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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