1. 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

3. This is Tom’s side: “Keep taking it Until Something Better Comes Along”

4. 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

5. UPMC and Pittsburgh on a typical summer morning

6. Mt Sinai on that same, bright summer morning

7. 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……

8. 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

9. Pediatric CD: Prednisone induction and 6-MP maintenance 50% on placebo maintain remission
100
200
300
400
500
600
0.00
0.25
0.50
0.75
1.00
6MP
Control
Remission Duration (days)
Fractional Survival
Markowitz, et al. Gastroenterol. 2000;119(4):
David T. Rubin, MD 2007
Candy S et al. Gut. 1995;37:

10. Prednisone induction, MTX maintenance 39% on placebo maintain remission
100 90 80 70 60 50 40 30
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
65%
Percent Remaining in Remission
P=.044
39%
Placebo
MTX
Weeks Since Randomization
Feagan BG, et al. N Engl J Med. 2000;342:

11. Proportion of Patients
ACCENT I: IFX induction and maintenance ~20% on placebo maintain remission
Single Dose (n=102)
5 mg/kg q 8 wk (n=104)
10 mg/kg q 8 wk (n=105)
P < .001
P < .001 60
50% 50
P = .01
P = .021
38% 40
36%
Proportion of Patients
28% 30
20% 20
16% 10
Clinical Response
Clinical Remission
*Among patients responding at Week 2
Hanauer SB et al. Lancet. 2002;359:1541.

12. CLASSIC II: ADA induction and maintenance 44% on placebo maintain remission
Placebo (n=18)
40 mg EOW (n=19)
40 mg wkly (n=18)
LOCF; ITT population, n=55
*P<0.05 versus placebo
Sandborn WJ, Gut 2007.

13. PRECiSE 2: Certolizumab induction and maintenance 29% on placebo maintained remission
100
3 Injections + Placebo
Certolizumab Pegol 400 mg 80
p < 0.01
p < 0.01
% of Patients 60
47.9
42.0 40
28.6
25.7 20
All (N = 210/215)
CRP ≥ 10 (N = 101/112)
Schreiber S, et al, last and Senior Author Sandborn WJ NEJM 2007

14. 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

15. …but the debate is about stopping treatment in patients 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….

16. 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)

17. 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

18. >6 months of IFX and IMM Disease controlled (median CDAI 138)
Withdrawal of Immunosuppression in CD treated with Scheduled Infliximab Maintenance: A RCT Van Assche G, et al. Gastroenterol 2008;134:
>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

19. Clinical Outcomes at 2 yrs were no different between CON and DIS IMM

20. Retrospective, observational study
Predictors of Infliximab Failure after Azathioprine Withdrawal in CD Treated with Combination Rx Oussalah A et al. Am J Gastroenterol 2010;105:
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

21. The majority of pts (73%) did NOT fail IFX after AZA withdraw median duration without failure = 23m

22. >3 yrs of 6MP/AZA (no antiTNF) for UC or CD
Thiopurine withdrawal during sustained clinical remission in IBD: relapse rates and predictive factor Kennedy NA et al. AP&T 2014;40:
>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

23. 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

24. All Studies Suggest: Patients in Remission on combination antiTNF and IMM or IMM alone MAY stop the IMM

25. 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

26. Maintenance of Clinical Benefit in CD pts after Discontinuation of IFX Waugh et al. Aliment Pharmacol Ther 2010;32:
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

27. 1 yr after stopping IFX: 50% relapsed, BUT 50% remained in remission

28. 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

29. After Infliximab Withdraw: 50% do NOT relapse

30. 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

31. 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:
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

32. 45% relapsed/resumed antiTNF (median time 6m)

33. 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 = )
54.7% of relapses responded to retreatment with IFX/ADA
9.1% did undergo surgery

34. 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

35. 1 year after IFX Withdraw 61% CD and 75% UC do NOT relapse

36. All Studies Suggest: ONE – HALF OF PATIENTS ON COMBO MAY STOP ANTI-TNF
The trick is picking the right patient to stop the antiTNF

37. Who is the WRONG patient to consider stopping meds. (i. e
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

38. Who is the RIGHT patient to consider stopping antiTNF?
…..the patient in a deep remission without recent steroid use…..

39. Deep Remission is Key at 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:

40. 62.5% of pts with complete MH at yr 2 (SES = 0) had IFX-free remission yrs 3-4

41. Putting the data all together….

42. Study 50:50 Chance of Relapse whether you stop or continue 55% ~2yr
1st author
Stop IMM
Cont aTNF
Stop aTNF
Cont IMM
Cont ALL
Stop Nothing
(index)
Overall Chance:
Sustained Remission
Van Assche
55% ~2yr
45%
Oussalah
27% ~2yr
73%
Waugh
50% 1 yr
50%
Louis
Molnar
45% 1 yr
50%-55%
Steenholdt
39% CD 1 yr
25% UC 1 yr
61%-75%
Six Studies
CONTINUE
50%-58%
5 yr
42%-50%

43. 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

44. …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

45. When considering who wins this debate…….
…….I showed you a lot of evidenced based data, I tried to take a scientific approach…..

46. …don’t get fooled by Tom’s Smoke and Mirrors approach

47. 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: , JUN 2014

48. Monotx
Mucosal ds
Perianal ds
Complicated ds
Clinical remission
Mucosa better, not perfect
Short duration combo tx
Deep remission
Long duration combo tx