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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 - Gastroenterology

THE IMPORTANCE OF MUCOSAL HEALING IN CROHN’S DISEASE

Editorial review:

Subrata Ghosh, MD, FRCPC, FRCP(E)

Head, Division of Gastroenterology, Teaching Research Wellness Building, Professor of Medicine, University of Calgary, Calgary, Alberta

Crohn’s disease (CD) is a chronic inflammatory condition characterized by an unpredictable course involving intermittent flares with the potential to lead to irreversible damage to the gastrointestinal (GI) tract.¹ It typically has a segmental distribution that is more likely to extend beyond the large bowel, and produces transmural ulceration and GI complications, such as stricture and fistula.² Aggressive management is often required to control the substantial and diffuse inflammatory activity in order to avoid significant complications, including bowel resection and cancer.¹ An effective way of ensuring patients are being optimally treated is to raise treatment goals beyond symptomatic relief.

Treating beyond symptomatic relief and striving for complete mucosal healing has been correlated with better long-term outcomes. Evidence is accumulating that achieving complete mucosal healing with the therapeutic agents available can lead to a sustained remission for patients and a reduced need for hospitalizations and surgeries.

Beyond Symptom Control

Due to the burden imposed by CD even when disease severity is relatively mild, the major objective for acute treatment was once limited to control of acute symptoms. However, because of its relevance to sustained remission, mucosal healing has emerged as a critical goal in acute management and offers an opportunity to change the natural history of the disease. As in asthma, where control of subclinical inflammatory disease activity has been linked to better longterm outcome,³ mucosal healing signals the absence of inflammatory activity, keeping the underlying pathophysiological process in check, leading to enduring disease control. This is supported by several trials, including a study that compared long-term outcomes in CD patients with mucosal healing at one year (Figure 1). Mucosal healing was significantly associated with less inflammation after 5 years (P=0.02) and decreased future steroid treatment (P=0.02).⁴

Figure 1.

As in other inflammatory processes, the degree to which inflammatory activity is controlled corresponds with the degree of risk of adverse outcomes. While complete mucosal healing is the optimal outcome, a persistently severe disease course predicts future severity if mucosal healing is not achieved. For example, CD patients with extensive penetrating lesions had a fivefold increase in risk of colectomy at two years relative to those with mild lesions (Figur
sup>

Figure 2.

<img3980|center>

However, one of the most important reasons to gauge treatment success by mucosal healing rather than by symptom control is that patients can have active disease without symptoms. In one study of 142 CD patients of which 92% were in clinical remission, no correlation was found between clinical severity and nature, surface or severity of endoscopic lesions.⁶ Of the 131 patients in clinical remission only 38 were also in endoscopic remission. Moreover, there was no significant difference in the Crohn’s Disease Activi
n those who did and did not have lesions (Figure 3).

Figure 3.

<img3981|center>

The importance of prolonging mucosal healing has been demonstrated after surgery, which is considered to reset the clock regarding disease activity. Although healing may be prolonged after surgery, disease recurs endoscopically before it becomes symptomatic.⁷ In a double-blind study testing active therapy to maintain mucosal healing, the tumour necrosis factoralpha (TNF-a) inhibitor infliximab (IFX) was associated with significant protection against endoscopic recurrence, severe endoscopic recurrence, histological recurrence and clinical recurrence at one year relative to placebo (Figure 4).⁸ It is notable that the rate of clinical remission, defined as a CDAI =150, was greater in the TNF-a-treated group but not significantly superior to placebo. This is likely to be due to the fact that an increase in signs and symptoms of CD had not yet become sign
en though endoscopic studies demonstrated that control was being lost at the level of the mucosa.

Figure 4.

<img3982|center>

Several definitions of complete mucosal healing have been offered with some definitions requiring an endoscopic score of 0 for all end points, including both symptoms and mucosal appearance. Others permit a score of 1 for mucosal appearance, which signifies mild friability.9 However, there are a variety of data to suggest the degree of healing is important, making strict definitions useful.

In a study of CD patients taking the TNF-a inhibitor, complete mucosal healing, defined as a simple endoscopic score of 0 after two years of therapy, was the only factor that predicted steroid-free remission after three to four years
s achieved in 70.8% of those with healing vs. 27.3% of those without complete mucosal healing (P=0.036) (Figure 5).¹⁰

Figure 5.

<img3983|center>

Therapeutic Choice for Achieving Complete Mucosal Healing

Corticosteroids are effective for suppressing symptoms in CD, but they have not been found to be effective for mucosal healing, possibly due to a lack of effect on submucosal inflammatory processes.¹¹ Although immunosuppressive agents such as AZA, 6-mercaptopurine and methotrexate have demonstrated fairly limited efficacy when complete mucosal healing has been the primary end point,¹² the introduction of the biologics have played a critical role in correlating mucosal healing with an improvement in long-term outcomes, including a reduced risk of relapse and need for resection.

