biomarkers managing ibd stephen b. hanauer, md university of chicago

Biomarkers Managing IBD

Stephen B. Hanauer, MD

University of Chicago

+

IBD subtype:

UC UC

1 23

412

3 41 2 3

CD/UCCD/UC

Crohn’s Diseases

and

Ulcerative Colitides

Traditional Clinical Parameters:

CDCD

Genetic markers

Serum immune markers

Cytokine profile

Enzyme activity

Metabolite levels

Genetic, Serologic, and Biochemical Profiles:

Role of Biomarkers in IBD

• Disease Classification

• Disease Activity

• Prognosis

Defining IBD

CDCDUCUC

20th Century

Classic names

Abreu MT, et al. Clin Perspect Gastroenterol. May/June 2001;155-164.

IBD1IBD1 IBD2IBD2 IBD3IBD3 IBD4IBD4

SevereDisease

MildDisease

21st Century

Names based on mechanisms

IBD Serologies

pANCA

ASCA

OMPc

Anti-I2

CBir1

Differential Diagnosis: Serological Markers

Quinton J-F et al. Gut. 1998;42:788.

% P

atie

nts

wit

h P

osi

tive

AS

CA

and

AN

CA

Tes

t R

esu

lts

100

80

60

40

20

0CD UC Miscellaneous Controls

(n=100) (n=101) non-IBD (n=163) (n=28)

Anti-saccharomycescervisiae antibody(ASCA)

Perinuclear anti-neutrophilcytoplasmic antibody(p-ANCA)

ASCA Specific for CD

ANCA Sensitive For Colitis

Per

cen

tag

e (%

)

100

40

60

20

80

6969

9191

7878

50505656

4444

8888

6060

Accuracy of ANCA and ASCA to Differentiate UC from CD

Peeters M, et al. Am J Gastroenterol. 2001;96:730-734.

ASCA+(CD)

pANCA+(UC)

ASCA+/pANCA-(CD)

pANCA+/ASCA-(UC)

0

Sensitivity Specificity PPV

9595 94949797

9191

The Value of Serologic Markers in Indeterminate Colitis (IC)

Study Design: 97 patients with IC from 3 centers analyzed for pANCA and ASCA Patients prospectively analyzed since 1996 Follow-up time from inclusion 1 year for each patient Mean disease duration at time of publication, 10.7 years

Marker Diagnosis Sensitivity Specificity PPV NPV

ASCA+/pANCA– CD 67% 78% 80% 64%

ASCA–/pANCA+ UC 78% 67% 64% 80%

Joossens S, et al. Gastroenterology. 2002;122:1242-1247.

The Value of Serologic Markers in IC

pANCA+/ASCA–

ASCA+/pANCA–

Standard Markers

70%UC

67%CD

PPVDiagnosis

83%

75%

PPV

pANCA+/ASCA-/OmpC-

/I2-

OmpC

New Markers

72% remain IC

Joossens SB, et al. Gastroenterology. 2003;124(suppl1):A-323. Abstract M1174.

Summary of pANCA/ASCA

• pANCA is sensitive for “colitis”– Does not differentiate UC from CD– High titers associated with risk of pouchitis

• ASCA is specific for “classic” (small bowel) Crohn’s– Rarely positive in indeterminate colitis without

small bowel disease

Antibody AntigenNon-

IBD (%)CD (%)

UC (%)

DNase Sensitive pANCA

Histone H1, bacterial antigen?

<5%10–25%

50–65%

ASCA

Anti-Saccharomyces cerevisiae antibody

5%55–65%

5%

OmpC E. coli <5%38–50%

2%

Anti-I2Pseudomonas fluorescens

<5% 54% 2%

Anti-Flagellin CBir 1 Antigen 8-14% 50% 6%

IBD Specific Serologic Immune Markers

Interrelationships of Serum Immune Responses toMicrobial Antigens in CD

ASCA+

I 2 +

OmpC+

Landers et al, Gastro. 123:689-699, 2002

All Negative22%

12%

2%

7%26%

9%

9% 13%

CBir1???

Serology as a predictor of Disease Behavior

0

20

40

60

80

100F

req

ue

ncy

of

Dis

ea

se B

eh

av

ior

%

Number of Immune Responses

Antibody Sum and Disease Behavior

NPNSIPS

* 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 et al, Gastroenterology 2007; 132: 82

ASCA and Surgery

Amre et al, Am J Gastroenterol. 2006;101:645.

Significant difference in time to first surgery observed in patients ASCA positive

Time in Days

Pro

po

rtio

n A

cqu

irin

g F

irst

S

urg

ery

5000 1000 20000.00

0.25

0.50

0.75

1.00

P < 0.001

Either ASCA negativeEither ASCA positive

56

22 16

22

19

6

0

10

20

30

40

50

60

70

80

90

High (100) Medium (40-100)

Low (< 40)

Acute pouchitis

Chronic pouchitis

78 %

22 %

High Level Pre-operative pANCA Predicts Chronic Pouchitis

Incidence of Pouchitis (%)

41 %

P=0.03

Fleshner PR et al., Gut 2001;49

IBD-7 Panel

• Combines pANCA/ASCA/OmpC/Anti-I2/CBir1 profiles

• Provides composite prediction of UC/CD patterns vs. non-IBD

• Does NOT provide individual probabilities

• Not clinically intuitive– e.g. Low titer OmpC + alone may predict UC?

