Infliximab for Ulcerative Colitis: Finally Some Answers

Abstract

Ulcerative colitis (UC) is a common inflammatory condition of the colon, which, in the majority of cases, can be treated successfully with aminosalicylates/sulphasalazine, glucocorticosteroids, and/or immunomodulators. A small but significant proportion of patients with UC, however, develop steroid dependence or severe attacks requiring hospitalization, intensive intravenous corticosteroid treatment, and sometimes colectomy.1Langholz E. Munkholm P. Davidsen M. Binder V. Course of ulcerative colitis analysis of changes in disease activity over years.Gastroenterology. 1994; 107: 3-11Abstract PubMed Google Scholar In the past decade, a few controlled trials and many case series have shown that treatment with cyclosporine in patients who do not respond to intensive corticosteroid treatment leads to clinical improvement in more than 70% of patients so that (at least in the short run) colectomy can often be avoided.2Lichtiger S. Present D.H. Kornbluth A. et al.Cyclopsporine in severe ulcerative colitis refractory to steroid therapy.N Engl J Med. 1994; 330: 1841-1851Crossref PubMed Scopus (1512) Google Scholar, 3Carbonnel F. Boruchowitz A. Duclos B. Soulé J.C. Lerebours E. Lémann M. Belaïche J. Colombel J.F. Cosnes J. Gendre J.P. Intravenous cyclosprine in attacks of ulcerative colitis short-term and long-term responses.Dig Dis Sci. 1996; 41: 2471-2476Crossref PubMed Scopus (136) Google Scholar Nonetheless, a recent Cochrane analysis questioned the benefit of cyclosporine, stating that, “the long-term benefit is unclear, when adverse events such as cyclosporine-induced nephrotoxicity may become more obvious.”4Shibolet O. Regushevskaya E. Brezis M. Soares-Weiser K. Cyclosporine A for induction of remission in severe ulcerative colitis.Cochrane Database Syst Rev. 2005; 1: CD004277PubMed Google Scholar Most institutions have restricted the use of cyclosporine to patients whose disease is refractory to corticosteroids, given the important risk of toxicity and the high cost of cyclosporine. Cyclosporine treatment indeed requires hospitalization for 10–14 days in the majority of patients, intensive monitoring, frequent blood work, and measurement of cyclosporine blood levels. Moreover, recent retrospective series showed that, despite an initial response to cyclosporine, many patients would eventually undergo proctocolectomy a few years down the line.5Arts J. D’Haens G. Zeegers M. Van Assche G. Hiele M. D’Hoore A. Penninckx F. Vermeire S. Rutgeerts P. Long-term outcome of treatment with intravenous cyclosporin in patients with severe ulcerative colitis.Inflammatory Bowel Dis. 2004; 10: 73-78Crossref PubMed Scopus (208) Google Scholar In Europe, the introduction of cyclosporine does not seem to have affected the need for surgery; the colectomy rate in the large European Collaborative-Study on Inflammatory Bowel Disease cohort has remained stable for patients diagnosed from 1979–1987 compared with patients diagnosed between October 1991 and September 1993.6Katsanos K.H. Christodoulou D.K. Economou M. Wolters F. Vermeire S. Rijis L. Munkholm P. Solberg C. Moum B. Mouzas I. Odes S. Bodini P. O’Morain C. Russel M. et al.Dysplasia and cancer in inflammatory bowel disease the EC-IBD study group 10-year prospective patient cohort results.Gastroenterology. 2005; 128 (abstract).: A-327Google Scholar Although patients with UC are often considered to be cured by restorative proctocolectomy, the quality of life after this procedure (with ileoanal pouch) is generally poorer than in patients who can save their colon with medical therapy.7Cohen R.D. Brodsky A.L. Hannauer S.B. A comparison of the quality of life in patients with severe ulcerative colitis after total colectomy versus medical treatment with intravenous cyclosporin.Inflamm Bowel Dis. 1999; 5: 1-10Crossref PubMed Scopus (81) Google Scholar All together, the unmet clinical need for an effective therapy for patients with refractory UC is therefore significant. More than 10 years ago, the potent anti-inflammatory effects of anti-tumor necrosis factor (TNF) therapy with the chimeric antibody infliximab were shown in Crohn’s disease (CD) and in rheumatoid arthritis. Most clinical programs with this drug further focused on CD, based on the belief that this condition is a typical Th1-type disease driven by proinflammatory cytokines such as interleukin (IL) 12, interferon γ, and TNF. Blocking TNF was shown to prevent granuloma formation in vitro, and fecal TNF concentrations were found to correlate with clinical disease activity in children with inflammatory bowel disease (IBD).8Braegger C.P. Nicholls S. Murch S.H. Stephens S. MacDonald T.T. Tumour necrosis factor alpha in stool as a marker of intestinal inflammation.Lancet. 