Presentation on theme: "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."— Presentation transcript:
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. 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 Cochrane Database Syst Rev. 2013 Apr 30;4:CD000545. “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. 2009 Jan 21;(1):CD000067.. 2.5mg/kg 2mg/kg 1mg/kg
Post-operative studies with thiopurines Prevention of Clinical Recurrence Prevention of Endoscopic 1 Year Recurrence Am J Gastroenterol. 2009 Aug;104(8):2089-96 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. 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.
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 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 30 44 57 0 20 40 60 80 100 Patients (%) Azathioprine + Placebo Infliximab + Placebo Infliximab + Azathioprine P<0.001 P=0.006P=0.022 51/17075/16996/169 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):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
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):1459-63
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