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1. Lack of complete biochemical response in autoimmune hepatitis leads to adverse outcome: First report of the IAIHG retrospective registry

Author

Slooter, C.D., Brand, F.F. van den, Lleo, A., Colapietro, F., Lenzi, M., Muratori, P., Kerkar, N., Dalekos, G.N., Zachou, K., Lucena, M.I., Robles-Díaz, M., Zeo-Sánchez, D.E. Di, Andrade, R.J., Montano-Loza, A.J., Lytvyak, E., Lissenberg-Witte, Birgit I., Maisonneuve, P., Bouma, G., Macedo, G., Drenth, J.P.H., Liberal, R., Boer, Y.S. de, Slooter, C.D., Brand, F.F. van den, Lleo, A., Colapietro, F., Lenzi, M., Muratori, P., Kerkar, N., Dalekos, G.N., Zachou, K., Lucena, M.I., Robles-Díaz, M., Zeo-Sánchez, D.E. Di, Andrade, R.J., Montano-Loza, A.J., Lytvyak, E., Lissenberg-Witte, Birgit I., Maisonneuve, P., Bouma, G., Macedo, G., Drenth, J.P.H., Liberal, R., and Boer, Y.S. de

Abstract

Contains fulltext : 305452.pdf (Publisher’s version ) (Closed access), BACKGROUND AND AIMS: The International Autoimmune Hepatitis Group retrospective registry (IAIHG-RR) is a web-based platform with subjects enrolled with a clinical diagnosis of autoimmune hepatitis (AIH). As prognostic factor studies with enough power are scarce, this study aimed to ascertain data quality and identify prognostic factors in the IAIHG-RR cohort. METHODS: This retrospective, observational, multicenter study included all patients with a clinical diagnosis of AIH from the IAIHG-RR. The quality assessment consisted of external validation of completeness and consistency for 29 predefined variables. Cox regression was used to identify risk factors for liver-related death and liver transplantation (LT). RESULTS: This analysis included 2559 patients across 7 countries. In 1700 patients, follow-up was available, with a completeness of individual data of 90% (range: 30-100). During a median follow-up period of 10 (range: 0-49) years, there were 229 deaths, of which 116 were liver-related, and 143 patients underwent LT. Non-White ethnicity (HR 4.1 95% CI: 2.3-7.1), cirrhosis (HR 3.5 95% CI: 2.3-5.5), variant syndrome with primary sclerosing cholangitis (PSC) (HR 3.1 95% CI: 1.6-6.2), and lack of complete biochemical response within 6 months (HR 5.7 95% CI: 3.4-9.6) were independent prognostic factors. CONCLUSIONS: The IAIHG-RR represents the world's largest AIH cohort with moderate-to-good data quality and a relevant number of liver-related events. The registry is a suitable platform for patient selection in future studies. Lack of complete biochemical response to treatment, non-White ethnicity, cirrhosis, and PSC-AIH were associated with liver-related death and LT.

Published
2024

2. Incidence and predictors of hepatocellular carcinoma in autoimmune hepatitis: A multicenter international study

Author

Colapietro, F., primary, Maisonneuve, P., additional, Lytvyak, E., additional, Beuers, U., additional, Verdonk, R., additional, van der Meer, A., additional, van Hoek, B., additional, Kuiken, S.J., additional, Brouwer, H., additional, van der Wouden, E.J., additional, Muratori, P., additional, Aghemo, A., additional, van den Berg, A., additional, Dalekos, G. N, additional, Robles, M., additional, Andrade, R.J., additional, Montano-Loza, A.J., additional, van den Brand, F.F., additional, Slooter, C.D., additional, Macedo, G., additional, Liberal, R., additional, de Boer, Y., additional, and Lleo, A., additional

Published
2023
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3. Risk factors and outcomes associated with recurrent autoimmune hepatitis following liver transplantation

Author

Montano-Loza, A.J., Ronca, V., Ebadi, M., Hansen, B.E., Hirschfield, G., Elwir, S., Alsaed, M., Milkiewicz, P., Janik, M.K., Marschall, H.U., Burza, M.A., Efe, C., Caliskan, A.R., Harputluoglu, M., Kabacam, G., Terrabuio, D., Onofrio, F.D., Selzner, N., Bonder, A., Pares, A., Llovet, L., Akyildiz, M., Arikan, C., Manns, M.P., Taubert, R., Weber, A.L., Schiano, T.D., Haydel, B., Czubkowski, P., Socha, P., Oldak, N., Akamatsu, N., Tanaka, A., Levy, C., Martin, E.F., Goel, A., Sedki, M., Jankowska, I., Ikegami, T., Rodriguez, M., Sterneck, M., Weiler-Normann, C., Schramm, C., Donato, M.F., Lohse, A., Andrade, R.J., Patwardhan, V.R., Hoek, B. van, Biewenga, M., Kremer, A.E., Ueda, Y., Deneau, M., Pedersen, M., Mayo, M.J., Floreani, A., Burra, P., Secchi, M.F., Beretta-Piccoli, B.T., Sciveres, M., Maggiore, G., Jafri, S.M., Debray, D., Girard, M., Lacaille, F., Lytvyak, E., Mason, A.L., Heneghan, M., Oo, Y.H., and Int Autoimmune Hepatitis Grp IAIHG

Subjects
Adult, Male, Hepatology, liver transplantation, recurrent disease, autoimmune liver disease, graft survival, Mycophenolic Acid, survival, Hepatitis, Autoimmune, Recurrence, Risk Factors, Immunoglobulin G, Humans, Female, Immunosuppressive Agents
Abstract

Background & Aims: Autoimmune hepatitis can recur after liver transplantation (LT), though the impact of recurrence on patient and graft survival has not been well characterized. We evaluated a large, international, multicenter cohort to identify the probability and risk factors associated with recurrent AIH and the association between recurrent disease and patient and graft survival.Methods: We included 736 patients (77% female, mean age 42 +/- 1 years) with AIH who underwent LT from January 1987 through June 2020, among 33 centers in North America, South America, Europe and Asia. Clinical data before and after LT, biochemical data within the first 12 months after LT, and immunosuppression after LT were analyzed to identify patients at higher risk of AIH recurrence based on histological diagnosis.Results: AIH recurred in 20% of patients after 5 years and 31% after 10 years. Age at LT

Published
2022

4. Systematic review of response criteria and endpoints in autoimmune hepatitis by the International Autoimmune Hepatitis Group

Author

Pape, S., Snijders, R.J.A.L.M., Gevers, T.J.G., Chazouilleres, O., Dalekos, G.N., Hirschfield, G.M., Lenzi, M., Trauner, M., Manns, M.P., Vierling, J.M., Montano-Loza, A.J., Lohse, A.W., Schramm, C., Drenth, J.P.H., Heneghan, M.A., Pape, S., Snijders, R.J.A.L.M., Gevers, T.J.G., Chazouilleres, O., Dalekos, G.N., Hirschfield, G.M., Lenzi, M., Trauner, M., Manns, M.P., Vierling, J.M., Montano-Loza, A.J., Lohse, A.W., Schramm, C., Drenth, J.P.H., and Heneghan, M.A.

