IV Cyclosporin Vs IV SteroidsIV Cyclosporin Vs IV Steroidsas Single Therapy for Severe as Single Therapy for Severe Attacks of UCAttacks of UCGastroenterology 2001;120:1541-1552Gastroenterology 2001;120:1541-1552

Matt Johnson

and Dr. M. Smith

IntroductionIntroduction

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

Cyclo Vs SteroidsCyclo 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

Materials and MethodsMaterials 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

Inclusion +Concurrent TreatmentInclusion +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

Exclusion CriteriaExclusion 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

Initial testsInitial 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)

MonitoringMonitoring 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)

TreatmentsTreatments

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

TreatmentsTreatments

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

StatisticsStatistics

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

ResultsResults

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

ResultsResults 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

Long Term ResponseLong 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

Long Term ResponseLong 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

Other ResultsOther 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

SummarySummary

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)

DiscussionDiscussion

With short courses of Cyclosporin renal impairment is transient

Treatment acts as a bridge until the delayed effects of Azathioprine become effective

ProblemsProblems 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