IV Cyclosporin Vs IV Steroids as Single Therapy for Severe Attacks of UC Gastroenterology 2001;120:1541-1552

1. IV Cyclosporin Vs IV Steroidsas Single Therapy for Severe Attacks of UCGastroenterology 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 • 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 didn’t 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