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Serological Markers in IBD: Are They Ready for Prime Time?
Raymond Cross, M.D.
Assistant Professor of Medicine
Division of Gastroenterology and Hepatology
Director, IBD Program
Acting Chief, VA GI Service
What are the Serological Markers in IBD?
pANCA (perinuclear staining pattern)
– Loss of perinuclear pattern after DNAase
– Differentiate from the “other pANCAs”
» Antibody against myeloperoxidase
» Antibody against cathepsin G, elastase, lysozyme, and lactoferrin
ASCA (anti-Saccharomyces cerevisiae)
– Both IgG and IgA
– Recognize mannose in the cell wall mannan of Saccharomyces cerevisiae
What are the Serological Markers in IBD-2?
Omp C
– IgG only
– Recognize outer membrane porin C protein in E. coli
I2
– IgA only
– Recognizes novel homologue of bacterial transcription-factor families from a Pseudomonas fluorescens-associated sequence
Cbir 1 flagellin
– IgG
Why Use Serological Markers in Clinical Practice?
Differentiate IBD from functional bowel disorders
Accurately diagnose Crohn’s or UC in a patient with:
– Severe colitis
– Indeterminate colitis Predict disease course or complications in IBD
– CD phenotype
– Severity of disease
– Risk of pouchitis
Frequency of pANCA in UC Patients and Controls in a Referral Center
0
10
20
30
40
50
60
70
Normal UC
UC with
Cole
ctom
y
Collage
nous
Colonic
CD
Infe
ctiou
sIB
SM
isc
% o
f P
atie
nts
Duerr, R. H., S. R. Targan, et al. (1991). Gastroenterology 100(6): 1590-6.
60% sensitive 94% specific for UC
Prevalence of ASCA in Patients with CD and UC and Controls in the Different Assays
Vermeire, S., S. Joossens, et al. (2001). Gastroenterology 120(4): 827-33
Sensitivity, Specificity, and Positive and Negative Predictive Value of ASCA
61 61
94 93
78
9087
71
0
10
20
30
40
50
60
70
80
90
100
CD vs. Non-CD CD vs. UC
Per
cent
Sensitivity Specificity PPV NPV
Vermeire, S., S. Joossens, et al. (2001). Gastroenterology 120(4): 827-33
*Using the Prometheus Assay
Accuracy of Serological Markers in Differentiating IBD from Controls
0
20
40
60
80
100
120
pANCA+ ASCA+ ASCA+/pANCA- pANCA+/ASCA-
% o
f Pat
ient
s
Sensitivity
Specif icity
PPV
NPV
Peeters, M., S. Joossens, et al. (2001). Am J Gastroenterol 96(3): 730-4.
Utility of Serodiagnostics in Pediatric IBD: Use of a Two-Step Assay
Dubinsky MC, Ofman JJ, Urman M, et al. Am J Gastroenterol 2001;96(3):758-65
IgA Antibody to I2 in Patients with CD or UC and Controls
Sutton, C. L., J. Kim, et al. (2000). Gastroenterology 119(1): 23-31.
54
4
10
19
0
10
20
30
40
50
60
CD Control UC Inflammatory
Per
cen
t o
f P
atie
nts
Can Serological Markers Differentiate IBD from Non-IBD?
pANCA and ASCA are specific for and have high positive predictive value for UC and CD respectively
– Rule in disease The low sensitivity and negative predictive
value preclude them as a screening test
– Cannot rule out disease Potential application in pediatric disease to
avoid invasive work up
Why Use Serological Markers in Clinical Practice?
Differentiate IBD from functional bowel disorders
Accurately diagnose Crohn’s or UC in a patient with:
– Severe colitis
– Indeterminate colitis Predict disease course or complications in IBD
– CD phenotype
– Severity of disease
– Risk of pouchitis
Criteria for Indeterminate Colitis
No evidence of small bowel involvement, fistula, or perianal disease
Absence of diagnostic criteria for CD or UC by microscopy
Presentation of Ulcerative Colitis
Classic presentation
– Bloody diarrhea!
