Pro: All medications may be
stopped for Crohn’s disease
patients in remission
Miguel Regueiro, M.D.
Professor of Medicine
Associate Chief for Education
Clinical Head and Co-Director, IBD Center
University of Pittsburgh School of Medicine
This is Tom’s side: “Keep taking it
Until Something Better Comes Along”
UPMC vs Mt Sinai
Pittsburgh vs New York City
Based on the name, the storied
success of Mt Sinai IBD Center
should win this debate, but….look
beyond the name
4
UPMC and Pittsburgh on a typical
summer morning
Mt Sinai on that same, bright summer
morning
Why even have this debate?
• Safety
• Cost
• Maybe there ARE patients who can stop
all treatment and do well.
• …..and this is probably the #1 question
asked by patients starting meds……
7
Prior to considering
discontinuation of treatment, is it
possible that we are OVERtreating
a subset of patients?
What happens to patients NOT
maintained on Biologics?
In essence, pts brought into
remission but then maintained
on placebo?
- Focus on placebo rates
8
Pediatric CD: Prednisone induction
and 6-MP maintenance
50% on placebo maintain remission
1.00
Fractional Survival
6MP
Control
0.75
0.50
0.25
0.00
0
100
200
300
400
Remission Duration (days)
9
Markowitz, et al. Gastroenterol. 2000;119(4):895-902.
500
600
Prednisone induction, MTX maintenance
39% on placebo maintain remission
100
• 76 patients in
remission
following MTX 25
mg IM x 16 wk
• Patients steroiddependent
• Randomized to
maintenance
MTX 15 mg IM
(N=36) or placebo
(N=40) x 40 wk
90
80
70
60
65%
50
40
P=.044
30
39%
Placebo
MTX
0
4
8
12
16
20
24
28
32
36
40
Weeks Since Randomization
Feagan BG, et al. N Engl J Med. 2000;342:1627-32.
ACCENT I: IFX induction and maintenance
~20% on placebo maintain remission
Proportion of Patients
Single Dose (n=102)
5 mg/kg q 8 wk (n=104)
P < .001
60
50
P = .01
20
P < .001
50%
P = .021
36%
40
30
10 mg/kg q 8 wk (n=105)
38%
28%
20%
16%
10
0
Clinical Response
*Among patients responding at Week 2
Hanauer SB et al. Lancet. 2002;359:1541.
Clinical Remission
CLASSIC II: ADA induction and maintenance
44% on placebo maintain remission
100
94
%Subjects
84
83
74
75
50
50
44
25
24 Weeks
Sandborn WJ, Gut 2007.
40 mg EOW
(n=19)
40 mg wkly (n=18)
0
LOCF; ITT population, n=55
*P<0.05 versus placebo
Placebo
(n=18)
56 Weeks
PRECiSE 2: Certolizumab induction and
maintenance
29% on placebo maintained remission
3 Injections + Placebo
100
Certolizumab Pegol 400 mg
80
p < 0.01
p < 0.01
% of
Patients
60
47.9
42.0
40
28.6
25.7
20
0
All (N = 210/215)
CRP ≥ 10 (N = 101/112)
Schreiber S, et al, last and Senior Author Sandborn WJ NEJM 2007
20%-50% patients from the IMM and
antiTNF studies maintain remission
WITHOUT medication
This means that maybe there are a cohort of
pts we OVERtreat – once they are in remission
on IMM/antiTNF, they can stop Rx
The problem:
correctly identifying the patients
who can stop rx once they are in
remission
14
We could end the debate here and
agree that up to 50% of pts may
not need long term treatment –
…but the debate is about stopping
treatment in patients in
remission….
15
Three Possible Scenarios
• Stop AZA/6MP and continue antiTNF
• Stop antiTNF and continue AZA/6MP
• Stop BOTH meds (no data at present)
• All antiTNF “stop” studies with IFX/ADA
• Most data in Crohn’s (less data in UC)
16
What are the data on stopping
AZA/6MP in COMBO antiTNF?
