1. IV Cyclosporin Vs IV Steroids as Single Therapy for Severe Attacks of UC Gastroenterology 2001;120:1541-1552 Matt Johnson and Dr. M. Smith

2. Introduction IV Hydrocortisone has been for a long time the gold standard treatment of acute UC. Approximately 60% recover acutely within 5/7 Those that fail to respond go on to require colectomy with ileoanal pouch Uncontrolled studies suggest an 80% success in using Cyclo acutely in steroid non-responders

3. Cyclo Vs Steroids Corticosteroids –suppress release of inflammatory mediators –decrease veascular permeability –inhibit proliferation of B+Tcells Cyclosporin –Inhibits IL2 –Inhibits T helper cells –decreases cytotoxic recruitment and release of lymphokines Combination = block multiple pathways

4. Materials and Methods Single center prospective, double blind, controlled randomised trial 8/7 of IV steroids or Cyclo Inclusion Criteria –All patients 18-70y admitted to Gasthisberg, Belgium, who were hospitalised with severe UC –Clinical activity index > 10 –Response was defined as a score <10 with a drop of at least 3 points

5. Inclusion +Concurrent Treatment Azathioprine –If prescibed for > 3/12 –and if dose not changed within the last 1/12 Mesalazine or Sulphasalazine PO Steroids –If used for < 2/52 –provided no clinical improvement Rectal steroids –but not in the 4/52 prior to admission –mesalazine enemas allowed

6. Exclusion Criteria –Uncontrolled hypertension –Renal F with Cr > 2mg/dl –LFTs twice their normsal range –Active infection –Pregnancy –Positive stool cultures –AXR = dilatation or perforation

7. Initial tests AXR Stool Cultures Lichtiger Symptom Score (1,8,and 28/7) Endoscopy (1,8,and 28/7) Biopsy Histology (1,8,and 28/7) Urinary Inulin Clearance (1,8,and 28/7) HMPAO wbc Scan (1,8,and 28/7)

8. Monitoring Endoscopy –0 = normal –1 = mild ( disturbed vascular pattern ) –2 = moderate ( spontaneous bleeding ) –3 = sever (ulcers ) Histology –Blinded GI Pathologist –Standard scoring system HMPAO wbc Scan –the colon was divided into 5 segments –0 = normal –1 = inflammation (lower intensitity than BM) –2 = inflam (equal to BM) –3 = inflam (uptake greater than BM)

9. Treatments Cyclo IV –4 mg/kg per day in 250ml 0f Nsaline –dose adjusted to reach blood levels of 250 to 450 ng/ml (measured every 2/7) –those that responded by the 8/7 were discharged on PO 4 mg/kg bd and blood levels between 200 - 350 were aimed for (measured every week for 1/12 then monthly thereafter) –stopped after 3/12

10. Treatments Steriods IV –The equivalent of 40mg methylpred or 50mg pred in 250ml of Nsaline) –Discharged on PO Methylpred 32mg/day for 3/52 and then tapered by 4mg/week Non-Responders –Offered Combination Therapy for 8/7 Azathioprine –At discharge both steroid and Cyclo groups were given 2-2.5mg/kg/day Aza PO od

11. Statistics Proportions were compared by means of Chi squared test with Yates correction for variability Quantitative variables were compared with the 2 tailed Student t test Signed Rank test was used to compare renal function Spearmans Rank correlation Coefficient was used for Scintigraphy and Biopsy comparisons

12. Results 30 patients reached inclusion criteria, and all took part 1 patient in the cyclosporin group got excluded on day 2 when CDT was found in his Stool cultures (went on to have Sx) 9 of 14 Cyclo responded (64%) 8 of 15 Steroids responded (53%) Serum [cyclo] were not significantly different in non-responders

13. Results Cyclo Failures = 5 –2 had colectomies –3 went for Combined Therapy 1 success 2 were well enough for discharge but didnt reach criteria for clinical response ( 1 went home with PO cyclo the other with PO steroids) Steroid Failures –7 went for Combination Therapy 3 responded 1 well enough for discharge on PO steroids 3 colectomies

14. Long Term Response Remission in 8/9 (89%) of Cyclos at 6/12 7/9 (78%) 12/12 Remission in 4/8 (50%) of Preds at 6/12 3/8 (37%) 12/12 –but only 3/8 of the steroid responders had continued with the azathioprine Of the non-responders 4/10 were treated with Combination therapy, 3 of which remained in remission at 6/12

15. Long Term Response Colectomy rates 5 of 14 (36%) of Cyclo at 12/12 –3 then 2 5 of 14 (40%) of Preds at 12/12 –3 then 3 Quantitative variables were compared with the 2 tailed Student t test

16. Other Results Endoscopy and Histology –The 2 treatments were comparable –Significant differences were not seen until the 1/12 checks Scintigraphy –Changes correlated closely with histology Renal Impairment –No changes in serum Cr –Inulin Clearance significantly dropped at day 8 but fully normalised after Cyclo discontinuation

17. Summary IV Cyclosporin was as effective as IV glucocorticosteroids in the acute stages of UC treatment 8 day treatment regime proved as effective with similar response times as compared to trials using longer treatment periods Endoscopic and histological improvement lag behind clinical improvement No serious episodes of sepsis were noted with monotherapy (+/- Azathioprine)

18. Discussion With short courses of Cyclosporin renal impairment is transient Treatment acts as a bridge until the delayed effects of Azathioprine become effective

19. Problems Small numbers 3rd Trial arm should have been included with combination therapy frontline The suprisingly few steroid patients that were successfully maintained on azathioprine Blinding ended after the 8th day The imbalance in patients taking concomitant mesalazine Response criteria