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Efe C, Lytvyak E, Eşkazan T, Liberal R, Androutsakos T, Turan Gökçe D, Terziroli Beretta-Piccoli B, Janik M, Bernsmeier C, Arvaniti P, Milkiewicz P, Batibay E, Yüksekyayla O, Ergenç I, Arikan Ç, Stättermayer AF, Barutçu S, Cengiz M, Gül Ö, Heurgue A, Heneghan MA, Verma S, Purnak T, Törüner M, Akdogan Kayhan M, Hatemi I, Zachou K, Macedo G, Drenth JPH, Björnsson E, Montano-Loza AJ, Wahlin S, Higuera-de la Tijera F. Efficacy and safety of infliximab in patients with autoimmune hepatitis. Hepatology 2025; 81:1660-1670. [PMID: 39250458 DOI: 10.1097/hep.0000000000001089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 08/24/2024] [Indexed: 09/11/2024]
Abstract
BACKGROUND AND AIMS A limited number of drugs are used as standard or alternative therapies in autoimmune hepatitis (AIH). No specific recommendations are available for patients failing to respond to these therapies. We analyzed the efficacy and safety of infliximab in patients with AIH. APPROACH AND RESULTS We performed a retrospective study of 42 patients with AIH who received infliximab at 21 liver centers in 12 countries. Patients were categorized according to the reason for infliximab therapy. Patients in group 1 (n=20) had failed standard, second-line (mycophenolate mofetil and 6-mercaptopurine) or third-line (tacrolimus or cyclosporine) therapy. In group 2 (n=22), infliximab was given for treatment of concomitant extrahepatic autoimmune diseases. Patients received a median of 17 (range: 3-104) infliximab infusions. Complete biochemical response (CR) was achieved or maintained in 33 (78%) patients during infliximab therapy. In group 1, infliximab induced CR in 11 of 20 (55%) patients. In group 2, 16 patients with CR prior to infliximab maintained remission, and the remaining 6 patients with active AIH (5 on standard and 1 on both second-line and third-line therapy) showed CR following infliximab therapy. Infliximab led to CR in 75% (6/8) of nonresponders to second-line and in 46% (6/13) of failing third-line therapy. Overall, 65% (17/26) of the patients with active AIH achieved CR on infliximab. Infliximab was discontinued in 3 patients of group 1. One patient had a severe allergic reaction and 2 developed anti-infliximab autoantibodies. CONCLUSIONS Our study suggests that infliximab may be an effective and safe rescue therapy in AIH.
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Affiliation(s)
- Cumali Efe
- Department of Gastroenterology, Harran University Hospital, Şanliurfa, Turkey
| | - Ellina Lytvyak
- Division of Gastroenterology, University of Alberta, Liver Unit, Edmonton, Alberta, Canada
| | - Tuğçe Eşkazan
- Department of Gastroenterology, Cerrahpaşa School of Medicine, İstanbul, Turkey
| | - Rodrigo Liberal
- Gastroenterology and Hepatology Department, Centro Hospitalar e Universitário de São João, Porto, Portugal
- World Gastroenterology Organization (WGO) Porto Training Center, Porto, Portugal
| | - Theodoros Androutsakos
- Department of Pathophysiology, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | | | - Benedetta Terziroli Beretta-Piccoli
- Faculty of Biomedical Sciences, Università Della Svizzera Italiana, Epatocentro Ticino, Lugano, Switzerland. Collaborative Partner European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Maciej Janik
- Department of Hepatology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland. Full member European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Christine Bernsmeier
- Department of Biomedicine, University of Basel, Basel, Switzerland
- University Centre for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Pinelopi Arvaniti
- Department of Medicine and Research Laboratory of Internal Medicine, Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; Full member European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Piotr Milkiewicz
- Department of Hepatology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland. Full member European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- Translational Medicine Group, Pomeranian Medical University in Szczecin, Poland
| | - Ersin Batibay
- Department of Gastroenterology, Harran University Hospital, Şanliurfa, Turkey
| | - Osman Yüksekyayla
