Julian Panes Department of Gastroenterology Hospital Clínic Barcelona Julián Panés Professor of Gastroenterology Research contracts Abbvie Boehringer Ingelheim Genentech MSD Pfizer Roche ID: 930739
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Slide1
Measures and markers of prediction in Inflammatory Bowel Disease
Julian PanesDepartment of GastroenterologyHospital Clínic, Barcelona
Slide2Julián Panés
Professor of Gastroenterology
Research contracts:
Abbvie
,
Boehringer Ingelheim, Genentech, MSD, Pfizer, RocheConsulting:Abbvie, BMS, Boehringer Ingelheim, Genentech, MSD, Novo-Nordisk, NSP, Pfizer, Roche, Topivert, Tygenics,Employment in industry:NoneStockholder of a healthcare company:NoneOwner of a healthcare company:NoneOther:None
Disclosure of potential conflicts of interest
Slide3Why assess prognosis initially?
Assessing prognosis at an early stage is essential for the development of an appropriate management plan
Avoid intensive therapy, immunosuppression,
adverse
events
Assure early intensive therapy to avoid complications IndolentAggressive
Slide4Relapse
Disease
complications
therapeutic
requirementsSurgerY
Slide5Solberg IC,
et al. Clin Gastroenterol Hepatol
2007;5:1430–8
IBSEN: disease course in Crohn’s disease over 10 years
Disease activity
01010Years
0
Years
45%
19%
3%
32%
Patterns of severity of bowel symptoms in CD
Slide6Disease characteristics associated with higher relapse rates
Age
Use of systemic steroids 1
st
flare
Cumulative rate (%) of patients relapsingSolberg IC, et al. Clin Gastroenterol Hepatol 2007;5:1430–8p=0.03p=0.02p=0.008
Slide7Phenotype at diagnosis andrecurrence rates in Crohn’s disease
Ten year clinical follow-up project13 centers from 7 EU countries358
CD patients classified for phenotype at
diagnosis
262
(73.2%) a first clinical recurrence113 (31.6%) a first surgical interventionWolters FL et al. Gut 2006;55:1124–30.Colonic disease (L2)Age > 40Upper GI Disease (L4)1
Surgery
Clinical recurrence
2
0.5
0.2
Proportion in each group
5.6%
32.6%
42.2%
Slide8Aggressive course Crohn’s disease
Munkholm P. et al.
Scand J Gastroenterol
1995:30:699-706
D
1
2
3
4
8
Years after diagnosis
active
p
<0.001
45%
50%
5%
inactive
Courtesy of Pia Munkholm
Slide9Indolent course Crohn’s disease
D
1
2
3
4
8
Years after diagnosis
active
inactive
8%
48%
44%
Munkholm P. et al.
Scand J Gastroenterol
1995:30:699-706
Courtesy of Pia Munkholm
Slide10Long term
disease behaviour in CD
Ileal
Colon
Ileocolon
ProximalPenetratingStricturingInflammatoryLouis E et al Gut 2001; 49:777-32Disease behaviorDisease locationPercent
Slide11Factors influencing the development of stricturing or penetrating pattern in Crohn’s disease
%
Louis E et al
Gut 2001;
49:777-32
DiagnosisAfter 10 years
Slide12Predictors of «
disabling» (severe) CD
Derivation cohort
Retrospective
262 for prevalence
seen from diagnosis1123 patients (factors)Validation cohortProspective302 patientsDefinition disabling (any)≥ 2 steroid coursessteroid dependencehospitalizationchronic (>12 mo) symptomsneed immunosuppressantsneed surgery64.9% - 80.5%CI 59.1% - 92.2%PPVDerivationValidation2 factors0.910.843 factors
0.93
0.91
Beaugerie L et al.
Gastroenterology
2006;130:650–6.
Independent
factors
at diagnosis
Steroid requirement
Age < 40
Perianal Disease
1
2
3
4
5
Slide13Predictors of very severe
Crohn’s DiseaseCriteria:
>70 cm
resection
, >2
resections, colectomy, stoma, complex perianal diseasePrevalence: 18% of patients at 5 yearsIndependent predictors at diagnosis:Age <40Stricturing or intra-abdominal penetratingFeverLoss of >5 kgIncreased platelet countsLoly C, et al. Scand J Gastroenterol. 2008 43:948-54
Slide14Serum Immune Responses and
Disease Progression in Pediatric CD
196 pediatric CD patients
Penetrating or stricturing disease: 38 (19%) at diagnosis; 58 (30%) at the end of follow-up.