1992; 339: 89-91Abstract PubMed Scopus (661) Google Scholar Unlike CD, UC colitis has long been considered to be a Th2-type of disease with a more prominent role of cytokines Il-10, IL-5, and IL-4, and much less of TNF and IL-12. Contrary to this hypothesis, however, median TNF serum concentrations in patients with an attack of UC have been at least as high as in CD disease, and increased concentrations of TNF-producing cells have been reported in UC as well as in CD.9Reinecker H.C. Steffen M. Witthoeft T. Pflueger I. Schreiber S. MacDermott R.P. Raedler A. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease.Clin Exp Immunol. 1993; 94: 174-181Crossref PubMed Scopus (787) Google Scholar Furthermore, recent investigations showed that the mechanism of action of TNF-blocking agents is probably not the binding and inactivation of TNF but rather apoptosis of TNF-expressing inflammatory cells. This concept was proven by the inefficacy of etanercept, a recombinant p75 TNF receptor that binds TNF without inducing apoptosis, in CD. In the same study, infliximab was highly effective in inducing T-cell apoptosis.10Van den Brande J.M. Braat H. van den Brink G.R. Versteeg H.H. Bauer C.A. Hoedemaeker I. van Montfrans C. Hommes D.W. Peppelenbosch M.P. van Deventer S.J. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease.Gastroenterology. 2003; 124: 1774-1785Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar Programmed cell death (apoptosis) in IBD has been the subject of an important body of recent research. Resistance to apoptosis has been shown in both CD and UC, but the mechanism behind this phenomenon seems to differ between both conditions. The intrinsic defect in CD occurs in the mitochondrial pathway of apoptosis (imbalance of mitochondrial bcl-2/bax), whereas the problem in UC results from overexpression of FLICE-inhibitory protein (FLIP) and impairment of the caspase mediated pathway of apoptosis.11Peppelenbosch M.P. van Deventer S.J. T cell apoptosis and inflammatory bowel disease.Gut. 2004; 53: 1556-1558Crossref PubMed Scopus (61) Google Scholar For these and other conceptual reasons, the efficacy of anti-TNF agents in UC has been a subject of scepticism and debate. An early controlled trial was discontinued prematurely because of slow recruitment.12Sands B.E. Tremaine W.J. Sandborn W.J. Rutgeerts P.J. Hanauer S.B. Mayer L. Targan S.R. Podolsky D.K. Infliximab in the treatment of severe, steroid-refractory ulcerative colitis a pilot study.Inflammatory Bowel Dis. 2001; 7: 83-88Crossref PubMed Scopus (384) Google Scholar Four of 8 infliximab-treated patients had a response and avoided surgery versus 0 of 3 placebo-treated patients. It was not until clinicians began to administer infliximab off label to patients with refractory UC that the interest in anti-TNF treatment in UC was reactivated and a number of controlled trials were launched. The first series of case observations was reported from Austria, France, Italy, and the US. All of 6 Austrian patients with active steroid-refractory UC who received a single infusion of infliximab showed marked clinical improvement by day 7; 4 of 6 patients had long-term remission (up to 6 months).13Kaser A. Mairinger T. Vogel W. Tilg H. Infliximab in severe steroid-refractory ulcerative colitis a pilot study.Wien Klin Wochenschr. 2001; 113: 930-933PubMed Google Scholar Thirty French patients were treated with infliximab for UC or indeterminate colitis because of steroid resistance, dependence, or intolerance. Seventy-five percent of the patients with active disease had a response at day 7 after the infusion and 50% at day 28. Relapse rates at 6 months were quite high (73%). One-third of the patients needed colectomy at the end of 1 year.14Gornet J.M. Couve S. Hassani Z. Delchier J.C. Marteau P. Cosnes J. Bouhnik Y. Dupas J.L. Modigliani R. Taillard F. Lemann M. Infliximab for refractory ulcerative colitis or indeterminate colitis an open-label multicentre study.Aliment Pharmacol Ther. 2003; 18: 175-181Crossref PubMed Scopus (111) Google