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

Carbone, M.; Nardi, A.; Flack, S.; Carpino, G.; Varvaropoulou, N.; Gavrila, C.; Spicer, A.; Badrock, J.; Bernuzzi, F.; Cardinale, V.; Holly, F.A.; Michael, A.H.; Thorburn, D.; Bathgate, A.; Jones, R.; James, M.N.; Battezzati, P.M.; Zuin, M.; Taylor-Robinson, S.; Donato, M.F.; 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.; Deborah, D.S.; Heather, J.C.; Gideon, M.H.; Graeme, J.A.; Richard, N.S.; David, E.J.; Invernizzi, P.; George, F.M.; Thomas, C.; Rahman, M.; Yapp, T.; Chin Lye Ch'ng,; 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.; Greta Van Duyvenvoorde,; 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.; Lai Ting Tan,; 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, H.; Curtis, H.; Heneghan, M.; Gess, M.; Durant, E.; Drake, I.; 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, S.D.; 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.; Voi Shim Wong,; Warner, K.; Netherton, K.; Mandal, A.; Jain, S.; Gupta, H.; Sanghi, P.; Pereira, S.; Neuberger, J.; Gunson, B.; Hirschfield, G.; Reina Teegan Lim,; 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.; Andy, L.; 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.; Maria Consiglia Bragazzi,; Andreone, P.; Muratori, L.; Azzaroli, F.; Floreani, A.; Galli, A.; Tarocchi, M.; Giannini, E.; Miele, L.; Gasbarrini, A.; Grieco, A.; Marrone, G.; Maria Francesca Donato,; Valenti, L.; Marra, F.; Marzioni, M.; Maroni, L.; Rigamonti, C.; Zuin, M.; Pier Maria Battezzati,; Picciotto, A.

doi:10.1016/S2468-1253(18)30163-8

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 1Â·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<0Â·0001), higher total bilirubin concentration (p=0Â·0003), lower aminotransferase concentration (p=0Â·0012), younger age (p<0Â·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0Â·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0Â·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 0Â·83 (95% CI 0Â·79â€“0Â·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=â€“0Â·556, p=0Â·0130) and intermediate hepatocytes (probability of response was 0Â·90 if intermediate hepatocytes were absent vs 0Â·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.

Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score / M. Carbone, A. Nardi, S. Flack, G. Carpino, N. Varvaropoulou, C. Gavrila, A. Spicer, J. Badrock, F. Bernuzzi, V. Cardinale, H. F Ainsworth, M. A Heneghan, D. Thorburn, A. Bathgate, R. Jones, J. M Neuberger, P.M. Battezzati, M. Zuin, S. Taylor-Robinson, M.F. Donato, J. Kirby, R. Mitchell-Thain, A. Floreani, F. Sampaziotis, L. Muratori, D. Alvaro, M. Marzioni, L. Miele, F. Marra, E. Giannini, E. Gaudio, V. Ronca, G. Bonato, L. Cristoferi, F. Malinverno, A. Gerussi, D. D Stocken, H. J Cordell, G. M Hirschfield, G. J Alexander, R. N Sandford, D. E Jones, P. Invernizzi, G. F Mells, C. Thomas, M. Rahman, T. Yapp, C. Lye Ch'ng, M. Harrison, R. Sturgess, R. Galaska, C. Healey, J. Whiteman, M. Czaijkowski, C. Gray, A. Gunasekera, P. Gyawli, P. Premchand, S. Mann, K. Elliott, K. Kapur, A. Watson, G. Foster, P. Trembling, J. Subhani, R. Harvey, R. Mccorry, C. Adgey, L. Hobson, C. Mulvaney-Jones, R. Evans, T. Mathialahan, D. Ramanaden, J. Gasem, G. Van Duyvenvoorde, C. Shorrock, K. Seward, P. Southern, J. Tibble, R. Penn, D. Gorard, J. Maiden, R. Damant, A. Palegwala, S. Jones, G. Alexander, G. Mells, R. Sandford, J. Whiteman, S. Dolwani, M. Prince, V. Silvestre, M. Foxton, E. Dungca, H. Mitchison, N. Wheatley, I. Gooding, H. Doyle, M. Karmo, M. Kent, S. Saksena, D. Braim, M. Patel, S. Lord, R. Ede, A. Paton, A. Austin, N. Lancaster, J. Sayer, A. Gibbins, K. Hogben, C. Hovell, N. Fisher, M. Carter, K. Koss, J. Musselwhite, F. Muscariu, A. Piotreowicz, A. Mckay, C. Grimley, D. Neal, L. Ting Tan, G. Lim, J. Brighton, C. Foale, A. Ala, A. Saeed, K. Flahive, G. Wood, P. Townshend, C. Ford, J. Brown, J. Kordula, J. Bowles, M. Wilkinson, C. Palmer, J. Ramage, H. Gordon, J. Featherstone, J. Ridpath, T. Ngatchu, S. Levi, S. Shaukat, J. Sadeghian, R. Shidrawi, B. Williams, G. Abouda, S. Jones, C. Duggan, A. Hynes, M. Narain, I. Rees, I. Salam, M. Crossey, S. Taylor-Robinson, A. Brown, C. Macnicol, S. Williams, E. Wilhelmsen, P. Banim, P. Raymode, A. Chilton, D. Das, H. Lee, H. Curtis, M. Heneghan, M. Gess, E. Durant, I. Drake, R. Bishop, M. Davies, R. Jones, M. Aldersley, N. Ncube, A. Mcnair, R. Srirajaskanthan, S. Sen, R. Casey, G. Bird, M. Mendall, C. Cowley, A. Barnardo, P. Kitchen, K. Yoong, K. Amore, D. Sirdefield, J. Orpe, R. Mathew, G. Macfaul, A. Wrigth, A. Shah, C. Evans, J. Keggans, B. Bird, G. Baxter, S. Saha, K. Pollock, M. Hughes, P. Bramley, E. Grieve, K. Young, A. Fraser, A. Mukhopadhya, K. Ocker, P. Mills, F. Hines