Activity assessing in IBD

PRO – CONTRO
Risposta clinica o mucosal
healing nelle IBD?
Maria Cappello
Marco Daperno
UOC Gastroenterologia ed Epatologia
Policlinico Paolo Giaccone
Palermo
SC Gastroenterologia
AO Ordine Mauriziano
Torino
Activity assessing in IBD
Activity indices in IBD: what’s best?
•
•
•
•
•
•
•
Few variables
Easily obtainable at bedside
Applicable in the majority of patients
Validated
Objective
Reproducible
Accepted by physicians and investigators
40% derives from subjective criteria
Truelove and Witts score for UC
Activity
Mild
Severe
N. stools
<4
>6
Blood in the feces
-/+
+++
Body temperature
No fever
> 37.5°C
Heart rate
No tachycardia
> 90 bpm
Hemoglobin
No anemia
< 75% normal value
ESR
< 30 mm/h
> 30 mm/h
Intermediate presentations are defined as moderate
Evolving goals of therapy for Crohn’s disease
Goal
Clinical parameters
Outcomes
Response
Improved symptoms
Improved QoL
Remission
No symptoms
Normal labs
Decreased
hospitalisation
Deep remission
Normal endoscopy
Mucosal healing
Avoidance of surgery
Minimal/no disability
SUSTAINED
Panaccione R. Abbott Symposium at ECCO, Prague, Czech Republic; February 2010
7
IBS-like symptoms in IBD in remission
• In a cohort of 43 IBD patients in stable remission
(< 1 year), 33% of UC and 57% of CD patients
reported IBS symptoms (p < 0,05)
• Previous surgery in CD, female gender and
disease duration, reduced psychological wellbeing and higher levels of anxiety and
depression were significantly associated with
IBS symptoms
MH and treatment of IBD
• MH is a more objective way of assessing
disease inflammatory activity
• Can discriminate IBS-like symptoms,
intercurrent infections or obstruction
• Can overcome the placebo effect
associated with traditional clinical indices
MH in IBD
There is no validated definition of MH in patients with IBD
The „ideal“ definition of Mucosal Healing (MH) could be complete
endoscopic healing of all inflammatory and ulcerative lesions of the
gut mucosa in CD and UC
In CD, an endoscopic response to treatment can be defined as
“absence of ulcers” or a significant change of endoscopic disease
activity score, such as the CDEIS or the SES-CD
In UC, an endoscopic response to treatment can be defined as a
significant change of endoscopic disease activity score, such as the
Baron score or the Mayo endoscopic subscore
Pineton de Chambrun G, et al. Nat Rev Gastroenterol Hepatol 2010; 7: 15-29.
Measurement of Endoscopic
Disease Activity in Crohn’s Disease
Different scoring systems for different clinical scenarios:
The Crohn’s Disease Endoscopic Index of Severity
(CDEIS)
The Simple Endoscopic Index for Crohn‘s Disease
(SES-CD)
The Rutgeerts’ score for postoperative recurrence
Crohn's Disease Endoscopic Index Of
Severity (CDEIS)
Mary JY, et al. Gastroenterology 1990
Score range from 0-44 (higher=more severe)
The Simple Endoscopic Score for Crohn’s
Disease (SES-CD)
Ileum
Right
colon
Transverse
colon
Left
colon
Rectum
Presence and size
of ulcers (03)
__+
____+
_____+
____+
___+
+
Extent of ulcerated
surface (03)
__+
____+
_____+
____+
___+
+
Extent of affected
surface (03)
__+
____+
_____+
____+
___+
+
Presence and type
of stenosis (03)
__+
____+
_____+
____+
___+
=
SUM OF ALL VARIABLES =
Daperno M, et al. Gastrointest Endosc 2004
Total
SES-CD
Endoscopic Assessment Following Surgery:
Rutgeerts’ Score
RUTGEERTS’ SCORE
• Developed for lesions in the neoterminal ileum and at the ileocolonic anastomosis
• i0 – i4
• Correlates with clinical behavior in the future
Degree
Endoscopic characteristics
i0
No lesion in neoterminal ileum
i1
5 aftoid lesions
i2
>5 aftoid lesions with normal mucosa in-between, or skip areas with larger
lesions, or lesions confined to ileocolonic anastomosis
i3
Diffuse aftous ileitis with extensively inflamed mucosa
i4
Diffuse inflammation with large ulcers, nodules and/or stenoses
Rutgeerts P, et al. Gastroenterology 1990;99(4): 956-63.
