Anti-GP2 IgA autoantibodies are associated with poor survival and cholangiocarcinoma in primary sclerosing cholangitis

Abstract

ObjectivePancreatic autoantibodies (PABs), comprising antibodies against glycoprotein 2 (anti-GP2), are typically associated with complicated phenotypes in Crohn's disease, but have also been observed with variable frequencies in patients with UC. In a previous study, we observed a high frequency of primary sclerosing cholangitis (PSC) in patients with anti-GP2-positive UC. We therefore aimed to characterise the role of anti-GP2 in PSC.DesignIn an evaluation phase, sera from 138 well-characterised Norwegian patients with PSC were compared with healthy controls (n=52), and patients with UC without PSC (n=62) for the presence of PABs by indirect immunofluorescence. Further, 180 German patients with PSC served as a validation cohort together with 56 cases of cholangiocarcinoma without PSC, 20 of secondary sclerosing cholangitis (SSC) and 18 of autoimmune hepatitis.ResultsAnti-GP2 IgA specifically occurred at considerable rates in large bile duct diseases (cholangiocarcinoma=36%, PSC and SSC about 50%). In PSC, anti-GP2 IgA consistently identified patients with poor survival during follow-up (Norwegian/German cohort: p Log Rank=0.016/0.018). Anti-GP2 IgA was associated with the development of cholangiocarcinoma in both PSC cohorts, yielding an overall OR of cholangiocarcinoma in patients with anti-GP2 IgA-positive PSC of 5.0 (p=0.001). Importantly, this association remained independent of disease duration, bilirubin level and age.ConclusionsAnti-GP2 IgA can be hypothesised as a novel marker in large bile duct diseases. In particular, in PSC, anti-GP2 IgA identified a subgroup of patients with severe phenotype and poor survival due to cholangiocarcinoma. Anti-GP2 IgA may therefore be a clinically valuable tool for risk stratification in PSC.

Circulating Biomarkers for Cholangiocarcinoma

“…Jendrek et al [57] just recently demonstrated that anti-glycoprotein (GP)-2 immunoglobuline G autoantibodies are associated with the presence of CCA in patients with primary sclerosing cholangitis. In a large study comprising over 250 patients from Norway and Germany, it was shown that anti-GP2 positive PSC patients yield a significantly higher risk for CCA development than anti-GP2 negative patients.…”

The Role of Genetic and Immune Factors for the Pathogenesis of Primary Sclerosing Cholangitis in Childhood

“…The second commonest autoantibodies are anti- Saccharomyces cerevisiae antibodies (ASCA), which also exhibit high frequency even in the absence of advanced disease or inflammatory bowel disease (IBD) [16]. Recently, Jendrek et al [17] also found an association between antibodies against glycoprotein 2 (anti-GP2) and large bile duct diseases with considerable rates. In PSC, anti-GP2 IgA was consistently identified in patients with poor survival during follow-up, being associated with cholangiocarcinoma [17].…”

“…Recently, Jendrek et al [17] also found an association between antibodies against glycoprotein 2 (anti-GP2) and large bile duct diseases with considerable rates. In PSC, anti-GP2 IgA was consistently identified in patients with poor survival during follow-up, being associated with cholangiocarcinoma [17]. Other autoantibodies including antinuclear antibody (ANA) and liver kidney microsomal type 1 antibody (anti-LKM1) can be positive in PSC patients, but with low specificity for the diagnosis of the disease [18].…”

Emerging therapies for the treatment of cholangiocarcinoma

“…Such treatments are more selective against malignant cells and generally less toxic than traditional chemotherapy [82]. Conversely, antibodies against glycoprotein 2 are associated with more severe phenotype and poor survival due to cholangiocarcinoma [83].…”