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Infliximab as Rescue Therapy in Severe to Moderately Severe Ulcerative Colitis: A Randomized, Placebo-Controlled Study

2005; Elsevier BV; Volume: 128; Issue: 7 Linguagem: Inglês

10.1053/j.gastro.2005.03.003

1528-0012

Gunnar Järnerot, Erik Hertervig, Ingalill Friis–Liby, Lars Blomquist, Per Karlén, Christer Grännö, M. Vilien, Magnus Ström, Åke Danielsson, Hans Verbaan, Per M. Hellström, Anders Magnuson, Bengt Curman,

Liver Diseases and Immunity

Background & 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. Results were analyzed according to the intention-to-treat principle. The primary end point was colectomy or death 3 months after randomization. Secondary end points were clinical and endoscopic remission at that time in patients who did not undergo operation. Results: Forty-five patients were included (24 infliximab and 21 placebo). No patient died. Seven patients in the infliximab group and 14 in the placebo group had a colectomy (P = .017; odds ratio, 4.9; 95% confidence interval, 1.4–17) within 3 months after randomization. No serious side effects occurred. Three patients in the placebo group required operation for septic complications. Conclusions: Infliximab 4–5 mg/kg is an effective and safe rescue therapy in patients experiencing an acute severe or moderately severe attack of ulcerative colitis not responding to conventional treatment. Background & 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. Results were analyzed according to the intention-to-treat principle. The primary end point was colectomy or death 3 months after randomization. Secondary end points were clinical and endoscopic remission at that time in patients who did not undergo operation. Results: Forty-five patients were included (24 infliximab and 21 placebo). No patient died. Seven patients in the infliximab group and 14 in the placebo group had a colectomy (P = .017; odds ratio, 4.9; 95% confidence interval, 1.4–17) within 3 months after randomization. No serious side effects occurred. Three patients in the placebo group required operation for septic complications. Conclusions: Infliximab 4–5 mg/kg is an effective and safe rescue therapy in patients experiencing an acute severe or moderately severe attack of ulcerative colitis not responding to conventional treatment. Traditionally, acute attacks of ulcerative colitis (UC) have been treated intensively with high doses of corticosteroids intravenously (IIVT). Despite IIVT, severe attacks had a high colectomy rate varying from 38% to 47% in 2 frequently quoted series. 1Truelove S.C. Jewell D.P. Intensive intravenous regimen for severe attacks of ulcerative colitis.Lancet. 1974; 1: 1067-1070Abstract PubMed Scopus (453) Google Scholar, 2Järnerot G. Rolny P. Sandberg-Gertzén H. Intensive intravenous treatment of ulcerative colitis.Gastroenterology. 1985; 89: 1005-1013Abstract Full Text PDF PubMed Scopus (310) Google Scholar Of patients with UC affecting the entire colon, 60% had surgery within 3 months. 2Järnerot G. Rolny P. Sandberg-Gertzén H. Intensive intravenous treatment of ulcerative colitis.Gastroenterology. 1985; 89: 1005-1013Abstract Full Text PDF PubMed Scopus (310) Google Scholar Also, a moderately severe attack was associated with a risk for operation in approximately 20% of the patients. 2Järnerot G. Rolny P. Sandberg-Gertzén H. Intensive intravenous treatment of ulcerative colitis.Gastroenterology. 1985; 89: 1005-1013Abstract Full Text PDF PubMed Scopus (310) Google Scholar Cyclosporin A (CyA) was shown to be an effective rescue therapy in acute attacks of UC not responding to steroids. 3Lichtiger S. Present D.H. Kornbluth A. Gelernt I. Bauer J. Galler G. Michelassi F. Hanauer S. Cyclosporine in severe ulcerative colitis refractory to steroid therapy.N Engl J Med. 1994; 330: 1841-1845Crossref PubMed Scopus (1514) Google Scholar However, this increases the risk of side effects 4Sandborn W.J. A critical review of cyclosporine therapy in inflammatory bowel disease.Inflamm Bowel Dis. 1995; 1: 48-63Google Scholar and of CyA-related mortality. 5Blomberg B. Järnerot G. Clinical evaluation and management of acute severe colitis.Inflamm Bowel Dis. 2000; 6: 214-227Crossref PubMed Scopus (27) Google Scholar, 6Arts 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.Inflamm Bowel Dis. 2004; 10: 73-78Crossref PubMed Scopus (209) Google Scholar For this reason, CyA has not been adopted as rescue therapy for patients with failed steroid treatment in Sweden and most Danish centers, because the risks were considered greater than those for surgical therapy. Infliximab (Remicade; Centocor Inc, Malvern, PA) has become an established treatment in Crohn’s disease (CD). It is a chimeric monoclonal antibody to human tumor necrosis factor (TNF)-α that is constructed by linking the variable regions of a mouse antihuman TNF monoclonal antibody to human immunoglobulin G1 with light κ chains. 