (UC) fail to make an adequate response to intravenous corticosteroids. Ciclosporin or infliximab are currently employed as salvage therapy in this clinical scenario.

Cited by 87 publications

References 41 publications

Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial

Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial

Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: pragmatic randomised Trial and economic evaluation (CONSTRUCT)

Impact of Modern Drug Therapy on Surgery: Ulcerative Colitis

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