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

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 Submucosal plexus Myenteric plexus 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= % 59% 93% 75% months12 months No plexitisPlexitis % Endoscopic recurrence 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 factorRR Duration+++ Anatomic extent+++ Primary sclerosing cholangitis4.8 Family history of CRC2.5 Family history of CRC at age < 50years9.2 Pseudopolyps a 2.5 Histologic severity of inflammation b ++ a Velayos FS et al. Gastroenterology 2006; 130: b 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: 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 groupControl groupP Number of patients Median Follow-up (yrs)4.1 ( )4.8 ( )NS Median nb colo/patient6 (1-8)4 (1-7)NS Total lesions155801NS Entry/Follow-up82%/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% <0.001 NS

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: 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 Crohns disease Use of immunosuppressors with time 2000 Dx 5-ASA SteroidsThiopurines Surgery MTX 5-ASA... IFX 2004 Dx Steroids Thiopurines Surgery MTX 5-ASA?... IFX Dx5-ASA Steroids Thiopurines Surgery5-ASA… MTX ? Dx Steroids or anti-TNF? Thiopurines Surgery... Anti-TNF/biologics MTX

Variable Percent of Patients Non disabling (n = 166) Disabling (n = 957) Male Age < 40 yr Disease location Small bowel only Small bowel & colon Colon only Smoker Systemic findings Perianal lesions Steroids for first flare Independent Risk Factors Odds Ratio (95% CI) (P = ) 1.8 (P = 0.01) 2.1 (P = ) Beaugerie L et al. Gastro 2006;130:650-6 Predictors of disabling Crohns disease 1.8 (P = 0.01) 2.1 (P = ) 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 P < P = Lemann M et al. Gastroenterology 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 Week 26–30 N = 113 N = 215 Remission (CDAI<150) N = 172 Response ( Δ 100) Reduction ( 70 pts and 25% in CDAI) Percent of Patients 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 ( ) Odds Ratio (95% CI)P value Corticosteroids3.35( )< AZA/6MP3.07( ) Infliximab4.43( )0.03 One medication2.65( ) Two medications9.66(3.31–28.19)< 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 1Trend ACCENT 2 - fistulesNS –Adalimumab (CLASSIC, CHARM)NS –Certolizumab (PRECISE I & II)NS Less immunisation ? –Infliximab (ATI)Yes –Adalimumab (AAA)? –Certolizumab? Toxicity of the association +++

IS + IS - 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 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 homingCytokine 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-870 Celltech-UCB Alicaforsen/ Isis Oprelvekin/ Wyeth Infliximab/ Centocor/Schering- Plough ADDITIONAL OTHER INDICATIONS: Oprelvekinthrombocytopenia post-chemo (launched) CDP-870rheumatoid 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)