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  • In a larger (N=796), more recent prospective study of children with Crohn’s disease, Dubinsky and colleagues again showed that the frequency and progression of complications increased in a statistically significant manner and were directly proportional to the number of positive serologic markers 1 Disease behavior included (a) nonpenetrating, nonstricturing disease (NPNS); (b) internal penetrating disease (IP); (c) stricturing disease, and (d) surgery. The serologic markers used in the study were ASCA, anti-OmpC a , anti-CBir1 a , and pANCA Odds ratio for NPNS with 1, 2, and 3 immune responses are: 0.4, 0.3, and 0.1, respectively; P <0.0001. Baseline antibody sum=0 (odds ratio=1.0) Odds ratio for IP with 1, 2, and 3 immune responses are: 2.2, 5.2, and 9.5, respectively; P <0.0001 Odds ratio for stricturing disease with 1, 2, and 3 immune responses are: 1.7, 4.2, and 6.1, respectively; P <0.0001 Odds ratio for surgery with 1, 2, and 3 immune responses are: 2.7, 4.5, 10.3, respectively; P <0.0001 Reference Dubinsky MC, et al. Clin Gastroenterol Hepatol . 2008;6:1105-1111 a Patented
  • In a larger (N=796), more recent prospective study of children with Crohn’s disease, Dubinsky and colleagues again showed that the frequency and progression of complications increased in a statistically significant manner and were directly proportional to the quartile sum score for positive serologic markers 1 Disease behavior included (a) nonpenetrating, nonstricturing disease (NPNS); (b) internal penetrating disease (IP); (c) stricturing disease, and (d) surgery. The serologic markers used in the study were ASCA, anti-OmpC a , anti-CBir1 a , and pANCA Odds ratio for NPNS for quartile sum score groups 2, 3, and 4 are: 0.3, 0.3, and 0.2, respectively; P <0.0001. Baseline quartile sum score group is 1 (odds ratio=1.0) Odds ratio for IP for quartile sum score groups 2, 3, and 4 are: 3.2, 4.0, and 8.5, respectively; P <0.0001 Odds ratio for stricturing disease for quartile sum score groups 2, 3, and 4 are: 6.8, 8.6, and 12.5, respectively; P <0.0001 Odds ratio for surgery for quartile sum score groups 2, 3, and 4 are: 4.4, 4.8, 8.4, respectively; P <0.0001 Reference Dubinsky MC, et al. Clin Gastroenterol Hepatol . 2008;6:1105-1111 a Patented
  • Disease progression was significantly faster in pediatric patients expressing immune reactivity This slide shows survival estimates for internal penetrating (IP)/stricturing (S) disease (panel A on the left) and for surgery (panel B on the right) by number of antibody immune responses (Ab sum=0, 1, 2, or 3) in prospective patients only. The serologic markers used in the study were ASCA, anti-OmpC a , anti-CBir1 a , and pANCA Since incidence of IP/S and surgery are both increased the longer the duration of disease, and not all patients are followed for the same duration of time, survival estimates were evaluated to a take into consideration the length of follow-up time. Time to IP/S Given the same length of follow-up, patients with 2 or 3 immune responses had faster time to IP/S than patients with 0 or 1 antibody immune response; P <0.0001 (left panel) Patients with 3 immune responses showed the most rapid disease progression: median time (range) to IP/S was 20 (4-65) months Time to surgery As with IP/S disease, the patients with 2 or 3 antibody immune responses had faster time to surgery than patients with 0 or 1 immune response; P <0.0001 The Cox proportional hazard ratios for IP/S by 1, 2, or 3 immune responses versus 0 immune response were 1.1 (not significant), 5.5 ( P =0.005), and 6.0 ( P <0.005), respectively. The Cox proportional hazard ratios for any Crohn’s disease-related surgery by 1, 2, or 3 immune responses versus 0 immune response were 3.2 ( P <0.04), 3.4 ( P <0.03), and 6.6 ( P= 0.001), respectively. Reference Dubinsky MC, et al. Clin Gastroenterol Hepatol . 2008;6:1105-1111 a Patented
  • Mow and colleagues performed a similar study based on a US population. For the data analysis, the investigators used quartile analysis to group patients into percentiles. In any sample cohort, concentrations of a marker are arranged from lowest to highest. The samples with marker values in the lowest 25% represent the first quartile (in a sample of 100, the first 25 patients make up the first quartile) and are given a score of 1. In this study, three markers were used in the quartile analysis: ASCA, anti-OmpC*, and anti-I2 antibodies. Each marker receives a score from 1 (<25%) to 4 (>75%). Since more than one marker was used, the quartile sum depicted in the slide represents the sum of the scores for all three markers. Scores of 0 were not assigned. The minimum score is 3 (all three markers have levels that are in the first quartile), and the maximum score is 12 (all markers are in the 4th quartile). The scores are graphed against frequency of disease behavior for patients with small-bowel disease, fibrostenosis, small-bowel surgery, internal perforation, and ulcerative colitis–like disease. The slide indicates that the quartile sum is related to disease severity. The prognostic value of these data is that high-level immune responses for these markers are associated with more severe, complicated Crohn’s disease phenotypes. Reference Mow WS, Vasiliauskas EA, Lin YC, et al. Association of antibody responses to microbialantigens and complications of small bowel Crohn's disease. Gastroenterology. 2004;126:414-424. *Patented.