- Department of Gastroenterology, Harran University Hospital, Şanliurfa, Turkey
| | - Ilkay Ergenç
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK; Collaborative Partner European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Çiğdem Arikan
- Department of Pediatric Gastroenterology and Hepatology, Koc University School of Medicine, Istanbul, Turkey
| | - Albert F Stättermayer
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; Rare Liver Disease (RALID), Affiliated Partner European Reference Network for Rare Hepatological Diseases (ERN RARE-LIVER)
| | - Sezgin Barutçu
- Department of Gastroenterology, University of Gaziantep Medical Faculty, Gaziantep, Turkey
| | - Mustafa Cengiz
- Department of Gastroenterology Gülhane Training and Research Hospital Ankara, Turkey
| | - Özlem Gül
- Department of Gastroenterology, Lokman Hekim Üniversitesi Ankara Hastanesi, Ankara, Turkey
| | | | - Michael A Heneghan
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK; Collaborative Partner European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Sumita Verma
- Brighton and Sussex Medical School, University Hospitals Sussex NHS Foundation Trust, Brighton, UK
| | - Tuğrul Purnak
- Division of Gastroenterology, Hepatology and Nutrition, McGovern Medical School, Houston, Texas, USA
| | - Murat Törüner
- Department of Gastroenterology, Ankara University Medical Faculty, Ankara, Turkey
| | | | - Ibrahim Hatemi
- Department of Gastroenterology, Cerrahpaşa School of Medicine, İstanbul, Turkey
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; Full member European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Guilherme Macedo
- Gastroenterology and Hepatology Department, Centro Hospitalar e Universitário de São João, Porto, Portugal
- World Gastroenterology Organization (WGO) Porto Training Center, Porto, Portugal
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, The Netherlands; Collaborative Partner European Reference Network RARE-LIVER, Hamburg, Germany
| | - Einar Björnsson
- Faculty of Medicine, University of Iceland, Reykjavik
- Department of Gastroenterology and Hepatology, Landspitali University Hospital, Reykjavik, Iceland
| | - Aldo J Montano-Loza
- Division of Gastroenterology, University of Alberta, Liver Unit, Edmonton, Alberta, Canada
| | - Staffan Wahlin
- Department of Upper GI Diseases, Hepatology Division, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. Full member European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
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Chen Y, Chen R, Li H, Shuai Z. Clinical management of autoimmune liver diseases: juncture, opportunities, and challenges ahead. Immunol Res 2025; 73:67. [PMID: 40195209 PMCID: PMC11976385 DOI: 10.1007/s12026-025-09622-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 03/14/2025] [Indexed: 04/09/2025]
Abstract
The three major autoimmune liver diseases are autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC).These conditions are assumed to result from a breakdown in immunological tolerance, which leads to an inflammatory process that causes liver damage.The self-attack is started by T-helper cell-mediated identification of liver autoantigens and B-cell production of autoantibodies,and it is maintained by a reduction in the number and activity of regulatory T-cells.Infections and environmental factors have been explored as triggering factors for these conditions, in addition to a genetic predisposition.Allelic mutations in the HLA locus have been linked to vulnerability, as have relationships with single nucleotide polymorphisms in non-HLA genes.Despite the advances in the management of these diseases, there is no curative treatment for these disorders, and a significant number of patients eventually progress to an end-stage liver disease requiring liver transplantation.In this line, tailored immune-therapeutics have emerged as possible treatments to control the disease.In addition, early diagnosis and treatment are pivotal for reducing the long-lasting effects of these conditions and their burden on quality of life.Herein we present a review of the etiology, clinical presentation, diagnosis, and challenges on ALDs and the feasible solutions for these complex diseases.
