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Point–counterpoint: Are we overtreating patients with mild ulcerative colitis?
Journal of Crohn's and Colitis (2014) 8, 80–84
Available online at www.sciencedirect.com
ScienceDirect
VIEWPOINT
Point–counterpoint: Are we overtreating patients with mild ulcerative colitis?☆ Akbar K. Waljee a,b,⁎, Ryan W. Stidham b , Peter D.R. Higgins b , Sandeep Vijan a,c , Sameer D. Saini a,b a
VA Ann Arbor Health Services Research & Development Center for Clinical Management Research, Ann Arbor, MI, United States Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States c Division of General Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States b
Received 18 June 2013; accepted 3 July 2013 KEYWORDS Ulcerative colitis Inflammatory Bowel Disease Mesalamine 5-ASA
studies, including inflammatory markers and complete blood count, are normal. Upon questioning, you learn that he sees little benefit in taking a daily medication. His symptoms flare infrequently and improve quickly with initiation of mesalamine. He asks you if continuous, long-term mesalamine use confers any advantage or disadvantage over intermittent use based on symptoms, as he is currently doing.
Clinical vignette Background A 26 year-old man with a history of mild, left-sided ulcerative colitis presents to your clinic for a routine follow-up appointment. He initially presented approximately 5 years ago with intermittent rectal bleeding and diarrhea, which led to a diagnostic colonoscopy. His symptoms resolved in 1–2 weeks with a combination of oral and rectal mesalamine, and you have seen him annually since that time. At today's visit, he readily admits that he fails to take his medication on a regular basis, opting instead to use oral mesalamine as needed in response to symptoms. He estimates that he uses the medication for several weeks at a time, once or twice a year. Currently, he is having 1–2 formed bowel movements a day, with no blood and no nocturnal symptoms. His laboratory ☆ Grant support: Dr. Saini's and Dr. Waljee's research is funded by a VA HSR&D CDA-2 Career Development Award. Dr. Stidham's research is funded through the Crohn's and Colitis Foundation of America Career Development Award. ⁎ Corresponding author at: VA Center for Clinical Management Research, Ann Arbor VA Medical Center, 2215 Fuller Road, IIID, Ann Arbor, MI 48105, United States. Tel.: + 1 7348455865. E-mail address: [email protected] (A.K. Waljee).
Over the last several decades, we have seen a dramatic increase in the number and variety of medications available for the treatment of inflammatory bowel disease (IBD). This increase in therapeutic options is the result of concerted and coordinated efforts by dedicated researchers, patient advocacy groups, and the pharmaceutical industry. As a result, patients with IBD now have more options for treatment than ever before. But like most chronic diseases, IBD has a wide spectrum of disease severity. For conceptual simplicity, we can dichotomize this spectrum according to whether the natural history of the disease is favorable or unfavorable. In individuals with severe disease, where the natural history is unfavorable (e.g., ulcerative pancolitis that is refractory to corticosteroids), aggressive systemic immunomodulatory treatment is often needed. High-quality care in these patients should ideally lead to resolution of symptoms, a prolonged remission, and avoidance of long-term disease complications. On the other hand, in individuals with established quiescent or mild disease, which has a favorable prognosis even without therapy, the benefits of long-term maintenance treatment are less certain.
1873-9946/$ - see front matter. Published by Elsevier B.V. on behalf of European Crohn's and Colitis Organisation. http://dx.doi.org/10.1016/j.crohns.2013.07.003
Point–counterpoint: Are we overtreating patients with mild ulcerative colitis? Though it is difficult to precisely estimate the prevalence of mild disease with a favorable prognosis, these patients are common in clinical practice. Current guidelines recommend that these patients be treated with continuous 5-ASA therapy, with the goal of preventing disease flares and potentially reducing long-term complications.1,2 But complications such as colectomy or colorectal cancer (CRC) are exceedingly uncommon in this population, and (as detailed below) available data have failed to show a clear benefit from continuous 5-ASA maintenance therapy. In this piece, we will examine the pros and cons of long-term, continuous 5-ASA use in patients with established mild UC. Because the benefits of such therapy are likely to be small, and our ability to precisely quantify these benefits is limited, we propose a more shared, informed, and individualized approach to decision-making in these patients that explicitly acknowledges these uncertainties.