MH or endoscopic response (ER)?
CFREM = corticosteroid
free remission
ER = reduction in SESCD or CDEIS > 50%
Gastroenterology 2013; 145:978-986
Ulcerative Colitis:
Mayo Endoscopic Activity Score
Score 0
normal or healed mucosa
Score 1
faded vascular pattern
mild friability
erythema
Score 2
absent vascular pattern
marked friability
erosions
Score 3
spontaneous bleeding
large ulcers
Schroeder KW, et al. N Engl J Med 1987
Ulcerative Colitis Activity Scores: UCEIS
Gut 2012; 61:535-542
MD
Issues with MH:
Reproducibility Endoscopic Scores
& Correlations to Clinical Indices
Osada T, et al. Inflamm Bowel Dis 2010;16(2):192-7
Intraobserver agreement
Interobserver agreement
Ulcerative Colitis:
Reproducibility Endoscopic Scores
Ulcerative Colitis: Effects of reproducibility
Clinical Remission
Proportion of patients (%)
In the original trial, 281 patients randomized to 5ASA/PBO. 35% (98, balanced across treatment
harms) were over-judged by local endoscopists (with a Mayo>2 score ), while central reviewers
100
judgment would have led to exclusion from the study for 85% of them (83/98)
Central-reader
confirmed eligible
75
ITT
50
P = 0.011
*P = 0.069
25
P <0.001
P <0.001
40,7
P = 0.072
30
40,2
P = 0.040
29
21,3
20,6
25
24,3
16,3
13,8
16,1
12,6
0
Week 6
Week 10
Feagan B, et al Gastroenterology 2013
Weeks 6 & 10
Week 6
Week 10
Weeks 6 & 10
Ulcerative Colitis: Intra- and Inter-rater
agreement with different scores
Intra-rater
Inter-rater
1
1
0,75
0,75
0,5
0,5
Baron
Mayo
UCEIS
VAS
Baron
Mayo
UCEIS
VAS
Inter-rater
Intra-rater
Baron
0.74 (0.65 to 0.82)
0.87 (0.82 to 0.91)
Mayo
0.75 (0.66 to 0.83)
0.89 (0.84 to 0.92)
UCEIS
0.80 (0.72 to 0.87)
0.88 (0.83 to 0.92)
VAS
0.77 (0.68 to 0.84)
0.91 (0.85 to 0.94)
Feagan B, et al Gastroenterology 2013
Interobserver agreement (UCCIS score)
• Prospective study, 51 patients (videos) examined (analysis
of 5 colonic segments)
• 7 gastroenterologist blindly rated severity of damage to
each segment and overall, and for different lesions
(edema, erythema, stricture, loss of haustral folds, rigidity,
pseudopolyps, vascular pattern, granularity, bleedingfriability, and ulceration)
• Global assessment of endoscopic severity (GAES) was
based on 4-point scale and 10-cm visual analogue scale
Thia KT, et al. Inflamm Bowel Dis 2011;17:1257-64
Interobserver agreement (UCCIS score)
Thia KT, et al. Inflamm Bowel Dis 2011;17:1257-64
Reproducibility of endoscopic features (UCEIS)
• Reliability of the score is good if intra-observer variation is
the issue
• Inter-investigator agreement is lower, and it is possible to
increase agreement if clinical details are known (age,
