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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
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
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
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
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
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.
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
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
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)
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.
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)