Median follow-up period within the study: 18 months
Immune Responses: ASCA, anti-OmpC, anti-I2, pANCAOdds of having B2/B3≥ 1 Immune Response: OR=5.5 [1.3–23.6]4 Immune Responses: OR=11.0 [1.5–80.4] Dubinsky MC et al Am J Gastroenterol 2006; 101:360–70
0.25
0.5
0.75
1
0
a
ll negative
20
40
60
80
100
120
1-3 positive
Time to disease progression (months)
140
Probability
of non-
progressive
CD
p
=0.03
n=70
n=93
Number
immune
responses
Slide15Serological Makers in the Prediction of Complications and Surgery in Pediatric CD
139
patients
.
Age
11.1±3.4 yr. Complications (fistula / abscess): 31 patients during follow-up First Surgery: 35 patients duging follow up ASCA and pANCA measurements every 3 monthsAmre DK et al Am J Gastroenterol 2006; 101:645–520 500 1000 1500 2000 Days020406080
100
Proportion free of first complication
0
500 1000 1500 2000
Days
0
20
40
60
80
100
Proportion free of first surgery
ASCA
negative
ASCA positive
l
ogrank
test p<0.001
l
ogrank
test p<0.001
Slide16The prognostic
power of the NOD2 genotype for
complicated
CD: a meta-
analysis49 studies, 8893 subjects, 2897 with NOD2 mutationsAdler J et al. Am J Gastroenterol 2011; 106:699-7120,811,21,41,61,82
Complicated
Disease
Stricturing
Penetrating
Perianal
Surgery
RR (95% CI) p
1.17
(1.10, 1.24) < 0.001
1.33 (1,15, 1.55) < 0.001
1.16 (1.05, 1.28) < 0.003
1.03 (0.92, 1.16) 0.6
1.58 (1.38, 1.80) < 0.001
Slide17Risk factors for surgery
Variable
RR
Age at diagnosis
0-14
0.8 (0.6 - 0.96) 15-291 45-691.2 (1.0 – 1.4)Disease location Colorectal
1
Ileocolonic
1.7 (1.4 – 2.0
Ileocecal
3.2 (2.7 – 3.6)
Small bowel
3.2 (2.5 – 4.0)
Perianal fistulas
No
1
Yes
1.2 (1.04 – 1.3)
Retrospective
. 1936
patients
.
Diagnosed
1955 -1989. Final
evaluation
1993-4
Median
follow
-up 14.9
yr
. Complete in 99.2% cases
Bernell O et al.
Ann Surg
2000;231:38–45.
0
3 6 9 12 15Years02040
6080100Cumulative risk of surgery (%)
Slide18Henriksen
M,
et al.
Gut
200
8;57:1518–1523 CRP>23 mg/L at diagnosis in extensive UC and risk for colectomy in 5 years (n=129)CRP a Marker of Disease Outcome?1
Percent
0
10
20
30
40
50
2
3
4
6
7
4
26
CRP>
5
3
mg/L at diagnosis
in
L1
CD
and
risk for
surgery i
n
5 years (n=
46
)
1
Percent
0
20
40
60
80
100
2
3
4
36
44
50
82
Quartile
Quartile
Slide19Risk of Early Surgery for Crohn’s Disease
Retrospective331 patients new diagnosis CD followed since diagnosis69 (20.1%) surgery within 3 yr
Sands BE et al.
Am J Gasroenterol
2003;981:2712–8.
Independent risk factorsMultivariate analysisSmoking OR 3.42 (1.54–6.35)Colonic localization OR 0.36 (0.22–0.57)**No Yes Any SB Colon onlySmoking Disease location% operated
Slide20Significance of granulomas in incident CD cases
188 consecutive incident CD casesEpithelioid gralulomas:69 (37%)46 (25%) at diagnosis
Slide21Severity of Endoscopic Lesions and Long Term Outcome in CD
Allez M et al.
Am J Gastroenterol
2002;97:947–53.
Colectomy
Patients: 102 (all colonoscopies 1990-1996)Severe Endoscopic Lesions: Deep ulcerations > 10% surface of one segmentPrevalence: 52%
Slide220
,2
,4
,6
,8
1% patients wihout surgery
0
20
40
60
80
100
120
Months
p =0.0089
Wild
type
NOD2/CARD15
Variants
Álvarez-Lobos M et al.
Ann Surg
2005;242: 693–700
Surgery-free survival in Crohn’s disease according to
NOD2/CARD15
variants
Slide23Need of reoperationGenetic factors: NOD-2
0
,2
,4
,6
,81
0
10
20
30
40
50
60
Months
p =0.03
Wild
type
CARD15 Variants
Survival free of reoperation after first surgery
Álvarez-Lobos M et al.