Abstract

Item does not contain fulltext, BACKGROUND & AIMS: 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. METHODS: A systematic review was performed and a modified Delphi consensus process was used to identify and redefine the response criteria in autoimmune hepatitis. RESULTS: 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'. CONCLUSIONS: 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. LAY SUMMARY: Consensus 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 statemen

Published
2022

5. Effects of immunosuppressive drugs on COVID-19 severity in patients with autoimmune hepatitis

Author

Efe, C., Lammert, C., Taşçılar, K., Dhanasekaran, R., Ebik, B., Higuera-de la Tijera, F., Calışkan, A.R., Peralta, M., Gerussi, A., Massoumi, H., Catana, A.M., Purnak, T., Rigamonti, C., Aldana, A.J. Gomez, Khakoo, N., Nazal, L., Frager, S., Demir, N., Irak, K., Melekoğlu-Ellik, Z., Kacmaz, H., Balaban, Y., Atay, K., Eren, F., Alvares-da-Silva, M.R., Cristoferi, L., Urzua, Á., Eşkazan, T., Magro, B., Snijders, R.J.A.L.M., Barutçu, S., Lytvyak, E., Zazueta, G.M., Demirezer-Bolat, A., Aydın, M., Heurgue-Berlot, A., Martin, E., Ekin, N., Yıldırım, S., Yavuz, A., Bıyık, M., Narro, G.C., Kıyıcı, M., Akyıldız, M., Kahramanoğlu-Aksoy, E., Vincent, M., Carr, R.M., Günşar, F., Reyes, E.C., Harputluoğlu, M., Aloman, C., Gatselis, N.K., Üstündağ, Y., Brahm, J., Vargas, N.C.E., Güzelbulut, F., Garcia, S.R., Aguirre, J., Anders, M., Ratusnu, N., Hatemi, I., Mendizabal, M., Floreani, A., Fagiuoli, S., Silva, M., Idilman, R., Satapathy, S.K., Silveira, M., Drenth, J.P.H., Dalekos, G.N., Assis, D.N., Björnsson, E., Boyer, J.L., Yoshida, E.M., Invernizzi, P., Levy, C., Montano-Loza, A.J., Schiano, T.D., Ridruejo, E., Wahlin, S., Efe, C., Lammert, C., Taşçılar, K., Dhanasekaran, R., Ebik, B., Higuera-de la Tijera, F., Calışkan, A.R., Peralta, M., Gerussi, A., Massoumi, H., Catana, A.M., Purnak, T., Rigamonti, C., Aldana, A.J. Gomez, Khakoo, N., Nazal, L., Frager, S., Demir, N., Irak, K., Melekoğlu-Ellik, Z., Kacmaz, H., Balaban, Y., Atay, K., Eren, F., Alvares-da-Silva, M.R., Cristoferi, L., Urzua, Á., Eşkazan, T., Magro, B., Snijders, R.J.A.L.M., Barutçu, S., Lytvyak, E., Zazueta, G.M., Demirezer-Bolat, A., Aydın, M., Heurgue-Berlot, A., Martin, E., Ekin, N., Yıldırım, S., Yavuz, A., Bıyık, M., Narro, G.C., Kıyıcı, M., Akyıldız, M., Kahramanoğlu-Aksoy, E., Vincent, M., Carr, R.M., Günşar, F., Reyes, E.C., Harputluoğlu, M., Aloman, C., Gatselis, N.K., Üstündağ, Y., Brahm, J., Vargas, N.C.E., Güzelbulut, F., Garcia, S.R., Aguirre, J., Anders, M., Ratusnu, N., Hatemi, I., Mendizabal, M., Floreani, A., Fagiuoli, S., Silva, M., Idilman, R., Satapathy, S.K., Silveira, M., Drenth, J.P.H., Dalekos, G.N., Assis, D.N., Björnsson, E., Boyer, J.L., Yoshida, E.M., Invernizzi, P., Levy, C., Montano-Loza, A.J., Schiano, T.D., Ridruejo, E., and Wahlin, S.

Abstract

Item does not contain fulltext, BACKGROUND: We investigated associations between baseline use of immunosuppressive drugs and severity of Coronavirus Disease 2019 (COVID-19) in autoimmune hepatitis (AIH). PATIENTS AND METHODS: Data of AIH patients with laboratory confirmed COVID-19 were retrospectively collected from 15 countries. The outcomes of AIH patients who were on immunosuppression at the time of COVID-19 were compared to patients who were not on AIH medication. The clinical courses of COVID-19 were classified as (i)-no hospitalization, (ii)-hospitalization without oxygen supplementation, (iii)-hospitalization with oxygen supplementation by nasal cannula or mask, (iv)-intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v)-ICU admission with invasive mechanical ventilation or (vi)-death and analysed using ordinal logistic regression. RESULTS: We included 254 AIH patients (79.5%, female) with a median age of 50 (range, 17-85) years. At the onset of COVID-19, 234 patients (92.1%) were on treatment with glucocorticoids (n = 156), thiopurines (n = 151), mycophenolate mofetil (n = 22) or tacrolimus (n = 16), alone or in combinations. Overall, 94 (37%) patients were hospitalized and 18 (7.1%) patients died. Use of systemic glucocorticoids (adjusted odds ratio [aOR] 4.73, 95% CI 1.12-25.89) and thiopurines (aOR 4.78, 95% CI 1.33-23.50) for AIH was associated with worse COVID-19 severity, after adjusting for age-sex, comorbidities and presence of cirrhosis. Baseline treatment with mycophenolate mofetil (aOR 3.56, 95% CI 0.76-20.56) and tacrolimus (aOR 4.09, 95% CI 0.69-27.00) were also associated with more severe COVID-19 courses in a smaller subset of treated patients. CONCLUSION: Baseline treatment with systemic glucocorticoids or thiopurines prior to the onset of COVID-19 was significantly associated with COVID-19 severity in patients with AIH.

Published
2022

6. Systematic review of response criteria and endpoints in autoimmune hepatitis by the International Autoimmune Hepatitis Group

Author

Arıkan, Çiğdem (ORCID 0000-0002-0794-2741 & YÖK ID 240198), Pape, S.; Snijders R.J.; Gevers, T.J.; Chazouilleres, O.; Dalekos, G.N.; Hirschfield, G.M.; Lenzi, M.; Trauner, M.; Manns, M.P.; Vierling, J.M.; Montano Loza, A.J.; Lohse, A.W.; Schramm, C.; Drenth, J.P.; Heneghan, M.A.; International Autoimmune Hepatitis Group (IAIHG), School of Medicine, Arıkan, Çiğdem (ORCID 0000-0002-0794-2741 & YÖK ID 240198), Pape, S.; Snijders R.J.; Gevers, T.J.; Chazouilleres, O.; Dalekos, G.N.; Hirschfield, G.M.; Lenzi, M.; Trauner, M.; Manns, M.P.; Vierling, J.M.; Montano Loza, A.J.; Lohse, A.W.; Schramm, C.; Drenth, J.P.; Heneghan, M.A.; International Autoimmune Hepatitis Group (IAIHG), and School of Medicine

Abstract

Background and aims: 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. Methods: a systematic review was performed and a modified Delphi consensus process was used to identify and redefine the response criteria in autoimmune hepatitis. Results: 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'. Conclusions: 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. Lay summary: consensus 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 statem, YAEL Foundation

Published
2022

7. Autoimmune hepatitis cholestatic variant syndromes recurrence following liver transplantation affects graft and patient survival in an international multicentre cohort

Author

Ronca, V., Parente, A., Ebadi, M., Hansen, B.E., Hirschfield, G., Elwir, S., Alsaed, M., Milkiewicz, P., Janik, M.K., Marschall, H.U., Burza, M.A., Efe, C., Kan, Ali Rıza Calıs, Harputluoglu, M., Kabaçam, G., Terrabuio, D., Onofrio, F. de Quadros, Selzner, N., Bonder, A., Parés, A., Llovet, L., Akyıldız, M., Arikan, C., Manns, M.P., Taubert, R., Weber, A.L., Schiano, T.D., Haydel, B., Czubkowski, P., Socha, P., Ołdak, N., Akamatsu, N., Tanaka, A., Levy, C., Martin, E.F., Goel, A., Sedki, M., Jankowska, I., Ikegami, T., Rodriguez, M., Sterneck, M., Weiler-Normann, C., Schramm, C., Donato, M.F., Lohse, A., Andrade, R.J., Patwardhan, V.R., van Hoek, B., Biewenga, M., Kremer, A.E., Ueda, Y., Deneau, M., Pedersen, M., Mayo, M.J., Floreani, A., Burra, P., Secchi, M.F., Beretta-Piccoli, B. Terziroli, Sciveres, M., Maggiore, G., Jafri, S.M., Debray, D., Girard, M., Lacaille, F., Lytvyak, E., Mason, A.L., Heneghan, M., Montano-Loza, A.J., and Oo, Y. Htun

