Natural History of IBD=

Inflammatory bowel disease

Ulcerative colitis(UC)

Crohn’s disease

Inflam bowel disease unclassified(IBDU)

Are the definitions of MH reproducible?

- On an individual or group level

Localisation of Crohn’s disease

Classification of CD at inclusion in the IBSEN study (1990 – 1994)

L1, terminal ileum: 64L2, colon: 115L3, ileocolon: 54L4, upper GI: 4 Total: 237

Localisation of inflammation in UC in the IBSEN- study (1990-1994)

Proctitis: 17 Proctosigmoiditis: 101Left sided: 81Total colitis: 166Total: 519

Ulcerative colitis

The frequency of IBD over time

Recording by the IBSEN study

group

BjM, 93

GP

G-1

G-1

1 year

G 2 PL

Communication

Incidence according to age and

genderUC / IBDU CD

Moum B et al, Scand J Gastroenterol; 1996;31:362-66Moum B et al, Scand J Gastroenterol; 1996;31:355-61

20-35 år 15-25 år

Incidence of CD

2.7(1990-93)

6.7(2005-07)

2.8(1993-04)

1.9(1987-03)

4.9(1990-01)

2.5(1984-85)

3.1(1998-06)

Ref. Table 2

Fig. 3

IBD Incidence 0-16 years

0

2

4

6

8

10

12

In

cid

en

ce

/1

00

00

0/

ye

ar

CD UC IBDU total IBD

CD 2,7 1,9 3,6 6,7

UC 2 3,7 2,1 3,3

IBDU 0 0 0 0,7

total IBD 4,7 5,6 5,7 10,6

IBSEN 1990-93 Ahus 1994-98 Ahus 1999-04 IBSEN-II 2005-07

Incidence 0-16 years

Incidence of CD

2.5(1981-95)

2.2(1980-90)4.4(1990-99)

3.1(1998-99)

0.25(1990-99)1.25(1999-2001)

3.6(1996-2003)

2.1(1999-2001)2.3(1988-99)

8.5(1990-94)

1.4(1996-97)

Ref. Table 3

Fig. 4

Incidence of IBD in Europe - adults

32

24

2221

12

6 14

11

4

14

14

12

9

45

8

17

8 8

5

13

11

11

14

11

211.5

20 1919

16

11

29

22

4

20

19

Fig. 7

7.5

4.2

8.4

20

20

14.4

6.5

0

4.8

11.4

5.9

6.1

2.63.7

Incidence of IBD in the USFig. 6

Fig.5

20

30

40

5

4

12

6

5.5

4.5

2.2

5.5

19

12.5

5

2.5

2

32

6

1.5

6

24

Global incidence of IBD

Balance between the bacterial-flora of the gut and a dysfunctional immune-system in a genetically disposed host

Patogenesis of IBD

12.5

7.2 5.5

4.3 4.5

3.3

127.2

8.8

16

9.7

11.5

12.2

6.8

0

10

15.1

Etnicity and NOD2 mutations

The frequency of CARD15 (R702W) in Crohns Disease in European countries

GENETICS and IBD

• Having a family member with IBD represents the strongest risc factor (”dose respons effekt”)– First degree relative with IBD gives approx. 15% risc

• λs-”relative sibling risc” – (Crohn: 20-35, Ulcerative Colitis: 6-9)

• Twin studies:– Monozygotic twins risc vs dizygotic

• Crohn 35% vs dizygotic 7%

• Ulcerative Colitis 11% vs dizygotic 3%

NOD2/CARD15OCTN1/2ATG16LIL23R

Zahng et al, Br Med Bulletin, 2008;87, Rosenstiel et al, Sem Immunology 2009;21

The Hygiene hypothesis

The theory of reduced diversity of bakterial

stimulation as an explanation for increased allergic

and immunologic diseases

Faktors influencing our bakterial flora:

• Modern lifestyle

• Food consumption (milk- and meat products) and

industrialisation of food products

• Antibiotics

• Birth release

Environmental factors

• Smoking gives increased risc for

CD, but ”protects” against UC

• Breast feeding >3 mnd gives reduced

risc for IBD (bifidobact , anaerobe bact

)

• Antibiotics early in life may give

increased risc for IBD

Gearry et al,J Gastroent Hepatol,2010;25

Drinking water and IBD

• Analysis of drinkingwater and occurrence

of IBD showed:

By increase of iron concentration in

drinking

water by 0.1mg/L, the relative risc for

development of IBD increased by 21%

– Iron catalysis oksidativt stress

(inflammasjon and cell mutation)

– Iron stimulates bacterial growth (influence

on epithelial cell barrier and immune

response)

Aamodt et al, Am J Epidemiol,2008;168

Disease behaviour of IBD within

a region

Cum

ulati

ve

prob

abilit

y of

first

surg

ery

Years after diagnosis of CD

40 %

60 %

80 %

100 %

20 %

0 %

Risk factors for surgery in CDSolberg IC et al. Clin.Gastroenterol Hepatol. 2007;5:1430-38.

