Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDICAL OPTIONS In Ulcerative Colitis

June 2008

Endoscopic Healing as Treatment Goal in Ulcerative Colitis

Dr. Remo Panaccione, University of Calgary, Alberta

Facilitating Adherence to Ulcerative Colitis Therapy: Education Through Benefits and Consequences

Dr. A. Hillary Steinhart, University of Toronto, Ontario

Mild-to-Moderate Ulcerative Colitis: Optimizing Induction and Maintenance Medical Therapy

Dr. Alain Bitton, McGill University, Montreal, Quebec

Editorial Overview:

Remo Panaccione, MD, FRCPC, Director, Inflammatory Bowel Disease Clinic, Associate Professor of Medicine, University of Calgary, Calgary, Alberta

Mucosal healing, or endoscopic remission, is an attractive therapeutic goal in the treatment of ulcerative colitis (UC). The evidence that outcomes are improved in those who achieve both clinical and endoscopic remission relative to clinical remission alone is modest but accumulating. These data include a prospective study and a patient-cohort analysis that each compared long-term outcomes in patients who did or did not achieve mucosal healing. Both associated endoscopic remission with a reduction in relapses relative to clinical remission alone. The larger patient-cohort analysis also associated endoscopic remission with a relative reduction in the rate of complications, including the need for surgery. In administering first-line therapies, including 5-aminosalicylates (5-ASA), for an acute episode of UC, these findings support the expectation that complete mucosal healing provides a more durable remission than control of clinical symptoms alone.

Immediate and Long-term Goals of Treatment

The immediate goal in newly diagnosed UC, a chronic, potentially debilitating disease with an unpredictable course, is control of symptoms in order to restore an acceptable quality of life. The long-term goal of maintenance therapy is to preserve this quality of life, but a sustained remission also has the potential to reduce the risk of complications from repeated flares, including the need for surgery or the potential for malignant transformation. Although the influence of acute treatment on sustained remission is not well documented, it has been hypothesized that mucosal healing may increase the likelihood of sustained remission relative to a clinical remission without healing. This rational expectation has made mucosal healing a test of treatment efficacy. Even though mucosal healing after an acute flare is not typically verified in clinical practice, therapeutic trials with 5-ASA and other UC treatments that have demonstrated mucosal healing provide reassurance that these are an appropriate first step in treatment that will achieve and then sustain disease control.

Due to its chronicity, UC typically requires lifetime monitoring and treatment. Although the majority of individuals have mild to moderate disease as judged by the intensity of periodic flares, failure to intervene effectively to suppress disease activity might increase the frequency of these flares, reduce quality of life, and lead to complications such as surgical resection. Disease control also appears to have relevance to risk of colon cancer. Compared to a lifetime risk of approximately 5% in individuals without UC, the probability of colon cancer in UC patients climbs to 2% after 10 years, 8% after 20 years, and 18% at 30 years (Eaden et al. Gut 2001;48:526-35) (Figure 1). The correlation between risk of colon cancer and inflammatory activity is an impetus to define therapies that sustain remission (Ekbom et al. N Engl J Med 1990;323:1228-33).

Figure 1.

Clinical and Endoscopic Remission

Clinical remission is an important therapeutic goal, but this outcome correlates imperfectly with endoscopic remission, which is typically described as an UC Disease Activity Index (UC-DAI) score of =1, which means no symptoms, such as rectal bleeding, and no mucosal friability on sigmoidoscopy. In treatment trials that have employed multiple definitions of efficacy, clinical remission may be achieved two or more times more frequently than endoscopic remission (Katz et al. Gastroenterology 2006;130:A482). The difference between clinical and endoscopic remission is potentially important because of the likelihood that the latter outcome, representing a more complete state of disease quiescence, may sustain remissions more effectively. This rational expectation is now supported by some data.

