- Email: [email protected]
Disease Modification in Inflammatory Bowel Disease
Comment From the Editor Disease Modification in Inflammatory Bowel Disease
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used to describe the treatment of Crohn’s disease (CD) as “the treatment of symptoms.” This was in contrast to the treatment of ulcerative colitis (UC), where clinical trials had discriminated between “induction of remission” and “maintenance of remission.” Indeed, Sidney Truelove in his original controlled trials of cortisone for UC described remissions both from clinical and endoscopic standpoints.1 Clinical remissions were described as “one or two stools a day without blood . . .” with normalization of hemoglobin, sedimentation rate, and absence of systemic symptoms; whereas endoscopic remissions were described as a “normal or near normal” sigmoidoscopic appearance. Even Truelove noted discrepancies between individuals who achieved clinical and/or endoscopic remissions. In contrast, in clinical trials CD has primarily been evaluated based on symptoms utilizing the Crohn’s Disease Activity Index (CDAI), which is comprised of clinical criteria aside from measurement of hematocrits.2 The CDAI has been shown to have poor correlation with either endoscopy or C-reactive protein.3 Furthermore, when remissions were based on CDAI criteria in a large clinical trial, 94% of patients achieved a clinical remission within 7 weeks on corticosteroids, but only 29% achieved endoscopic healing. Continuing corticosteroids in patients who had clinical remission, but not endoscopic healing, did not alter the course after steroid withdrawal, leading the authors to conclude “. . . the clear-cut findings of this painstaking study will put an end to the ritual endoscopic monitoring of CD . . .”.4 Henceforth, over the past 2 decades, treatment for CD has been based on clinical parameters despite the observations that 1) laboratory parameters can predict the risk of relapse for patients in a clinical remission5 and 2) even in the setting of a complete clinical remission, ie, after an ileo-cecal resection, without maintenance therapy there is a nearly inevitable progression from histologic to endoscopic to clinical recurrence.6 However, it
was not until recent trials with anti–tumor necrosis factor (TNF) biologic agents that, despite discrepancies between clinical and biologic (endoscopic and C-reactive protein normalization) remissions, the achievement of endoscopic remission had greater impact on longterm outcomes, such as the need for hospitalizations and surgeries.7,8 Similarly, there is evidence from observational series in CD and UC that achievement of endoscopic remissions have improved outcomes related to hospitalizations and surgeries,9 and in UC the risk of neoplasia is diminished with both endoscopic and histologic remissions.10 What are clearly needed for both UC and CD are noninvasive and costeffective surrogates for endoscopic healing (calprotectin?11). These observations have led to new terminologies for inflammatory bowel disease (IBD), including the concept of “deep remissions,” whereby both symptoms and biologic parameters are normalized.12 No longer are clinical symptoms sufficient to assess IBD for long-term outcomes. Furthermore, the concept of treating toward a biologic remission has entered into the world of IBD, similar to the potential in rheumatoid arthritis and psoriasis, with the real possibility of “disease modification” of the natural history of IBD toward the transmural complications of CD and the risks of colectomy and neoplasia in UC. Some have termed the concept “treating to target.”13 With the current potential to alter the natural history and modify (prevent or stabilize) structural damage (in CD, at least), the next question becomes “how to” in the context of both CD and UC. The scenario is both easy and complex for UC. The colonic mucosa is readily accessible by endoscopy, although there has yet to be a validated scoring system to classify mucosal healing. As an example, the early studies from Oxford did not really define a “healed or almost healed” mucosa. Furthermore, studies going back several decades have demonstrated that even in the setting of an intact mucosa, the presence of residual neutrophils portend a greater risk of relapse on maintenance therapy. Nevertheless, even without histology, and without debating the validities of recent scoring systems, evidence of mucosal healing by
