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

被引：138

作者：

Carbone, Marco ^{[1
,4
]}

Nardi, Alessandra ^{[5
]}

Flack, Steve ^{[1
]}

Carpino, Guido ^{[6
]}

Varvaropoulou, Nikoletta ^{[1
]}

Gavrila, Caius ^{[8
]}

Spicer, Ann ^{[1
]}

Badrock, Jonathan ^{[1
]}

Bernuzzi, Francesca ^{[4
]}

Cardinale, Vincenzo ^{[9
]}

Ainsworth, Holly F. ^{[10
]}

Heneghan, Michael A. ^{[14
]}

Thorburn, Douglas ^{[15
]}

Bathgate, Andrew ^{[16
]}

Jones, Rebecca ^{[17
]}

Neuberger, James M. ^{[18
]}

Battezzati, Pier Maria ^{[19
,20
]}

Zuin, Massimo ^{[19
,20
]}

Taylor-Robinson, Simon ^{[21
]}

Donato, Maria F. ^{[22
]}

Kirby, John ^{[11
]}

Mitchell-Thain, Robert ^{[23
]}

Floreani, Annarosa ^{[24
]}

Sampaziotis, Fotios ^{[2
]}

Muratori, Luigi ^{[25
]}

Alvaro, Domenico ^{[9
]}

Marzioni, Marco ^{[26
]}

Miele, Luca ^{[27
]}

Marra, Fabio ^{[28
]}

Giannini, Edoardo ^{[29
]}

Gaudio, Eugenio ^{[7
]}

Ronca, Vincenzo ^{[19
,20
]}

Bonato, Giulia ^{[4
]}

Cristoferi, Laura ^{[4
]}

Malinverno, Federica ^{[4
]}

Gerussi, Alessio ^{[4
]}

Stocken, Deborah D. ^{[10
]}

Cordell, Heather J. ^{[12
]}

Hirschfield, Gideon M. ^{[30
,31
,32
]}

Alexander, Graeme J. ^{[3
]}

Sandford, Richard N. ^{[1
]}

Jones, David E. ^{[13
]}

Invernizzi, Pietro ^{[4
]}

Mells, George F. ^{[1
]}

机构：

[1] Univ Cambridge, Acad Dept Med Genet, Cambridge, England

[2] Univ Cambridge, Dept Surg, Wellcome Trust Med Res Council, Stem Cell Inst,Anne McLaren Lab, Cambridge, England

[3] Univ Cambridge, Dept Med, Cambridge, England

[4] Univ Milano Bicocca, Div Gastroenterol & Hepatol, Dept Med & Surg, I-20126 Milan, Italy

[5] Univ Roma Tor Vergata, Dept Math, Rome, Italy

[6] Univ Rome Foro Italico, Dept Movement Human & Hlth Sci, Rome, Italy

[7] Sapienza Univ Rome, Dept Anat Histol Legal Med & Orthoped, Rome, Italy

[8] IC Antonio Rosmini, Rome, Italy

[9] Polo Pontino Sapienza Univ Rome, Dept Med Surg Sci & Biotechnol, Rome, Italy

[10] Newcastle Univ, Inst Hlth & Soc, Newcastle Upon Tyne, Tyne & Wear, England

[11] Newcastle Univ, Appl Immunobiol & Transplantat Res Grp, Inst Cellular Med, Fac Med Sci, Newcastle Upon Tyne, Tyne & Wear, England

[12] Newcastle Univ, Inst Genet Med, Newcastle Upon Tyne, Tyne & Wear, England

[13] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England

[14] Kings Coll Hosp NHS Fdn Trust, Inst Liver Studies, London, England

[15] Royal Free London NHS Fdn Trust, Sheila Sherlock Liver Ctr, London, England

[16] Royal Infirm Edinburgh NHS Trust, Scottish Liver Transplant Unit, Edinburgh, Midlothian, Scotland

[17] St James Univ Hosp, Liver Unit, Leeds, W Yorkshire, England

[18] Queen Elizabeth Hosp, Liver Unit, Birmingham, W Midlands, England

[19] Osped San Paolo, Div Internal Med, Milan, Italy

[20] Osped San Paolo, Liver Unit, Milan, Italy

[21] Imperial Coll London, Liver Unit, Div Diabet Endocrinol & Metab, Dept Med, London, England

[22] Univ Milan, CRC Am & Migliavacca Ctr Study Liver Dis, Div Gastroenterol & Hepatol, Fdn IRCCS Ca Granda Osped Maggiore Policlin, Milan, Italy

[23] PBC Fdn, Edinburgh, Midlothian, Scotland

[24] Univ Padua, Dept Surg Oncol & Gastroenterol, Padua, Italy

[25] Policlin St Orsola Malpighi, Liver Unit, Bologna, Italy

[26] Osped Riuniti Univ Hosp, Div Gastroenterol & Hepatol, Ancona, Italy

[27] Gemelli Univ Hosp, Dept Internal Med & Gastroenterol, Rome, Italy

[28] Univ Florence, Dept Clin & Expt Med, Florence, Italy

[29] IRCCS Azienda Osped Univ San Martino IST, Div Gastroenterol, Dept Internal Med, Genoa, Italy

[30] Univ Birmingham, NIHR Birmingham Biomed Res Ctr, Birmingham, W Midlands, England

[31] Univ Hosp Birmingham NHS Fdn Trust, Birmingham, W Midlands, England

[32] Univ Birmingham, Inst Immunol & Immunotherapy, Birmingham, W Midlands, England

来源：

LANCET GASTROENTEROLOGY & HEPATOLOGY | 2018年 / 3卷 / 09期

基金：

英国医学研究理事会;

关键词：

CONTROLLED-TRIAL; CIRRHOSIS; PROGRESSION; PHENOTYPE; URSODIOL; OUTCOMES; CELLS; TREE;

D O I：

10.1016/S2468-1253(18)30163-8

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

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. Copyright (C) 2018 Elsevier Ltd. All rights reserved.

引用

页码：626 / 634

页数：9

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