Disease behavior in adult patients- are there predictors for stricture or fistula formation? Falk Symposium 168, Madrid, Spain Iris Dotan, M.D., Head, IBD Center, Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Crohn s s disease behavior: Vienna and Montreal classifications Age at dianosis (A) A1<16 yr A2 17 40 yr A3 >40yr Location (L) L1 ileal L2 colonic L3 ileocolonic L4 isolated upper Behavior (B) Inflammatory B1 nonstricturingnonpenetrating B2 stricturing B3 penetrating P perianal disease Stricturing Silverberg MS, et al. Can J Gastroenterol 2005; 9 Suppl A:5-36 Gasche C, et al. Inflamm Bowel Dis 200;6:8-15 Penetrating Age at Diagnosis (A) A1< 40 yr A2 40 yr Location (L) L1 terminal ileum L2 colonic L3 ileocolonic L4 upper gastrointestinal Behavior (B) B1 nonstricturingnonpenetrating B2 stricturing B3 penetrating
Natural history of Crohn s s disease: 90% of patients develop stricturing or penetrating complications Disease behavior is not a stable given. More than 70% of CD patients develop complications within 10 y 100 Probability (%) 80 60 40 20 Inflammatory Penetrating Stricturing 0 0 24 48 72 Cosnes J, et al. Inflamm Bowel Dis 2002;8:244 250 Wolters F, et al EC-IBD. Scand J Gastroenterol 2006 96 120 144 Months 168 192 216 240
Changes in Crohn s s disease behavior and location 100 Behavior 100 Disease location Patients (%) 80 60 40 20 B1 inflammatory B3 penetrating B2 stenosing Patients (%) 80 60 40 20 L3 ileocolon L2 colon L1 ileal 0 0 1 3 5 10 15 20 25 0 0 1 3 5 10 15 20 25 Years from diagnosis Years from diagnosis = L4 upper GI Louis E, et al. Gut 2001;49:777 782
Stricture or fistula both reflect and predict severe/aggressive disease Adults: 361 CD patients HR of ~2.1 for strictures and severe CD Pediatric population: 989 CD patients median follow-up 2.8 y HR of ~2.5 for stricture or fistula and the risk for surgery Loly C, Scand J Gastroenterol 2008;43:948-954 Gupta N, et al. Gastroenterol 2006;130:1069-1077
Predicting severe Crohn s s disease [the development of non reversible serious lesions] Non severe Crohn s disease 1.0 0.8 0.6 0.4 0.2 0 Non B2 and no weight loss Non B2 and weight loss B2 and no weight loss B2 and weight loss 0 10 20 30 40 Time (years) Loly C, et al. Scand J Gastroenterol 2008;43:948-954
Stricture or fistula are associated with an increased risk for surgery 60% of patients require surgery within 10 years 100 100 Probability (%) 80 60 40 20 First surgery Second surgery Probability (%) 80 60 40 20 Stricturing Inflammatory Penetrating 0 0 0 2 4 6 8 10 12 14 16 0 Years after diagnosis 2 4 6 8 10 12 14 16 Years after diagnosis Veloso FT, et al. Inflamm Bowel Dis 2001;7:306 313
Stricture or fistula at diagnosis predict surgery Population-based study, 476 CD patients, diagnosed in 12y Mean age at CD diagnosis 34, 71% diagnosed before 40 y Inflammatory disease behavior in 76% Perianal fistula prevalence: 4.8% within 6 months, 10.3% at final follow up Predictors for surgery stricturing and penetrating phenotypes Predictors for disease recurrence: Small bowel localization Stricturing disease Young age<40y Romberg-Camps MJL et al, Am J Gastroenterol 2009;104:371-383
Why do we need disease course and behavior prediction? Patient information Closer follow-up of patients with worse prognosis Top down therapy suggested for patients with predicted aggressive course, may modulate disease course in adult and pediatric CD Baert F, et al. Dig Dis 2007;25:260-6 Gupta N, et al. Gastroenterol 2006;130:1069-1077
How can we predict disease behavior? Clinical [Endoscopic] Serologic Genetic
Clinical factors associated with development of stricture or fistula Stricture Recent diagnosis (after 1987) (HR 1.3 [1 1.6]) Jejunal involvement (HR 3.2 [2.2 4.7]) Ileal involvement (HR 2.5 [1.9 3.3]) No colonic involvement (HR 2.0 [1.6 2.4]) No anoperineal disease (HR 1.4 [1.1 1.8]) Fistula Age <40 yr (HR 1.3 [1 1.5]) Non-caucasian (HR 1.3 [1.1 1.6]) Anoperineal lesions (HR 2.6 [2.3 3.0]) No oesophagogastroduodenal involvement (HR 1.4 [1.1 1.9]) Cosnes J, et al. Inflamm Bowel Dis. 2002;8:244 50
