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Grand Rounds 10 th March 2005

Grand Rounds 10 th March 2005. A/Prof Anne Duggan Director of Gastroenterology Dr Rob Gibson Gastroenterology Registrar. Diseasing on the edge of the bell shaped curve. Drugs, Dollars & Disappointment. Crohn’s Disease. Gaussian / Normal Distribution Curve. Hypothesis:.

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Grand Rounds 10 th March 2005

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  1. Grand Rounds10th March 2005 A/Prof Anne Duggan Director of Gastroenterology Dr Rob Gibson Gastroenterology Registrar

  2. Diseasing on the edge of the bell shaped curve Drugs, Dollars & Disappointment

  3. Crohn’s Disease

  4. Gaussian / Normal Distribution Curve

  5. Hypothesis: • Living “ on the edge” can be exciting • Diseasing “on the edge” can be dangerous • Some crohn’s patients dis-ease “on the edge” • Of QOL • Of equitable access to drugs • Of the health agenda c => b => a

  6. Crohn’s prevalence 100/100,000 Severe crohn’s

  7. PBS drug costs (end June 04)

  8. Logan 2004

  9. COST • Infliximab - $20 000/year (70kg) • CABG - $13 000 • Bowel Resection $9319 • Total Hip Replacement $8075 • Interferon/Ribavirin $10000/6mth

  10. Question Should we (DOM) target low volume expensive drugs of great benefit? OR High volume inexpensive drugs of little benefit? OR ?

  11. Monoclonal Antibodies Infliximab – Anti TNF Natiluzimab – Anti alpha4 Integrin Adalimumab – Recombinant Anti TNF Fontolizumab – Anti Interferon Gamma Anti Interleukin 12 Anti Interleukin 6 Anti Interleukin 18

  12. Other Biological Agents • Etanercept – Soluble TNF receptor • Onercept – Recombinant TNF receptor • Interleukin 10 • Interleukin 11 • GM – CSF • Pegylated Anti TNF

  13. Natalizumab • Recombinant monoclonal antibody against alpha4 integrin • Integrins are receptors involved in migration and activation of leukocytes. • Found on vascular endothelium and in extracellular matrix • Integrins are up regulated at sites of chronic inflammation

  14. Natalizumab • On the basis of 2 positive pilot studies a double blinded RCT was undertaken to examine the efficacy in moderate to severe crohns disease • Gosht et al NEJM 2003

  15. Natalizumab • Inclusion criteria • Over 18 years • Moderate to severe crohns • CDAI (220 – 450) • Azathioprine and 6-mercaptopurine in stable dose for 4 months prior

  16. Natalizumab • Exclusion criteria • Methotrexate or cyclosporine in the previous 3 months • Past Mab or investigational agent • Infectious or neoplastic disease • Obstructive symptoms • Prednisone dose over 25mg • Bowel surgery - previous 3 months

  17. Natalizumab • Endpoints at 6 weeks • Primary • Remission (CDAI<150) • Response (CDAI fall by 70) • Secondary • CRP • Quality of life

  18. Natalizumab

  19. Natalizumab • Safety • Adverse events similar across all groups • SAEs –mainly escalation of treatment • Arthralgia • Itch • Infusion reaction • Influenza type syndrome

  20. Conclusion • Efficacious in the short term • Safe • Long term therapy yet to be tested => CDP 351 Antegren trial

  21. Case Presentation 1a • Mr DL 25 years • Recently graduated from University • Now working as postman • Now in a relationship • Moved from home • Soccer coach

  22. Case Presentation 1b • Diagnosed aged 18 • Mucoid, blood stained diarrhoea 10 to12 motions daily • Generalised colicky abdominal pain • Weight loss 15kg in 2months from symptom onset • Erythema Nodosum

  23. Case Presentation 1c • Colonoscopy

  24. Case Presentation 1d • Ileoscopy

  25. Case Presentation 1e • Histology

  26. Case Presentation 1f • Treatments included • Salazopyrine • Prednisone • doses up to 75mg • Initially 8 months before weaning but rapid flare • Rarely below 12.5mg • Azathioprine

  27. Case Presentation 1g • Hospitalizations 5 in JHH in 5 years • Varied from 8 to 12 days • IV cyclosporine Seen 5 Australian Opens in Hospital

  28. Case Presentation 1h • Uncontrolled Disease • Dropped out of University • Unemployed • Depressed • Barely left the house

  29. Case Presentation 2a • Mr CR 38 years • Married • 3 children under 10 • Non smoker • Employed by Telstra • Installs and maintains Communications systems • Travels widely by car

  30. Case Presentation 2b • Presented aged 34 • Initially arthralgia and fatigue • Within days – diarrhoea, faecal urgency and associated abdominal cramps • No other extra luminal features • Stool examination – White cells only

  31. Case Presentation 2c • Colonoscopy

  32. Case Presentation 2d • Ileoscopy

  33. Case Presentation 2e • Histology

  34. Case Presentation 2f • Clinical progress • Chronic Diarrhoea (14/day) • Chronic fatigue • Weight loss ( 10kg first 5 months)

  35. Case Presentation 2g • Multiple treatments • Salazopyrine => Intolerant • Prednisone dependant for 2 years • Azathioprine => Pancreatitis • Mesalazine

  36. Case Presentation 2h • Planned his travel routes around toilets • Urgent stops by the road side • Sick leave 1 or 2 days a fortnight • Avoided hospitalization because he refused

  37. Progress on Natalizumab • All became asymptomatic within 1 to 3 months and have been so since ( all 2 to 3 years) • All on no other medication • 3 of 5 on antidepressants now off medication

  38. Infliximab morbidity and mortality in 500 patients : Serious adverse events – 8.6% Infusion reactions – 3.8% Development of drug induced lupus 1.5% Subsequent infection – 8.2% Mortality – 1%1

  39. Question Should we (DOM) target low volume expensive drugs of great benefit? OR High volume inexpensive drugs of little benefit? OR ?

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