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The Use of Cyclosporin and Heparin in Severe Ulcerative Colitis

The Use of Cyclosporin and Heparin in Severe Ulcerative Colitis. Matt Johnson and Col. Fabricius. Topic Areas. Case Presentation Cyclosporin Studies Introduction/ Who/ When/ Where Contraindications (Hx, Ex, Ix) Treatment Regimes Inpatient Management Outpatient Management Heparin Studies

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The Use of Cyclosporin and Heparin in Severe Ulcerative Colitis

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

  2. Topic Areas • Case Presentation • Cyclosporin Studies • Introduction/ Who/ When/ Where • Contraindications (Hx, Ex, Ix) • Treatment Regimes • Inpatient Management • Outpatient Management • Heparin Studies • Discussion

  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.

  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

  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

  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

  7. 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

  8. 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

  9. 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

  10. Clinical Activity Index for UC

  11. 11 9 Cyclosporin Placebo 2 4 No response:surgery No response:surgery 1 Elective colectomy Results 20 9 5 Response No response:open label IV(crossover) 5 8 Response Oral Cyclosporin 5 Oral Cyclosporin

  12. 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

  13. Results 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

  14. Adverse 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

  15. Trail Faults • Relatively few numbers • Largely subjective clinical-activity score (not previously validated) • No objective qualification of the disease (endoscopic, histologic or haematological)

  16. Conclusion • 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

  17. 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 <18/12 (mean of 6/12) • In all 62% avoided colectomy, 72% of cyclo responders, 80% with 6MP or Aza

  18. Oxford 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

  19. Cyclosporin for Severe Ulcerative Colitis: A User’s Guide • Clinical Review in Am J Gastroenterology 1997, 92,1424-8

  20. 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

  21. 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 )

  22. Contra-indications - Examination • Poorly Controlled Hypertension • Infection ( regular examinations of central lines)

  23. Contra-indication - Investigations • Pregnancy Test • Stool Cultures • ESR • U+Es • LFTs • Others: • Cholesterol < 120 mg/dl • Magnesium < 1.5 mg/dl

  24. 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

  25. 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

  26. 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

  27. 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

  28. Side Effects • Nephrotoxicity • Hepatotoxicity • Paraesthesia • Hypertension • Grand Mal Seizures • Septicaemia • Opportunistic Infections (PCP and herpetic oesophagitis)

  29. 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

  30. 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

  31. 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, cryptitis, abscesses, goblet cell depletion, regenerative hyperplasia • General Well Being • 0 (very poor) to 5 (excellent) • 9 Rectal Bx (fibrin thrombi)

  32. Mean Scores on Disease Variables Slide 1

  33. Results • 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)

  34. Treatment of Corticosteroid - Resistant 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

  35. Conclusion • 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

  36. 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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