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Lancet Gastroenterol Hepatol. 2018 Sep;3(9):626-634. doi: 10.1016/S2468-1253(18)30163-8. Epub 2018 Jul 13.

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

Collaborators (360)

Thomas C, Rahman M, Yapp T, Lye Ch'ng C, Harrison M, Sturgess R, Galaska R, Healey C, Whiteman J, Czaijkowski M, Gray C, Gunasekera A, Gyawli P, Premchand P, Mann S, Elliott K, Kapur K, Watson A, Foster G, Trembling P, Subhani J, Harvey R, McCorry R, Adgey C, Hobson L, Mulvaney-Jones C, Evans R, Mathialahan T, Ramanaden D, Gasem J, Van Duyvenvoorde G, Shorrock C, Seward K, Southern P, Tibble J, Penn R, Gorard D, Maiden J, Damant R, Palegwala A, Jones S, Alexander G, Mells G, Sandford R, Whiteman J, Dolwani S, Prince M, Silvestre V, Foxton M, Dungca E, Mitchison H, Wheatley N, Gooding I, Doyle H, Karmo M, Kent M, Saksena S, Braim D, Patel M, Lord S, Ede R, Paton A, Austin A, Lancaster N, Sayer J, Gibbins A, Hogben K, Hovell C, Fisher N, Carter M, Koss K, Musselwhite J, Muscariu F, Piotreowicz A, McKay A, Grimley C, Neal D, Ting Tan L, Lim G, Brighton J, Foale C, Ala A, Saeed A, Flahive K, Wood G, Townshend P, Ford C, Brown J, Kordula J, Bowles J, Wilkinson M, Palmer C, Ramage J, Gordon H, Featherstone J, Ridpath J, Ngatchu T, Levi S, Shaukat S, Sadeghian J, Shidrawi R, Williams B, Abouda G, Jones S, Duggan C, Hynes A, Narain M, Rees I, Salam I, Crossey M, Taylor-Robinson S, Brown A, MacNicol C, Williams S, Wilhelmsen E, Banim P, Raymode P, Chilton A, Das D, Lee HJ, Curtis H, Heneghan M, Gess M, Durant E, Drake IM, Bishop R, Davies M, Jones R, Aldersley M, Ncube N, McNair A, Srirajaskanthan R, Sen S, Casey R, Bird G, Mendall M, Cowley C, Barnardo A, Kitchen P, Yoong K, Amore K, Sirdefield D, Orpe J, Mathew R, MacFaul G, Wrigth A, Shah A, Evans C, Keggans J, Bird B, Baxter G, Saha S, Pollock K, Hughes M, Bramley P, Grieve E, Young K, Fraser A, Mukhopadhya A, Ocker K, Mills P, Hines F, Shallcross C, Wilkins J, Grellier L, Campbell S, Martin K, Bathgate A, Innes C, Shepherd A, Rushbrook S, Valliani T, Przemioslo R, Fairlamb H, Macdonald C, Eastick A, Metcalf J, Tanqueray E, Shmueli U, Holbrook B, Davis A, Browning J, Naqvi A, Walker K, Lee T, Verheyden J, Slininger S, Ryder SD, Chapman R, Collier J, O'Donnell D, Stafford L, Williamson K, Kent L, Klass H, Ninkovic M, March L, Cramp M, Simpson D, Dickson C, Sharer N, Hayes M, Goggin P, Quinne M, Pearson S, Hoeroldt B, Jones L, Wright A, Booth J, Loftus A, Lipscomb G, Dewhurst H, Gunter E, Williams E, Fouracres A, Farrington L, Graves L, Hussaini H, Stableforth B, Marriott S, Ayres R, Leoni M, Burroughs A, Marshall E, Thorburn D, Tyrer D, Martin K, Lombard M, Patanwala I, Dali-Kemmery L, Lambourne V, Maltby J, Vyas S, Colley J, Shinder B, Singhal S, Jones J, Mills M, Gleeson D, Carnahan M, Butterworth J, Boulton K, Taylor N, George K, Harding T, Tregonning J, Douglass A, Brown C, Clifford G, Panter S, Gocher D, Shearman J, Bray G, Hamilton M, Butcher G, Forton D, Mclindon J, Curtis J, Das D, Shewan T, Cowan M, Whatley G, Nasseri M, Grover B, Sivaramakrishnan N, Ducker S, Houghton K, Jones D, Griffiths L, Tripoli S, Pitcher M, Shpuza E, White N, Ghosh D, Douds A, Green M, Brookes M, Cumlat L, Wong VS, Warner K, Netherton K, Mandal A, Jain S, Gupta H, Sanghi P, Pereira S, Neuberger J, Gunson B, Hirschfield G, Lim RT, Gallagher S, Clement D, Brind A, Watts G, Mupudzi M, Wright M, Gitahi J, Gordon F, Gocher D, Unitt E, Pateman H, Batham S, Delahooke T, Grant A, Conder J, Higham A, Cox M, O'Donohoe L, Currie L, King A, Oblak M, Collins C, Whalley S, Quinn M, Baird Y, Amey I, Fraser J, Li A, Cotterill D, Bell A, Watson A, Singhal A, Gee I, Greer S, Ang Y, Ransford R, Allison J, Gotto J, Dyer S, Sweeting H, Millson C, Invernizzi P, Carbone M, Cristoferi L, Bonato G, Malinverno F, Bernuzzi F, Alvaro D, Labbadia G, Bragazzi MC, Andreone P, Muratori L, Azzaroli F, Floreani A, Galli A, Tarocchi M, Giannini E, Miele L, Gasbarrini A, Grieco A, Marrone G, Donato MF, Valenti L, Marra F, Marzioni M, Maroni L, Rigamonti C, Zuin M, Battezzati PM, Picciotto A.

Author information

1
Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK; Division of Gastroenterology and Hepatology, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy. Electronic address: marco.carbone@unimib.it.
2
Department of Mathematics, University of Rome Tor Vergata, Rome, Italy.
3
Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.
4
Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy.
5
IC Antonio Rosmini, Rome, Italy.
6
Division of Gastroenterology and Hepatology, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy.
7
Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza University of Rome, Rome, Italy.
8
Institute of Health & Society, Newcastle University, Newcastle-upon-Tyne, UK.
9
Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK.
10
Sheila Sherlock Liver Centre, The Royal Free London NHS Foundation Trust, London, UK.
11
Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK.
12
Liver Unit, St James's University Hospital, Leeds, UK.
13
Liver Unit, Queen Elizabeth Hospital, Birmingham, UK.
14
Division of Internal Medicine and Liver Unit, Ospedale San Paolo, Milan, Italy.
15
Liver Unit, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UK.
16
CRC "AM e A Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
17
Applied Immunobiology and Transplantation Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle-upon-Tyne, UK.
18
PBC Foundation, Edinburgh, UK.
19
Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy.
20
Department of Surgery, Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory, University of Cambridge, Cambridge, UK.
21
Liver Unit, Policlinico di Sant'Orsola-Malpighi, Bologna, Italy.
22
Division of Gastroenterology and Hepatology, Ospedali Riuniti University Hospital, Ancona, Italy.
23
Department of Internal Medicine and Gastroenterology, Gemelli University Hospital, Rome, Italy.
24
Department of Clinical and Experimental Medicine, University of Florence, Florence, Italy.
25
Division of Gastroenterology, Department of Internal Medicine, IRCCS-Azienda Ospedaliera Universitaria San Martino-IST, Genoa, Italy.
26
Department of Anatomy, Histology, Legal Medicine, and Orthopedics, Sapienza University of Rome, Rome, Italy.
27
Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
28
NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK; University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
29
Department of Medicine, University of Cambridge, Cambridge, UK.
30
Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.

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.

PMID:
30017646
DOI:
10.1016/S2468-1253(18)30163-8
[Indexed for MEDLINE]
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