7Sandborn W.J. Hanauer S.B. Antitumor necrosis factor therapy for inflammatory bowel disease a review of agents, pharmacology, clinical results, and safety.Inflamm Bowel Dis. 1999; 5: 119-133Crossref PubMed Scopus (441) Google Scholar TNF-α has also been shown to play an important role in the inflammatory process in UC. Increased levels of TNF-α have been found in feces from patients with active UC. 8Braegger C.P. Nicholls S. Murch S.H. Stephens S. MacDonald T.T. Tumor necrosis factor alpha in stool as a marker of intestinal inflammation.Lancet. 1992; 339: 89-91Abstract PubMed Scopus (661) Google Scholar, 9Nielsen O.H. Gionchetti P. Ainsworth M. Vainer B. Campieri M. Borregaard N. Kjeldsen L. Rectal dialysate and faecal concentrations of neutrophil gelatinase-associated lipocalin interleukin-8, and tumor necrosis factor-α in ulcerative colitis.Am J Gastroenterol. 1999; 94: 2923-2928Crossref PubMed Google Scholar The TNF-α reactivity in UC was most pronounced subepithelially, whereas in CD expression it has also been found deeper in the mucosa or submucosa. 10Murch S.H. Braegger C.P. Walker-Smith J.A. MacDonald T.T. Location of tumor necrosis factor α by immunochemistry in chronic inflammatory bowel disease.Gut. 1993; 34: 1705-1709Crossref PubMed Scopus (498) Google Scholar The correlation between TNF-α expression and the histological findings was good but was less so with the endoscopic appearance. 11Woywodt A. Ludwig D. Neustock P. Kruse A. Schwerting K. Jantschek G. Kirchner H. Stange E.F. Mucosal cytokine expression, cellular markers and adhesion molecules in inflammatory bowel disease.Eur J Gastroenterol Hepatol. 1999; 11: 267-276Crossref PubMed Scopus (81) Google Scholar Normally the inflammatory response to an increased TNF-α production is counteracted by inhibitors. One study strongly indicated that in inflammatory bowel disease, the production of TNF-α inhibitors is down-regulated. 12Noguchi M. Hiwatashi N. Lin Z. Toyota T. Secretion imbalance between tumor necrosis factor and its inhibition in inflammatory bowel disease.Gut. 1998; 43: 203-209Crossref PubMed Scopus (108) Google Scholar Thus, there is good theoretical evidence to test infliximab also in acute attacks of UC. Only 1 small placebo-controlled study has been published, and it was stopped because of slow enrollment. 13Sands B.E. Tremaine W.J. Sandborn W.J. Rutgeerts P.J. Hanauer S.B. Mayer L. Mayer L. Targan S. Podolsky D.K. Infliximab in the treatment of severe, steroid-refractory ulcerative colitis a pilot study.Inflamm Bowel Dis. 2001; 7: 83-88Crossref PubMed Scopus (385) Google Scholar Three uncontrolled studies support the effect of infliximab in acute attacks of UC. 14Chey W.Y. Hussain A. Ryan C. Potter G.D. Shah A. Infliximab for refractory ulcerative colitis.Am J Gastroenterol. 2001; 96: 2373-2381Crossref PubMed Google Scholar, 15Kohu A. Prantera C. Pera A. Cosintino R. Sostegni R. Daperno M. Anti-tumor necrosis factor alpha (infliximab) in the treatment of severe ulcerative colitis result of an open study on 13 patients.Dig Liver Dis. 2003; 34: 626-630Google Scholar, 16Järnerot G. Blomberg B. Bohr J. Curman B. Sandberg-Gertzén H. Infliximab (Remicade) as rescue therapy in acute corticosteroid-resistant ulcerative colitis.Scand J Gastroenterol. 2001; 36 (:08.): 233Google Scholar In a prospective uncontrolled study, 8 of 11 (73%) patients with severe UC similar to those included in the present placebo-controlled study escaped immediate colectomy. 16Järnerot G. Blomberg B. Bohr J. Curman B. Sandberg-Gertzén H. Infliximab (Remicade) as rescue therapy in acute corticosteroid-resistant ulcerative colitis.Scand J Gastroenterol. 2001; 36 (:08.): 233Google Scholar This study engaged patients with an acute severe or moderately severe attack of UC that did not respond quickly to IIVT. The study had a parallel design so that half of the patients were randomized to additional treatment with infliximab to the ongoing corticosteroid therapy, and the other half were randomized to additional placebo. The Seo index 17Seo M. Okada M. Yao T. Ueki M. Arima S. Okumura M. An index of disease activity in patients with ulcerative colitis.Am J Gastroenterol. 