Crohn s disease is a chronic, progressive, destructive

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1 Mini-Reviews and Perspectives Current Directions in IBD Therapy: What Goals Are Feasible With Biological Modifiers? WILLIAM J. SANDBORN Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota Crohn s disease is a chronic, progressive, destructive disease, and current treatment strategies are inadequate. The historic treatment goals of induction and maintenance of clinical response and remission do not change the natural history of Crohn s disease. Current evolving treatment goals include steroid-free remission, endoscopic healing, and reduction in hospitalization and surgery. An evolution to early treatment with either azathioprine and/or anti-tumor necrosis factor (TNF) agents (infliximab, adalimumab, certolizumab) in most patients is likely, with potential future treatment goals of reduction in bowel damage, prevention of complications (stricture, fistula, abscess), and maintaining normal gastrointestinal (GI) physiology. Ulcerative colitis is a disease with a variable course that, in a subgroup of patients, results in colectomy with ileoanal pouch or stoma. The historic treatment goals of induction and maintenance of clinical response and remission are satisfactory for some but not all patients. Current evolving treatment goals include steroid-free remission, endoscopic healing, and reduction in hospitalization and surgery. An evolution to treatment goals of sustained clinical remission, sustained mucosal healing with a reduction in colorectal dysplasia and cancer, and maintaining normal GI physiology is likely. Although mesalamine remains the first-line therapy, the preferred second-line treatment strategy (azathioprine and/or anti-tnf therapy) is uncertain. Disease Course Crohn s disease and ulcerative colitis are chronic, immune-mediated inflammatory diseases of the GI tract. 1,2 Crohn s disease is characterized by mucosal ulceration and transmural inflammation of the terminal ileum and/or colon. In early Crohn s disease, the pathology is inflammatory and the disease course is relapsing and remitting with intermittent symptoms of abdominal pain and diarrhea. 3 In late Crohn s disease, the pathology frequently includes complications of chronic inflammation such as stricture and penetration of the bowel wall with obstruction, fistula, and abscess. Approximately 80% of patients develop these complications and most require surgery. 4 After surgery, approximately 90% of patients develop recurrent ulcers. 5 Crohn s disease can be described as a chronic, progressive, destructive disease that, in most patients, leads to irreversible structural damage to the bowel, surgical resection of bowel with loss of intestinal function, and variably resection or bypass of the anal sphincter with stoma and loss of continence. Ulcerative colitis is characterized by mucosal inflammation of the colon. The pathology is inflammatory and the disease course is relapsing and remitting with intermittent symptoms of rectal bleeding and diarrhea. Approximately 25% of patients develop a chronic active or a rapidly fulminate disease course. 6 Chronic inflammation can lead to dysplasia and cancer. Approximately 20% of patients require colectomy with ileoanal pouch or stoma. 7 After colectomy with ileoanal pouch, approximately 50% of patients develop pouchitis and cuffitis. 8 The ileoanal pouch is also associated with increased risk of fecal incontinence, high stool frequency, anastomotic stricture, and reduced female fertility. 9,10 Ulcerative colitis can be described as a disease with a variable course that, in a subgroup of patients, results in surgical resection of the colon with ileoanal pouch or stoma with loss of continence. Historic Treatment Goals The historic treatment goals for Crohn s disease were to eliminate symptoms with as few side effects and longterm sequelae as possible (Table 1). 11 Therapy for mild to moderate disease comprised mesalamine, antibiotics, and topical corticosteroids; therapy for moderate to severe disease consisted of systemic corticosteroids and immunosuppressives (azathioprine, 6-mercaptopurine, methotrexate), thereby reserving biologics (infliximab, adalimumab, certolizumab, natalizumab ) for patients who had failed these agents. 11 The principles of treatment included maximizing the use of medications with a more favorable side effect profile (mesalamine and antibiotics), minimizing the use of medications with a less favorable side effect profile by limiting the duration of treatment (corticosteroids), acceptance of surgical resection as a highly effective and durable treatment with low morbidity, and reservation of immunosuppressive and biologic medications for patients who failed other treatments. This treatment paradigm does not alter the progression of Crohn s disease from inflammation to complications of stricture, fistula, and abscess that require surgery. Mesalamine is not effective. Corticosteroids are effective short term, but fail in most patients long term. 26 Immunosuppressives maintain symptomatic remission in approximately 40% of patients over 1 year, 27 but do not achieve high rates of endoscopic (mucosal) heal by the AGA Institute /08/$34.00 doi: /j.gastro GASTROENTEROLOGY 2008;135:

2 Table 1. Treatment Goals for and Treatment Goal Crohn s Disease Ulcerative Colitis Historic treatment goals Induction and maintenance of clinical response Induction and maintenance of clinical remission Current evolution of treatment goals Steroid-free remission Induction and maintenance of endoscopic healing Reduction in hospitalization Reduction in surgery Potential future treatment goals Reduction in bowel damage Prevention of complications (stricture, fistula, abscess) Prevention of colorectal dysplasia and cancer Maintain normal gastrointestinal physiology Reduce risk of serious infection and cancer ing and have not decreased surgery. 28,29 Anti-TNF biologic therapy with infliximab, adalimumab, and certolizumab in patients refractory to conventional therapy result in shortterm response and remission rates of approximately 60% and 30%, respectively, and net remission rates at 6 12 months of 25% 30%. 30 Whether the use of these agents, serving as salvage therapy, has changed the natural history of Crohn s disease is unknown currently. The historic treatment goals for ulcerative colitis were to induce and maintain remission of symptoms and mucosal inflammation (Table 1). 31 Therapy for mild to moderate disease comprised oral and topical mesalamine and topical corticosteroids; therapy for moderate to severe disease was composed of systemic corticosteroids and immunosuppressives (azathioprine, 6-mercaptopurine), reserving biologics (infliximab) for patients who had failed these agents. 31 The principles of treatment included maximizing the use of medications with a more favorable side effect profile (mesalamine and topical corticosteroids), minimizing the use of medications with a less favorable side effect profile by limiting the duration of treatment (corticosteroids), acceptance of surgical resection as a highly effective and curative treatment with low morbidity, and reservation of immunosuppressive and biologic medications for patients who failed other treatments. In contrast to Crohn s disease, mesalamine is effective for ulcerative colitis. 32 For patients who fail mesalamine, corticosteroids are effective short term but fail in most patients long term. 26 Immunosuppressives have variable efficacy in ulcerative colitis. 33 Anti-TNF biologic therapy with infliximab in patients refractory to conventional therapy results in short-term response and remission rates of approximately 60% and 30%, respectively, and remission rates at 6 12 months of 25% 30%. 34 The use of infliximab as salvage therapy has reduced the need for colectomy. 35 Data on the efficacy of adalimumab and certolizumab in ulcerative colitis are lacking. Current Evolution of Treatment Goals The current evolution of treatment goals for Crohn s disease include steroid sparing, endoscopic healing, and reducing hospitalization and surgery (Table 1). Mesalamine is not steroid sparing. Steroid sparing for azathioprine has been demonstrated only as prophylactic therapy. 27 Methotrexate, infliximab, adalimumab, and natalizumab are all effective for maintenance of steroid-free remission. 13,19,24,36 Steroid-sparing data are lacking for certolizumab. Future treatment strategies may emphasize non steroid-based treatment strategies to avoid the toxicity (increased relative risk of serious infection and death) associated with steroid therapy (although it should be noted that the absolute risk is still small). 37,38 The rates of endoscopic healing in patients receiving steroids are low, and correlate poorly with clinical remission. 39 Infliximab can induce and maintain endoscopic healing, which is associated with reduced hospitalization and surgery. 40,41 Combination therapy with azathioprine (induction plus maintenance) and infliximab (induction only) resulted in greater rates of endoscopic healing at 2 years compared with standard therapy (steroids, then azathioprine then infliximab). 28 Endoscopic healing data are lacking for adalimumab, certolizumab, and natalizumab. Hospitalization and surgery are infrequent events associated with high costs, and surgery results in irreversible structural damage to the bowel. Infliximab and adalimumab reduce the rates of hospitalization and surgery over 1 year Natalizumab reduces hospitalization over 3 months 45 ; surgery data are lacking. Hospitalization and surgery data are lacking for certolizumab. The current evolution of treatment goals for ulcerative colitis include steroid sparing, endoscopic healing, and reduction in hospitalization and surgery (Table 1). There are no controlled data demonstrating that mesalamine is steroid sparing, and only limited data that azathioprine is steroid sparing. 33,46 Infliximab is effective for maintenance of steroid-free remission. 34 Data on adalimumab and certolizumab are lacking. Future treatment strategies may emphasize non steroid-based treatment strategies to avoid the toxicity (increased risk of serious infection and death) associated with steroid therapy (although it should be noted that the absolute risk is still small). 37,38 Endoscopic healing is variable with mesalamine. 32 Steroids are effective for induction of endoscopic healing in the short term, 47 but are not effective as maintenance therapy. There are limited data that azathioprine might induce and maintain endoscopic healing. 46 Infliximab is effective for induction and maintenance of endoscopic healing. 34 Early endoscopic healing with infliximab is associated with subsequent increased rates of clinical remission. 48 Hospitalization and surgery are infrequent events associated with high costs, and surgery results in irreversible structural damage to the bowel. Infliximab reduces the rates of hospitalization and surgery over 1 year. 35 Data on adalimumab and certolizumab are lacking. 1443

