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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. 5-Aminosalicylic acid (5-asa or mesalazine) compounds
  5. Azathioprine and 6-mercaptopurine (6-mp)
  6. Maintaining remission after a severe episode of colitis controlled with cyclosporin
  7. Maintaining remission by altering the gut bacterial environment – probiotics
  8. Conclusion
  9. References

Seventy percent of patients with ulcerative colitis can expect to experience a relapse over a 12 month period. Sulfasalazine was the first drug demonstrated to reduce this relapse rate to 21 percent. Subsequent studies have demonstrated that 5-aminosalicylic acid (5-ASA) is the main active component, and preparations containing only 5-ASA have similar efficacy to sulfasalazine. 5-ASA is readily absorbed from the small intestine; to achieve high a colonic lumenal concentration therefore requires special release formulation. A variety of 5-ASA preparations is available, differing in their release mechanism, efficacy and side effect profile. Most patients can be maintained in remission using oral 5-ASA medication. For patients with distal or left sided disease the use of rectal 5-ASA is also of proven benefit in maintaining remission. Some patients with frequent or severe relapses require stronger immunosuppression, and in these patients azathioprine or 6-mercaptopurine (6-MP) are of proven benefit. Azathioprine is also invaluable for maintaining remission in patients who have been treated with cyclosporin for a fulminant acute episode of colitis. The exciting spectre of natural bacterial therapies (probiotics) deserves further exploration.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. 5-Aminosalicylic acid (5-asa or mesalazine) compounds
  5. Azathioprine and 6-mercaptopurine (6-mp)
  6. Maintaining remission after a severe episode of colitis controlled with cyclosporin
  7. Maintaining remission by altering the gut bacterial environment – probiotics
  8. Conclusion
  9. References

Once an acute episode of ulcerative colitis has resolved, the challenge is to maintain well being. Seventy per cent of patients given no treatment can expect to experience a relapse over a 12-month period.1 Patients who have not relapsed for several years appear to be at decreased risk than those who have had a relapse during the previous 12 months.

Patients who experience flare ups only every few years probably do not require maintenance medication, unless the flare ups are severe and difficult to control. When medications are used to maintain remission they can be considered in terms of their efficacy and potential toxicity. The hierarchy begins with 5-aminosalycyclic acid compounds and is followed by azathioprine. Alternative approaches to immunosuppression may involve the prevention of bacterial mucosal shifts, which are likely to be responsible for the flare-up of disease. Such an approach may involve the use of concentrated preparations of ‘favourable’ bacteria (probiotics).

5-Aminosalicylic acid (5-asa or mesalazine) compounds

  1. Top of page
  2. Summary
  3. Introduction
  4. 5-Aminosalicylic acid (5-asa or mesalazine) compounds
  5. Azathioprine and 6-mercaptopurine (6-mp)
  6. Maintaining remission after a severe episode of colitis controlled with cyclosporin
  7. Maintaining remission by altering the gut bacterial environment – probiotics
  8. Conclusion
  9. References

Oral formulations

The original definitive study which established the value of 5-aminosalicyclic acid in preventing relapse was published by Misiewicz and colleagues in 1965.1 In this first placebo-controlled maintenance trial, patients were randomised to receive sulfasalazine or placebo for one year. Seventy-three per cent of patients taking the placebo relapsed during that time, compared to 21% taking the active drug.

The benefit from sulfasalazine was subsequently shown to persist regardless of how long a patient had already been taking it.

The Oxford group demonstrated a dose–response relationship, in that higher doses of sulfasalazine appeared to be more protective, although the differences that were demonstrated between 2 and 4 g/day were not significant.2

The Oxford group also showed that the active moiety in sulfasalazine was the 5-aminosalicyclic acid, rather than the sulphur component,3 which was also found to be responsible for many of the side-effects of sulfasalazine, such as headaches, rash, gastrointestinal effects (especially nausea), and male infertility. Side-effects were experienced by about 20% of patients taking this drug. This led to the development of a new generation of 5-aminosalicylic acid drugs which did not contain sulphur.

Because 5-aminosalicylic acid is readily absorbed from the upper gastrointestinal tract, and because it works via a luminal mechanism, it needed to be formulated in a preparation allowing it to be delivered intact to the large bowel. Subsequent formulations included coating the 5-ASA with a pH sensitive coating (Eudragit) that would allow mesalazine (5-aminosalicyclic acid) to be liberated in the mid and distal small bowel at a pH of 6 or more (Claversal or Salofalk) or in the terminal ileum at a pH 7 or more (Asacol). An alternative approach involved substituting the sulphonamide part of the sulfasalazine molecule with either an inert carrier molecule (balsalazide, Colazide) or another 5-ASA molecule (olsalazine, Dipentum), with the azo bond still broken to release the active drug by bacteria in the proximal colon. A third approach involved formulating the 5-ASA in ethylcellulose microgranules which are liberated progressively through the small bowel and colon (mesalazine, Pentasa). Each of these drugs has a different profile with regard to release, potential side-effects, and concentration in different parts of the intestine.