gender, bleeding, number of bowel movements, treatment
status as pre/post-treatment)
• Only 4% of UCEIS variation is due to intra-observer
variation, while only 12% is linked to interobserver
agreement
Travis SPL, et al. Gastroenterology 2013
Reproducibility of luminal Crohn’s scores
• 50 luminal CD videos assessed 3-times by 4 reviewers
• CDEIS, SES-CD and GELS scored
1
0,9
0,91
CDEIS
SES-CD
0,89
0,83
0,8
0,71
0,7
0,6
Intra-rater
Inter-rater
ICCs (95% CI)
Intra-rater
Inter-rater
CDEIS
0.89 (0.86 to 0.93) 0.71 (0.61 to 0.79)
SES-CD
0.91 (0.87 to 0.94) 0.83 (0.75 to 0.89)
Khanna R, et al. ECCO 2014
Reproducibility of luminal Crohn’s scores
Sources of disagreement
Lesions between segments/anastomosis
Superficial ulcers
Courtesy: Khanna R, Robarts Trial. From ECCO 2014 oral communication slideset
Anal lesions
Stenosis
Reproducibility Endoscopic Scores:
Preliminar data to IG-IBD project
•
•
14 expert endoscopists reviewed endoscopic
videos:
• 13 ulcerative colitis (with Mayo subscore)
• 10 post-surgical Crohn's disease (with
Rutgeerts’ score)
• 8 luminal Crohn clips (with CDEIS & SES-CD)
30 endoscopists un-experienced in endoscopic
scores examined a subset of the colonoscopic
clips
Daperno M, et al. ECCO 2012 (P 289)
Reproducibility Endoscopic Scores: Preliminar IG-IBD project
Experts
Non experts
Median
95%CI
Median
95%CI
0.53
0.47-0.54
0.71
0.67-0.72
31.49%
28.84-33.43
22.36%
21.27-23.45
0.57
0.51-0.65
0.67
0.60-0.67
20.76%
18.18-22.81
11.31%
11.28-15.38
CDEIS (ICC)
0.83
0.54-1.00
0.67
0.36-0.97
CDEIS (CV)
24.68%
21.21-27.13
31.48%
29.34-34.34
SES-CD (ICC)
0.93
0.76-1.00
0.68
0.89-1.00
SES-CD (CV)
17.91%
16.35-18.66
31.61%
28.92-35.75
Mayo endoscopic
subscore (kappa)
Mayo endoscopic
subscore (CV)
Rutgeerts score (kappa)
Rutgeerts score (CV)
95%CI: 95% confidence interval; kappa: median kappa statistics value; CV: median coefficient of variation value; ICC: intraclass correlation coefficient, single measure;
CDEIS: Crohn’s disease endoscopic index of severity; SES-CD: simple endoscopic score for Crohn’s disease
Daperno M, et al. ECCO 2012 (P 289)
IG-IBDEndo: results at-a-glance
Agreement
at 1st round
Agreement
at 2nd round
p value
Kappa at
1st round
Kappa at
2nd round
UC
(Mayo)
75%
87%
<0.0001
0.445
0.713
Post-surgical CD
(Rutgeerts’)
86%
96%
<0.0001
0.656
0.853
Luminal Crohn
SES-CD
0.725 (Intraclass correlation coefficient)
Luminal Crohn
CDEIS
0.740 (Intraclass correlation coefficient)
Daperno M, et al. FISMAD 2014 (PC.01.8)
Crohn – IFX – SONIC post-hoc
Endoscopic activity scores from SONIC
