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 remis-
`sion. defined as the absence of inflammatory symptoms
`(diarrhoea, bleeding, rectal urgency) and the mainten-
`ance of an intact mucosa, with the absence of ulcers.
`friability or significant granularity at endoscopy.The
``optimal' maintenance strategy will depend on the
`therapy needed to induce remission. Thus, the trans-
`ition 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 symp-
`toms. 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 immuno-
`modulation 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. preven-
`tion 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.' 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 'remission'. 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
``regeneration' of an intact mucosa without ulcers,
`granularity or significant friability. Although histolog-
`ical 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 improve-
`ment 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.
`
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`98 S. B. HANAUER
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`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 (azathiop-
`rine 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 'withdrawing' 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 main-
`tenance 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 ulcer-
`ative colitis has been compromised by dose-related side-
`effects. Therefore, optimal dosing may not be possible in
`patients with nausea, headache, arthralgia or sulpha-
`related 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 sulfasal-
`azine.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 mWday (com-
`parable with 2 g of sulfasalazine) vs. placebo.1° Both
`doses of mesalazine were superior to placebo, but the
`study was not 'powered' 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 dose-
`related toxicity.". 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." 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." 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 main-
`tenance 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 aminosali-
`cylate therapy for ulcerative colitis is the expanding
`evidence in favour of chemoprevention against the
`development of dysplasia and colorectal cancer."' 16
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`REVIEW: MAINTENANCE THERAPY IN ULCERATIVE COLITIS 99
`
`The absolute risk reduction with aminosalicylate ther-
`apy 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 cohort17 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 aminosal-
`icylate as maintenance therapy. As previously dis-
`cussed, 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 Wday of mesalazine to achieve remis-
`sion. 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 steroid-
`dependent ulcerative colitis. A second indication for their
`use is following ciclosporin induction therapy.22. 23
`However, the dose and duration of therapy have yet to
`be investigated and the requisite for concurrent amino-
`salicylate treatment has not been established.
`Controlled clinical trials by the Oxford Group demon-
`strated 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 main-
`tained remission on azathioprine vs. 40% of pati-
`ents randomized to placebo: P < 0.01).25 A similar
`
`proportion of patients (60-70%) have maintained
`remission in uncontrolled series from New York,21
`Italy26 and the UK.27
`Recent studies have also demonstrated the additional
`benefit of azathioprine or mercaptopurine in maintain-
`ing remissions for patients after ciclosporin induction
`therapy.22' 23 Consistent results from both North Amer-
`ica 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 cigar-
`ette 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 'pseudo-
`refractory' 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 intoler-
`ance.29' 3° These factors need to be considered prior to
`defining a patient as being 'refractory' 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
`
`© 2004 Blackwell Publishing Ltd. Aliment Pharmacol 7'her 20 (Suppl. 4). 97-101
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`100 S. B. HANAUER
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`of cigarette smoking (between 5 and 10 cigarettes per
`day), which have not been demonstrated to have
`significant health risks. Finally, although many clini-
`cians are reluctant to recommend surgery for patients
`with 'only distal colitis', 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 aminosali-
`cylate, 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 adher-
`ence (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 'high-dose' 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 individual-
`ized 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 remis-
`sion, 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 aminosal-
`icylate 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.
`
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