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

6-thiouric acid
XO
AZA 6-MP
HPRT
6-TGNs
TPMT
6-MMP

Wild type
Heterozygous mutation
Homozygous mutation

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 1-1.5 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, 2014. Abstract Su1416.

P< 0.001
100%
80%
60%
40%
20%
41%
78%
Odds Ratio 5.0 for treatment response when 6-TGN > 235
0% n=44
0-173
Dubinsky MC et al. Gastroenterol2000;118: n=42
174-235 n=43
236-367
6-TGN QUARTILES n=44
368-1203

Association of 6-thioguanine nucleotide levels and IBD activity: a meta-analysis
· Osterman MT. Gastroenterology 2006;130:1047-53.

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 – 250-400 pmol/8 x 10 8 RBC)
• Powered for 226 subjects, 50 subjects randomized, 27 subjects completed
Individualised Weight-Based
100
Individualised Weight-Based
80
60 p=0.11
40
40
20
16
0
Clinical Remission at 16 weeks(%)
Dassopoulos T, et al. Aliment Pharmacol Ther 2014;39: 163-175
30
20
10
0
70
60
50
40
60
25 p=0.12
Clinical Remission at 16 weeks(%)

6-TGN
450
235
6-MMP
5700
Dose Too Low;
Noncompliant
Therapeutic
Range
Toxicity Preferential
6MMP

AZA/6-MP as Maintenance Therapy in
Crohn’s Disease after Steroid Induction
ADULTS CHILDREN
1.00
100
80
AZA 2.5 mg/kg/d (n=33)
Placebo (n=30)
0.75
60
0.50
40
20
P=0.001
0.25
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Duration of Trial (months)
0.00
0 100 200
Remission Duration (days)
300
*Remission induced by prednisolone tapered over 12 wk.
9
400
Candy S et al. Gut. 1995;37(5):674-678.
Markowitz, et al. Gastroenterology. 2000;119(4):895-902.
6MP
Control
500 600

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

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

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. 2014 Jan;109:23-34

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

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

Predictors
6-TGN > 250 pmol per 8 . 10 8 RBC
Relative Leukopenia
Absence of lymphopenia
Platelet (K/ul)
TPMT activity (nmole/n/ml)
AST (UI/L)
6MeMPN:6-TGN ratio
OR (95%)
4.14 (1.49-11.46)
14.01 (3.77-52.10)
3.71 (1.26-10.89)
0.995 (0.991-0.999)
0.89 (0.80-0.98)
1.05 (1.01-1.09)
0.95 (0.85-1.04)
Nguyen TV, et al R Inflamm Bowel Dis. 2013 Oct;19(:2404-10

Time To Relapse post Thiopurine Withdrawal
Kennedy NA et al APT 2014:40;1313-2013

Predictors of Relapse post Thiopurine Withdrawal
Kennedy NA et al APT 2014:40;1313-2013

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);371:660-667.

SONIC: Corticosteroid-free Clinical Remission in CD at Week 26
Median disease duration 2.4 years
Clinical Remission
100
P<.001
P=.02
P=.006
56,8
44,4
30.0
0
51/170
AZA + PBO
75/169
IFX + PBO
96/169
IFX + AZA
Colombel JF, et al. N Engl J Med. 2010; 362(15):1383-1395.

Infliximab in Children Study (REACH)
Shorter Disease Duration
Median disease duration 2 years
Response Remission
100
90
88 p=0.002
80
70
60
59
64
56
50
40
30
20
10 n=99 n=66 n=33 n=29
33 n=17 24 n=12
0
Week 10
Overall number of subjects n=112
Week 54 q8 Week 54 q12
• 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):863-873.
P<0.001

SONIC: Infliximab Trough Levels at Week 30
10
8
6
4
2
0
1,6
(n=97)
IFX + placebo
3,5
(n=109)
IFX + AZA
Colombel JF, et al. N Engl J Med. 2010;362(15):1383.

SONIC: Immunogenicity Results at Week 30
100
80
60
40
20
0
98
1/89
1
87/89
0/89
0
AZA + placebo
Positive Negative Inconclusive
68
14
15
15/106 16/106 72/106
IFX + placebo
1/120
1
94
2/120
2
113/120
AZA + IFX
Colombel JF, et al. N Engl J Med. 2010;362(15):1383.

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.

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
Induction of Remission
Maintenance of Remission
(Semester Analysis)
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/8x10 8 RBC)
Kariyawasam V, et al. Presented at DDW; May 4, 2014 Abstract 343.

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

Drobne D. et al CGH 2014 epub ahead of print

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

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