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MESH Headings
- Humans
- Hepatitis, Autoimmune/therapy
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/immunology
- Hepatitis, Autoimmune/etiology
- Cholangitis, Sclerosing/therapy
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/immunology
- Liver Cirrhosis, Biliary/therapy
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/immunology
- Animals
- Immunotherapy/methods
- Autoimmune Diseases/therapy
- Autoimmune Diseases/diagnosis
- Disease Management
- Genetic Predisposition to Disease
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Affiliation(s)
- Yangfan Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Ruofei Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Haiyan Li
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Zongwen Shuai
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, China.
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Cananzi M, Jørgensen MH, Buescher G, De Bruyne R, Samyn M. Current practice in the management of paediatric autoimmune liver disease in Europe. J Pediatr Gastroenterol Nutr 2025; 80:260-270. [PMID: 39618087 DOI: 10.1002/jpn3.12424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 11/10/2024] [Accepted: 11/13/2024] [Indexed: 02/04/2025]
Abstract
OBJECTIVE Paediatric autoimmune liver disease (pAILD) is a rare condition with serious health implications. Notwithstanding treatment advancements, areas of uncertainty and knowledge gaps still exist. We here investigated the real-life approach to pAILD management in Europe. METHODS A survey was distributed to members of the European Rare Liver Disease Reference Network (ERN RARE-LIVER) and the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) Hepatology Interest Group. Information was gathered regarding clinical activity, medications used, and access to paediatric drug formulations at each site. RESULTS Thirty-six centres from 22 European countries responded to the survey. The majority are exclusively paediatric units (86%). Among participants, 80% follow <50 children with pAILD, of which 25%-50% are <10 years old in 44% of centres. All centres use predniso(lo)ne as first-line therapy, alone (15/36) or with azathioprine (21/36). Azathioprine and mycophenolate are the preferred second-line options in centres using first-line steroid monotherapy (11/15) or combined steroid-azathioprine (19/21), respectively. Tacrolimus is used as third-line agent in 15/36 centres. Proactive measurement of drug metabolites and target levels vary widely among centres. Paediatric predniso(lo)ne formulations are commercially available in 7/22 European countries, azathioprine in 3, mycophenolate in 14, tacrolimus in 15 and ursodeoxycholic acid in 14. When paediatric formulations are unavailable, children are treated with magisterial preparations or 'solid' formulations (crushed or intact). CONCLUSIONS Treatment of pAILD in Europe varies widely in terms of medications used and treatment monitoring. Availability of paediatric drug formulations across Europe is limited. Collaborative initiatives are needed to define evidence-based strategies for management of pAILD and to promote an equal, age-appropriate treatment for affected children.
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Affiliation(s)
- Mara Cananzi
- Unit of Paediatric Gastroenterology, Digestive Endoscopy, Hepatology and Care of the Child with Liver Transplantation, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy
| | | | - Gustav Buescher
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Ruth De Bruyne
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Ghent University Hospital, Belgium
| | - Marianne Samyn
- Paediatric Liver, GI and Nutrition Centre, King's College Hospital NHS Trust, London, UK
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Sandler YG, Vinnitskaya EV, Raikhelson KL, Ivashkin KV, Batskikh SN, Aleksandrova EN, Abdurakhmanov DT, Abdulganieva DI, Bakulin IG, Bueverov AO, Vorobyev SL, Gerasimova OA, Dolgushina AI, Zhuravleva MS, Ilchenko LY, Karev VE, Korochanskaya NV, Kliaritskaia IL, Karnaukhov NS, Lapin SV, Livzan MA, Maevskaya MV, Marchenko NV, Nekrasova TP, Nikitin IG, Novikov AA, Saifutdinov RG, Skazyvaeva EV, Syutkin VE, Prashnova MK, Khaymenova TY, Khomerik SG. Diagnosis and Treatment of Patients with Autoimmune Hepatitis (Experts’ Agreement). RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2024; 34:100-119. [DOI: 10.22416/1382-4376-2024-34-6-100-119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2025]
Abstract
Background. In the last decade, the understanding of the pathogenesis of autoimmune hepatitis (AIH) has significantly deepened, based on the results of new clinical studies some diagnostic issues have been revised and immunosuppressive therapy regimens have been optimized.Materials and methods. The latest Russian clinical guidelines for the diagnosis and treatment of AIH were presented in 2013; and in 2017, the first Russian agreement on the diagnosis and treatment of AIH was held. Updating approaches to the management of patients with AIH necessitated next systematization for use in clinical practice. In February 2024, the final session was held to discuss the provisions of the second agreement on the diagnosis and treatment of AIH.Results. This publication presents the main discussion points of the agreement regarding methods and algorithms for detecting autoantibodies, the role of liver biopsy, revised morphological criteria for AIH, optimized immunosuppressive therapy regimens, updated criteria for assessing the response to therapy.Conclusions. The agreement was the result of the work of a group of experts on the diagnosis and treatment of AIH and represents the basis for the creation of updated federal clinical guidelines.
