the use of cyclosporin and heparin in severe ulcerative colitis matt johnson and col. fabricius
TRANSCRIPT
The Use of Cyclosporin and The Use of Cyclosporin and Heparin in Severe Ulcerative Heparin in Severe Ulcerative ColitisColitis
Matt Johnson
and Col. Fabricius
Topic AreasTopic Areas
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. Case 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.
P.C. InpatientP.C. Inpatient
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> InpatientP.C> Inpatient
Treated with– IV Hydrocortisone 100mg qds– Predfoam Enemas
Transfused 6uDeveloped a G-ive (rod) septicaemia– IV Gent + Met + Ampicillin
NOT a candidate for cyclosporinStarted on IV Heparin
Predicting Outcome in Severe UCPredicting 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
– >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
IntroductionIntroduction
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
Cyclosporin in Severe Ulcerative Cyclosporin in Severe Ulcerative Colitis Refractory to Steroid Colitis Refractory to Steroid TherapyTherapy
Simon Lichtiger, M.D., Daniel Present et al Mount Sinai Hospital and the University of Chicago hospital
NEJM No26 Vol 330 1994 1841-5
The Clinical TrialThe 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 >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 UCClinical Activity Index for UC
20
9 2No response:
surgery
4No response:
surgery
11Cyclosporin
9Placebo
8Oral Cyclosporin
1Elective
colectomy
5
5
5Oral Cyclosporin
ResultsResults
Response No response:open label IV(crossover)
Response
Results of Cyclosporin TreatmentResults 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
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
Results of Placebo TreatmentResults of Placebo Treatment
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
Adverse EffectsAdverse Effects
Trail FaultsTrail Faults
Relatively few numbers Largely subjective clinical-activity score (not
previously validated) No objective qualification of the disease
(endoscopic, histologic or haematological)
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
ConclusionConclusion
A 5 Year Experience A 5 Year Experience AJG 94 (6) 1587 June99AJG 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 <18/12 (mean of 6/12) In all 62% avoided colectomy, 72% of cyclo responders, 80% with 6MP or Aza
Oxford 6 year ExperienceOxford 6 year ExperienceEJGH 10(5): 411-3, 1998EJGH 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
Cyclosporin for Severe Cyclosporin for Severe Ulcerative Colitis: Ulcerative Colitis: A User’s GuideA User’s Guide
Clinical Review in Am J Gastroenterology 1997, 92,1424-8
WHO, WHEN and WHEREWHO, 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 < 48hrs with direct access to
an experienced medical + surgical teams
Contra-indications - HistoryContra-indications - History
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 - ExaminationContra-indications - Examination
Poorly Controlled HypertensionInfection ( regular examinations of
central lines)
Contra-indication - InvestigationsContra-indication - Investigations
Pregnancy TestStool CulturesESRU+EsLFTsOthers:– Cholesterol < 120 mg/dl– Magnesium < 1.5 mg/dl
Treatment RegimeTreatment Regime
Informed consent and risksCyclosporin = 4mg/kg/24hrs IVDecrease dose according to the %
reduction in Cr ClearanceIn conjunction with:- High dose
steriods IV Steroid Enemas Mesalazine
Stop Aza and 6-mercaptopurine
In Patient MonitoringIn Patient Monitoring
Check for anaphylaxis in the first hrCheck [Cyclo] every 2 daysAim for 300 - 400 ng/mlDecrease Cyclosporin by 25% if:-
• levels >500 ng/ml for 2 consecutive days• Creat increases by > 30%• LFTs double• DBP > 90mmHg • SBP > 150
Switching to OralSwitching to Oral
Clinical improvement - 4 to 5 daysChange 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
Outpatient MonitoringOutpatient Monitoring
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 EffectsSide Effects
NephrotoxicityHepatotoxicityParaesthesiaHypertensionGrand Mal SeizuresSepticaemia Opportunistic Infections (PCP and
herpetic oesophagitis)
Heparin in Severe UCHeparin 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
Paradoxical Response to Heparin Paradoxical Response to Heparin in 10 Patients with UCin 10 Patients with UC
Peter R Gaffney, FRCS et al at Cork Regional Hospital, AJG Vol90, No2, 1995 220 -223
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
Assessment of EfficacyAssessment 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 (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 VariablesMean Scores on Disease Variables
Slide 1
M ean scores on disease variables pre- and post treatm ent w ith heparin and sulfasalazine . Vertical barsrepresent SLM : p values are based on Student’s t test for paired data
5.3
1.8 2.40.2
2.6
1
11
4.4
0.8
3.8
Stool Frequency Rectal Bleeding Sigmoidoscopy Ristology (UCS) Well Being
Pre Post
ResultsResults
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 - Treatment of Corticosteroid - Resistant UC with HeparinResistant UC with Heparin
R.C. Evans et al at The Royal Liverpool, AlPharmTher 1997: 11:1037-1040
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
ConclusionConclusion
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
DiscussionDiscussion
The need for urgent surgery in IP P.C.
Prognostic markers The use of cyclosporin in UC in this
hospitalThe use of heparin in UC in this
hospital