3 Figure 1. Correlation between fecal weight and postoperative handicap index. The regression equation. The regression equation was: y log [75 x]. (n 112; r 0.60; P.001). Reprinted with permission from: Cosnes J, de Parades V, Carbonnel F, et al. Classification of the sequelae of bowel resection for Crohn s disease. Br J Surg 1994;81: What Treatment Goals Are Feasible in the Future? Potential future treatment goals for Crohn s disease include reduction in bowel damage and prevention of complications (stricture, fistula, abscess) and maintaining normal GI physiology (Table 1). Achievement of these treatment goals requires early therapy with effective maintenance agents. Mesalamine is not effective. Steroids are effective for induction but not maintenance. 26 Combination therapy with steroids (induction) and 6-mercaptopurine (maintenance) have demonstrated superior rates of sustained clinical remission over 1 year compared with standard therapy with steroids (induction) in children with early Crohn s disease. 49 Combination therapy with infliximab (induction) and azathioprine (maintenance) demonstrated superior rates of sustained clinical remission over 1 year and endoscopic healing over 2 years compared with standard therapy (2 cycles of steroids, then azathioprine, then infliximab) in patients with early Crohn s disease. 28 Infliximab monotherapy and combination therapy with azathioprine and infliximab were both superior to azathioprine monotherapy in patients with Crohn s disease failing first line therapy with mesalamine and/or steroids (combination therapy was also more effective than infliximab monotherapy). 50,51 Adalimumab and certizumab demonstrated greater absolute efficacy in subgroups of patients with early Crohn s disease. 52,53 A bowel damage score that uses colonoscopy and computed tomographic or magnetic resonance imaging enterography to quantitatively measure the extent and severity of mucosal and transmural disease, the development of complications (stricture, fistula, abscess), and the amount of surgically resected bowel over time is needed. A prototype bowel damage score demonstrated correlation between loss of bowel from surgery and fecal fat and weight (Figure 1). 54 A composite endpoint (steroid-free remission, endoscopic healing, no complications, and no surgical resection) that reflects normal GI tract physiology might be achievable. Prevention of bowel damage and complications and maintaining normal bowel physiology in patients with Crohn s disease will likely require azathioprine or 6-mercaptopurine and/or anti-tnf therapy. These agents have an increased realative risk of toxicity, including serious and opportunistic infection, 37,38,55 non-hodgkin s lymphoma, 56,57 hepatosplenic T-cell lymphoma, 58 and death (although it should be noted that the absolute risk is still small). 37,38 Strategies to increase efficacy and reduce risk are required. To increase efficacy, early treatment (within 2 years) with azathioprine or 6-mercaptopurine and/or anti-tnf therapy with infliximab, adalimumab, or certolizumab increases the absolute response rates. 28,52,53 Among patients naïve to immunosuppressives and biologics, combination therapy with an anti-tnf agent and azathioprine appears to give the best result. 50,51 Clinical predictors of poor prognosis include age 40 years, steroid treatment, and perianal disease. 59 Biomarkers might also be useful. 60 Monotherapy with azathioprine or 6-mercaptopurine or infliximab may reduce the relative risk of opportunistic infection 55 and hepatosplenic T-cell lymphoma 58 as compared with combination therapy, however, in patients naive to both agents, monotherapy with either agent is less effective than combination therapy. 50,51 Steroids as monotherapy or in combination with immunosuppressives and/or anti-tnf agents are associated with an increased relative risk of opportunistic and serious infections and death (although it should be noted that the absolute risk is still small). 37,38,55 Monotherapy with azathioprine and 6-mercaptopurine is associated with an increased relative risk of non-hodgkin s lymphoma, 56 attributable in large part to Epstein Barr virus associated lymphoma (although again, it should be noted that the absolute risk is still small). 