whatever criteria has consistently demonstrated long-term benefits.14 Aminosalicylates and anti-TNF biological therapies have induced mucosal healing in different patient populations (aminosalicylates in patients with mild-moderate disease and anti-TNF therapies in the setting of disease refractory to aminosalicylates, steroids and/or thiopurines).15 CD is, by nature, more complex and heterogeneous with regard to assessing mucosal healing and deep biological remissions. The transmural complications of CD, strictures, and fistulae may not be amenable to our most effective treatments for mucosal disease and can affect residual symptoms, even in the presence of mucosal healing and normalization of biological inflammatory parameters. Furthermore, earlier treatment in the course of the disease amplifies clinical benefits and provides optimism for the potential to prevent transmural complications that are strongly correlated with the need for surgical resections.16 The ability to improve outcomes for IBD with individualized medical therapies requires 2 criteria: 1) prediction of an individual’s disease course and 2) means to optimize therapy. Recent evidence suggests that both criteria can be, increasingly, accomplished. From the standpoint of prognostication, the disease course can be predicted for both UC and CD, and has considerable overlap between the disease spectra.17 Extensive disease and deep ulcerations, an early need for corticosteroids, high serologic titers against intestinal microbes or pANCA, and smoking (CD) or ex-smoking (UC) predict a bad course. Extra-intestinal manifestations predict a greater risk of pouchitis after ileo-anal anastomoses in UC, and primary sclerosing cholangitis is a risk factor for colonic dysplasia. Although it remains to be determined whether individuals afflicted with predictors of a bad prognosis will benefit from more aggressive therapies, we know that they respond poorly to a conventional “step-up” approach. There are also promising results from the standpoint of optimizing effective therapies. Aminosalicylates can be used at more effective doses in the absence of sulfasalazine’s sulfa moiety. Corticosteroids, while still the drugs we love to hate, can be formulated to improve risks
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10:954 –955
Comment From the Editor, continued and benefits. Thiopurines can be optimized by predefining thiopurine methyltransferase functional activity and by optimizing 6-mercaptopurine metabolites.18 Maintaining trough levels can optimize biologic therapy.19 Combining anti-TNF biologics with immunosuppressives can improve outcomes without increasing serious adverse effects.20 Switching therapeutic mechanisms of action can be effective when initial mechanisms lose response.21 Therapy for IBD has come a long way and is no longer simply the treatment of symptoms. Evolutions in end points for clinical trials and clinical practice goals, along with improved disease prognostication and optimization of medical therapies, provide examples of how our field has taken a lead in the personalization of medicine that will alter the course of these chronic immune-inflammatory disorders. With the availability of highly effective biologic therapies used earlier in the course of our patients, a remaining question is: “at what cost?”
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STEPHEN B. HANAUER Associate Editor Professor of Medicine and Clinical Pharmacology Chief, Section of Gastroenterology, Hepatology and Nutrition University of Chicago Medicine Chicago, Illinois References 1. Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J 1955;2:1041–1048. 2. Sandborn WJ, Feagan BG, Hanauer SB, et al. A review of activity indices and efficacy endpoints for clinical trials of medical
8.
9.
10.
11.
therapy in adults with Crohn’s disease. Gastroenterology 2002;122:512–530. 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; 98:811– 818. Landi B, Anh TN, Cortot A, et al. Endoscopic monitoring of Crohn’s disease treatment: a prospective, randomized clinical trial. The Groupe d’Etudes Therapeutiques des Affections Inflammatoires Digestives. Gastroenterology 1992;102: 1647–1653. Desai D, Faubion WA, Sandborn WJ. Review article: biological activity markers in inflammatory bowel disease. Aliment Pharmacol Ther 2007;25:247–255. Rutgeerts P, Geboes K, Vantrappen G, et al. Predictability of the postoperative course of Crohn’s disease. Gastroenterology 1990;99:956 –963. Rutgeerts P, Diamond RH, Bala M, et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn’s disease. Gastrointest Endosc 2006;63:433– 442. 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 –1201. Froslie KF, Jahnsen J, Moum BA, et al. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007;133:412– 422. Rutter M, Saunders B, Wilkinson K, et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 2004;126:451– 459. Abraham BP, Kane S. Fecal markers: calprotectin and lactoferrin. Gastroenterol Clin North Am 2012;41:483– 495.
