Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score

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Title: Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score
Authors: Carbone, M
Nardi, A
Flack, S
Carpino, G
Varvaropoulou, N
Gavrila, C
Spicer, A
Badrock, J
Bernuzzi, F
Cardinale, V
Ainsworth, HF
Heneghan, MA
Thorburn, D
Bathgate, A
Jones, R
Neuberger, JM
Battezzati, PM
Zuin, M
Taylor-Robinson, S
Donato, MF
Kirby, J
Mitchell-Thain, R
Floreani, A
Sampaziotis, F
Muratori, L
Alvaro, D
Marzioni, M
Miele, L
Marra, F
Giannini, E
Gaudio, E
Ronca, V
Bonato, G
Cristoferi, L
Malinverno, F
Gerussi, A
Stocken, DD
Cordell, HJ
Hirschfield, GM
Alexander, GJ
Sandford, RN
Jones, DE
Invernizzi, P
Mells, GF
Italian PBC Study Group and the UK–PBC Consortium
Item Type: Journal Article
Abstract: BACKGROUND: Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. METHODS: We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. FINDINGS: 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79-0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=-0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present). INTERPRETATION: We have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis. FUNDING: UK Medical Research Council and University of Milan-Bicocca.
Issue Date: Sep-2018
Date of Acceptance: 3-May-2018
URI: http://hdl.handle.net/10044/1/61299
DOI: https://doi.org/10.1016/S2468-1253(18)30163-8
ISSN: 2468-1253
Publisher: Elsevier
Start Page: 626
End Page: 634
Journal / Book Title: Lancet Gastroenterology and Hepatology
Volume: 3
Issue: 9
Copyright Statement: © 2018 Elsevier Ltd. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: BH124127
Keywords: Science & Technology
Life Sciences & Biomedicine
Gastroenterology & Hepatology
CONTROLLED-TRIAL
CIRRHOSIS
PROGRESSION
PHENOTYPE
URSODIOL
OUTCOMES
CELLS
TREE
Age of Onset
Alkaline Phosphatase
Area Under Curve
Bilirubin
Cholagogues and Choleretics
Decision Support Techniques
Female
Humans
Linear Models
Liver Cirrhosis, Biliary
Male
Middle Aged
ROC Curve
Risk Factors
Time-to-Treatment
Transaminases
Treatment Outcome
Ursodeoxycholic Acid
Italian PBC Study Group and the UK–PBC Consortium
Humans
Liver Cirrhosis, Biliary
Bilirubin
Ursodeoxycholic Acid
Alkaline Phosphatase
Transaminases
Cholagogues and Choleretics
Treatment Outcome
Area Under Curve
Linear Models
Risk Factors
ROC Curve
Age of Onset
Decision Support Techniques
Middle Aged
Female
Male
Time-to-Treatment
Publication Status: Published
Conference Place: Netherlands
Online Publication Date: 2018-07-13
Appears in Collections:Faculty of Medicine



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