Published
2024
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20. Genome-Wide Association Study (Gwas) of Liver Fibrosis Phenotypes in Patients with Primary Sclerosing Cholangitis (Psc) Reveals Common Genetic Variation Influencing Serum Levels of Lysyl Oxidase-Like-2 (Loxl2)

Author

Shea, P.R., primary, Eksteen, B., additional, Hirschfield, G.M., additional, Shiftman, M.L., additional, Janssen, H.L.A., additional, Montano-Loza, A.J., additional, Goodman, Z., additional, Kleinstein, S.E., additional, Myers, R.P., additional, Subramanian, G.M., additional, McHutchison, J.G., additional, Bowlus, C.L., additional, Manns, M., additional, Chapman, R., additional, Levy, C., additional, Muir, A.J., additional, and Goldstein, D.B., additional

Published
2016
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21. Liver Stiffness Measurement by Transient Elastography for the Prediction of Fibrosis in Patients with Primary Sclerosing Cholangitis in a Randomized Trial of Simtuzumab

Author

Bowlus, C.L., primary, Montano-Loza, A.J., additional, Invernizzi, P., additional, Chazouillères, O., additional, Hirschfield, G., additional, Metselaar, H.J., additional, Goodman, Z., additional, Myers, R.P., additional, Aguilar, R., additional, Mani Subramanian, G., additional, McHutchison, J.G., additional, Chapman, R., additional, Muir, A.J., additional, Eksteen, B., additional, and Levy, C., additional

Published
2016
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26. PS093 - Genome-Wide Association Study (Gwas) of Liver Fibrosis Phenotypes in Patients with Primary Sclerosing Cholangitis (Psc) Reveals Common Genetic Variation Influencing Serum Levels of Lysyl Oxidase-Like-2 (Loxl2)

Author

Shea, P.R., Eksteen, B., Hirschfield, G.M., Shiftman, M.L., Janssen, H.L.A., Montano-Loza, A.J., Goodman, Z., Kleinstein, S.E., Myers, R.P., Subramanian, G.M., McHutchison, J.G., Bowlus, C.L., Manns, M., Chapman, R., Levy, C., Muir, A.J., and Goldstein, D.B.

Published
2016
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33. Systematic review of response criteria and endpoints in autoimmune hepatitis by the International Autoimmune Hepatitis Group

Author

Simon Pape, Romée J.A.L.M. Snijders, Tom J.G. Gevers, Oliver Chazouilleres, George N. Dalekos, Gideon M. Hirschfield, Marco Lenzi, Michael Trauner, Michael P. Manns, John M. Vierling, Aldo J. Montano-Loza, Ansgar W. Lohse, Christoph Schramm, Joost P.H. Drenth, Michael A. Heneghan, P. Almasio, F. Alvarez, R. Andrade, C. Arikan, D. Assis, E. Bardou-Jacquet, M. Biewenga, E. Cancado, N. Cazzagon, O. Chazouillères, G. Colloredo, M. Cuarterolo, G. Dalekos, D. Debray, M. Robles-Díaz, J. Drenth, J. Dyson, C. Efe, B. Engel, S. Ferri, R. Fontana, N. Gatselis, A. Gerussi, E. Halilbasic, N. Halliday, M. Heneghan, G. Hirschfield, B. van Hoek, M. Hørby Jørgensen, G. Indolfini, R. Iorio, S. Jeong, D. Jones, D. Kelly, N. Kerkar, F. Lacaille, C. Lammert, B. Leggett, M. Lenzi, C. Levy, R. Liberal, A. Lleo, A. Lohse, S. Ines Lopez, E. de Martin, V. McLin, G. Mieli-Vergani, P. Milkiewicz, N. Mohan, L. Muratori, G. Nebbia, C. van Nieuwkerk, Y. Oo, A. Ortega, A. Páres, T. Pop, D. Pratt, T. Purnak, G. Ranucci, S. Rushbrook, C. Schramm, A. Stättermayer, M. Swain, A. Tanaka, R. Taubert, D. Terrabuio, B. Terziroli, M. Trauner, P. Valentino, F. van den Brand, A. Villamil, S. Wahlin, H. Ytting, K. Zachou, M. Zeniya, Pape, S, Snijders, R, Gevers, T, Chazouilleres, O, Dalekos, G, Hirschfield, G, Lenzi, M, Trauner, M, Manns, M, Vierling, J, Montano-Loza, A, Lohse, A, Schramm, C, Drenth, J, Heneghan, M, Almasio, P, Alvarez, F, Andrade, R, Arikan, C, Assis, D, Bardou-Jacquet, E, Biewenga, M, Cancado, E, Cazzagon, N, Colloredo, G, Cuarterolo, M, Debray, D, Robles-Diaz, M, Dyson, J, Efe, C, Engel, B, Ferri, S, Fontana, R, Gatselis, N, Gerussi, A, Halilbasic, E, Halliday, N, van Hoek, B, Horby Jorgensen, M, Indolfini, G, Iorio, R, Jeong, S, Jones, D, Kelly, D, Kerkar, N, Lacaille, F, Lammert, C, Leggett, B, Levy, C, Liberal, R, Lleo, A, Ines Lopez, S, de Martin, E, Mclin, V, Mieli-Vergani, G, Milkiewicz, P, Mohan, N, Muratori, L, Nebbia, G, van Nieuwkerk, C, Oo, Y, Ortega, A, Pares, A, Pop, T, Pratt, D, Purnak, T, Ranucci, G, Rushbrook, S, Stattermayer, A, Swain, M, Tanaka, A, Taubert, R, Terrabuio, D, Terziroli, B, Valentino, P, van den Brand, F, Villamil, A, Wahlin, S, Ytting, H, Zachou, K, Zeniya, M, Arıkan, Çiğdem (ORCID 0000-0002-0794-2741 & YÖK ID 240198), Pape, S., Snijders R.J., Gevers, T.J., Chazouilleres, O., Dalekos, G.N., Hirschfield, G.M., Lenzi, M., Trauner, M., Manns, M.P., Vierling, J.M., Montano Loza, A.J., Lohse, A.W., Schramm, C., Drenth, J.P., Heneghan, M.A., International Autoimmune Hepatitis Group (IAIHG), School of Medicine, Gastroenterology and hepatology, AII - Infectious diseases, and Amsterdam Gastroenterology Endocrinology Metabolism

Subjects
autoimmune hepatitis, Hepatology, endpoints, endpoint, insufficient response, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], remission, non-response, complete biochemical response, intolerance, Autoimmune hepatitis, Complete biochemical response, Endpoints, Insufficient response, Intolerance, Non-response, Remission, Medicine, autoimmune hepatiti
Abstract

Background and aims: 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. Methods: a systematic review was performed and a modified Delphi consensus process was used to identify and redefine the response criteria in autoimmune hepatitis. Results: 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 ', YAEL Foundation

Published
2022
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34. Extrahepatic autoimmune diseases in primary biliary cholangitis: Prevalence and significance for clinical presentation and disease outcome

Author

Fredrik Rorsman, Ellina Lytvyak, Mårten Werner, Aldo J. Montano-Loza, Fatema Alalkim, Benedetta Terziroli Beretta-Piccoli, Paolo Muratori, Thomas Berg, Thomas D. Schiano, Emma Nilsson, Tugrul Purnak, Ida Henriksson, David Semela, Staffan Wahlin, Eric M. Yoshida, Luigi Muratori, Alan Bonder, Murat Kiyici, Kristina Önnerhag, Janett Fischer, Ersan Ozaslan, Maneerat Chayanupatkul, Hanns-Ulrich Marschall, Murat Torgutalp, Claudia Coppo, Alexandra Heurgué-Berlot, Hirsh D. Trivedi, Nurhan Demir, Cumali Efe, Fatih Eren, Efe C., Torgutalp M., Henriksson I., Alalkim F., Lytvyak E., Trivedi H., Eren F., Fischer J., Chayanupatkul M., Coppo C., Purnak T., Muratori L., Werner M., Muratori P., Rorsman F., Onnerhag K., Nilsson E., Heurgue-Berlot A., Demir N., Semela D., Kiyici M., Schiano T.D., Montano-Loza A.J., Berg T., Ozaslan E., Yoshida E.M., Bonder A., Marschall H.-U., Beretta-Piccoli B.T., Wahlin S., Bursa Uludağ Üniversitesi/Tıp Fakültesi/İç Hastalıkları Anabilim Dalı., CPU-6796-2022, and Eren, Fatih

