Transcript The Use of Cyclosporin in Severe Ulcerative Colitis

The Use of Cyclosporin and
Heparin in Severe Ulcerative
Colitis
Matt Johnson
and Col. Fabricius
Topic Areas
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Case Presentation
Cyclosporin Studies
Introduction/ Who/ When/ Where
Contraindications (Hx, Ex, Ix)
Treatment Regimes
Inpatient Management
Outpatient Management
Heparin Studies
Discussion
Case Presentation of P.C.
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1995 Diagnosed with UC
 1996 Colonoscopy + Biopsy + Ba enema severe pancolitis with ulceration
pseudopolyps and very friable mucosa.
Started on azathioprine but almost
certainly a surgical candidate
 1997 DNA 6 OPAs after being told he
would need surgery
 Oct 1997 Lost to follow up.
P.C. Inpatient
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No medication for 3 years
1/12 History of:– >6 stools a day
– watery motions with blood + mucus
– central cramp like pain
Ex and Ix
– PR 140 + BP 110/60
– Abdo soft and non-tender
– Hb 5.3, Plat 1039, Alb 18
– ESR 109, CRP 55
P.C> Inpatient
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Treated with
– IV Hydrocortisone 100mg qds
– Predfoam Enemas
Transfused 6u
 Developed a G-ive (rod) septicaemia
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– IV Gent + Met + Ampicillin
NOT a candidate for cyclosporin
 Started on IV Heparin
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Predicting Outcome in Severe UC
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S.P.L.Travis et al at the John Radcliffe Hospital,
Oxford
– Gut 1996; 38: 905 - 910
 On the 3rd day if
– >8 stools
– 3 to 8 stools + CRP > 45
 = 85% would require colectomy
 After 7 days of treatment
– >3 stools
– visible PR blood
 = 40%chance of colectomy
Introduction
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The exact cause for UC is unknown but it is likely to
involve primary epithelial abnormalities, critically
impaired barrier function, mucosal inflammation and
inflammatory mediators
Cyclosporin selectively blocks the activation of T
helper cells and cytotoxic lymphocytes ( by
inhibiting the calcium dependent transcription of IL2 and IFN gamma
80% short term success in steroid refractory UC
66% long term success in steroid refractory UC
Cyclosporin in Severe Ulcerative
Colitis Refractory to Steroid
Therapy
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Simon Lichtiger, M.D., Daniel Present et al
 Mount Sinai Hospital and the University of
Chicago hospital
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NEJM No26 Vol 330 1994 1841-5
The Clinical Trial
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20 patients 18 - 65y 0f mixed sexes
Criteria included;• No response after 7/7 of IV hydrocortisone
300mg
• Re-admitted after a relapse on PO steroids and
failure to respond to 3/7 of IV hydrocortisone
• All patients had a score of >10 on a clinical
activity index
Continued on usual treatment
Cyclosporin 4mg / kg / day or Placebo
If after 14/7 the CAS had not fallen to < 10 they
underwent colectomy or open-label cyclosporin
Clinical Activity Index for UC
Diarrhoea (No. of daily stools)
0-2
0
3 or 4
1
5 or 6
2
7-9
3
10
4
Nocturnal diarrhea
No
0
Yes
1
Visible blood in stool (% of movements)
0
0
<50
1
>50
2
100
3
Fecal incontinence
No
0
Yes
1
Abdominal pain or cramping
None
0
Mild
1
Moderate
2
Severe
3
General well-being
Perfect
Very good
Good
Average
Poor
Terrible
Abdominal tenderness
None
Mild and localized
Mild/moderate and diffuse
Severe or rebound
Need for antidiarrheal drugs
No
Yes
Maximum
0
1
2
3
4
5
0
1
2
3
0
1
21
Results
20
11
9
Cyclosporin
Placebo
9
Response
2
4
5
No response:
surgery
No response:
surgery
No response:
open label IV
(crossover)
5
8
1
Oral Cyclosporin
Elective
colectomy
Response
5
Oral Cyclosporin
Results of Cyclosporin Treatment
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The mean clinical activity score in the Cyclosporin group
fell from 13 (range, 10 to 16) to 6 (range, 2 to 8)
The mean time to response was less than 7 days
One patient who responded to Cyclosporin opted for an
elective colectomy
Of the 2 non-responders in the Cyclosporin group:
• One had a grand mal seizure and later went for
surgery
– This patient had hypocholesterolaemia and
should have been excluded (intention-to-treat
criteria)
• The second patient deteriorated after eight days
Results of Placebo Treatment
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The placebo group fell from 14 (range,
12 to 17) to 13 (range, 11 to 18)
 4 of the 9 underwent colectomy
– 1 toxic megacolon on the 3rd day
– 1 G-septicaemia with superimposed CMV
– 2 refractory symptoms
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The remaining 5 were stable and had
open-label Cyclosporin therapy.