Selection of SONIC cases with lesions at basal endoscopy & w26 endoscopy (172/508,
34% original study population)
W26 predictors
MH
ER-SESCD
ER-CDEIS
SMH
AUC
95%CI
0.606
0.611
0.599
0.607
0.532-0.680
0.538-0.683
0.526-0.671
0.538-0.675
MH: complete disappearance of all ulcerations in ll segments (original definition); ERSESCD: reduction of SES-CD score of at least 50% from baseline; ER-CDEIS:
reduction of CDEIS score of at least 50% from baseline; SMH: disappearance of
ulceration in at least onesegment
Ferrante M, et al. Gastroenterology 2013;145:978-86
Crohn – IFX – SONIC post-hoc
Endoscopic activity vs CDAI/CRP
Selection of SONIC cases with lesions at basal endoscopy & CDAI and CRP complete
data (188/508, 37% original study population)
100%
P=0.002
P=NS
CD>2 years
No resections
Previous resections
78%
76%
75%
CD<2 years
69%
P=NS
P=NS
P=0.031
P=0.011
56%
58%
56%
53%
53%
63%
61%
50%
41%
30%
25%
0%
CDAI<150
Peyrin-Biroulet L, et al. Gut 2014;63:88-95
MH
CRP
MC
Clinical implications of mucosal
healing
Clinical implications of MH in CD
• There is emerging evidence that MH improves short
and long-term outcomes in CD («disease outcome
modifier»)
• In the short-term is associated with reduction in
CDAI and in steroid use
• In the mid–term MH is associated with durable
remission, reduced complication rate and the need
for hospitalization and surgery
• In the long-term could prevent bowel damage
Symptomatic recurrence and
endoscopic lesions
no lesions (0)
< 5 aphtous lesions (1)
% symptom free 1
0.8
> 5 aphtous lesions (2)
0.6
0.4
diffuse ileitis (3)
0.2
ulcers, nodules
narrowing (4)
0
1
2
3
4
5
6
7
8
Years
Rutgeerts P, et al. Gastroenterology 1990; 99: 956-83.
Long term outcome of patients with active Crohn's disease exhibiting
extensive and deep ulcerations at colonoscopy
Survival without colectomy
Survival without penetrating
complications
100
100
Mild endoscopic lesions
80
80
Severe endoscopic lesions
P < 0.0001
60
P = 0.003
60
Severe endoscopic lesions
40
40
20
20
at risk
0
Mild endoscopic lesions
0
12
24
36
48
60
72
84
96
0
0
12
24
36
Months
49
53
46
36
41
32
36
27
31
22
48
60
72
84
96
17
14
15
10
11
3
Months
22
17
17
14
Independent risk factors of colectomy
SELs
RR = 5.43, 95% CI = 2.64-11.18)
CDAI>288
RR = 2.21, 95% CI = 1.09-4.47
Bo ISS
RR = 2.44, 95% CI = 1.20-5.00
15
10
11
3
49
53
46
36
41
32
36
27
31
22
22
17
Allez M et al, Am J Gastroenterol 2002; 97(4): 947-53.
“Patients with active CD exhibiting deep and extensive ulcerations are,
over a long period of time, at a greatly increased relative risk (5-fold) to
undergo colectomy relative to patients free of such lesions.”