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Affiliation(s)
| | | | | | - K. V. Ivashkin
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | | | | | | | | | - I. G. Bakulin
- North-Western State Medical University named after I.I. Mechnikov
| | - A. O. Bueverov
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - S. L. Vorobyev
- OOO National Center for Clinical Morphological Diagnostics
| | - O. A. Gerasimova
- Saint Petersburg State University;
Russian Scientific Center for Radiology and Surgical Technologies named after Academician A.M. Granov
| | | | - M. S. Zhuravleva
- North-Western State Medical University named after I.I. Mechnikov
| | | | - V. E. Karev
- Pediatric Research and Clinical Center for Infectious Diseases under the Federal Medical Biological Agency
| | | | | | | | - S. V. Lapin
- Academician I.P. Pavlov First St. Petersburg State Medical University
| | | | - M. V. Maevskaya
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - N. V. Marchenko
- Russian Scientific Center for Radiology and Surgical Technologies named after Academician A.M. Granov
| | - T. P. Nekrasova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - I. G. Nikitin
- N.I. Pirogov Russian National Research Medical University
| | | | - R. G. Saifutdinov
- Kazan State Medical Academy — Branch Campus of the Russian Medical Academy of Continuous Professional Education
| | - E. V. Skazyvaeva
- North-Western State Medical University named after I.I. Mechnikov
| | - V. E. Syutkin
- Medical and Biological University of Innovation and Continuous Education, State Research Center — Byrnasyan Federal Medical Biophysical Center of Federal Biological Agency;
N.V. Sklifosovsky Research Institute for Emergency Care of the Moscow City Health Department
| | - M. K. Prashnova
- Russian Scientific Center for Radiology and Surgical Technologies named after Academician A.M. Granov
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Costaguta A, Costaguta G, Álvarez F. Autoimmune hepatitis: Towards a personalized treatment. World J Hepatol 2024; 16:1225-1242. [PMID: 39606175 PMCID: PMC11586748 DOI: 10.4254/wjh.v16.i11.1225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 09/02/2024] [Accepted: 10/11/2024] [Indexed: 11/06/2024] Open
Abstract
Autoimmune hepatitis is an uncommon condition that affects both adults and children and is characterized by chronic and recurrent inflammatory activity in the liver. This inflammation is accompanied by elevated IgG and autoantibody levels. Historically, treatment consists of steroids with the addition of azathioprine, which results in remission in approximately 80% of patients. Despite significant advancements in our understanding of the immune system over the past two decades, few modifications have been made to treatment algorithms, which have remained largely unchanged since they were first proposed more than 40 years ago. This review summarized the various treatment options currently available as well as our experiences using them. Although steroids are the standard treatment for induction therapy, other medications may be considered. Cyclosporin A, a calcineurin inhibitor that decreases T cell activation, has proven effective for induction of remission, but its long-term side effects limit its appeal for maintenance. Tacrolimus, a drug belonging to the same family, has been used in patients with refractory diseases with fewer side effects. Sirolimus and everolimus have interesting effects on regulatory T cell populations and may become viable options in the future. Mycophenolate mofetil is not effective for induction but is a valid alternative for patients who are intolerant to azathioprine. B cell-depleting drugs, such as rituximab and belimumab, have been successfully used in refractory cases and are useful in both the short and long term. Other promising treatments include anti-tumor necrosis factors, Janus kinases inhibitors, and chimeric antigen receptor T cell therapy. This growing armamentarium allows us to imagine a more tailored approach to the treatment of autoimmune hepatitis in the near future.