In an as-yet unpublished study from an Italian group presented almost two years ago (Meucci et al. Gastroenterology 2006;130 (suppl 2):A197, Abstract S1302), risk of relapse was compared in patients who did or did not continue to show active disease on endoscopy after a course of oral and topical mesalazine. Of the 78 participants in this multicentre study, 8.5% had persistent endoscopic activity at the end of the six-week trial despite clinical remission. When compared at the end of one year of follow-up, the cumulative relapse rate was 23% in those with both clinical and endoscopic remission vs. 80% in those with clinical remission alone (P<0.0001). The authors concluded that failure to achieve endoscopic remission is a strong predictor of early relapse.

In a recently published retrospective study, mucosal healing was evaluated as a predictor of outcome in 740 patients with inflammatory bowel disease who were diagnosed between 1990 and 1994 (Froslie et al. Gastroenterology 2007;133:412-22). Although this population included both Crohn’s disease and UC, mucosal healing after one year of treatment was associated with less inflammation after five years (P=0.02), decreased future steroid use (P=0.02), and reduced risk of colectomy (P=0.02) (Table 1). The investigators specifically evaluated a population treated before the introduction of biologic therapy to test the importance of this outcome in the absence of therapies most like
healing.

Table 1.

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In a phase III study of the biologic infliximab in UC, mucosal healing at eight weeks was highly correlated with sustained remission at 52 weeks (Rutgeerts et al. N Engl J Med 2005;353:2462-76). This finding has also been observed with biologics in Crohn’s disease, which has a more aggressive course over the short term. Mucosal healing was also associated with fewer hospitalizations, fewer surgeries, and fewer stays in an intensive care unit (Rutgeerts et al. Gastroenterology 2004;126:402-13). This important correlation between mucosal healing at the time of the acute flare and the evidence for an improved long-term outcome led to a recent editorial suggesting that healing may be appropriate as a primary outcome measure in all studies of inflammatory bowel diseases (Rutgeerts et al. Gut 2007;56:453-5).

However, these data are not yet sufficient to encourage evaluation of mucosal healing in UC patients as a routine step in management of an acute flare. In particular, it is unclear whether intensifying or changing therapy in individuals who did not achieve complete healing despite clinical remission would alter outcome. However, these data support the expectation that healing reduces the risk of subsequent relapse and provide a rationale for considering evidence of mucosal healing when seeking first-line therapies. The potential importance of healing has not only been a basis for employing rigorous definitions of healing and lesion resolution in the evaluation of the therapeutic effects of biologics, but also in testing the efficacy of 5-ASA formulations, which remain first-line treatment for mild-tomoderate UC. As an outcome, healing is being evaluated both at the time of control of the acute flare and over the course of maintenance.

Definition and Potential Importance of Lesion Healing

In a recently completed study of a 5-ASA formulation for acute treatment and for maintenance, the potential importance of lesion healing was the basis for modifying the UC-DAI to provide a stricter definition of disease control at the endoscopic level (Panaccione et al. Can J Gastroenterol 2008;22(suppl A):A98, Abstract 80). In the acute treatment phase and the maintenance phase, remission was defined as a score of 0 for rectal bleeding and stool frequency and a combined Physician’s Global Assessment and sigmoidoscopy score of =1. Any mucosal friability was defined as a score of =2, which deviates from the conventional UC-DAI scoring system for which mild friability was given a score of 1. In this study, patients were randomized to mesalamine MMX 1.2 g b.i.d. or 2.4 g q.d. The study demonstrated that the two dosing schedules were equally efficacious for maintaining healing at 12 months, but it also confirmed a high degree of efficacy for 5-ASA. With this stringent definition of healing, 60% of patients remained healed at 12 months.

With trials that compare treatment success using different definitions of remission, which might not only include clinical vs. endoscopic remission but also different grades of endoscopic appearance, we may learn more about the quality of remission in predicting outcome. Theoretically, some of the variability in treatment course observed in UC may relate to the degree of initial flare control. Prospective studies that can show an ability to improve outcome by altering therapy in the absence of healing may change routine clinical care, justifying more frequent endoscopic evaluations and reconsidering step-down vs. step-up strategies for disease management.

In the absence of data to support verification of healing as a clinically useful marker for clinical management, it is reassuring to select therapies that have a high likelihood of achieving mucosal healing at the same time that they produce clinical remission. Although an increasing number of clinical trials are using endoscopic end points in testing treatment strategies, not all currently available treatments have confirmed healing in prospective studies. This may be an important criterion for differentiating 5-ASA formulations, which are dissimilar in chemical structure and delivery, and for differentiating treatment strategies, such as combining topical and oral 5-ASA preparations, or moving between 5-ASA and immunosuppressants according to endoscopic appearance.

Summary

There are increasing data to support the expectation that mucosal healing is a predictor of outcome in UC patients. While mucosal healing is already a commonly used end point to demonstrate efficacy of UC therapies, it may become an important end point to compare relative efficacy, including differences between 5-ASA formulations. Evidence that it is important to achieve both clinical and endoscopic remission will not negate the goal of selecting treatment that is well tolerated, but it may provide guidance for intensifying therapy to achieve healing or for stepping down therapy when normal endoscopic appearance has been restored.

Editorial Overview:

A. Hillary Steinhart, MD, FRCPC, Divisional Head of Gastroenterology, UHN-Mount Sinai Hospital, Associate Professor of Medicine, University of Toronto, Toronto, Ontario

Adherence to maintenance therapy for ulcerative colitis (UC) therapy is critical for sustained disease control. Although patients with acute disease are likely to comply closely with scheduled treatment, remitted patients who feel healthy may not only forget to take their medicine but also begin to question the need for therapy when faced with side effects, cost or inconvenience. In a relatively recent study, the risk of recurrence at one year was fivefold greater for non-adherent vs. adherent patients (Kane et al. Am J Med 2003;114:39-43).

Outlook on Long-term Adherence

Non-adherence is a pervasive problem in medicine, particularly in patients who do not recognize a relationship between failure to take their medication and its consequences. Extensive studies of non-adherence in hypertension, an often asymptomatic condition that requires chronic therapy, predictably demonstrate declining adherence over time from the last physician visit. While studies in several chronic conditions, including hypertension, support simplification of therapy such as once-daily over twice-daily dosing, the most important step for adherence may be education. In the context of a chronic therapy that provides optimal convenience and tolerability, patients who fully understand the purpose of their treatment and the consequences of failure may be best equipped to stay with their regimen indefinitely.

In UC, the immediate risk of non-adherence is symptomatic relapse. Although the unpredictability of the disease makes a breakthrough flare difficult to attribute to nonadherence in any single individual, sustained remissions for periods of two or more years appear to be achieved in most patients with mild-to-moderate UC who are adherent to firstline 5-aminosalicylate (5-ASA) therapy. In one study that defined adherence as filling more than 80% of the prescribed prescriptions for 5-ASA, the proportion of adherent patients who remained relapse-free at 24 months was 89% vs. 39% (P=0.001) of those who
this level (Kane et al. Am J Med 2003) (Figure 2).

Figure 2.

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The evidence that adherence can reduce the risk of long-term complications, such as bowel resection or colon cancer, is more inferential, although supportive data can be derived from case-control trials. The claim of protection from long-term complications through adherence is based on the relationship between uncontrolled inflammation, the consequence of non-adherence, and increased risk of a complicated disease course and cancer. In one study that compared UC patients with neoplasia to those without, signs of prolonged inflammation, including post-inflammatory polyps and strictures, were associated with a more than doubling of the risk of cancer (Rutter et al. Gut 2004;53:1813-16). On the level of pathophysiology, repeated episodes of inflammation is the putative mechanism for the increased rate of colon cancer in UC patients over time, which may explain why cancer risk in this patient group climbs from about 2% at 10 years to 18% at 30 years (Eaden et al. Gut 2001;48:526-35).

Relative adherence to 5-ASAs has been associated with a reduced risk of colon cancer, although attributing the observed risk reduction in patients adherent to 5-ASA therapy to a potential cancer chemoprophylactic property is problematic (Rubin et al. Clin Gastroenterol Hepatol 2006;4:1346-50). A meta-analysis of nine cohort or case-control studies with more than 1900 patients has associated long-term exposure to 5-ASA with a 49% reduction (95% CI: 0.37-0.69) in risk of colon cancer (Velayos et al. Am J Gastroenterol 2005;100:1345-53). In a single case-control study that evaluated “regular 5-ASA use,” there was a 75% reduction (P<0.00001) relative to non-regular use of 5-ASA (Eaden et al. Aliment Pharmacol Ther 2000;14:145-53).

Extended Quality of Life

While alerting patients to the potential cancer chemoprophylactic property of 5-ASA may be an important tool for eliciting adherence, the opportunity to sustain a high level of quality of life (QoL) may provide a more immediate and achievable goal. Several studies using objective QoL measures have identified disease activity as the single most important determinant of well-being. In one study of 111 patients with UC, symptom-related disease activity was the only variable that was found, in a multiregression analysis, to predict QoL as measured with the Short-Form 36 (SF-36) (Han et al. Inflamm Bowel Dis 2005;11:24-35). The strong relationship between disease symptoms and QoL was consistent across all four domains measured, and it was largely independent of age, gender, physiological markers of disease activity, or anatomic disease extent.

In most patients, UC is a progressive disease. In one multivariate regression analysis, more than 50% of patients followed for 25 years had progression (Hendrickson et al. Gut 1985;26:158-63). In the same population, the cumulative rate of surgery reached 31% after 18 years (Langholz et al. Scand J Gastroenterol 1996;31:260-6). It has been hypothesized, but not well demonstrated, that tight adherence to a first-line therapy of 5-ASA may reduce the risk of disease progression, whether measured as extent of colon involvement, the need for more aggressive therapies, or surgery. It is clear that patients who become inadequately controlled on 5-ASA face pharmacotherapies, such as immunosuppressants, that are, on average, less well tolerated. In those who progress to resection, the complications of surgery may further extend its associated costs and inconvenience (Turina et al. J Gastrointest Surg 2006;10:600-6).

Simplifying Treatment Regimens

The effort to fully inform patients of the risks of non-adherence is a critical but not necessarily a sufficient step toward eliciting compliance. When encouraging consistent use of first-line 5-ASA formulations, it is important to work with patients in developing a maintenance regimen with which they are comfortable and prepared to follow. For many patients, one of the most important characteristics of a convenient regimen may be once-daily dosing. There are now several 5-ASA formulations using a variety of strategies, such as time delay or pH-stimulated release, to extend exposure of the drug to the colon. These represent an important advance in the effort to improve compliance. The ability to reduce oral treatment to a single daily dose has been associated with improved adherence in numerous studies with a variety of medications in other disease states or conditions (Dezii CM. Manag Care 2000;9(suppl):7-12).

In UC, there is one small study that has provided preliminary evidence that once-daily therapy significantly reduces the risk of relapse relative to a multi-dose daily regimen (Kane et al. Clin Gastroenterol Hepatol 2003;1:170-3), but most comparisons of b.i.d. to q.d. regimens have been conducted in controlled trial settings in which potential differences in adherence are likely to be minimized by the close monitoring of patients in a research study setting. However, these studies have been useful in verifying that q.d. therapy can be as effective as b.i.d. therapy both for achieving and maintaining remission.

In two pivotal registration trials with mesalamine delivered in a multi-matrix system (MMX) that employs pH-stimulation and time-dependent strategies to increase delivery of active medication in the colon, a q.d. dose of four pills containing 5-ASA 1.2 g (daily total 4.8 g) was equivalent to a b.i.d. regimen of 1.2 g pills (daily total of 2.4 g) for remission (Lichtenstein et al. Clin Gastroenterol Hepatol 2007;5:95-102, Kamm et al. Gastroenterology 2007;132:66-75). In both studies, a relatively rigorous definition of remission was employed in which patients had to have a modified UC Disease Activity Index (UC-DAI) score of =1 with rectal bleeding and stool frequency score of 0 as well as a combined Physicians Global Assessment and sigmoidoscopy score of =1 in which no mucosal friability was permitted.

Regarding adherence, an open-label maintenance extension of the pivotal efficacy trials with MMX mesalamine 2.4 g that allowed patients to select either q.d. or b.i.d. therapy (1.2 g b.i.d.) demonstrated equivalent remission rates at the end of 12 months, whether patients had mild (69% vs. 72.2%; P=0.63) or moderate (61.4% vs. 66.7%; P=0.352) disease at entry (Panaccione et al. Can J Gastroenterol 2008;22(suppl A):98A, Abstract 80) (Figure 3). Compliance in both arms exceeded 95%. The data demonstrating that q.d. formulations of 5-ASA do not reduce efficacy relative to multi-dose regimens is reassuring for the goal of simplifying therapy, but it is important to recognize that there is no single answer to the challenge of adherence. Patients should be encouraged to engage in the discussion of personal preferences regarding therapeutic options. Patients who are active in selecting specific th
heir personal preferences may be more identified with and more directed toward therapeutic goals.

Figure 3.

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Summary

UC is a challenging and unpredictable inflammatory disease, but there is evidence that at least some degree of risk for disease flares stems directly from failure to adhere to maintenance therapies. Adherence to 5-ASA, the first-line therapy for mild to moderate UC, does not eliminate the risk of relapse, but it does reduce the risk, a benefit that has immediate implications for sustaining an optimal quality of life. Although the evidence that adherence to 5-ASA maintenance reduces the risk of complications, such as resection and cancer, is circumstantial, it makes biologic sense to minimize periods of inflammation to prevent disease progression.

Editorial Overview:

Alain Bitton, MD, FRCPC, Department of Gastroenterology, McGill University Health Centre, Montreal, Quebec

Published guidelines for the treatment of ulcerative colitis (UC) have advocated a step-up approach, which emphasizes the initial use of the least aggressive therapy for symptom control (Figure 4). The large proportion of patients with mild-to-moderate UC who are controlled on 5-aminosalicylates (5-ASA) first-line therapy permits clinicians to reserve use of more aggressive therapies, including corticosteroids, purine analogues and biologic therapy, for patients with more refractory disease. No formal guidelines for the medical management of mild-tomoderate UC have been published in Canada, but the agreement between the recently published guidelines in Europe (Travis et al. J Crohns Colitis 2008;2:24- 62) and those previously produced in the US (Kornbluth et al. Am J Gastroenterol 2004;99:1371-85) demonstrate a relatively consistent approach to the sequence in which treatments should be considered in acute symptom control and t
ndividualized therapy for patient needs and preferences should modify strategies within the ultimate goal of suppression of disease activity.

Figure 4.

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Initial Therapy

The initial treatment for mild-to-moderate active UC should be commensurate with extent of colonic involvement and severity. Topical 5-ASA is generally a sufficient initial treatment for proctitis (500 mg b.i.d. suppositories or 1 g 5-ASA q.d. suppositories) and proctosigmoiditis (2 g or 4 g 5-ASA enemas once nightly). Topical steroid regimens are also effective. Combining topical agents with oral 5-ASA may be beneficial when treatment escalation is warranted in distal colitis (Regueiro et al. Inflamm Bowel Dis 2006;12(10):979-94). Oral 5-ASA, often in combination with a topical agent, is appropriate for more extensive disease including left-sided colitis (Marteau et al. Gut 2005;54:960-5, Travis et al. J Crohns Colitis 2008;2:24-62)). Meta-analyses have reported a dose-dependent therapeutic effect for oral 5-ASA in the acute setting (Sutherland L, MacDonald JK, Cochrane Database Syst Rev 2006;(2):CD000543).

It is current practice to treat mild-tomoderately active UC with 4 to 4.8 g/day of oral 5-ASA to achieve maximal therapeutic benefit. However, more recent studies in mild-tomoderate UC have suggested that initiating therapy with lower doses (2.4 g/day) may suffice for induction of remission (Kamm et al. Gastroenterology 2007;132:66-75). In the phase III ASCEND (Assessing the Safety and Clinical Efficacy of a New Dose of 5-ASA) I and II studies, which were pooled for analysis, there was no difference in therapeutic effect between 2.4 and 4.8 g/day in mildly active UC (Hanauer et al. Gastroenterology 2005;128: A74-5). However, 4.8g/day of 5-ASA was superior to 2.4 g/day in achieving treatment success in moderately active UC. (Hanauer et al. Gastroenterology 2005;128:A74-5, Hanauer et al. Am J Gastroenterology 2005;100:2478-85).

In the acute setting, treatment success is defined as control of symptoms. Endoscopic evaluation to confirm healing is not standard practice. As of yet, there are no firm data to demonstrate that better outcomes can be achieved if treatment is intensified to achieve complete healing. However, there is a population-based study that has associated mucosal healing with reduced rates of colectomy (Froslie et al. Gastroenterology 2007;133:412-22). In addition, persistent mucosal microscopic inflammation has been associated with an increased risk of progression to dysplasia and neoplasia (Gupta et al. Gastroenterology 2007;133:1099-105). In the recently published European guidelines, trials which employed mucosal healing as an end point were cited as evidence of efficacy of 5-ASA treatment. These included two placebocontrolled studies with 5-ASA delivered in a Multi Matrix System (MMX) once or twice daily. These studies defined clinical remission as a UC Daily Activity Index (UC-DAI) score of =1. The endoscopic criterion for remission was a sigmoidoscopy score of =1 with no mucosal friability. In a combined analysis, clinical and endoscopic remission was achieved at eight weeks in 37.2% of those randomized to 2.4 g/day, 35.1% of those randomized to 4.8 g/day and 17.5% of those randomized to placebo (P<0.001 vs. either dose of mesalamine) (Sandborn et al. Aliment Pharmacol Ther 2007;26(2):205-15). As an indicator of disease quiescence, mucosal healing is at least theoretically appealing, and the evidence that 5-ASA formulations are capable of restoring normal mucosa is reassuring.

Maintenance

In the majority of patients with active UC who do respond to 5-ASA, it is reasonable to maintain these individuals on the same induction regimen that achieved control of the active disease. However, a trial of stepping down to lower doses or discontinuing topical treatment can be considered according to patient preference. Nightly or intermittent 5-ASA suppositories (500 mg/supp or 1 g/supp) or enemas (4 g/enema) are effective for ulcerative proctitis or proctosigmoiditis respectively. Oral 5-ASA is useful for maintaining remission in more extensive disease including left-sided colitis. When necessary, combination oral and topical 5-ASA may be a more effective regimen than either medication alone (D’Albasio et al. Am J Gastroenterol 1997:92(7);1143-7). Metaanalyses have demonstrated a clear benefit of oral or topical 5-ASA agents as maintenance treatment in UC with no clear dose-dependent effect (Sutherland L, McDonald JK. Cochrane Database Syst Rev 2006;(2):CD000544, Marshall JK, Irvine EJ. Aliment Pharmacol Ther 1995:9:293-300). Corticosteroids are not effective maintenance agents in UC.

Rationale for Optimal 5-ASA Use

Although there should be no hesitation in stepping up to more aggressive treatments in UC patients who do not achieve disease control on 5-ASA, there are other potential benefits for ensuring that 5-ASA use has been optimized. 5-ASA is the most well tolerated of currently available therapies in UC and there has been relatively little success in stepping back down to 5-ASA once patients move on to an immunosuppressant or biologic for disease control. Furthermore, there is evidence that 5-ASA may have chemopreventive properties against the development of dysplasia or colon cancer in UC. In a meta-analysis of nine cohort or case-control studies, long-term exposure to 5-ASA was associated with a 49% reduction (95% CI: 0.37-0.69) in risk of colon cancer (Velayos et al. Am J Gastroenterol 2005;100:1345-53). Although controversial, some clinicians consider the potential for prevention of colon cancer an indication for life-long 5-ASA even among those who are stepped up to another treatment.

The strategies for optimizing 5-ASA therapy in patients who are not controlled on their initial topical or oral regimen include establishing that patients are taking maximum acceptably tolerated doses of topical and/or oral 5-ASA. In patients with active disease, adherence is not typically a significant issue, but poor adherence during maintenance treatment may translate into higher rates of relapse (Kane et al. Am J Med 2003;114:39- 43). A variety of factors including dosing regimen have been reported as possible contributors to non-adherence to 5-ASA therapy (Kane et al. Alimemt Pharmacol Ther 2006;23(5):577-85). One potential approach to enhance adherence would be the use of oncedaily therapies made possible by delayedrelease strategies, such as pH dependence or timed dissolution (Kamm et al. Gut published online 13 February 2008, Kruis et al. Gastroenterology 2007;132(suppl 2):A-130-1, Abstract 898).

Regaining Control of UC

In patients who fail to respond to optimally tolerated 5-ASA in the acute setting or who have a more severe exacerbation, a short course of oral corticosteroids may provide an opportunity to rapidly regain control of UC but still step back down to 5-ASA maintenance. If symptoms return when steroids are tapered (steroiddependent) or the response to steroids is incomplete (steroid-resistant), stepping up to immunosuppressant therapy such as the purine analogues, including azathioprine or 6-mercaptopurine is indicated (Timmer et al. Cochrane Database Syst Rev 2007;(1): CD000478). In those patients who can be tapered off steroids, the interval to the next flare provides guidance for the adequacy of the maintenance regimen. Relatively short intervals on a maximally tolerated dose of 5-ASA may encourage a step-up in the pyramid of treatment choices. The need for two or more courses of oral steroids in a single year is regarded as an indication for stepping up therapy. However, patients should participate in the decision to consider the risk-to-benefit ratio of the regimen with the potential to reduce flares but produce side effects. The option of surgery with its benefits and potential adverse effects should always be considered in patients who require more intensive medical therapy.

Step-up to Biologic Therapy

Consistent with the step-up approach, patients who fail steroid and immunosuppressant therapy are candidates for biologic therapy. To date, infliximab is the only biologic agent which has been demonstrated to be beneficial in controlled trials for active UC. In two pivotal placebo-controlled studies conducted in mildto- moderate UC with infliximab administered at week 0, 2, 6 and every 8 weeks thereafter, clinical response rates were superior to placebo when measured at 8, 30, or 54 weeks. Whether delivered in a dose of 5 mg/kg or 10 mg/kg, response rates on infliximab were typically double those of placebo. At week 54, these response rates were 45% (5 mg/kg), 44% (10mg/kg), and 20% (placebo), respectively (P<0.001 for placebo vs. either dose). Mucosal healing was also superior in the infliximab treated group. Canadian guidelines for the use of infliximab in the treatment of UC have recently been published (Panaccione et al. Can J Gastroenterol March 2008;22:261-72).

Natural History of UC and Medical Therapy

When followed over several decades, about half of UC patients will demonstrate disease progression that includes a requirement for more aggressive medical therapies or an increased cumulative rate of bowel resection Hendrickson et al. Gut 1985;26:158-63). The reason for variability in colectomy rates reported by different centres is unknown (Hoie et al. Gastroenterology 2007;132:507-15), but relative success in achieving rapid disease control and preserving remission may be factors. It remains to be determined if tighter early control of mild-to-moderate UC, the most common form at initial diagnosis, can attenuate disease progression. A “top-down approach” emphasizing early, more aggressive therapy such as biologic therapy has been explored in early Crohn’s disease but as of yet has not been evaluated in UC.

Summary

The majority of patients with UC will require lifetime therapy. This is an important consideration in educating patients about the strategies for controlling symptoms and preventing relapse. While the goal is for patients to feel well, there is a risk of mistaking prolonged disease control as a cure that no longer requires chronic treatment. Specific strategies to maximize adherence to medical therapy should be an integral part of patient care.

A large proportion of UC patients have mildto- moderate disease for which the first-line therapy is 5-ASA, both for control of acute symptoms and maintenance to prevent relapse. Once immunosuppressant therapies (purine analogues or biologics) are required to control UC, stepping back down to 5-ASA is rarely an option. Therapeutic issues which remain to be resolved include optimal induction and maintenance 5-ASA dosing regimens and benefit of long-term 5-ASA therapy with respect to chemoprevention. The significance of sustained mucosal healing as a therapeutic goal remains to be determined before this is universally accepted.