48 CD from UC appears limited.13,30 Although these serological antibodies could help identify subsets of patients with similar clinical features, they typically do not occur in all patients and, consequently, differential antibody reactivities may also reflect differences in the underlying immunopathogenesis. As a result, serological testing is not currently recommended for routine diagnostic assessment of CD or UC.10 Nonetheless, multiple studies have attempted to find combinations of serological antibodies, e.g. parallel ASCA and pANCA measurements, that could be used to predict whether an indeterminate colitis would progress to either CD or UC.3133 Table 1 presents a detailed –but not exhaustive – overview of known serological antibodies in the context of IBD, with a description of their antigenic targets, IBD-subtype-specificity and associations to clinical phenotypes and outcomes (for details see the extensive reviews in15,34,35). Identification of at-risk individuals for IBD Using serological antibodies to identify at-risk individuals and predict future occurrence of IBD could be of great clinical benefit. To this end, previous studies demonstrated that ASCA, pANCA and selected antimicrobial antibodies, or combinations of them, may serve as predictors of the future onset of IBD.14,16,26,36,37 More recently, studies have emerged addressing the potential utility of anti-flagellin antibody signatures to define CD or predict the risk of developing CD years before the actual diagnosis.3,16,38 For example, increased anti-flagellin antibody responses have been strongly associated with the future onset of CD and are independent of signs of subclinical inflammation, gut permeability and genetic risk.16 This observation led to the speculation that serological antibody formation may reflect one of the earliest pathogenic events in IBD. Importantly, as serological antibody profiling may help identify individuals at-risk for IBD (prediagnostics), it opens up opportunities for primary disease prevention by identifying individuals for disease surveillance or early initiation of therapeutic intervention. The value of such efforts has previously been observed for other immune-mediated inflammatory diseases such as rheumatoid arthritis or type 1 diabetes.39,40 Associations with distinct clinical phenotypes and outcomes in IBD Looking at the serological antibodies listed in Table 1, there is a notably higher number of CDassociated serological indicators. Many of these antibodies are intimately associated with distinct clinical phenotypes characteristic for CD. Multiple studies have indicated that the combined presence and magnitude of titers of multiple positive antimicrobial antibodies is associated with disease severity and progression in CD.16,29 For instance, ASCA, anti-flagellin antibodies (like antiCBir-1 and anti-Fla-X), anti-OmpC and anti-I2, among others, are particularly associated with small bowel or ileal disease involvement, an increased risk of developing stricturing or penetrating disease complications, the presence of perianal disease and the risk of requiring IBD-related surgery.16,29 Furthermore, exocrine pancreatic autoantibodies have been associated with higher frequencies of penetrating and perianal disease, extraintestinal manifestations and antimicrobial antibody reactivity.41 Such associations, however, have also been reported for UC, e.g. pANCA antibodies are associated with a higher rate of complications and surgery in patients with postoperative ileal pouchitis.42 Chapter 2
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