Transcript Is there a future for thiopurines and methotrexate in IBD

Monotherapy using 6-MP or
azathioprine for Crohn’s disease
is dead: out with the old and in
with the new
Stephen B. Hanauer, MD
Professor of Medicine
Clinical Director, Digestive Health Center
Monotherapy is Dead!
Because it has NEVER been effective
Thiopurines in CD 1980s-1990s
• 1979 NCCD study: azathioprine not effective for
induction or maintenance in CD
• 1980 Present: 6MP effective as
induction/maintenance in CD
(n=83, dur=8y, f/u=2y)
 Mean time to response: 3.1 months
 Require < 6 months to reach maximal efficacy
• 1980s-1990s: contradictory data
Gastroenterology. 1979 Oct;77(4 Pt 2):847-69.
N Engl J Med. 1980 May 1;302(18):981-7.
Clinical Trials 2000s
• In patients with longstanding CD:
 Maximum clinical effect of thiopurines
plateaus after 8 weeks of therapy
 Absolute rates of remission 25-30%
 Unclear role in induction therapy
Cochrane Meta-Analysis 2013:
Induction
“Azathioprine and 6-mercaptopurine offer no advantage over placebo
for induction of remission or clinical improvement in active Crohn's
disease”
Cochrane Database Syst Rev. 2013 Apr 30;4:CD000545.
Cochrane Meta-Analysis 2009:
Maintenance with AZA
2.5mg/kg
2mg/kg
1mg/kg
Cochrane Database Syst Rev. 2009 Jan 21;(1):CD000067.
Cochrane Meta-Analysis 2009:
Maintenance (Post-Op)with 6MP
Cochrane Database Syst Rev. 2009 Jan 21;(1):CD000067.
Post-operative studies with thiopurines
Prevention of Clinical Recurrence
1 Year
Prevention of Endoscopic
Recurrence
I2-i4
I3-i4
Am J Gastroenterol. 2009 Aug;104(8):2089-96
Recent Cochrane Meta-analyses
• In patients with longstanding CD:
 Thiopurines NOT effective for induction
 Thiopurines ARE effective for maintenance
of remission and for steroid sparing
 Thiopurines ARE effective for prevention of
post-operative recurrence
Cochrane Database Syst Rev. 2013 Apr 30;4:CD000545.
Cochrane Database Syst Rev. 2009 Jan 21;(1):CD000067.
6MP Pediatric Study
• Markowitz 2000:
 55 pediatric patients with new-onset CD (<8
weeks) on tapering prednisone (f/u 18mos)
 6MP lessened need for prednisone and improved
maintenance of remission
 By 12 months, 89% of 6MP and placebo with
remission (p=ns)
• Relapse 9% vs 47% (p=0.007) after 6 months
Gastroenterology. 2000 Oct;119(4):895-902.
6MP Pediatric Study
 Proposed “accelerated step-up care”
Gastroenterology. 2000 Oct;119(4):895-902.
RAPID Trial
GETAID
France
• RAPID trial:
 3 years
 Open-label randomized trial
• GETAID: 24 French centers
• 147 adult patients (IMM/biologic naïve) with:
 newly diagnosed CD (<6 months)
 Risk factors for disabling disease (>2):
• Younger than 40
• Active perianal lesions
• Corticosteroids within 3 months of diagnosis
RAPID Trial
Two study arms:
 Early (Immediate) azathioprine
 Conventional azathioprine when:
• Corticosteroid dependence
• Chronic active disease with frequent flare
• Poor response to treatment with steroids
• Development of severe perianal disease
RAPID Trial
• Primary End Point:
 Proportion of trimesters in remission
during follow-up
• Secondary End Points:
 Proportion of trimesters with flare
 CD-related hospitalization
 Active perianal disease
 Perianal/Intestinal surgery
 Steroid/anti-TNF use
Rapid Trial
Results: Proportion of patients in corticosteroidfree, anti-TNF-free remission per trimester
AZTEC Trial
GETECCU
Spain
AZTEC trial:
Study Design
• GETECCU: 31 Spanish centers
 18 months
 Double-blind randomized trial
 Intended to replicate Markowitz study
• 131 adult patients (IMM/biologic naïve) with:
 newly diagnosed CD (<8 weeks)
• Two study arms (stratified by age and steroid use):
 Azathioprine
 Placebo
AZTEC Trial
Steroid Free of Relapse (CDAI>175)
AZTEC Trial
Results
• In Early AZA:
 44% with steroid-free remission at 76 weeks vs
37% for placebo (p=0.48)
 No difference in proportion of patients with SFR at
weeks 28 or 50, relapse-free survival rates, CDAI
scores or CRP over time
 Post-hoc analysis:
• Relapse after week 12 (defined as CDAI >220)
12% vs 30% (p=0.01)
Conclusions
RAPID + AZTEC
• Early “top-down” therapy with thiopurines
not more effective than conventional therapy
or placebo in adults with newly diagnosed
CD
• Cast doubt on applicability of 2000 pediatric
study
RAPID + AZTEC
Problems with Interpretations
• Inactive/mild disease (compared to Markowitz)
• Open-label (GETAID)
• Primary end point never used before (GETAID)
• No optimization of 6TGN levels
• Remission defined by CDAI
• Better predictors of high risk??