Mucosal Healing in CD:
Role of Conventional and Immunomodulator Therapy
No controlled studies of mucosal healing
Aminosalicylates and antibiotics: presumed no or limited healing
AZA/6-MP: slow but effective healing
MTX: presumed slow but effective healing
Controlled studies available
Corticosteroids, enteral nutrition (children) : short-term, limited
healing, no long-term impact
Anti-TNF: rapid healing, can be maintained
Mucosal healing in CD at year 2 predicts
sustained clinical remission through year 3 + 4
49 patients from SUTD trial underwent colonoscopy at year 2
FU through year 3 and 4
Percentage of patients (%)
P=0.036
100
80
P=0.089
OR 4.35 (95% CI 1.1-20.8)
70,8
60
27,3
40
20
17/24
6/22
0
Complete mucosal healing (SES=0 at year 2)
Endoscopic activity (SES=1-9 at year 2)
Clinical remission (CDAI<150, no
steroids, no resections) through Year
3+4
100
80
60
40
20
0
22,7
4,2
1/24
5/22
Complete mucosal healing (SES=0 at year 2)
Endoscopic activity (SES=1-9 at year 2)
New or active draining fistula
through Year 3+4
Baert F, et al. Gastroenterology 2010
Mucosal healing and long term outcome of infliximab
maintenance therapy (Leuven)
MH in 183 responders of 214 CD
32,2
45,4
22,4
Complete MH (n=83)
Partial MH (n=41)
No MH (n=59)
Schnitzler F, et al. IBD 2009
Steroid-free Clinical Remission and MH at wk 26
in Crohn’s disease patients naïve to biologics and
immunosuppressants
Primary Endpoint
80
p=0.009
20
p=0.022
57
60
40
100
p<0.001
Patients (%)
Patients (%)
100
45
30
52/170
75/169
96/169
0
p=0.023
60
20
n. 508
Steroid-free clinical remission
IFX + placebo
p=0.055
44
40
0
AZA + placebo
p<0.001
80
30
16
18/109
28/93
47/107
n. 309
Mucosal healing
IFX+ AZA
Colombel JF et al. NEJM 2010
Mucosal Healing after 1 year and risk of
surgery
ULCERATIVE COLITIS
CROHN’S DISEASE
HR = 0.34 (0.14-0.86) p=0.02
HR = 0.42 (0.20-0.89) p=0.027
1.0
Proportion of patients
not resected
Proportion of patients
not colectomised
1.00
0.96
MH
3.4%
0.94
0.90
No MH
9.7%
0.86
0
1
2
3
4
5
6
7
8
Years since 1-year visit
IBSEN
9
0.9
MH
0.8
16.9%
0.7
0.6
No MH
31.0%
0.5
10
0
1
2
3
4
5
6
7
8
9 10
Years since 1-year visit
Soldberg IC, et al. Scand J Gastroenterol 2009; 44(4): 431-40.
Endoscopic healing reduces the risk
of hospitalisation and surgery (ACCENT I)
28
Percent rates of hospitalizations and surgeries
Patients with no healing
Patients with healing at one visit (wk 10 or 54)
Patients with healing at both visits (wk 10 and 54)
%
19
0
Hospitalization
2
0
0
Surgery
Rutgeerts P, et al. Gastrointestinal Endoscopy 2006
Mucosal Healing Induced by IFX Results in a Lower Need for
Major Abdominal Surgeries Long-Term
45
40
38,4
OR=0.263 (0.136-0.509) p<0.0001
35
30
25
20
14,1
15
10
5
0
No MH
MH
Schnitzler F , IBD 2009
Adalimumab – EXTEND Trial
Patients who achieved deep remission* with adalimumab
at Week 12 and activity impairment
Activity
impairment at Week 52
p<0.05
50
43
40
30
20
18
10
0
n=11
Deep
remission*
(Week 12)
n=53
Non-deep
remission*
(Week 12)
LS mean WPAI score (%)
LS mean WPAI score (%)
50
Work productivity
impairment at Week 52
44
40
30
23
20
10
0
n=11
n=53
Deep
Non-deep
remission* remission*
(Week 12) (Week 12)
*Deep remission defined as clinical remission (CDAI <150) and complete mucosal healing in EXTEND
CDAI: Crohn’s disease activity index; LS: least squares; WPAI: Work Productivity and Activity Impairment
Colombel JF, et al. Gut 2010;59(Suppl 3):A80: OP371 at UEGW 2010
EXTEND:
Complete Mucosal Healing with Adalimumab
Mucosal Healing With Continuous Adalimumab Over 12 and 52 Weeks
• ITT: intention to treat; Treatment displayed is original treatment at randomisation.
Analysed using Cochran-Mantel-Haenszel (CMH) test
† Per protocol represents all ITT patients who did not have a significant protocol deviation.