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Affiliation(s)
- Alejandro Costaguta
- Department of Hepatology and Liver Transplant Unit, Sanatorio de Niños de Rosario, Rosario 2000, Santa Fe, Argentina.
| | - Guillermo Costaguta
- Department of Gastroenterology, Hepatology, and Nutrition, CHU Sainte-Justine, Montreal H3T 1C5, Quebec, Canada
| | - Fernando Álvarez
- Department of Pediatrics, CHU Sainte-Justine, Montreal H3T 1C5, Quebec, Canada
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Harrison L, Hoeroldt B, Dhaliwal H, Wadland E, Dube A, Gleeson D. Long-term Outcome of Autoimmune Hepatitis: Consecutive Patient Cohort and Data on the Second Twenty Years. Dig Liver Dis 2023; 55:1515-1520. [PMID: 37455155 DOI: 10.1016/j.dld.2023.06.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 06/14/2023] [Accepted: 06/16/2023] [Indexed: 07/18/2023]
Abstract
BACKGROUND Mortality rates for autoimmune hepatitis (AIH) vary. Data are lacking beyond 20 years follow-up. AIMS Analysis of a consecutively recruited large AIH cohort from a single non-transplant tertiary centre in England and an overlapping cohort, already followed for ≥ 20 years. METHODS We assessed 330 patients presenting 1987-2016 and 65 patients presenting 1971-96 already followed for 20 years. RESULTS Death/liver transplant rate was 51±4% (all-cause) and 21±4% (liver-related) over 20 years and was independently associated with: decompensation and lower serum ALT at diagnosis; and failure of serum ALT normalisation and higher relapse rate. There was excess mortality over the first year. Patients (n = 65) already followed for twenty years had similar subsequent rates of relapse, disease progression and mortality, to those followed from diagnosis. Azathioprine-intolerant patients (n = 23) switching to Mycophenolate did not have higher mortality over 4(1-17) years, than patients continuing Azathioprine. Following immunosuppression withdrawal (n = 26), six (23% patients) relapsed with no liver-related deaths over 2.3(0-23.1) years. CONCLUSIONS In this consecutive autoimmune hepatitis cohort, mortality was similar to that in national registry studies, disease progression continued after 20 years, and immunosuppression withdrawal did not compromise survival.
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Affiliation(s)
- Laura Harrison
- Liver Unit, Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Herries Road, Sheffield, S5 7AU, United Kingdom; Department of Infection, Immunity and Cardiovascular Disease, The University of Sheffield, Medical School, Beech Hill Road, Sheffield, United Kingdom.