In the pivotal ACCENT1 maintenance study, 573 patients with a score of =220 on the CDAI received a 5 mg/kg intravenous infusion of IFX at week 0. After assessment of response at week 2, patients were randomly assigned repeat infusions of placebo at weeks 2 and 6 and then every 8 weeks thereafter until week 46 (group I), repeat infusions of 5 mg/kg IFX at the same timepoints (group II), or 5 mg/kg IFX at weeks 2 and 6 followed by 10 mg/kg (group III). Overall, 58% of patients responded to a single infusion of IFX within 2 weeks. At week 30, 21% of group I, 39% of group II and 45% of group III patients were in remission. While patients in groups II and III combined were more likely to sustain clinical remission than patients in group I, the median time to loss of response in all groups was 38 weeks, climbing to more than 54 weeks in groups II and III.¹³

In the endoscopic substudy of ACCENT1, complete mucosal healing at 54 weeks was significantly higher in patients in the scheduled IFX treatment strategy than those who had received episodic treatment (44% vs. 18%, respectively, P=0.041).¹⁴ Relative to placebo, or episodic infusions of the TNF-a inhibitor, in which mucosal healing was uncommon, maintenance with the biologic was also associated with a non-significant decreased need for hospitalizations and surgery. Again, healing was a significant predictor of remission regardless of therapy with both complete and significant healing predic
relapse (Figure 6).¹⁵ Adalimumab and certolizumab pegol have also been shown to result in varying degrees of mucosal healing and the results await full publication.

Figure 6.

<img3984|center>

In subsequent studies, earlier use of the biologic has been evaluated in an effort to avoid steroid dependency, increase mucosal healing and provide better longterm outcomes. In the SONIC study, 508 patients naive to immunomodulator therapy were randomized to AZA plus placebo, IFX plus placebo or plus AZA. Mucosal healing differed markedly between strategies, ranging
ceiving AZA alone to 44% (P<0.001) in the arm that received both agents (Figure 7).¹⁶ The TNF-a inhibitor alone achieved mucosal healing in 30%, which was significantly greater than AZA alone (P=0.023).

Figure 7.

<img3985|center>

Selecting the best agent is important to ensure patients can achieve complete mucosal healing. In the randomized, open-label StepUp/TopDown (SUTD) study, an initial strategy of combined immunosuppression (step down) was compared to conventional therapy (step up) in 133 patients. In the step down arm, patients received IFX at 0, two and six weeks with AZA maintenance. On-demand IFX was provided for flares and systemic steroids were added only if patients did not respond. In the step up arm, corticosteroids as an initial strategy were followed by AZA and a TNF-a inhibitor if needed. At week 26, 60% of patients in the combined immunosuppression group vs. 35.9% in the conventional treatment arm (P=0.0062) were in remission without corticosteroids and without surgical resection. At week 52 t
d 42.2% (P=0.0278), respectively. Endoscopic evaluation showed that 73.1% of those in the top-down arm vs. 30.4% in the step-up arm remained in mucosal healing at year 2 (Figure 8).¹⁷ Those with mucosal healing had fewer relapses over the next 2 years.

Figure 8.

<img3986|center>

A recently published study from the Leuven group with 214 CD patients treated with IFX showed that those who achieved complete healing or partial healing had a dramatically reduced need for major abdominal surgery over those without initial healing over longterm follow-up.9 In t
conducted specifically in an unselected patient population with the intention of creating a reallife environment, 45.4% had complete and an additional 22.4% had partial mucosal healing. During follow-up, surgery was required in 14.1% of those with mucosal healing vs. 38.4% without mucosal healing (P<0.001) (Figure 9).

Figure 9.

<img3987|center>

Once healing is achieved with a biologic, continuous therapy appears to be appropriate. This has been shown in several studies, including new data from the CHARM (Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance) in which 778 patients who responded to adalimumab induction were randomized to placebo, continuous adalimumab 40 mg every week or every other week.¹⁸ Although all patients were permitted to initiate continuous adalimumab after 12 weeks, those who were randomized to either one of the continuous regimens after induction were in remission at week 56 (49%/51% vs. 38%; P<0.01). Continuous adalimumab was also associated with fewer surgeries (P<0.05) and fewer CD-related hospitalizations (P<0.05) or hospitalizations of any kind (P<0.05). Importantly, there is objective evidence that these benefits translate into an improvement in quality of life (QOL). In data from the open-label study called EXTEND (Efficacy of adalimumab through Endoscopic Healing), 62 patients with mucosal ulceration at baseline were evaluated for the impact of mucosal healing on QOL at 12 weeks over subsequent follow-up using predefined =16-point increase in the Inflammatory Bowel Disease Questionnaire (IBDQ) score. Of the 17 with healing, 77% scored the threshold of QOL improvement at 28 weeks and 65% at 52 weeks. In contrast, the figures were only 44% and 33%, respectively, for the 45 patients who continued to demonstrate ulceration at 12 weeks.¹⁹