Maintenance 5-ASA therapy to prevent symptomatic relapse of disease Point: Maintenance 5-ASA therapy prevents disease flares in patients with established mild UC UC is characterized by a wide spectrum of disease severity, with episodes of relapse and remission. Occurrence of relapse is unpredictable, and the likelihood is high. Across all degrees of UC severity, relapse rates without maintenance therapy are between 38% and 76%.3 Of those achieving remission with 5-ASA agents, a prospective study demonstrated that patients who were subsequently non-adherent had an approximately 5-fold greater risk of relapse, with an absolute risk reduction of approximately 40% for patients who were adherent with therapy.4 Admittedly, the vast majority of these patients will have resolution of symptoms with re-initiation of 5-ASA therapy. However, some nonadherent patients may also be risking escalation of disease severity. In a retrospective study, patients who had been in remission on 5-ASA therapy for at least 6 months were twice as likely to require high-dose oral or parenteral steroids when later becoming non-adherent.5
Counterpoint: Many patients perceive little clinical benefit from maintenance 5-ASA therapy There is little doubt that 5-ASA therapy is effective for induction and maintenance of clinical remission in mild UC. In patients who are responsive to 5-ASAs, however, the primary question is whether disease flares are frequent enough and severe enough to warrant continuous, daily medication use, particularly if such therapy is also effective when used on an as-needed basis. Though it is difficult to directly address this question, studies of 5-ASA adherence and cost–utility suggest that many patients have already decided for themselves that the answer is “no”. For instance, studies examining adherence to 5-ASA medications among patients with mild UC have demonstrated that many patients (up to 60%) often fail to take their medications as prescribed.6,7 Though the reasons for non-adherence are multifactorial, a substantial proportion of non-adherent patients believe that the benefits are limited, and that these limited benefits are outweighed by the harms of inconvenient
81
dosing regimens, large numbers of pills, and cost.4,8 The high placebo response rates reported in clinical trials (up to 77%) further support the notion that 5-ASA therapy is of limited benefit for disease maintenance in some patients with established mild disease.9,10 Finally, it is important to note that the burden of daily medication use can have an important negative effect on a patient's quality of life.11–13 A simulation model that weighed the disutility (burden) of continuous 5-ASA therapy against the frequency and severity of disease flares provided quantitative evidence for this phenomenon, with mild UC patients achieving a similar quality of life, on average, with or without 5-ASA maintenance.14
Maintenance 5-ASA therapy to reduce colectomy rates Point: Maintenance of remission with 5-ASA agents is likely to reduce the rate of colectomy in mild UC Colectomy rates in UC range from 9% to 25% within 10 years following diagnosis,15 with the vast majority (approximately 90%) performed to address unremitting disease activity.16 Though the use of 5-ASA agents has not been shown to reduce colectomy rates, these agents have been shown to lead to variable degrees of mucosal healing.17 Achieving mucosal healing has been associated with lower rates of colectomy in both retrospective and prospective studies,18,19 though it should be noted that evaluating and treating for mucosal healing are not without risk and cost. Taking these data into account, it is reasonable to treat patients to potentially modify their disease course and prevent colectomy, especially when we consider the favorable safety profile of 5-ASA agents.
Counterpoint: Maintenance of remission with 5-ASA agents is unlikely to substantially reduce the rate of colectomy in mild UC Many providers fear that patients who discontinue therapy will develop a disease flare that does not respond to medical therapy, ultimately requiring colectomy. Outcome data on long-term colectomy rates in patients with established mild UC are limited, but we would expect that absolute rate of colectomy in these patients to be low (meaning that the absolute benefit of therapy is also low). The strongest observational data on this topic comes from a European cohort that examined outcomes over 10 years after diagnosis among 5-ASA users and non-users. Indeed, this study found that 5-ASA medications had no significant effect on colectomy rates in patients with UC.20
Maintenance 5-ASA therapy to reduce colorectal cancer risk Point: 5-ASA maintenance therapy may reduce the rate of colorectal cancer in UC patients Colorectal cancer (CRC) is one of the most feared outcomes in patients with long-standing UC. Historically, large population
82 based studies have estimated that the lifetime incidence of CRC is up to 5 times greater in UC patients than in unaffected populations.21–23 Mechanistically, there is strong evidence that chronic inflammation leads to the development of colonic dysplasia and, ultimately, CRC.24,25 Fortunately, the incidence of CRC appears to be dropping in the UC population with the advent of modern medical therapy and endoscopic surveillance.26 Though some have questioned the chemopreventive properties of 5-ASA agents in UC,27,28 it is reasonable to use these agents in light of their relative safety and tolerability, particularly when weighed against the consequences of a new cancer diagnosis.
Counterpoint: 5-ASA maintenance therapy does not reduce the rate of colorectal cancer in UC patients Prior studies demonstrated that chronic colonic inflammation is associated with the development of colonic dysplasia, a precursor of CRC. But population-based outcome data have failed to support the role of chronic inflammation as an important risk factor for CRC in UC.29,30 Other studies, including a recent meta-analysis, have called into question the chemopreventive effects of 5-ASA agents.31–33 Thus, the theoretical benefits of chemoprevention for CRC in UC are not borne out by the sum of available outcome data.
