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

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

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

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 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

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

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

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

29

After Infliximab Withdraw: 50% do NOT relapse

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

32

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

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 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

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

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…..

…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 & TherapeuticsPariente B and Laharie D, 10:338-353, JUN 2014

47

Deep remissionLong duration combo tx

Clinical remissionMucosa better, not perfectShort duration combo tx

MonotxMucosal dsPerianal dsComplicated ds