The results of studies encouraging early induction of mucosal healing with biologics are consistent with evidence that the natural history of CD is progressive. By earlier control, this progression appears to be attenuated, reducing the potential need for steroids, complications and morbidity. By using the most effective therapies earlier in the course of the disease, there is an opportunity to avoid or delay the advanced stages of disease, which are more difficult to control.

Summary

The introduction of biologics in the treatment of IBD has created an opportunity to strive beyond the goal of symptomatic relief. By raising our treatment goals and using treatment strategies that focus on intervening earlier with agents such as biologics, we now have the potential to heal the mucosa and change the course of the disease. These goals will give patients a greater chance of improving their QOL and minimizing disease burden.

References

1. Podolsky DK. Medical progress: Inflammatory bowel disease. N Engl J Med 2002;347:417-29.

2. Hanauer SB. Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm Bowel Dis 2006;12(suppl 1): S3-S9.

3. Elias et al. New insights into the pathogenesis of asthma. J Clin Invest 2003;111:291-7.

4. Frøslie et al. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007;133:412-22.

5. Allez et al. Long term outcome of patients with active Crohn’s disease exhibiting extensive and deep ulcerations at colonoscopy. Am J Gastroenterol 2002;97:947-53.

6. Modigliani et al. Clinical, biological, and endoscopic picture of attacks of Crohn’s disease: evolution on prednisolone. Gastroenterology 1990;98:811-8.

7. Ruffolo et al. Subclinical intestinal inflammation in patients with Crohn’s disease following bowel resection: a smoldering fire. J Gastrointest Surg 2010;14(1):24-31.

8. Regueiro et al. Infliximab prevents Crohn’s disease after ileal resection. Gastroenterology 2009;136:441- 50.

9. Schnitzler et al. Mucosal healing predicts long-term outcome of maintenance therapy with infliximab in Crohn’s disease. Inflamm Bowel Dis 2009;15:1295- 301.

10. Baert et al. Mucosal healing predicts sustained clinical remission in patients with early stage Crohn’s disease. Gastroenterology 2010;138(2):463-8.

11. Agrawal et al. Effect of systemic corticosteroid therapy on risk for intra-abdominal or pelvic abscess in nonoperated Crohn’s disease. Clin Gastroenterol Hepatol 2005;3:1215-20.

12. Vermeire S, van Assche G, Rutgeerts P. Review article: Altering the natural history of Crohn’s disease— evidence for and against current therapies. Aliment Pharmacol Ther 2007;25:3-12.

13. Hanauer et al. Maintenance infliximab for Crohn’s disease: the ACCENT1 randomized trial. Lancet 2002;359:1541-9.

14. Rutgeerts et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease. Gastroenterology 2004;126:402-13.

15. D’Haens et al. Endoscopic healing after infliximab treatment for Crohn’s disease provides a longer time to relapse. Gastroenterology 2002;122:A100.

16. Colombel et al. SONIC: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathioprine to azathioprine in patients with Crohn’s disease naive to immunomodulators and biologic therapy. Gut 2008;57:A1,abstract OP001.

17. D’Haens et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet 2008;371:660-7.

18. Colombel et al. Comparison of two adalimumab treatment schedule strategies for moderate-to-severe Crohn’s disease: results from the CHARM trial. Am J Gastroenterol 2009;104:1170-9.

19. Geboes et al. Adalimumab-treated patients with mucosal healing experienced quality-of-life improvements: subgroup analysis of the EXTEND trial for Crohn’s disease. CDDW 2010, abstract A118.

MAXIMIZING THERAPEUTIC OUTCOMES IN ULCERATIVE COLITIS

Editorial Review:

Mark Silverberg, MD, PhD, FRCPC

Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Assistant Professor of Medicine, University of Toronto, Toronto, Ontario

Effective management of ulcerative colitis (UC) requires an appreciation of the substantial range of disease severity. Therapy has been traditionally driven by symptom control. Compelling data now suggest that therapy should be stepped up to heal tissue with the goal of sustained disease quiescence. First line therapies such as 5-aminosalicylic acid (5-ASA) agents are often effective in mild to moderate disease for the goals of symptom control and for mucosal healing. With increasing disease severity and more significant inflammation, the twin goals of symptom relief and healing the mucosa remain unchanged but require more intensive therapies, including corticosteroids, immunomodulators and biologics, to achieve and sustain remission and reduce the risk of colectomy. In a chronic disease, quality of life (QOL) must be evaluated over the long term which requires attention to how therapeutic choices affect the immediate disease state and the risk of relapse.

