Review article: the long-term management of ulcerative colitis

Aliment Pharmacol Ther 2004; 20 (Suppl. 4): 97 101. Review article: the long-term management of ulcerative colitis S. B. HANAUER Section of Gastroenterology, University of Chicago, Chicago, IL, USA SUMMARY After the induction of remission, the second priority of therapy for ulcerative colitis is sustained clinical remission, defined as the absence of inflammatory symptoms (diarrhoea, bleeding, rectal urgency) and the maintenance of an intact mucosa, with the absence of ulcers, friability or significant granularity at endoscopy.the ÔoptimalÕ maintenance strategy will depend on the therapy needed to induce remission. Thus, the transition from induction to maintenance therapy will be determined by the intensity of acute therapy necessary to induce remission and the duration of therapy required to complete the resolution of clinical symptoms. There are few controlled clinical trials pertaining to maintenance after each induction regimen. However, experience dictates that aminosalicylates are efficacious after aminosalicylate-induced remissions, that steroids should be tapered according to the time required to induce remission, that patients requiring ciclosporin will benefit from the addition of long-term immunomodulation with azathioprine or mercaptopurine, and that many patients with distal colitis who require topical mesalazine (mesalamine) will continue to need topical therapy to maintain remission, albeit at reduced frequency.the expectations for maintenance therapy require patient adherence to the prescribed treatment regimen. Patients require education with regard to the long-term goals of maintenance therapy (e.g. prevention of relapse, reduction of long-term complications of disease activity or risks of acute therapy with steroids), and should be warned against the use of nonsteroidal anti-inflammatory drugs and cautioned about the cessation of smoking, when applicable, due to potential risks of relapse or chronic activity. INTRODUCTION Ulcerative colitis is a chronic, medically incurable, but maintainable, condition. At any point in time, over 50% of a patient population with ulcerative colitis will be in medical remission. 1 The goals of maintenance therapy are, first and foremost, to maintain remission, but also to sustain the quality of life for patients, prevent complications of long-term disease activity or medical therapy and, when necessary in a minority of patients, to optimize the timing of surgical intervention. Despite many years of research and clinical trials in ulcerative colitis, there has yet to be a standardized Correspondence to: Professor S. B. Hanauer, University of Chicago, Section of Gastroenterology, 5758 South Maryland Avenue MC 9028, DCAM Room 6601, Chicago, IL 60637, USA. E-mail: shanauer@medicine.bsd.uchicago.edu definition of ÔremissionÕ. A working definition according to the Food and Drug Administration draft guidelines includes: the absence of inflammatory symptoms (inflammatory diarrhoea, bleeding, rectal urgency or the passage of mucopus). 2 This also includes the exclusion of patients with irritable bowel symptoms. The definition also requires endoscopic evidence of the ÔregenerationÕ of an intact mucosa without ulcers, granularity or significant friability. Although histological findings are not typically used in clinical practice, a clinical trial, or regulatory definition of histological remission, would include the absence of crypt abscesses. In observational studies, such pathological improvement has been associated with improved outcomes (e.g. reduced risk of clinical relapse). 3 An important clinical symptom of remission in ulcerative colitis is the ability to pass gas (flatus) without requiring the use of a toilet. Ó 2004 Blackwell Publishing Ltd 97