Scholar In an Italian trial, 13 patients with severe UC refractory to intravenous therapy with methylprednisolone were treated with a single infliximab infusion (5 mg/kg). Ten of 13 patients (77%) had a clinical response. During the follow-up period of 2 years, 8 of 10 patients with a response (80%) continued to be in clinical remission and could discontinue corticosteroid treatment.15Kohn A. Prantera C. Pera A. Cosintino R. Sostegni R. Daperno M. Infliximab in the treatment of severe ulcerative colitis a follow-up study.Eur Rev Med Pharmacol Sci. 2004; 8: 235-237PubMed Google Scholar Finally, 12 pediatric patients with UC received infliximab between July 2001 and November 2003 at the Johns Hopkins Children’s Center for treatment of fulminant, steroid-dependent, or steroid-refractory UC. Nine patients had a complete short-term response and 3 had partial improvement. Eight patients were classified as long-term responders with a median follow-up time of 10.4 months.16Eidelwein A.P. Cuffari C. Abadom V. Oliva-Hemker M. Infliximab efficacy in pediatric ulcerative colitis.Inflammatory Bowel Dis. 2005; 11: 213-218Crossref PubMed Scopus (82) Google Scholar In fact, the overall short-term response rates in the observational studies were quite similar to what had been observed in the CD trials and this prompted groups of investigators to set up a number of controlled and randomized trials. Ochsenkühn et al17Ochsenkuhn T. Sackmann M. Goke B. Infliximab for acute, not steroid-refractory ulcerative colitis a randomized pilot study.Eur J Gastroenterol Hepatol. 2004; 16: 1167-1171Crossref PubMed Scopus (109) Google Scholar evaluated whether infliximab could induce remission in patients with acute UC but who were not refractory to steroids. Thirteen patients with active disease were randomized to receive either 3 infusions of infliximab at 5 mg/kg or high-dose prednisolone (1.5 mg/kg body weight per day for 2 weeks, followed by a tapering schedule). Five of 6 patients improved with infliximab versus 6 of 7 with corticosteroids. Probert et al18Probert C.S. Hearing S.D. Schreiber S. Kuhbacher T. Ghosh S. Arnott I.D. Forbes A. Infliximab in moderately severe glucocorticoid resistant ulcerative colitis a randomised controlled trial.Gut. 2003; 7: 998-1002Crossref Scopus (334) Google Scholar conducted a randomized, placebo-controlled trial of infliximab in the treatment of glucocorticoid-resistant UC in patients who did not require imminent surgery. Two infliximab/placebo infusions were administered at weeks 0 and 2. After 6 weeks, remission rates were 39% with infliximab versus 30% with placebo (NS). This study was the first negative trial and, it remains unclear why these results were so disappointing. The study by Järnerot et al,19Järnerot G. Hertevig E. Friis-Liby I. Blomquist L. Karlén P. Grännö C. Vilien M. Ström M. Danielsson A. Verbaan H. Hellström P.M. Magnuson A. Curman B. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis a randomized placebo-controlled study.Gastroenteroloy. 2005; 128: 1805-1811Abstract Full Text Full Text PDF PubMed Scopus (929) Google Scholar reported in the current issue of Gastroenterology, used a somewhat similar study design as the Probert et al18Probert C.S. Hearing S.D. Schreiber S. Kuhbacher T. Ghosh S. Arnott I.D. Forbes A. Infliximab in moderately severe glucocorticoid resistant ulcerative colitis a randomised controlled trial.Gut. 2003; 7: 998-1002Crossref Scopus (334) Google Scholar trial. In this investigator-initiated trial, infliximab was administered as a single infusion to corticosteroid-refractory patients. The study population was different in that the patients were hospitalized, failed intensive glucocorticosteroids treatment, and would undergo surgery in case additional treatment failed. For this reason, the hard primary endpoint of colectomy or death within 3 months after randomization could be used. Unfortunately, and similarly to the original Centocor trial,12Sands B.E. Tremaine W.J. Sandborn W.J. Rutgeerts P.J. Hanauer S.B. Mayer L. Targan S.R. Podolsky D.K. Infliximab in the treatment of severe, steroid-refractory ulcerative colitis a pilot study.Inflammatory Bowel Dis. 2001; 7: 83-88Crossref PubMed Scopus (384) Google Scholar this study was also discontinued prematurely because of slow enrollment. Nonetheless, statistical analysis showed a significant effect of infliximab treatment on the colectomy