Discussion 5-ASA agents have long been the mainstay of treatment in patients with mild UC. Though these agents are less potent than other available therapies for UC, they have a favorable side-effect profile, leading to their widespread use. The potential benefits of 5-ASA agents include: (1) symptom control,34,35 and associated improvements in quality of life and health care utilization; (2) reduction in colectomy rates; and, (3) reduction in CRC incidence. However, the absolute benefit of any intervention is dependent on the baseline risk of the condition. In individuals with mild UC, a prevalent patient population with a favorable long-term prognosis, the absolute risk of CRC and colectomy is low. Therefore, the long-term benefits of therapy are small at best and deserve to be weighted against the potential clinical and economic harms. We propose that the decision of whether or not to treat patients with established mild UC is more complex than the treatment decision in individuals who have more severe disease (in whom the benefits clearly outweigh the harms). Braddock et al. have defined complex decisions as those in which the effect on the patient is extensive, the medical consensus is controversial, and the outcomes are uncertain.36 In mild UC treated with 5-ASA therapy, the patient is asked to take daily medication, often at significant cost, for a small benefit. There is reasonable consensus that daily use of 5-ASA agents can reduce the risk of flares. However, there is also evidence that on-demand use of 5-ASA may be an effective strategy, decreasing the marginal benefits of daily medication use.36 Arguments that daily 5-ASA use may be effective in reducing the risk of more feared UC outcomes
A.K. Waljee et al. such as colectomy and CRC risk are largely theoretical and are not consistently supported by existing (though limited) data. While there is substantial uncertainty about the exact magnitude of the benefit of 5-ASA therapy, the sum of available evidence suggests that the overall benefit is likely to be small. On the other hand, there is a small but real potential for harm (renal injury, and in some instances, end-stage renal disease),37–39 and there is a daily burden and cost to taking medication. It is clear that for many patients, daily medication use is viewed as being of relatively little benefit, as patients who achieve remission in the short-term often fail to adhere to their medication in the long-term. While this non-adherence is certainly multifactorial, there is reasonable evidence that some patients perceive little benefit to continuous medication use in a low-risk setting. Based on the evidence outlined above, we believe that patients warrant a shared, informed approach to decisionmaking about chronic therapy for mild UC.40 Current guidelines suggest a relatively one-size fits all approach — namely that nearly all patients with mild UC take daily 5-ASA medications. Instead, a shared approach to decision-making considers both potential benefits and potential clinical and economic harms on a case-by-case basis, allowing doctor and patient to make the best decision for a given individual. One widely endorsed approach to complex decision-making is the use of decision aids, interventions that help individuals explicitly consider the pros and cons of treatment in order to improve informed decision-making. High-quality decision aids educate patients on the decision context and present tailored risk and benefit information in various ways. They also help patients more explicitly weigh the factors that are important in making an informed decision. Decision aids have been used in a variety of healthcare contexts, including treatment for IBD.41 Studies of decision aids for IBD have shown that they are effective in educating patients and, in some instances may influence decision-making behavior.42,43 However, prior work on decision aids in IBD has focused primarily on high-risk patients who have an unfavorable prognosis and are making a choice between treatment strategies with varying degrees of toxicity. We believe that such an approach is also needed in patients with established, mild UC, a prevalent population in whom the benefits of long-term 5-ASA therapy are small or uncertain. Though a more informed approach to decision-making is needed in this patient population, we must also contend with gaps in our understanding of established mild UC. For instance, we have limited data on the absolute long-term prognosis in terms of colectomy and CRC. We also have no direct data to support or refute the notion that disease activity may accelerate in these patients if untreated, requiring more aggressive therapies. Finally, we have insufficient quantitative data on the optimal balance between the benefits and risks of 5-ASA therapy. Prior work in this area has largely ignored the renal risks of long-term 5-ASA therapy, a clinical harm that could have important consequences.37–39 Of course, the uncertainty that currently exists in the literature on this topic does not preclude efforts to develop decision aids to more systematically inform patients about the potential benefits, harms, and uncertainty associated with use of these medications.
Point–counterpoint: Are we overtreating patients with mild ulcerative colitis?
Clinical vignette You explain to your patient that continuous, long-term mesalamine use has several potential benefits, but the supporting data are limited. For symptom control, studies suggest that, on average, remission is more likely in patients who use mesalamine regularly. On the other hand, there is less data to suggest that treating on demand is less efficacious. Furthermore, the data on long-term benefits in terms of colectomy rate and CRC risk are also controversial. The risks of the medication are small, but renal toxicity is possible. It is important that renal function be monitored periodically to assess for the interval development of renal injury. Finally, if cost is an issue, lower cost alternatives (such as sulfasalazine or balsalazide) could be considered. The patient appreciates your honesty and time in explaining these issues. He decides to begin taking mesalamine more regularly, primarily due to concern for CRC. He tells you that his friend, who also suffered from UC, recently developed CRC unexpectedly.