5-year disabling Crohn s s disease Disabling Non-disabling 100 % of patients 80 60 40 20 0 St-Antoine (Paris) Olmsted County CHU Liège Beaugerie L, et al. Gastroenterology 2006;130:650-656 Seksik, et al. Gastroenterology 2007; 132 a17.80 Loly C, Scand J Gastroenterol 2008;43:948-954
Predictors of disabling Crohn s s disease Proportion of patients & positive predictive value 100 90 80 70 60 50 40 30 20 10 0 Score 0 Score 1 Score 2 Score 3 Proportion of pts Positive predictive value Score is based on the number of predictive factors at diagnosis: age <40, steroid treatment, perianal lesions Beaugerie L, et al. Gastroenterol 2006;130:650-656
Deep colonic ulcers are risk factors for colectomy in Crohn s s disease Probability of colectomy in patients with or without Severe Endoscopic Lesions (SELs) defined by deep ulcers covering >10% of at least 1 colonic segment 70 60 50 SELs No SELs Percent 40 30 20 10 0 1 year 2 year 3 year Allez M, et al. Am J Gastroenterol 2002;97:947-953
Mucosal healing predicts remission In patients with CD, fever at diagnosis and medical treatment without steroids were significant predictors for mucosal healing Mucosal healing significantly associated with less inflammation after 5 years Proportion of CD patients not resected 1.0 0.9 0.8 0.7 0.6 Mucosal healing at 1 year No mucosal healing 0 1 2 3 4 5 6 7 Time in years after 1 year visit p =0.02 Froslie KS. Gastroenterology 2007;133:412
Clinical predictors of stricture or fistula Age<40 Disease location (small bowel-strictures) Perianal disease Steroid use [No mucosal healing?]
Antibody Directed against Sensitivity/ specificity (%) panca ASCA OmpC Anti-I2 CBir1 Neutrophil cytoplasm (colonic bacteria?) Mannans, Saccharomyces cerevisiae Outer membrane porin C, E coli I2 protein, Pseudomonas fluorescens Flagellin of commensal Rump JA, Immunobiology, 1990 Duerr RH, Gastroenterology 1991 Rutgeerts P, Gastroenterology 1998 Sendid B, Clin Diagn Lab Immunol 1996 Vermeire S, Gastroenterology 2001 Serologic response can predict disease behavior 60-70 in UC 90 60-70 (can be as low as 35) 95 Young diagnosis age Need for surgery FS, IP NOD2 association 31-55% IP disease, need for surgery Longer duration bacteria (clostridium?) Cohavy O, Infect Immun 2000 Landers CJ, Gastroenterology 2002 Lodes MJ, JCI 2005 Targan SR, Gastroenterology 2005 Papp M, Am J Gastroenterol 2008 Amre DK, Am J Gastroenterol 2006 Forcione DG, et al. GUT 2004 Gupta N, et al. Gastroenterol 2006 FS disease, need for surgery SB IP FS panca+cd> panca+uc
Antibody Directed against Sensitivity/ specificity (%) gasca covalently-bound mannan 50-56 Young diagnosis age Shorter duration perianal disease AZA use FS/IP NOD2 association ALCA Laminaribioside 15-27 Young diagnosis age FS/IP ACCA Chitobioside 11-20 Longer duration (high levels) non inflammatory behavior AMCA Mannobioside 11-28 NOD2 association Shorter duration Dotan I, Gastroenterology 2006;131:366-378 Ferrante M, GUT 2007;56:1394-1403 Papp M, Am J Gastroenterol 2008;103:665-681
Crohn s s disease stratification: it s s quality and quantity Cumulative reactivities (higher levels/more markers) were associated with: Stricturing or penetrating disease behavior in adult and pediatric populations small bowel location need for surgery relapsing course of pediatric CD NOD2 and TLR4 variants (controversy) Dotan I, Gastroenterology 2006;131:366-378: Ferrante M,GUT 2007;56:1394 1403. Dubinsky MC, Am J Gastroenterol 2006;101:360-367 Forcione DG, GUT 2004;53:1117-22 Desir B, CGH 2004;2:139-46 Henckaerts L, GUT 2007;56:1536-42 Dassopoulos T, Inflamm Bowel Dis 2007;13:143-151 Papp M, Am J Gastroenterol 2008;103:665-681