Numerous subsequent studies have demonstrated a similar therapeutic efficacy in maintaining remission in ulcerative colitis for sulphasalzine and the range of newer 5-ASA preparations. Sutherland et al. have recently undertaken a systematic review of all the double-blind randomised controlled studies of the 5-ASA containing drugs, conducted between 1981 and 1998, for this indication.4 5-aminosalycylic acid was superior to placebo in reducing the chance of relapse. There appeared to be a marginal superiority of sulfasalazine over newer 5-SASA drugs.

Although each of the mesalazine preparations is superior to placebo in maintaining remission, there may be differences in efficacy between these preparations.

For patient convenience and compliance, twice daily dosing is probably optimal to maintain remission. It may be that once daily dosing would also be effective, but there are too few data to be certain about this. A dose of 1 g twice per day appears to be an effective compromise which decreases relapse rate while not producing too many side-effects. Higher doses can be employed if a patient still experiences frequent relapses.

Rectal preparations

Rectal preparations of mesalazine have been shown to be effective in acute episodes of colitis, and in maintaining remission. Marshall & Irvine undertook a meta-analysis of five controlled trials comparing rectal mesalazine with placebo in maintaining remission for distal colitis.5 There was a clear superiority of mesalazine over placebo.

Maintenance of remission has usually involved the daily use of medication. However, given the unpleasantness and inconvenience of using rectal preparations each day or night, it may be possible to maintain remission using less frequent administration. Slow release 1 g mesalazine suppositories used three times per week were compared with placebo in maintaining remission in patients with proctitis.6 Patients were treated for 1 year. If they experienced a flare up they used their suppositories each night, and then reverted to three times per week when the condition had settled. The relapse rate was lower in the mesalazine group for the first three quarters of the year, but not at 1 year. However, 61% of patients on mesalazine, and 28% of patients on placebo remained in the protocol and were in remission at 1 year.

Azathioprine and 6-mercaptopurine (6-mp)

  1. Top of page
  2. Summary
  3. Introduction
  4. 5-Aminosalicylic acid (5-asa or mesalazine) compounds
  5. Azathioprine and 6-mercaptopurine (6-mp)
  6. Maintaining remission after a severe episode of colitis controlled with cyclosporin
  7. Maintaining remission by altering the gut bacterial environment – probiotics
  8. Conclusion
  9. References

Earlier trials which assessed the benefit of maintaining remission in ulcerative colitis using azathioprine, or its metabolite 6-mercaptopurine (6-MP), were negative due to a lack of appreciation that the drug can take 2–6 months to achieve a therapeutic effect. Subsequently numerous studies of longer duration have demonstrated that the drug is effective in maintaining remission in ulcerative colitis.

Almost certainly the required therapeutic dose varies from patient to patient. A standard dose of 2 mg/kg/day of azathioprine has traditionally been used, including in my own institution. This is thought to be roughly equivalent to 1.5 mg/kg/day of 6-MP, although equivalence studies have not been undertaken. There are no known predictors of benefit from this drug. There is a suggestion of a modest correlation between therapeutic benefit and reduction in white cell count, but this remains controversial, and is certainly not true for all patients. Recent studies suggest that a proportion of patients who have not benefited from standard dose treatment will benefit from a progressive increase in dose, provided white cell count is monitored.

The length of treatment with azathioprine remains controversial. Although it has been claimed that the therapeutic benefit diminishes after 4 years, these claims have been based on very small numbers and are likely to be incorrect. It is more likely that the benefit is maintained as long as the patient is taking the drug, and withdrawal studies have tended to confirm this.

Ten per cent of patients do not tolerate azathioprine. In the remainder, the drug is usually very well tolerated. There are two main concerns with its long-term use. The first relates to its predictable suppressive effect on the bone marrow, particularly its effect in reducing white cell count. In a large cohort series of 739 patients with inflammatory bowel disease (ulcerative colitis and Crohn's disease) followed prospectively for 29 years, a record was kept of the monthly full blood count.7 Four per cent of patients experienced leucopenia with a white cell count of less than 3 × 109 per L. Three patients who did not comply with the blood count monitoring experienced major sepsis related to bone marrow suppression; two died and one had pneumonia but recovered. One of these patients experienced a fall in white cell count 11 years after starting the drug. I therefore recommend that patients continue to have a full blood count assessment each month for as long as they take the drug. The drug can then be stopped, or the dose lowered, if the white cell count falls excessively.

