Monotherapy using 6-MP or
azathioprine for IBD is not dead yet:
long live the tried and true
Jean-Frederic Colombel
Icahn School of Medicine at Mount Sinai
New York, NY
Conflicts of interest
J-F Colombel has served as consultant, advisory board member or speaker for
Abbvie, ABScience, Amgen, Bristol Meyers Squibb, Celltrion, Danone, Ferring, Genentech,
Giuliani SPA, Given Imaging, Janssen, Immune Pharmaceuticals, Medimmune, Merck & Co.,
Millenium Pharmaceuticals Inc., Neovacs, Nutrition Science Partners Ltd., Pfizer Inc.
Prometheus Laboratories, Protagonist, Receptos, Sanofi, Schering Plough Corporation, Second
Genome, Shire, Takeda, Teva Pharmaceuticals, Tigenix, UCB Pharma, Vertex, Dr. August Wolff
GmbH & Co.
Are we still using azathioprine monotherapy ?
Evolution of prescription of drugs in IBD during the last 20 years
Maximal prescription during the 4-yr calendar period
100%
80%
no IS
AZA
a-TNF
60%
40%
20%
Crohn’s disease (n=3852)
Courtesy J.Cosnes
-9
19 6
97
-0
20 0
01
-0
20 4
05
-0
20 8
09
-1
2
19
93
-0
20 0
01
-0
20 4
05
-0
20 8
09
-1
2
19
97
19
93
-9
6
0%
Ulcerative Colitis (n=1880)
Hôpital St-Antoine,
Paris
What should we consider ?
• Efficacy
• Safety
• Practicality and cost
For the sake of time let’s concentrate on Crohn’s disease
Efficacy of AZA/6MP vs placebo at inducing remission
in Crohn’s disease
NNT = 5
Prefontaine E et al. Cochrane database of systematic reviews 2010
Efficacy of AZA/6MP vs placebo for steroid sparing effect
Prefontaine E et al. Cochrane database of systematic reviews 2010
Efficacy of AZA/6MP vs placebo for fistula improvement
or healing
Prefontaine E et al. Cochrane database of systematic reviews 2010
Efficacy of AZA/6MP vs placebo at maintaining remission in
Crohn’s disease
NNT = 6
NNT = 5
Prefontaine E et al. Cochrane database of systematic reviews 2010
AZA for the prevention of post-operative recurrence of
Crohn’s disease
Mean difference (CI 95%)
with control arms (%)
p
NNT
Clinical recurrence
(1 year)
8 (1–15)
0.021
13
Clinical recurrence
(2 years)
13 (2–24)
0.018
8
Endoscopic recurrence
(1 year)
23 (9–37)
0.0016
4
15 (1.8–29)
0.026
7
Endpoint
Severe endoscopic
recurrence (i2–i4)
NNT = number needed to treat
Peyrin-Biroulet L et al. Am J Gastroenterol 2009
Why should we abandon a
drug that works ?
Gastroenterology 2013
Sonic: steroid-free remission at week 26
AZA + placebo
IFX + placebo
IFX + AZA
Primary endpoint
100
Proportion of patients (%)
p<0.001
80
p=0.009
p=0.022
57
60
44
40
31
20
0
52/170
75/169
96/169
Steroid-free remission = CDAI <150 points
Colombel JF et al. NEJM 2010
Sonic : complete mucosal healing at week 26
AZA + placebo
IFX + placebo
IFX + AZA
Proportion of patients (%)
100
80
p<0.001
p=0.023
60
p=0.055
44
40
20
0
30
17
18/109
28/93
47/107
Mucosal healing: complete absence of mucosal ulcerations in the colon and terminal ileum as assessed by
video endoscopy
Colombel JF et al. NEJM 2010
The
study
TheRapid
RAPID study
≤6 months
≥2/3 criteria
• Age <40 years
• Perineal disease
• Need for steroids
• During first 3 months
Randomisation
Diagnosis
of CD
Cosnes J et al. Gastroenterology 2013;145: 758-65
Primary endpoint:
• Number of trimesters without
– activity
– steroids
– IFX
– surgery
– hospitalisation
AZA if needed (n=60)
36 months
AZA early 2.5mg/kg (n=60)
Early “top-down” therapy with azathioprine is not more
effective than placebo or conventional therapy
RAPID
Cosnes J et al. Gastroenterology 2013;145: 758-65
Cosnes J et al. Gastroenterology 2013;145: 758-65
AZTEC
Panes J et al. Gastroenterology 2013;145: 766-74
The tortoise and the hare
Rien ne sert de courir, il faut partir a point !
