Monotherapy using 6-MP or azathioprine for IBD is not dead yet:
long live the tried and true
Jean-Frederic ColombelIcahn 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.
0%
20%
40%
60%
80%
100%
no IS
AZA
a-TNF
Maximal prescription during the 4-yr calendar period
Crohn’s disease (n=3852) Ulcerative Colitis (n=1880)
Are we still using azathioprine monotherapy ?Evolution of prescription of drugs in IBD during the last 20 years
Hôpital St-Antoine, Paris Courtesy J.Cosnes
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 = 5
Prefontaine E et al. Cochrane database of systematic reviews 2010
NNT = 6
EndpointMean 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
Severe endoscopic recurrence (i2–i4) 15 (1.8–29) 0.026 7
Peyrin-Biroulet L et al. Am J Gastroenterol 2009NNT = number needed to treat
AZA for the prevention of post-operative recurrence of Crohn’s disease
Why should we abandon a drug that works ?
Gastroenterology 2013
p=0.022p=0.009
31
44
57
p<0.001
52/170 75/169 96/169
AZA + placeboIFX + placeboIFX + AZA100
80
60
40
20
0
Steroid-free remission = CDAI <150 points
Primary endpoint
Prop
ortio
n of
pati
ents
(%)
Colombel JF et al. NEJM 2010
Sonic: steroid-free remission at week 26
p=0.055p=0.023
17
30
44
p<0.001
18/109 28/93 47/107
AZA + placeboIFX + placeboIFX + AZA100
80
60
40
20
0
Colombel JF et al. NEJM 2010
Mucosal healing: complete absence of mucosal ulcerations in the colon and terminal ileum as assessed by video endoscopy
Prop
ortio
n of
pati
ents
(%)
Sonic : complete mucosal healing at week 26
Diagnosis
of CD
• Age <40 years• Perineal disease• Need for steroids • During first 3 months
≤6 monthsRa
ndom
isati
on
AZA early 2.5mg/kg (n=60)
≥2/3 criteria
AZA if needed (n=60)
Primary endpoint:• Number of trimesters without – activity – steroids – IFX – surgery – hospitalisation
36 m
onth
s
The Rapid studyThe RAPID study
Cosnes J et al. Gastroenterology 2013;145: 758-65
RAPIDAZTEC
Cosnes J et al. Gastroenterology 2013;145: 758-65 Panes J et al. Gastroenterology 2013;145: 766-74Cosnes J et al. Gastroenterology 2013;145: 758-65
Early “top-down” therapy with azathioprine is not more effective than placebo or conventional therapy
Jean Dela Fontaine 1625
The tortoise and the hareRien ne sert de courir, il faut partir a point !
Progression of digestive damage and inflammatory activity in a theoretical patient with Crohn’s disease
Pariente B, et al. Inflamm Bowel Dis 2011
Inflamm
atory activity (CDAI, CD
EIS, CRP)
Surgery
Stricture
Stricture
Fistula/abscess
Diseaseonset
Diagnosis Earlydisease
Crohn’s disease as a progressive disease
years
Short duration….
12 months
Limitations of current clinical trials in evaluating long-term impact of therapies
Use of azathioprine delays phenotype progression in Crohn’s disease
No treatmentbefore change
N = 344
AZA Before change
N = 349
AntiTNF + AZA before change
N = 100
P<0.
01
P<0.
01
ns
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
Lichtenstein G et al. DDW 2010
Infections and azathioprine
Lymphomas and azathioprine
Beaugerie L et al. Gastroenterology 2013
Avoid 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
How to reduce the risk of lymphomas associated with azathioprine ?
0.66
2.59
4.04
0.38
1.96
5.70
0
0.600.84
Continuing
Discontinued
Never received
<50 years
50-65 years
>65 yearsThiopurine therapy
Cases of NMSC (n) 039 336 233
6
3
4
5
1
2
0
Peyrin-Biroulet L et al. Gastroenterology 2011
Yea
rly
inci
den
ce r
ate
(pe
r 1,
000
pat
ien
t-ye
ars)
Azathioprine and non-melanoma skin cancers
How to reduce the risk of skin cancers associated with azathioprine ?
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 ageNew medical skin exam in 3-5 years
Surveillance based on risk stratification
Skin examination every other year
Very high-risk patients
History of cutaneous malignancies
Manage on individual
basis
Torres J et al. Inflam Bowel Dis 2013
More about thiopurines safety…
Beaugerie L et al. Gut 2014
• Azathioprine does not increase the risk of new or recurrent cancers in patients with past history of cancer
• Azathioprine is safe during pregnancy Jharap B et al. Gut 2014
Firstexposure
Drug development
Phase I-IIIatrials
healthy volunteers
selectedpatients
Num
ber o
f sid
e-eff
ects
repo
rted
Launch Firstrenewal
rare ADRs (< 1/1.000)
different population, risk groups
long-term use
co-medication & interactions
medication errors, misuse
The learning curve of side-effects
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 cantreat efficiently 1 patient with anti-TNFAnd 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
Daperno M et al. Gastrointestinal Endosc 2004
1
1
1
1
1
1
3
33 yr old. Non smoker. CD of ileum since 2004. CDAI = 200. No perianal disease. Some bloating and nauseaTPMT : 37; EBV serology +.
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
Algorithm for post-operative CD
Ileocolonic resection
High risk* Low risk***Moderate risk**
Anti-TNF agent Azathioprine No treatment
Endoscopy 6mo-1year
Anti-TNF agent
Anti-TNF agent + IS
Azathioprine
Anti-TNF agent
No treatment
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
Algorithm for the prevention of post-operative recurrence of Crohn’s disease
Azathioprine versus aminosalicylates for steroid-dependent active UC
Series10
20
40
60
80
100
19
53
p=0.006
Patie
nts
trea
ted
succ
essf
ully
at 6
mon
ths
(%)
Patie
nts
trea
ted
succ
essf
ully
at 6
mon
ths
(%)
Treatment success defined as clinical remission (Powell-Tuck Index score of 0) and endoscopic remission (Baron Index score ≤1), plus steroid discontinuation
Ardizzone S, et al. Gut 2006;55:47–53
72 patients treated with concurrent tapering doses of steroids
*0.8g at breakfast and lunch, and 1.6g at dinner
5-ASA 3.2 g/d(in 3 divided doses)*
AZA 2 mg/kg/day
5-ASA, 5-aminosalicylic acid ; AZA, azathioprine
Azathioprine, infliximab and combination in early ulcerative colitis: UC SUCCESS trial
Panaccione R, et al. Gastroenterology 2014
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.
Steroid-free remission at Week 16
0AZA (N=76)
20
40
60
80
100
n=18
24%
IFX (N=77)
n=17
22%
IFX + AZA (N=78)
n=31
40%p=0.813
p=0.032
p=0.017
Prop
ortio
n of
pati
ents
(%)
Azathioprine, infliximab and combination in early ulcerative colitis: UC SUCCESS trial
Mucosal healing at Week 16
0AZA (N=76)
20
40
60
80
100
n=28
37%
IFX (N=77)
n=42
55%
IFX + AZA (N=78)
n=78
63%p=0.028
p=0.001
p=0.295
Prop
ortio
n of
pati
ents
(%)
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
Respond and taperMaintenance 5-ASA
Fail
Prednisone
10–12 weeks
Steroiddependent
AZA x 10–12weeks
2‒4 weeks
Steroidrefractory
Anti-TNF+/-
Immunomodulators
Adapted from: Panaccione R et al. Aliment Pharmacol Ther 2008;28:674–88.
Moderate
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