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2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive...

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2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy
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Page 1: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

2006 News in IBDClinical aspects

Yoram BOUHNIK Gastroentérologie et Assistance nutritive

Université Paris VIIHôpital Beaujon, Clichy

Page 2: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

2006 News in IBD

• Myenteric plexitis and prediction of post-operative relapse in CD

• Colorectal cancer in IBD

• MMX mesalamine

• Immunosuppressors and biotherapies

Page 3: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

Enteric nervous system and CD

• Nerve fiber hypertrophy and hyperplasia

• Inflammatory infiltrates in the vicinity of ganglia and nerve bundles (plexitis)

• Increased number of myenteric ganglia

• Perineural inflammation in otherwise uninflamed resection margins

Highly organized integrative system in the wall of the gastro-intestinal tract

Submucosalplexus

Myentericplexus

Previous observations in CD

Page 4: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

Role of myenteric plexitis of the proximal section margin in endoscopic recurrence

P=0.008

(n=15)(n=17)(n=27) (n=32)

P=0.041

41%

59%

93%

75%

0

20

40

60

80

100

3 months 12 months

No plexitis Plexitis

% E

nd

osc

op

ic r

ecu

rre

nc

e

Plexitis : presence of one or more inflammatory cells adjacent to or within an enteric ganglion or nerve bundle

Ferrante M et al. Gastroenterology 2006; 130:1595–1606

Page 5: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

Correlation between the severity of myenteric plexitis in the proximal resection margin (pl0 – pI3) and the severity of

postoperative endoscopic recurrence (i0–4)

The surface of the

circles represents the number of cases.

Ferrante M et al. Gastroenterology 2006; 130:1595–1606

Endoscopic recurrence at 3 months

Endoscopic recurrence at 12 months

Page 6: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

Predictive (Risk) Factors Associated With Increased CRC in UC

Risk factor RR

Duration +++Anatomic extent +++Primary sclerosing cholangitis 4.8Family history of CRC 2.5Family history of CRC at age < 50years 9.2Pseudopolyps a 2.5Histologic severity of inflammation b ++

a Velayos FS et al. Gastroenterology 2006; 130:1941-9b Rubin DT et al. Gastroenterology 2006;130:A2

Page 7: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

Thirty-Year Analysis of a Colonoscopic Surveillance Program for Neoplasia in UC

Rutter MD et al. Gastroenterology 2006; 130:1030-8

• N=600, 2627 colonoscopy, 5932 patient-yrs of FU• 8 biopsy specimens per colonoscopy (median)

• Compliance to surveillance colonoscopy : 94.3% •Neoplasia 12.3%, 30 CRCs• Cumulative incidence of CRC

– 2.5 % at 20yrs– 7.6% at 30yrs– 10.8% at 40 yrs

• 5-yr survival rate : 73%• 16 of 30 CRCs were interval cancers

Page 8: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

Endoscopic mucosal resection for flat neoplasia in chronic UC

Hurlstone DP et al. Gut 2006; online

UC group Control group P

Number of patients 736 1675

Median Follow-up (yrs) 4.1 (3.6-5.2) 4.8 (2.9-5.2) NSMedian nb colo/patient 6 (1-8) 4 (1-7) NS

Total lesions 155 801 NS

Entry/Follow-up 82%/18% 66%/24% NS

0-II lesions– prevalence– diameter (mm)– PR recurrence rate

82/155(61%)8 (2-24)

2.7%

285/801(35%)9.5 (2-22)

2.6%

<0.001NSNS

Page 9: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

Hurlstone DP et al. Gut 2006; online

Endoscopic mucosal resection for flat neoplasia in chronic UC

Page 10: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

Protective Factors Associated With Reduced CRC in Chronic Ulcerative

ColitisEvidence for Chemoprevention

• In a pooled analysis of 334 CRC cases among patients with chronic UC, regular use of 5-ASA reduced the risk of CRC by approximately 50% (P <.05)

• A recent case-control study suggested that 5-ASA may be chemopreventive in Crohn's disease as well

Velayos FS et al. Am J Gastroenterol 2005;100:1345-53. Siegel CA et al. IBD 2006;12:491-6.

Page 11: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

MMX mesalamine

• a novel formulation of 5-ASA

• Combines a gastro-resistant polymer film

and MMX Multi Matrix System technology

to delay and extend drug delivery

throughout the entire colon.

Page 12: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

Once-Daily High Concentration MMX Mesalamine in active mild or moderate,

left-sided or extensive UC

Kamm M et al. Gastroenterology 2007; in press

Percentage of patients in clinical and endoscopic remission at W8(Intent-to-Treat Population, n = 341). **P < .01; ***P < .001.

Page 13: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

Immunosuppressors and biotherapies

• increasing use of immunosuppressants

• Infliximab as a « bridge »

• Immunosuppressors and biotherapies in association ?

Page 14: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

Immunosuppression

Crohn’s diseaseUse of immunosuppressors with time

2000 Dx 5-ASA Steroids Thiopurines SurgeryMTX 5-ASA...IFX

2004 Dx Steroids Thiopurines SurgeryMTX 5-ASA?...IFX

Dx 5-ASA Steroids Thiopurines Surgery 5-ASA…MTX1990

200? DxSteroids or anti-TNF?