Jean Dela Fontaine 1625
Crohn’s disease as a progressive disease
Progression of digestive damage and inflammatory activity in a
theoretical patient with Crohn’s disease
Stricture
Surgery
Stricture
Disease
onset
Diagnosis
Pariente B, et al. Inflamm Bowel Dis 2011
Early
disease
Inflammatory activity
(CDAI, CDEIS, CRP)
Fistula/abscess
years
Limitations of current clinical trials in
evaluating long-term impact of therapies
Short duration….
12 months
Use of azathioprine delays phenotype progression
in Crohn’s disease
ns
AZA
Before change
N = 349
P<0.01
P<0.01
No treatment
before change
N = 344
AntiTNF + AZA
before change
N = 100
Magro F , et al. Am J Gastroenterol 2014
Thiopurine use is associated with a 40% lowered risk of
surgical resection in Crohn’s disease
Chatu S , et al. Am J Gastroenterol 2014
What should we consider ?
• Efficacy
• Safety
• Practicality and cost
TREAT
Infections and azathioprine
Lichtenstein G et al. DDW 2010
Lymphomas and azathioprine
Beaugerie L et al. Gastroenterology 2013
How to reduce the risk of lymphomas
Avoid with
azathioprine
associated
azathioprine ?
• Young males
– HSTLs (1/5000)
• EBV-negative young males
– Fatal Epstein Barr virus-associated hemophagocytic syndrome (1/500)
• Patients >65 yrs
– Lymphoma
– Infections
Beaugerie L et al. Lancet 2009
Azathioprine and non-melanoma skin cancers
Yearly incidence rate (per 1,000 patient-years)
>65 years
6
Thiopurine therapy
5.70
Continuing
5
Discontinued
4.04
Never received
4
50-65 years
3
2.59
<50 years
2
1.96
1
0.84
0.66
0.60
0.38
0
Cases of NMSC (n)
0
9
3
0
6
3
3
3
3
2
Peyrin-Biroulet L et al. Gastroenterology 2011
How to reduce the risk of skin cancers
associated with azathioprine ?
Surveillance based on risk
stratification
Low-risk patients
• Dark skin
• No pre-malignant lesions
• No history of BCC/SCC
• No outdoor occupation
• Young age
Moderate-high risk patients
• Sunburns/exposure to ionizing radiation
• Light skin, freckling or facial telangiectasia
• Outdoor occupations
• Living in high sun exposure countries
• High exposure to sun as a child
• Psoriasis treatment with oral psoralen and
PUVA
• High cumulative exposure to thiopurines
• Combination therapy
• Increasing age
New medical skin
exam in 3-5 years
Skin examination every other
year
Torres J et al. Inflam Bowel Dis 2013
Very high-risk
patients
History of cutaneous
malignancies
Manage on
individual
basis
More about thiopurines safety…
• Azathioprine does not increase the risk of new or
recurrent cancers in patients with past history of
cancer
Beaugerie L et al. Gut 2014
• Azathioprine is safe during pregnancy
Jharap B et al. Gut 2014
Number of side-effects reported
The learning curve of side-effects
First
exposure
medication errors, misuse
co-medication & interactions
long-term use
healthy
volunteers
selected
patients
different population, risk groups
Drug development
Phase I-IIIa
trials
Launch
First
renewal
rare ADRs (< 1/1.000)
What should we consider ?
• Efficacy
• Safety
• Practicality and cost
Healthcare costs of IBD have shifted from hospitalisation
and surgery towards anti-TNFa therapy
Anti-TNF use accounts for 64% and 31% of total costs in CD and UC
Van der Valke ME et al. Gut 2012
We cannot exclude cost considerations…
With the same 1-year budget one can
treat efficiently 1 patient with anti-TNF
And 100 with AZA !