98 S. B. HANAUER This ability assumes that the rectum has regained its normal compliance, and can be a useful clinical tool in assessing patient responses. To date, only two classes of medication have been demonstrated to prevent relapse in ulcerative colitis: the aminosalicylates and purine antimetabolites (azathioprine and mercaptopurine). 4 There is some clinical trial experience with probiotics and clinical experience with nicotine replacement or resumption of smoking, which may also provide a role in the maintenance of remission in ulcerative colitis. When considering these therapeutic options, the therapy used to induce remission, the response of patients to previous treatments and their history of relapse and adherence, duration of remission and the extent of mucosal disease are important factors. 5 However, the most important consideration prior to initiating maintenance therapy for ulcerative colitis is that the patient completed induction therapy before ÔwithdrawingÕ to maintenance treatment. Failure to complete the induction of remission will ensure the failure of maintenance therapy. 6 A final consideration is the distinction between steroid dependence and maintenance therapy. Steroid dependence implies the failure of an individual patient to taper off steroids without disease recurrence. In contrast, maintenance therapy pertains to a population of patients for whom therapy prevents relapse. 6 AMINOSALICYLATES Sulfasalazine has been used for nearly 40 years as maintenance therapy for ulcerative colitis. Cochrane analyses have demonstrated that sulfasalazine can prevent the relapse of ulcerative colitis in 65 80% of patients, is more effective than olsalazine or mesalazine (mesalamine) and is associated with a dose response. 7 However, the dose response for sulfasalazine in ulcerative colitis has been compromised by dose-related sideeffects. Therefore, optimal dosing may not be possible in patients with nausea, headache, arthralgia or sulpharelated hypersensitivity. In contrast with the documented dose response for sulfasalazine as a maintenance agent in ulcerative colitis, there are fewer available studies assessing the dose response for mesalazine formulations. Most of the mesalazine formulations have been compared with sulfasalazine and, in individual trials, there have been numerical, but not statistical, differences in favour of sulfasalazine. 7, 8 However, one trial with Pentasa demonstrated a nonstatistically significant advantage for the mesalazine formulation compared with sulfasalazine. 9 The only placebo-controlled, dose-ranging trial of mesalazine as maintenance therapy for ulcerative colitis compared Asacol at 1.6 g day (comparable with 4 g of sulfasalazine) with Asacol at 800 mg day (comparable with 2 g of sulfasalazine) vs. placebo. 10 Both doses of mesalazine were superior to placebo, but the study was not ÔpoweredÕ to assess differences between the active dosing. Trials of higher doses of mesalazine have not, as yet, been performed. Likewise, trials have not been undertaken to examine the dosing required in patients who need more than 2.4 g of Asacol or 4 g of Pentasa to achieve remission. In contrast with clinical trial data, there is extensive experience with the clinical utility of mesalazine as maintenance therapy for ulcerative colitis. Unlike sulfasalazine, mesalazine can be used safely in doses up to 4.8 g daily without doserelated toxicity. 11, 12 Our approach at the University of Chicago is to continue for maintenance therapy the mesalazine dose that induced remission. Topical (rectal) mesalazine can also be used as maintenance therapy for patients with distal ulcerative colitis. 13 In this setting, there does not appear to be a dose response above doses of 1 g nightly for topical therapy; however, the dose frequency is more relevant in this setting than daily dosing. Although daily (nightly) therapy is more effective than treatment every other or every third night, approximately 60% of patients can be maintained with the application of topical mesalazine every third night. 13 In addition, a combination of oral and topical mesalazine has been utilized and is more efficacious than oral mesalazine alone. 14 Mesalazine maintenance therapy for ulcerative colitis can therefore be used effectively at doses of up to 4.8 g daily without increasing toxicity or adverse events. When topical (rectal) mesalazine is employed as maintenance therapy, the dose frequency is more relevant than topical dosing, although up to 4 g nightly can be utilized without dose-related side-effects. In clinical practice for refractory patients, combination therapy with 4.8 g of oral mesalazine and 4 g enema therapy has been used without identifiable long-term side-effects (personal experience). A recently identified, additional benefit of aminosalicylate therapy for ulcerative colitis is the expanding evidence in favour of chemoprevention against the 15, 16 development of dysplasia and colorectal cancer.