Subjects
Male, Anti-nuclear antibody, PBC, Gastroenterology, Inflammatory bowel disease, 0302 clinical medicine, Lichen sclerosus et atrophicus, Antiphospholipid syndrome, Ascites, Undifferentiated connective tissue disease, Temporal arteritis, Myasthenia gravis, Hepatic encephalopathy, Hashimoto disease, Addison disease, Crohn disease, Pemphigus vulgaris, IgA nephropathy, Prognosis, Liver cell carcinoma, Management, Risk-factors, Retrospective study, Blood, Cirrhosis, Smooth muscle antibody, Biochemical response, Ursodeoxycholic acid, Primary biliary cirrhosis, 030220 oncology & carcinogenesis, Rheumatoid arthritis, Graves disease, Systemic sclerosis, 030211 gastroenterology & hepatology, Cohort analysis, Lichen planus, Anti-phospholipid syndrome, Human, Sex factor, medicine.medical_specialty, Cholangitis, Biliary Liver Cirrhosis, Obeticholic Acid, Sarcoidosis, Immunology, Major clinical study, Aspartate aminotransferase, Article, Dermatomyositis, Multiple sclerosis, 03 medical and health sciences, Humans, Clinical significance, Aspartate Aminotransferases, Autoimmune hemolytic anemia, Autoantibodies, Polymyositi, Ankylosing spondylitis, Bullous pemphigoid, Wegener granulomatosis, Medical record, Biliary cirrhosis, Follow up, medicine.disease, Event free survival, Ankylosing spondyliti, Ulcerative colitis, Pernicious anemia, Idiopathic thrombocytopenic purpura, Gastroenterology & hepatology, Complication, Biomarkers, Sarcoidosi, Autoantibody, Immunoglobulin A nephropathy, Autoimmune disease, Prevalence, Celiac disease, Middle aged, Variceal bleeding, Liver Cirrhosis, Biliary, Chronic urticaria, Mitochondria, Gastritis, Antibodies, Antinuclear, Female, medicine.symptom, Adult, Vitiligo, Autoimmune Diseases, Antinuclear antibody, Systemic lupus erythematosus, Sex Factors, Decompensated liver cirrhosis, Mitochondrion antibody, Internal medicine, Psoriasis, medicine, Multiple sclerosi, Collagenous colitis, Mitochondrion, Membranous glomerulonephritis, Hepatology, business.industry, Bleeding, Bilirubin, Polyarteritis nodosa, Alkaline Phosphatase, Polymyositis, Biological marker, business, Controlled study, Sjoegren syndrome
Abstract

Background and Aim: The prevalence and clinical significance of extrahepatic autoimmune diseases (EHAIDs) have not been evaluated in a large cohort of primary biliary cholangitis (PBC). Methods: The medical records of 1554 patients with PBC from 20 international centers were retrospectively reviewed. Development of decompensated cirrhosis (ascites, variceal bleeding, and/or hepatic encephalopathy) and hepatocellular carcinoma were considered clinical endpoints. Results: A total of 35 different EHAIDs were diagnosed in 440 (28.3%) patients with PBC. Patients with EHAIDs were more often female (92.5% vs 86.1%, P&nbsp

Published
2021

35. Validation of risk scoring systems in ursodeoxycholic acid-treated patients with primary biliary Cholangitis

Author

Fatema Alalkim, Benedetta Terziroli Beretta-Piccoli, Thomas Berg, Cumali Efe, Fulya Gunsar, Ellina Lytvyak, Janett Fischer, Fredrik Rorsman, Ali Riza Caliskan, Hanns-Ulrich Marschall, Kristina Önnerhag, Tugrul Purnak, Ida Henriksson, Maneerat Chayanupatkul, Claudia Coppo, Can Gonen, David Semela, Staffan Wahlin, Murat Kiyici, Ersan Ozaslan, Alexandra Heurgué-Berlot, Emma Nilsson, Alan Bonder, Koray Tascilar, Luigi Muratori, Fatih Güzelbulut, Murat Aladağ, Aldo J. Montano-Loza, Fatih Eren, Mårten Werner, Nurhan Demir, Henriette Ytting, Paolo Muratori, Thomas D. Schiano, Hirsh D. Trivedi, Eric M. Yoshida, Johanna Eliasson, Bursa Uludağ Üniversitesi/Tıp Fakültesi/Dahili Tıp Bilimleri., Eren, Fatih, AAS-6286-2020, Ege Üniversitesi, Efe C., Tascilar K., Henriksson I., Lytvyak E., Alalkim F., Trivedi H., Eren F., Eliasson J., Beretta-Piccoli B.T., Fischer J., Caliskan A.R., Chayanupatkul M., Coppo C., Ytting H., Purnak T., Muratori L., Werner M., Muratori P., Rorsman F., Onnerhag K., Gunsar F., Nilsson E., Heurgue-Berlot A., Guzelbulut F., Demir N., Gonen C., Semela D., Aladag M., Kiyici M., Schiano T.D., Montano-Loza A.J., Berg T., Ozaslan E., Yoshida E.M., Bonder A., Marschall H.-U., and Wahlin S.

Subjects
Male, Scoring system, Survival rate, Kaplan Meier method, Cholagogues and choleretics, Gastroenterology, 0302 clinical medicine, Cholagogue, Pathology, Histological progression, Treatment outcome, Child, Hepatic encephalopathy, Prognosis, Ursodeoxycholic acid, Multicenter study, Clinical trial, Retrospective study, Cirrhosis, Biochemical response, Primary biliary cirrhosis, liver, autoimmune, human, 030220 oncology & carcinogenesis, Predictive value of tests, Risk stratification, Disease Progression, Dose-response relationship, drug, Cohort studies, 030211 gastroenterology & hepatology, Cohort analysis, Human, medicine.medical_specialty, Sex factor, Cholangitis, Biliary Liver Cirrhosis, Obeticholic Acid, Major clinical study, Article, Adverse outcome, 03 medical and health sciences, Age, Severity of illness, Dose response, Humans, Disease exacerbation, Survival analysis, Confidence interval, Biliary cirrhosis, Follow up, Globe, digestive system diseases, Event free survival, United States, Retrospective studies, International cooperation, Gastroenterology & hepatology, Internationality, Survival, Middle aged, Priority journal, Risk assessment, Liver Cirrhosis, Biliary, Ascites, Validation study, Europe, Female, France, Sex factors, Age factors, medicine.drug, Adult, Canada, Proportional hazards models, Adolescent, Kaplan-Meier estimate, Hazard ratio, Placebo-controlled trial, Predictive value, macromolecular substances, Outcomes, Proportional hazards model, Internal medicine, medicine, Mortality, Hepatology, business.industry, Drug administration, Bleeding, Drug administration schedule, Retrospective cohort study, Severity of illness index, Spain, Bezafibrate, business, Prediction, Controlled study
Abstract

EgeUn###, INTRODUCTION: Risk stratification based on biochemical variables is a useful tool for monitoring ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC). Several UDCA response criteria and scoring systems have been proposed for risk prediction in PBC, but these have not been validated in large external cohorts. METHODS: We performed a study on data of 1746 UDCA-treated patients with PBC from 25 centers in Europe, United States, and Canada. The prognostic performance of the risk scoring systems (GLOBE and UK-PBC) and the UDCA response criteria (Barcelona, Paris I, Paris II, Rotterdam, and Toronto) were evaluated. We regarded cirrhosis-related complications (ascites, variceal bleeding, and/or hepatic encephalopathy) as clinical end points. RESULTS: A total of 171 patients reached a clinical end point during a median 7 years (range 1-16 years) of follow-up. The 5-, 10- and 15-year adverse outcome-free survivals were 95%, 85%, and 77%. The GLOBE and UK-PBC scores predicted cirrhosis-related complications better than the UDCA response criteria. The hazard ratio (HR) for a 1 standard deviation increase was HR 5.05 (95% confidence interval (CI): 4.43-5.74, P < 0.001) for the GLOBE score and HR 3.39 (95% CI: 3.10-3.72, P < 0.001) for the UK-PBC score. Overall, the GLOBE and UK-PBC risk scores showed similar and excellent prognostic performance (C-statistic, 0.93; 95% CI: 0.91%-95% vs 0.94; 95% CI: 0.91%-0.96%). DISCUSSION: In our international, multicenter PBC cohort, the GLOBE and UK-PBC risk scoring systems were good predictors of future cirrhosis-related complications.