• Van Assche et al Gastroenterol 2008
• Oussalah et al Am J Gastro 2010
• Kennedy et al Aliment Pharmacol Ther 2014
– This last study evaluated stopping thiopurines alone
17
Withdrawal of Immunosuppression in CD treated
with Scheduled Infliximab Maintenance: A RCT
Van Assche G, et al. Gastroenterol 2008;134:1861-1868
• >6 months of IFX and IMM
• Disease controlled (median CDAI 138)
• Randomized 1:1
–
–
–
–
IFX 5mg/kg q 8wk with CONtinued IMM
IFX 5mg/kg q 8wk with DIScontinued IMM
Duration of study: 104 weeks (~ 2 yrs)
Primary endpoint: decrease in interval or
increase in dose or stopped IFX
18
Clinical Outcomes at 2 yrs were no
different between CON and DIS IMM
19
Predictors of Infliximab Failure after Azathioprine
Withdrawal in CD Treated with Combination Rx
Oussalah A et al. Am J Gastroenterol 2010;105:1142-1149
• Retrospective, observational study
• 48 pts >6 mos AZA/IFX in remission
• AZA withdrawn in all (no control arm,
part of investigator’s standard of care)
• IFX 5mg/kg continued every 8 weeks
• Primary endpoint: infliximab failure
– Change interval or dose in response to flare
– Intolerance of infliximab
– Abdominal surgery due to progression of CD
20
The majority of pts (73%) did NOT
fail IFX after AZA withdraw
median duration without failure = 23m
21
Thiopurine withdrawal during sustained clinical
remission in IBD: relapse rates and predictive factor
Kennedy NA et al. AP&T 2014;40:1313-1323
• >3 yrs of 6MP/AZA (no antiTNF) for UC
or CD
• Sustained remission at time of
withdrawal
• Retrospective 11 center clinical audit
– Minimum follow-up after withdrawal 12 mos.
– Primary endpoint: relapse at 12 months
22
77% CD and 88% UC still in remission at 1 yr
CD 23% 1 yr relapse
CRP predicted relapse
UC 12% 1 yr relapse
WBC predicted relapse
23
All Studies Suggest:
Patients in Remission on
combination antiTNF and IMM or
IMM alone
MAY stop the IMM
24
What are the data on stopping
antiTNFs from COMBO Rx?
• Crohn’s disease studies
– Waugh AP&T 2010
– Louis Gastroenterol 2011
 only study that prospectively withdrew
infliximab in pts on combo therapy in remission
– Molnar AP&T 2012
– Steenholdt Scand J Gastro 2012
25
Maintenance of Clinical Benefit in CD pts
after Discontinuation of IFX
Waugh et al. Aliment Pharmacol Ther 2010;32:1129-1134
• 48 CD pts in remission on IFX stopped
IFX after 1 yr.
– 67% on concomitant IMM
 44% on concomitant AZA
 19% on concomitant MTX
 4 % on concomitant 6MP
– 33% on no concomitant IMM
• Remission and relapse rates assessed
over 7 years
26
1 yr after stopping IFX: 50% relapsed,
BUT 50% remained in remission
27
Maintenance of CD Remission on AZA
after Infliximab is Stopped (STORI)
Louis et al. Gastroenterology 2011
• 115 pts in remission on IFX and AZA
– At least 1 year on IFX/AZA and > 6mos
remission off of steroids
– Followed for at least 30 months
28
After Infliximab Withdraw: 50% do NOT relapse
29
STORI Study Conclusions –
Infliximab Withdraw, AZA continue
• 50% did NOT relapse (maintained
remission) after stopping IFX
• 50% relapsed within 1 yr of stopping
IFX
• 88% of relapsers responded to
retreatment with IFX
30
Predictors of relapse in pts with Crohn’s ds in
remission after 1 year of biological therapy
Molnar T et al. Aliment Pharmacol Ther 2013;37:225-233
• 121 CD pts in clinical remission on antiTNF
stopped antiTNF after 1 year (Relapse After Stopping
biologics in Hungary = RASH study)
– 87 IFX pts and 34 ADA (79% naïve to biologics)
– 103 pts (85.1%) on concom thiopurines
• Primary endpoints:
– time to clinical relapse that necessitated restarting