| | - Barbara Hoeroldt
- Liver Unit, Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Herries Road, Sheffield, S5 7AU, United Kingdom
| | - Harpreet Dhaliwal
- Department of Hepatology, Manchester University NHS Foundation Trust, Cobbett House, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL
| | - Elaine Wadland
- Liver Unit, Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Herries Road, Sheffield, S5 7AU, United Kingdom
| | - Asha Dube
- Liver Unit, Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Herries Road, Sheffield, S5 7AU, United Kingdom
| | - Dermot Gleeson
- Liver Unit, Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Herries Road, Sheffield, S5 7AU, United Kingdom
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The Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines for management of autoimmune hepatitis 2022. Clin Mol Hepatol 2023; 29:542-592. [PMID: 37137334 PMCID: PMC10366804 DOI: 10.3350/cmh.2023.0087] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/27/2023] [Accepted: 04/03/2023] [Indexed: 05/05/2023] Open
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Winnicki W, Fichtenbaum A, Mitulovič G, Herkner H, Regele F, Baier M, Zelzer S, Wagner L, Sengoelge G. Individualization of Mycophenolic Acid Therapy through Pharmacogenetic, Pharmacokinetic and Pharmacodynamic Testing. Biomedicines 2022; 10:2882. [PMID: 36359401 PMCID: PMC9687418 DOI: 10.3390/biomedicines10112882] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/03/2022] [Accepted: 11/08/2022] [Indexed: 09/09/2024] Open
Abstract
Mycophenolic acid (MPA) is a widely used immunosuppressive agent and exerts its effect by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH), the main regulating enzyme of purine metabolism. However, significant unexplained differences in the efficacy and tolerability of MPA therapy pose a clinical challenge. Therefore, broad pharmacogenetic, pharmacokinetic, and pharmacodynamic approaches are needed to individualize MPA therapy. In this prospective cohort study including 277 renal transplant recipients, IMPDH2 rs11706052 SNP status was assessed by genetic sequencing, and plasma MPA trough levels were determined by HPLC and IMPDH enzyme activity in peripheral blood mononuclear cells (PBMCs) by liquid chromatography-mass spectrometry. Among the 277 patients, 84 were identified with episodes of biopsy-proven rejection (BPR). No association was found between rs11706052 SNP status and graft rejection (OR 1.808, and 95% CI, 0.939 to 3.479; p = 0.076). Furthermore, there was no association between MPA plasma levels and BPR (p = 0.69). However, the patients with graft rejection had a significantly higher predose IMPDH activity in PBMCs compared to the controls without rejection at the time of biopsy (110.1 ± 50.2 vs. 95.2 ± 45.4 pmol/h; p = 0.001), and relative to the baseline IMPDH activity before transplantation (p = 0.042). Our results suggest that individualization of MPA therapy, particularly through pharmacodynamic monitoring of IMPDH activity in PBMCs, has the potential to improve the clinical outcomes of transplant patients.
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Affiliation(s)
- Wolfgang Winnicki
- Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, 1090 Vienna, Austria
| | - Andreas Fichtenbaum
- Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria
| | - Goran Mitulovič
- Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria
| | - Harald Herkner
- Department of Emergency Medicine, Medical University of Vienna, 1090 Vienna, Austria
| | - Florina Regele
- Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, 1090 Vienna, Austria
| | - Michael Baier
- Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, 1090 Vienna, Austria
| | - Sieglinde Zelzer
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria
| | - Ludwig Wagner
- Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, 1090 Vienna, Austria
| | - Guerkan Sengoelge
- Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, 1090 Vienna, Austria
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Zhang K, Li J, Shi Z, Zhu Y, Yang J, Liu X, Que R, Lin L, Chen Y, Li Y. Ginsenosides Regulates Innate Immunity to Affect Immune Microenvironment of AIH Through Hippo-YAP/TAZ Signaling Pathway. Front Immunol 2022; 13:851560. [PMID: 35222444 PMCID: PMC8874200 DOI: 10.3389/fimmu.2022.851560] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 01/24/2022] [Indexed: 12/02/2022] Open
Abstract