The other potential concern with long-term immunosuppressive drug use is the possible increased risk of malignancy. Patients with rheumatoid arthritis are known to have an increased risk of malignancy, and azathioprine use increases that risk. Patients who undergo renal transplantation also have an increased risk of malignancy, particularly lymphoma and skin cancer. These patients have received foreign tissue and often receive more than one immunosuppressive drug. These data have prompted an evaluation of the risk of malignancy associated with azathioprine use in patients with inflammatory bowel disease.8

Seven hundred and fifty-five patients with inflammatory bowel disease (ulcerative colitis and Crohn's disease) were followed in a prospective study, and compared to a matched community population for cancer incidence.8 Patients had been treated with a standard dose of 2 mg/kg/day, had received a mean of 2 years treatment, and had been followed-up for a mean of 9 years. There were 31 cancers in the patients with inflammatory bowel disease, compared with an expected 24. All the excessive cancers were colorectal cancer, which was to be expected in patients with long standing colitis. There was no excessive incidence of cancers normally associated with immunosuppression. In a separate part of this study patients with extensive colitis who were treated with azathioprine were compared with patients who had not received azathioprine; azathioprine did not appear to cause an increase in colorectal cancer.

This study8 therefore provides some reassurance about the risk of malignancy in relation to azathioprine use in patients with inflammatory bowel disease. However, very long-term use may still be associated with a small increase in cancer risk. It is therefore probably still prudent to try tapering the drug after 2–3 years if possible.

Maintaining remission after a severe episode of colitis controlled with cyclosporin

  1. Top of page
  2. Summary
  3. Introduction
  4. 5-Aminosalicylic acid (5-asa or mesalazine) compounds
  5. Azathioprine and 6-mercaptopurine (6-mp)
  6. Maintaining remission after a severe episode of colitis controlled with cyclosporin
  7. Maintaining remission by altering the gut bacterial environment – probiotics
  8. Conclusion
  9. References

For fulminant episodes of ulcerative colitis, intravenous cyclosporin is now an established drug in effectively controlling inflammation and inducing remission. Long-term follow-up studies have demonstrated that 40–50% of such patients continue to avoid colectomy.9, 10 An important issue relates to the best means of maintaining remission in patients once a colectomy has been avoided using cyclosporin.

In one study of 10 patients with severe colitis treated with intravenous cyclosporin, followed by oral azathioprine for a mean of 16 months, only one patient relapsed.11 This patient's relapse was easily controlled and remission restored.

In another study, 86% of 42 patients treated 9–5 years previously with intravenous cyclosporin responded.12 Twenty-five of 36 responders received 6-MP. Subsequent colectomy was performed in 20% of patients taking 6-MP compared to 45% not taking 6-MP. Of all those treated with cyclosporin and 6-MP, 80% avoided colectomy.

The key to maintaining remission after acute cyclosporin therapy therefore rests with the use of azathioprine. I tend to start azathioprine while the patient is still in hospital, after the episode has been fully brought under control with cyclosporin. Risk of infection from potent combined immunosuppression is an important consideration. Because I tend to use cyclosporin in isolation, without concomitant steroid therapy, this risk is partly attenuated. However, caution still needs to be exercised.

The patient remains on oral cyclosporin for approximately 3 months while the azathioprine takes full effect. A close eye needs to be kept on the blood count while the patient receives both these drugs. Cyclosporin can then be tapered and azathioprine continued to maintain remission.

Maintaining remission by altering the gut bacterial environment – probiotics

  1. Top of page
  2. Summary
  3. Introduction
  4. 5-Aminosalicylic acid (5-asa or mesalazine) compounds
  5. Azathioprine and 6-mercaptopurine (6-mp)
  6. Maintaining remission after a severe episode of colitis controlled with cyclosporin
  7. Maintaining remission by altering the gut bacterial environment – probiotics
  8. Conclusion
  9. References

There is accumulating evidence that the mucosal inflammation in inflammatory bowel disease is driven by the continuous antigenic drive of endogenous luminal bacteria. It is tempting to speculate that relapses are related to changes or ‘shifts’ in the luminal and mucosal bacterial populations.

There is increasing interest in the use of therapeutically administered ‘beneficial’ bacteria, or ‘probiotics’, to modify the luminal bacterial milieu. Preliminary evidence suggests that such an approach can prevent recurrent inflammation, and possibly modify existing inflammation. Controlled data already exist demonstrating that recurrent pouchitis can be prevented by the administration of such a probiotic preparation.

Preliminary data are emerging about the value of such an approach in maintaining remission in patients with ulcerative colitis. Rembacken and colleagues treated 116 patients with either mesalazine or a viable strain of E. coli Nissle for up to 12 months.13 Seventy-three per cent of patients on mesalazine relapsed compared with 66% on E. coli. These data suggest that neither treatment was particularly effective in preventing relapse.

