6001 International randomised phase III study of capecitabine (Cap), bevacizumab (Bev) and mitomycin C (MMC) in first line treatment of metastatic colorectal cancer (mCRC): final results of the AGITG MAX trial

Abstract

Background/Aims: Antineutrophil cytoplasmic antibodies are reported in patients with chronic liver disease, but controversy exists about their prevalence and specificity. We aimed to find the prevalence and specificity of antineutrophil cytoplasmic antibodies in chronic liver diseases by determination of antineutrophil cytoplasmic antibody titre and IgG subclass.Methods: One hundred and eight-four sera were studied: 63 primary sclerosing cholangitis, 28 autoimmune hepatitis, 34 primary biliary cirrhosis, 12 alcoholic liver disease, five large duct obstruction, four haemochromatosis, one chronic cholestatic syndrome, one cryptogenic cirrhosis and 36 normal individuals. Antineutrophil cytoplasmic antibodies were detected on alcohol-fixed neutrophils using an alkaline phosphates technique. The IgG subclass of antineutrophil cytoplasmic antibodies was determined using monoclonal antibodies: HP 6001 for IgG1, HP 6002 for IgG2, HP 6050 for IgG3 and SK 44 for IgG4 (Sigma Immunochemicals).Results: Antineutrophil cytoplasmic antibodies were detected in 65% of primary sclerosing cholangitis patients at a serum dilution of 1:5, dropping to 49% at 1:50. For autoimmune hepatitis, antineutrophil cytoplasmic antibodies were detected in 49% at 1:5, dropping to 11% at 1:50. Only 6% of primary biliary cirrhosis patients were antineutrophil cytoplasmic antibody-positive at 1:5, dropping to 3% at 1:50. All other controls were antineutrophil cytoplasmic antibody negative at 1:5. The presence of antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis correlated with involvement of the intra- and extrahepatic biliary tree (p=0.016, Fisher's exact test), but no other clinical parameters. Determination of the IgG subclass of antineutrophil cytoplasmic antibody in 33 primary sclerosing cholangitis and 11 autoimmune hepatitis patients revealed a predominance of IgG1 in both groups (94% and 82% of all IgG antineutrophil cytoplasmic antibodies, respectively), with a similar distribution of IgG2, IgG3 and IgG4 antineutrophil cytoplasmic antibodies between the groups.Conclusions: Antineutrophil cytoplasmic antibodies are specific to the autoimmune liver diseases, particularly primary sclerosing cholangitis and autoimmune hepatitis. Titres are highest in primary sclerosing cholangitis, with a diagnostic sensitivity of 49% and specificity of 89% at 1:50, making it a useful serological marker for this disease. The lack of correlation with any marker of activity and the association of antineutrophil cytoplasmic antibody with extent of biliary tract involvement suggest that antineutrophil cytoplasmic antibodies arises as a result of the disease or related process rather than being a cause of it. The detection of antineutrophil cytoplasmic antibodies in autoimmune hepatitis, together with a similar IgG subclass distribution of primary sclerosing cholangitis and autoimmune hepatitis antineutrophil cytoplasmic antibodies, may reflect similar mechanisms of immune regulation and a possible overlap syndrome. Future identification of the antigens against which this antineutrophil cytoplasmic antibody are directed should help to clarify this point, as well as allowing the development of a more sensitive and specific serological test for diagnostic purposes.