Anti-tumor necrosis factor therapy in ulcerative colitis
- Yousif I A-Rahim, MD, PhD
Yousif I A-Rahim, MD, PhD
- Assistant Professor of Medicine
- John A. Burns School of Medicine, University of Hawaii
- Richard J Farrell, MD
Richard J Farrell, MD
- Gastroenterology Consultant, Connolly Hospital
- Associate Clinical Professor, Royal College of Surgeons in Ireland
Tumor necrosis factor-alpha (TNF-a) has a central role in the pathogenesis of mucosal inflammation in Crohn disease. Therapy with the chimeric monoclonal antibody to TNF (infliximab) has profoundly changed the management of refractory luminal and fistulizing Crohn disease. Over two-thirds of patients with Crohn disease treated with infliximab show response to the drug whereas one-third achieve remission, and maintenance therapy has been approved on account of its glucocorticoid-sparing efficacy in refractory luminal and fistulizing Crohn disease. (See "Infliximab in Crohn disease".)
The efficacy in Crohn disease provided the rationale for clinical trials of infliximab (and other anti-TNF agents) in patients with ulcerative colitis (UC), a disorder in which TNF may also have an important role. TNF-a is expressed at high levels in the colonic mucosa of patients with UC . There is also an increased production of TNF-a by colonic lamina propria mononuclear cells and high concentrations of TNF-a in stools, rectal dialysates, and urine of patients with UC [2-5].
This topic review will focus on experience with infliximab (and other anti-TNF agents) in the management of UC . An approach to the management of UC is presented separately. (See "Management of severe ulcerative colitis in adults".)
CLINICAL TRIALS OF INFLIXIMAB
Several open-label clinical trials evaluated the efficacy of infliximab in ulcerative colitis (UC) and provided the rational for subsequent controlled trials [7-13]. At least five placebo-controlled trials of infliximab in active UC have been reported as abstracts or in final form [14-17]. A meta-analysis examined the role of infliximab in UC . Failure to achieve remission was less likely in patients treated with infliximab compared with placebo (43 versus 70 percent; RR 0.72). The meta-analysis estimated that in order to achieve one remission, four patients would need to be treated. In a network meta-analysis of seven randomized trials that compared the efficacy of biologic agents in moderate to severe UC, infliximab was more likely to induce a clinical response and mucosal healing as compared with adalimumab (OR 2.79 and 2.02, respectively) . However, this evidence needs to be interpreted with caution because it is based on indirect comparisons and there are no head-to-head trials comparing infliximab with adalimumab.
ACT 1 and ACT 2 trials — The two largest trials (ACT 1 and ACT 2, each with 364 patients) focused on patients with active ulcerative colitis treated with glucocorticoids and/or 6-mercaptopurine/azathioprine (ACT 1) or with ulcerative colitis refractory to at least one standard therapy including 5-aminosalicylic acid (5-ASA) medications, glucocorticoids, or immunosuppressants (ACT 2) .
- Masuda H, Iwai S, Tanaka T, Hayakawa S. Expression of IL-8, TNF-alpha and IFN-gamma m-RNA in ulcerative colitis, particularly in patients with inactive phase. J Clin Lab Immunol 1995; 46:111.
- Reinecker HC, Steffen M, Witthoeft T, et al. 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.
- Reimund JM, Wittersheim C, Dumont S, et al. Mucosal inflammatory cytokine production by intestinal biopsies in patients with ulcerative colitis and Crohn's disease. J Clin Immunol 1996; 16:144.
- Nielsen OH, Gionchetti P, Ainsworth M, et al. Rectal dialysate and fecal concentrations of neutrophil gelatinase-associated lipocalin, interleukin-8, and tumor necrosis factor-alpha in ulcerative colitis. Am J Gastroenterol 1999; 94:2923.
- Saiki T, Mitsuyama K, Toyonaga A, et al. Detection of pro- and anti-inflammatory cytokines in stools of patients with inflammatory bowel disease. Scand J Gastroenterol 1998; 33:616.
- Danese S, Colombel JF, Peyrin-Biroulet L, et al. Review article: the role of anti-TNF in the management of ulcerative colitis -- past, present and future. Aliment Pharmacol Ther 2013; 37:855.
- Chey WY, Hussain A, Ryan C. Infliximab is an effective therapeutic agent for ulcerative colitis (abstract). Am J Gastroenterol 2000; 95:A2530.
- Chey WY. Infliximab for patients with refractory ulcerative colitis. Inflamm Bowel Dis 2001; 7 Suppl 1:S30.
- Rutgeerts P. Infliximab for ulcerative colitis: the need for adequately powered placebo-controlled trials. Am J Gastroenterol 2002; 97:2488.
- Su C, Salzberg BA, Lewis JD, et al. Efficacy of anti-tumor necrosis factor therapy in patients with ulcerative colitis. Am J Gastroenterol 2002; 97:2577.
- Kaser A, Mairinger T, Vogel W, Tilg H. Infliximab in severe steroid-refractory ulcerative colitis: a pilot study. Wien Klin Wochenschr 2001; 113:930.
- Actis GC, Bruno M, Pinna-Pintor M, et al. Infliximab for treatment of steroid-refractory ulcerative colitis. Dig Liver Dis 2002; 34:631.
