Achieving Deep Remission In Crohn’s Disease - GIHF · Achieving Deep Remission In Crohn’s...

Achieving Deep Remission In Crohn’s Disease

William J. Sandborn, M.D.

Chief, Division of Gastroenterology

Director, UCSD IBD Center

University of California San Diego

La Jolla, California

• How do we define remission? Clinical (CDAI) versus mucosal healing versus sustained deep remission

• What are impacts of these endpoints on other outcomes?

• How do we achieve deep remission in Crohn’s disease?

Outline

CDAI: Crohn’s Disease Activity Index

How Do We Define Remission?

Clinical (CDAI) vs

Mucosal Healing vs

Sustained Deep Remission

Assessment Of Efficacy Of Medical Therapy: CDAI

Versus CDEIS During Treatment With Prednisolone

CDAI, Crohn’s Disease Activity Index; CDEIS, Crohn’s disease endoscopic index of severity Modigliani R et al. Gastroenterology. 1990;98:811-817.

CD

AI

600

500

400

300

200

100

0

0 5 10 15 20 25 30 35

r = 0.13 ; N5

CDEIS

Figure 1. Correlation of CDAI vs. CDEIS at D0 (n = 142)

Correlations Between hsCRP, IL-6, Fecal

Markers, CDAI, and Endoscopic Activity in CD

CDAI, Crohn’s Disease Activity Index; SES-CD, Simple Endoscopic Score for Crohn's Disease

Jones JL et al. Clin Gastroenterol Hepatol. 2008;6:1218-1224.

IL-6 Calprotectin Lactoferrin CDAI SES-CD

hsCRP 0.65 0.47 0.52 0.16 0.46

IL-6 0.45 0.55 0.15 0.43

Calprotectin 0.76 0.23 0.45

Lactoferrin 0.19 0.48

CDAI 0.15

Correlation coefficients highlighted in red were significant (P<0.05).

When stratified by extent, correlation coefficients were highest for colonic disease.

(N=164)

Inflammatory Activity and Progression of Damage in a Theoretical Patient with CD

CDAI, Crohn’s Disease Activity Index; CDEIS, Crohn’s disease endoscopic index of severity CRP; C-reactive protein

Pariente B et al. Inflamm Bowel Dis. 2011;17:1415-1423.

Infla

mm

ato

ry a

ctiv

ity

(CD

AI, C

DE

IS, C

RP

)

Surgery

Stricture

Stricture

Fistula/abscess

Disease

onset

Dig

esti

ve D

am

ag

e

Diagnosis Early

disease

• In patients with no bowel damage

‒ Prevention of bowel damage (stricture, fistula,

abscess)

‒ No surgical resection

• In patients with existing bowel damage (stricture,

fistula, abscess, prior surgical resection)

‒ Prevent further damage and reverse damage

if possible

‒ Prevention additional surgical resection

The Evolving Goal of Therapy is Disease Modification

Working Definition of Deep Remission

• Overall, aiming for deep remission (DR) is

managing disease beyond symptom control

‒ In patients with no bowel damage or disability, DR is

resolution of one or more objective measures of

inflammation (endoscopy, markers, imaging) AND

resolution of symptoms

• To prevent damage and disability

‒ In patients with existing bowel damage and disability, DR

is resolution of one or more objective measures of

inflammation (endoscopy, markers, imaging) AND

improvement of symptoms if possible

• To prevent further damage and disability, and reverse

damage if possible

What Are the Impacts of These Endpoints on Other Outcomes?

Impact of Therapy will Depend on Degree of Structural Damage & Velocity of Progression

Cosnes J et al. Inflamm Bowel Dis. 2002;8:244-254.

240 228 216 204 192 180 168 156 144 132 120 108 96 84 72 60 48 36 24 12 0

0

10

20

30

40

50

60

70

80

90

100

Cu

mu

lati

ve P

rob

ab

ilit

y (

%)

Patients at risk: Months

2002 552 229 95 37 N =

Penetrating

Stricturing

Inflammatory

High Potential Low Potential

Cumulative Probability of Surgery for Crohn’s

Disease and for Recurrence Following Surgery

Sx=surgery

Munkholm P et al. Gastroenterology. 1993;105:1716-1721.

Years

Pro

ba

bil

ity (

%)

±2 SD

D

Classification of the Sequelae of Bowel Resection for Crohn’s Disease

Cosnes J et al. Br J Surg. 1994;81:1627-1631.

Duodenum = 8

Jejunoileum = 50

Colon = 21

(7 x 3)

Rectum = 11

Ileocolonic junction = 10

Pyloris

Duodenojejunal flexure

5 cm from ileocecal valve

Ileocecal valve

Anus

Rectosigmoid junction

0

100

50

Sco

re

Classification of the Sequelae of Bowel Resection for Crohn’s Disease

Cosnes J et al. Br J Surg. 1994;81:1627-1631.

