Infliximab or ciclosporin for acute severe ulcerative colitis?
Authors: Ashwin N Ananthakrishnan
Journal: The Lancet. Gastroenterology & hepatology (2016)

Acute severe ulcerative colitis remains one of the most challenging patient populations to treat. Despite significant therapeutic advances that have resulted in higher rates of remission and lower rates of surgery in patients with Crohn's disease and ulcerative colitis,1Kaplan GG Seow CH Ghosh S et al.Decreasing colectomy rates for ulcerative colitis: a population-based time trend study.Am J Gastroenterol. 2012; 107: 1879-1887Crossref PubMed Scopus (140) Google Scholar this improvement in outcomes is modest in those with severe disease requiring hospitalization, and rates of treatment response remain inadequate.2Ananthakrishnan AN McGinley EL Binion DG et al.A nationwide analysis of changes in severity and outcomes of inflammatory bowel disease hospitalizations.J Gastrointest Surg. 2011; 15: 267-276Crossref PubMed Scopus (56) Google Scholar There exist two effective options for treating steroid refractory acute severe ulcerative colitis—ciclosporin and infliximab—both of which have individually established efficacy in the short and medium terms in rigorously conducted randomised controlled trials.3Narula N Marshall JK Colombel JF et al.Systematic review and meta-analysis: infliximab or cyclosporine as rescue therapy in patients with severe ulcerative colitis refractory to steroids.Am J Gastroenterol. 2016; 111: 477-491Crossref PubMed Scopus (116) Google Scholar, 4Seah D De Cruz P The practical management of acute severe ulcerative colitis.Aliment Pharmacol Ther. 2016; 43: 482-513Crossref PubMed Scopus (57) Google Scholar However until recently, there was little data on the comparative efficacy of both agents and choice was informed primarily by individual and institutional experience. In 2012, Laharie and colleagues5Laharie D Bourreille A Branche J et al.Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial.Lancet. 2012; 380: 1909-1915Summary Full Text Full Text PDF PubMed Scopus (429) Google Scholar published the CYSIF trial, the first open-label randomised trial including 115 patients with steroid refractory acute severe ulcerative colitis, randomised to ciclosporin or infliximab. Rates of treatment failure and need for colectomy were similar in both groups at the end of 98 days. In The Lancet Gastroenterology & Hepatology, Williams and colleagues6Williams JG Alam MF Alrubaiy L et al.for the CONSTRUCT investigatorsInfliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial.Lancet Gastroenterol Hepatol. 2016; (published online June 22.)http://dx.doi.org/10.1016/S2468-1253(16)30003-6Google Scholar present the results of a second trial—CONSTRUCT—similarly comparing infliximab and ciclosporin for acute steroid refractory colitis. Adopting a pragmatic design, the authors select a primary outcome of quality-adjusted survival, defined as the area under the curve described by the score from the Crohn's and Ulcerative Colitis Questionnaire till year 3. Secondary outcomes included changes in general quality of life (using EQ-5D and SF-12 scales), need for surgery, length of stay, and cost-effectiveness. 270 patients were recruited from 52 hospitals over the 3 years of the study (135 in each group) with the primary outcome being analysable in 242 patients. Over a median follow-up of 765 days, there was no difference in quality-adjusted survival between the two groups (p=0.63). For secondary outcomes, there was no difference in the proportion requiring colectomy (41% with infliximab vs 48% with cyclosporine, p=0.223) or in time to colectomy, and no differences were noted in adverse effects between both groups. The cost-effectiveness analysis showed significantly higher health-care costs with infliximab. The novel pragmatic trial design and quality-adjusted survival as outcomes are directly relevant to real-world practice, where restoration of normal quality of life is an important goal of therapy in inflammatory bowel diseases, and cost-effectiveness of treatment strategies is an important determinant of position of various therapies in the treatment pyramid. However, a few aspects of the trial design leave some important key questions unanswered. Many of the endpoints we now recognize as important in inflammatory bowel diseases, such as mucosal healing and quantification of disease activity (through clinical or proxy measures such as calprotectin or C-reactive protein), are not included as outcomes in this trial.7Shah SC Colombel JF Sands BE et al.Mucosal healing is associated with improved long-term outcomes of patients with ulcerative colitis: a systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2016; (published online Jan 30.)https://doi.org/10.1016/S1542-3565(16)00107-5Crossref Google Scholar Time to symptom response, an important outcome in the ill, hospitalised patient, is also not presented. The use of a quality-of-life measure as a primary outcome also raises questions about the accuracy of a measure to inform comparative efficacy that is affected not just by disease activity (the main treatment effect) but also substantially by co-morbidity (eg, depression or functional bowel disease), with the potential for both under and over-estimating treatment effects without an accompanying objective endpoint. Both the CONSTRUCT trial6Williams JG Alam MF Alrubaiy L et al.for the CONSTRUCT investigatorsInfliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial.Lancet Gastroenterol Hepatol. 2016; (published online June 22.)http://dx.doi.org/10.1016/S2468-1253(16)30003-6Google Scholar and the CYSIF trial5Laharie D Bourreille A Branche J et al.Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial.Lancet. 2012; 380: 1909-1915Summary Full Text Full Text PDF PubMed Scopus (429) Google Scholar are landmark publications in a challenging patient population where there is dearth of high-quality comparative data. The equivalence of both treatments in the two studies provide reassurance to the treating clinician about comparability of ciclosporin and standard-dose infliximab, and that choice can continue to be determined by provider and institutional experience. However, factors in the trial design in both trials (inclusion of previously thiopurine-exposed patients in the CYSIF trial and lack of a defined post-hospitalisation treatment plan in the CONSTRUCT trial) preclude both from being the final answers to this question. It is possible that response rates may be higher with aggressive optimisation of care. With the recognition of substantial fecal loss of infliximab in acute severe ulcerative colitis,8Brandse JF van den Brink GR Wildenberg ME et al.Loss of infliximab into feces is associated with lack of response to therapy in patients with severe ulcerative colitis.Gastroenterology. 2015; 149: 350-355Summary Full Text Full Text PDF PubMed Scopus (291) Google Scholar it is possible that a more aggressive upfront infliximab strategy,9Gibson DJ Heetun ZS Redmond CE et al.An accelerated infliximab induction regimen reduces the need for early colectomy in patients with acute severe ulcerative colitis.Clin Gastroenterol Hepatol. 2015; 13: 330-335Summary Full Text Full Text PDF PubMed Scopus (183) Google Scholar perhaps in conjunction with an immunomodulator, may improve the outcomes in infliximab-treated patients with acute severe ulcerative colitis. Furthermore, whether the efficacy of ciclosporin can be amplified by maintenance treatment with agents such as vedolizumab remains to be established, having demonstrated promise in small cohorts.10Wichmann A Kinnucan J Rubin D Novel use of cyclosporine induction therapy as a bridge to vedolizumab in severe ulcerative colitis.Inflamm Bowel Dis. 2014; 20 (P-005.)Google Scholar Examination of personalised strategies guided by therapeutic drug monitoring is essential to further inform our practice and improve outcomes in this ill group of patients. In parallel, there is the need for clinical, genetic, and other -omics based tools that can a priori predict an individual patient's likelihood of response to either therapy, allowing the treating physician to precisely match the patient to the treatment with highest likelihood of benefit. I declare no competing interests. Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trialThere was no significant difference between ciclosporin and infliximab in clinical effectiveness. Full-Text PDF Open Access