  • Transcript

    • 1. Adapted from Cuffari et al. Gastroenterology Int. 1997 Site of Crohn’s Disease in Children and Adults
    • 2. Step-Up and Top-Down Therapy Approaches for Crohn’s Disease Infliximab Immunosuppressives Steroids 5-ASA/SPS Infliximab Immunosuppressives Steroids Combination Step-up therapy Top-down therapy Adapted from Lichtenstein GR et al. Inflamm Bowel Dis . 2004;10:S2–S10.
    • 3. 0 1 2 3 anti-CBir1 antibody (O.D.) Normal Controls Inflammatory Controls UC CD P vs CD: % Positive <0.001 <0.02 <0.001 n/a Level <0.001 <0.003 <0.001 n/a Adapted from Targan SR et al. Gastroenterology . 2005;128:2020-2028. Anti-CBir1 Presence CD Patients N=100 N=50 N=21 N=40 8% 14% 6% 50%
    • 4. Independent Associations of Antibody Responses, NOD2 Genotype, and CD Phenotypes Anti-I2 Anti-OmpC ASCA pANCA Fibrostenosis Small Bowel Small Bowel Surgery Internal Perforation UC-like Behavior NOD2 Data from Mow S et al., Gastroenterology . 2004;126:414-424. Papadakis KA et al., Inflamm Bowel Dis . 2007:13;524-530. Anti-CBir1 P =0.018 P =0.05 P =0.008 - P =0.027 P =0.01 - - - - - P <0.02 - - - - - P <0.001 P <0.003 - - - - P =0.023 P <0.001 P <0.001 P <0.001 -
    • 5. ASCA and Surgery Adapted from Amre et al. Am J Gastroenterol. 2006;101:645-652. Significant difference in time to first surgery observed in patients ASCA-positive Time in Days Proportion Requiring First Surgery 500 0 1000 2000 0.00 0.25 0.50 0.75 1.00 P < 0.001 Either ASCA negative Either ASCA positive
    • 6. Frequency of CD Complications in Children Increases With Number of Serologic Markers Adapted from Dubinsky MC, et al. Clin Gastroenterol Hepatol . 2008;6:1105-1111 p trend < 0.0001 (n=199) (n=262) (n=194) (n=57) 0 20 40 60 80 100 0 1 2 3 Number of Immune Responses Frequency of Disease Behavior, % Nonpenetrating/nonstricturing Internal penetrating Stricturing Surgery ASCA Anti-OmpC Anti-CBir1 pANCA Serologic markers
    • 7. Frequency of CD Complications in Children with Increased Marker Titres Adapted from Dubinsky MC, et al. Clin Gastroenterol Hepatol . 2008;6:1105-1111 P trend < 0.0001 (n=167) (n=195) (n=189) (n=162) ASCA Anti-OmpC Anti-CBir1 pANCA 0 20 40 60 80 100 1 (QS 3-5) Quartile Sum Score Groups Frequency of Disease Behavior, % Stricturing Surgery Serologic markers 2 (QS 6,7) 3 (QS 8,9) 4 (QS 10-12) Nonpenetrating/nonstricturing Internal penetrating
    • 8. Faster Disease Progression In Children With Increasing Number of Serologic Markers Serology markers: ASCA, anti-OmpC a , anti-CBir1 a , pANCA Ab sum=number of antibody immune responses; IP/S=internal penetrating/stricturing a Patented Reproduced with permission from Dubinsky MC, et al. Clin Gastroenterol Hepatol . 2008;6:1105-1111 Probability of Non-Progressive Disease Time to IP/S, months Time to surgery, months Probability of Non-Progressive Disease P <0.0001 P <0.0001 A B Ab sum=0 Ab sum=1 Ab sum=3 Ab sum=2 Ab sum=1 Ab sum=0 Ab sum=2 Ab sum=3
    • 9. Antibody Responses and Complications of Small-Bowel Crohn’s Disease Adapted from Mow, et al. Gastroenterology . 2004;126:414-424. *Patented. 100 90 80 70 60 50 40 30 20 10 0 3 4 5 6 7 8 9 10 11 12 Internal Perforating Frequency of disease behavior (%) Quartile Sum <0.001 Small-Bowel Surgery <0.001 Fibrostenosing <0.001 Markers: ASCA Anti-OmpC* Anti-I2 The frequency of complicated small-bowel disease increased with antibody reactivity, as represented by the quartile sum score. P trend
    • 10. Disease Behavior Association With Marker Expression Markers Associated With Complicated Disease X= statistically significant Adapted from Targan SR, et al. Gastroenterology . 2005;128:2020-2028 . Anti-OmpC ASCA Anti-CBir1 X X X X X X X X Small-Bowel Surgery Internal Perforating Fibrostenosis Small-Bowel Disease

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