Disease Assessment

UC is a chronic disease with an unpredictable course characterized by exacerbation and remission.¹ Up to 25% of patients with UC may have a severe disease course as defined by steroid dependency² and as many as one fifth of patients may go on to require a colectomy. To capture differences in presentation, it is useful to classify UC by disease extent. Ulcerative proctitis is defined as inflammation limited to the rectum; left-sided UC or distal UC, involves inflammation extending up to the splenic flexure; and extensive UC, is inflammation extending proximal to the splenic flexure. Utilizing the Montreal Classification these would be categorized as E1, E2 and E3, respectively.³ In most cases, the inflammation is contiguous starting at the rectum, so that 95% of UC patients have rectal involvement.⁴

In ulcerative proctitis, the major symptom is often bloody diarrhea.⁵ In patients with an initial diagnosis of proctitis, extension into more proximal sections of the colon over long-term follow-up is relatively common with 20% demonstrating proximal extension at five years and 50% at 10 years.⁶ However, only 10% of patients had extension beyond the splenic flexure even after 10 years of followup. Distal UC, also called proctosigmoiditis, in which inflammation is confined to the rectum and sigmoid colon, is a common form, representing more than 40% of cases of UC in some series.⁷ While the severity of symptoms correlates with the severity of the inflammation, the risk of progression is associated with onset at a relatively young age and the presence of sclerosing cholangitis.⁸ Extensive colitis, which describes inflammation for the full length of the colon, is a risk factor for a more complicated course, including higher rates of colon cancer,⁹ although a substantial minority may have regression of colitis over time.¹⁰

Relevance of Mucosal Healing

Until recently, treatment was largely concentrated on exerting control over acute symptoms, but equal attention is now being directed at strategies that yield sustained remission with mucosal healing. This proactive approach is associated with reduced risk of relapse and the more serious complications such as the need for surgery.¹¹ In mild to moderate disease, there is a growing body of data from clinical trials indicating that mucosal healing yields a greater likelihood of sustained remission than symptom resolution alone. In a study with 495 patients that compared outcomes in patients who did or did not achieve mucosal healing with any type of therapy, those who did had significantly less inflammation, significantly fewer colectomies and received less steroid treatment¹² (Figure 1). In moderate to severe disease, achieving mucosal healing is more difficult, but it is suspected that complete healing also provides a degree of protection from disease flares.¹³

Figure 1. Incidence of Colectomy in UC Patients with or Without Mucosal Healing at One Year

These data encourage efforts to provide adequate therapy in patients at all strata of disease severity, from mild to severe, for the goal of mucosal healing and ultimately reduced risk of hospitalization and colectomy. The general goals of inflammatory bowel disease (IBD) therapy then are: induction and maintenance of clinical remission without steroids, complete healing of the intestinal mucosa, and avoidance of surgeries and other complications such as cancer and death.

Treatment Algorithm

5-ASA agents are acknowledged as first-line therapy for mild to moderate UC in most guidelines, including those from the European Crohn’s and Colitis Organization (ECCO)¹⁴ and the American College of Gastroenterology (ACG).¹⁵ In patients with proctitis only, suppositories provide direct targeting of the involved tissues and may be more effective than oral agents,¹⁶ but a combination of suppositories and oral agents appears to be advantageous when the inflammation extends beyond the sigmoid.¹⁷

Steroids are highly effective in the acute control of symptoms and should be introduced when 5-ASA agents are not adequately effective alone as steroids can dramatically shorten the time to symptom resolution relative to 5-ASA alone.¹⁸ However, steroid dependency, i.e. the inability to taper or the need to receive another course of steroid within one year, is a substantial concern. In addition to the risk of dependency, steroid courses should also be of limited duration due to a long list of potential complications that include increased risk of infection, hypertension, impaired glucose metabolism and osteoporosis.^19,20 Failure to achieve control of symptoms suggests steroid resistance, making a timely switch to alternative treatments necessary,²¹ a goal rendered more pertinent by evidence that steroids are not effective for maintenance of remission.²²

Azathioprine (AZA) is useful in maintenance regimens and should be considered when there is steroid dependency²³ (Figure 2). In a placebo controlled study of patients who had been in remission for at least six months before enrolling, relapse rates after one year were 31% in the AZA group vs. 61% in controls (P<0.01).²⁴ On the basis of this and other studies, the ACG guidelines suggest this agent might be useful as a maintenance agent in patients not sufficiently controlled on a sulfasalazine.¹⁵

