What Role do Serological Markers Play in IBD- Pediatric ... · What Role do Serological Markers Play in IBD- Pediatric ... – Gastroduodenitis ... 20090327_1400_Dubinsky.ppt
Post on 04-May-2018
215 Views
Preview:
Transcript
What Role do Serological Markers Play in IBD- Pediatric
and Adult data
Marla C. Dubinsky, MD
Cedars-Sinai Medical Center
Pathophysiology of IBD
Innate Immune Response
Adaptive Immune
Response
ASCAAnti-I2 Anti-OmpC
Anti-CBir1NOD2/CARD15TLR 4/TLR
5/ATG16L1/IRGM
NOD2
Commensal bacteria
TNF-αIL-12IFN-γ
ImmuneResponse
I
ImmuneResponse
I
ImmuneResponse
ll
ImmuneResponse
ll
ImmuneResponse
lll
ImmuneResponse
lll
Immune Responses
ClinicalPhenotypes
IBD l
IBD ll
IBDlll
IBD PATHOGENESIS:DEFINITION OF IBD SUBTYPES
Bacterial
Bacteriall
Bacterialll
Luminal Antigenic Drive
Gene l
Genell
Genelll
Genetic Susceptibility
IBD SerologiespANCA perinuclear Antineutrophil Cytoplasmic AbASCA Anti Saccharomyces cerevisiae IgA & IgGAnti-OmpC Outer Membrane Porin C AbAnti C-Bir Anti Flagellin AbAnti I2 Fragment of Pseudo. fluorescens bacterial DNA
gASCA IgG anti-covalently attached mannanALCA IgG anti-laminaribioside Glc(β1,3)Glc(β)AMCA IgG antimannobioside Man(α1,3) Man(α)ACCA IgA anti-chitobioside GlcNAc(β1,4)GlcNAc(β)
Anti‐laminarincarbohydrate antibody (Anti‐L IgA)Anti‐chitincarbohydrate antibody (Anti‐C IgA)
SigmaMA Synthetic mannoside antibodies
Serologic Markers by Age at Dx#
**
#
**
0%
10%
20%
30%
40%
50%
60%
70%
pANCA anti-ompC
ASCAIgA
ASCAIgG
anti-CBir1
Perc
ent o
f Sub
ject
s
0-7 yrs
8-15 yrs
* p<0.0001# p<0.05
Markowitz JM et al IBD 2009
Serologic Response by Year of Age
0
20
40
60
80
100
1 3 5 7 9 11 13 15
Age (yrs)
Subj
ects
pos
itive
(%)
ASCA IgAanti-CBir1
Markowitz JM et al IBD 2009
Predicting Behavior Rx Response
Need forSurgery & Outcome
Monitoringactivity, response
The Spectrum of Utility in IBD
Israeli et al. Gut 2005;54:1232–1236
Pre-Clinical: Immune Risk Factor
ASCA to Dx: 38 months
• IBD vs infection • IBD vs IBS• IBD vs non-infectious inflammation
• Ischemic• Lymphocytic• Microscopic• Vasculitis• Allergic/esosinophilic• Neoplasm• NSAID
Differential Diagnosis
Prevalence %
CD UC HC Sensitivity Specificity
ASCA IgA & IgG 50–70 5–15 0–5 50–70 80–85
pANCA 6–20 50–70 0–2.5 65–70 80–85
Anti OMP-C IgA & IgG
20-55 10 5 20–55 88.5
Anti-I2 IgA 54 10 4 42 76
Anti CBir IgG 50 5 8
ALCA IgG 18–27 4–7 2 18 93
ACCA IgA 20-25 5-15 12-15 21 85
AMCA IgG 28 18 8 28 82
Peyrin-Biroulet Inflamm Bowel Dis 2007;13:1561–1566
Serology as Initial Test?