Conflict of interest None.
References 1. Kornbluth A, Sachar DB. Practice Parameters Committee of the American College of Gastroenterology, ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 2010;105(3):501–23 [quiz 24]. 2. Mowat C, Cole A, Windsor A, Ahmad T, Arnott I, Driscoll R, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60(5):571–607. 3. Su C, Lewis JD, Goldberg B, Brensinger C, Lichtenstein GR. A meta-analysis of the placebo rates of remission and response in clinical trials of active ulcerative colitis. Gastroenterology 2007;132(2):516–26. 4. Kane S, Huo D, Aikens J, Hanauer S. Medication nonadherence and the outcomes of patients with quiescent ulcerative colitis. Am J Med 2003;114(1):39–43. 5. Khan N, Abbas AM, Bazzano LA, Koleva YN, Krousel-Wood M. Long-term oral mesalazine adherence and the risk of disease flare in ulcerative colitis: nationwide 10-year retrospective cohort from the Veterans Affairs Healthcare System. Aliment Pharmacol Ther 2012;36(8):755–64. 6. Shale MJ, Riley SA. Studies of compliance with delayed-release mesalazine therapy in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2003;18(2):191–8. 7. Kane SV, Cohen RD, Aikens JE, Hanauer SB. Prevalence of nonadherence with maintenance mesalamine in quiescent ulcerative colitis. Am J Gastroenterol 2001;96(10):2929–33. 8. Levy RL, Feld AD. Increasing patient adherence to gastroenterology treatment and prevention regimens. Am J Gastroenterol 1999;94(7):1733–42. 9. Feagan BG, Macdonald JK. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2012;10:CD000544. 10. Bebb JR, Scott BB. How effective are the usual treatments for ulcerative colitis? Aliment Pharmacol Ther 2004;20(2):143–9. 11. Matza LS, Boye KS, Yurgin N, Brewster-Jordan J, Mannix S, Shorr JM, et al. Utilities and disutilities for type 2 diabetes treatmentrelated attributes. Qual Life Res 2007;16(7):1251–65.
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12. Vijan S, Hayward RA, Ronis DL, Hofer TP. Brief report: the burden of diabetes therapy: implications for the design of effective patient-centered treatment regimens. J Gen Intern Med 2005;20(5):479–82. 13. Hayward RA, Krumholz HM, Zulman DM, Timbie JW, Vijan S. Optimizing statin treatment for primary prevention of coronary artery disease. Ann Intern Med 2010;152(2):69–77. 14. Saini SD, Waljee AK, Higgins PD. Cost utility of inflammationtargeted therapy for patients with ulcerative colitis. Clin Gastroenterol Hepatol 2012;10(10):1143–51 [.9]. 15. Langholz E, Munkholm P, Davidsen M, Binder V. Course of ulcerative colitis: analysis of changes in disease activity over years. Gastroenterology 1994;107(1):3–11. 16. Waljee AK, Higgins PD, Waljee JF, Tujios SR, Saxena A, Brown LK, et al. Perceived and actual quality of life with ulcerative colitis: a comparison of medically and surgically treated patients. Am J Gastroenterol 2011;106(4):794–9. 17. Romkens TE, Kampschreur MT, Drenth JP, van Oijen MG, de Jong DJ. High mucosal healing rates in 5-ASA-treated ulcerative colitis patients: results of a meta-analysis of clinical trials. Inflamm Bowel Dis 2012;18(11):2190–8 [Epub 2012/03/16]. 18. Froslie KF, Jahnsen J, Moum BA, Vatn MH, IBSEN Group. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007;133(2): 412–22. 19. Ardizzone S, Cassinotti A, Duca P, Mazzali C, Penati C, Manes G, et al. Mucosal healing predicts late outcomes after the first course of corticosteroids for newly diagnosed ulcerative colitis. Clin Gastroenterol Hepatol 2011;9(6):483–9 [e3]. 20. Hoie O, Wolters FL, Riis L, Bernklev T, Aamodt G, Clofent J, et al. Low colectomy rates in ulcerative colitis in an unselected European cohort followed for 10 years. Gastroenterology 2007;132(2): 507–15. 21. Bernstein CN, Blanchard JF, Kliewer E, Wajda A. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 2001;91(4):854–62. 22. Karlén P, Löfberg R, Broström O, Leijonmarck CE, Hellers G, Persson PG. Increased risk of cancer in ulcerative colitis: a population-based cohort study. Am J Gastroenterol 1999;94(4):1047–52. 23. Herrinton LJ, Liu L, Levin TR, Allison JE, Lewis JD, Velayos F. Incidence and mortality of colorectal adenocarcinoma in persons with inflammatory bowel disease from 1998 to 2010. Gastroenterology 2012;143(2):382–9. 24. Rutter M, Saunders B, Wilkinson K, Rumbles S, Schofield G, Kamm M, et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 2004;126(2): 451–9. 25. Gupta RB, Harpaz N, Itzkowitz S, Hossain S, Matula S, Kornbluth A, et al. Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study. Gastroenterology 2007;133(4):1099–105 [quiz 340-1]. 26. Jess T, Simonsen J, Jørgensen KT, Pedersen BV, Nielsen NM, Frisch M. Decreasing risk of colorectal cancer in patients with inflammatory bowel disease over 30 years. Gastroenterology 2012;143(2): 375–81 [e1- quiz e13-4]. 27. Velayos FS, Terdiman JP, Walsh JM. Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and meta-analysis of observational studies. Am J Gastroenterol 2005;100(6):1345–53. 28. Ullman T, Croog V, Harpaz N, Hossain S, Kornbluth A, Bodian C, et al. Progression to colorectal neoplasia in ulcerative colitis: effect of mesalamine. Clin Gastroenterol Hepatol 2008;6(11):1225–30 [quiz 177]. 29. Bergeron V, Vienne A, Sokol H, Seksik P, Nion-Larmurier I, Ruskone-Fourmestraux A, et al. Risk factors for neoplasia in inflammatory bowel disease patients with pancolitis. Am J Gastroenterol 2010;105(11):2405–11.
