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