• No prospectively supported data• Diagnostic algorithms not
published• ↓ prevalence: ↑ false positives• ↑ in autoimmune disorders
– ASCA: celiac, Behcet's, PBC, hepatitis– ANCA: eosinophilic & collagenous colitis– OMP-C & I2: infection, diverticulitis
• CostAustin et al. Clin Gastr Hep 2007;5:545–547Damoiseaux et al. J Clin Immunol 2002; 2(5):281-8
IBD UNSPECIFIED
– Periappendicial with proctitis– Patchy colitis– Rectal Sparing in UC– Gastroduodenitis– Ileitis– Transmural inflammation
Sands. Gastroenterology 2004;126:1518–1532Simpson et al. Inflamm Bowel Dis 2008;14 (9) 1287-1297
Clinical Dilemas: IBDU
IBD Duration 11.4 yrs (2.5‐40.5)Follow‐up 4 yrs
Joossens et al. Gastroenterology 2002;122:1242–7Joossens et al. Gut 2006;55:1667-1669
Diagnosis reached–50% (32/64) if markers present
–Min added value of OMP-C & I2
–100% UC or UC-like UC if pANCA positive
–26% (6/23) if no markersJoossens et al. Gastroenterology 2002;122:1242–7Joossens et al. Gut 2006;55:1667-1669
The evolution of Crohn's disease:Inflammation leads to structural damage
Louis et al, GUT 2001; 49: 777Louis et al, GUT 2001; 49: 777
B1 non-stricturing, non-penetrating
B2 stricturing
B3 penetrating
n=125
0
20
40
60
80
Diagnosis 5 years 10 years
Patients (%)100
73.7
10.315.5
52.0
21.2 26.8
30.632.2
37.2
5-year clinical course after diagnosisAge at onset
– <40 years vs ≥40 years; p=0.0004Location of disease
– small bowel + colon vs small bowel only; p=0.002Smoking status
– smoker vs ex- or non-smoker; p=0.09Perianal lesion at diagnosis
– yes vs no; p=0.01Required steroids for first flare
– yes vs no; p=0.0001Beaugerie et al, Gastroenterology 2006; 130: 650
Predictors of disabling disease:
Reference Predictors OutcomeMunkholm PL, Gastroenterology 1993
extensive (>100cm), gastroduodenal or jejunal disease
Mortality
Franchimont D, Eur J Gastro & Hepatol 1998
Smoking, colitis, non-fibrostenotic type, young age at diagnosis
Corticodependency
Sands B et al, Am J Gastroenterol 2003
Steroid use in first 6 months, smoking, ileal disease, nausea/vomiting, abdominal pain
Rapid progressionto surgery
Lichtenstein G, Am J Gastroenterol 2006
Disease severity, ileal disease, corticosteroid use Stenosis or obstruction
Beaugerie L, Gastroenter,ology2006
Need for steroids, perianal disease, age at diagnosis <40 yrs
Disabling disease (>2 steroids, IMs, hospitalisation, surgery within 5 yr)
Louis E, Gastroenterology 2007Age <40, stricturing disease or intra-abdominal fistulae, perianal disease, fever, weight loss >5kg, high platelet count
Severe disease (>2 resections or >70cm, stoma, complex perianal disease 5 yr
Clinical predictors of disabling disease
Independent Associations of Antibody Responses, NOD2 Genotype and CD Phenotypes
Anti-I2
Anti-OmpC
ASCA
pANCA
Fibrosten.SB SB Surg.Int. Perf. UC-like
- P=0.027 P=0.01- -
- - -p<0.02 -
- - -- p<0.001
NOD2 p<0.003 - -- -
p=0.023 P<0.001 P<0.001P<0.001 -
Mow S et al., Gastro2004;126Papadakis et al IBD 2007:13
Anti-CBir1 P=0.018 P=0.05 P=0.008
0
20
40
60
80
100Fr
eque
ncy
of D
isea
se B
ehav
ior %
Number of Immune Responses
Antibody Sum and Disease BehaviorNPNSIPS
* Odds Ratio
0N=199
1N=262
2N=194
3N=57
Surgery
P trend < 0.0001
*2.2*
1.0
*5.0
*9.5
*1.7*
1.0
*4.2
*6.1
P trend < 0.0001
Dubinsky MC et al CGH 2008;6:1105
Ferrante et al, Gut 2007; 56: 1394Ferrante et al, Gut 2007; 56: 1394
Serological markers to carbohydrate Agscan be used to predict Crohn’s disease course
OR=odds ratio; p-value (Chi-square)
Complicated disease course Need for abdominal surgery
Patients (%) Patients (%)
Group A (n=181) Group B (n=200) Group C (n=184) Group D (n=173)
<1.5 1.5 or 2.0 2.5 or 3.0 >3.0 <1.5 1.5 or 2.0 2.5 or 3.0 >3.0Score Score
100
0
100
0
42.0
53.0
71.7
83.2OR: 2.00p=0.001
OR: 1.96p=0.010
OR: 1.56p=0.033
OR: 1.45p=0.072
OR: 2.81p<0.001
OR: 1.76p=0.006
38.1
49.058.2
79.8
Dubinsky et al, CGH 2008
Antibody sum and surgery
p<0.0001Time to surgery (months)
Probability of non-progressive CD
0.00
0.25
0.50
0.75
1.00
0 25 50 75 100 125 150 175
Antibody sum=0(n=189)
Antibody sum=1(n=243)Antibody sum=2(n=174)Antibody sum=3(n=47)
Papp et al. Am J Gastroenterol 2008;103:665–681
Non-Inflammatory CD Behavior
Serology Present? Risk
Yes 68 %No 49 %
OR 2.27 (1.6-3.21)
N=557
Serology Present? Risk
Yes 48 %No 31 %
OR 2.03 (1.43‐2.90)
Need for Surgery in CD
N=557 Papp et al. Am J Gastroenterol 2008;103:665–681
56
22 16
22
19
6
010
203040
506070
8090
High (100) Medium (40-100)
Low (< 40)
Acute pouchitis
Chronic pouchitis
78 %
22 %
High Level Pre-operative pANCA Predicts Chronic Pouchitis
Inci
denc
e of
Pou
chiti
s (%
)
41 %
P=0.03
Fleshner PR et al., Gut 2001;49
0
1
2
3
pANCA+
UCpANCA+
CD
Ant
i-CB
ir1 (O
.D.)
