Monotherapy using 6-MP or azathioprine for Crohn’s disease is dead: out with the old and in

with the newStephen B. Hanauer, MDProfessor of MedicineClinical 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

Cochrane Meta-Analysis 2009: Maintenance (Post-Op)with 6MP

Cochrane Database Syst Rev. 2009 Jan 21;(1):CD000067.

Post-operative studies with thiopurinesPrevention 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.

6MP Pediatric Study

Proposed “accelerated step-up care”

Gastroenterology. 2000 Oct;119(4):895-902.

RAPID TrialGETAIDFrance

• 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 TrialResults: Proportion of patients in corticosteroid-free, anti-TNF-free remission per trimester

AZTEC TrialGETECCUSpain

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 TrialSteroid 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

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-AnalysisHazard 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

Pat

ien

ts (

%)

Azathioprine + Placebo

Infliximab+ Placebo

Infliximab+ Azathioprine

P<0.001

P=0.006 P=0.022

51/170 75/169 96/169

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

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