Figure 2. Time-structured Treatment Algorithm for Moderate UC

In those who become refractory to steroids and/or azathioprine, restoring acute symptom control may be required, but long-term outcome should be considered in the choice of treatment strategies. A biological therapy may be useful in this scenario to both induce and maintain a sustained remission. For patients with acute, severe UC not controlled on steroids, biologics may be appropriate as a rescue therapy to avoid colectomy. In up to 50% of patients who were steroid-refractory, therapy with the TNF-a inhibitor infliximab (IFX) has reduced the need for surgery.²⁵

Anti-TNF Treatment and Outcomes

As a result of a new appreciation for the importance of initial and sustained mucosal healing, biologics are no longer reserved for rescue therapy in severe UC. The appropriate UC patient for a biologic is one with moderate to severe disease who has become refractory to either steroids or AZA or who is steroid-dependent. In these patients, biologics demonstrate a substantial rate of sustained remission and mucosal healing which, in turn, is associated with improved outcomes. Specifically, the ACT 1 and 2 trials randomized patients with moderateto- severe disease activity (despite concurrent treatment with corticosteroids alone or corticosteroids in combination with AZA or 6-mercaptopurine [6-MP]) to one of two doses of IFX or placebo.²⁶ At week 8, mucosal healing, defined as an absolute subscore for endoscopy of 0 or 1,was achieved in about 60% of patients on either 5 or 10 mg/kg of the TNF-a inhibitor vs. 34% (P<0.001) of those on placebo. At 54 weeks, colectomy rates were 21% in patients treated with the biologic vs. 34% in placebo patients (P=0.03), while hospitalization rates were 20% vs. 40% (P=0.003) (Figure 3).²⁷

Figure 3. ACT 1 and 2: Results at 54 Weeks

Inducing Remission and Mucosal Healing: Strategies for Long-term Disease Control

The choice of maintenance treatment should be, in part, influenced by the severity of disease during the index presentation, the interval of time the disease remained controlled prior to the recurrence and the severity of the recurrence. In mild to moderate disease with a prolonged remission following 5-ASA therapy, 5-ASA maintenance is a reasonable approach. In patients who relapse within three months of an initial course of 5-ASA, an immunosuppressive treatment, such as AZA or 6-MP, may be more appropriate for both healing and reducing the risk of future relapses. Controlled data demonstrate that AZA is more effective than 5-ASA for achieving both clinical and endoscopic remission in steroid-dependent UC.²⁸

In moderate-to-severe disease, early relapse after an initial course of an immunosuppressant such as AZA or steroid dependence despite an immunosuppressant provides a basis for considering a biologic as a maintenance strategy. The ACT 1 and 2 trials demonstrated that IFX as an every-eight- week maintenance regimen was more effective than conventional therapy alone for inducing remission, healing the mucosa and reducing the need for steroids at 54 weeks in patients with moderate-to-severe UC who were failing first-line therapies (Figure 4, 5).²⁶

Figure 4. ACT 1 and 2: Mucosal Healing Results

Figure 5. ACT 1 and 2: Patients in Clinical Remission with Discontinued Steroid Use

Recent reports of a diminishing rate of colectomy may be a product of more aggressive recent use of immunosuppressants and biologics.²⁹ Although it is unclear whether effective control of UC reduces the risk of cancer, its risk has been associated with both the extent and the duration of disease,⁹ providing another source of support for use of therapies that will achieve and sustain healing. In addition, the risk of dysplasia and malignancy may be related to longstanding, uncontrolled inflammation making the goal of mucosal healing important.³⁰ The efficacy of biologics in UC is supported by a study of 115 corticosteroid-refractory UC patients who received a three-dose induction of IFX followed by scheduled maintenance.³¹ Outcomes were significantly better in ambulatory patients with moderately severe disease compared to those hospitalized for acute severe disease (Figure 6). In addition, this study demonstrated that detectable trough IFX levels were significantly associated with improved outcomes suggesting that adequate dosing and scheduling of therapy may be critical to successful outcomes. These results are part of an increasing body of evidence suggesting that the use of biologics in UC patients not controlled on first-line therapies is an effective strategy to achieving optimal results.

Figure 6. Outcomes at Week 10 After Three-dose Induction

Biologic therapies, such as TNF-a inhibitors, are associated with a variety of side effects, such as headache and nausea, but these tend to be mild and self-limited.³² The major concern generated by these agents is for impaired immune function. However, data from the large TREAT (Therapy Resource Evaluation Assessment Tools) registry of 6290 CD patients has not found the risk of serious adverse events related to immunological function to be greater in patients receiving IFX relative to those not receiving it.³³ Although IFX was associated with a greater risk of infection than other therapies, it was not found to persist as an independent risk factor for serious infection after a multivariate logistic regression. In this analysis, only prednisone (OR 2.1; 95% CI, 1.15-3.83; P=0.016) was associated with an increased risk of mortality.