12. Colombel JF, Rutgeerts P, Sandborn W, et al. Adalimumab treatment results in deep remission for patients with moderate to severe ileocolonic Crohn’s disease: results from EXTEND. Gastroenterology 2010;138:S-518. 13. Smolen JS, Aletaha D, Bijlsma JW, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis 2010;69:631– 637. 14. Ha C, Kornbluth A. Mucosal healing in inflammatory bowel disease: where do we stand? Curr Gastroenterol Rep 2010; 12:471– 478. 15. Armuzzi A, Van Assche G, Reinisch W, et al. Results of the 2nd scientific workshop of the ECCO (IV): therapeutic strategies to enhance intestinal healing in inflammatory bowel disease. J Crohns Colitis 2012;6: 492–502. 16. Kakkar A, Wasan SK, Farraye FA. Targeting mucosal healing in Crohn’s disease. Gastroenterol Hepatol (N Y) 2011;7:374 –380. 17. Blonski W, Buchner AM, Lichtenstein GR. Clinical predictors of aggressive/disabling disease: ulcerative colitis and Crohn disease. Gastroenterol Clin North Am 2012; 41:443– 462. 18. Dassopoulos T, Sninsky CA. Optimizing immunomodulators and anti-TNF agents in the therapy of Crohn disease. Gastroenterol Clin North Am 2012;41:393– 409. 19. Colombel JF, Feagan BG, Sandborn WJ, et al. Therapeutic drug monitoring of biologics for inflammatory bowel disease. Inflamm Bowel Dis 2012;18:349 –358. 20. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010;362:1383–1395. 21. Targan SR, Feagan BG, Fedorak RN, et al. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE Trial. Gastroenterology 2007; 132:1672–1683. http://dx.doi.org/10.1016/j.cgh.2012.06.011
955
I
used to describe the treatment of Crohn’s disease (CD) as “the treatment of symptoms.” This was in contrast to the treatment of ulcerative colitis (UC), where clinical trials had discriminated between “induction of remission” and “maintenance of remission.” Indeed, Sidney Truelove in his original controlled trials of cortisone for UC described remissions both from clinical and endoscopic standpoints.1 Clinical remissions were described as “one or two stools a day without blood . . .” with normalization of hemoglobin, sedimentation rate, and absence of systemic symptoms; whereas endoscopic remissions were described as a “normal or near normal” sigmoidoscopic appearance. Even Truelove noted discrepancies between individuals who achieved clinical and/or endoscopic remissions. In contrast, in clinical trials CD has primarily been evaluated based on symptoms utilizing the Crohn’s Disease Activity Index (CDAI), which is comprised of clinical criteria aside from measurement of hematocrits.2 The CDAI has been shown to have poor correlation with either endoscopy or C-reactive protein.3 Furthermore, when remissions were based on CDAI criteria in a large clinical trial, 94% of patients achieved a clinical remission within 7 weeks on corticosteroids, but only 29% achieved endoscopic healing. Continuing corticosteroids in patients who had clinical remission, but not endoscopic healing, did not alter the course after steroid withdrawal, leading the authors to conclude “. . . the clear-cut findings of this painstaking study will put an end to the ritual endoscopic monitoring of CD . . .”.4 Henceforth, over the past 2 decades, treatment for CD has been based on clinical parameters despite the observations that 1) laboratory parameters can predict the risk of relapse for patients in a clinical remission5 and 2) even in the setting of a complete clinical remission, ie, after an ileo-cecal resection, without maintenance therapy there is a nearly inevitable progression from histologic to endoscopic to clinical recurrence.6 However, it
was not until recent trials with anti–tumor necrosis factor (TNF) biologic agents that, despite discrepancies between clinical and biologic (endoscopic and C-reactive protein normalization) remissions, the achievement of endoscopic remission had greater impact on longterm outcomes, such as the need for hospitalizations and surgeries.7,8 Similarly, there is evidence from observational series in CD and UC that achievement of endoscopic remissions have improved outcomes related to hospitalizations and surgeries,9 and in UC the risk of neoplasia is diminished with both endoscopic and histologic remissions.10 What are clearly needed for both UC and CD are noninvasive and costeffective surrogates for endoscopic healing (calprotectin?11). These observations have led to new terminologies for inflammatory bowel disease (IBD), including the concept of “deep remissions,” whereby both symptoms and biologic parameters are normalized.12 No longer are clinical symptoms sufficient