Anti‐glycoprotein 2 (anti‐GP2) IgA and anti‐neutrophil cytoplasmic antibodies to serine proteinase 3 (PR3‐ANCA): antibodies to predict severe disease, poor survival and cholangiocarcinoma in primary sclerosing cholangitis

Abstract

SummaryBackgroundPrimary sclerosing cholangitis (PSC) is associated with progressive liver disease and cholangiocarcinoma. Although risk stratification is crucial for making clinical decisions, it is hindered by a scarcity of proven prognostic markers.AimsTo assess the value of novel anti‐glycoprotein 2 (anti‐GP2) and anti‐neutrophil cytoplasmic antibodies to serine proteinase 3 (PR3‐ANCA) in combination with PSC‐specific clinical and laboratory markers as predictors of quality of life, disease severity, and cholangiocarcinoma in two large, independent cohorts of PSC patientsMethodsDiscovery (338 Polish patients) and validation (178 German patients) cohorts with PSC were evaluated. Anti‐GP2 (isoforms 1/4) was detected by ELISAs and PR3‐ANCA by chemiluminescence immunoassay. Clinical and laboratory data were collected and analysed. The outcome was defined as liver transplantation‐free survival and occurrence of cholangiocarcinoma during follow‐up.ResultsIn the discovery group, anti‐GP21/4 IgA and PR3‐ANCA were associated with liver dysfunction, anti‐GP21/4 IgA with risk scores for PSC and anti‐GP24 IgA with cirrhosis. All cholangiocarcinoma patients were positive for PR3‐ANCA and/or anti‐GP24 IgA. The association between anti‐GP2 IgA and liver biochemistry, risk scores, cirrhosis, impaired survival, and cholangiocarcinoma was confirmed in the validation cohort. Cox proportional‐hazards regression indicated anti‐GP21 IgA as an independent variable of poor outcome in both study cohorts. Analysis of the combined data showed that anti‐GP24 IgA and PR3‐ANCA were independent predictors for cholangiocarcinoma, while anti‐GP21 IgA and PR3‐ANCA were indicators for poor survival.ConclusionsAnti‐GP2 and PR3‐ANCA are prognostic antibodies in PSC as they identify patients at risk of severe disease, poor survival and biliary cancer.

A Review on Biomarkers for the Evaluation of Autoimmune Cholestatic Liver Diseases and Their Overlap Syndromes

“…However, one recent study evaluated and subsequently validated ANCA (PR3) in combination with anti-GP2 IgA in PSC patients of European descent. In this study both autoantibodies were found to be associated with worse liver function tests, higher MELD scores, lower transplant free survival, and higher risk of cholangiocarcinoma (Wunsch et al, 2021). Whether this will translate to regular use within the clinical setting and/or international consensus guidelines for PSC management remains to be seen.…”

EASL Clinical Practice Guidelines on sclerosing cholangitis

“…45 ANCA positivity may be associated with worse cholestasis and more severe biliary stricturing 46,47 , and it has been suggested as a marker for PSC-IBD subphenotypes 48 as well as increased risk for CCA. 49 IgA antibodies against glycoprotein 2 have been observed in approximately 50% of people with PSC independent of the presence of IBD; these antibodies may identify a subgroup of patients at increased risk of CCA 49,50 and decreased transplantfree survival. 49 Thus, anti-glycoprotein 2 and PR3-ANCA might have prognostic relevance but demonstration of additional value in comparison with known prognostic markers is required.…”

Autoimmune Lebererkrankungen – ein Update (Teil 2)

“…Auch wenn die PSC häufig positive Autoantikörper (p-ANCA in bis zu 93%, ANA in 8 – 77% und Anti-SMA in 0 – 83% der Patient*innen) aufweist, so haben diese im Gegensatz zur Diagnostik der autoimmunen Hepatitis (AIH) und der primär biliären Cholangitis hier eine geringe Relevanz 32 , 33 . Eine besondere Rolle könnte in Zukunft dem Anti-Glycoprotein-2-Antikörper (Anti-GP2 IgA) und dem antineutrophilen zytoplasmatischen Antikörper gegen Proteinase 3 (PR3-ANCA) zukommen, welche als prognostische Antikörper Hinweise auf einen schwereren Krankheitsverlauf sowie ein erhöhtes Risiko für hepatobiliäre Tumoren liefern können 34 .…”

“…Die transiente Elastografie zeigt eine im Verlauf der folgenden 12 Monate mit 7,5 kPa gebesserte Lebersteifigkeit.FALLBEISPIEL Fall 2Der 33-jährige Herr L. stellt sich mit seit einem Monat bestehenden rezidivierenden leicht-bis mittelgradigen Oberbauchschmerzen sowie einem ausgeprägten nächtlichen Juckreiz vor. In der klinischen Untersuchung zeigt sich eine leichte Druckdolenz im kunft dem Anti-Glycoprotein-2-Antikörper (Anti-GP2 IgA) und dem antineutrophilen zytoplasmatischen Antikörper gegen Proteinase 3 (PR3-ANCA) zukommen, welche als prognostische Antikörper Hinweise auf einen schwereren Krankheitsverlauf sowie ein erhöhtes Risiko für hepatobiliäre Tumoren liefern können[34].…”