11109876543210

Time in years since diagnosis

1,0

0,8

0,6

0,4

0,2

0,0

Cu

mu

lati

ve

ha

zard A2 (>40 yrs)

A1 (<40 yrs)

Age

One Minus Survival Function for patterns 1 - 211109876543210

Time in years since diagnosis

1,0

0,8

0,6

0,4

0,2

0,0

Cu

mu

lati

ve h

azard

Ileocolonic (L3)

Colonic (L2)

Small bowel (L1 or L4)

Disease location

One Minus Survival Function for patterns 1 - 3

11109876543210

Time in years since diagnosis

1,0

0,8

0,6

0,4

0,2

0,0

Cu

mu

lati

ve h

azard

B3: Penetrating

B2: Stricturing

B1: Pure inflammatory

Disease behaviour

One Minus Survival Function for patterns 1 - 3

Non significant

variables

Gender

Smoking status,

Familial IBD,

Systemic steroids

P = 0.03

P = 0.001

P = 0.001

11109876543210

Time in years since diagnosis

1,0

0,8

0,6

0,4

0,2

0,0

Cu

mu

lati

ve

ris

k o

f in

testi

na

l re

secto

in

One Minus Survival Function

13.6%

27.0%

37.9%

N = 237

E = 85 65%

34%

23%

IBSEN study: Disease course during

the first 10-year period, patients’ perceptive

CD 43%

CD 19% CD 37%

CD 3%

Remission rate(grey) during the

first and second 5 years period

of CD

(50)(4)(94)(N) (148) (49) (51) (94) (48) (4) (127) (50)

p = 0.7p = 0.2

I. First 5-years

period

p = 0.8p = 0.9p = 0.08

85

15

0 %

10 %

20 %

30 %

40 %

50 %

60 %

70 %

80 %

90 %

100 %

B1

78

22

0 %

10 %

20 %

30 %

40 %

50 %

60 %

70 %

80 %

90 %

100 %

A2

49

51

0 %

10 %

20 %

30 %

40 %

50 %

60 %

70 %

80 %

90 %

100 %

L2

83

17

0 %

10 %

20 %

30 %

40 %

50 %

60 %

70 %

80 %

90 %

100 %

L2

87

13

0 %

10 %

20 %

30 %

40 %

50 %

60 %

70 %

80 %

90 %

100 %

L3

100

0 %

10 %

20 %

30 %

40 %

50 %

60 %

70 %

80 %

90 %

100 %

L4

85

15

0 %

10 %

20 %

30 %

40 %

50 %

60 %

70 %

80 %

90 %

100 %

B1

84

16

0 %

10 %

20 %

30 %

40 %

50 %

60 %

70 %

80 %

90 %

100 %

B2

90

10

0 %

10 %

20 %

30 %

40 %

50 %

60 %

70 %

80 %

90 %

100 %

B3

61

39

0 %

10 %

20 %

30 %

40 %

50 %

60 %

70 %

80 %

90 %

100 %

A1

43

57

0 %

10 %

20 %

30 %

40 %

50 %

60 %

70 %

80 %

90 %

100 %

A2

57

43

0 %

10 %

20 %

30 %

40 %

50 %

60 %

70 %

80 %

90 %

100 %

L1

49

51

0 %

10 %

20 %

30 %

40 %

50 %

60 %

70 %

80 %

90 %

100 %

L2

69

31

0 %

10 %

20 %

30 %

40 %

50 %

60 %

70 %

80 %

90 %

100 %

L3

75

25

0 %

10 %

20 %

30 %

40 %

50 %

60 %

70 %

80 %

90 %

100 %

L4

54

46

0 %

10 %

20 %

30 %

40 %

50 %

60 %

70 %

80 %

90 %

100 %

B1

64

36

0 %

10 %

20 %

30 %

40 %

50 %

60 %

70 %

80 %

90 %

100 %

B2

55

45

0 %

10 %

20 %

30 %

40 %

50 %

60 %

70 %

80 %

90 %

100 %

B3

p = 0.03 *

(20) (N) (148) (49) (51) (48) (127) (20)

II. Second 5-years period

Figure V. Cumulative drug consumption (after initial treatment) in CD patients during the first 5 years period

(patterned bars) vs. the second 5 years period (grey bars) (): = percentage of total number (N)

0

20

40

60

80

100

120

140

160

180

200

First 5-year

Second 5-year

5-ASA Systemic

steroids

Azathioprine TNF-blocker

175(88)

125(64)

143(73)

82(42)

42(21)51(26)

8(4)

p<0.001

p<0.001

Ns

Num

ber of

patie

nts

treate

d

Conventional treatment in IBD:• Combination of general guidelines and individual

experience with a patient

• A close follow up from start of treatment should aim at

detecting intolerance or lack of effect

• Drug therapy should aim at the lowest dose(s) giving relief

of symptoms

• Biologics are the most effective drugs on disease activity

and QoL short term, and anti-metabolites effective long

term, in the complicated patient.

• Documented and experienced

increased efficacy

– an indication of top down

strategy

• Still recommendation of step up

strategy:

– adverse reactions

(hypersensitivity, infections)

– long term complications

(neoplasisia)

– cost benefit (prize,

resources)

The introduction of biologics in

the treatment of IBD

Antimetabolites

Biologics

Steroids

Budesonide

5-ASA/Sasp/

Antibiotics/Local

5-ASA/ SASP/

Antibiotics/ Local

Budesonide

Steroids

Antimetabolites

Biologics

MV-11-01

Gs1

GP

Gs1

Gs2 Pc

C-C

GP Gs2Gs1

Epidemiology of IBD in SE Norway in 1990’s

1 yr

Gs15 yr

Gs110 yr

Diagnose

Rheu

QoL IBD 2TK

Genetics

National registration of IBD

Quartiles of incidences of ulcerative

colitis in the study area

The municipalities in

black represent the

upper quartile etc

USA

Iowa

Germany:

RegensburgSpain:

Gijon

Switzerland

Zurich

Greece:

Athens

Croatia:

Rijeka

Zagreb

Argentina:

Buenos Aires

Uruguay

Monevideo

Israel:

Telaviv

Norway:

Oslo

Czech

Prague

Hungary:

Budapest

Early IBD – International Concortium

USA

Rhode Island

Crete