Infliximab | place in therapy review Place in therapy Although the clinical development of anti-TNF agents in Crohn’s disease has clearly outpaced the progress in UC, a lot of progress has been achieved in recent years. The role of anti-TNF in the effector phase of the inflammatory reaction in both UC and Crohn’s disease provides a scientific rationale to investigate the therapeutic potential of anti-TNF agents in UC. However, the initial data obtained in retrospective and prospective open-label trials yielded conflicting results. More recently, data from two large, controlled trials with infliximab in patients with moderate to severe UC has clearly shown clinical efficacy of the antibody to induce clinical response and remission short term and long term, to induce and maintain mucosal healing, and to spare steroids. Moreover, the first fully conducted, randomized controlled trial in patients with fulminant steroid-refractory UC has demonstrated that infliximab is efficacious at inducing clinical improvement and at preventing colectomy. Outstanding issues in patients with fulminant colitis are associated with the relative role of infliximab and cyclosporine in medical management. In general, it appears that the same rules for timing of infliximab and cyclosporine therapy should be followed (initiation after 3–5 days of unsuccessful intravenous steroid therapy). No trials comparing the relative efficacy of both drugs are available at present. Also, data on the use of infliximab in patients failing cyclosporine or vice versa are extremely scant. Theoretical concerns have arisen about the long half-life of a monoclonal antibody in patients considered for additional immunosuppressive therapy, but prospective safety data are lacking. Since the patient population included in the large ACT-1 and ACT-2 trial was quite heterogeneous, a more broad population may be eligible for treatment. It is clear that 5-aminosalicylates will remain first-line therapy for mild to moderate UC. Patients with moderate disease failing oral corticosteroids, who are dependent on corticosteroids, or who are considered for their second course of steroids within 6 months after failing the previous course should be considered for infliximab therapy. Previous antimetabolite therapy should not prevent infliximab therapy since in ACT-1 and ACT-2 such patients were clearly responding. Although not all patients achieve clinical remission with infliximab, it should influence clinical practice particularly in patients with refractory disease. No new safety issues specific for UC patients have arisen from the combined experience reported in the literature, but the side effect profile of anti-TNF agents should be known to every clinician using this potent therapy. Acknowledgments Professor Van Assche has received honoraria from Schering- Plough, Centocor, Abbott, and UCB, and has received grants from Abbott, Schering-Plough, and Centocor. He has served as a consultant and on advisory boards for PDL Biopharma, Novartis, and Shire. References Actis GC, Volpes R, Rizzetto M. Oral microemulsion cyclosporin to reduce steroids rapidly in chronic active ulcerative colitis. Eur J Gastroenterol Hepatol. 1999;11:905–908. 160 Actis GC, Bruno M, Pinna-Pintor M, Rossini FP, Rizzetto M. Infliximab for treatment of steroid-refractory ulcerative colitis. Dig Liver Dis. 2002;34:631–634. Anon. Remicade Prescribing Information. Centocor, Inc.: Malvern, PA: April 2007. Available at: http://www.centocor.com/centocor/assets/remicade.pdf#zoom=100 (accessed June 2007). Armuzzi A, Lupascu A, De Pascalis B, et al. Infliximab in the treatment of moderate to severe glucocorticoid dependent ulcerative colitis: a randomized methylprednisolone controlled trial. Gastroenterology. 2004;126(Suppl. 2):A464. Abstract. Arts J, D'Haens G, Zeegers M, et al. Long-term outcome of treatment with intravenous cyclosporin in patients with severe ulcerative colitis. Inflamm Bowel Dis. 2004;10:73–78. Baumgart DC, Pintoffl JP, Sturm A, Wiedenmann B, Dignass AU. Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease – a long-term follow-up. Am J Gastroenterol. 2006;101:1048–1056. Bermejo F, Lopez-Sanroman A, Hinojosa J, Castro L, Jurado C, Gomez-Beldal AB. Infliximab induces clinical, endoscopic and histological responses in refractory ulcerative colitis. Rev Esp Enferm Dig. 2004;96:94–101. Biancone L, Orlando A, Kohn A, et al. Infliximab and newly diagnosed neoplasia in Crohn’s disease: a multicentre matched pair study. Gut. 2006;55:228–233. Boirivant M, Marini M, Di Felice G, et al. Lamina propria T cells in Crohn’s disease and other gastrointestinal inflammation show defective CD2 pathway- induced apoptosis. Gastroenterology. 1999;116:557–565. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti- TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006;295:2275–2285. Breese EJ, Michie CA, Nicholls SW, et al. Tumor necrosis factor alpha-producing cells in the intestinal mucosa of children with inflammatory bowel disease. Gastroenterology. 1994;106:1455–1466. Brynskov J, Foegh P, Pedersen G, et al. Tumour necrosis factor alpha converting enzyme (TACE) activity in the colonic mucosa of patients with inflammatory bowel disease. Gut. 2002;51:37–43. Campbell S, Travis S, Jewell D. Ciclosporin use in acute ulcerative colitis: a long-term experience. Eur J Gastroenterol Hepatol. 2005;17:79–84. Casellas F, Papo M, Guarner F, Antolin M, Armengol JR, Malagelada JR. Intraluminal colonic release of immunoreactive tumour necrosis factor in chronic ulcerative colitis. Clin Sci (Lond). 1994;87:453–458. Chey WY. Infliximab for patients with refractory ulcerative colitis. Inflamm Bowel Dis. 2001;7(Suppl. 1):S30–S33. Chey WY, Hussain A, Ryan C, Potter GD, Shah A. Infliximab for refractory ulcerative colitis. Am J Gastroenterol. 2001;96:2373–2381. Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporin in ulcerative colitis: a five-year experience. Am J Gastroenterol. 1999;94:1587–1592. Cohen RD. Infliximab in ulcerative colitis: is there a placebo (effect) in the house? Gastroenterology. 2003;124:1990–1991. Cummings JR, Herrlinger KR, Travis SP, Gorard DA, McIntyre AS, Jewell DP. Oral methotrexate in ulcerative colitis. Aliment Pharmacol Ther. 2005;21:385–389. Das KM, Dasgupta A, Mandal A, Geng X. Autoimmunity to cytoskeletal protein tropomyosin: a clue to the pathogenic mechanism for ulcerative colitis. J Immunol. 1993;150:2487–2493. D’Haens G, Lemmens L, Geboes K, et al. Inravenous cyclosporine versus intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis. Gastroenterology. 2001;120:1323–1329. Edwards FC, Truelove SC. The course and prognosis of ulcerative colitis. Gut. 1963;4:299–315. Eidelwein AP, Cuffari C, Abadom V, Oliva-Hemker M. Infliximab efficacy in pediatric ulcerative colitis. Inflamm Bowel Dis. 2005;11:213–218. Evans RC, Clarke L, Heath P, Stephens S, Morris AI, Rhodes JM. Treatment of ulcerative colitis with an engineered human anti-TNF alpha antibody CDP571. Aliment Pharmacol Ther. 1997;11:1031–1035. © 2007 Core Medical Publishing Limited