84 30. Winther KV, Jess T, Langholz E, Munkholm P, Binder V. Long-term risk of cancer in ulcerative colitis: a population-based cohort from Copenhagen County. Clin Gastroenterol Hepatol 2004;2(12): 1088–95. 31. Bernstein CN, Nugent Z, Blanchard JF. 5-Aminosalicylate is not chemoprophylactic for colorectal cancer in IBD: a population based study. Am J Gastroenterol 2011;106(4):731–6. 32. Terdiman JP, Steinbuch M, Blumentals WA, Ullman TA, Rubin DT. 5-Aminosalicylic acid therapy and the risk of colorectal cancer among patients with inflammatory bowel disease. Inflamm Bowel Dis 2007;13(4):367–71. 33. Nguyen GC, Gulamhusein A, Bernstein CN. 5-Aminosalicylic acid is not protective against colorectal cancer in inflammatory bowel disease: a meta-analysis of non-referral populations. Am J Gastroenterol 2012;107(9):1298–304 [quiz 7, 305]. 34. Robinson M, Hanauer S, Hoop R, Zbrozek A, Wilkinson C. Mesalamine capsules enhance the quality of life for patients with ulcerative colitis. Aliment Pharmacol Ther 1994;8(1):27–34 [Epub 1994/02/01]. 35. Pruitt R, Hanson J, Safdi M, Wruble L, Hardi R, Johanson J, et al. Balsalazide is superior to mesalamine in the time to improvement of signs and symptoms of acute mild-to-moderate ulcerative colitis. Am J Gastroenterol 2002;97(12):3078–86 [Epub 2002/12/21]. 36. Braddock III CH, Edwards KA, Hasenberg NM, Laidley TL, Levinson W. Informed decision making in outpatient practice:
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time to get back to basics. JAMA 1999;282(24):2313–20 [Epub 1999/12/28]. Gisbert JP, Gonzalez-Lama Y, Mate J. 5-Aminosalicylates and renal function in inflammatory bowel disease: a systematic review. Inflamm Bowel Dis 2007;13(5):629–38 [Epub 2007/01/24]. Corrigan G, Stevens PE. Review article: interstitial nephritis associated with the use of mesalazine in inflammatory bowel disease. Aliment Pharmacol Ther 2000;14(1):1–6. Van Staa TP, Travis S, Leufkens HG, Logan RF. 5-Aminosalicylic acids and the risk of renal disease: a large British epidemiologic study. Gastroenterology 2004;126(7):1733–9 [Epub 2004/06/10]. Charles C, Gafni A, Whelan T. Shared decision-making in the medical encounter: what does it mean? (or it takes at least two to tango). Soc Sci Med 1997;44(5):681–92 [Epub 1997/03/01]. Siegel CA, Marden SN, Siegel LS. Development of the first Crohn's disease decision aid: helping patients make informed, preference-based decisions for their treatment. Gastroenterology 2011;140:S769. Siegel CA, Siegel LS, Hyams JS, Kugathasan S, Markowitz J, Rosh JR, et al. Real-time tool to display the predicted disease course and treatment response for children with Crohn's disease. Inflamm Bowel Dis 2011;17(1):30–8. Siegel CA, Marden SN. Crohn's disease patients report their definitions of “rare” adverse event, remission and the importance of mucosal healing: a quantitative and qualitative study of what patients really think. Gastroenterology 2011;140:S:141.