Percentages rounded to nearest whole per cent
Rutgeerts, P. et al. Gastroenterology 2012; 142:1102.
Endoscopic Healing & Remission
Among patients treated with anti-TNF, the best endoscopic response at w12 is
associated to highest chances of clinical remission at 1 year (CDAI<150 alla w52)
p<0.0001
OR 19.6 (95%CI 4.79-80.2)
100%
90%
Remission
75%
Activity
68%
50%
32%
25%
10%
0%
21/31
10/31
SES-CD<5
Rutgeerts P, et al. ECCO 2010
3/31
28/31
SES-CD>5
Clinical implications of MH in UC
• MH is associated with lower rates of relapse
• MH is associated with less hospitalizations and
surgery
• MH is associated with a lower risk of
colorectal cancer
Endoscopic Healing in UC After 5-ASA
Meucci G, et al. DDW 2006 (A)
Mucosal healing predicts late outcomes after
the first course of corticosteroids for newly
diagnosed ulcerative colitis
Early outcome (3 months, n=157)
Complete responders (group A: PT = 0-1, Baron = 0)
38%
Partial responders
(group B: PT = 0-1, Baron = 1-3)
25%
No response
(group C: PT >1, Baron 1-3)
37%
Ardizzone et al. CGH 2011 in press
Mucosal healing predicts late outcomes
after the first course of corticosteroids for
newly diagnosed ulcerative colitis
Late outcome: combined endpoint A vs B
A
B
p = 0.0166
Ardizzone et al. CGH 2011 in press
IFX – ACT Studies
Early (w8) mucosal healing is associated with improved longterm clinical outcomes in UC
50%
46%
Percentage of patients (%)
Clinical remission w30
40%
Colectomy rates
34%
30%
20%
11%
10%
5%
13%
12%
6,50%
5%
0%
(n=120)
(n=175)
(n=114)
(n=57)
Mayo 0
Mayo 1
Mayo 2
Mayo 3
Colombel JF et al. Gastroenterology 2011;141:1194–201
MD
MH:
Issues with clinical outcomes
Mucosal healing: a possible outcome?
Mucosal healing:
• Which patient?
• Which outcome?
• Which treatment?
How ultimate is MH as a goal?
Patients without lesions, %
Early combined
immunosuppression
73%
Conventional management
30%
0%
20%
40%
60%
80%
D’Haens G, et al. Lancet 2008; 371: 660-.
Which patient is more suitable to reach Clinical
Remission?
50%
Gap to 100%
Remission (%)
60%
65%
52% 50%
40%
33%
38%
Placebo
Adalimumab eow
20%
17%
11%
Adalimumab ew
0%
< 2 years
≥ 5 years
Modified from Schreiber S et al. Gastroenterol 2007;132(4 Suppl 2):A-147
Which patient is more suitable to reach MH?
56%
Gap to 100%
Patients with mucosal healing
at week 12 (%)
40
50
45
40
35
30
25
20
15
10
5
0
79%
60%
44
40
Adalimumab,
every other week
Adalimumab,
induction-only (placebo)
18
21
7
0
4/9
<2 years
1/14
4/10
2 to <5 years
7/39
9/43
5 years
p=0.029 for adalimumab vs placebo for disease duration <5 years vs ≥5years
All patients (n=135) received open-label adalimumab 160-/80- mg induction therapy at Weeks 0/2 and 129 patients
were randomised at Week 4 to maintenance therapy with adalimumab 40 mg every other week or placebo
Sandborn WJ, et al. J Crohn’s Colitis 2010;4:S36
Which patient is more suitable to reach Deep
Remission?
Gap to 100% 67%
82%
84%
Patients in deep remission at
week 52 (%)
40
33
30
18
20
16
p<0.001 vs
placebo
10
0/9
3/9
0/15
2/11
0/41
0
<2 years
2–5 years
7/44
≥5 years
Deep remission defined as complete mucosal healing and clinical remission (CDAI <150)
Adalimumab induction-only (placebo)
Continuous adalimumab 40 mg eow
Colombel JF, et al. Clin Gastroenterol Hepatol 2014
Mucosal healing: a possible outcome?
