A comprehensive evaluation of serum autoantibodies in primary biliary cirrhosis Nancy Agmon-Levin a, b , Yinon Shapira a , Carlo Selmi c , Ori Barzilai a , Maya Ram a , Martine Szyper-Kravitz a, b , Sara Sella a , Bat-sheva Porat Katz d , Pierre Youinou e, c , Yves Renaudineau e, c , Bruno Larida f , Pietro Invernizzi c , M. Eric Gershwin g , Yehuda Shoenfeld a, b, h, * a Center for Autoimmune Diseases Sheba Medical Center, Israel b Department of Medicine 'B', Sheba Medical Center, Israel c Department of Internal Medicine, IRCCS Istituto Clinico Humanitas, University of Milan, Italy d Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Israel e Laboratoire d'immunologie, Brest University Medical School Hospital, Brest, France f Bio-Rad Laboratories, CA, USA g Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA h Sackler Faculty of Medicine, Incumbent of the Laura Schwarz-Kip Chair for Research of Autoimmune Diseases, Tel-Aviv University, Israel article info Article history: Received 19 August 2009 Accepted 24 August 2009 Keywords: Primary biliary cirrhosis Anti-prothrombin antibodies Autoimmune cholangitis Anti-phospholipid antibodies Anti-nuclear antibodies abstract In primary biliary cirrhosis (PBC) serum markers other than anti-mitochondrial antibodies (AMA) are prom- ising in terms of disease severity and comorbidities, as well represented by anti-nuclear antibodies (ANA). The aim of the present study was thus to evaluate the prevalence and clinical significance of a large profile of serum autoantibodies in PBC sera. We utilized 69 sera from European patients with PBC (including 20 AMA-negative) and 297 sera from geographically and sex-matched healthy controls. All sera were tested for the presence of ANA and autoantibodies associated with thrombophilia, vasculitis, and gastrointestinal disease. Autoanti- bodies other than AMA were detected in 53/69 (76%) PBC sera vs. 105/297 (35%) among controls. The preva- lence of ANA (targeting dsDNA, Sm, chromatin, ribosomal-P, RNP, SmRNP, SSA, SSB, and centromere) and thrombophilia-associated autoantibodies (i.e. anti-b2GPI, phosphatydilserine, prothrombin) was common among patients with PBC. When clinical features were compared, the presence of anti-prothrombin IgM was associated with a worse prognosis as represented by a higher Mayo score. We demonstrate an increased prevalence of ANA and thrombophilia-associated autoantibodies in PBC sera and an association between the latter autoantibodies and PBC stage. The role of thrombophilia-associated antibodies will warrant further studies, based in particular on the incidence of portal hypertension at early stages of PBC. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction Determining the diagnosis and prognosis of primary biliary cirrhosis (PBC) remains challenging. Several authors have attemp- ted to identify non-invasive markers to allow a more accurate diagnosis, particularly when anti-mitochondrial antibodies (AMA) are not detected, or to predict disease severity. Indeed, AMA are the serum hallmark for PBC and this antibody at titres above 1:40 is highly specificity for PBC [1] and can be observed long before the disease is clinically overt [2]. Nevertheless, AMA fail to predict the clinical phenotype or the prognosis of PBC [3] and do not determine clinically different populations [4] nor change during progression [5]. The search for additional serum markers is well represented by anti-nuclear antibodies (ANA) [6] which are associated with disease severity regardless of the AMA status [7]. The identification of new non-invasive markers for disease severity remains a priority in PBC as patients may manifest an indolent or very aggressive disease [8]. Another fascinating issue in PBC is the appearance of portal hypertension at early disease stages, i.e. when no sign of cirrhosis is present [9,10], yet no clear mechanism has been identified for this unique feature among progressing liver diseases. To address these issues we investigated the autoantibody profile in sera from patients with PBC and performed a cross-sectional analysis of the significance of observed reactivities. 2. Materials and methods 2.1. Subjects Sera were obtained from 69 European patients with an estab- lished diagnosis of PBC [11]; sera were randomly chosen but * Corresponding author at: Department of Medicine 'B' & Center for Autoim- mune Diseases, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel. Tel.: þ972 3 5302652; fax: þ972 3 5352855. E-mail address: shoenfel@post.tau.ac.il (Y. Shoenfeld). Contents lists available at ScienceDirect Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm ARTICLE IN PRESS 0896-8411/$ e see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.jaut.2009.08.009 Journal of Autoimmunity xxx (2009) 1e4 Please cite this article in press as: Agmon-Levin N, et al., A comprehensive evaluation of serum autoantibodies in primary biliary cirrhosis, Journal of Autoimmunity (2009), doi:10.1016/j.jaut.2009.08.009