, C. Shallcross, J. Wilkins, L. Grellier, S. Campbell, K. Martin, A. Bathgate, C. Innes, A. Shepherd, S. Rushbrook, T. Valliani, R. Przemioslo, H. Fairlamb, C. Macdonald, A. Eastick, J. Metcalf, E. Tanqueray, U. Shmueli, B. Holbrook, A. Davis, J. Browning, A. Naqvi, K. Walker, T. Lee, J. Verheyden, S. Slininger, S.D. Ryder, R. Chapman, J. Collier, D. O'Donnell, L. Stafford, K. Williamson, L. Kent, H. Klass, M. Ninkovic, L. March, M. Cramp, D. Simpson, C. Dickson, N. Sharer, M. Hayes, P. Goggin, M. Quinne, S. Pearson, B. Hoeroldt, L. Jones, A. Wright, J. Booth, A. Loftus, G. Lipscomb, H. Dewhurst, E. Gunter, E. Williams, A. Fouracres, L. Farrington, L. Graves, H. Hussaini, B. Stableforth, S. Marriott, R. Ayres, M. Leoni, A. Burroughs, E. Marshall, D. Thorburn, D. Tyrer, K. Martin, M. Lombard, I. Patanwala, L. Dali-Kemmery, V. Lambourne, J. Maltby, S. Vyas, J. Colley, B. Shinder, S. Singhal, J. Jones, M. Mills, D. Gleeson, M. Carnahan, J. Butterworth, K. Boulton, N. Taylor, K. George, T. Harding, J. Tregonning, A. Douglass, C. Brown, G. Clifford, S. Panter, D. Gocher, J. Shearman, G. Bray, M. Hamilton, G. Butcher, D. Forton, J. Mclindon, J. Curtis, D. Das, T. Shewan, M. Cowan, G. Whatley, M. Nasseri, B. Grover, N. Sivaramakrishnan, S. Ducker, K. Houghton, D. Jones, L. Griffiths, S. Tripoli, M. Pitcher, E. Shpuza, N. White, D. Ghosh, A. Douds, M. Green, M. Brookes, L. Cumlat, V. Shim Wong, K. Warner, K. Netherton, A. Mandal, S. Jain, H. Gupta, P. Sanghi, S. Pereira, J. Neuberger, B. Gunson, G. Hirschfield, R. Teegan Lim, S. Gallagher, D. Clement, A. Brind, G. Watts, M. Mupudzi, M. Wright, J. Gitahi, F. Gordon, D. Gocher, E. Unitt, H. Pateman, S. Batham, T. Delahooke, A. Grant, J. Conder, A. Higham, M. Cox, L. O'Donohoe, L. Currie, A. King, M. Oblak, C. Collins, S. Whalley, M. Quinn, Y. Baird, I. Amey, J. Fraser, A. Li, D. Cotterill, A. Bell, A. Watson, A. Singhal, I. Gee, S. Greer, Y. Ang, R. Ransford, J. Allison, J. Gotto, S. Dyer, H. Sweeting, C. Millson, P. Invernizzi, M. Carbone, L. Cristoferi, G. Bonato, F. Malinverno, F. Bernuzzi, D. Alvaro, G. Labbadia, M. Consiglia Bragazzi, P. Andreone, L. Muratori, F. Azzaroli, A. Floreani, A. Galli, M. Tarocchi, E. Giannini, L. Miele, A. Gasbarrini, A. Grieco, G. Marrone, M. Francesca Donato, L.V.C. Valenti, F. Marra, M. Marzioni, L. Maroni, C. Rigamonti, M. Zuin, P. Maria Battezzati, A. Picciotto. - In: THE LANCET. GASTROENTEROLOGY & HEPATOLOGY. - ISSN 2468-1253. - 3:9(2018 Sep), pp. 626-634. [10.1016/S2468-1253(18)30163-8]