to assess IBD for long-term outcomes. Furthermore, the concept of treating toward a biologic remission has entered into the world of IBD, similar to the potential in rheumatoid arthritis and psoriasis, with the real possibility of “disease modification” of the natural history of IBD toward the transmural complications of CD and the risks of colectomy and neoplasia in UC. Some have termed the concept “treating to target.”13 With the current potential to alter the natural history and modify (prevent or stabilize) structural damage (in CD, at least), the next question becomes “how to” in the context of both CD and UC. The scenario is both easy and complex for UC. The colonic mucosa is readily accessible by endoscopy, although there has yet to be a validated scoring system to classify mucosal healing. As an example, the early studies from Oxford did not really define a “healed or almost healed” mucosa. Furthermore, studies going back several decades have demonstrated that even in the setting of an intact mucosa, the presence of residual neutrophils portend a greater risk of relapse on maintenance therapy. Nevertheless, even without histology, and without debating the validities of recent scoring systems, evidence of mucosal healing by
whatever criteria has consistently demonstrated long-term benefits.14 Aminosalicylates and anti-TNF biological therapies have induced mucosal healing in different patient populations (aminosalicylates in patients with mild-moderate disease and anti-TNF therapies in the setting of disease refractory to aminosalicylates, steroids and/or thiopurines).15 CD is, by nature, more complex and heterogeneous with regard to assessing mucosal healing and deep biological remissions. The transmural complications of CD, strictures, and fistulae may not be amenable to our most effective treatments for mucosal disease and can affect residual symptoms, even in the presence of mucosal healing and normalization of biological inflammatory parameters. Furthermore, earlier treatment in the course of the disease amplifies clinical benefits and provides optimism for the potential to prevent transmural complications that are strongly correlated with the need for surgical resections.16 The ability to improve outcomes for IBD with individualized medical therapies requires 2 criteria: 1) prediction of an individual’s disease course and 2) means to optimize therapy. Recent evidence suggests that both criteria can be, increasingly, accomplished. From the standpoint of prognostication, the disease course can be predicted for both UC and CD, and has considerable overlap between the disease spectra.17 Extensive disease and deep ulcerations, an early need for corticosteroids, high serologic titers against intestinal microbes or pANCA, and smoking (CD) or ex-smoking (UC) predict a bad course. Extra-intestinal manifestations predict a greater risk of pouchitis after ileo-anal anastomoses in UC, and primary sclerosing cholangitis is a risk factor for colonic dysplasia. Although it remains to be determined whether individuals afflicted with predictors of a bad prognosis will benefit from more aggressive therapies, we know that they respond poorly to a conventional “step-up” approach. There are also promising results from the standpoint of optimizing effective therapies. Aminosalicylates can be used at more effective doses in the absence of sulfasalazine’s sulfa moiety. Corticosteroids, while still the drugs we love to hate, can be formulated to improve risks
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10:954 –955
Comment From the Editor, continued and benefits. Thiopurines can be optimized by predefining thiopurine methyltransferase functional activity and by optimizing 6-mercaptopurine metabolites.18 Maintaining trough levels can optimize biologic therapy.19 Combining anti-TNF biologics with immunosuppressives can improve outcomes without increasing serious adverse effects.20 Switching therapeutic mechanisms of action can be effective when initial mechanisms lose response.21 Therapy for IBD has come a long way and is no longer simply the treatment of symptoms. Evolutions in end points for clinical trials and clinical practice goals, along with improved disease prognostication and optimization of medical therapies, provide examples of how our field has taken a lead in the personalization of medicine that will alter the course of these chronic immune-inflammatory disorders. With the availability of highly effective biologic therapies used earlier in the course of our patients, a remaining question is: “at what cost?”