Autoimmune hepatitis (AIH) is characterized by chronic progressive liver inflammatory, but there is still no safe and effective medicine. Therefore, glucocorticoid remains the top choice for AIH treatment. In previous studies, it has been confirmed that ginsenosides (GSS) can produce glucocorticoid-like effects and therapeutic effects on various autoimmune diseases. However, the mechanism of GSS for AIH remains unclear. As an important part of the innate immune system, bone marrow-derived suppressor cells (MDSC) have been identified as an important driver of follow-up acquired immune response in many autoimmune diseases, including AIH. Herein, it was found out that GSS intervention can be effective in regulating the immune microenvironment and liver impairment induced by Con A in AIH mice. In vitro, the MDSCs derived from healthy mice and the T cells deried from AIH mice were co-cultured. Then, different drugs were intervened with to explore the therapeutic mechanism. Besides, the proliferation and differentiation of MDSCs and T cells were analyzed by flow cytometry, while GR, Hippo-YAP signal pathway and the expression of MDSC-related genes and proteins were detected through qRT-PCR and Western Blot. The changes in NO and ROS levels were further analyzed. The trend of related cytokines expression (IFN- γ, TGF- β, IL-10, IL-6, IL-17) was detected by ELISA. Furthermore, an analysis was conducted as to the ALT and liver pathology of mice for evaluating the liver function of mice. It was discovered that MDSCs proliferation was inhibited, and that T cells tended to differentiate into Th17 rather than Treg in AIH mice. Moreover, the intervention of GSS activated GR and Yap, in addition to promoting the proliferation of MDSCs, especially M-MDSCs. This further promoted the differentiation of Treg to enable immune tolerance, thus alleviating liver impairment. Therefore, it was proposed that GSS can alleviate AIH by modulating the innate immunity and adaptive T cell immunity, which may be the underlying mechanism for GSS to mitigate the liver impairment induced by AIH.
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Affiliation(s)
- Kehui Zhang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiacheng Li
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhe Shi
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yingying Zhu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Yang
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Vascular Surgery, The Seventh People’s Hospital of Shanghai, Shanghai, China
| | - Xiaolin Liu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Renye Que
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Liubing Lin
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yirong Chen
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yong Li
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Yong Li,
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. Autoimmmune hepatitis. Cell Mol Immunol 2022; 19:158-176. [PMID: 34580437 PMCID: PMC8475398 DOI: 10.1038/s41423-021-00768-8] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 08/29/2021] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a T-cell mediated, inflammatory liver disease affecting all ages and characterized by female preponderance, elevated serum transaminase and immunoglobulin G levels, positive circulating autoantibodies, and presence of interface hepatitis at liver histology. AIH type 1, affecting both adults and children, is defined by positive anti-nuclear and/or anti-smooth muscle antibodies, while type 2 AIH, affecting mostly children, is defined by positive anti-liver-kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody. While the autoantigens of type 2 AIH are well defined, being the cytochrome P4502D6 (CYP2D6) and the formiminotransferase cyclodeaminase (FTCD), in type 1 AIH they remain to be identified. AIH-1 predisposition is conferred by possession of the MHC class II HLA DRB1*03 at all ages, while DRB1*04 predisposes to late onset disease; AIH-2 is associated with possession of DRB1*07 and DRB1*03. The majority of patients responds well to standard immunosuppressive treatment, based on steroid and azathioprine; second- and third-line drugs should be considered in case of intolerance or insufficient response. This review offers a comprehensive overview of pathophysiological and clinical aspects of AIH.
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Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- Epatocentro Ticino & Facoltà di Scienze Biomediche, Università della Svizzera Italiana, Lugano, Switzerland.
- Institute for Research in Biomedicine, Bellinzona, Switzerland.
- King's College London Faculty of Life Sciences & Medicine at King's College Hospital, London, UK.
| | - Giorgina Mieli-Vergani
- King's College London Faculty of Life Sciences & Medicine at King's College Hospital, London, UK
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, London, UK
| | - Diego Vergani
- King's College London Faculty of Life Sciences & Medicine at King's College Hospital, London, UK
- Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK
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11
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Dorsey YC, Oloruntoba O, Pendse AA, King LY. More Than Meets the Eye? Clin Liver Dis (Hoboken) 2021; 18:173-178. [PMID: 34745573 PMCID: PMC8549717 DOI: 10.1002/cld.1107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 02/12/2021] [Indexed: 02/04/2023] Open
Abstract
Content available: Author Audio Recording.
