1. Azathioprine for IBD : Better the devil you know Jeremy D. Sanderson

2. Azathioprine for inducing remission in active IBD 425 patients (209 AZA/6-MP, 216 placebo) End-points: steroid sparing effect, clinical response Overall response Aza/6-MP54% (CI 47%-61%) placebo 33% (CI 27%-40%) Pooled OR2.36 (CI 1.57 – 3.53) Time to respondPresent 1980av. 3.1 months OR 1.54 if <17 weeks Rx OR 2.51 if >17 weeks Rx Steroid sparingAza/6-MP65% (CI 56%-74%) placebo36% (CI 27%-45%) Pooled OR3.86 (CI 2.14 – 6.96) Sandborn et al, Cochrane Library, Issue 4, 2000

3. Background Azathioprine effective in 70% patients with IBD 30% failure due to:Intolerance 15% No response 15% IntoleranceBone marrow suppression Nausea Myalgia, flu-like symptoms Pancreatitis Hepatotoxicity Other Azathioprine failuresMTX, anti-TNF  Surgery

4. Azathioprine 6-Mercaptopurine 6-thioinosine nucleotide 6-thioguanine nucleotides Thiouric acid 6-Me MP TPMT*** Xanthine oxidase HGPRT IMPDH - - - ImmunosppressionClinical benefit

5. Intermediate High (Normal) Very High Low

6. TPMT (thiopurine methyl transferase) allelic polymorphism High TPMT 89% Intermediate TPMT 11% Low TPMT 1/300 ?very high TPMT Severe Bone Marrow Suppression !! High risk of marrow suppression Low risk ? poor responders - + clinical response

7. Initiate at 100mg Build to 2mg/kg AZA treatment ? Check TPMT Enzyme / genotype Check TPMT Enzyme / genotype Homozygous deficient Heterozygous deficient Normal Initiate at 25mg Build to 1mg/kg Consider 2.5 – 5mg AZA ? Thioguanine Alternative Rx Consider 2.5 – 5mg AZA ? Thioguanine Alternative Rx TolerantIntolerant Very high Flu-like illness Pancreatitis Hepatitis Flu-like illness Pancreatitis Hepatitis Nausea Reduce dose Switch to 6-MP Alternative Rx ? Thioguanine Marrow suppression Reduce dose Check for drugs, 5’-nucleotidase def Parvovirus infection Repeat TPMT 6mo – 1yr. InducedNo change Increase AZAContinue Initiate at 100mg Build to 2.5 – 3mg/kg Non-response…...

8. Bargain Azathioprine …….. still the best and getting better

9. IBD medical therapy …… …… the Bridge approach

10. Crohn’s disease : the Bridge approach Antibiotics Nutritional Rx Steroids Methotrexate Anti-TNF  Azathioprine Mycophenolate ?? Methotrexate

11. Conclusions Many new and potentially exciting therapies for refractory IBD But before you use them …….. Make sure you get the best out of existing approaches