J KMA Pharmacotherapeutics Medical Treatment of Inflammatory Bowel Disease Jong Beom Park, MD Hyo Jong Kim, MD Department of Internal Medicine, Kyung Hee University College of Medicine E mail : parkjb@khu.ac.r.kr hjkim@khmc.or.kr J Korean Med Assoc 2006; 49(12): 1164-1174 Abstract U lcerative colitis (UC) and Crohn's disease (CD), the primary constituents of inflammatory bowel disease (IBD), are precipitated by a complex interaction of environmental, genetic, and immunoregulatory factors. A growing body of data implicates a dysfunctional mucosal immune response to commensal bacteria in the pathogenesis of IBD, especially CD. Medical management of IBD includes two treatment strategies: induction and maintenance of remission. 5 Aminosalycilates are mostly used for mild active IBD and for maintenance treatment of UC. Glucocorticoids remain, despite their frequent (and occasionally severe) side effects, as the mainstay for induction of remission in moderate to severe active IBD, both UC and CD. However, these agents, although beneficial for many patients with IBD, are not effective for the majority of patients over the long term. Immunomodulators including azathioprine(aza), 6 mercaptopurine(6 MP), or methotrexate are effective in the treatment of CD or UC. Cyclosporine and infliximab have emerged as the main, rapid acting, alternatives in steroid refractory UC and CD, respectively. In addition, infliximb was approved recently in the treatment of UC. The large number of new agents presents a bewildering challenge to practitioners anticipating their use in the clinic. Unfortunately, in spite of recent remarkable advances in medical therapy of IBD, there have been no any curative therapeutic agents for IBD up to now. Therefore, the treatment is should be individualized according to the severity of the disease and clinical course of the patients with IBD. And, it is also very important to prescribe the therapeutic agents correctly and appropriately for the patients with IBD. Keywords : Ulcerative colitis; Crohn's disease; Inflammatory bowel disease 1164
Medical Treatment of Inflammatory Bowel Disease Main factors influencing therapeutic decisions in active IBD Ulcerative colitis Disease activity (mild, moderate, severe) Disease extent (distal vs. extensive) Lack of response to other drugs in the same flare up Drug intolerance and /or contraindications Time from diagnosis Crohn's disease Pattern of disease behaviour (penetrating, stenosing, inflammatory) Disease activity (mild, moderate, severe) Disease location (ileal, colonic, ileocolonic) Patient's age Lack of response to other drugs in the same flare up Drug intolerance and / or contraindications 1165
Park JB Kim HJ Oral 5 aminosalicylate formulations Generic name Proprietary name Formulation Sites of delivery Unit strength Mesalazine Asacol Eudragit S coated tablets Terminal ileum, colon 400mg (release at ph 7.0) Mesalazine Salofalk, Mesasal, Eudragit L coated tablets Distal ileum, colon 250mg, 500mg Claversal (release at ph 6.0) Mesalazine Pentasa Ethylcellulose coated Duodenum, jejunum, 250mg and microgranules available as ileum, colon 500mg tablets, a tablet, capsule, or sachet 1,000mg sachets Olsalazine Dipentum 5 ASA dimer linked by azo bond, Colon 250mg available as a gelatin capsule Sulfasalazine Salazopyrin, 5 ASA linked to sulfapyridine by Colon 500mg Azulfidine azo bond, available as a tablet (200mg 5 ASA) Balsalazide Colazide, Colazal 5 ASA linked to 4 aminobenzoyl Colon 750mg alaine (4 ABA) by azo bond, (262mg 5 ASA) available as a capsule 1166
Medical Treatment of Inflammatory Bowel Disease 1167
Park JB Kim HJ 1168
Medical Treatment of Inflammatory Bowel Disease Infliximab treatment algorithm for Crohn s disease 1169
