1. Grand Rounds 10th March 2005 A/Prof Anne Duggan Dr Rob Gibson
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

8. PBS drug costs (end June 04)
Volume
Cost ($)
Atorvastatin
Simvastatin
Omeprazole

9. Logan 2004

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

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

13. 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

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

15. 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

16. 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

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

18. 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

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

20. Natalizumab

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

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

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

25. 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

27. Case Presentation 1c
Colonoscopy

28. Case Presentation 1d
Ileoscopy

29. Case Presentation 1e
Histology

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

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

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

33. 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

34. 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

35. Case Presentation 2c
Colonoscopy

36. Case Presentation 2d
Ileoscopy

37. Case Presentation 2e
Histology

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

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

40. 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

41. 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

42. 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

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