Available online at www.sciencedirect.com
ScienceDirect
VIEWPOINT
Point–counterpoint: Are we overtreating patients with mild ulcerative colitis?☆ Akbar K. Waljee a,b,⁎, Ryan W. Stidham b , Peter D.R. Higgins b , Sandeep Vijan a,c , Sameer D. Saini a,b a
VA Ann Arbor Health Services Research & Development Center for Clinical Management Research, Ann Arbor, MI, United States Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States c Division of General Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States b
Received 18 June 2013; accepted 3 July 2013 KEYWORDS Ulcerative colitis Inflammatory Bowel Disease Mesalamine 5-ASA
studies, including inflammatory markers and complete blood count, are normal. Upon questioning, you learn that he sees little benefit in taking a daily medication. His symptoms flare infrequently and improve quickly with initiation of mesalamine. He asks you if continuous, long-term mesalamine use confers any advantage or disadvantage over intermittent use based on symptoms, as he is currently doing.
Clinical vignette Background A 26 year-old man with a history of mild, left-sided ulcerative colitis presents to your clinic for a routine follow-up appointment. He initially presented approximately 5 years ago with intermittent rectal bleeding and diarrhea, which led to a diagnostic colonoscopy. His symptoms resolved in 1–2 weeks with a combination of oral and rectal mesalamine, and you have seen him annually since that time. At today's visit, he readily admits that he fails to take his medication on a regular basis, opting instead to use oral mesalamine as needed in response to symptoms. He estimates that he uses the medication for several weeks at a time, once or twice a year. Currently, he is having 1–2 formed bowel movements a day, with no blood and no nocturnal symptoms. His laboratory ☆ Grant support: Dr. Saini's and Dr. Waljee's research is funded by a VA HSR&D CDA-2 Career Development Award. Dr. Stidham's research is funded through the Crohn's and Colitis Foundation of America Career Development Award. ⁎ Corresponding author at: VA Center for Clinical Management Research, Ann Arbor VA Medical Center, 2215 Fuller Road, IIID, Ann Arbor, MI 48105, United States. Tel.: + 1 7348455865. E-mail address: [email protected] (A.K. Waljee).
Over the last several decades, we have seen a dramatic increase in the number and variety of medications available for the treatment of inflammatory bowel disease (IBD). This increase in therapeutic options is the result of concerted and coordinated efforts by dedicated researchers, patient advocacy groups, and the pharmaceutical industry. As a result, patients with IBD now have more options for treatment than ever before. But like most chronic diseases, IBD has a wide spectrum of disease severity. For conceptual simplicity, we can dichotomize this spectrum according to whether the natural history of the disease is favorable or unfavorable. In individuals with severe disease, where the natural history is unfavorable (e.g., ulcerative pancolitis that is refractory to corticosteroids), aggressive systemic immunomodulatory treatment is often needed. High-quality care in these patients should ideally lead to resolution of symptoms, a prolonged remission, and avoidance of long-term disease complications. On the other hand, in individuals with established quiescent or mild disease, which has a favorable prognosis even without therapy, the benefits of long-term maintenance treatment are less certain.
1873-9946/$ - see front matter. Published by Elsevier B.V. on behalf of European Crohn's and Colitis Organisation. http://dx.doi.org/10.1016/j.crohns.2013.07.003
Point–counterpoint: Are we overtreating patients with mild ulcerative colitis? Though it is difficult to precisely estimate the prevalence of mild disease with a favorable prognosis, these patients are common in clinical practice. Current guidelines recommend that these patients be treated with continuous 5-ASA therapy, with the goal of preventing disease flares and potentially reducing long-term complications.1,2 But complications such as colectomy or colorectal cancer (CRC) are exceedingly uncommon in this population, and (as detailed below) available data have failed to show a clear benefit from continuous 5-ASA maintenance therapy. In this piece, we will examine the pros and cons of long-term, continuous 5-ASA use in patients with established mild UC. Because the benefits of such therapy are likely to be small, and our ability to precisely quantify these benefits is limited, we propose a more shared, informed, and individualized approach to decision-making in these patients that explicitly acknowledges these uncertainties.
