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Primary biliary cholangitis, formerly designated primary biliary cir-rhosis, represents a model cholestatic liver disease characterized by chronic, progressive immune-mediated bile duct destruction mainly affecting middle-aged women. Though its distinct pathogenesis remains to be fully defined, complex environmental-host immunogenic interactions have been highlighted by large-scale genome-wide association studies (GWAS) identifying a total of at least 27 disease-associated human leukocyte antigen (HLA) and non-HLA risk loci (Gulamhusein et al., 2015). The diagnosis can be firmly assumed in the presence of at least two of three criteria including biochemical evidence of chronic cholestasis, presence of pathognomonic anti-mitochondrial antibodies (AMA, targeting the E2 and/or E3BP subunits of the pyruvate dehydro-genase complex) and/or supportive liver histology including florid bile duct lesions. The well-established standard of care consists of the oral hydrophilic bile acid (BA) ursodeoxycholic acid (UDCA), the hitherto only Food and Drug Administration (FDA)-approved agent for PBC treatment, with proven beneficial effects on disease progression as well as transplant-free survival and liver-related mortality. A convincing long-term response to UDCA identifies a low-risk subgroup without disease progression and survival rates comparable to the general population. By contrast, an estimated one in three PBC individuals reveals UDCA suboptimal or non-response as assessed by variable biochemical surrogate endpoints with a special emphasis on serum alkaline phos-phatase (ALP) activity (e.g. Paris or Barcelona criteria), thus conferring high risk of continued disease progression despite treatment (" high risk PBC "). Novel prognostic tools, such as the GLOBE score, predictive of transplant-free survival in a large cohort of 4119 UDCA-treated individuals , or the UK-PBC risk score have recently been reported (Lammers et al., 2015; Carbone et al., 2016). The major drawback, however, remains the post hoc nature of determining UDCA response, traditionally after one year, although smaller studies reported adequate reflection of long-term prognosis assessing UDCA response as early as after six months (Zhang et al., 2013). Therefore, an unmet clinical need in PBC research lies in the identification of adequate biomarkers for high-risk disease at diagnosis and prediction criteria of UDCA response applicable early on or even before treatment (Dyson et al., 2015). The reliable a priori identification of non-responders represents an opportunity to actively alter future disease trajectories and may be of key importance in prioritizing patients for novel and/or re-purposed second-line treatments. The changing and vital landscape of second-line options in PBC treatment is underscored by the recent conditional FDA licensing of obeticholic acid (OCA) as …

Looking Into the Crystal Ball: Predicting Non-response to Ursodeoxycholic Acid in Primary Biliary Cholangitis