Methotrexate for Primary Biliary Cirrhosis: Who Is to Be Trusted?

Abstract

Primary biliary cirrhosis (PBC) remains a puzzling disease. Its etiology recognizes both genetic and environmental influences, as well epitomized by the incomplete concordance rate among monozygotic twins [1]. Most recently, genomewide association studies provided a number of candidate genes which, however, are found only in subgroups of patients [2]. In a complementary fashion, several environmental factors have also been identified as putative triggers of PBC [3]. Nevertheless, numerous enigmas remain in PBC pathogenesis and clinical features. Among the latter, poor response of PBC to immunosuppressants, despite evidence supporting the immune-mediated injury and the proinflammatory cascade, remains a clinical challenge. Ursodeoxycholic acid (UDCA) is currently the only accepted treatment for PBC and may delay but not halt the progression of the disease [4]. A few studies suggested increased transplant-free survival, but a meta-analysis of published trials did not confirm this finding [5]. Interestingly, UDCA has limited immunomodulatory effects while acting on biliary secretion and protecting from the potentially membranolytic detergent effect of retained endogenous bile acids [6]. For these reasons, the combination of UDCA and immunosuppressants appeared an obvious and rational development but substantially failed for most drugs [7], while longer study periods are warranted for recent candidates such as budesonide [8], B cell depleting rituximab [9], and farnesoid X receptor agonist obeticholic acid [10]. The study by Dr. Kaplan and Colleagues included in this issue of Digestive Diseases and Sciences [11] raises some doubt against these quite established observations. All randomized clinical trials designed to evaluate proposed medical treatments in PBC are hampered by major difficulties in establishing long-term benefits, as the disease manifests a widely variable natural history which may span several decades. Furthermore, surrogate markers of PBC prognosis are scarcely predictive, especially at earlier stages [12], while signs of liver failure are not observed until very late. Similarly, limited predictivity, sampling errors, and inherent invasiveness of liver biopsy limit the role of histology. When immunosuppressants were tested, some efficacy was observed for immunosuppressive treatments including azathioprine, cyclophosphamide, chlorambucil, and prednisone, but their potential toxicity discouraged further studies after the initial ones. An arbitrary representation of the efficacy and safety of the proposed immunomodulatory treatments is presented in Table 1. Apart from ursodeoxycholic acid (UDCA) and the agents currently undergoing confirmation studies, no drug shows a favorable margin in the ratio between efficacy and toxicity with a narrow therapeutic index. Methotrexate (MTX) is a substantially different story. After preliminary encouraging data coming from a pilot study [13], others reported disappointing results. The beneficial effects of MTX in the treatment of PBC, alone or in combination with UDCA, could not be confirmed by randomized clinical trials performed by other groups [7, 14, 15]. It should be noted, however, that substantial sideeffects were not observed in these studies, probably due also to low doses [7]. Finally, a recent meta-analysis reported no improvement in transplant-free survival or other clinical end-points, albeit with less severe and consistent adverse events [16]. C. Selmi (&) M. Podda Department of Internal Medicine and Hepatobiliary Immunopathology Unit, IRCCS-Istituto Clinico Humanitas, University of Milan, via A. Manzoni 56, 20089 Rozzano, Milan, Italy e-mail: carlo.selmi@unimi.it