Maintenance 5-ASA therapy to prevent symptomatic relapse of disease Point: Maintenance 5-ASA therapy prevents disease flares in patients with established mild UC UC is characterized by a wide spectrum of disease severity, with episodes of relapse and remission. Occurrence of relapse is unpredictable, and the likelihood is high. Across all degrees of UC severity, relapse rates without maintenance therapy are between 38% and 76%.3 Of those achieving remission with 5-ASA agents, a prospective study demonstrated that patients who were subsequently non-adherent had an approximately 5-fold greater risk of relapse, with an absolute risk reduction of approximately 40% for patients who were adherent with therapy.4 Admittedly, the vast majority of these patients will have resolution of symptoms with re-initiation of 5-ASA therapy. However, some nonadherent patients may also be risking escalation of disease severity. In a retrospective study, patients who had been in remission on 5-ASA therapy for at least 6 months were twice as likely to require high-dose oral or parenteral steroids when later becoming non-adherent.5
Counterpoint: Many patients perceive little clinical benefit from maintenance 5-ASA therapy There is little doubt that 5-ASA therapy is effective for induction and maintenance of clinical remission in mild UC. In patients who are responsive to 5-ASAs, however, the primary question is whether disease flares are frequent enough and severe enough to warrant continuous, daily medication use, particularly if such therapy is also effective when used on an as-needed basis. Though it is difficult to directly address this question, studies of 5-ASA adherence and cost–utility suggest that many patients have already decided for themselves that the answer is “no”. For instance, studies examining adherence to 5-ASA medications among patients with mild UC have demonstrated that many patients (up to 60%) often fail to take their medications as prescribed.6,7 Though the reasons for non-adherence are multifactorial, a substantial proportion of non-adherent patients believe that the benefits are limited, and that these limited benefits are outweighed by the harms of inconvenient
81
dosing regimens, large numbers of pills, and cost.4,8 The high placebo response rates reported in clinical trials (up to 77%) further support the notion that 5-ASA therapy is of limited benefit for disease maintenance in some patients with established mild disease.9,10 Finally, it is important to note that the burden of daily medication use can have an important negative effect on a patient's quality of life.11–13 A simulation model that weighed the disutility (burden) of continuous 5-ASA therapy against the frequency and severity of disease flares provided quantitative evidence for this phenomenon, with mild UC patients achieving a similar quality of life, on average, with or without 5-ASA maintenance.14
Maintenance 5-ASA therapy to reduce colectomy rates Point: Maintenance of remission with 5-ASA agents is likely to reduce the rate of colectomy in mild UC Colectomy rates in UC range from 9% to 25% within 10 years following diagnosis,15 with the vast majority (approximately 90%) performed to address unremitting disease activity.16 Though the use of 5-ASA agents has not been shown to reduce colectomy rates, these agents have been shown to lead to variable degrees of mucosal healing.17 Achieving mucosal healing has been associated with lower rates of colectomy in both retrospective and prospective studies,18,19 though it should be noted that evaluating and treating for mucosal healing are not without risk and cost. Taking these data into account, it is reasonable to treat patients to potentially modify their disease course and prevent colectomy, especially when we consider the favorable safety profile of 5-ASA agents.
Counterpoint: Maintenance of remission with 5-ASA agents is unlikely to substantially reduce the rate of colectomy in mild UC Many providers fear that patients who discontinue therapy will develop a disease flare that does not respond to medical therapy, ultimately requiring colectomy. Outcome data on long-term colectomy rates in patients with established mild UC are limited, but we would expect that absolute rate of colectomy in these patients to be low (meaning that the absolute benefit of therapy is also low). The strongest observational data on this topic comes from a European cohort that examined outcomes over 10 years after diagnosis among 5-ASA users and non-users. Indeed, this study found that 5-ASA medications had no significant effect on colectomy rates in patients with UC.20
Maintenance 5-ASA therapy to reduce colorectal cancer risk Point: 5-ASA maintenance therapy may reduce the rate of colorectal cancer in UC patients Colorectal cancer (CRC) is one of the most feared outcomes in patients with long-standing UC. Historically, large population
82 based studies have estimated that the lifetime incidence of CRC is up to 5 times greater in UC patients than in unaffected populations.21–23 Mechanistically, there is strong evidence that chronic inflammation leads to the development of colonic dysplasia and, ultimately, CRC.24,25 Fortunately, the incidence of CRC appears to be dropping in the UC population with the advent of modern medical therapy and endoscopic surveillance.26 Though some have questioned the chemopreventive properties of 5-ASA agents in UC,27,28 it is reasonable to use these agents in light of their relative safety and tolerability, particularly when weighed against the consequences of a new cancer diagnosis.
Counterpoint: 5-ASA maintenance therapy does not reduce the rate of colorectal cancer in UC patients Prior studies demonstrated that chronic colonic inflammation is associated with the development of colonic dysplasia, a precursor of CRC. But population-based outcome data have failed to support the role of chronic inflammation as an important risk factor for CRC in UC.29,30 Other studies, including a recent meta-analysis, have called into question the chemopreventive effects of 5-ASA agents.31–33 Thus, the theoretical benefits of chemoprevention for CRC in UC are not borne out by the sum of available outcome data.