3.
4.
5.
6.
7.
STEPHEN B. HANAUER Associate Editor Professor of Medicine and Clinical Pharmacology Chief, Section of Gastroenterology, Hepatology and Nutrition University of Chicago Medicine Chicago, Illinois References 1. Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J 1955;2:1041–1048. 2. Sandborn WJ, Feagan BG, Hanauer SB, et al. A review of activity indices and efficacy endpoints for clinical trials of medical
8.
9.
10.
11.
therapy in adults with Crohn’s disease. Gastroenterology 2002;122:512–530. 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; 98:811– 818. Landi B, Anh TN, Cortot A, et al. Endoscopic monitoring of Crohn’s disease treatment: a prospective, randomized clinical trial. The Groupe d’Etudes Therapeutiques des Affections Inflammatoires Digestives. Gastroenterology 1992;102: 1647–1653. Desai D, Faubion WA, Sandborn WJ. Review article: biological activity markers in inflammatory bowel disease. Aliment Pharmacol Ther 2007;25:247–255. Rutgeerts P, Geboes K, Vantrappen G, et al. Predictability of the postoperative course of Crohn’s disease. Gastroenterology 1990;99:956 –963. Rutgeerts P, Diamond RH, Bala M, et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn’s disease. Gastrointest Endosc 2006;63:433– 442. 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 –1201. Froslie KF, Jahnsen J, Moum BA, et al. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007;133:412– 422. Rutter M, Saunders B, Wilkinson K, et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 2004;126:451– 459. Abraham BP, Kane S. Fecal markers: calprotectin and lactoferrin. Gastroenterol Clin North Am 2012;41:483– 495.
12. Colombel JF, Rutgeerts P, Sandborn W, et al. Adalimumab treatment results in deep remission for patients with moderate to severe ileocolonic Crohn’s disease: results from EXTEND. Gastroenterology 2010;138:S-518. 13. Smolen JS, Aletaha D, Bijlsma JW, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis 2010;69:631– 637. 14. Ha C, Kornbluth A. Mucosal healing in inflammatory bowel disease: where do we stand? Curr Gastroenterol Rep 2010; 12:471– 478. 15. Armuzzi A, Van Assche G, Reinisch W, et al. Results of the 2nd scientific workshop of the ECCO (IV): therapeutic strategies to enhance intestinal healing in inflammatory bowel disease. J Crohns Colitis 2012;6: 492–502. 16. Kakkar A, Wasan SK, Farraye FA. Targeting mucosal healing in Crohn’s disease. Gastroenterol Hepatol (N Y) 2011;7:374 –380. 17. Blonski W, Buchner AM, Lichtenstein GR. Clinical predictors of aggressive/disabling disease: ulcerative colitis and Crohn disease. Gastroenterol Clin North Am 2012; 41:443– 462. 18. Dassopoulos T, Sninsky CA. Optimizing immunomodulators and anti-TNF agents in the therapy of Crohn disease. Gastroenterol Clin North Am 2012;41:393– 409. 19. Colombel JF, Feagan BG, Sandborn WJ, et al. Therapeutic drug monitoring of biologics for inflammatory bowel disease. Inflamm Bowel Dis 2012;18:349 –358. 20. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010;362:1383–1395. 21. Targan SR, Feagan BG, Fedorak RN, et al. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE Trial. Gastroenterology 2007; 132:1672–1683. http://dx.doi.org/10.1016/j.cgh.2012.06.011
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