Park JB Kim HJ Biological compounds in development for inflammatory bowel disease Compound name Infliximab Molecular structure chimeric, anti TNF Efficacy in Crohn's disease efficacious in PCT, marketed luminal and fistulizing CD Efficacy in ulcerative colitis efficacious in PCT, marketed Development phase marketed CDP 870 Fab fragment, peginylated efficacious in patients with high CRP(PCT) phase III Adalimumab human, anti TNF, efficacious in PCT phase III Natalizumab humanized mouse anti-human 4 integrin monoclonal Ab efficacious in open label trial development halted for safety reasons LDP 02(MLN 02) humanized mouse antihuman 4 7 integrin monoclonal Ab efficacious in PCT development halted ISIS 2303 antisense oligonucleotide to ICAM 1 mrna failed PCTs efficacious as topical agent in PCT for leftsided UC phase II/III trials in ulcerative colitis ongoing with enemas Daclizumab humanized anti CD25 efficacious in open-label trial, negative PCT development in UC stopped Basiliximab humanized anti CD25 efficacious in open label trial ABT 874 human anti IL 12/IL 23 efficacious in PCT Fontolizumab humanized anti IFN efficacious in patients with elevated CRP (PCT) phase III Visilizumab humanized anti CD3 IgG2 monoclonal Ab efficacious in phase I/II open label trial phase II dose finding study ongoing MRA humanized anti IL 6 receptor Ab efficacious in phase II PCT Sargramostim recombinant human granulocyte macrophage colony stimulating factor possible efficacy in PCT PCT : Placebo controlled trial 1170
Medical Treatment of Inflammatory Bowel Disease 1171
Park JB Kim HJ proctitis. Am J Gastroenterol 1987; 1: 3-6 8. Campieri M, Lanfranchi GA, Bazzochi G, Brignola C, Sarti F, Franzin G, et al. Treatment of ulcerative colitis with high dose 5 aminosalicylic acid enemas. Lancet 1981; 2: 270-3 9. Danish 5 ASA study group. Topical 5 ASA vs. prednisolone in ulcerative proctosigmoiditis. Dig Dis Sci 1982; 32: 598-604 1. Jay M. Retrograde spreading of hydrocortisone enema in inflammatory bowel disease. Dig Dis Sci 1986; 31: 139-44 2. Champman NJ. Distribution of mesalmaine enemas in patients with active distal ulcerative colitis. Mayo Clin Proc 1992; 67: 245-8 3. Williams CN, Haber G, Aquino JA. Double blind, placebo controlled evaluation of 5 ASA suppositories in active distal proctitis and measurement of extent of spreading using TC labeled 5 ASA suppositories. Dig Dis Sci 1987; 32: 71S - 5S 4. Campieri M, De Franchis R, Bianchi Porro G, Ranzi T, Brunetti G, Barbara L. Mesalazine (5 ASA) suppositories in the treatment of ulcerative proctitis or distal proctosigmoiditis. A randomized controlled trial. Scand J Gastroenterol 1990; 25: 663-8 5. D Arienzo A, Panares A, D'Armiento FP, Lancia C, Quattrone P, Giannattasio F, et al. 5 Aminosalicylic acid suppositories in the maintenance of remission in idiopathic proctitis or proctosigmoiditis: a double blind placebo controlled clinical trial. Am J Gastroenterol 1990; 85: 1079-82 6. Sutherland LR, Martin F, Greer S, Robinson M, Greenberger N, Saibil F, et al. 5 Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology 1987; 92: 1894-8 7. Surtherland LR, Martin F. 5 Aminosalicylic acid enenmas in the maintenance of remission in distal ulcerative colitis and 10. Marshall JK, Irvine EJ. Rectal corticosteroids versus alternative treatments in ulcerative colitis: A meta analysis. Gut 1997; 40: 775-80 11. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5 aminosalicylic therapy for mildly to moderately ulcerative colitis. A randomised trial. N Engl J Med 1987; 317: 1625-9 12. Rosenberg JL, Wall AJ, Levin B, Binder HJ, Kirsner JB. A controlled trial of azathioprine in the management of chronic ulcerative colitis. Gastroenterology 1975; 69: 96-9 13. Adler DJ, Korelitz BI. The therapeutic efficacy of 6 mercaptopurine in refractory ulcerative colitis. Am J Gastroenterol 1990; 85: 717-22 14. Fraser AG, Jewell DP. Side effects of azathioprine given for inflammatory bowel disease A 30 year audit. Gastroenterology 2000; 118: A787 15. Conelll WR, Kamm MA, Dickson M, Balkwill AM, Ritchie JK, Lennard Jones JE. Long term neoplasia risk azathioprine treatment in inflammatory bowel disease. Lancet 1994; 343: 1249-52 16. Oren R, Arber N, Odes S, Moshkowitz M, Keter D, Pomeranz I, et al. Methotrexate in chronic active ulcerative colitis: a double blind, randomized, Israeli multicenter trial. Gastroenterology 1996; 110: 1416-21 17. Eaden J. The data supporting a role for aminosalicylates in the chemoprevention of colorectal cancer in patients with inflam- 1172