– Never or former smoker
– Tenesmus (dry heaves of the rectum)
Red Flags
– Active smoker
– Perianal disease
– Abdominal mass on examination
DISTINGUISHING FEATURES OF CROHN’S DISEASE
Crohn’s Disease Red Flags
Onset after stopping smoking
Bleeding only
Diverticulosis
Atherosclerosis
Prolapse
INDETERMINATE COLITIS
Sensitivity, Specificity, and Positive and Negative Predictive Value of ASCA
61 61
94 93
78
9187
71
0102030405060708090
100
CD vs. Non-CD CD vs. UC
Per
cen
t
Sensitivity Specificity PPV NPV
Vermeire, S., S. Joossens, et al. (2001). Gastroenterology 120(4): 827-33
*Using the Prometheus Assay
Results of ASCA and pANCA in the Study Population
Joossens, S., W. Reinisch, et al. (2002). Gastroenterology 122(5): 1242-7
0
10
20
30
40
50
60
70
80
90
n CD UC IC
% o
f P
atie
nts
ASCA+/pANCA- ASCA-/pANCA+ ASCA+/pANCA+ ASCA-/pANCA-
Relationship Between Marker Antibodies and CD Cohort
Landers, C. J., O. Cohavy, et al. (2002). Gastroenterology 123(3): 689-99
Conclusions-2 pANCA and ASCA have low sensitivity in CD and
UC
pANCA and ASCA have good specificity and PPV in CD and UC
In patients with indeterminate colitis, available serological markers do not accurately predict the subsequent disease course
– Is indeterminate colitis a different form of IBD?
– Will performance of serological markers improve with introduction of other markers?
Why Use Serological Markers in Clinical Practice?
Differentiate functional from organic disorders
Differentiate type of IBD
– Implications for medical and surgical therapy
Predict disease course or complications in IBD
– CD phenotype
– Severity of disease
– Pouchitis
Antibody Expression Stratifies Homogeneous Subgroups with Distinct Clinical Characteristics
100
79
14
58
41 39
14
29
86
0
20
40
60
80
100
120
Fibrostenosing Internal Perforating UC Like
Disease Behavior
Per
cen
t
ASCA+/ANCA- All Others ANCA+/ASCA-
Vasiliauskas, E. A., L. Y. Kam, et al. (2000). Gut 47(4): 487-96
Relative Contribution of Antibody Responses and Complicated Small Bowel Disease
Mow, W. S., E. A. Vasiliauskas, et al. (2004). Gastroenterology 126(2): 414-24
Disease Characteristics in Patients with Antibodies to Multiple Microbial Antigens
3.7
8.6
3.7
8.6
0.20
1
2
3
4
5
6
7
8
9
10
SB FS IP SBS UC
Od
ds
Rat
io (
3 vs
. 0)
Mow, W. S., E. A. Vasiliauskas, et al. (2004). Gastroenterology 126(2): 414-24
Incidence of Pouchitis in pANCA+ and pANCA- Patients
1711
25
9
0
5
10
15
20
25
30
35
40
45
pANCA+ pANCA-
Per
cen
t
Acute Chronic
Fleshner, P. R., E. A. Vasiliauskas, et al. (2001). Gut 49(5): 671-7
Conclusions-3
Antibody profiles can predict disease behavior in IBD
– ASCA and I2 generally predict small bowel disease, fibrostenotic behavior, and need for surgery
»Multiple antibodies associated with an even higher risk
– pANCA predicts “UC-like” behavior pANCA+ associated with risk of pouchitis after
IPAA
Summary
pANCA and ASCA are specific for UC and CD respectively
Neither pANCA nor ASCA are sensitive enough to exclude IBD
In patients with IC, available serological markers do not accurately predict the subsequent disease course
Antibody profiles can predict disease behavior in IBD