Ann Surg
2005;242: 693–700
Slide24Predictors CD summary
Relapse
Complications
Surgery
Age
++++Location++++++B2, B3 at diagnosis+++Smoking+N flares+++CRP+Perianal++++Steroids+++Genetics++
Slide2525
Disease
Course
in UC
Solbert
IG, et al. Scand J Gastroenterol, 2009; 44: 431-40Remission after initial activity55%
0
5 yrs
Increase in severity
1%
0
5 yrs
Chronic
contiuous
6%
0
5 yrs
Chronic
intermitent
37%
0
5 yrs
younger
age
at diagnosis (p<0.009)
Slide26Clinical course
of UC during the first year
after
diagnosis
Age
on risk of relapseDisease extent on therapeutic requirementsMoum B et al Scand J Gastroenterol 1997; 32:1005-12p=0.005p=0.011p=0.03
Slide27Aggressive course, IUlcerative colitis
D
1
2
3
4
8
Years after diagnosis
active
p
<0.001
32%
61%
6%
inactive
Langholz E et al.
Gastroenterology
. 1994;107:3.
Slide28Indolent course, III
Ulcerative colitis
D
1
2
3
4
8
Years after diagnosis
6%
46%
48%
Langholz E et al.
Gastroenterology
. 1994;107:3.
active
inactive
Slide2929
Colonoscopy for Predicting Disease Outcome of Moderate-to-Severe UC After Steroid Treatment
Parente F, et al.
Am J Gastroenterol
2010;105:1150–1157
Baron at 15 monthsBaron at 3 months
0–1
2–3
OR
0–1
84%
40%
1
2–3
16%
60%
5.22
(1.55–17.6)
3 months
20
40
60
80
100
0
9 months
15 months
Baron 3 mo 0–1
Baron 3
mo
2–3
cumulative probability of
endoscopic
remission
Slide30Early mucosal healing
and long-term remission in UC
Colombel
JF
et al.
Gastroenterology 2011;141:1194–201.ACT 1/2: steroid-free remission at Week 30 with infliximabRemission was defined as a total Mayo score ≤2, with no individual subscore >1ACT 1/2 subanalysis; primary endpoint was clinical response at Week 8 (p<0.001); patients randomised to placebo or infliximab induction and maintenance therapy at Week 00(n=120)4660100
0
20
40
80
Patients
(%)
p
<0.0001
1
(n=175)
34
2
(n=114)
11
3
(n=57)
6.5
Endoscopic score at Week 8
Slide3131
Predictors of Relapse in UC
Hazard ratio (95% CI)
P value
Age
0.4a (0.2–0.7)0.003Basal plasmacytosis
4.5 (1.7–11.9)
0.003
No. of prior relapses (women)
1.6
b
(1.2–1.9)
<0.001
No. of prior relapses (men)
0.93 (0.7–1.3)
0.64
Bitton A, et al.
Gastroenterology
2001;120:13–20
0
0.25
0.5
0.75
1
0
Absence
Proportion of patients in remission
2
4
6
8
10
12
Presence
Basal Plasmacytosis
Months on study
a
Per
decade.
b
No
significant differences in WBC,
Hb
, and albumin.
Slide32Cumulative rate of colectomy
32
0
5
10
15
20
25
Proportion of UC patients not
colectomised
0
2
4
11
Time since diagnosis (years)
6
8
10
9
7
5
3
1
Solbert
IG,
et
al.
Scand
J
Gastroenterol
,
2009; 44:
431-40
Colectomy at 10
years
9.8 %
Slide3333
Szamosi T, et al.
Eur J Gastro
20
1
0;22:872–879Smoking and Need for Surgery in UCpLogRank=0.0420
0.2
0.4
0.6
0.8
1.00
Survival without colectomy
0.00
100.00
200.00
300.00
400.00
Follow-up (months)
No-smoking
Smoking
Censored
Censored
Slide3434
ESR and disease extend at diagnosis:
Markers of colectomy risk
Solbert
IG, et al. Scand J Gastroenterol, 2009; 44: 431-400.50.6
0.7
0.8
0.9
1.0
Fraction of patients not operated
0
2
4
10
Time to operation (years)
6
8
ESR > 30 mm/h
ESR ≤ 30 mm/h
12
ESR > 30 mm
:
H
R
:
2
.
94
(95%CI:
1.58
–
5.46
),
p
=0.00
1
Extensive
colitis
:
H
R
:
2
.
98
(95%CI:
1.
25
–
7.08
),
P
=
0.01
3
Slide3535
Henriksen
M,
et al.
