2006 News in IBDClinical aspects

Yoram BOUHNIK Gastroentérologie et Assistance nutritive

Université Paris VIIHôpital 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

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

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

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

Predictive (Risk) Factors Associated With Increased CRC in UC

2.5Pseudopolyps a

9.2Family history of CRC at age < 50years

++Histologic severity of inflammation b

2.5Family history of CRC4.8Primary sclerosing cholangitis

+++Anatomic extent+++Duration

RRRisk factor

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

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

Endoscopic mucosal resection for flat neoplasia in chronic UC

Hurlstone DP et al. Gut 2006; online

NS4 (1-7)6 (1-8)Median nb colo/patient

NS66%/24%82%/18%Entry/Follow-up

NS801155Total lesions

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

2.6%

4.8 (2.9-5.2)

1675

Control group

<0.001NSNS

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

2.7%

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

NS4.1 (3.6-5.2)Median Follow-up (yrs)

736Number of patients

PUC group

Hurlstone DP et al. Gut 2006; online

Endoscopic mucosal resection for flat neoplasia in chronic UC

Protective Factors Associated With Reduced CRC in Chronic Ulcerative Colitis

Evidence 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.

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.

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.

Immunosuppressors and biotherapies

• increasing use of immunosuppressants

• Infliximab as a « bridge »

• Immunosuppressors and biotherapies in association ?

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

65.237.3Steroids for first flare

26.417.5Perianal lesions

48.644.6Systemic findings

57.450.3Smoker

27.829.5Colon only

39.425.9Small bowel & colon

32.844.6Small bowel only

Disease location

87.777.1Age < 40 yr

37.340.4Male

Disabling(n = 957)

Non disabling(n = 166)Variable

Percent of Patients

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

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)

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

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

(3.31–28.19)

(1.45-4.82)

(1.15-17.09)

(1.72-5.48)

(1.82-6.16)

<0.00019.66Two medications

0.00142.65One medication

0.034.43Infliximab

0.00013.07AZA/6MP

<0.00013.35Corticosteroids

P valueOdds Ratio (95% CI)

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

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

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

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 +++

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

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

therapy ?

STORI

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)