57 Rapidly acting steroids (induction) and slowacting immunosuppressive agents azathioprine and 6-mercaptopurine (maintenance) are often given as combination therapy. The increased relative risks of steroids and azathioprine or 6-mercaptopurine both individually and in combination raise the question of whether the preferred early treatment strategy would be combination therapy with steroids plus an immunosuppressive agent or treatment with an anti-tnf biological agent (either monotherapy or combination therapy). Episodic biologic therapy with infliximab, certolizumab, and natalizumab as monotherapy is associated with increased immunogenicity. 22,24,61 Data on episodic therapy with adalimumab are lacking. By contrast, when the biologic agents infliximab, adalimumab, certolizumab, or natalizumab are administered as monotherapy with a induction loading dose and then systematic maintenance therapy, the rates of immunogenicity are relatively low and generally comparable with patients receiving combination therapy with an immunosuppressive. 13,18,21,22,24 Subgroup analyses of patients who previously failed azathioprine (or other immunosuppressives) and receiving systematic maintenance biologic therapy with infliximab, adalimumab, certolizumab, or natalizumab with or without a concomitant immunosuppressive demonstrate similar clinical outcomes over 6 12 months. 13,19,21,22,24,62 A randomized trial demonstrated no synergistic efficacy between infliximab and methotrexate in patient s naïve to both immunosuppressives and biologics 63 whereas another randomized trial did demonstrated synergistic efficacy between infliximab and azathioprine in patients naïve to both agents. 50,51 In contrast, a 1444

4 Table 2. Agents in Development for and Name Mechanism of Action Golimumab Anti-TNF antibody Abatacept (Orencia) Blockade of CD28 costimulatory pathway by CTLA4 fusion protein ABT 874 (J695) Anti-interleukin 12/23 p40 antibody Ustekinumab (CNTO 1275) Anti-interleukin 12/23 p40 antibody CC282-B Chemokine receptor 9 antagonist MLN-0002 (MLN-02, LDP-02) Anti -4-7 antibody rumab -7 Anti -7 antibody Anti-MAdCAM-1 CP-690,550 Antagonist to Janus kinase 3 (JAK3) AIN476 Anti IL-7 antibody Basiliximab (Simulect) Anti IL-2 receptor (CD25) antibody randomized withdrawal trail demonstrated no clinical benefit to continuing azathioprine in patients who had previously failed azathioprine and were receiving combination maintenance therapy with infliximab and azathioprine. 64 Among patients who have previously failed azathioprine or other immunosuppressive agents, a shift in practice from combination therapy with immunosuppressives plus biologics to monotherapy with biologics has the potential to improve the safety profile of biologic therapy. Among patients with early Crohn s disease who have failed first line therapy with mesalamine and/or steroids, a shift in practice from combination therapy with steroids and immunosuppressives to anti-tnf therapy, either as monotherapy or in combination with an immunosuppressive has the potential to maximize the treatment effect. Using this strategy, patients who wish to maximize safety may prefer anti-tnf monotherapy whereas patients who prefer to maximize efficacy may prefer combination therapy. Other biotechnology agents currently under development for Crohn s disease are shown in Table 2. Potential future treatment goals for ulcerative colitis include sustained clinical remission, sustained mucosal healing with a reduction in colorectal dysplasia and cancer, and maintaining normal GI physiology (Table 1). It should be noted that chronic mucosal inflammation is associated with increased risk of dysplasia and cancer. 65 Achievement of these treatment goals requires an evolution from symptom-based treatment to treatment regimens aimed at achieving endoscopic healing. Mesalamine therapy is sufficient in approximately 50% of patients. 32 Mesalamine also has a chemoprevention effect. 66 There are limited data that azathioprine might induce and maintain clinical remission and endoscopic healing, 33,46 but may not have chemoprevention properties. 67 Infliximab is effective for induction and maintenance of clinical remission and endoscopic healing. 34 The effect of infliximab upon colorectal dysplasia and cancer is unknown. In contrast with Crohn s disease, infliximab has similar efficacy in both early and long duration ulcerative colitis, 68 and the use of infliximab later in the course of ulcerative colitis can still result in reduced rates of hospitalization and surgery. 35 Thus, unless clear clinical or biologic predictors can be found that predict future need for surgery in a subset of patients with ulcerative colitis, the current treatment paradigm of mesalamine as the first-line agent is likely to persist. It remains an open question as to whether the preferred course of therapy for patients failing mesalamine is combination therapy with steroids plus azathioprine, or infliximab (anti-tnf) either as monotherapy or in combination with azathioprine. Other biotechnology agents currently under development for ulcerative colitis are shown in Table 2. Conclusions Crohn s disease is a chronic progressive destructive disease and current treatment strategies are inadequate. An evolution to early treatment with either azathioprine and/or anti-tnf is likely, with the goals of reduction in bowel damage, prevention of complications, and maintaining normal GI physiology. Ulcerative colitis is a disease with a variable course, which in a subgroup of patients results in colectomy with ileoanal pouch or stoma. An evolution to treatment goals to sustained clinical remission, sustained mucosal healing with a reduction in colorectal dysplasia and cancer, and maintaining normal GI physiology is likely. Although mesalamine remains the first-line therapy, the preferred second line treatment strategy (azathioprine and/or anti-tnf monotherapy) is uncertain. References 1. Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet 2007;369: Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet 2007; 369: Munkholm P, Langholz E, Davidsen M, et al. 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Infliximab reduces colectomy in patients with moderate-to-severe ulcerative colitis: an analysis from ACT 1 and ACT 2. Am J Gastroenterol 2007; 102(S2):S [abstract 984]. 36. Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn s disease. The North American Crohn s Study Group Investigators. N Engl J Med 1995;332: Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infections and mortality in association with therapies for Crohn s disease: TREAT registry. Clin Gastroenterol Hepatol 2006;4: Lewis JD, Gelfand JM, Troxel AB, et al. Immunosuppressant medications and mortality in inflammatory bowel disease. Am J Gastroenterol 2008;103: Modigliani R, Mary JY, Simon JF, et al. Clinical, biological, and endoscopic picture of attacks of Crohn s disease. Evolution on prednisolone. Groupe d Etude Therapeutique des Affections Inflammatoires Digestives. Gastroenterology 1990;98: D Haens G, Van Deventer S, Van Hogezand R, et al. 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6 45. Sands BE, Siegel CA, Spencer M, et al. Natalizumab reduces the hospitalization rate in moderate to severe Crohn s disease patients a pooled analysis of the ENACT-1 and ENCORE studies. Gastroenterology 2008;134(Suppl 1):A Ardizzone S, Maconi G, Russo A, et al. Randomised, controlled trial, of azathioprine and 5- aminosalicylic acid for treatment of steroid-dependent ulcerative colitis. Gut 2006;55: Truelove SC, Witts LJ. Cortisone in ulcerative colitis. Final report on a therapeutic trial. BMJ 1955;2: Rutgeerts P, Colombel JF, Reinisch W, et al. Infliximab induces and maintains mucosal healing in patients with active ulcerative colitis: the ACT trial experience. Gut 2005;54(Suppl VII):A Markowitz J, Grancher K, Kohn N, et al. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn s disease. Gastroenterology 2000;119: Sandborn W, Rutgeerts P, Reinisch W, Kornbluth A, Lichtiger S, D Haens G, van der Woude C, Diamond R, Broussard D, Colombel J. Sonic: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathioprine to azathioprine in patients with Crohn s disease naïve to immunomodulators and biologic therapy. American Journal of Gastroenterology 2008; 103(S1):S436 [Abstract 1117]. 51. PRNewswire. [Press release], October 6, New findings shor efficacy of Remicade compared with azathioprine in treatment of Crohn s disease according to first-of-its-kind study & STORY /www/story/ / &edate. Accessed October 6, Schreiber S, Reinisch W, Colombel JF, et al. Early Crohn s disease shows high levels of remission to therapy with adalimumab: sub-analysis of CHARM. Gastroenterology 2007;132:A Sandborn WJ, Colombel JF, Panes J, et al. Higher remission and maintenance of response rates with subcutaneous monthly certolizumab pegol in patients with recent-onset Crohn s disease: data from PRECiSE 2. Am J Gastroenterol 2006;101:S (Abstract 1109). 54. Cosnes J, de Parades V, Carbonnel F, et al. 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Withdrawal of immunosuppression in Crohn s disease treated with scheduled infliximab maintenance: a randomized trial. Gastroenterology 2008;134: Rutter M, Saunders B, Wilkinson K, et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 2004;126: Velayos FS, Terdiman JP, Walsh JM. Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and metaanalysis of observational studies. Am J Gastroenterol 2005;100: Matula S, Croog V, Itzkowitz S, et al. Chemoprevention of colorectal neoplasia in ulcerative colitis: the effect of 6-mercaptopurine [see comment]. Clin Gastroenterol Hepatol 2005;3: Reinisch W, Sandborn WJ, Rutgeerts P, et al. Infliximab treatment for ulcerative colitis: comparable clinical response, clinical remission, and mucosal healing in patients with disease duration 3 years vs 3 years. Gastroenterology 2008;134(Suppl 1): A495. Address requests for reprints to: William J. Sandborn, MD, Mayo Clinic, 200 First Street SW, Rochester, MN sandborn. william@mayo.edu; fax: (507) The author discloses the following: Dr Sandborn is supported by Procter & Gamble Pharmaceuticals, Shire Pharmaceuticals, Centocor, Abbott Laboratories, UCB Pharma. Dr Sandborn is a consultant for Procter & Gamble Pharmaceuticals, Shire Pharmaceuticals, Salix Pharmaceuticals, Centocor, Abbott Laboratories, UCB Pharma, and Elan. 1447