REVIEW: MAINTENANCE THERAPY IN ULCERATIVE COLITIS 99 The absolute risk reduction with aminosalicylate therapy ranges from 1.6% at 10 years after diagnosis to 14.6% after 30 years. The number needed to treat to avoid one case of colorectal cancer after 30 years of ulcerative colitis in a Danish cohort 17 equals seven. 18 There also appears to be a dose response above 2 g of sulfasalazine or 1.2 g of mesalazine daily. Despite the evidence stated above, a number of controversies remain regarding the utility of aminosalicylate as maintenance therapy. As previously discussed, a dose response for mesalazine maintenance therapy has yet to be established and, in particular, for the expanding subgroup of patients who require doses greater than 2.4 g day of mesalazine to achieve remission. Similarly, to date, there is no clinical trial evidence to support the role of mesalazine after steroid-induced remission in ulcerative colitis. A recent trial comparing 2.4 g mesalazine daily with a probiotic did not identify maintenance benefit for mesalazine compared with the Nissle strain of Escherichia coli. 19 Finally, adherence to maintenance therapy is an important consideration for long-term benefits, as patients who continue to adhere have a far superior prognosis than patients who discontinue maintenance therapy. 20 IMMUNOMODULATORS The purine antimetabolites have been evaluated in clinical trials and in clinical series as maintenance therapies for ulcerative colitis. 4, 21 To date, their benefit has been primarily explored in patients with steroiddependent ulcerative colitis. A second indication for their 22, 23 use is following ciclosporin induction therapy. However, the dose and duration of therapy have yet to be investigated and the requisite for concurrent aminosalicylate treatment has not been established. Controlled clinical trials by the Oxford Group demonstrated a numerical, but not statistical, benefit for azathioprine (at a dose of 2.5 mg kg) compared with placebo at maintaining remission in ulcerative colitis. 24 The most compelling data, however, come from a double-blind withdrawal trial enrolling patients who required azathioprine to achieve remission. In patients who continued on azathioprine maintenance therapy (together with an aminosalicylate), remissions were prolonged when compared with patients who were randomized to placebo therapy (64% of patients maintained remission on azathioprine vs. 40% of patients randomized to placebo; P < 0.01). 25 A similar proportion of patients (60 70%) have maintained remission in uncontrolled series from New York, 21 Italy 26 and the UK. 27 Recent studies have also demonstrated the additional benefit of azathioprine or mercaptopurine in maintaining remissions for patients after ciclosporin induction therapy. 22, 23 Consistent results from both North America and Europe have demonstrated that over two-thirds of patients who achieve remission with ciclosporin are able to maintain remission with purine antimetabolite therapy. NICOTINE Nicotine therapy has had modest benefits for patients with ulcerative colitis, but has failed to demonstrate significant maintenance effects. 28 In contrast, and without controlled trial evidence, resumption of cigarette smoking has been of clinical benefit for patients with ulcerative colitis who developed colitis after smoking cessation (personal observations). The risk and benefit, as well as any dose response for cigarette smoking, need to be established. MAINTENANCE IN REFRACTORY COLITIS The assessment of maintenance therapies for ulcerative colitis requires adequate therapeutic dosing, duration of therapy and delivery system. In addition, as mentioned above, the distinction between steroid dependence and steroid maintenance therapy needs to be clarified. There are also a number of factors that lead to a ÔpseudorefractoryÕ state. These include patients with concurrent irritable bowel syndrome symptoms, women with variations in their bowel symptoms associated with the menstrual cycle, poor adherence to medical therapy, concurrent use of nonsteroidal anti-inflammatory drugs and rare individuals with aminosalicylate intolerance. 29, 30 These factors need to be considered prior to defining a patient as being ÔrefractoryÕ to medical maintenance therapy. The options for maintaining remission in patients with refractory colitis are different for patients with distal and extensive disease. For patients with distal ulcerative colitis, the most effective maintenance therapy is the continuation of topical mesalazine treatment. 13 In addition, a purine antimetabolite may be added, but requires 3 6 months for the optimization of benefit. Patients who are ex-smokers may also resume low doses