Crohn s s disease progression: Serologic response predicts timing Antibodies (gasca, ALCA) appear >10 years before CD onset in CD but not control patients Average level of serologic markers before and after diagnosis 54.5 107.6 23.0 36.7 71.7 96.6 Steady increase in antibody levels as disease progresses Serologic markers units by year post onset 44 62 79 91 37 38 45 47 57 66 76 77 gasca ALCA ACCA Before disease onset After disease onset Time to first complication (fistula or abscess) Shorter for ASCA+ vs ASCA- Shorter for panca- vs panca+ gasca 0-3 years (n=98) 4-9 years (n=103) 10-15 years (n=82) >15 years (n=90) ACCA AMCA Israeli E, Gastroenterology 2006 (abstr) Amre DK, Am J Gastroenterol 2006;101:645-52 Dassopoulos T, Inflamm Bowel Dis 2007;13:143-51 Dubinsky MC, Am J Gastroenterol 2006;101:360-367
Proportion of patients Serologic predictors of stricture or fistula 913 Adult CD patients ALCA ACCA AMCA gasca OmpC Score 0=no serologic markers Score 5-all markers positive 100 80 60 40 20 42.0 OR: 1.76 p=0.006 56.0 OR: 2.00 p=0.001 71.7 OR: 1.96 p=0.010 83.2 Frequency of disease behaviour 80 60 40 20 Children: ASCA, Omp, I2, CBir1 100 p trend = 0.002 * 1.9 * 2.3 NPNS PP only IPS only * 11.0 * 5.5 0 Score <1.5 Score 1.5 or 2.0 Score 2.5 or 3.0 Score >3.0 0 0 (n=40) 1 (n=60) 2 (n=42) 3 (n=29) 4 (n=12) Number of immune responses Ferrante M, et al. Gut 2007;56:1394 1403. Dubinsky MC, et al. Am J Gastroenterol 2006;101:360-7
Genotype-phenotype phenotype correlations Presence of NOD2 variants determined seroreactivity gasca, ALCA, AMCA associated with NOD2 NOD2 genotype and seroreactivity synergism in predicting fibrostenotic disease Dose response between the number of mutant NOD2 alleles and ASCA prevalence and titers DevIin SM, Gastroenterology 2007 Papp M, Am J Gastroenterol 2008;103:665-681 Ferrante M, GUT 2007;56:1394-1403. Ippoliti AF, Gastroenterol 2006 (abstr) Dassopoulos T, Inflamm Bowel Dis 2007;13:143-51
Genotype-phenotype phenotype % gasca positivity in CD patients with NOD2/CARD15 variants n=850, p<0.0001, Titers 62 vs 84 U p<0.0001 % ALCA positivity in CD patients with NOD2/CARD15 variants n=800, p=0.002 Titers 41 vs 47 U p=0.003 % ACCA positivity in CD patients with TLR4 variants n=791, p=0.003 correlations 50% Mutation type 0 1 2 33% 64% 45% Mutation type 0 1 2 34% 25% 72% 47% Mutation type 0 1 2 9% low Degree of genetic mutation high Henckaerts L, et al. GUT 2007;56:1536-42
Genetics predictors of stricture or fistula 1684 CD patients, The Netherlands: NOD2, IBD5, DLG5, ATG16L1, IL23R CD patients with stricturing or penetrating disease-significantly more risk alleles Patients needing surgical interventionmore risk alleles ATG16L1 -associated with stricturing and perianal disease Weersma RK, et al. GUT 2009;58:388-395
Risk stratified approach for treatment decisions Step up 5ASA Antibiotics Steroids AZA/MTX Biologics Surgery Top Down Biologics AZA/MTX Steroids Surgery Top Down: early treatment with immunomodulators Complication Risk Test : combined clinical, serologic, genetic factors May assist in deciding whom to treat top down vs. step up May enable improved matching of aggressive, expensive treatment specifically to potentially complicated patients Prevent complications Increase patients quality of life
Summary Disease behavior in adult patients-are are there predictors for stricture or fistula formation? Stricture or fistula are complicated CD phenotypes Stricture or fistula are aggressive CD, and predict disabling/complicated CD Stricture or fistula may be predicted using clinical, serologic and genetic markers Combined serologic and genetic markers and higher titers- predict disease aggressiveness, behavior,rate of development Long term, prospective studies are required
Conclusions Disease behavior in adult patients-are are there predictors for stricture or fistula formation? Should we predict disease course? Yes we should Can we predict disease course Yes we can (as good as it gets..) Future perspectives: better combination of clinical, genetic and serologic indices for a prospectively effective risk score
Thank You!