rate. Seven of 24 patients needed colectomy in the infliximab group versus 14 of 21 in the placebo group (P = .017). Of note, patients who needed surgery underwent it within the first month of the study. The authors do not give any details on the further course of most patients, so it remains unclear how long the effect of infliximab rescue therapy lasted. The Danish and Swedish investigators used 2 different scores in their initial assessment of patients and the decision to enroll them in the trial: the fulminant colitis index, which was calculated on day 3 of intravenous steroid treatment,20Lindgren S.C. Flood L.M. Kilander A.F. Löfberg R. Persson T.B. Sjödahl R.I. Early predictors of glucosteroid treatment failure in severe to moderately severe attacks of ulcerative colitis.Eur J Gastroenterol Hepatol. 1998; 10: 831-835Crossref PubMed Scopus (223) Google Scholar and the Seo-index (calculated on day 5–7), a score that was originally developed as a clinical tool to predict the likelihood of colectomy. The validity of the score was confirmed in the current trial because the colectomy rate in the placebo-treated patients (69%) approached that of the study in which the score was developed (72%).21Seo M, Okada M, Yao T, Ueki M, Arima S, Okumura M. An index of disease activity in patients with ulcerative colitis. Am J Gastroenterol 192;87:971–976.Google Scholar Despite the complexity and the lack of earlier validation, this score proved to be useful in the setting of severe UC. The authors do not state on what basis the decision to perform colectomy in the individual patients was made but mentioned that is was a joint medical-surgical decision. Nor do we receive information on the pathologic findings in the resection specimens: were these truly very severe cases and were the findings similar in both groups of patients? Despite all this, the conclusion of this study was rather convincing: anti-TNF therapy with infliximab is active in severe UC, particularly in patients with steroid refractory disease. During the recruitment period of the study reported by Järnerot et al,19Järnerot G. Hertevig E. Friis-Liby I. Blomquist L. Karlén P. Grännö C. Vilien M. Ström M. Danielsson A. Verbaan H. Hellström P.M. Magnuson A. Curman B. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis a randomized placebo-controlled study.Gastroenteroloy. 2005; 128: 1805-1811Abstract Full Text Full Text PDF PubMed Scopus (929) Google Scholar 2 large international placebo-controlled trials with infliximab for UC were performed, the results of which have been reported at this year’s Digestive Disease Week in Chicago. In Act-1 (studying patients with active UC refractory to immunomodulators and/or corticosteroids), 3 infusions of infliximab at week 0, 2, and 6 weeks induced clinical improvement in almost 70% of patients at week 8, with endoscopic healing in 62%.22Rutgeerts P. Feagan B.F. Olson A. Johanns J. Travers S. Present D. Sands B. Sandborn W. A randomized placebo-controlled trial of infliximab for active ulcerative colitis Act 1 trial.Gastroenterology. 2005; 128 (abstract).: A-105Abstract Full Text Full Text PDF Scopus (347) Google Scholar In Act-2, similar results were obtained in a cohort that also included mesalamine-refractory patients.23Sandborn W.J. Rachmilewitz D. Hanauer S. Lichtenstein G. de Villiers W. Olson A. Johanns J. Travers S. Colombel J.F. Infliximab induction and maintenance therapy for ulcerative colitis the Act 2 trial.Gastroenterology. 2005; 128 (abstract).: A-104Abstract Full Text Full Text PDF Google Scholar Both studies clearly showed the efficacy of anti-TNF treatment in active UC. Why are response and remission rates in UC apparently as good as what has been observed in CD, whereas mucosal immunologists forecasted the role of TNF to be of much less importance in this disease? A likely explanation is that the classic Th1/Th2 hypothesis is incorrect and needs to be revised. A second plausible explanation is that anti-TNF therapy with infliximab induces the same degree of apoptosis of activated mononuclear cells in UC as in CD. As a consequence, maintenance treatment with repeated infliximab infusions will probably be necessary in UC as well, which seems particularly important in patients who escape a colectomy to avoid further hospitalizations and risk of later surgery. It can be expected that the majority of patients will suffer from another UC attack once the biologic effect of infliximab has disappeared. For this reason, it is unlikely that the way in which infliximab was used in the study by Järnerot et al19Järnerot G. Hertevig E. Friis-Liby I. Blomquist L. Karlén P. Grännö C. Vilien M. Ström M. Danielsson A. Verbaan H. Hellström P.M. Magnuson A. Curman B. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis a randomized placebo-controlled study.Gastroenteroloy. 2005; 128: 1805-1811Abstract Full Text Full Text PDF PubMed Scopus (929) Google Scholar represents the ideal approach to severe UC. What is the impact of the current findings and the recent controlled trials on the clinical management of UC? The majority of patients with active disease, despite corticosteroid and immunomodulator treatment, can successfully be treated with infliximab. Patients who have failed to respond to immunomodulators will probably benefit from repeated maintenance therapy, ideally on an every-8-week basis. Given the immunogenicity of infliximab,20Lindgren S.C. Flood L.M. Kilander A.F. Löfberg R. Persson T.B. Sjödahl R.I. Early predictors of glucosteroid treatment failure in severe to moderately severe attacks of ulcerative colitis.Eur J Gastroenterol Hepatol. 1998; 10: 831-835Crossref PubMed Scopus (223) Google Scholar it is recommended that patients are started on immunomodulators before or at least simultaneously with infliximab treatment. In this way, patients who are corticosteroid dependent can often be weaned from steroids. Moreover, patients who suffer from an intractable disease and may need a colectomy can be rescued with (as little as) a single infliximab infusion in up to 70% of cases. This success rate is similar to what has been observed with intravenous cyclosporine treatment.2Lichtiger S. Present D.H. Kornbluth A. et al.Cyclopsporine in severe ulcerative colitis refractory to steroid therapy.N Engl J Med. 1994; 330: 1841-1851Crossref PubMed Scopus (1512) Google Scholar, 21Seo M, Okada M, Yao T, Ueki M, Arima S, Okumura M. An index of disease activity in patients with ulcerative colitis. Am J Gastroenterol 192;87:971–976.Google Scholar As outlined above, the latter treatment has serious shortcomings. For the same reasons, cyclosporine is not considered an acceptable maintenance therapy. Once infliximab is reimbursed for UC, the use of cyclosporine will probably only be justified in patients who have failed to respond to the anti-TNF antibody. The trials have indeed shown that infliximab is not the solution for all patients. Further development of other safe and effective treatments is therefore warranted: extracorporeal treatments, anti-CD3 antibodies such as visilizumab, and other biologic agents may even prove to be more effective than infliximab and possibly exert a more prolonged effect. Undoubtedly, the advent of infliximab in the therapeutic armamentarium of UC means a significant step forward in the management of this disease. Nonetheless, a word of caution is appropriate in a situation in which prolonged medical treatment replaces surgery for a premalignant condition. The longer patients can keep their colon and, hence, enjoy a better quality of life than with an ileoanal pouch, the higher the physicians’ index of suspicion with regard to dysplasia and cancer development should become. Organized surveillance programs, optimalization of early dysplasia detection, and prospective trials on chemoprevention will be more than necessary in the new era of UC treatment. Infliximab as Rescue Therapy in Severe to Moderately Severe Ulcerative Colitis: A Randomized, Placebo-Controlled StudyGastroenterologyVol. 128Issue 7PreviewBackground & Aims: Despite treatment with corticosteroids, severe to moderately severe attacks of ulcerative colitis have a high colectomy rate. We intended to find a rescue therapy other than cyclosporin A, which imposes a high risk of side effects and cyclosporine-related mortality. Methods: This was a randomized double-blind trial of infliximab or placebo in severe to moderately severe ulcerative colitis not responding to conventional treatment. Patients were randomized to infliximab/placebo either on day 4 after the initiation of corticosteroid treatment if they fulfilled the index criteria for fulminant ulcerative colitis on day 3 or on day 6–8 if they fulfilled index criteria on day 5–7 for a severe or moderately severe acute attack of ulcerative colitis. Full-Text PDF