1. 6-MP and AZA Applications and Approaches
Marla Dubinsky, MD
Chief, Pediatric GI and Hepatology
Co-Director, Susan and Leonard Feinstein IBD Clinical Center
Icahn School of Medicine
Mount Sinai Hospital, New York

2. Metabolism of AZA/6-MP 6-thiouric acid XO HPRT AZA 6-MP 6-TGNs TPMT
6-MMP

3. TPMT Activity Distribution
Wild type
Homozygous
mutation
Heterozygous
journal/ /1324/
Cies C et al. NZ Med J 2005;118:1324

4. Adverse Event Comparison*
Safety of Starting Full Weight-Based Dosing vs. Low-Dose Thiopurines in Normal Metabolizers (TPMT >25)
Complication Rates in Patients Starting Full-Dose Thiopurines vs. Controls (Gradual Increase)
Retrospective study of 134 adult CD patients with TPMT > 25 (normal metabolizers) and > 1 year follow-up
Dose initiation at 2-2.5mg/kg AZA or mg/kg 6MP (therapy) compared with gradual increase (control)
Results
Overall similar rates of AEs
90% of complications in both groups occurred in first 3 months
Adverse Event Comparison*
Benmassauod A, et al. Presented at DDW; May 4, Abstract Su1416.

5. Target 6-TGN Level to Optimize Efficacy: >235
78%
Frequency of Response
Odds Ratio 5.0 for treatment response when 6-TGN > 235
41%
n=44
0-173
n=42
n=43
n=44
6-TGN QUARTILES
Dubinsky MC et al. Gastroenterol2000;118:

6. Association of 6-thioguanine nucleotide levels and IBD activity: a meta-analysis
Osterman MT. Gastroenterology 2006;130:

7. Prospective Data Supporting Metabolite-Based Dose Optimization of Thiopurines are Inconclusive
Multicenter RCT comparing AZA dosing - weight-based (2.5 mg/kg/day)
versus individualized (stratified by TPMT, then optimized to target
6TGN – pmol/8 x 108RBC)
Powered for 226 subjects, 50 subjects randomized, 27 subjects completed
p=0.11
p=0.12
Per Protocol
Intention To Treat
Dassopoulos T, et al. Aliment Pharmacol Ther 2014;39:

8. 6-MP Metabolite Profiles
6-TGN
450
235
5700
6-MMP
Dose Too Low;
Noncompliant
Therapeutic
Range
Preferential
6MMP
Toxicity

9. AZA/6-MP as Maintenance Therapy in Crohn’s Disease after Steroid Induction
Duration of Trial (months) Remission Duration (days) 80 60 40 20
% Patients Not Failing Trial 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
AZA 2.5 mg/kg/d (n=33)
Placebo (n=30)
100
P=0.001
*Remission induced by prednisolone tapered over 12 wk.
200
300
400
500
600
0.00
0.25
0.50
0.75
1.00
6MP
Control
Fractional Survival
ADULTS
CHILDREN
Candy S et al. Gut. 1995;37(5):
Markowitz, et al. Gastroenterology. 2000;119(4):

10. Cosnes J et al. Gastroenterology 2013;145: 758-65
Early “top-down” therapy with azathioprine is not
more effective than placebo or conventional therapy
RAPID
AZTEC
Cosnes J et al. Gastroenterology 2013;145:

11. Predictors of surgery within 5 years of Crohn’s diagnosis
Chatu S et al Am J Gastroenterol 2014;109:409-16

12. The Role of Thiopurines in Reducing the Need for Surgical
Resection in Crohn’s disease: Systematic review and meta-analysis
Chatu S et al. Am J Gastroenterol Jan;109:23-34

13. Thiopurines Use and Surgical Rates: UK
Chatu S et al Am J Gastroenterol 2014;109:409-16

14. Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in Crohn's disease
Gordon M et al Cochrane database syst rev 2014;8:CD010233

15. Predictors of Thiopurine response
6-TGN > 250 pmol per RBC
4.14 ( )
Relative Leukopenia
14.01 ( )
Absence of lymphopenia
3.71 ( )
Platelet (K/ul)
0.995 ( )
TPMT activity (nmole/n/ml)
0.89 ( )
AST (UI/L)
1.05 ( )
6MeMPN:6-TGN ratio
0.95 ( )
Nguyen TV, et al R Inflamm Bowel Dis Oct;19(:

16. Time To Relapse post Thiopurine Withdrawal
Kennedy NA et al APT 2014:40;

17. Predictors of Relapse post Thiopurine Withdrawal
Kennedy NA et al APT 2014:40;

18. Combined Immunosuppressive Therapy versus Conventional Management in Early Crohn’s Disease Clinical Results at 2 Years
Primary Endpoint:
Proportion of patients in remission
CDAI < 150
No Steroids, No Surgery
methylprednisolone
Azathioprine/6-MP
infliximab
D’Haens et al. Lancet. 2008(9613);371:

19. Median disease duration 2.4 years
SONIC: Corticosteroid-free Clinical Remission in CD at Week 26
Median disease duration 2.4 years
P=.006
P=.02
P<.001
Patients (%)
51/170
75/169
96/169
Colombel JF, et al. N Engl J Med. 2010; 362(15):

20. Median disease duration 2 years
Infliximab in Children Study (REACH) Shorter Disease Duration
Median disease duration 2 years
p=0.002
Patients (%)
P<0.001
n=99
n=66
n=33
n=29
n=17
n=12
Overall number of subjects n=112
Antibodies to infliximab in 3 (2.9%) patients (1 in each maintenance arm and another not randomized)
Hyams J, et al. Gastroenterology. 2007;132(3):

21. SONIC: Infliximab Trough Levels at Week 30
Colombel JF, et al. N Engl J Med. 2010;362(15):1383.

22. Percent of Patients (%)
SONIC: Immunogenicity Results at Week 30
100 98
Positive
Negative
Inconclusive 94 80 68 60
Percent of Patients (%) 40 20 14 15
1/89
2/120
0/89
1/120 1 1 2
87/89
15/106
16/106
72/106
113/120
AZA + placebo
IFX + placebo
AZA + IFX
Colombel JF, et al. N Engl J Med ;362(15):1383.

23. 6-Thioguanine Concentrations Are Associated With Higher Trough Infliximab Concentrations In IBD Patients On Combination Therapy
Cross-sectional study of IBD patients (N=72, 63% CD) receiving IFX in combination with a thiopurine for ≥4 months
Correlation Between 6-TGN and IFX Concentrations
Comparison Between Groups With
and Without Detectable Antibodies to IFX (ATI)
Higher 6-TGN levels correlate with higher IFX trough concentrations but levels of 125 may maximize IFX levels
Patients with detectable IFX antibodies had significantly lower 6TGN levels
Yarur A, et al. Presented at DDW, May 5, 2014 Abstract 788.

24. Maintenance of Remission Induction of Remission
Azathioprine Decreases the Risk of Adalimumab Primary Non-Response and Secondary Loss of Response If Adequately Dosed 
CD patients on combination immunomodulator (IM) plus adalimumab (n=76) vs. adalimumab monotherapy (n=46) followed for mean of 21 months
Maintenance of Remission
(Semester Analysis)
Induction of Remission
IM for 3 months prior to starting adalimumab improves response at 12 weeks
Semester analysis showed lower flare and failure rates only if thioguanine (TGN) levels were therapeutic (>235 pmol/8x108 RBC)
Kariyawasam V, et al. Presented at DDW; May 4, 2014 Abstract 343.

25. Withdrawal of Immunomodulator and Infliximab Dose Escalation and Discontinuation
Drobne D. et al CGH 2014 epub ahead of print

26. Levels Pre and Post IMM withdrawal
Drobne D. et al CGH 2014 epub ahead of print

27. Trough Levels at Time of IMM Withdrawal Predict Infliximab Dose Escalation
Drobne D. et al CGH 2014 epub ahead of print

28. 6-MP/AZA Approaches and Applications :Summary
Thiopurine Levels are associated with improved efficacy
Role of thiopurines as steroid sparing maintenance strategy questionable
Thiopurines protective of surgery but post operative effectiveness needs further exploration
Combination therapy with thiopurine and anti-TNF is more effective than monotherapy
Combination therapy decreased ATI and improves Anti TNF drug levels
Anti-TNF levels remain stable after stopping thiopurine