• Median delay of 11 months between 2 groups in
GETAID study
• Early termination of AZTEC
In additon….
Assimilating results from observational series
The Role of Thiopurines in Reducing the Need for
Surgical Resection in Crohn's Disease: A Systematic
Review and Meta-Analysis
Hazard ratio associated with thiopurine use and risk of surgery in CD patients
TP use is associated with a 40% lowered risk
of surgical resection in patients with CD
Am J Gastroenterol 2014; 109: 23–34
Conclusions
Remaining indications for thiopurines:
 Maintenance of steroid-induced
remission/steroid sparing in patients
with CD (?not newly diagnosed) –
modest effect
 Prevention of postoperative
recurrence- modest effect
Strongest indication: in combination with
biologics
SONIC: Clinical Remission
Without Corticosteroids at Week 26
100
P<0.001
Patients (%)
80
P=0.006
P=0.022
57
60
44
40
30
20
0
51/170
75/169
96/169
Azathioprine
+ Placebo
Infliximab
+ Placebo
Infliximab
+ Azathioprine
• Moderate to severe Crohn’s disease
• No prior exposure to biologic agents or immunomodulators
• At least 1 corticosteroid-dependent second course of steroids within 1 yr being
considered, 5-ASA failure, or budesonide 9-mg failure
Colombel J et al. N Engl J Med. 2010; 362:1383.
Risk Benefits of Thiopurines
Benefits/Indication
Risks/Indication
Risks of Thiopurines and Methotrexate
Neoplastic
• Thiopurines
 Skin Cancer
• NMSC/Melanoma
 Lymphoma
• EBV
• HSTC (with biologics)
 Myelodysplasia
AGA Guideline on the Use of Thiopurines,
Methotrexate, and Anti–TNF-α Biologic Drugs for
Induction and Maintenance of Remission in Crohn's
Disease
• We Suggest Against Using Thiopurine Monotherapy to
Induce Remission in Patients With Moderately Severe CD
(Weak Recommendation, Moderate-Quality Evidence)
Gastroenterology. 2013;145(6):1459-63
AGA Guideline on the Use of Thiopurines, Methotrexate,
and Anti–TNF-α Biologic Drugs for Induction and
Maintenance of Remission in Crohn's Disease
• We Suggest Using Anti–TNF-α Drugs in Combination With
Thiopurines Over Anti–TNF-α Drug Monotherapy to
Induce Remission in Patients Who Have Moderately
Severe CD
(Weak Recommendation, Moderate-Quality Evidence)
Gastroenterology. 2013;145(6):1459-63
AGA Guideline on the Use of Thiopurines,
Methotrexate, and Anti–TNF-α Biologic Drugs for
Induction and Maintenance of Remission in Crohn's
Disease
• We Recommend Using Thiopurines Over No
Immunomodulator Therapy to Maintain a CorticosteroidInduced Remission in Patients With CD
• (Strong Recommendation, Moderate-Quality Evidence)
Gastroenterology. 2013;145(6):1459-63
Where is the EVIDENCE for thiopurine
therapy?
Defined Roles
•Maintenance of Steroid-induced
remissions when used with steroids to
induce remissions
•Maintenance of Post-operative remissions
Most effective with metronidazole
•Combined with anti-TNF (infliximab) to
induce and sustain 1-year remissions
Il suffit de dire non à la monothérapie