Discussion 5-ASA agents have long been the mainstay of treatment in patients with mild UC. Though these agents are less potent than other available therapies for UC, they have a favorable side-effect profile, leading to their widespread use. The potential benefits of 5-ASA agents include: (1) symptom control,34,35 and associated improvements in quality of life and health care utilization; (2) reduction in colectomy rates; and, (3) reduction in CRC incidence. However, the absolute benefit of any intervention is dependent on the baseline risk of the condition. In individuals with mild UC, a prevalent patient population with a favorable long-term prognosis, the absolute risk of CRC and colectomy is low. Therefore, the long-term benefits of therapy are small at best and deserve to be weighted against the potential clinical and economic harms. We propose that the decision of whether or not to treat patients with established mild UC is more complex than the treatment decision in individuals who have more severe disease (in whom the benefits clearly outweigh the harms). Braddock et al. have defined complex decisions as those in which the effect on the patient is extensive, the medical consensus is controversial, and the outcomes are uncertain.36 In mild UC treated with 5-ASA therapy, the patient is asked to take daily medication, often at significant cost, for a small benefit. There is reasonable consensus that daily use of 5-ASA agents can reduce the risk of flares. However, there is also evidence that on-demand use of 5-ASA may be an effective strategy, decreasing the marginal benefits of daily medication use.36 Arguments that daily 5-ASA use may be effective in reducing the risk of more feared UC outcomes
A.K. Waljee et al. such as colectomy and CRC risk are largely theoretical and are not consistently supported by existing (though limited) data. While there is substantial uncertainty about the exact magnitude of the benefit of 5-ASA therapy, the sum of available evidence suggests that the overall benefit is likely to be small. On the other hand, there is a small but real potential for harm (renal injury, and in some instances, end-stage renal disease),37–39 and there is a daily burden and cost to taking medication. It is clear that for many patients, daily medication use is viewed as being of relatively little benefit, as patients who achieve remission in the short-term often fail to adhere to their medication in the long-term. While this non-adherence is certainly multifactorial, there is reasonable evidence that some patients perceive little benefit to continuous medication use in a low-risk setting. Based on the evidence outlined above, we believe that patients warrant a shared, informed approach to decisionmaking about chronic therapy for mild UC.40 Current guidelines suggest a relatively one-size fits all approach — namely that nearly all patients with mild UC take daily 5-ASA medications. Instead, a shared approach to decision-making considers both potential benefits and potential clinical and economic harms on a case-by-case basis, allowing doctor and patient to make the best decision for a given individual. One widely endorsed approach to complex decision-making is the use of decision aids, interventions that help individuals explicitly consider the pros and cons of treatment in order to improve informed decision-making. High-quality decision aids educate patients on the decision context and present tailored risk and benefit information in various ways. They also help patients more explicitly weigh the factors that are important in making an informed decision. Decision aids have been used in a variety of healthcare contexts, including treatment for IBD.41 Studies of decision aids for IBD have shown that they are effective in educating patients and, in some instances may influence decision-making behavior.42,43 However, prior work on decision aids in IBD has focused primarily on high-risk patients who have an unfavorable prognosis and are making a choice between treatment strategies with varying degrees of toxicity. We believe that such an approach is also needed in patients with established, mild UC, a prevalent population in whom the benefits of long-term 5-ASA therapy are small or uncertain. Though a more informed approach to decision-making is needed in this patient population, we must also contend with gaps in our understanding of established mild UC. For instance, we have limited data on the absolute long-term prognosis in terms of colectomy and CRC. We also have no direct data to support or refute the notion that disease activity may accelerate in these patients if untreated, requiring more aggressive therapies. Finally, we have insufficient quantitative data on the optimal balance between the benefits and risks of 5-ASA therapy. Prior work in this area has largely ignored the renal risks of long-term 5-ASA therapy, a clinical harm that could have important consequences.37–39 Of course, the uncertainty that currently exists in the literature on this topic does not preclude efforts to develop decision aids to more systematically inform patients about the potential benefits, harms, and uncertainty associated with use of these medications.
Point–counterpoint: Are we overtreating patients with mild ulcerative colitis?
Clinical vignette You explain to your patient that continuous, long-term mesalamine use has several potential benefits, but the supporting data are limited. For symptom control, studies suggest that, on average, remission is more likely in patients who use mesalamine regularly. On the other hand, there is less data to suggest that treating on demand is less efficacious. Furthermore, the data on long-term benefits in terms of colectomy rate and CRC risk are also controversial. The risks of the medication are small, but renal toxicity is possible. It is important that renal function be monitored periodically to assess for the interval development of renal injury. Finally, if cost is an issue, lower cost alternatives (such as sulfasalazine or balsalazide) could be considered. The patient appreciates your honesty and time in explaining these issues. He decides to begin taking mesalamine more regularly, primarily due to concern for CRC. He tells you that his friend, who also suffered from UC, recently developed CRC unexpectedly.
Conflict of interest None.
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