ThiopurinesSurgery ...Anti-TNF/biologics

MTX

Page 15: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

Variable

Percent of Patients

Non disabling(n = 166)

Disabling(n = 957)

Male 40.4 37.3

Age < 40 yr 77.1 87.7

Disease location

Small bowel only 44.6 32.8

Small bowel & colon

25.9 39.4

Colon only 29.5 27.8

Smoker 50.3 57.4

Systemic findings 44.6 48.6

Perianal lesions 17.5 26.4

Steroids for first flare 37.3 65.2

Independent Risk FactorsOdds Ratio (95% CI)

1 2 3 4 50.5

3.1 (P = 0.0001)

1.8 (P = 0.01)

2.1 (P = 0.0004)

Beaugerie L et al. Gastro 2006;130:650-6

Predictors of disabling Crohn’s disease

1.8 (P = 0.01)

2.1 (P = 0.0004)

RAPID

Page 16: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

115 steroid-dependent Crohn's disease patients 10 mg/d 6 mo

failure stratum or naive stratum

primary end point was remission off steroids at week 24

38

2922

75

57

40

0

10

20

30

40

50

60

70

80

Week 12 Week 24 Week 52

% i

n R

emis

sio

n &

off

Ste

roid

s

P < 0.001

P = 0.003

Lemann M et al. Gastroenterology. 2006

P = 0.04

Infliximab plus azathioprine for steroid-dependent Crohn's disease patients: a randomized placebo-controlled trial

AZA/6MP + placebo (week 0, 2, 6)

AZA/6MP + infliximab (week 0, 2, 6)

Page 17: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

Improvement/Remission of CD with anti-TNF

0

20

40

60

80

100

Week 26–30

N = 113 N = 113N = 215 N = 215

Remission(CDAI<150)

N = 172 N = 172

Response(Δ100)

Reduction(≥ 70 pts and

≥ 25% in CDAI)

Per

cen

t o

f P

atie

nts

21 17 29362627

51 52

63

39 4048

Infliximab 5 mg / kg / 8 weeks (ACCENT I)

Certolizumab 400 mg / 4 weeks (PRECISE 2)Adalimumab 40 mg / 2 weeks (CHARM)

Placebo

Page 18: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

Ex : from Risk Factors for Opportunistic Infections in IBD A Case-Control Study of 100 Patients (1998-2003)

Odds Ratio (95% CI) P valueCorticosteroids 3.35 (1.82-6.16) <0.0001

AZA/6MP 3.07 (1.72-5.48) 0.0001

Infliximab 4.43 (1.15-17.09) 0.03

One medication 2.65 (1.45-4.82) 0.0014

Two medications 9.66 (3.31–28.19) <0.0001

Opportunistic infections and anti-TNF therapies : The problem with confounding factors

Toruner M et al. Gastroenterology 2006;128 (suppl.2):A71.

Page 19: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

The effectiviness of concomitant immunosuppressive therapy to suppress formation of ATI in CD in patients treated with IFX in an on demand schedule (n=174)

Vermeire S et al. Gut 2007; on line

ATI titers in function of co-treatment with MTX or AZA

Page 20: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

Do we have to associate IS in CD patients with IFX as maintenance therapy ?

• Clinical benefit ? – Infliximab

• ACCENT 1 Trend• ACCENT 2 - fistules NS

– Adalimumab (CLASSIC, CHARM) NS– Certolizumab (PRECISE I & II) NS

• Less immunisation ?– Infliximab (ATI) Yes– Adalimumab (AAA) ?– Certolizumab ?

• Toxicity of the association +++

Page 21: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

IS +IS -

0

1

2

3

4

5

6

7

8

0 20 40 60 80weeks

IS + IS -

mg/L

IFX levels before infusionNegative correlation with failure

•N=80

•IFX + AZA/6MP or MTX stable for more than 6 mo

•Randomised open trial

Do we have to interrupt IS in patients treated with IFX as maintenance therapy ?

Van Assche et al. DDW 2006

Page 22: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

Or do we have to interrupt IFX in patients treated with IFX and IS as maintenance

therapy ?

STORI

Page 23: 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive Université Paris VII Hôpital Beaujon, Clichy.

The pipeline of IBDThe pipeline of IBD

Pre-clinical Phase I Phase II Phase III Pre-reg. Launched

12

Biologicals

Small molecules

Natalizumab/Elan/Biogen

STA5236/Syntha

Kappaproct/Index/Serono

OCP 6535/Otsuka

RDP58/Genzyme/SangStat

Lecithin/Dr. Stremmel

Cytokine/chemokine

Adhesion molecules

Transcription factors

Anti TNF

Mucosal barrier

Phosphodiesterase IV inhibition

Cell homing Cytokine release

Onercept/Serono

MLN-2/Millenium

EGF/Hitachi-Nippon

Fontolizumab/PDL

Basilixmab/Novartis

ABT-874/J695/Abbott-Wyeth

Visilizumab/PDL

CNI1493/Pharma Science

Early pipelines not empty but specific IBD information is lacking on the plethora of anti-inflammatory approaches. Most such compounds are patented for IBD which does not infer IBD development intent.

Adalimumab/Abbott

Sargamostim/Schering-Berlex

CDP-870Celltech-UCB

Alicaforsen/Isis

Oprelvekin/Wyeth

Infliximab/Centocor/Schering- Plough

ADDITIONAL OTHER INDICATIONS:Oprelvekin thrombocytopenia post-chemo (launched)CDP-870 rheumatoid arthritis (Ph III)Adalimumab rheumatoid arthritis (launched)Sargamostim neutropenias post-chemo (launched)Natalizumab multiple sclerosis (pre-reg)Infliximab rheumatoid arthritis (launched)

psoriasis/psoriatic arthritis (pre-reg/Ph III)


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