Mucosal healing:
• Which patient?  Only ‘new’ patients (with
disease duration up-to-2-2.5 years)?
• Which outcome?
• Which treatment?
MH impacts equally on Clinical and Surgical
outcomes?
Schnitzler F, et al. IBD 2009
Concomitant immunosuppression:
no impact on (clinic/endoscopic) outcomes of
maintenance infliximab therapy in Crohn’s disease
80 CD patients treated with IFX+ IS and in clinical remission for ≥ 6 months
Results at week 104
80
70
60
60
64
61
55
%
50
40
28
30
23
20
12,5
5
10
0
Change in IFX dosing
Discontinued IFX
Continuos IMM (n=40)
Mucosal healing
ATI
Discontinued IMM (n=40)
Van Assche G, et al. Gastroenterology 2008
Concomitant immunosuppression: no impact on
(clinic/endoscopic) outcomes of maintenance infliximab
therapy in Crohn’s disease
BUT significant impact on CRP and TL: who is telling the
truth?
80 CD patients treated with IFX+ IS and in clinical remission for ≥ 6 months
Results at week 104
80
60
60
64
61
55
%
50
40
28
30
23
20
12,5
5
10
0
Change in IFX dosing
Discontinued IFX
Continuos IMM (n=40)
Mucosal healing
Discontinued IMM (n=40)
ATI
Serum levels
70
10
9
8
7
6
5
4
3
2
1
0
P<0.005
P<0.005
4,8
2,8
2,5
1,6
Median IFX levels
(ug/ml)
Median CRP levels
(mg/L)
Van Assche G, et al. Gastroenterology 2008
Risk matrix model for prediction of colectomy
The IBSEN® cohort
• Population based study of 464 UC patients
• Ten years FU / 45 colectomized patients, multiple regression to select risk factors,
fitted into a prediction model
Correct prediction in
90.3% of the cases
ESR
Under 30
Age at
diagnosis
<40
years
>40
years
Over 30
8.0%
29.9%
95% CI 5.5–10.5
95% CI 25.8–34.1
2.3%
10.5%
95% CI 1.0–3.7
95% CI 7.7–13.5
Yes
No
Systemic
steroids
at
diagnosis
Proctitis and
Extensive colitis
left-sided colitis
Extent of disease at diagnosis
Conclusions: Risk is 15 times higher in young patients, with extensive colitis, ESR
>30 and who needed CS at diagnosis
Cvancarova M et al. Gut 2010;59 Suppl III:A36
Where are mucosal lesions and mucosal healing?
Mucosal healing: a possible outcome?
Mucosal healing:
• Which patient?  Only ‘new’ patients (with
disease duration up-to-2-2.5 years)?
• Which outcome?  Not impacting on all
outcomes …
• Which treatment?
Effects of steroids at 1 mg/kg/day for 3-to-7 weeks:
Perfect clinical outcomes, poor healing
Patients in remission (%)
Steroids do not induce/maintain MH: <1/3 of patients in clinical
remission showed endoscopic healing with steroids at 7 Weeks
100
90
80
70
60
50
40
30
20
10
0
92%
88%
80%
9%
worsened
63%
29%
Endoscopic
improvement
weeka 4
week 5
week 6
Prednisolone 1 mg/kg up to clinical remission
Modigliani R, et al. Gastroenterology 1990; 98: 811-8.
