Prediction and evaluation of high-risk patients with primary biliary cholangitis receiving ursodeoxycholic acid therapy: an early criterion

Abstract

Background and aims: Current treatment guidelines recommend ursodeoxycholic acid (UDCA) as the first-line treatment for new-diagnosed primary biliary cholangitis (PBC) patients. However, up to 40% patients are insensitive to UDCA monotherapy, and evaluation of UDCA response at 12 months may result in long period of ineffective treatment. We aimed to develop a new criterion to reliably identify non-response patients much earlier.

Methods: Five hundred sixty-nine patients with an average of 59 months (Median: 53; IQR:32-79) follow-up periods were randomly divided into either the training (70%) or the validation cohort (30%). The efficiency of different combinations of total bilirubin (TBIL), alkaline phosphatase (ALP), and aspartate aminotransferase (AST) threshold values to predict outcomes was assessed at 1, 3 or 6 month after the initiation of UDCA therapy. The endpoints were defined as adverse outcomes, including liver-related death, liver transplantation and complications of cirrhosis. Adverse outcome-free survival was compared using various published criteria and a proposed new criterion.

Results: A new criterion of evaluating UDCA responses at 1 month was established as: ALP ≤ 2.5 × upper limit of normal (ULN) and AST ≤ 2 × ULN, and TBIL ≤ 1 × ULN (Xi'an criterion). The 5 year adverse outcome-free survival rate of UDCA responders, defined by Xi'an criterion, was 97%, which was significantly higher than that of those non-responders (64%). An accurate distinguishing high-risk patients' capacity of Xi'an criterion was confirmed in both early and late-stage PBC.

Conclusions: Xi'an criterion has a similar or even higher ability to distinguish high-risk PBC patients than other published criteria. Xi'an criterion can facilitate early identification of patients requiring new therapeutic approaches.

Keywords: Adverse outcome; Autoimmune liver disease; Biochemical response; Complication; Early prediction; Primary biliary cholangitis; Prognosis; Retrospective cohort study; Stratified therapy; Therapeutics.

Fig. 1

Flow chart of study design

Fig. 2

The dynamic change of the levels of ALP, GGT (a), AST, ALT (b), ALB, RBC (c), TBIL (d), TBA (e) and IgM/G (f) within 1 year in PBC patients. Data are expressed as mean ± SD. *p < .001 versus baseline. ^#p < 0.05 versus baseline

Fig. 3

Time-dependent AUROC values of the Xi’an and other published criteria in entire cohort (a), training cohort (b) and validation cohort (c). AUROC area under receiver operating characteristic curve

Fig. 4

Biochemical response according different criteria in patients with adverse outcomes over time in training cohort (a) and validation cohort (b). PBC patients with an endpoints within 2 years (left), 2–5 years (median), and over 5 years after diagnosis (right)