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