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

Alessandra Nardi;Steve Flack;Guido Carpino;Nikoletta Varvaropoulou;Caius Gavrila;Ann Spicer;Jonathan Badrock;F. Bernuzzi;Vincenzo Cardinale;Holly F Ainsworth;Michael A Heneghan;Douglas Thorburn;Andrew Bathgate;Rebecca Jones;James M Neuberger;P.M. Battezzati;M. Zuin;Simon Taylor-Robinson;Maria F. Donato;John Kirby;Robert Mitchell-Thain;Annarosa Floreani;Fotios Sampaziotis;Luigi Muratori;Domenico Alvaro;Marco Marzioni;Luca Miele;Fabio Marra;Edoardo Giannini;Eugenio Gaudio;V. Ronca;G. Bonato;L. Cristoferi;F. Malinverno;Alessio Gerussi;Deborah D Stocken;Heather J Cordell;Gideon M Hirschfield;Graeme J Alexander;Richard N Sandford;David E Jones;P. Invernizzi;George F Mells^Ultimo;Caradog Thomas;Meshbah Rahman;Tom Yapp;Chin Lye Ch'ng;Melanie Harrison;Richard Sturgess;Roman Galaska;Chris Healey;Jessica Whiteman;Marek Czaijkowski;Catherine Gray;Anton Gunasekera;Pranab Gyawli;Purushothaman Premchand;Steven Mann;Keith Elliott;Kapil Kapur;Alan Watson;Graham Foster;Paul Trembling;Javaid Subhani;Rory Harvey;Roger McCorry;Carolyn Adgey;Lucie Hobson;Caroline Mulvaney-Jones;Richard Evans;Thiriloganathan Mathialahan;David Ramanaden;Jaber Gasem;Greta Van Duyvenvoorde;Christopher Shorrock;Katie Seward;Paul Southern;Jeremy Tibble;Ruth Penn;David Gorard;Jane Maiden;Rose Damant;Altaf Palegwala;Susan Jones;Graeme Alexander;George Mells;Richard Sandford;Jessica Whiteman;Sunil Dolwani;Martin Prince;Valeria Silvestre;Matthew Foxton;Eleanor Dungca;Harriet Mitchison;Natalie Wheatley;Ian Gooding;Helen Doyle;Mazn Karmo;Melanie Kent;Sushma Saksena;Delyth Braim;Minesh Patel;Susan Lord;Roland Ede;Alison Paton;Andrew Austin;Nicola Lancaster;Joanna Sayer;Andrew Gibbins;Karen Hogben;Chris Hovell;Neil Fisher;Martyn Carter;Konrad Koss;Janine Musselwhite;Florin Muscariu;Andrzej Piotreowicz;Alexandra McKay;Charles Grimley;David Neal;Lai Ting Tan;Guan Lim;Jacqueline Brighton;Carole Foale;Aftab Ala;Athar Saeed;Kerry Flahive;Gordon Wood;Paula Townshend;Chris Ford;Jonathan Brown;Jean Kordula;Jane Bowles;Mark Wilkinson;Caroline Palmer;John Ramage;Harriet Gordon;James Featherstone;Jo Ridpath;Theodore Ngatchu;Sass Levi;Syed Shaukat;Joy Sadeghian;Ray Shidrawi;Bronwen Williams;George Abouda;Sarah Jones;Claire Duggan;Abigail Hynes;Mark Narain;Ian Rees;Imroz Salam;Mary Crossey;Simon Taylor-Robinson;Ashley Brown;Carolyn MacNicol;Simon Williams;Elva Wilhelmsen;Paul Banim;Parizade Raymode;Andrew Chilton;Debasish Das;Hye-Jeong Lee;Howard Curtis;Michael Heneghan;Markus Gess;Emma Durant;IM Drake;Rebecca Bishop;Mervyn Davies;Rebecca Jones;Mark Aldersley;Noma Ncube;Alistair McNair;Raj Srirajaskanthan;Sambit Sen;Rebecca Casey;George Bird;Mike Mendall;Caroline Cowley;Adrian Barnardo;Paul Kitchen;Kevin Yoong;Kelly Amore;Dawn Sirdefield;Jacky Orpe;Ray Mathew;George MacFaul;Aruna Wrigth;Amir Shah;Chris Evans;Janie Keggans;Bridget Bird;Gwen Baxter;Subrata Saha;Katharine Pollock;Maggie Hughes;Peter Bramley;Emma Grieve;Karin Young;Andrew Fraser;Ashis Mukhopadhya;Kate Ocker;Peter Mills;Francis Hines;Chris Shallcross;Joy Wilkins;Leonie Grellier;Stewart Campbell;Kirsty Martin;Andrew Bathgate;Caron Innes;Alan Shepherd;Simon Rushbrook;Talal Valliani;Robert Przemioslo;Helen Fairlamb;Chris Macdonald;Anne Eastick;Jane Metcalf;Elizabeth Tanqueray;Udi Shmueli;Becky Holbrook;Andrew Davis;Julie Browning;Asifabbas Naqvi;Kirsten Walker;Tom Lee;Juliette Verheyden;Susan Slininger;Stephen D. Ryder;Roger Chapman;Jane Collier;Denise O'Donnell;Lizzie Stafford;Kate Williamson;Linda Kent;Howard Klass;Mary Ninkovic;Linda March;Matthew Cramp;Diane