New serologic markers: carbohydrate antigens

Anti-glycan antibodies:• Anti-laminaribioside

carbohydrate (ALCA)• Anti-chitobioside

carbohydrate (ACCA)• Anti-mannobiodside

(AMCA)

• IgG gASCA• IgA Omp

ALCA8.9%

2.7%

4.9%

8.0%

15.9%

AMCA

6.8%

ACCA

gASCA positive CD

n=515

Ferrante M, et al. DDW 2006, Los Angeles. Abstract #129

913 well-characterized patients

Only gASCA 43.9%

8.9%

Serological markers can be used to discriminate IBD vs non-IBD

gASCA ALCA ACCA AMCA

Sens Spec PPV Sens Spec PPV Sens Spec PPV Sens Spec PPV

CD vs UC 56 90 95 18 93 90 21 85 82 28 82 84

IBD vs non-IBD

GI45 98 100 15 99 99 19 84 93 26 93 98

IBD vs HC 45 99 100 15 99 98 19 86 89 26 91 95

CSS ≥1.0 CSS ≥1.5 CSS ≥2.0 CSS ≥2.5

Sens Spec PPV Sens Spec PPV Sens Spec PPV Sens Spec PPV

CD vs UC 74 61 86 54 83 91 37 93 94 20 97 96

IBD vs non-IBD

GI66 82 98 45 98 100 30 100 100 16 100 100

IBD vs HC 66 86 97 45 99 99 30 100 100 16 100 100

Individual markers

Combined scores


Serological markers to carbohydrate Ags can be used to predict CD course

42.0

71.7

83.2

56.0

0

25

50

75

100

Group A(n=181)

Group B(n=200)

Group C(n=184)

Group D(n=173)

Complicated disease course

OR: 2.00p=0.001

OR: 1.96p=0.010


% p

atie

nts

38.1

58.2

79.8

49.0

0

25

50

75

100

Group A(n=181)

Group B(n=200)

Group C(n=184)

Group D(n=173)

Need for abdominal surgery

OR: 1.56p=0.033

OR: 1.45p=0.072

OR: 2.81p<0.001

Score <1.5

Score 1.5 or 2.0

Score 2.5 or 3.0

Score >3.0

Score <1.5

Score 1.5 or 2.0

Score 2.5 or 3.0

Score >3.0

OR=odds ratio; p-value (Chi-square)

OR: 1.76p=0.006

Serologic Markers: Current Status

• pANCA is sensitive for colitis and high titers are bad prognosis for pouchitis

• ASCA is specific for small bowel Crohn’s disease and high titers are bad prognosis for transmural complications

• OmpC, Anti-Flagellin and I2 add sensitivity and specificity for Crohn’s disease

• Predictive value is too low for clinical utility

ECCO Recommendations

• No evidence based recommendation can be made with regards to the routine clinical use of:- genetic tests- stool markers- serologic markers (ASCA, ANCA,…ompC, I2, flagellin)- permeability testing- Phenotype driven classifications

• (5,D)

C-Reactive Protein

• High CRP better separates placebo from drug responders– Natiluzimab, CDP-571, CDP-870, Infliximab,

Adalimumab, HuZaf

• No distinct cut-off for CRP• Other biologic markers if low CRP

– Fistula response, mucosal healing?

• Currently not a regulatory criteria but improves “efficiency” of trials

CDAI and CRP Relationship at Baseline

(logarithmic scale)

Baseline CDAI

150 200 250 300 350 400 450 500

Lo

g C

RP

mg

/L

0.01

0.1

1

10

100

1000

How to assess/treat these patients?CDAI/CRP at Baseline

ULN

High CDAI-High CRP

High CDAI-Low CRP

Low CDAI-High CRP

Low CDAI-Low CRP

Baseline CDAI

150 200 250 300 350 400 450 500

Log C

RP

mg/L

0.01

0.1

1

10

100


ULN

High CDAI-High CRP

High CDAI-Low CRP

Low CDAI-High CRP

Low CDAI-Low CRP

Baseline CDAI

150 200 250 300 350 400 450 500

Log C

RP

mg/L

0.01

0.1

1

10

100

High Responder


ULN

High CDAI-High CRP

High CDAI-Low CRP

Low CDAI-High CRP

Low CDAI-Low CRP

Baseline CDAI

150 200 250 300 350 400 450 500

Log C

RP

mg/L

0.01

0.1

1

10

100

High PlaceboResponse


ULN

High CDAI-High CRP

High CDAI-Low CRP

Low CDAI-High CRP

Low CDAI-Low CRP

Baseline CDAI

150 200 250 300 350 400 450 500

Log C

RP

mg/L

0.01

0.1

1

10

100

ClinicalRemission

How to treat these various patients?CDAI/CRP at Baseline

ULN

High CDAI-High CRP

High CDAI-Low CRP

Low CDAI-High CRP

Low CDAI-Low CRP

Baseline CDAI

150 200 250 300 350 400 450 500

Log C

RP

mg/L

0.01

0.1

1

10

100Early Relapse

Conclusions CRP

• CRP is a predictor of placebo response

• Efficacy signals in recent clinical trails may have been obscured by placebo responses in CRPlow patients

ECCO Recommendations Regarding CRP

• Serum levels of CRP are useful to assess the patients’ risk for a relapse (B).

• High CRP levels are indicative of active disease (B) or a bacterial complication (C).

• CRP levels can be assessed to guide therapy and follow up (B).

biomarkers managing ibd stephen b. hanauer, md university of chicago

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