Medical Treatment of Inflammatory Bowel Disease matory bowel disease. Aliment Pharmacol Ther 2003; 18(S2): 15-21 18. Velayos FS, Terdiman JP, Walsh JM. Effect of 5 aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and meta-analysis of observation studies. Am J Gastroenterol 2005; 100: 1345-53 19. Meyers S, Sachar DB, Goldberg JD, Janowitz HD. Corticotropin versus hydrocortisone in the intravenous treatment of ulcerative colitis. A prospective, randomized, double-blind clinical trial. Gastroenterology 1983; 85: 351-7 20. Kaplan HP, Portnoy B, Binder HJ, Amatruda T, Spiro H. A controlled evaluation of intravenous adrenocorticotropic hormone and hydrocortisone in the treatment of acute colitis. Gastroenterology 1975; 69: 91-5 21. Powell Tuck J, Bucknell NA, Lennard Jones JE. A conrolled comparison of corticotropin and hydrocortisone in the treatment of severe proctocolitis. Scand J Gastroenterol 1977; 12: 971-5 22. Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994; 330: 1841-5 23. Van Assche G, D'Haens G, Noman M, Vermeire S, Hiele M, Asnong K, et al. Randomized, double blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis. Gastroenterology 2003; 125: 1025-31 24. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353: 2462-76 25. Hanauer SB, Stromberg U. Oral Pentasa in the treatment of active Crohn s disease: a meta analysis of double blind, placebo controlled trials. Clin Gastroenterol Hepatol 2004; 2: 379-88 26. Markowitz J, Grancher K, Kohn N, Lesser M, Daum F. A multicenter trial of 6 mercaptopurine and prednosone in children with newly diagnosed Crohn s disease. Gastroenterology 2000; 119: 895-902 27. Sandborn W, Sutherland L, Pearson D, May G, Modigliani R, Prantera C. Azathioprine or 6 mercaptopurine for inducing remissions of Crohn s disease. Cochrane Database Syst Rev 2000; 2: CD000545 28. Feagan BG, Rochon J, Fedorak RN, Irvine EJ, Wild G, Sutherland L, et al. Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study Group of Investigators. N Engl J Med 1995; 332: 292-7 29. Feagan BG, Fedorak RN, Irvine EJ, Wild G, Sutherland L, Steinhart AH, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn s disease. North American Crohn's Study Group of Investigators. N Engl J Med 2000; 342: 1627-32 30. Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, et al. A short term study of chimeric monoclonal antibody ca2 to tumor necrosis factor alpha for Crohn's disease. Crohn s Disease ca2 Study Group. N Engl J Med 1997; 337: 1029-35 31. Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer LL, van Hozegand RA, et al. Infliximab for the treatment of fistulas in patients with Crohn s disease. N Engl J Med 1999; 340: 1398-1405 32. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. Maintenance infliximab for Crohn s disease: the ACCENT I randomised trial. Lancet 2002; 359: 1541-9 1173
Park JB Kim HJ 33. Sands BE, Anderson FH, Bernstein CN, Che WY, Fegan BG, Fedorak RN, et al. Infliximab maintenance therapy for fistulizing Crohn s disease. N Engl J Med 2004; 350: 876-85 34. Sands BE, Blank MA, Patel K, van Deventer SJ. Long term treatment of rectovaginal fistula in Crohn's disease: response to infliximab in the ACCENT II Study. Clin Gastroenterol Hepatol 2004; 2: 912-20 35. Sandborn WJ, Present DH, Isaacs KL, Wolf DC, Greenberg E, Hanauer SB, et al. Tacrolimus for the treatment of fistulas in patients with Crohn s disease: a randomised, placebo controlled trial. Gastroenterology 2003; 125: 380-8 Peer Reviewer Commentary 1174