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Medical Management of Ulcerative Colitis

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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!

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