2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive...
-
Upload
matthew-hunter -
Category
Documents
-
view
221 -
download
0
Transcript of 2006 News in IBD Clinical aspects Yoram BOUHNIK Gastroentérologie et Assistance nutritive...
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)