Simpson;Christine Dickson;Nicholas Sharer;Maria Hayes;Patrick Goggin;Mary Quinne;Sallyanne Pearson;Barbara Hoeroldt;Linda Jones;Alice Wright;Jonathan Booth;Alison Loftus;George Lipscomb;Hannah Dewhurst;Emma Gunter;Earl Williams;Anna Fouracres;Liz Farrington;Lyn Graves;Hyder Hussaini;Bill Stableforth;Suzie Marriott;Reuben Ayres;Marina Leoni;Andrew Burroughs;Eileen Marshall;Douglas Thorburn;David Tyrer;Kate Martin;Martin Lombard;Imran Patanwala;Lola Dali-Kemmery;Victoria Lambourne;Julia Maltby;Samir Vyas;Julie Colley;Bal Shinder;Saket Singhal;Jayne Jones;Marisa Mills;Dermot Gleeson;Mandy Carnahan;Jeff Butterworth;Kerenza Boulton;Natalie Taylor;Keith George;Tim Harding;Julie Tregonning;Andrew Douglass;Carly Brown;Gayle Clifford;Simon Panter;Denise Gocher;Jeremy Shearman;Gary Bray;Maria Hamilton;Graham Butcher;Daniel Forton;John Mclindon;Janette Curtis;Debashis Das;Tracey Shewan;Matthew Cowan;Gregory Whatley;Mariam Nasseri;Bob Grover;Nurani Sivaramakrishnan;Samantha Ducker;Kathryn Houghton;David Jones;Laura Griffiths;Sherill Tripoli;Maxton Pitcher;Ervin Shpuza;Nikki White;Deb Ghosh;Andrew Douds;Marie Green;Matthew Brookes;Lourdes Cumlat;Voi Shim Wong;Karen Warner;Kimberley Netherton;Adtya Mandal;Snjiv Jain;Hemant Gupta;Pradeep Sanghi;Steve Pereira;James Neuberger;Bridget Gunson;Gideon Hirschfield;Reina Teegan Lim;Susan Gallagher;Darren Clement;Alison Brind;Gill Watts;Mcdonald Mupudzi;Mark Wright;Jane Gitahi;Fiona Gordon;Denis Gocher;Esther Unitt;Hilary Pateman;Sally Batham;Toby Delahooke;Allister Grant;Jill Conder;Andrew Higham;Mark Cox;Lynn O'Donohoe;Lynn Currie;Alistair King;Metod Oblak;Carole Collins;Simon Whalley;Marie Quinn;Yolanda Baird;Isobel Amey;Jocelyn Fraser;Andy Li;Donna Cotterill;Andrew Bell;Alan Watson;Amit Singhal;Ian Gee;Sandra Greer;Yeng Ang;Rupert Ransford;Joanna Allison;James Gotto;Simon Dyer;Helen Sweeting;Charles Millson;Pietro Invernizzi;Marco Carbone;Laura Cristoferi;Giulia Bonato;Federica Malinverno;Francesca Bernuzzi;Domenico Alvaro;Giancarlo Labbadia;Maria Consiglia Bragazzi;Pietro Andreone;Luigi Muratori;Francesco Azzaroli;Annarosa Floreani;Andrea Galli;Mirko Tarocchi;Edoardo Giannini;Luca Miele;Antonio Gasbarrini;A. Grieco;Giuseppe Marrone;Maria Francesca Donato;L.V.C. Valenti;Fabio Marra;Marco Marzioni;Luca Maroni;Cristina Rigamonti;Massimo Zuin;Pier Maria Battezzati;Antonino Picciotto

2018

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 1Â·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<0Â·0001), higher total bilirubin concentration (p=0Â·0003), lower aminotransferase concentration (p=0Â·0012), younger age (p<0Â·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0Â·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0Â·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 0Â·83 (95% CI 0Â·79â€“0Â·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=â€“0Â·556, p=0Â·0130) and intermediate hepatocytes (probability of response was 0Â·90 if intermediate hepatocytes were absent vs 0Â·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.

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				Settore MED/12 - Gastroenterologia
Settore MED/09 - Medicina Interna
			
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				set-2018
			
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				12-lug-2018
			
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				THE LANCET. GASTROENTEROLOGY & HEPATOLOGY
			
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				https://dx.doi.org/10.1016/S2468-1253(18)30163-8
			
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