week 7
13% MH
CD – IFX – SONIC trial
Rates of endoscopic healing in SONIC Trial: a gap to
the unmet need (MH w26)
Gap to 100%
84%
70%
56%
% of patients with endoscopic healing
80%
60%
P<0.001
44%
P=0.02
40%
30%
20%
16%
0%
AZA
N=309
IFX
IFX + AZA
Colombel N Engl J Med 2010
IFX – ACT 1+2 trials – Moderate-to-Severe UC
Efficacy of infliximab in active ulcerative colitis
Efficacy studied in ACT trials, 728 moderately active UC cases
ACT 2
ACT 1
100
Proportion of Patients (%)

80
100
Mucosal healing
Complete mucosal healing
* p<0.001
** p=0.009
*
60
80
*
*
*
60
*
*
*
*
**
40
40
20
20
0
*
0
Week 8
Week 30
Placebo
Week 54
5 mg/kg Infliximab
Week 8
Week 30
10 mg/kg Infliximab
Rutgeerts P, et al. N Engl J Med 2005;353(23):2462-76
Which is the magnitude of mucosal healing in UC? 25% or
50% (Mayo 0 or 0+1)? And the gap to PBO? 20%?
ADA – ULTRA Trials
Mucosal Healing at Week 52 through the perspective
100 week 8 response to ADA
of
% of patients
80
ADA
Overall ITT
ADA
Week 8 Responders
60
Endoscopy subscore = 1
40
20
Endoscopy subscore = 0
17,9
16,8
25,2
24
N=123
N=125
Partial
Mayo
Score
Full
Mayo
Score
11,3
13,7
0
N=248
NRI for missing or OL data
D’Haens G, et al. UEGW 2012
Which is the magnitude of mucosal healing?
However MH greater among w8 clinical responders!
IFX – UC-SUCCESS trial – Combo treatment
Mono or combo-therapy: still a gap to the unmet
need?
60%
78%
76%
23%
31%
50%
37%
45%
63%
100%
*
77%
Percent of patients
75%
50%
25%
*
*
69%
63%
55%
50%
*
*
40%
37%
22%
24%
0%
CS-free REMISSION w16
Clinical RESPONSE
IFX+AZA
IFX
Endoscopic Healing
AZA
Panaccione R. et al. J Crohns Colitis 2011 (A)
Is Endoscopic Healing a surrogate for Clinical Response?
How to manage 40-60% of cases not reaching endpoints?
Anti-TNF exit strategies
• Predictors of clinical relapse in 52/115 (45%) patients stopping
treatment in stable remission after a median anti-TNF duration of 24
months
Louis E, et al. Gastroenterology 2011
… And what happens without normal endoscopy ? …
Anti-TNF exit strategies
• Performance of ‘full’ and ‘simplified’ model equally good
• Patients responded well on re-treatment
Louis E, et al. Gastroenterology 2011
… Almost nothing at all ? …
Mucosal healing
in IBD: conclusions
Mucosal healing in IBD : conclusions
• MH has been associated with positive
outcomes in IBD
• MH should be one of the primary end-points
in clinical trials
• In routine clinical practice MH should always
be evaluated in case of persistent symptoms
in spite of adequate therapy to discriminate
inflammatory
versus
non-inflammatory
symptoms
and
when
treatment
discontinuation is being considered
MH in clinical practice
Unsolved issues:
• Definition
• Setting cut-off values of scoring systems
• Agreement on grading activity
• Optimal timing of endoscopic assessment
• Escalation of therapy to achieve MH can be
cause of safety concern and its usefulness
needs to be demonstrated
Beyond mucosal healing
… how to step forward with MH …
Setting up a common language is critical
… how to step forward with MH …
Setting up a common language is critical
Potential solutions:
• Looking for automated (computer-assisted)
reading systems?
… how to step forward with MH …
Setting up a common language is critical
Potential solutions:
• Looking for automated (computer-assisted)
reading systems?
• Central review?
… how to step forward with MH …
Setting up a common language is critical
Potential solutions:
• Looking for automated (computer-assisted)
reading systems?
• Central review?
• Educational programs to increase a common
perception of endoscopic activity?

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