1992; 87: 971-976PubMed Google Scholar for the preceding day was calculated from the following formula 60×blood ;in ;feces+13×bowel ;movements/day+0.5×ESR−0.4×Hb(g/l)−1.5×albumin(g/l)+200, where ESR indicates erythrocyte sedimentation rate and Hb indicates hemoglobin. Constants were as follows: for blood in feces, 0 indicated none and 1 indicated present; for bowel movements, 0 indicated 0–3; 1 indicated 4; 2 indicated 5–7; and 3 indicated ≥8. A value 220 corresponds to severe UC. The fulminant colitis index 18Lindgren S.C. Flood L.M. Kilander A.F. Löfberg R. Persson T.B. Sjödahl R.I. Early predictors of glucosteroid treatment failure in severe and moderately severe attacks of ulcerative colitis.Eur J Gastroenterol Hepatol. 1998; 10: 831-835Crossref PubMed Scopus (223) Google Scholar was calculated on day 3 after the institution of IIVT according to the following formula: number ;of ;bowel ;movements/day+(0.14×CRP>8mg/L), where CRP indicates C-reactive protein. Seventy-two percent of patients with a value ≥8.0 had a colectomy. Only patients with a definite or strong suspicion of UC were screened. Inclusion criteria were age 18–75 years, a diagnosis of certain or probable UC verified by a typical clinical history, appearance on endoscopy, and exclusion of an infectious cause. At hospitalization, patients had a severe or moderately severe attack of UC according to the Seo index. 17Seo M. Okada M. Yao T. Ueki M. Arima S. Okumura M. An index of disease activity in patients with ulcerative colitis.Am J Gastroenterol. 1992; 87: 971-976PubMed Google Scholar For treatment with infliximab/placebo, the patients had to have a fulminant colitis index 18Lindgren S.C. Flood L.M. Kilander A.F. Löfberg R. Persson T.B. Sjödahl R.I. Early predictors of glucosteroid treatment failure in severe and moderately severe attacks of ulcerative colitis.Eur J Gastroenterol Hepatol. 1998; 10: 831-835Crossref PubMed Scopus (223) Google Scholar ≥8.0 on day 3 after institution of IIVT or a Seo index on day 5, 6, or 7 that was compatible with a severe or moderately severe attack of UC that was not responding to corticosteroid treatment. Exclusion criteria were age 75 years, pregnancy or planned pregnancy in the next 12 months, breast-feeding unless it was stopped, known or probable Crohn’s colitis, infectious colitis, ongoing infection such as an abscess, central line infection, febrile urinary tract infection, active tuberculosis, or exposure to tuberculosis. A pulmonary radiograph was to precede infliximab/placebo. If there were signs of past tuberculosis or a primary complex, prophylactic treatment against tuberculosis was to be given. PPD tests were not performed. Furthermore, multiple sclerosis, malignancy, heart failure or treated heart failure, earlier treatment with infliximab or another antibody, another disease according to the investigator’s judgment, psychiatric disease, alcoholism, or anything else whereby the patient was judged incapable of completing the trial resulted in exclusion. Approximately 40 Swedish and Danish centers located within 8 hospital regions expressed an interest in participation. Finally, 9 Swedish centers and 1 Danish center, covering 7 hospital regions, recruited patients. In each of the regions, a local randomization list was placed in 1 pharmacy. Randomization, which was performed in blocks of 4, was known only by the statistician. Patients to be treated were reported to the pharmacy with their birth number, name, and weight for correct dosing. Preparation of the solution for infusion was performed in the pharmacy and delivered to the ward to blind the investigator. The day of hospitalization was denoted as day 0. Bowel movements and fecal blood were registered daily, and body temperature and heart rate were recorded twice daily. Blood samples were drawn for hematology, liver function tests, albumin, CRP, and erythrocyte sedimentation rate. Fecal samples were sent for analyses of possible pathogens and Clostridium difficile toxin, which gave the laboratory 3–4 days to finish the analysis. No sample was positive after that time. Analysis for parasites was performed when clinically indicated. Biopsies were not performed to exclude cytomegalovirus infection. A plain abdominal and lung radiograph was taken. A severity index using the criteria of Seo et al 17Seo M. Okada M. Yao T. Ueki M. Arima S. Okumura M. An index of disease activity in patients with ulcerative colitis.Am J Gastroenterol. 1992; 87: 971-976PubMed Google Scholar was calculated on day 0. Patients with an index of >150, corresponding to severe to moderately severe UC, were potential candidates for enrollment if IIVT failed. IIVT was started on day 0. During days 0–3, a colonoscopy was performed to determine the extent and severity of disease according to GETAID (Groupe dÉtude Thérapeutique des Affections Inflammatoires Digestives) criteria. 