100 S. B. HANAUER of cigarette smoking (between 5 and 10 cigarettes per day), which have not been demonstrated to have significant health risks. Finally, although many clinicians are reluctant to recommend surgery for patients with Ôonly distal colitisõ, it should be emphasized that the indication for colectomy in ulcerative colitis is not dependent only on the extent of disease. For patients with extensive colitis who are refractory to maintenance therapy, higher doses of aminosalicylate (up to 4.8 g) can be administered without dose-related toxicity. In addition, the purine antimetabolites have been successful at maintaining remission and, as described above, ex-smokers can resume smoking between 5 and 10 cigarettes per day. For truly refractory patients, colectomy is advocated. Before deciding whether a patient is refractory to aminosalicylate, consideration should be made for the rare patient with aminosalicylate intolerance. Therefore, before deliberation of surgery, a trial without aminosalicylate treatment may be attempted if a patient has not demonstrated the ability to maintain remission with aminosalicylate therapy alone. Finally, lack of adherence (compliance) should be considered for patients with unexpected relapse; in particular, males with a short duration of remission have been found to be less compliant than other groups of patients. CONCLUSIONS Corticosteroids are ineffective as maintenance therapy for ulcerative colitis, and the distinction between steroid dependence and maintenance benefit needs to be understood. Aminosalicylates are the foundational maintenance therapy for ulcerative colitis and, in patients requiring Ôhigh-doseÕ aminosalicylate therapy to induce remission, maintenance at the same dose can be continued without dose-related toxicity. Patients requiring topical mesalazine to achieve remission will often require maintenance therapy with topical dosing. The benefits of aminosalicylates, although typically used in clinical practice, have not been established after steroid-induced remission. In the latter group of patients, the purine antimetabolites are more likely to be effective. Maintenance therapy should be individualized for patients according to their previous response to treatment and history of relapse and adherence, the inductive therapy used to achieve remission and the mucosal extent of disease. The induction of remission should be established before initiating maintenance treatment. Steroid tapering will need to be tailored according to individual responses to treatment and, for patients requiring topical mesalazine to achieve remission, steroids should be tapered before consideration of the tapering of mesalazine treatment. Ultimately, a sequential strategy is a useful long-term approach in patients with ulcerative colitis. Patients requiring oral aminosalicylates to induce remission can continue on the same dose to prevent relapse. Patients requiring rectal mesalazine to achieve remission will typically require topical maintenance therapy, although a transition to oral treatment may be attempted. After corticosteroid induction therapy, attempts at aminosalicylate maintenance therapy have been the standard approach in clinical practice, although many patients may require a purine antimetabolite with or without aminosalicylate maintenance. Purine antimetabolites are also a standard addition to aminosalicylates after ciclosporin induction. Finally, as ex-smokers are the most refractory group of patients, the consideration of resumption of low-dose cigarette smoking may be necessary in ex-smokers with refractory disease. REFERENCES 1 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. 2 Fredd S. Standards for Approval of New Drugs for IBD. Inflamm Bowel Dis 1995; 1(4): 284 94. 3 Riley SA, Mani V, Goodman MJ, Dutt S, Herd ME. Microscopic activity in ulcerative colitis: what does it mean? Gut 1991; 32(2): 174 8. 4 Kamm MA. Review article: maintenance of remission in ulcerative colitis. Aliment Pharmacol Ther 2002; 16(Suppl. 4): 21 4. 5 Ardizzone S, Petrillo M, Imbesi V, Cerutti R, Bollani S, Bianchi Porro G. Is maintenance therapy always necessary for patients with ulcerative colitis in remission? Aliment Pharmacol Ther 1999; 13(3): 373 9. 6 Hanauer SB. Inflammatory bowel disease. N Engl J Med 1996; 334(13): 841 8. 7 Sutherland L, Roth D, Beck P, May G, Makiyama K. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2002; 4: CD000544. 8 Gisbert JP, Gomollon F, Mate J, Pajares JM. Role of 5-aminosalicylic acid (5-ASA) in treatment of inflammatory bowel disease: a systematic review. Dig Dis Sci 2002; 47(3): 471 88. 9 Mulder CJ, Tytgat GN, Weterman IT, et al. Double-blind comparison of slow-release 5-aminosalicylate and sulfasalazine in remission maintenance in ulcerative colitis. Gastroenterology 1998; 95(6): 1449 53.