4000

3000

2000

1000

0 20 40 60

Index Value

Feca

l W

eig

ht,

g/d

Correlation between fecal weight and postoperative handicap index in the retrospective series. The

regression equation was: y = 3793 – 866 × log [75 – x]. (n = 112, r = 0.60, P < 0.001)

Benjamin Pariente, Jacques Cosnes, Silvio Danese, William J Sandborn, Maıté Lewin, Joel G Fletcher, Yehuda Chowers, Geert D’Haens, Brian G Feagan, Toshifumi Hibi, Daniel W Hommes, E. Jan Irvine, Michael A. Kamm, Edward V Loftus, Edouard Louis,

Pierre Michetti, Pia Munkholm, Tom Oresland, Julian Panés, Laurent Peyrin-Biroulet, Walter Reinisch, Bruce E Sands, Juergen Schoelmerich, Stefan Schreiber, Herbert Tilg, Simon Travis, Gert

van Assche, Maurizio Vecchi, Jean-Yves Mary, Jean-Frédéric Colombel, Marc Lémann

Development of the Crohn’s Disease

Digestive Damage Score, the Lémann Score

Peyrin-Biroulet L et al. Gut. 2012;61:241-247.

Peyrin-Biroulet L et al. GUT. 2011; (June):in press.

How Do We Achieve Deep Remission in Crohn’s Disease?

Net Remission at Six Months:

Certolizumab Pegol; Adalimumab; Infliximab

ADA=adalimumab

Czp=certolizumab pegol

IFX=inflximab

1. Schreiber et al. New Engl J Med 2007;357:239-250 2. Hanauer et al. Lancet 2002;359:1541-49 3. Colombel et al.

Gastroenterology 2007;132:52-65 4. Sandborn et al. New Engl J Med 2007;357:228-38

Infliximab – ACCENT I2 Certolizumab Pegol – PRECISE 21

Adalimumab - CHARM3

28.6 18.3

64.1

47.9

30.7

0

20

40

60

80

100

Open-label

Induction

Week 6

Week 26

remission

Net

remission

week 26

% o

f P

ati

en

ts

Pbo CzP

21.0 12.3

58.5

39.0

22.8

0

20

40

60

80

100

Open-label

Induction

Week 2

Week 30

remission

Net

remission

week 30

% o

f P

ati

en

ts

Pbo IFX

17.0 9.9

58.0

40.0

23.2

0.0

20.0

40.0

60.0

80.0

100.0

Open Label

Induction

Week 4

Week 26

remission

Net

remission

week 26

% o

f P

ati

en

ts

Pbo ADA

Certolizumab Pegol – PRECISE 14

18.3

29.5

0

20

40

60

80

100

Net

remission

week 26

% o

f P

ati

en

ts

Pbo CzP

EXTEND: Deep Remission* Rates With

Adalimumab at 1 Year

eow=every other week

Colombel JF, et al. J Crohn’s Colitis 2010;4:S11: OP31 at ECCO 2010

* Deep remission defined as clinical remission (CDAI <150) and complete mucosal healing in EXTEND

All patients (n=135) received adalimumab 160/80 mg induction therapy, before randomisation (n=129) to adalimumab

40 mg eow or to placebo. Deep remission was assessed in those who had ulceration at baseline (n=123).

CDAI: Crohn’s disease activity index; eow: every other week

0

5

10

15

20

25

Pati

en

ts in

deep

rem

issio

n*

(%)

Week 12

6/61 10/62

10

16

P=.34

12/62 0/61

19

P<.001

Week 52

Placebo Adalimumab 40 mg eow

EXTEND: Patients Who Achieved Deep Remission* With

Adalimumab at Week 12 and Hospitalization Rates

Colombel JF, et al. Gut 2010;59(Suppl 3):A80: OP371 at UEGW 2010

All-cause hospitalization

through Week 52

CD-related hospitalization

through Week 52

17

0

5

10

15

20

0/11 9/53 All h

osp

italizati

on

(%

)

9

0

5

20

0/11 5/53

CD

-rela

ted

ho

sp

italizati

on

(%

)

Deep

remission*

(Week 12)

Non-deep

remission*

(Week 12)

Deep

remission*

(Week 12)

Non-deep

remission*

(Week 12)

10

15

* Deep remission defined as clinical remission (CDAI <150) and complete mucosal healing in EXTEND

CD: Crohn’s disease; CDAI: Crohn’s disease activity index

CHARM Adalimumab in Active Crohn’s Disease Clinical Remission at 26

and 54 Weeks in Week 4 Responders by Duration of Crohn’s Disease

Schreiber S. Gastroenterology 2007 Abstract #985

*P=.002; **P<.001; †P=.014; ‡P=.001; all vs placebo

Week 26 Week 56

Placebo All Adalimumab

<2 years 2 to <5 years 5 years

†

‡

<2 years: PBO n=23, Adalimumab n=39; 2 to <5 years: PBO n=36, Adalimumab n=57;

5 years: PBO n=111, Adalimumab n=233

<2 years 2 to <5 years 5 years

*

** **

PRECISE 2 Certolizumab Pegol in Active Crohn’s Disease

Clinical Response at 26 Weeks in Week 6 Responders by

Duration of Crohn’s Disease

Schreiber S. Am J Gastroenterol. 2010;105:1574-82.

Mucosal Healing at Week 26

AZA = azathioprine

Colombel J-F et al. N Engl J Med. 2010;362:1383-1395.

16

30

44

0

20

40

60

80

100

Pro

po

rtio

n o

f P

ati

en

ts (

%)

AZA + placebo IFX + placebo IFX+ AZA

P<.001

P=.023 P=.055

18/109 28/93 47/107

• Remission is best defined by endoscopy, or the

composite definition of deep remission

• Preliminary evidence suggests that deep

remission reduces hospitalization, and may

reduce surgery, bowel damage, and disability

• Maintenance therapy with a combination of

azathioprine and an anti-TNF agent yields the

best long term outcomes, discontinuation of

either agent increases the risk of relapse

Conclusions