Transcript The Use of Cyclosporin in Severe Ulcerative Colitis

IV Cyclosporin Vs IV Steroids
as Single Therapy for Severe
Attacks of UC
Gastroenterology 2001;120:1541-1552
Matt Johnson
and Dr. M. Smith
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
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
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
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
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
Initial tests

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


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)
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)
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
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
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
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
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
Long Term Response
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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 Response

Colectomy rates
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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 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
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)
Discussion

With short courses of Cyclosporin renal
impairment is transient

Treatment acts as a bridge until the
delayed effects of Azathioprine become
effective
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
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Response criteria