Title: The Use of Cyclosporin and Heparin in Severe Ulcerative Colitis
1The Use of Cyclosporin and Heparin in Severe
Ulcerative Colitis
- Matt Johnson
- and Col. Fabricius
2Topic Areas
- Case Presentation
- Cyclosporin Studies
- Introduction/ Who/ When/ Where
- Contraindications (Hx, Ex, Ix)
- Treatment Regimes
- Inpatient Management
- Outpatient Management
- Heparin Studies
- Discussion
3Case Presentation of P.C.
- 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.
4P.C. Inpatient
- No medication for 3 years
- 1/12 History of-
- gt6 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
5P.Cgt Inpatient
- Treated with
- IV Hydrocortisone 100mg qds
- Predfoam Enemas
- Transfused 6u
- Developed a G-ive (rod) septicaemia
- IV Gent Met Ampicillin
- NOT a candidate for cyclosporin
- Started on IV Heparin
6Predicting Outcome in Severe UC
- S.P.L.Travis et al at the John Radcliffe
Hospital, Oxford - Gut 1996 38 905 - 910
- On the 3rd day if
- gt8 stools
- 3 to 8 stools CRP gt 45
- 85 would require colectomy
- After 7 days of treatment
- gt3 stools
- visible PR blood
- 40chance of colectomy
7(No Transcript)
8Introduction
- 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
IL-2 and IFN gamma - 80 short term success in steroid refractory UC
- 66 long term success in steroid refractory UC
9Cyclosporin in Severe Ulcerative Colitis
Refractory to Steroid Therapy
- Simon Lichtiger, M.D., Daniel Present et al
- Mount Sinai Hospital and the University of
Chicago hospital - NEJM No26 Vol 330 1994 1841-5
10The Clinical Trial
- 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 gt10 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 lt 10 they
underwent colectomy or open-label cyclosporin
11Clinical Activity Index for UC
12Results
20
9
5
Response
No responseopen label IV(crossover)
5
8
Response
Oral Cyclosporin
5
Oral Cyclosporin
13Results of Cyclosporin Treatment
- 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
14Results of Placebo Treatment
- 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
- 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
15Adverse Effects
- 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
16Trail Faults
- Relatively few numbers
- Largely subjective clinical-activity score
(not previously validated) - No objective qualification of the disease
(endoscopic, histologic or haematological)
17Conclusion
- 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
18A 5 Year Experience AJG 94 (6) 1587 June99
- 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 lt18/12 (mean of 6/12)
- In all 62 avoided colectomy, 72 of cyclo
responders, 80 with 6MP or Aza
19Oxford 6 year ExperienceEJGH 10(5) 411-3, 1998
- 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 - Short term efficacy 56
- Long term efficacy 40
- NB no comment on 6MP or Aza
20Cyclosporin for Severe Ulcerative Colitis A
Users Guide
- Clinical Review in Am J Gastroenterology 1997,
92,1424-8
21WHO, WHEN and WHERE
- 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 lt
48hrs with direct access to an experienced
medical surgical teams
22Contra-indications - History
- Elderly gt 50y ( impaired creat clearance)
- Malignancy ( except Rx BCC SCC )
- Pregnancy and Women of child bearing age
- Poorly controlled epilepsy (epileptogenic)
- Non compliance ( cost )
23Contra-indications - Examination
- Poorly Controlled Hypertension
- Infection ( regular examinations of central lines)
24Contra-indication - Investigations
- Pregnancy Test
- Stool Cultures
- ESR
- UEs
- LFTs
- Others
- Cholesterol lt 120 mg/dl
- Magnesium lt 1.5 mg/dl
25Treatment 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
26In 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-
- levels gt500 ng/ml for 2 consecutive days
- Creat increases by gt 30
- LFTs double
- DBP gt 90mmHg
- SBP gt 150
27Switching to Oral
- Clinical improvement - 4 to 5 days
- Change to PO steroids - 7 days
- Prednisone 20mg tds
- Change to oral Cyclo - 7 to 10 days
- 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
28Outpatient Monitoring
- Outpatients
- 4x in 1st month, 2x in 2nd, then monthly
- Check
- SEs, FBC, UEs, 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
29Side Effects
- Nephrotoxicity
- Hepatotoxicity
- Paraesthesia
- Hypertension
- Grand Mal Seizures
- Septicaemia
- Opportunistic Infections (PCP and herpetic
oesophagitis)
30(No Transcript)
31Heparin in Severe UC
- 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
32Paradoxical Response to Heparin in 10 Patients
with UC
- Peter R Gaffney, FRCS et al at Cork Regional
Hospital, AJG Vol90, No2, 1995 220 -223 - 10 Patients (7m3f) 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
33Assessment of Efficacy
- 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 (granularityfriability)
- 3 severe (ulcerationbleeding)
- 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)
34Mean Scores on Disease Variables
Slide 1
35Results
- 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 lt 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)
36Treatment of Corticosteroid - Resistant UC with
Heparin
- R.C. Evans et al at The Royal Liverpool,
AlPharmTher 1997 111037-1040 - 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
37Conclusion
- 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
38Discussion
- 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