- Gornet JM, Couve S, Hassani Z, et al. Infliximab for refractory ulcerative colitis or indeterminate colitis: an open-label multicentre study. Aliment Pharmacol Ther 2003; 18:175.
- Probert CS, Hearing SD, Schreiber S, et al. Infliximab in moderately severe glucocorticoid resistant ulcerative colitis: a randomised controlled trial. Gut 2003; 52:998.
- Sands BE, Tremaine WJ, Sandborn WJ, et al. Infliximab in the treatment of severe, steroid-refractory ulcerative colitis: a pilot study. Inflamm Bowel Dis 2001; 7:83.
- Ochsenkuhn T, Sackmann M, Goeke B. Infliximab for acute severe ulcerative colitis: A randomized pilot study in non-steroid refractory patients (abstract). Gastroenterology 2003; 124:A62.
- Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353:2462.
- Ford AC, Sandborn WJ, Khan KJ, et al. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol 2011; 106:644.
- Danese S, Fiorino G, Peyrin-Biroulet L, et al. Biological agents for moderately to severely active ulcerative colitis: a systematic review and network meta-analysis. Ann Intern Med 2014; 160:704.
- Colombel JF, Rutgeerts P, Reinisch W, et al. Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Gastroenterology 2011; 141:1194.
- Sandborn WJ, Rutgeerts P, Feagan BG, et al. Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab. Gastroenterology 2009; 137:1250.
- Järnerot G, Hertervig E, Friis-Liby I, et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology 2005; 128:1805.
- Gustavsson A, Järnerot G, Hertervig E, et al. Clinical trial: colectomy after rescue therapy in ulcerative colitis - 3-year follow-up of the Swedish-Danish controlled infliximab study. Aliment Pharmacol Ther 2010; 32:984.
- Panaccione R, Ghosh S, Middleton S, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology 2014; 146:392.
- Laharie 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.
- Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994; 330:1841.
- Stack WA, Long RG, Hawkey CJ. Short- and long-term outcome of patients treated with cyclosporin for severe acute ulcerative colitis. Aliment Pharmacol Ther 1998; 12:973.
- Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporin in ulcerative colitis: a five-year experience. Am J Gastroenterol 1999; 94:1587.
- Schluender SJ, Ippoliti A, Dubinsky M, et al. Does infliximab influence surgical morbidity of ileal pouch-anal anastomosis in patients with ulcerative colitis? Dis Colon Rectum 2007; 50:1747.
- Maser EA, Deconda D, Lichtiger S, et al. Cyclosporine and infliximab as rescue therapy for each other in patients with steroid-refractory ulcerative colitis. Clin Gastroenterol Hepatol 2008; 6:1112.
- Herrlinger KR, Barthel DN, Schmidt KJ, et al. Infliximab as rescue medication for patients with severe ulcerative/indeterminate colitis refractory to tacrolimus. Aliment Pharmacol Ther 2010; 31:1036.
- Afif W, Leighton JA, Hanauer SB, et al. Open-label study of adalimumab in patients with ulcerative colitis including those with prior loss of response or intolerance to infliximab. Inflamm Bowel Dis 2009; 15:1302.
- Oussalah A, Laclotte C, Chevaux JB, et al. Long-term outcome of adalimumab therapy for ulcerative colitis with intolerance or lost response to infliximab: a single-centre experience. Aliment Pharmacol Ther 2008; 28:966.
- Reinisch W, Sandborn WJ, Hommes DW, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut 2011; 60:780.
- Sandborn WJ, van Assche G, Reinisch W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2012; 142:257.
- FDA approves Humira to treat ulcerative colitis (FDA news release September 28, 2012). Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm321650.htm.
- Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2014; 146:85.
- Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2014; 146:96.
- Arnott ID, McDonald D, Williams A, Ghosh S. Clinical use of Infliximab in Crohn's disease: the Edinburgh experience. Aliment Pharmacol Ther 2001; 15:1639.
- Viscido A, Habib FI, Kohn A, et al. Infliximab in refractory pouchitis complicated by fistulae following ileo-anal pouch for ulcerative colitis. Aliment Pharmacol Ther 2003; 17:1263.
- Barreiro-de Acosta M, García-Bosch O, Souto R, et al. Efficacy of infliximab rescue therapy in patients with chronic refractory pouchitis: a multicenter study. Inflamm Bowel Dis 2012; 18:812.
- Mamula P, Markowitz JE, Cohen LJ, et al. Infliximab in pediatric ulcerative colitis: two-year follow-up. J Pediatr Gastroenterol Nutr 2004; 38:298.
- McGinnis JK, Murray KF. Infliximab for ulcerative colitis in children. 2nd World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition. 2004, abstract P0593.
- Eidelwein AP, Cuffari C, Abadom V, Oliva-Hemker M. Infliximab efficacy in pediatric ulcerative colitis. Inflamm Bowel Dis 2005; 11:213.
- Fanjiang G, Russell GH, Katz AJ. Short- and long-term response to and weaning from infliximab therapy in pediatric ulcerative colitis. J Pediatr Gastroenterol Nutr 2007; 44:312.