Editorial: serologic microbial‐associated markers to predict Crohn's disease behaviour

Serologic microbial-associated markers have been identified in patients with Crohn's disease for many years.1 Several studies have shown that multiple serological markers at diagnosis are associated with a more aggressive course.2, 3 The interpretation of serological studies at diagnosis has been debated with the suggestion that the complication itself may lead to an alteration in mucosal permeability and hence to sero-reactivity to microbial antigens. This study, and two other smaller studies, have shown the presence of serological markers before clinical diagnosis.4-6 Choung et al. present novel data to show that the gradual accumulation of serological markers over several years is associated with complications at, or soon after, clinical diagnosis.6 This observation shows that Crohn's disease has an extended pre-clinical period, perhaps for 5–10 years. Over this time, there is gradual immune dysregulation and loss of tolerance of the gut immune system to normal microbiological flora. This could be considered to be analogous to the notion of epitope spreading that has been shown to occur before the diagnosis of rheumatoid arthritis.7 In both conditions, there appears to be an increase in the number of antibody responses and an increase in the titre of antibody response prior to diagnosis that becomes most apparent 2–4 years before diagnosis.6, 7 Similarly, there is no specific order to the recognition of different peptides (for rheumatoid arthritis) or microbiological antigens (for Crohn's disease) indicating that epitope spreading or increasing immune dysregulation to the gut microbiome occurs in a random manner. It is unlikely that the clinician will have the opportunity to test for serological markers prior to diagnosis. Testing at the time of diagnosis may be helpful but many patients present with complicated disease.2 This study showed that the positive predictive value for individual antibodies is low. A combination of antibodies has stronger predictive value, but fewer patients will fall into the category of multiple antibodies. A study of 796 paediatric patients who had serological testing at diagnosis showed that only 8% had three positive antibodies.2 Even if the prediction of complicated disease at diagnosis was accurate, there is often a reluctance to start more aggressive treatment such as anti-TNF's without some clinical evidence of the severity of disease. These serologic microbial markers appear to have better negative predictive value. This could help the decision to withhold anti-TNF treatment where the risks are considered to be high. A combination of clinical features may have equally good predictive value and are easier to identify. There have been several attempts to combine clinical factors, serology and genetic tests to improve the predictive value.7, 8 A web-based tool has been developed to predict outcome for patients with Crohn's disease based on clinical, serologic and genetic variables. This was validated with two external cohorts.8 It is interesting to note that two clinical features, small bowel disease and peri-anal disease, had much stronger predictive value than the serological markers (ASCA and CBir1). The hazard ratios for small bowel disease and peri-anal disease were 2.12 and 4.12, respectively, compared with the hazard ratios for ASCA and CBir1 of 1.35 and 1.29 respectively. The NOD2 frameshift mutation had a hazard ratio of 2.13 (1.33–3.40). There may be an interaction between genetic mutations and serology. One study showed significantly higher cumulative serologic responses to ASCA, I2, OmpC and CBir1 antigens in patients carrying the NOD2 variants.9 This paper studied a selected population of 100 US military personnel. These findings may therefore not apply to all patients with Crohn's disease. Ethnicity is a potential confounder. Asian populations in England have low sensitivity for ASCA, Omp-C and pANCA.10 Despite the limitations on clinical applicability, this paper gives significant new insights into our understanding of Crohn's disease in the pre-clinical period. Declaration of personal and funding interests: None.