– Their mean clinical activity score fell from
11 (range, 11 to 13) to 7 (range, 2 to 9)
– Their mean time to response was 7 days
Adverse Effects
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The dosage was decreased in 5 patients
due to elevated Cyclosporin levels
 4 out of 11 (36%) had Paraesthesia
 4 out of 11 (36%) developed hypertension
 1 patient in the placebo group developed
hypertension (11%)
 2 developed headaches (18%)
 Nausea and vomiting was reported equally
 There was no nephro/hepatic toxicity
 1 grand mal seizure
Trail Faults
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Relatively few numbers
 Largely subjective clinical-activity score
(not previously validated)
 No objective qualification of the disease
(endoscopic, histologic or
haematological)
Conclusion
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80% responded to IV Cyclosporin in the
short term
60% responded to oral Cyclosporin in the
long term
The trial was called to a close after an
ethical committee had reviewed the data
Although there was evidence of known side
effects, this study demonstrates that
Cyclosporin is an effective drug in steroid
resistant ulcerative colitis
A 5 Year Experience AJG 94 (6) 1587 June99
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42 patients
36 responded to cyclo (86%)
10 of these required colectomy
– 11/36 (31%) had cyclo alone
– 45% required elective colectomy
– 25 /36 (69%) had 6-MP or Azathioprine
– 20% required elective colectomy
31 continued on PO cyclosporin
5 developed reversible complications
All colectomies were done <18/12 (mean of 6/12)
In all 62% avoided colectomy, 72% of cyclo responders,
80% with 6MP or Aza
Oxford 6 year Experience
EJGH 10(5): 411-3, 1998
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216 patients
 132 (61%) responded to steroids
 34 (40%) required urgent colectomy
 50 (23%) received cyclosporin
– 28/50 (56%) responded
– 8/50 (29%) later required colectomy after
discharge
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Short term efficacy = 56%
 Long term efficacy = 40%
 NB no comment on 6MP or Aza
Cyclosporin for Severe
Ulcerative Colitis:
A User’s Guide
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Clinical Review in Am J Gastroenterology
1997, 92,1424-8
WHO, WHEN and WHERE
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WHO - Persistent severe UC
–psychologically ill-prepared
–Left-sided colitis that has
previously been easy to control
–Not suitable as surgical candidates
 WHEN - After 7-10 days of [high] steroids
 WHERE - In centers able to measure
[cyclo] in < 48hrs with direct access to an
experienced medical + surgical teams
Contra-indications - History
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Elderly > 50y ( impaired creat clearance)
Malignancy ( except Rx BCC + SCC )
Pregnancy and Women of child bearing
age
Poorly controlled epilepsy (epileptogenic)
Non compliance ( cost )
Contra-indications - Examination
Poorly Controlled Hypertension
 Infection ( regular examinations of
central lines)
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Contra-indication - Investigations
Pregnancy Test
 Stool Cultures
 ESR
 U+Es
 LFTs
 Others:
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– Cholesterol < 120 mg/dl
– Magnesium < 1.5 mg/dl
Treatment Regime
Informed consent and risks
 Cyclosporin = 4mg/kg/24hrs IV
 Decrease dose according to the %
reduction in Cr Clearance
 In conjunction with:High dose steriods IV
Steroid Enemas
Mesalazine
 Stop Aza and 6-mercaptopurine
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In Patient Monitoring
Check for anaphylaxis in the first hr
 Check [Cyclo] every 2 days
 Aim for 300 - 400 ng/ml
 Decrease Cyclosporin by 25% if:
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levels >500 ng/ml for 2 consecutive days
Creat increases by > 30%
LFTs double
DBP > 90mmHg
SBP > 150
Switching to Oral
Clinical improvement - 4 to 5 days
 Change to PO steroids - 7 days
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• Prednisone 20mg tds
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Change to oral Cyclo - 7 to 10 days
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Stop IVs at 8pm the night before
Check [Cyclo] at 8am
Start PO dosing at 2x the IV dose bd
Discharge once stable after 2 days
monitoring
Outpatient Monitoring
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Outpatients
• 4x in 1st month, 2x in 2nd, then monthly
Check
• SEs, FBC, U+Es, Mg, 12 hr trough [Cyclo]
• Aim for a trough level of 150 - 300 ng/ml
Prednisolone Reducing Dose
• Decrease by 10mg a week to 30mg
• Then decrease by 5mg a week
Add 6-MP (or Azathioprine) at 2/12
Then Reduce Cyclosporin
• Decrease by 50% for 2 weeks then stop
• Flex sig at 6 weeks, Colonoscopy at 6 months
Side Effects
Nephrotoxicity
 Hepatotoxicity
 Paraesthesia
 Hypertension
 Grand Mal Seizures
 Septicaemia
 Opportunistic Infections (PCP and
herpetic oesophagitis)
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Heparin in Severe UC
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Heparin is a group of sulphated
glycosaminoglycans
They have anti-inflammatory effects by inhibiting
neutrophil elastases and inactivating chemokines
Its antithrombotic effects are mediated by
activation of anti thrombin III
It has long been known that there is an increased
risk of thromboemboli in IBD with Bx showing
numerous colonic mucosal thrombi in UC.
