the use of cyclosporin and heparin in severe ulcerative colitis matt johnson and col. fabricius

Download The Use of Cyclosporin and Heparin in Severe Ulcerative Colitis Matt Johnson and Col. Fabricius

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  • Slide 1
  • The Use of Cyclosporin and Heparin in Severe Ulcerative Colitis Matt Johnson and Col. Fabricius
  • Slide 2
  • Topic Areas Case Presentation Cyclosporin Studies Introduction/ Who/ When/ Where Contraindications (Hx, Ex, Ix) Treatment Regimes Inpatient Management Outpatient Management Heparin Studies Discussion
  • Slide 3
  • 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.
  • Slide 4
  • P.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
  • Slide 5
  • P.C> 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
  • Slide 6
  • Predicting 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
  • Slide 7
  • Slide 8
  • Introduction 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
  • Slide 9
  • Cyclosporin 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
  • Slide 10
  • The 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
  • Slide 11
  • Clinical Activity Index for UC
  • Slide 12
  • 20 9 2 No response: surgery 4 11 Cyclosporin 9 Placebo 8 Oral Cyclosporin 1 Elective colectomy 5 5 5 Oral Cyclosporin Results Response No response: open label IV (crossover) Response
  • Slide 13
  • Results 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
  • Slide 14
  • 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 Treatment
  • Slide 15
  • 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 Effects
  • Slide 16
  • Trail Faults Relatively few numbers Largely subjective clinical-activity score (not previously validated) No objective qualification of the disease (endoscopic, histologic or haematological)
  • Slide 17
  • 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 Conclusion
  • Slide 18
  • A 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
  • Slide 19
  • Oxford 6 year Experience EJGH 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
  • Slide 20
  • Cyclosporin for Severe Ulcerative Colitis: A Users Guide Clinical Review in Am J Gastroenterology 1997, 92,1424-8
  • Slide 21
  • WHO, 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
  • Slide 22
  • Contra-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 )
  • Slide 23
  • Contra-indications - Examination Poorly Controlled Hypertension Infection ( regular examinations of central lines)
  • Slide 24
  • Contra-indication - Investigations Pregnancy Test Stool Cultures ESR U+Es LFTs Others: Cholesterol < 120 mg/dl Magnesium < 1.5 mg/dl
  • Slide 25
  • 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
  • Slide 26
  • 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:- levels >500 ng/ml for 2 consecutive days Creat increases by > 30% LFTs double DBP > 90mmHg SBP > 150
  • Slide 27
  • Switching 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
  • Slide 28
  • Outpatient 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
  • Slide 29
  • Side Effects Nephrotoxicity Hepatotoxicity Paraesthesia Hypertension Grand Mal Seizures Septicaemia Opportunistic Infections (PCP and herpetic oesophagitis)
  • Slide 30
  • Slide 31
  • Heparin 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
  • Slide 32
  • Paradoxical 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 (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
  • Slide 33
  • Assessment 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, crypt