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