19Carbonnel F. Lavergne A. Lémann M. Bitoun A. Valleur P. Hautefeuille P. Galian A. Modigliani R. Rambaud J.-C. Colonoscopy of acute colitis. A safe and reliable tool for assessment of severity.Dig Dis Sci. 1994; 39: 1550-1557Crossref PubMed Scopus (248) Google Scholar Endoscopic inflammation was graded as severe, moderately severe, mild, or in remission. After day 0, daily monitoring continued. On the morning of day 4, the fulminant colitis index 18Lindgren S.C. Flood L.M. Kilander A.F. Löfberg R. Persson T.B. Sjödahl R.I. Early predictors of glucosteroid treatment failure in severe and moderately severe attacks of ulcerative colitis.Eur J Gastroenterol Hepatol. 1998; 10: 831-835Crossref PubMed Scopus (223) Google Scholar was calculated. When it was ≥8, the patient was randomized to infliximab/placebo. If the fulminant colitis index was 150 on any of these days, the patient was randomized to infliximab/placebo. There were no new inclusions after day 8. On day 0, IIVT with betamethasone 4 mg intravenously twice daily was started. No rectal treatment was given. When a patient was randomized to infliximab/placebo, a dose as close as possible to 5 mg/kg was given as a slow infusion (Table 1).Table 1Dosing of InfliximabNo. ampoulesDose (mg)Weight (kg)Dose given (mg/kg)220040–49.95–42+50–59.95–5aOnly weight interval for which an ampoule had to be divided.330060–74.95–4440075–99.95.3–45500100–1255–4a Only weight interval for which an ampoule had to be divided. Open table in a new tab The patients were monitored clinically on a daily basis by the gastroenterologist and the surgeon. Decisions about continued medical treatment or emergency colectomy were made on clinical grounds. When switching to oral medication, prednisolone 40 mg daily was given with a dose reduction of 5 mg/day each week. Maintenance treatment with a mesalamine-based drug was started or continued. Azathioprine 1.5–2 mg/kg body weight could be added according to the individual investigator’s judgment. As prophylaxis against opportunistic infections, trimethoprim 160 mg and sulfamethoxazole 800 mg was prescribed daily for 8 weeks. In patients who did not receive surgical therapy, a new endoscopy was performed 10–14, 30, and 90 days after the infliximab/placebo infusion. At the same time, blood tests were taken, and the Seo index 17Seo M. Okada M. Yao T. Ueki M. Arima S. Okumura M. An index of disease activity in patients with ulcerative colitis.Am J Gastroenterol. 1992; 87: 971-976PubMed Google Scholar was calculated. All analyses were conducted on an intention-to-treat basis. The primary end point was colectomy or death within 90 days after infusion. Secondary end points were clinical remission according to the Seo index 17Seo M. Okada M. Yao T. Ueki M. Arima S. Okumura M. An index of disease activity in patients with ulcerative colitis.Am J Gastroenterol. 1992; 87: 971-976PubMed Google Scholar and endoscopic remission 1 and 3 months after the infliximab/placebo infusion. The study was also designed to provide information on the importance of the endoscopic appearance for outcome, the possible influence of infliximab on the postoperative course, and a prospective evaluation of the fulminant colitis index. However, these were not considered hard end points. The study was performed according to the Helsinki Declaration of 1975, as revised in 1983. The study protocol was approved by the research ethics committee for each center and by the Swedish and Danish medical products agencies. All patients gave written informed consent before recruitment. On the basis of published results, it was assumed that 35% in the infliximab group and 60% in the placebo group would have a colectomy. Seventy patients in each group would provide a statistical power of 80% and a significance level at 5%. It was planned that interim analysis would be performed and that the future of the study would be decided after 70 patients had been treated. The inclusion time was calculated as 1.5–2 years. Categorical data were analyzed with the Fisher exact test (2-sided). The log-rank test, paired t test (2 sided), and logistic regression analysis were also used as appropriate. Because this was an interim analysis, to reduce the risk of false-positive findings and to keep the overall significance level at 5%, a statistically significant P value should be <.029 instead of .05. 20Pocock S.J. Clinical trials. Wiley, Chichester1983Google Scholar The study was initiated, planned, and undertaken by the investigators. The sponsors provided economic help for pharmaceutical work, investigators’ meetings, monitoring during and after the study was closed, and secretarial and other administrative work. The local hospitals paid for the infliximab/placebo.