Medical Therapy

Conrad Beckett MD FRCP, Consultant Gastroenterologist, Bradford

Powerpoint File

The majority of patients with ulcerative colitis (UC) can be managed medically. The disease is characterised by acute exacerbations punctuating variable periods of remission. The aim of medical therapy is to treat acute attacks and maintain remission.

Mild: BO 4-5/day with blood/mucus but systemically well

Moderate:  6 BO/day with no systemic illness

Severe:  6 BO/day with systemic illness

Refractory: Steroid dependant/ rapid relapse off steroids

Evidence from meta-analysis has shown that 5-ASA enemas are effective in inducing remission in distal disease (1) and that they were more effective than topical steroids (2). The 5-ASA preparations have several different mechanisms of release. There is good meta-analysis data (Grade A) that 5-ASAs are effective in the induction and maintenance of remission of UC (3). A recent trial has demonstrated a 72% response rate in moderate UC when 4.8g of mesalazine used compared to 59% when 2.4g used (4). When maintaining remission, 2.4g/day was no more effective than 1.2g/day at reducing recurrence, but the higher dose delays the time to relapse by over a month (5). Adherence to therapy is probably the overriding factor as relapse increases five fold when <80% compliance (6). Topical mesalazine should be added to oral therapy in frequently relapsing UC as has been shown to lead to a 10-fold reduction in relapse over 2 years (7). There is now also evidence that regular 5-ASA’s reduces the risk of colorectal cancer in UC by up to 81% (8). Nicotine has been shown to be of benefit in the induction of remission of UC but not when compared to steroids (9).

Steroids remain the standard of therapy for inducing remission in moderate to severe UC based on the studies of Truelove (10) and Lennard-Jones (11). There is evidence to suggest that 60mg of prednisolone is no better than 40mg, but both were better than 20mg (12). There is no evidence to support the use of steroids in the maintenance of remission (Grade A). The evidence for Azathioprine has been weak, and is most convincing in chronic steroid dependent patients (13). Retrospective reviews have added weight to its use (14). Further evidence for its use in maintaining remission came from a withdrawal trial (15). A recent study has shown 53% entered remission on azathioprine at six months compared to 21% with 5-ASA in steroid dependent UC (16). The only trial data regarding methotrexate use in UC was negative, but retrospective data suggests it may have efficacy (17).

A role of cyclosporin (CyA) in acute UC was first tested in a small RCT and 9 of 11 CyA treated patients avoided surgery (18). There is a significant toxicity profile and in longer term follow-up, over 50% come to colectomy (19). There are small series suggesting CyA enemas may be of benefit in resistant proctitis.

Infliximab as rescue therapy in steroid resistant UC is looking promising. A recent study demonstrated that 7/24 in the Infliximab group but 14/21 in the placebo group had a colectomy within 3 months (20). The ACT 1 and 2 trials also support these findings. The key to Infliximab use appears to be the use of an index that predicts poor outcome (21). There are other treatments on the horizon such as leucocyte apheresis, Visilizumab (anti CD3) and Trichuris suis (22) but further data is awaited with interest.

References

1. Marshall JK et al Rectal aminosalicylate therapy for distal ulcerative colitis: A meta-analysis.Aliment Pharmacol Ther 1995; 9: 293-300

2. Marshall JK et al Rectal steroids versus alternative treatments in ulcerative colitis: a meta-analysis Gut 1997;40: 775-81

3. McDonald J et al Evidence based Gastroenterology and Hepatology Chapter 9. Ulcerative colitis:Diagnosis, prognosis and treatment. BMJ Books

4. Hanauer S et al Efficacy and safety of mesalazine 4.8g/day (800mg tablet) compared with 2.4g/day (400mg tablet) when treating moderately active ulcerative colitis: ASCEND 11 study. Gut 2005; 53 (suppl 2): A3

5. Paoluzi OA et al Comparison of 2 different daily doses (2.4 vs 1.2g) of oral mesalazine in maintenance of remission in ulcerative colitis patients: 1- year follow-up study. Aliment Pharmacol Ther 2005; 21: 1111-1119

6. Kane SL et al Medication nonadherence and the outcomes of patients with quiescent ulcerative colitis Am J Med 2003: 114; 39-43

7. Frieri G et al Long-term oral plus topical mesalazine in frequently relapsing ulcerative colitis Dig Liver Dis 2005; 37: 92-96

8. Eaden et al.Colorectal cancer prevention in ulcerative colitis: a case control study. Aliment Pharmacol Ther 2000; 14: 145-53

9. Thomas GA et al. Transdermal nicotine compared with oral prednisolone therapy for active ulcerative colitis. Eur J Gastroenterol Hepatol 1996; 8: 769-76

10. Truelove SC et al Cortisone in ulcerative colitis. Final report on a therapeutic trial. Br Med J 1955; no4947: 1041-8

11. Lennard-Jones et al An assessment of prednisolone, salazopyrin and topical hydrocortisone used as outpatient treatment of ulcerative colitis. Gut 1960; 1: 217-22

12. Baron JH et al Out-patient treatment of ulcerative colitis. Comparison between three doses of oral steroids. Br Med J 1962; 2: 441-3

13. Jewell DP et al Azathioprine in ulcerative colitis: final report on controlled therapeutic trial. Br Med J 1974; iv: 627-30

14. Frazer AG et al The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30-year review Gut 2002; 50: 485-9

15. Hawthorne et al Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. Br Med J 1992; 305:20-2

16. Ardizzone S et al Randomised controlled trial of azathioprine and 5-aminosalicylic acid for the treatment of steroid dependent ulcerative colitis. Gut 2006; 55: 47-53

17. Cummings JR et al Oral methotrexate in ulcerative colitis Aliment Pharmacol Ther 2005; 21: 385-9

18. Lichtiger et al Cyclosporin in severe ulcerative colitis refractory to steroid therapy N Engl J Med 1994; 330: 1841-5

19. Campbell S et al Cyclosporin use in acute ulcerative colitis: a long-term experience. Eur J Gastroenterol hepatol 2005; 17: 79-84

20. Jarnerot G et al Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomised placebo controlled study Gastroenterology 2005; 128: 1805-11

21. Travis SPL et al Predicting outcome in severe ulcerative colitis Gut 1996; 38: 905-10

22. Summers RW et al Trichuris suis therapy for active ulcerative colitis: a randomised control trial Gastroenterology 2005; 128(4): 825-32