Published
2019

36. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Author

Zobair M Younossi, Vlad Ratziu, Rohit Loomba, Mary Rinella, Quentin M Anstee, Zachary Goodman, Pierre Bedossa, Andreas Geier, Susanne Beckebaum, Philip N Newsome, David Sheridan, Muhammad Y Sheikh, James Trotter, Whitfield Knapple, Eric Lawitz, Manal F Abdelmalek, Kris V Kowdley, Aldo J Montano-Loza, Jerome Boursier, Philippe Mathurin, Elisabetta Bugianesi, Giuseppe Mazzella, Antonio Olveira, Helena Cortez-Pinto, Isabel Graupera, David Orr, Lise Lotte Gluud, Jean-Francois Dufour, David Shapiro, Jason Campagna, Luna Zaru, Leigh MacConell, Reshma Shringarpure, Stephen Harrison, Arun J Sanyal, Manal Abdelmalek, Gary Abrams, Humberto Aguilar, Aijaz Ahmed, Elmar Aigner, Guruprasad Aithal, Aftab Ala, William Alazawi, Agustin Albillos, Michael Allison, Sfa Al-Shamma, Raul Andrade, Pietro Andreone, Mario Angelico, Victor Ankoma-Sey, Quentin Anstee, Rodolphe Anty, Victor Araya, Juan Ignacio Arenas Ruiz, Perttu Arkkila, Marty Arora, Tarik Asselah, Jennifer Au, Oyekoya Ayonrinde, Robert James Bailey, Maya Balakrishnan, Kiran Bambha, Meena Bansal, Sidney Barritt, John Bate, Jorge Beato, Jaideep Behari, Pablo Bellot, Ziv Ben Ari, Michael Bennett, Marina Berenguer, Benedetta Terziroli Beretta-Piccoli, Thomas Berg, Maurizio Bonacini, Lucia Bonet, Brian Borg, Marc Bourliere, William Bowman, David Bradley, Marija Brankovic, Marius Braun, Jean-Pierre Bronowicki, Savino Bruno, Cindy Cai, Amy Calderon, José Luis Calleja Panero, Elizabeth Carey, Michal Carmiel, Jose Antonio Carrión, Matthew Cave, Cristina Chagas, Tawfik Chami, Alan Chang, Allan Coates, Jeremy Cobbold, Charlote Costentin, Kathleen Corey, Lynsey Corless, Javier Crespo, Oscar Cruz Pereira, Victor de Ledinghen, Andrew deLemos, Moises Diago, Mamie Dong, Jean-François Dufour, Predrag Dugalic, Winston Dunn, Magby Elkhashab, Michael Epstein, Maria Desamparados Escudero-Garcia, Ohad Etzion, Larry Evans, Robert Falcone, Conrado Fernandez, Jose Ferreira, Scott Fink, Kevin Finnegan, Roberto Firpi-Morell, Annarosa Floreani, Thierry Fontanges, Ryan Ford, Ewan Forrest, Andrew Fowell, Anna Ludovica Fracanzani, Sven Francque, Bradley Freilich, Juan Frias, Michael Fuchs, Javier Fuentes, Michael Galambos, Juan Gallegos, Anja Geerts, Jacob George, Maged Ghali, Reem Ghalib, Pierre Gholam, Pere Gines, Norman Gitlin, Tobias Goeser, John Goff, Stuart Gordon, Frederic Gordon, Odile Goria, Shaun Greer, Alla Grigorian, Henning Gronbaek, Maeva Guillaume, Naresh Gunaratnam, Dina Halegoua-De Marzio, Bilal Hameed, Stephanie Hametner, James Hamilton, Marek Hartleb, Tarek Hassanein, Dieter Häussinger, Paul Hellstern, Robert Herring, Eva Heurich, Christophe Hezode, Holger Hinrichsen, Peter Holland Fischer, Yves Horsmans, Jonathan Huang, Hyder Hussaini, Antoine Jakiche, Lennox Jeffers, Blake Jones, Rosa Jorge, Francisco Jorquera, Shoba Joshi, Alisan Kahraman, Kelly Kaita, Nicholas Karyotakis, Zeid Kayali, Stergios Kechagias, Thomas Kepczyk, Mandana Khalili, Hicham Khallafi, Johannes Kluwe, Anita Kohli, Kevin Korenblat, Kris Kowdley, Aleksander Krag, Richard Krause, Andreas Kremer, Karen Krok, Miodrag Krstic, Marcelo Kugelmas, Sonal Kumar, Scott Kuwada, Damien Labarriere, Michelle Lai, Wim Laleman, Pietro Lampertico, Alice Lee, Vincent Leroy, Steven Lidofsky, Tina Huey Lim, Joseph Lim, Donald Lipkis, Ester Little, Amadeo Lonardo, Michelle Long, Velimir Anthony Christopher Luketic, Yoav Lurie, Guilherme Macedo, Joana Magalhaes, Mihály Makara, Benedict Maliakkal, Michael Manns, Pinelopi Manousou, Parvez Mantry, Giulio Marchesini, Carla Marinho, Paul Marotta, Hanns-Ulrich Marschall, Linda Martinez, Marlyn Mayo, Mark McCullen, William McLaughlin, Uta Merle, Raphael Merriman, Apurva Modi, Esther Molina, Aldo Montano-Loza, Carlos Monteverde, Amilcar Morales Cardona, Sulleman Moreea, Christophe Moreno, Filomena Morisco, Abdullah Mubarak, Beat Muellhaupt, Sandeep Mukherjee, Tobias Müller, Aleksandar Nagorni, Jahnavi Naik, Guy Neff, Moises Nevah, Philip Newsome, Eric Nguyen-Khac, Mazen Noureddin, Jude Oben, Hans Orlent, James Orr, Grisell Ortiz-Lasanta, Violaine Ozenne, Prashant Pandya, Angelo Paredes, James Park, Joykumar Patel, Keyur Patel, Sonali Paul, Heather Patton, Markus Peck-Radosavljevic, Salvatore Petta, Stephen Pianko, Anna Piekarska, Neville Pimstone, Joseph Pisegna, Paul Pockros, Stanislas Pol, Michael Porayko, John Poulos, David Pound, Joe Pouzar, Jose Presa Ramos, Nikolaos Pyrsopoulos, Nila Rafiq, Kate Muller, Alnoor Ramji, Ravi Ravinuthala, Chakradhar Reddy, Gautham Reddy K G, K. Rajender Reddy K R, Frederic Regenstein, Robert Reindollar, Justin Reynolds, Andres Riera, Jose Rivera Acosta, Geert Robaeys, Stuart Roberts, Federico Rodriguez-Perez, Sandor Romero, Manuel Romero-Gomez, Raymond Rubin, Mariagrazia Rumi, Simon Rushbrook, Christian Rust, Michael Ryan, Rifaat Safadi, Adnan Said, Kimmo Salminen, Didier Samuel, John Santoro, Arun Sanyal, Souvik Sarkar, Cynthia Schaeffer, Jörn Schattenberg, Ingolf Schiefke, Eugene Schiff, Wolfgang Schmidt, Jeffrey Schneider, Jeoffrey Schouten, Michael Schultz, Giada Sebastiani, David Semela, Thomas Sepe, Aasim Sheikh, Muhammad Sheikh, Kenneth Sherman, Oren Shibolet, Mitchell Shiffman, Asma Siddique, Cyril Sieberhagen, Samuel Sigal, Katarzyna Sikorska, Krzysztof Simon, Marie Sinclair, Richard Skoien, Joel Solis, Siddharth Sood, Bob Souder, James Spivey, Per Stal, Laura Stinton, Simone Strasser, Petar Svorcan, Gyongzi Szabo, Andrew Talal, Edward Tam, Brent Tetri, Paul Thuluvath, Hillel Tobias, Krzysztof Tomasiewicz, Dawn Torres, Albert Tran, Michael Trauner, Christian Trautwein, Emanuel Tsochatzis, Esther Unitt, Victor Vargas, Istvan Varkonyi, Ella Veitsman, Umberto Vespasiani Gentilucci, David Victor, John Vierling, Catherine Vincent, Aron Vincze, Manfred von der Ohe, Natasha Von Roenn, Raj Vuppalanchi, Michael Waters, Kymberly Watt, Julia Wattacheril, Martin Weltman, Amanda Wieland, Gregory Wiener, Alonzo Williams A, Jeffrey Williams J, Jason Wilson, Maria Yataco, Eric Yoshida, Ziad Younes, Liyun Yuan, Adam Zivony, Donald Zogg, Heinz Zoller, Fabien Zoulim, Eli Zuckerman, Massimo Zuin, Younossi Z.M., Ratziu V., Loomba R., Rinella M., Anstee Q.M., Goodman Z., Bedossa P., Geier A., Beckebaum S., Newsome P.N., Sheridan D., Sheikh M.Y., Trotter J., Knapple W., Lawitz E., Abdelmalek M.F., Kowdley K.V., Montano-Loza A.J., Boursier J., Mathurin P., Bugianesi E., Mazzella G., Olveira A., Cortez-Pinto H., Graupera I., Orr D., Gluud L.L., Dufour J.-F., Shapiro D., Campagna J., Zaru L., MacConell L., Shringarpure R., Harrison S., Sanyal A.J., Abdelmalek M., Abrams G., Aguilar H., Ahmed A., Aigner E., Aithal G., Ala A., Alazawi W., Albillos A., Allison M., Al-Shamma S., Andrade R., Andreone P., Angelico M., Ankoma-Sey V., Anstee Q., Anty R., Araya V., Arenas Ruiz J.I., Arkkila P., Arora M., Asselah T., Au J., Ayonrinde O., Bailey R.J., Balakrishnan M., Bambha K., Bansal M., Barritt S., Bate J., Beato J., Behari J., Bellot P., Ben Ari Z., Bennett M., Berenguer M., Beretta-Piccoli B.T., Berg T., Bonacini M., Bonet L., Borg B., Bourliere M., Bowman W., Bradley D., Brankovic M., Braun M., Bronowicki J.-P., Bruno S., Cai C., Calleja Panero J.L., Carey E., Carmiel M., Carrion J.A., Cave M., Chagas C., Chami T., Chang A., Coates A., Cobbold J., Corey K., Corless L., Crespo J., Cruz Pereira O., de Ledinghen V., deLemos A., Diago M., Dugalic P., Dunn W., Elkhashab M., Epstein M., Escudero-Garcia M.D., Etzion O., Evans L., Falcone R., Fernandez C., Ferreira J., Fink S., Finnegan K., Firpi-Morell R., Floreani A., Fontanges T., Ford R., Forrest E., Fowell A., Fracanzani A.L., Francque S., Freilich B., Frias J., Fuchs M., Fuentes J., Galambos M., Gallegos J., Geerts A., George J., Ghali M., Ghalib R., Gholam P., Gines P., Gitlin N., Goeser T., Goff J., Gordon S., Gordon F., Goria O., Greer S., Grigorian A., Gronbaek H., Guillaume M., Gunaratnam N., Halegoua-De Marzio D., Hameed B., Hametner S., Hamilton J., Hartleb M., Hassanein T., Haussinger D., Hellstern P., Herring R., Heurich E., Hezode C., Hinrichsen H., Holland Fischer P., Horsmans Y., Huang J., Jakiche A., Jeffers L., Jones B., Jorge R., Jorquera F., Kahraman A., Kaita K., Karyotakis N., Kayali Z., Kechagias S., Kepczyk T., Khalili M., Khallafi H., Kluwe J., Kohli A., Korenblat K., Kowdley K., Krag A., Krause R., Kremer A., Krok K., Krstic M., Kugelmas M., Kumar S., Labarriere D., Lai M., Lampertico P., Lee A., Leroy V., Lidofsky S., Lim T.H., Lim J., Lipkis D., Little E., Lonardo A., Long M., Lurie Y., Macedo G., Makara M., Maliakkal B., Manns M., Manousou P., Mantry P., Marchesini G., Marinho C., Marotta P., Marschall H.-U., Mayo M., McCullen M., McLaughlin W., Merriman R., Modi A., Molina E., Montano-Loza A., Monteverde C., Moreea S., Moreno C., Morisco F., Mubarak A., Muellhaupt B., Mukherjee S., Muller T., Nagorni A., Naik J., Neff G., Nevah M., Newsome P., Nguyen-Khac E., Noureddin M., Oben J., Orlent H., Orr J., Ortiz-Lasanta G., Ozenne V., Pandya P., Paredes A., Park J., Patel J., Patel K., Uta M., Patton H., Peck-Radosavljevic M., Petta S., Pianko S., Piekarska A., Pimstone N., Pockros P., Pol S., Porayko M., Poulos J., Pound D., Pouzar J., Presa Ramos J., Pyrsopoulos N., Rafiq N., Muller K., Ramji A., Ravinuthala R., Reddy C., Reddy K G G., Reddy K R K.R., Regenstein F., Reindollar R., Riera A., Rivera Acosta J., Robaeys G., Roberts S., Rodriguez-Perez F., Romero-Gomez M., Rubin R., Rumi M., Rushbrook S., Rust C., Ryan M., Safadi R., Said A., Salminen K., Samuel D., Santoro J., Sanyal A., Sarkar S., Schaeffer C., Schattenberg J., Schiefke I., Schiff E., Schmidt W., Schneider J., Schouten J., Schultz M., Sebastiani G., Semela D., Sepe T., Sheikh A., Sheikh M., Sherman K., Shibolet O., Shiffman M., Siddique A., Sieberhagen C., Sigal S., Sikorska K., Simon K., Sinclair M., Skoien R., Solis J., Sood S., Souder B., Spivey J., Stal P., Stinton L., Strasser S., Svorcan P., Szabo G., Talal A., Tam E., Tetri B., Thuluvath P., Tobias H., Tomasiewicz K., Torres D., Trauner M., Trautwein C., Tsochatzis E., Unitt E., Vargas V., Varkonyi I., Veitsman E., Vespasiani Gentilucci U., Victor D., Vierling J., Vincent C., Vincze A., von der Ohe M., Von Roenn N., Vuppalanchi R., Waters M., Watt K., Weltman M., Wieland A., Wiener G., Williams A A., Williams J J., Wilson J., Yataco M., Yoshida E., Younes Z., Yuan L., Zivony A., Zogg D., Zoller H., Zoulim F., Zuckerman E., Zuin M., Repositório da Universidade de Lisboa, Younossi, Z. M., Ratziu, V., Loomba, R., Rinella, M., Anstee, Q. M., Goodman, Z., Bedossa, P., Geier, A., Beckebaum, S., Newsome, P. N., Sheridan, D., Sheikh, M. Y., Trotter, J., Knapple, W., Lawitz, E., Abdelmalek, M. F., Kowdley, K. V., Montano-Loza, A. J., Boursier, J., Mathurin, P., Bugianesi, E., Mazzella, G., Olveira, A., Cortez-Pinto, H., Graupera, I., Orr, D., Gluud, L. L., Dufour, J. -F., Shapiro, D., Campagna, J., Zaru, L., Macconell, L., Shringarpure, R., Harrison, S., Sanyal, A. J., Abdelmalek, M., Abrams, G., Aguilar, H., Ahmed, A., Aigner, E., Aithal, G., Ala, A., Alazawi, W., Albillos, A., Allison, M., Al-Shamma, S., Andrade, R., Andreone, P., Angelico, M., Ankoma-Sey, V., Anstee, Q., Anty, R., Araya, V., Arenas Ruiz, J. I., Arkkila, P., Arora, M., Asselah, T., Au, J., Ayonrinde, O., Bailey, R. J., Balakrishnan, M., Bambha, K., Bansal, M., Barritt, S., Bate, J., Beato, J., Behari, J., Bellot, P., Ben Ari, Z., Bennett, M., Berenguer, M., Beretta-Piccoli, B. T., Berg, T., Bonacini, M., Bonet, L., Borg, B., Bourliere, M., Bowman, W., Bradley, D., Brankovic, M., Braun, M., Bronowicki, J. -P., Bruno, S., Cai, C., Calleja Panero, J. L., Carey, E., Carmiel, M., Carrion, J. A., Cave, M., Chagas, C., Chami, T., Chang, A., Coates, A., Cobbold, J., Corey, K., Corless, L., Crespo, J., Cruz Pereira, O., de Ledinghen, V., Delemos, A., Diago, M., Dugalic, P., Dunn, W., Elkhashab, M., Epstein, M., Escudero-Garcia, M. D., Etzion, O., Evans, L., Falcone, R., Fernandez, C., Ferreira, J., Fink, S., Finnegan, K., Firpi-Morell, R., Floreani, A., Fontanges, T., Ford, R., Forrest, E., Fowell, A., Fracanzani, A. L., Francque, S., Freilich, B., Frias, J., Fuchs, M., Fuentes, J., Galambos, M., Gallegos, J., Geerts, A., George, J., Ghali, M., Ghalib, R., Gholam, P., Gines, P., Gitlin, N., Goeser, T., Goff, J., Gordon, S., Gordon, F., Goria, O., Greer, S., Grigorian, A., Gronbaek, H., Guillaume, M., Gunaratnam, N., Halegoua-De Marzio, D., Hameed, B., Hametner, S., Hamilton, J., Hartleb, M., Hassanein, T., Haussinger, D., Hellstern, P., Herring, R., Heurich, E., Hezode, C., Hinrichsen, H., Holland Fischer, P., Horsmans, Y., Huang, J., Jakiche, A., Jeffers, L., Jones, B., Jorge, R., Jorquera, F., Kahraman, A., Kaita, K., Karyotakis, N., Kayali, Z., Kechagias, S., Kepczyk, T., Khalili, M., Khallafi, H., Kluwe, J., Kohli, A., Korenblat, K., Kowdley, K., Krag, A., Krause, R., Kremer, A., Krok, K., Krstic, M., Kugelmas, M., Kumar, S., Labarriere, D., Lai, M., Lampertico, P., Lee, A., Leroy, V., Lidofsky, S., Lim, T. H., Lim, J., Lipkis, D., Little, E., Lonardo, A., Long, M., Lurie, Y., Macedo, G., Makara, M., Maliakkal, B., Manns, M., Manousou, P., Mantry, P., Marchesini, G., Marinho, C., Marotta, P., Marschall, H. -U., Mayo, M., Mccullen, M., Mclaughlin, W., Merriman, R., Modi, A., Molina, E., Montano-Loza, A., Monteverde, C., Moreea, S., Moreno, C., Morisco, F., Mubarak, A., Muellhaupt, B., Mukherjee, S., Muller, T., Nagorni, A., Naik, J., Neff, G., Nevah, M., Newsome, P., Nguyen-Khac, E., Noureddin, M., Oben, J., Orlent, H., Orr, J., Ortiz-Lasanta, G., Ozenne, V., Pandya, P., Paredes, A., Park, J., Patel, J., Patel, K., Uta, M., Patton, H., Peck-Radosavljevic, M., Petta, S., Pianko, S., Piekarska, A., Pimstone, N., Pockros, P., Pol, S., Porayko, M., Poulos, J., Pound, D., Pouzar, J., Presa Ramos, J., Pyrsopoulos, N., Rafiq, N., Muller, K., Ramji, A., Ravinuthala, R., Reddy, C., Reddy K G, G., Reddy K R, K. R., Regenstein, F., Reindollar, R., Riera, A., Rivera Acosta, J., Robaeys, G., Roberts, S., Rodriguez-Perez, F., Romero-Gomez, M., Rubin, R., Rumi, M., Rushbrook, S., Rust, C., Ryan, M., Safadi, R., Said, A., Salminen, K., Samuel, D., Santoro, J., Sanyal, A., Sarkar, S., Schaeffer, C., Schattenberg, J., Schiefke, I., Schiff, E., Schmidt, W., Schneider, J., Schouten, J., Schultz, M., Sebastiani, G., Semela, D., Sepe, T., Sheikh, A., Sheikh, M., Sherman, K., Shibolet, O., Shiffman, M., Siddique, A., Sieberhagen, C., Sigal, S., Sikorska, K., Simon, K., Sinclair, M., Skoien, R., Solis, J., Sood, S., Souder, B., Spivey, J., Stal, P., Stinton, L., Strasser, S., Svorcan, P., Szabo, G., Talal, A., Tam, E., Tetri, B., Thuluvath, P., Tobias, H., Tomasiewicz, K., Torres, D., Trauner, M., Trautwein, C., Tsochatzis, E., Unitt, E., Vargas, V., Varkonyi, I., Veitsman, E., Vespasiani Gentilucci, U., Victor, D., Vierling, J., Vincent, C., Vincze, A., von der Ohe, M., Von Roenn, N., Vuppalanchi, R., Waters, M., Watt, K., Weltman, M., Wieland, A., Wiener, G., Williams A, A., Williams J, J., Wilson, J., Yataco, M., Yoshida, E., Younes, Z., Yuan, L., Zivony, A., Zogg, D., Zoller, H., Zoulim, F., Zuckerman, E., Zuin, M., Younossi, Zobair M, Ratziu, Vlad, Loomba, Rohit, Rinella, Mary, Anstee, Quentin M, Goodman, Zachary, Bedossa, Pierre, Geier, Andrea, Beckebaum, Susanne, Newsome, Philip N, Sheridan, David, Sheikh, Muhammad Y, Trotter, Jame, Knapple, Whitfield, Lawitz, Eric, Abdelmalek, Manal F, Kowdley, Kris V, Montano-Loza, Aldo J, Boursier, Jerome, Mathurin, Philippe, Bugianesi, Elisabetta, Mazzella, Giuseppe, Olveira, Antonio, Cortez-Pinto, Helena, Graupera, Isabel, Orr, David, Gluud, Lise Lotte, Dufour, Jean-Francoi, Shapiro, David, Campagna, Jason, Zaru, Luna, MacConell, Leigh, Shringarpure, Reshma, Harrison, Stephen, Sanyal, Arun J, Abdelmalek, Manal, Abrams, Gary, Aguilar, Humberto, Ahmed, Aijaz, Aigner, Elmar, Aithal, Guruprasad, Ala, Aftab, Alazawi, William, Albillos, Agustin, Allison, Michael, Al-Shamma, Sfa, Andrade, Raul, Andreone, Pietro, Angelico, Mario, Ankoma-Sey, Victor, Anstee, Quentin, Anty, Rodolphe, Araya, Victor, Arenas Ruiz, Juan Ignacio, Arkkila, Perttu, Arora, Marty, Asselah, Tarik, Au, Jennifer, Ayonrinde, Oyekoya, Bailey, Robert Jame, Balakrishnan, Maya, Bambha, Kiran, Bansal, Meena, Barritt, Sidney, Bate, John, Beato, Jorge, Behari, Jaideep, Bellot, Pablo, Ben Ari, Ziv, Bennett, Michael, Berenguer, Marina, Beretta-Piccoli, Benedetta Terziroli, Berg, Thoma, Bonacini, Maurizio, Bonet, Lucia, Borg, Brian, Bourliere, Marc, Bowman, William, Bradley, David, Brankovic, Marija, Braun, Mariu, Bronowicki, Jean-Pierre, Bruno, Savino, Cai, Cindy, Calleja Panero, José Lui, Carey, Elizabeth, Carmiel, Michal, Carrión, Jose Antonio, Cave, Matthew, Chagas, Cristina, Chami, Tawfik, Chang, Alan, Coates, Allan, Cobbold, Jeremy, Corey, Kathleen, Corless, Lynsey, Crespo, Javier, Cruz Pereira, Oscar, de Ledinghen, Victor, deLemos, Andrew, Diago, Moise, Dufour, Jean-Françoi, Dugalic, Predrag, Dunn, Winston, Elkhashab, Magby, Epstein, Michael, Escudero-Garcia, Maria Desamparado, Etzion, Ohad, Evans, Larry, Falcone, Robert, Fernandez, Conrado, Ferreira, Jose, Fink, Scott, Finnegan, Kevin, Firpi-Morell, Roberto, Floreani, Annarosa, Fontanges, Thierry, Ford, Ryan, Forrest, Ewan, Fowell, Andrew, Fracanzani, Anna Ludovica, Francque, Sven, Freilich, Bradley, Frias, Juan, Fuchs, Michael, Fuentes, Javier, Galambos, Michael, Gallegos, Juan, Geerts, Anja, George, Jacob, Ghali, Maged, Ghalib, Reem, Gholam, Pierre, Gines, Pere, Gitlin, Norman, Goeser, Tobia, Goff, John, Gordon, Stuart, Gordon, Frederic, Goria, Odile, Greer, Shaun, Grigorian, Alla, Gronbaek, Henning, Guillaume, Maeva, Gunaratnam, Naresh, Halegoua-De Marzio, Dina, Hameed, Bilal, Hametner, Stephanie, Hamilton, Jame, Hartleb, Marek, Hassanein, Tarek, Häussinger, Dieter, Hellstern, Paul, Herring, Robert, Heurich, Eva, Hezode, Christophe, Hinrichsen, Holger, Holland Fischer, Peter, Horsmans, Yve, Huang, Jonathan, Jakiche, Antoine, Jeffers, Lennox, Jones, Blake, Jorge, Rosa, Jorquera, Francisco, Kahraman, Alisan, Kaita, Kelly, Karyotakis, Nichola, Kayali, Zeid, Kechagias, Stergio, Kepczyk, Thoma, Khalili, Mandana, Khallafi, Hicham, Kluwe, Johanne, Kohli, Anita, Korenblat, Kevin, Kowdley, Kri, Krag, Aleksander, Krause, Richard, Kremer, Andrea, Krok, Karen, Krstic, Miodrag, Kugelmas, Marcelo, Kumar, Sonal, Labarriere, Damien, Lai, Michelle, Lampertico, Pietro, Lee, Alice, Leroy, Vincent, Lidofsky, Steven, Lim, Tina Huey, Lim, Joseph, Lipkis, Donald, Little, Ester, Lonardo, Amadeo, Long, Michelle, Lurie, Yoav, Macedo, Guilherme, Makara, Mihály, Maliakkal, Benedict, Manns, Michael, Manousou, Pinelopi, Mantry, Parvez, Marchesini, Giulio, Marinho, Carla, Marotta, Paul, Marschall, Hanns-Ulrich, Mayo, Marlyn, McCullen, Mark, McLaughlin, William, Merriman, Raphael, Modi, Apurva, Molina, Esther, Montano-Loza, Aldo, Monteverde, Carlo, Moreea, Sulleman, Moreno, Christophe, Morisco, Filomena, Mubarak, Abdullah, Muellhaupt, Beat, Mukherjee, Sandeep, Müller, Tobia, Nagorni, Aleksandar, Naik, Jahnavi, Neff, Guy, Nevah, Moise, Newsome, Philip, Nguyen-Khac, Eric, Noureddin, Mazen, Oben, Jude, Orlent, Han, Orr, Jame, Ortiz-Lasanta, Grisell, Ozenne, Violaine, Pandya, Prashant, Paredes, Angelo, Park, Jame, Patel, Joykumar, Patel, Keyur, Uta, Merle, Patton, Heather, Peck-Radosavljevic, Marku, Petta, Salvatore, Pianko, Stephen, Piekarska, Anna, Pimstone, Neville, Pockros, Paul, Pol, Stanisla, Porayko, Michael, Poulos, John, Pound, David, Pouzar, Joe, Presa Ramos, Jose, Pyrsopoulos, Nikolao, Rafiq, Nila, Muller, Kate, Ramji, Alnoor, Ravinuthala, Ravi, Reddy, Chakradhar, Reddy K G, Gautham, Reddy K R, K. Rajender, Regenstein, Frederic, Reindollar, Robert, Riera, Andre, Rivera Acosta, Jose, Robaeys, Geert, Roberts, Stuart, Rodriguez-Perez, Federico, Romero-Gomez, Manuel, Rubin, Raymond, Rumi, Mariagrazia, Rushbrook, Simon, Rust, Christian, Ryan, Michael, Safadi, Rifaat, Said, Adnan, Salminen, Kimmo, Samuel, Didier, Santoro, John, Sanyal, Arun, Sarkar, Souvik, Schaeffer, Cynthia, Schattenberg, Jörn, Schiefke, Ingolf, Schiff, Eugene, Schmidt, Wolfgang, Schneider, Jeffrey, Schouten, Jeoffrey, Schultz, Michael, Sebastiani, Giada, Semela, David, Sepe, Thoma, Sheikh, Aasim, Sheikh, Muhammad, Sherman, Kenneth, Shibolet, Oren, Shiffman, Mitchell, Siddique, Asma, Sieberhagen, Cyril, Sigal, Samuel, Sikorska, Katarzyna, Simon, Krzysztof, Sinclair, Marie, Skoien, Richard, Solis, Joel, Sood, Siddharth, Souder, Bob, Spivey, Jame, Stal, Per, Stinton, Laura, Strasser, Simone, Svorcan, Petar, Szabo, Gyongzi, Talal, Andrew, Tam, Edward, Tetri, Brent, Thuluvath, Paul, Tobias, Hillel, Tomasiewicz, Krzysztof, Torres, Dawn, Trauner, Michael, Trautwein, Christian, Tsochatzis, Emanuel, Unitt, Esther, Vargas, Victor, Varkonyi, Istvan, Veitsman, Ella, Vespasiani Gentilucci, Umberto, Victor, David, Vierling, John, Vincent, Catherine, Vincze, Aron, von der Ohe, Manfred, Von Roenn, Natasha, Vuppalanchi, Raj, Waters, Michael, Watt, Kymberly, Weltman, Martin, Wieland, Amanda, Wiener, Gregory, Williams A, Alonzo, Williams J, Jeffrey, Wilson, Jason, Yataco, Maria, Yoshida, Eric, Younes, Ziad, Yuan, Liyun, Zivony, Adam, Zogg, Donald, Zoller, Heinz, Zoulim, Fabien, Zuckerman, Eli, Zuin, Massimo, and REGENERATE Study Investigators

Subjects
Male, Biopsy, Clinical Trial, Phase III, Administration, Oral, 030204 cardiovascular system & hematology, Chronic liver disease, Settore MED/04, Biomarkers/analysis, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Liver Function Tests, Non-alcoholic Fatty Liver Disease, Clinical endpoint, Medicine, 030212 general & internal medicine, 610 Medicine & health, Chenodeoxycholic Acid/administration & dosage, education.field_of_study, Liver Function Test, Research Support, Non-U.S. Gov't, Fatty liver, Obeticholic acid, NASH, OBETICHOLIC ACID, General Medicine, Middle Aged, Multicenter Study, Randomized Controlled Trial, Administration, Female, Biomarkers, Chenodeoxycholic Acid, Double-Blind Method, Humans, Human, Oral, medicine.medical_specialty, Population, Placebo, 03 medical and health sciences, Research Support, N.I.H., Extramural, Internal medicine, Journal Article, education, Intention-to-treat analysis, business.industry, Biomarker, Interim analysis, medicine.disease, Non-alcoholic Fatty Liver Disease/drug therapy, chemistry, Human medicine, business
Abstract

© 2019 Elsevier Ltd. All rights reserved., Background: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.

Published
2019
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