Clotting disorders appear to be protective against
UC
Paradoxical Response to Heparin
in 10 Patients with UC
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Peter R Gaffney, FRCS et al at Cork Regional Hospital,
AJG Vol90, No2, 1995 220 -223
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10 Patients (7m+3f) 25 - 74y
All with histologically confirmed disease
8 with severe + 2 with moderate UC
4 were given 30,000u IV
6 were given 10,000u S/C bd
All were discharged on 10,000u S/C bd
Plat + Clotting was monitored daily for 1/52, weekly for
1/12 and then monthly
9 were on sulphasalazine + 6 on prednisolone
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Assessment of Efficacy
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1) Stool frequency
2) Rectal Bleeding
– 0 = absent
– 1 = occasional steaks
– 2 = blood most of the time
– 3 = bloody stools
Sigmoidoscopy
– 0 = normal
– 1 = mild (mucosal oedema)
– 2 = moderate (granularity+friability)
– 3 = severe (ulceration+bleeding)
Histology
– 5 changes each scored 0 to 3 (severe)
– infiltration, cryptitis, abscesses, goblet cell depletion, regenerative hyperplasia
General Well Being
– 0 (very poor) to 5 (excellent)
9 Rectal Bx (fibrin thrombi)
Mean Scores on Disease Variables
Slide 1
P re
P o st
11
5 .3
4 .4
3 .8
2 .6
1 .8
2 .4
0 .2
p < 0001
1
p < 001
0 .8
p < 001
p < 0001
p < 0001
Sto o l Frequency
Rectal Bleeding
Sigmo ido sco py
Risto lo gy (UCS)
W ell Being
(Range 0 - 3)
(Range 0 - 3)
(Range 0 - 15)
(Range 0 - 5)
Mean scores on disease variables pre- and post treatment with heparin and sulfasalazine. Vertical bars
represent SLM: p values are based on Student’s t test for paired data
Results
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9 (90%) achieved remission
1 (10%) reduction in PR bleeding only
Mean time to improvement = 3/52
Mean time to remission = 6/52
6 remained on heparin < 6/12
2 could not be weaned off
Fibrin thrombi were found in 6/9 (66%)
No serious complications (2 patients had
increased rectal bleeding in the first week)
Treatment of Corticosteroid Resistant UC with Heparin
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R.C. Evans et al at The Royal Liverpool, AlPharmTher 1997:
11:1037-1040
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16 patients 22-79y, 9m + 1f
6 pan-colitis, 8 left-sided, 2 recto-sigmoid disease
Usual therapy + heparin (APTT 2-2.5)
12/16 (75%) marked clinical improvement
Of these 2 had total colitis + 10 left-sided disease
After 2/52 stool freq had decreased from 8 to 3.5, then to 2
stools after 4 weeks
4 failed to respond and had colectomies
Of these 3 had total colitis + 1 left-sided disease
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Conclusion
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These studies demonstrate a
promising response to standard
heparin in UC resistant to
conventional treatment
 It is currently unclear whether low
molecular weight (fractionated)
heparins have similar effects
(preliminary studies suggest this is
the case)
 We now await large control trials
Discussion
The need for urgent surgery in IP
P.C.
 Prognostic markers
 The use of cyclosporin in UC in this
hospital
 The use of heparin in UC in this
hospital
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