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Affiliation(s)
- Ying Claire Dorsey
- Division of Gastroenterology and HepatologyDuke University School of MedicineDurhamNC
| | - Omobonike Oloruntoba
- Division of Gastroenterology and HepatologyDuke University School of MedicineDurhamNC
| | - Avani A. Pendse
- Department of PathologyDuke University School of MedicineDurhamNC
| | - Lindsay Y. King
- Division of Gastroenterology and HepatologyDuke University School of MedicineDurhamNC
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12
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Liberal R, de Boer YS, Heneghan MA. Established and novel therapeutic options for autoimmune hepatitis. Lancet Gastroenterol Hepatol 2021; 6:315-326. [DOI: 10.1016/s2468-1253(20)30328-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 08/14/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023]
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13
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Efe C. Tacrolimus as second-line therapy in acute severe autoimmune hepatitis. Scand J Gastroenterol 2021; 56:298. [PMID: 33369499 DOI: 10.1080/00365521.2020.1867890] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 12/13/2020] [Accepted: 12/18/2020] [Indexed: 02/04/2023]
Affiliation(s)
- Cumali Efe
- Department of Gastroenterology, Harran University, Şanlıurfa, Turkey
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14
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Wahlin S, Efe C. Both tacrolimus and mycophenylate mophetil should be considered second-line therapy for autoimmune hepatitis. J Hepatol 2021; 74:753-755. [PMID: 33309114 DOI: 10.1016/j.jhep.2020.09.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 09/15/2020] [Indexed: 12/19/2022]
Affiliation(s)
- Staffan Wahlin
- Hepatology Division, Department of Upper GI Diseases, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
| | - Cumali Efe
- Department of Gastroenterology, Harran University, Şanlıurfa, Turkey
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15
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Demir N, Ekin N, Torgutalp M, Wahlin S, Efe C. Two decades of research on autoimmune liver disease in Turkey. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2020; 31:877-882. [PMID: 33626000 PMCID: PMC7928254 DOI: 10.5152/tjg.2020.19866] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 04/16/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND/AIMS Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are the 3 main autoimmune liver diseases (AILDs). The epidemiology of AILD in Turkey is not known. To determine the scientific status, we performed a scientometric analysis of AILD-related original articles that originated from Turkey. MATERIALS AND METHODS We searched the Web of Science database, the Science Citation Index Expanded (SCI-E), and the Social Sciences Citation Index (SSCI) by using the keywords "autoimmune hepatitis," "primary biliary cholangitis/primary biliary cirrhosis," and "primary sclerosing cholangitis" in conjunction with "Turkey." A scientometric analysis was done on the search results. RESULTS We identified 117 AILD-related papers that were published in Turkey from 1997 to 2019. Among these, 70 case reports, letters, and reviews and 2 original articles that were not cited in SCI-E/SSCI were excluded. The remaining 45 original articles were further analyzed. These studies were related to AIH (n=22), PBC (n=7), PSC (n=9), PBC-AIH overlap (n=5), and others (n=2). Four of the publications originated in pediatric settings; 9 of 45 papers were published from 1997 to 2008 and 36 papers were published from 2009 to 2019. Most papers (75%) were reported from 5 centers; 9 papers (20%) were published in journals with an impact factor of 3 or higher. CONCLUSION The overall number and quality of AILD-related papers in Turkey are unexpectedly low, although a number of papers have received considerable international recognition. More epidemiologic, prospective, and multicenter research projects are warranted to advance AILD knowledge and to produce high-quality research from Turkey.
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Affiliation(s)
- Nurhan Demir
- Department of Gastroenterology, Diyarbakir Health Science University Training and Research Hospital, