Systematic review of response criteria and endpoints in autoimmune hepatitis by the International Autoimmune Hepatitis Group
Simon Pape, Romée J.A.L.M. Snijders, Tom J.G. Gevers, Oliver Chazouilleres, George Ν. Dalekos, Gideon M. Hirschfield, Marco Lenzi, Michael Trauner, Michael P. Manns, John M. Vierling, Aldo J. Montaño‐Loza, Ansgar W. Lohse, Christoph Schramm, Joost P.H. Drenth, Michael A. Heneghan, Piero Luigi Almasio, Fernando Álvarez, Raúl J. Andrade, Çiğdem Arıkan, David N. Assis, Edouard Bardou‐Jacquet, Maaike Biewenga, Eduardo Luiz Rachid Cançado, Nora Cazzagon, Olivier Chazouillères, Guido Colloredo, Miriam Cuarterolo, George Ν. Dalekos, Dominique Debray, Mercedes Robles‐Díaz, Joost P.H. Drenth, Jessica Dyson, Cumali Efe, Bastian Engel, S. Ferri, R Fontana, Nikolaos Gatselis, Alessio Gerussi, Emina Halilbasic, Neil Halliday, Michael A. Heneghan, Gideon M. Hirschfield, Bart van Hoek, Marianne Hørby Jørgensen, G. Indolfini, Raffaele Iorio, Soo Jeong, D. Jones, Déirdre Kelly, Nanda Kerkar, Florence Lacaille, Craig Lammert, B. Leggett, Marco Lenzi, C Levy, Rodrigo Liberal, Ana Lleò, Ansgar W. Lohse, Susana López, Eléonora De Martin, Valérie A. McLin, Giorgina Mieli‐Vergani, Piotr Milkiewicz, Nitesh Mohan, Luigi Muratori, Gabriella Nebbia, C. van Nieuwkerk, Ye Htun Oo, Alberto Ortega, Albert Parés, Tudor Lucian Pop, Daniel S. Pratt, Tuğrul Pürnak, Giusy Ranucci, Simon Rushbrook, Christoph Schramm, Albert Friedrich Stättermayer, Mark G. Swain, Atsushi Tanaka, Richard Taubert, Débora Raquel Benedita Terrabuio, B. Terziroli, Michael Trauner, Pamela L. Valentino, F. van den Brand, A. Villamil, Staffan Wåhlin, Henriette Ytting, Kalliopi Zachou, Mikio Zeniya
Abstract
•Consensus among experts on response criteria in autoimmune hepatitis is lacking.•A consensus on endpoints is required to set a standard for reporting study results.•Herein, the IAIHG presents a statement on 5 agreed response criteria and endpoints. Background & AimsAutoimmune hepatitis (AIH) has been well characterised and codified through the development of diagnostic criteria. These criteria have been adapted and simplified and are widely used in clinical practice. However, there is a need to update and precisely define the criteria for both treatment response and treatment.MethodsA systematic review was performed and a modified Delphi consensus process was used to identify and redefine the response criteria in autoimmune hepatitis.ResultsThe consensus process initiated by the International Autoimmune Hepatitis Group proposes that the term ‘complete biochemical response’ defined as ‘normalization of serum transaminases and IgG below the upper limit of normal’ be adopted to include a time point at 6 months after initiation of treatment. An insufficient response by 6 months was a failure to meet the above definition. Non-response was defined as ‘<50% decrease of serum transaminases within 4 weeks after initiation of treatment’. Remission is defined as liver histology with a Hepatitis Activity Index <4/18. Intolerance to treatment was agreed to stand for ‘any adverse event possibly related to treatment leading to potential drug discontinuation’.ConclusionsThese definitions provide a simple and reproducible framework to define treatment response and non-response, irrespective of the therapeutic intervention. A consensus on endpoints is urgently required to set a global standard for the reporting of study results and to enable inter-study comparisons. Future prospective database studies are needed to validate these endpoints.Lay summaryConsensus among international experts on response criteria and endpoints in autoimmune hepatitis is lacking. A consensus on endpoints is urgently required to set a global standard for the reporting of study results and to enable the comparison of results between clinical trials. Therefore, the International Autoimmune Hepatitis Group (IAIHG) herein presents a statement on 5 agreed response criteria and endpoints: complete biochemical response, insufficient response, non-response, remission, and intolerance to treatment, which can be used to guide future reporting. Autoimmune hepatitis (AIH) has been well characterised and codified through the development of diagnostic criteria. These criteria have been adapted and simplified and are widely used in clinical practice. However, there is a need to update and precisely define the criteria for both treatment response and treatment. A systematic review was performed and a modified Delphi consensus process was used to identify and redefine the response criteria in autoimmune hepatitis. The consensus process initiated by the International Autoimmune Hepatitis Group proposes that the term ‘complete biochemical response’ defined as ‘normalization of serum transaminases and IgG below the upper limit of normal’ be adopted to include a time point at 6 months after initiation of treatment. An insufficient response by 6 months was a failure to meet the above definition. Non-response was defined as ‘<50% decrease of serum transaminases within 4 weeks after initiation of treatment’. Remission is defined as liver histology with a Hepatitis Activity Index <4/18. Intolerance to treatment was agreed to stand for ‘any adverse event possibly related to treatment leading to potential drug discontinuation’. These definitions provide a simple and reproducible framework to define treatment response and non-response, irrespective of the therapeutic intervention. A consensus on endpoints is urgently required to set a global standard for the reporting of study results and to enable inter-study comparisons. Future prospective database studies are needed to validate these endpoints.