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