biologics and >100 point increase in CDAI (the CDAI had to be
over 150)
– Identification of factors
associated with relapse
31
45% relapsed/resumed antiTNF (median time 6m)
32
RASH Study Conclusions –
IFX withdrawal in CD remission after 1 yr
• 55% did NOT relapse (did not require
resumption of antiTNF, CDAI<150)
• 45% DID relapse
– Previous antiTNF and dose intensification were
predictors of relapse (p < .05)
– Smoking, Elevated CRP, Corticosteroids were likely
predictors of relapse (p = .053 - .08)
• 54.7% of relapses responded to retreatment
with IFX/ADA
– 9.1% did undergo surgery
33
Outcome after discontinuation of
infliximab in IBD pts in clinical remission
Steenholdt C et al. Scand J Gastroenterol 2012;47:518-27
• 81 IBD (53 CD and 28 UC)
• Observational, single center, retrospective
• All pts had primary response to IFX and
were in a clinical remission
• Primary endpoints:
– Clinical relapse rate at 1 year
– Predictors of relapse
34
1 year after IFX Withdraw 61% CD and
75% UC do NOT relapse
35
All Studies Suggest:
ONE – HALF OF PATIENTS ON
COMBO MAY STOP ANTI-TNF
The trick is picking the right
patient to stop the antiTNF
36
Who is the WRONG patient to consider
stopping meds?
(i.e. high likelihood of relapse)
• Signs of Active CD prior to stopping IFX:
– Hgb <145 g/L
– CRP >5 mg/mL
– Calprotectin >300 ug/g
– CDEIS >0
• Smokers
• Prior Biologics
• Dose Intensification
• Need for steroids
Louis et al. Gastroenterol 2011 and Molnar et al. AP&T
Who is the RIGHT patient to
consider stopping antiTNF?
…..the patient in a deep remission
without recent steroid use…..
38
Deep Remission is Key
at predicting maintenance of “antiTNF free” remission
Mucosal Healing Predicts Sustained
Clinical Remission in Patients With
Early-Stage Crohn’s Disease (from “Step
Up vs Top Down Study”)
Baert et al. Gastroenterology 2010;138:463-468
39
62.5% of pts with complete MH at yr 2
(SES = 0) had IFX-free remission yrs 3-4
40
Putting the data all together….
41
50:50 Chance of Relapse whether you stop or continue
Study
1st author
Stop IMM
Cont aTNF
Stop aTNF
Cont IMM
Overall Chance:
Cont ALL
Stop Nothing Sustained
(index)
Remission
Van Assche 55% ~2yr
45%
Oussalah
73%
27% ~2yr
Waugh
50% 1 yr
50%
Louis
50% 1 yr
50%
Molnar
45% 1 yr
50%-55%
Steenholdt
39% CD 1 yr
25% UC 1 yr
61%-75%
Six Studies
CONTINUE
50%-58% 42%-50%
5 yr
42
What about stopping antiTNF and
IMM?
• No data at this time on stopping both
• There are data on stopping 6MP/AZA
monotherapy, > 75% still in remission
• Maybe this would be the group who could
stop everything?
–
–
–
–
–
Deep Remission for > 3 years
Endoscopic scores 0 (sustained mucosal healing)
Normal CBC, ESR/CRP, Fecal Calprotectin
Normal histology
Nonsmokers
43
…and as presented at the
beginning of my talk, I’d like to
leave you with something to think
about…..
Are we overtreating a subset of patients?
Once deep remission is achieved, could we
stop treatment?
I think it depends if you/your pt has the
“glass is half full or half empty” approach to
life
44
When considering who wins
this debate…….
…….I showed you a lot of
evidenced based data, I tried to
take a scientific approach…..
…don’t get fooled by Tom’s Smoke and
Mirrors approach
46
Synthesis and Consensus:
Algorithm from
Review article: why, when and how to
de‐escalate therapy in inflammatory bowel
diseases
Alimentary Pharmacology & Therapeutics
Pariente B and Laharie D, 10:338-353, JUN 2014
47
Deep remission
Long duration combo tx
Monotx
Mucosal ds
Perianal ds
Complicated ds
Clinical remission
Mucosa better, not
perfect
Short duration combo tx