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

Carbone, Marco and Nardi, Alessandra and Flack, Steve and Carpino, Guido and Varvaropoulou, Nikoletta and Gavrila, Caius and Spicer, Ann and Badrock, Jonathan and Bernuzzi, Francesca and Cardinale, Vincenzo and Ainsworth, Holly F and Heneghan, Michael A and Thorburn, Douglas and Bathgate, Andrew and Jones, Rebecca and Neuberger, James M and Battezzati, Pier Maria and Zuin, Massimo and Taylor-Robinson, Simon and Donato, Maria F and Kirby, John and Mitchell-Thain, Robert and Floreani, Annarosa and Sampaziotis, Fotios and Muratori, Luigi and Alvaro, Domenico and Marzioni, Marco and Miele, Luca and Marra, Fabio and Giannini, Edoardo and Gaudio, Eugenio and Ronca, Vincenzo and Bonato, Giulia and Cristoferi, Laura and Malinverno, Federica and Gerussi, Alessio and Stocken, Deborah D and Cordell, Heather J and Hirschfield, Gideon M and Alexander, Graeme J and Sandford, Richard N and Jones, David E and Invernizzi, Pietro and Mells, George F (2018) Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score. The lancet. Gastroenterology & hepatology, 3 (9). pp. 626-634. ISSN 2468-1253.

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Official URL: https://www.thelancet.com/journals/langas/issue/vo...

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.

Item Type: Article
Subjects: WI Digestive system. Gastroenterology
Divisions: Planned IP Care > Gastroentrology
Related URLs:
Depositing User: Beth Connors
Date Deposited: 21 Mar 2019 12:23
Last Modified: 21 Mar 2019 12:23
URI: http://www.repository.heartofengland.nhs.uk/id/eprint/1959

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