Signature biomarkers in Crohn's disease: toward a molecular classification

Abstract

In an effort to develop a molecular classification scheme for Crohn's disease (CD), mucosal biopsies from 69 CD patients and 28 normal controls were analyzed for expression of the RelA subunit of nuclear factor (NF)-kappaB, A20 (a negative regulator of NF-kappaB), polymeric immunoglobulin receptor (pIgR), tumor necrosis factor (TNF), and interleukin (IL)-8. Principal component analysis was used to classify individuals into three subsets based on patterns of biomarker expression. Set 1 included normal subjects and CD patients with mild disease and good responses to therapy, thus defining "normal" biomarker expression. CD patients in set 2, characterized by low expression of all five biomarkers, had moderate to severe disease and poor responses to immunosuppressive and anti-TNF therapy. Patients in set 3, characterized by low expression of RelA, A20, and pIgR, normal TNF and elevated IL-8, had acute inflammation that responded well to therapy. Classification of CD patients by these biomarkers may predict disease behavior and responses to therapy.

A20 controls intestinal homeostasis through cell-specific activities

“…In addition, lower expression levels of A20 seem predictive of primary response to infliximab, while non-responders display significantly higher and stable A20 expression levels. These data are in line with studies in rheumatoid arthritis patients 52 and Crohn's disease patients 53 where low A20 expression has been correlated to good anti-TNF response. Taken together, we identified A20 as a potential biomarker for the prognosis of anti-TNF therapy.…”

Clinical, Biological, and Laboratory Parameters as Predictors of Severity of Clinical Outcome and Response to Anti–TNF–Alpha Treatment in Ulcerative Colitis

“…Pretreatment mucosal TNF-α concentrations were negatively correlated to response to Infliximab in CD (Schmidt et al, 2007) and in UC (Olsen et al, 2007). These findings disagree with another report where low expression of TNF-α predicted a poor response to therapy in CD (Arsenescu et al, 2008). Increased levels of TNF-α were also observed in corticosteroid non-responders compared with responders to corticosteroid treatment in UC (Ishiguro, 1999), but not confirmed in another study (Raddatz et al, 2005).…”

The ubiquitin-editing enzyme A20 (TNFAIP3) is a central regulator of immunopathology

“…An earlier independent study on 260 IBD-affected pairs from 139 families also associated a region of human chromosome 6q with the IBD phenotype [34], with one of the candidate genes in this locus being A20. Finally, mucosal biopsies from 69 CD patients were analyzed and confirmed a consistent downregulation of mucosal A20 expression, which might hamper their ability to regulate pathological NF-kB activation induced by acute inflammatory responses [35]. Interestingly, single nucleotide polymorphisms (SNPs) in the A20 region on 6q23.3 were recently also identified as a disease risk factor in coeliac disease, an autoimmune disorder of the small intestine that occurs in genetically predisposed people and which is caused by intolerance to dietary gluten protein from wheat and related proteins from barley and rye [36].…”