In an uncontrolled pilot study from Bologna, Venturi and colleagues treated 20 patients with ulcerative colitis with a probiotic preparation containing three strains of bifidobacteria, four strains of lactobacilli, and one strain of Streptococcus salivarius.14 Fifteen patients remained in remission.

This approach, of using an apparently harmless ‘natural’ therapy, is aesthetically appealing and holds promise for the treatment of inflammatory disorders.

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. 5-Aminosalicylic acid (5-asa or mesalazine) compounds
  5. Azathioprine and 6-mercaptopurine (6-mp)
  6. Maintaining remission after a severe episode of colitis controlled with cyclosporin
  7. Maintaining remission by altering the gut bacterial environment – probiotics
  8. Conclusion
  9. References

Most patients can be maintained in remission using oral 5-ASA medication. For patients with distal or left-sided disease, the use of rectal 5-ASA is also of proven benefit in maintaining remission. Some patients with frequent or severe relapses require stronger immunosuppression, and in these patients azathioprine is of proven benefit. The exciting prospect of natural bacterial therapies deserves further exploration.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. 5-Aminosalicylic acid (5-asa or mesalazine) compounds
  5. Azathioprine and 6-mercaptopurine (6-mp)
  6. Maintaining remission after a severe episode of colitis controlled with cyclosporin
  7. Maintaining remission by altering the gut bacterial environment – probiotics
  8. Conclusion
  9. References
  • 1
    Misiewicz JJ, Lennard-Jones JE, Connell AM, Baron JH, Avery-Jones F. Controlled trial of sulphasalazine in maintenance therapy for ulcerative colitis. Lancet 1965; 1: 1858.
  • 2
    Azad Khan AK, Howes DT, Piris J, Truelove SC. Optimum dose of sulphasalazine for maintenance of ulcerative colitis. Gut 1980; 21: 23240.
  • 3
    Azad Khan AK, Piris J, Truelove SC. An experiment to determine the active therapeutic moiety of sulphasalazine. Lancet 1977; 1: 8925.
  • 4
    Sutherland L, Roth D, Beck P, May G, Makiyama K. Oral 5-aminosalicylic acid for maintaining remission in ulcerative colitis. Cochrane Database Syst Rev 2000; 2: CD000544 and The Cochrane Library 2001; 3.
  • 5
    Marshall JK, Irvine EJ. Rectal aminosalicylate therapy for distal ulcerative colitis: a meta-analysis. Aliment Pharmacol Ther 1995; 9: 293300.
  • 6
    Marteau P, Crand J. Foucault m, Rambaud JC. Use of mesalazine slow release suppositories 1gm three times per week to maintain remission of ulcerative proctitis: a randomised double blind placebo controlled multicentre study. Gut 1998; 42: 1959.
  • 7
    Connell W, Kamm MA, Lennard-Jones JE, Ritchie JK. Bone marrow toxicity from azathioprine: twenty-seven year experience in inflammatory bowel disease. Gut 1993; 34: 10815.
  • 8
    Connell WR, Kinlen LJ, Ritchie JK, Balkwill AM, Lennard-Jones JE, Kamm MA. Long term risk of neoplasia in patients treated with azathioprine for inflammatory bowel disease. Lancet 1994; 343: 124952.
  • 9
    Hyde GM, Thillainayagam AV, Jewell DP. Intravenous cyclosporin as rescue therapy in severe ulcerative colitis: time for a reappraisal? Eur J Gastroenterol Hepatol 1998; 10: 4113.
  • 10
    Stack WA, Long RG, Hawkey CJ. Short- and long-term outcome of patients treated with cyclosporin for severe acute ulcerative colitis. Aliment Pharmacol Ther 1998 October; 12: 9738.DOI: 10.1046/j.1365-2036.1998.00396.x
  • 11
    Fernandez-Banares F, Bertran X, Esteve-Comas M, et al. Azathioprine is useful in maintaining long-term remission induced by intravenous cyclosporine in steroid-refractory severe ulcerative colitis. Am J Gastroenterol 1996; 91: 24989.
  • 12
    Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporin in ulcerative colitis: a five-year experience. Am J Gastroenterol 1999; 94: 158792.
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  • 13
    Rembacken BJ, Snelling AM, Hawekey PM, Chalmers DM, Axon AT. Non-pathogenic E coli versus mesalazine for the treatment of ulcerative colitis. Lancet 1999; 354: 6359.
  • 14
    Venturi A, Gionchetti P, Rizzello F, et al. Impact on the composition of the faecal flora by a new probiotic preparation: preliminary data on maintenance treatment of patients with ulcerative colitis. Aliment Pharmacol Ther 1999; 13: 11038.DOI: 10.1046/j.1365-2036.1999.00560.x