REVIEW: MAINTENANCE THERAPY IN ULCERATIVE COLITIS 101 10 The Mesalamine Study Group. An oral preparation of mesalamine as long-term maintenance therapy for ulcerative colitis. A randomized, placebo-controlled trial. Ann Intern Med 1996; 124(2): 204 11. 11 Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults. American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 1997; 92(2): 204 11. 12 Hanauer SB. Aminosalicylate therapy for ulcerative colitis. In: Bayless TM, Hanauer SB, eds. Advanced Therapy of Inflammatory Bowel Disease. Hamilton, Ont.: B.C. Decker Inc, 2001: 123 6. 13 Cohen RD, Woseth DM, Thisted RA, Hanauer SB. A metaanalysis and overview of the literature on treatment options for left-sided ulcerative colitis and ulcerative proctitis. Am J Gastroenterol 2000; 95(5): 1263 76. 14 d Albasio G, Pacini F, Camarri E, et al. Combined therapy with 5-aminosalicylic acid tablets and enemas for maintaining remission in ulcerative colitis: a randomized, double-blind study. Am J Gastroenterol 1997; 92(7): 1143 7. 15 Eaden J. Review article: the data supporting a role for aminosalicylates in the chemoprevention of colorectal cancer in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2003; 18(Suppl. 2): 15 21. 16 Allgayer H. Review article: mechanisms of action of mesalazine in preventing colorectal carcinoma in inflammatory bowel disease. Aliment Pharmacol Ther 2003; 18(Suppl. 2): 10 4. 17 Langholz E, Munkhom P, Davidsen M, et al. Colorectal cancer risk and mortality in patients with ulcerative colitis. Gastroenterology 1992; 103: 1444 51. 18 Munkholm P. Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease. Aliment Pharmacol Ther 2003; 18(Suppl. 2): 1 5. 19 Rembacken BJ, Snelling AM, Hawkey PM, Chalmers DM, Axon AT. Non-pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomised trial. Lancet 1999; 354(9179): 635 9. 20 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. 21 George J, Present DH, Pou R, Bodian C, Rubin PH. The longterm outcome of ulcerative colitis treated with 6-mercaptopurine. Am J Gastroenterol 1996; 91(9): 1711 4. 22 Actis GC, Bresso F, Astegiano M, et al. Safety and efficacy of azathioprine in the maintenance of ciclosporin-induced remission of ulcerative colitis. Aliment Pharmacol Ther 2001; 15(9): 1307 11. 23 Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporin in ulcerative colitis: a five-year experience. Am J Gastroenterol 1999; 94(6): 1587 92. 24 Jewell DP, Truelove SC. Azathioprine in ulcerative colitis: final report on controlled therapeutic trial. Br Med J 1974; 4(5945): 627 30. 25 Hawthorne AB, Logan RF, Hawkey CJ, et al. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. Br Med J 1992; 305(6844): 20 2. 26 Ardizzone S, Molteni P, Imbesi V, Bollani S, Bianchi Porro G, Molteni F. Azathioprine in steroid-resistant and steroiddependent ulcerative colitis. J Clin Gastroenterol 1997; 25(1): 330 3. 27 Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut 2002; 50(4): 485 9. 28 Thomas GAJ, Rhodes J, Mani V, et al. Transdermal nicotine as maintenance therapy for ulcerative colitis. N Engl J Med 1995; 332(15): 988 92. 29 Miner PB Jr. Factors influencing the relapse of patients with inflammatory bowel disease. Am J Gastroenterol 1997; 92(12 Suppl.): 1S 4S. 30 Gelbmann CM. Prediction of treatment refractoriness in ulcerative colitis and Crohn s disease do we have reliable markers? Inflamm Bowel Dis 2000; 6(2): 123 31.