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Pro: All medications may be stopped for Crohn’s disease
patients in remission
Pro: All medications may be stopped for Crohn’s disease
patients in remission
Miguel Regueiro, M.D.Professor of MedicineAssociate Chief for EducationClinical Head and Co-Director, IBD CenterUniversity of Pittsburgh School of Medicine
UPMC vs Mt SinaiPittsburgh 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
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 rates8
Pediatric CD: Prednisone induction and 6-MP maintenance
50% on placebo maintain remission
9
0 100 200 300 400 500 600
0.00
0.25
0.50
0.75
1.00
6MP
Control
Remission Duration (days)
Fra
ctio
nal
Sur
viva
l
Markowitz, et al. Gastroenterol. 2000;119(4):895-902.
Prednisone induction, MTX maintenance39% on placebo maintain remission
• 76 patients in remission following MTX 25 mg IM x 16 wk
• Patients steroid-dependent
• Randomized to maintenance MTX 15 mg IM (N=36) or placebo (N=40) x 40 wk
Weeks Since Randomization
Per
cen
t R
e mai
ni n
g i
n R
e mis
s io
n
Placebo
MTX
P=.044
65%
39%
0 4 8 12 16 20 24 28 32 36 40
100
90
80
70
60
50
40
30
Feagan BG, et al. N Engl J Med. 2000;342:1627-32.
ACCENT I: IFX induction and maintenance~20% on placebo maintain remission
P = .01
Hanauer SB et al. Lancet. 2002;359:1541.
*Among patients responding at Week 2
P = .021
P < .001P < .001
36%
28%
50%
38%
20%16%
0
10
20
30
40
50
60
Clinical Response Clinical Remission
Pro
port
ion
of
Pat
ient
s
Single Dose (n=102) 5 mg/kg q 8 wk (n=104) 10 mg/kg q 8 wk (n=105)
CLASSIC II: ADA induction and maintenance 44% on placebo maintain remission
LOCF; ITT population, n=55 *P<0.05 versus placebo
5044
84
74
94
83
0
25
50
75
100
24 Weeks 56 Weeks
%S
ub
ject
s
Placebo (n=18)
40 mg EOW (n=19)
40 mg wkly (n=18)
Sandborn WJ, Gut 2007.
PRECiSE 2: Certolizumab induction and maintenance
29% on placebo maintained remission
28.6
47.9
25.7
42.0
0
20
40
60
80
100
All (N = 210/215) CRP ≥ 10 (N = 101/112)
% of Patients
3 Injections + Placebo Certolizumab Pegol 400 mg
Schreiber S, et al, last and Senior Author Sandborn WJ NEJM 2007
p < 0.01p < 0.01
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
14
The problem: correctly identifying the patients who can stop rx once they are in
remission
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 RCTVan 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
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
23
CD 23% 1 yr relapse CRP predicted relapse
UC 12% 1 yr relapseWBC predicted relapse
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
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
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
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
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 Keyat predicting maintenance of “anti-
TNF 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
42
Study1st author
Stop IMMCont aTNF
Stop aTNFCont IMM
Cont ALLStop Nothing(index)
Overall Chance:Sustained Remission
Van Assche 55% ~2yr 45%
Oussalah 27% ~2yr 73%
Waugh 50% 1 yr 50%
Louis 50% 1 yr 50%
Molnar 45% 1 yr 50%-55%
Steenholdt 39% CD 1 yr25% UC 1 yr
61%-75%
Six StudiesCONTINUE
50%-58%5 yr
42%-50%
50:50 Chance of Relapse whether you stop or continue
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
life44
When considering who wins this debate…….
When considering who wins this debate…….
…….I showed you a lot of evidenced based data, I tried to take a scientific approach…..
Synthesis and Consensus: Algorithm from
Review article: why, when and how to de‐escalate therapy in inflammatory bowel
diseases
Alimentary Pharmacology & TherapeuticsPariente B and Laharie D, 10:338-353, JUN 2014
47