1/25
11/25
4%
44%
p<0.001 (level)
0.255
0.623
pANCA: Distinguished by Anti-CBir1
Targan et al, Gastroenterology 2005; 128: 2020
Anti-CBir1 Affects Chronic Pouchitis in High-Level pANCA+ Patients
Fleshner Pet al, Gastroenterology 2006; 130: A24
HL-pANCA+/CBir+
Cum
ulat
ive
Inci
denc
e of
C
hron
ic P
ouch
itis
(%)
HL-pANCA+/CBir-
p=0.04
0
25
50
0 12 24 36 48 60 72 84Months After IPAA
Crohn’s Post IPAA
Melmed et al. Dis Colon Rectum 2008;51(1):100-8
Risk Factors for Crohn’s DiseaseMultivariate Analysis
Variable Hazard Ratio (CI) p value
Fam Hx of CD 8.4 (3 - 24.1) <0.0001
ASCA IgA+ 3.1 (1.1 - 9.8) 0.04
Melmed et al. Dis Colon Rectum 2008;51(1):100-8
0
50
100
0 12 24 36 48 60Months After IPAA
Risk Factors and the Cumulative Incidence of CD after IPAA
2 factors
No factor
1 factor
Cum
ulat
ive
Inci
denc
e of
C
rohn
’s D
isea
se (%
)
p=0.02
Melmed et al. Dis Colon Rectum 2008;51(1):100-8
Disease pathogenesis
Metabolism and Disposition of Medications
Blueprint for Individualized Drug Therapy
Drug Targets
Predictors of Response to Infliximab
Study N Weeks Antibody Response
Taylor 59 4 pANCA Poor
Ferrante 100 4-10 pANCA+/ASCA- Decreased early response
Esters 279 4/10 ASCA+/pANCA+ASCA-/pANCA+
NS Any/Combo
NS trend no
Papp 56 8 anti-OmpC/gASCAALCA/ACCA/AMCA
NS Any
Taylor et al. Gastroenterology 2001;120:1347–1355Esters et al. Am J Gastroenterol 2002;97:1458-1462Papp et al. Am J Gastroenterol 2008;103:665–681
Are prognostic markers ready for primetime?
• Always need more data• Adequately powered, prospective studies in
representative populations– Clinical factors, Genetics, serology etc
• However we do have some prognostic data in CD – We should use it!– At present we have a ‘reactive’ approach– Need to use these data to be ‘proactive’
• Prevent complications in those at risk of severe disease– Aggressive disease, surgery, hospitalizations etc
• Improve quality of life
Pathogenesis: Definition of IBD Subtypes
Genetic Variants/Mutations
ClinicalPhenotypes
Immunologic/BacterialPhenotypes
NOD2/?
Aggressive SB dz
High antibody combo quantile
TLR5/Chr 4 SB surgeryCBir1+
TLR5/?
Internal penetrating
diseaseOMPC+
Autophagydefect
Non-progressive
diseaseLow antibody
combo quantile
Refining The Role of Serological Immune responses: Targeting Therapy
IBD 1
IBD 2
IBD3
ClinicalPhenotypes
Bacteria XBacteria YBacteria Z
Gene II
Gene III
Gene I
RxIBD1
RxIBD2
RxIBD3
Mild Severe
top related