1. Medical Management of Ulcerative Colitis
Alistair Makin
Manchester Royal Infirmary

2. Treatment Choice Dependent on Acute attack or maintenance of remission
Assessment of Disease Severity (Truelove & Witts 1950’s)
Mild - < 4 stools /day, no systemic disturbance, normal ESR
Moderate - > 4 stools/day but with minimal systemic upset
Severe - > 6 stools/day with blood, evidence of systemic disturbance – fever, tachycardia, anaemia or ESR >30
Toxic dilatation
Extent of disease (topical v systemic)

3. The Acute Attack Mild to Moderate Disease Cochrane Review 4/1/03
Salicylates
Sulfasalazine (SASP) first used in 1942
Response rate of 60%
25-30% adverse effects
Newer 5-ASA fewer side effects ( 10%)
Topical + systemic dosing more effective
Cochrane Review 4/1/03
Newer 5-ASA preparations superior to placebo and trend to benefit over SASP. Considering relative costs a clinical advantage of newer 5-ASA v SASP is unlikely

4. New 5-ASA Preparations Balsalazide (azo-bonded prodrug) v mesalamine
46% v 44% achieved remission
Response rate 68% v 61% in new diagnosis
36% v 25% in relapse
Symptomatic remission 25 v 37 days
Pruitt et al 2002
Balsalazide v sulfasalazine
Similar response rate
Patient withdrawal 7% v 31%
Green et al 2002

5. The Acute Attack Role of Steroids First used in 1950’s
Severe attack mortality reduced from 37% to < 1%
Topical for left-sided disease
Oral for more extensive disease or failed local Rx
40mg/d more effective than 20mg/d
60mg/d > 40mg/d but more side effects
Baron et 1962
IV initially in severe disease

6. The Acute Attack – when Steroids Fail
Predictors of failed medical therapy
Failure Rate
> 8 stools/day 33%
Pulse > %
Albumin < 30g/l 42%
Temp > 38°C 56%
Mucosal islands on plain AXR 75%
Small bowel dilatation 73%
Colonic dilatation 75%
Lennard-Jones Chew et al 1991
Surgery - failure to respond after 5 days

7. Salvage Therapy Cyclosporin Oxford data New York Data
Initial pilot suggested benefit
Dual centre controlled trial of patients failing to respond at day 5
IV cyclosporin (4mg/kg) + steroids v conventional Rx
9/11 on cyclosporin responded v nil
60% still well at 6 months
New York Data
Similar benefit
54/111 patients major toxicity (2 deaths, 7 severe infections)

8. Cyclosporin St Marks Data – low dose 2mg/kg 31 patients
11 cyclosporin + steroids
2(18%) urgent - 5(25%) delayed colectomy
20 cyclosporin
5(25%) urgent – 5(25%) delayed colectomy
Benefit with concurrent azathioprine

9. Salvage Therapy Azathioprine Slow onset of action
Loading IV onset of action still 4 weeks
Methotrexate
No role
Infliximab
Anecdotal evidence but no convincing trial data

10. Cuckoo Land ? Antibiotics Probiotics – commensal bacterial species
No established role
Probiotics – commensal bacterial species
Possible role of VSL#3 (a combination of 4 lactobacillus species) in mild-moderate disease
Trichuris suis eggs
(Porcine Whipworm)
86% remission
85% relapse by 12 weeks
Remission maintained with 3/52 repeat doses

11. Remission No role for steroids
Sulfasalazine – reduced relapse rate 4-fold
Newer 5-ASA’s comparable
What Dose?
How long for?
Long-term at appropriate dose for preparation used

12. Novel Approaches Oral 5-ASA + twice weekly enemas v oral alone
Reduction in number and incidence of relapses
Higher chance of no relapse
More costly but decreased relapse & hospital costs
Piodi et al 2004
Patient-led variable dosing
Balsalazide 1.5g bd with 750mg increments up to 6g for 7 days if symptoms increased
Stable remission – 44% relapse by 3 years
Newly in remission %
Green et al 2004

13. Azathioprine
Converted to 6-MP in liver and then to thioinosinic acid which impairs purine biosynthesis
- inhibits cellular proliferation
- slow onset of action as act on newly differentiating cells
Induction & maintenance of remission in refractory disease
66% response rate
Need 3 months of treatment to determine response
10% intolerant
Myelosuppression 5% in first 6 months
Late complications so prolonged monitoring needed

14. Azathioprine Dose 2mg/kg 3 monthly FBC/LFT’s once stable
Stop if WBC <3•5 or neutrophils <1•5
How long for?
Relapse rates on AZA
11%-1 year 32%-5years
Relapse rates higher if AZA stopped than if continued up to year 4 of treatment
when AZA stopped when in remission but >6months Rx
38%-1 year 75%-5 years
No increase in relapse rates when Rx > 5 years
Treat for a minimum of 4 years

15. Conclusions Determine severity of attack and treat appropriately
Topical v systemic
Limit steroid use (DEXA scan if > 3months of 7.5mg.d)
Consider immunosuppression early
Duration of treatment important
Joint management with surgeons of severe and refractory cases
The worms are coming!