Inflammatory Bowel Disease


Figure 3: Cumulative Influence of (A) Number of Immune Responses (Antibody Sum Based on the Presence or Absence of Anti-CBir1, Anti-OmpC, ASCA, and pANCA) and (B) Magnitude of the Immune Response (Quartile Sum Score Group) on Frequency of Disease Behavior


A 100 p<0.0001 80 60 40 20 0 n=199 B 100 p<0.0001 80 60 40 20 0


1 (QS 3–5) n=167


2 (QS 6, 7) n=195


Non-penetrating non-stricturing Internal penetrating


3 (QS 8, 9) n=189


4 (QS 10–12) n=162


Stricturing Surgery


Reproduced with permission from Dubinsky et al., 2008.63 ASCA = anti-Saccharomyces cerevisiae antibody; CBir1 = CBir1-flagellin; OmpC = Escherichia coli outer membrane porin C; pANCA = perinuclear anti-neutrophil cytoplasmic antibody; QS = quartile sum.


for small bowel surgery (p=0.003).57 In the same study, patients with


antibodies against I2 were more likely to have fibrostenosing disease (p<0.001) and the need for surgical intervention (p<0.001). Patients triply positive for ASCA and antibodies to I2 and OmpC were the most likely to have undergone small bowel surgery compared with patients without reactivity (OR = 8.6; p<0.001).57


In another study, anti-CBir1 expression


was associated independently with small-bowel, internal penetrating, and fibrostenosing disease features.53


These results were extended into


the pediatric population by Dubinsky et al., who demonstrated that disease progression from uncomplicated to internal penetrating/ stricturing phenotypes and CD-related surgery was correlated with the magnitude of immune reactivity to CBir1, OmpC, ASCA, and pANCA.63 Importantly, this study (and others) emphasized the notion that it is not only the qualitative serologic response that is associated with aggressive or complicated disease but the quantitative response also, i.e. higher titers and several seroreactivities pose an increased risk for


20


0123 n=262


n=194 Quartile sum score groups Antibody study groups


Relationship between Genetic and Serologic Markers in Crohn’s Disease Prognosis


An increasing number of studies suggest that the adaptive immunologic response observed in many CD patients reflects underlying genetic determinants.64,65


Beckwith et al. demonstrated that a genetic defect in


innate immunity accompanying a mutation in the cytokine-deficiency- induced colitis susceptibility 1 gene results in a hyper-responsive adaptive immune response to bacterial ligands, including CBir1, in a mouse model of colitis.64


In humans, loss-of-function mutations of NOD2


could conceivably result in the same phenomenon, with a compensatory adaptive immunologic response to bacterial antigens.


n=57


Subsequent clinical investigations have lent support to this hypothesis, demonstrating associations between the immune response to microbial antigens, the presence of NOD2 variants, and complicated disease in CD patients. Devlin et al. observed a significantly elevated cumulative response to ASCA and antibodies to I2, OmpC, and CBir1 in those patients carrying any NOD2 variant compared with those carrying no variant (p=0.0008).66


Interestingly, this relationship can also be found in unaffected relatives of patients with CD:66 those relatives carrying a NOD2


variant had an elevated serologic response to the four antigens when compared with relatives carrying no variant, supporting the concept of a genetic basis for a link between innate immune defects and dysregulated, hyper-responsive adaptive immunity. In a later study, Papadakis and colleagues reported similar results, demonstrating an association between NOD2, reactivity to CBir1, and complicated disease.67


The value


of combining quantitative serologic immune responses and NOD2 genotype as a test to determine the probability of complicated CD was recently demonstrated by Lichtenstein and colleagues.68


Fecal Markers


In addition to genetic and serologic data, fecal markers such as fecal calprotectin (FC) and fecal lactoferrin (FL) have been investigated as non-invasive prognostic tools for predicting disease course in CD. Calprotectin and lactoferrin are both major proteins of neutrophils and macrophages and are found in both plasma and stool.69,70


These


markers have the advantage of showing excellent stability in feces and quantification is accomplished using an inexpensive and easy enzyme- linked immunosorbent assay (ELISA) technique.71


FC and FL are


Correlations between FC and FL and endoscopic disease activity were significant in a cross-sectional study of CD patients34


and


the utility of these markers for predicting clinical relapse of CD has been examined in a small number of studies. Tibble et al. found that FC was a reliable predictor of clinical or symptomatic relapse in UC and CD but a subsequent study concluded that this marker was considerably less useful for predicting CD relapses.73,74


Nevertheless, a recent


multicenter study found that FC was an equally reliable predictor of relapse in UC and CD; FC concentrations in CD or UC patients who


US GASTROENTEROLOGY & HEPATOLOGY REVIEW


sensitive markers of intestinal inflammation in patients with IBD and are useful in distinguishing inflammatory from non-inflammatory bowel disorders.69,72,73


complicating CD. The frequency of penetrating disease, stricturing disease, and surgery significantly increased (p<0.0001) as the number of immune responses (antibody sum based on the presence or absence of anti-CBir1, anti-OmpC, ASCA, and pANCA) and magnitude of immune response (quartile sum score) increased (see Figure 3).


Frequency of disease behavior (%)


Frequency of disease behavior (%)


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76