Bourrier A, Seksik P, Cosnes J. Current Drug Targets 2013
When should we use
thiopurine monotherapy ?
Prediction: profiling in order to take the best
therapeutic decision
Courtesy Tine Jess
Crohn’s disease evaluation and treatment:
clinical decision tool
Sandborn WJ . Gastroenterology 2014
Crohn’s disease evaluation and treatment:
clinical decision tool
Sandborn WJ . Gastroenterology 2014
Crohn’s disease evaluation and treatment:
clinical decision tool
Sandborn WJ . Gastroenterology 2014
Crohn’s disease evaluation and treatment:
clinical decision tool
Sandborn WJ . Gastroenterology 2014
Clinical case
33 yr old. Non smoker. CD of ileum since 2004. CDAI = 200. No perianal disease. Some bloating and nausea
TPMT : 37; EBV serology +.
1
1
1
1
1
1
3
Daperno M et al. Gastrointestinal Endosc 2004
Clinical case
Backup slides
Early “top-down” therapy with azathioprine decreases the
need for perianal surgery
Cosnes J et al. Gastroenterology 2013;145: 758-65
Crohn’s
disease
Algorithmoffor
post-operative
CD
Ileocolonic resection
High risk*
Moderate risk**
Low risk***
Anti-TNF agent
Azathioprine
No treatment
Endoscopy 6mo-1year
Anti-TNF agent
Azathioprine
No treatment
Anti-TNF agent + IS
Anti-TNF agent
Aza or anti-TNF
•: penetrating disease, prior surgery, smokers, failure to IS; ** : short duration of disease (<10yrs),
>10 cm resection; ***: long disease duration (>10 yrs) short fibrostenotic stricture
Swoger JM, Regueiro M. Expert Rev Clin Immunol 2010
Azathioprine versus aminosalicylates for
steroid-dependent active UC
Patients treated successfully
at 6 months (%)
72 patients treated with concurrent tapering doses of steroids
p=0.006
100
80
53
60
40
19
20
0
5-ASA 3.2 g/d
(in 3 divided doses)*
AZA 2 mg/kg/day
Treatment success defined as clinical remission (Powell-Tuck Index score of 0) and
endoscopic remission (Baron Index score ≤1), plus steroid discontinuation
*0.8g at breakfast and lunch, and 1.6g at dinner
5-ASA, 5-aminosalicylic acid ; AZA, azathioprine
Ardizzone S, et al. Gut 2006;55:47–53
Azathioprine, infliximab and combination in early
ulcerative colitis: UC SUCCESS trial
Steroid-free remission at Week 16
Proportion of patients (%)
100
p=0.017
80
p=0.032
60
40
p=0.813
40%
24%
22%
n=18
n=17
n=31
AZA (N=76)
IFX (N=77)
IFX + AZA (N=78)
20
0
Patients were biologic-naive with moderate-severe UC (Mayo score 6) who were failing corticosteroids and either naive to AZA,
or had stopped AZA 3 months before entry.
AZA, azathioprine; IFX, infliximab.
Panaccione R, et al. Gastroenterology 2014
Azathioprine, infliximab and combination in early
ulcerative colitis: UC SUCCESS trial
Mucosal healing at Week 16
Proportion of patients (%)
100
p=0.001
p=0.028
80
55%
60
40
p=0.295
63%
37%
20
0
n=28
n=42
n=78
AZA (N=76)
IFX (N=77)
IFX + AZA (N=78)
Patients were biologic-naive with moderate-severe UC (Mayo score 6) who were failing corticosteroids and either naive to AZA,
or had stopped AZA 3 months before entry.
AZA, azathioprine; IFX, infliximab.
Panaccione R, et al. Gastroenterology 2014
Proposed moderate UC algorithm
Moderate
Prednisone
2‒4 weeks
10–12 weeks
Steroid
refractory
Steroid
dependent
Respond and taper
Maintenance 5-ASA
AZA x 10–12
weeks
Adapted from: Panaccione R et al. Aliment Pharmacol Ther 2008;28:674–88.
Fail
Anti-TNF
+/Immunomodulators