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

Because it has NEVER been effective Monotherapy is Dead!

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 Oct;77(4 Pt 2): N Engl J Med 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 Cochrane Database Syst Rev Apr 30;4:CD “Azathioprine and 6-mercaptopurine offer no advantage over placebo for induction of remission or clinical improvement in active Crohn's disease”

Cochrane Meta-Analysis 2009: Maintenance with AZA Cochrane Database Syst Rev Jan 21;(1):CD mg/kg 2mg/kg 1mg/kg

Cochrane Meta-Analysis 2009: Maintenance (Post-Op)with 6MP Cochrane Database Syst Rev Jan 21;(1):CD

Post-operative studies with thiopurines Prevention of Clinical Recurrence Prevention of Endoscopic 1 Year Recurrence Am J Gastroenterol Aug;104(8): I2-i4 I3-i4

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 Apr 30;4:CD Cochrane Database Syst Rev Jan 21;(1):CD

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 Oct;119(4):

6MP Pediatric Study  Proposed “accelerated step-up care” Gastroenterology Oct;119(4):

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

 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 Two study arms: 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

Rapid Trial Results: Proportion of patients in corticosteroid- free, anti-TNF-free remission per trimester

AZTEC Trial GETECCU Spain

AZTEC trial:  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 Study Design GETECCU: 31 Spanish centers

AZTEC Trial Steroid Free of Relapse (CDAI>175)

AZTEC Trial 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) Results

Conclusions 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

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 Problems with Interpretations

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 Am J Gastroenterol 2014; 109: 23–34 TP use is associated with a 40% lowered risk of surgical resection in patients with CD

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 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 Patients (%) Azathioprine + Placebo Infliximab + Placebo Infliximab + Azathioprine P<0.001 P=0.006P= /17075/16996/169 Colombel J et al. N Engl J Med. 2010; 362:1383.

Risk Benefits of Thiopurines Benefits/Indication Risks/Indication

Risks of Thiopurines and Methotrexate Thiopurines  Skin Cancer NMSC/Melanoma  Lymphoma EBV HSTC (with biologics)  Myelodysplasia Neoplastic

We Suggest Against Using Thiopurine Monotherapy to Induce Remission in Patients With Moderately Severe CD (Weak Recommendation, Moderate-Quality Evidence) Gastroenterology. 2013;145(6): 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):

We Recommend Using Thiopurines Over No Immunomodulator Therapy to Maintain a Corticosteroid- Induced Remission in Patients With CD (Strong Recommendation, Moderate-Quality Evidence) AGA Guideline on the Use of Thiopurines, Methotrexate, and Anti–TNF-α Biologic Drugs for Induction and Maintenance of Remission in Crohn's Disease Gastroenterology. 2013;145(6):

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 Defined Roles Where is the EVIDENCE for thiopurine therapy? Il suffit de dire non à la monothérapie