Summary

Active UC often imposes a substantial symptom burden that makes urgent initiation of effective therapy a priority in patient management. While it is essential to employ therapies that provide an optimal balance of safety and efficacy, the equation should now include strategies to achieve complete mucosal healing, prevent relapse, slow disease progression and long-term disease complications. The choice of maintenance strategy, which depends on the previous response to therapy and the severity of the relapse, is potentially relevant to long-term outcome, including risk of complications, particularly colectomy. Disease control may also reduce the risk of UC-related cancer. While it is important to employ the simplest and most well-tolerated therapy in UC, it is equally vital to step up therapy for mucosal healing because of the potential long-term benefits of fully quiescent disease. In moderate- to- severe di sease, s teroi d dependence or failure to achieve control of symptoms after an initial course of an immunosuppressant provides a basis for considering a biologic as a useful strategy.

References

1. Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002;347:417-29.

2. Stonington et al. Chronic ulcerative colitis: incidence and prevalence in a community. Gut 1987;28:402-9.

3. Silverberg et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology Can J Gastroenterol 2005;19(suppl A):5A-36A.

4. Moum et al. Incidence of inflammatory bowel disease in southeastern Norway: evaluation of methods after one year of registration. Digestion 1995;56:377-81.

5. Ekbom et al. The epidemiology of inflammatory bowel disease: a large, population-based study in Sweden. Gastroenterology 1991;100:350-8.

6. Meucci et al. The natural history of ulcerative proctitis: a multicenter, retrospective study. Am J Gastroenterol 2000;95:469-73.

7. Farmer et al. Clinical patterns, natural history, and progression of ulcerative colitis. Dig Dis Sci 2005;38:1137-46.

8. Etchevers et al. Risk factors and characteristics of extent progression in ulcerative colitis. Inflamm Bowel Dis 2009;15:1320-5.

9. Ekbom et al. Ulcerative colitis and colorectal cancer: a population-based study. N Engl J Med 1990;323:1228-33.

10. Moum et al. Change in the extent of colonoscopic and histological involvement in ulcerative colitis over time. Am J Gastroenterol 1999;94:1564-9.

11. Meucci et al. Prognostic significance of endoscopic remission in patients with active ulcerative colitis treated with oral and topical mesalazine: preliminary results of a prospective, multicenter study. Gastroenterology 2006;130:S1302.

12. Frøslie et al. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007;133:412-22.

13. Rutgeerts P, Vermeire S, Van Assche G. Mucosal healing in inflammatory bowel disease: impossible ideal or therapeutic target? Gut 2007;56:453-5.

14. Travis et al. European evidence-based consensus on the management of ulcerative colitis: current management. J Crohn’s Colitis 2008;2:24-62.

15. Kornbluth A, Sacher DB. Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 2004;99:1371-85.

16. Gionchetti et al. Comparison of oral with rectal mesalazine in the treatment of ulcerative proctitis. Dis Colon Rectum 1998;41:93-7.

17. Safdi et al. A double-blind comparison of oral vs. rectal mesalamine vs. combination therapy in the treatment of distal ulcerative colitis. Am J Gastroenterol 1997;92(10):1867-71.

18. Truelove SC, Watkinson G, Draper G. Comparison of corticosteroid and sulphasalazine therapy in ulcerative colitis. Br Med J 1962;2:1708-11.

19. Lichtenstein et al. American Gastroenterological As sociat ion Ins t i tute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006;130:940-87.

20. Kusunoki et al. Steroid complications in patients with ulcerative colitis. Dis Colon Rectum 1992;35(10):1003-9.

21. Esteve M, Gisbert GP. Severe ulcerative colitis: at what point should we define resistance to steroids? World J Gastroenterol 2008;14(36):5504-7.

22. Lennard-Jones et al. Prednisone as maintenance treatment for ulcerative colitis in remission. Lancet 1965;285(7378):188-9.

23. Panaccione et al. Review article: treatment algorithms to maximize remission and minimize corticosteroid dependence in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2008;28:674-88.

24. Hawthorne et al. Randomized controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ 1992;305:20-2.

25. Järnerot et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology 2005;128:1805-11.

26. Rutgeerts et al. Infliximab for induction and maintenance therapy in ulcerative colitis. N Engl J Med 2005;353:2462-76.

27. Sandborn et al. Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab. Gastroenterology 2009;137:1250-60.

28. Ardizonne et al. Randomized controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid-dependent ulcerative colitis. Gut 2006;55:47-53.

29. Hoie et al. Low colectomy rates in ulcerative colitis in an unselected European cohort followed for 10 years. Gastroenterology 2007;132:507-15.

30. Rutter et al. Cancer surveillance in longstanding ulcerative colitis: endoscopic appearances help predict cancer risk. Gut 2004;53:1813-6.

31. Seow et al. Trough serum infliximab: a predictive factor of clinical outcome for infliximab therapy in corticosteroid-refractory acute ulcerative colitis. Gut 2009;59:20-34.

32. Hanauer SB. Review article: safety of infliximab in clinical trials. Aliment Pharmacol Ther 1999;13 (suppl 4):16-22.

33. Lichtenstein et al. Serious infections and mortality in association with therapies for Crohn’s disease: TREAT registry. Clin Gastroenterol Hepatol 2006;4:621-30.

ACCELERATED STEP CARE IN CROHN’S DISEASE: WHO AND WHY TO TREAT EARLIER

Editorial Review:

Brian Bressler, MD, MSc, FRCPC

Clinical Associate Professor, Department of Gastroenterology, University of British Columbia, Vancouver, British Columbia

After onset, Crohn’s disease (CD) in most individuals is a progressive and lifelong disorder. Although the course is variable, approximately 75% of patients will eventually require one or more surgeries.¹ While it most commonly involves the proximal colon and distal small bowel, CD can occur at any point along the digestive tract. The cause is multifactorial and not entirely understood, but once the inflammatory process is initiated the natural history of this disease typically involves repeated flares, each increasing the risk of strictures, fistulas and the need for bowel resection.

Predicting disease severity is important when selecting therapies that vary widely by efficacy, relative tolerability, risk of adverse events, cost and other factors relevant to therapeutic choices. In the past, a delayed step-up approach has been employed to reserve the most effective therapies for refractory patients.² However, the sequence of therapies is being reconsidered based on concerns that even therapies effective at controlling symptoms may not be offering adequate control of the disease process. A large amount of evidence has accumulated, showing that an accelerated step-up approach is the optimal way to treat CD.

Although steroids and immunomodulators are effective for symptom control, they are less reliable than biologics to induce and sustain mucosal healing in moderate to severe disease. Complete mucosal healing is thought to be our best indicator for altering the natural history of CD. In an acute flare, the initial goal beyond symptom control is healing of the mucosa, which appears to confer some protection against future relapse. The goal of maintenance therapy is to prevent the inflammatory relapses leading to strictures, fistulas and the need for surgery. Early use of biologics in the treatment of CD is based on their potential to alter the natural history of its progression. Not all CD patients are candidates for biologics, but the previously advocated step-up therapeutic approach for all patients may delay the opportunity for disease control and increase the risk of long-term adverse outcomes in the substantial proportion of patients who are likely to progress.

Evaluating Immunomodulator Use in CD

The use of immunomodulators—azathioprine (AZA) or methotrexate (MTX)—has been increasing over several decades with the goal of improving control of CD, but the increasing reliance on these medications has not been accompanied by a reduction in surgery, which is one of the most significant CD complications (Figure 1).³ The limitations of the efficacy of immunomodulators have been particularly pronounced in studies comparing these agents to biologics. In one of the most ambitious and well controlled studies, two distinct groups of steroid-dependent patients were randomized to receive three induction doses of the TNF-a inhibitor infliximab plus AZA or placebo plus AZA.⁴ One group had previously been treated with AZA and 6-mercaptopurine (6-MP) and were considered AZA/6-MP failures. The other group was naive to AZA/6-MP. At week 24, the proportion of patients in steroid-free remission was greater on the TNF-a inhibitor not only in those who had previously failed immunomodulators but also in those who were naive to AZA/6-MP (Figure 2). Due to the limitations of AZA in this and other studies, one consensus group has suggested that this agent should be replaced by a biologic if disease control has not been achieved within 12 to 16 weeks.⁵

Figure 1. Neutral Impact of Immunomodulator Use on Need for Intestinal Resection

Figure 2. Steroid-free Remission Rates in Those Naive to AZA or Who Had Failed AZA

In the landmark Step Up/Top Down (SUTD) study, two strategies were compared in CD patients who had not previously received steroids or a biologic.⁶ One group received three infusions of the biologic plus AZA, followed, if needed, by additional infliximal (IFX) and steroids. The other group was initiated on steroids; after a second flare requiring steroids, AZA was started and then the TNF-a inhibitor if needed to control disease. The early advantage of the top-down approach over initiating treatment with corticosteroids was substantial. The number of patients in sustained remission by the trial definition was almost twice as high at both 26 weeks (60% vs. 35.9%; P<0.006) and 52 weeks (61.5% vs. 42.2%; P<0.0278) in the topdown group (Figure 3). When patients were followed for up to 104 weeks, IFX exposure in the step-up group approached that of the top-down group, indicating that most patients required biologics for acceptable control and remission rates between the two groups were then similar.

Figure 3. SUTD: Patients in Remission

There was substantially less corticosteroid use in the top-down group. The ultimate rates of exposure to a biologic were similar over the course of the study. Although this study was not primarily designed to compare the safety of the two approaches, the rate and types of adverse events were similar in the two groups.

A SUTD endoscopic substudy in 49 patients demonstrated an absence of ulcers in 73.1% of the top-down group vs. 30.4% of the stepup group (P=0.0028) at week 104 (Figure 4).⁶ This difference supports the notion that the selection of the initial induction agent has potential long-term consequences.

Figure 4. SUTD: Endoscopic Substudy at Week 104—Absence of Ulcers

The advantage of early use of biologics is attributed to a greater likelihood of achieving and then sustaining mucosal healing. The importance of complete mucosal healing was suggested by the endoscopic SUTD substudy which demonstrated that complete mucosal healing at two years was a strong predictor of sustained disease control.⁷ In patients with complete mucosal healing, there were statistically significant advantages at year 3 and 4 for remission off steroids and development of fistulas.

In the ACCENT trial, which randomized patients to one of two infliximab regimens or placebo, mucosal healing was a predictor of a reduced risk of hospitalization over longterm follow-up regardless of treatment.⁸ The hypotheses generated by these results are that mucosal healing provides a greater relative barrier to relapse than absence of symptoms alone and that effective early treatment may also contribute to better long-term outcomes by reducing the risk of irreversible damage.

As a result of the evidence that early mucosal healing improves long-term outcome, this end point has become increasingly important for comparing treatment strategies. Again, biologics have consistently demonstrated an advantage over immunomodulators for the goal of healing. In the SONIC study, a double-blind, controlled trial comparing IFX, IFX plus AZA, or AZA in patients naive to both immunomodulators and biologic therapy, complete mucosal healing was assessed as a secondary end point (the primary end point was steroid-free remission).⁹ At 26 weeks, IFX increased the absolute rate of healing the mucosa compared to AZA alone by 14% (30% vs. 16%; P=0.023). The combination group of AZA/IFX provided the highest rate of mucosal healing (44%).

Figure 5. Time-structured Treatment Algorithm for Moderate CD

Who to Treat to Maximize Outcomes

As one would anticipate, the best rate of steroid-free remission for all groups in the SONIC study occurred in those patients with evidence of a significant inflammatory burden. Data collected at week 50 showed a particularly large advantage of IFXwith or without AZA over AZA plus placebo in the subgroup of patients with lesions and a high degree of inflammatory activity at baseline (determined by a C-reactive protein of =8 mg/L) (Figure 6).

Figure 6. SONIC: Steroid-free Remission at Week 50 in Patients with Increased Inflammatory Burden

Selecting CD patients with the greatest risk of progression is an inexact process, but there are several studies that have identified useful prognostic variables. In a study designed to identify risk factors for disabling disease, 1233 patients diagnosed with CD at a single institution over a 13-year period were evaluated.10 Patients who required surgery within the first month of diagnosis were excluded. The factors associated with disabling disease were the initial requirement for steroid use, which increased risk by about threefold; age below 40 at diagnosis, which doubled the risk; and the presence of perianal disease, which also almost doubled the risk (Table 1). These factors were additive so that two risk factors increased the likelihood of disabling disease relative to a single factor and three risk factors were more predictive than two.

Table 1. Independent Predictors of a Disabling CD Course Five Years’ Post-Diagnosis

The conventional delayed step-up strategy in those with a high likelihood of progression may have adverse repercussions on long-term outcome as a result of incomplete mucosal healing and an increased risk of relapse leading to complications. Based on these most recent data, the controversy in the management of CD is less directed at whether accelerated step-care is best for patients, but how best to select patients for optimal outcomes.

Summary

The potential of anti-TNF inhibitors to alter the natural history of progressive CD has major implications for preventing or reducing the risk of the most serious complications of this disease, including strictures and fistulas. Although the underlying mechanisms of CD are poorly understood, there is substantial evidence of a vicious cycle that correlates with the risk of complications with repeated flares. The evidence that initial complete mucosal healing predicts sustained complete mucosal healing provides a rationale for early use of the most effective therapies. Not all patients with CD can anticipate a complicated course, but identifying those with poor prognostic features and a high risk of relapse is an important step in efficiently evaluating and escalating therapies to provide the best short- and long-term management of their disease.

References

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