Gut 2008;57:1518–1523CRP: A Marker of Disease Outcome in UCP=0.020.5
0.6
0.7
0.8
0.9
1.0
Fraction of patients not operated
0
2
4
10
Time to operation (years)
6
8
C-reactive protein levels >23 mg/l (75% percentile)
C-reactive protein levels ≤23 mg/l
Slide36Serologic Markers in UC?
36
Solberg IC
, et al.
Inflamm Bowel Dis 2009;15:406–14Male gender : OR: 0.52 (95%CI: 0.32–0.82), P=0.005Azathioprine use: OR: 4.23 (95%CI: 1.73–10.02), P<0.0010.80
0.84
0.88
0.92
0.96
1.00
Proportion of UC patients not
colectomised
0
2
4
11
Time since diagnosis (years)
6
8
10
9
7
6
3
1
Log rank-test
, P
=0.52
pANCA negative
pANCA positive
OR=odds ratio; pANCA=
Anti-neutrophil cytoplasmic antibody
Slide3737
Predictors for mucosal healing: Education longer than 12 years and extensive disease at diagnosis
Froslie KF, et al.
Gastroenterology
2007;133:412
–422Mucosal Healing and Need for Surgery (IBSEN)P=0.020.90
0.92
0.94
0.96
0.98
1.00
Proportion of UC patients not
colectomised
0
1
2
3
4
5
6
7
8
Time in years after 1 year visit
Slide38Relationship Between Histologic Inflammation and Colectomy Risk?
University of Chicago IBD Endoscopy Database used to identify patients with UCOut of 106 patients (median age: 27 years, median duration of disease: 13.5 years) studiedIn Cox modeling with time-varying covariates
1-point increase in inflammation grade
*
resulted in a statistically significant increase in risk of colectomy (Hazard ratio =1.90,
95% CI 1.02–3.51; P=0.042) The grade of histologic inflammation was not correlated with number of endoscopies, clinic encounters, radiological exams or steroid exposureRubin DT, et al. DDW 2007. Abstract #103.* 6-point grading of histologic inflammation.
Slide39Progression of UC
disease extent over 5 years
Progresion
o
f
diseaseextent:41/146 (28%)28/90 (31%)Henriksen M, et al. Inflamm Bowel Dis 2006;12:543–50 Number of patientswith progresionNorwegian IBSEN cohort study, 1990–1994 (n=454)Disease extent after 5 years:ProctosigmoiditisLeft-sided colitisExtensive colitis
Slide40Extension
progression
(n=63)
Extensive
stable (n=63)PN bowel movements8.9 4.55.8 3.70.02CRP (mg/dl)5.1 6.92.3 3.60.01ESR (mm/h)46.0 30.3 29.8 25.50.03Albumin (g/L)38.2 6.941.2 7.70.03Hemoglobin (g/L)119.2 18.2123.9 20.1nsSteroid refractory/dependent (%)46270.026Cyclosporine (%)23.811.30.054Infliximab (%)6.31.6
nsHospitalization (%)
46.6
20.6
0.002
Hospital
stay
(
days
)
7.4
11.2
3.5
9.3
0.04
Surgery
(%)
19.0
4.8
0.015
Comparison
of cases
with
disease
progression
and
controls with stable extensive diseaseClinical characteristics of UC at time of progression from distal to extensive colitisEtchevers J et al. Inflamm Bowel Dis. 2009;15:1320-5Cyclosporine is not approved for treatment of ulcerative colitis
Slide4141
Polygenic Multifactorial Model Predicting
Medically Refractory UC
Haritunians T
, et al.
Inflamm Bowel Dis 2010;16:1830–1840
0
20
40
60
80
100
Proportion (%)
Risk-A
0.9%
(n=109)
Risk-B
17.2%
(n=373)
Risk-C
74.3%
(n=268)
Risk-D
100%
(n=50)
0
0.2
0.4
0.6
0.8
1.0
Cumulative Probability of
Avoiding Colectomy (MR-UC)
10
20
24
30
40
50
60
Risk-A; n=109
Risk-B; n=373
Risk-C; n=268
Risk-D; n=50
Time to Surgery (months)
Slide42Predictors UC summary
Relapse
Therapy
requirements
SurgeryCancerAge++/-Disease extent++++++++CRP /ESR++Steroids 1st flare+++Smoking+ (-)Mucosal healing++++N flares+Progression of extension++Genetics+/-
Slide43Age
Disease
extension
/
Location
(CD: perianal)Steroid requirementBiomarkersSmokingMucosal healingSustained remissionPredicting IBD at diagnosis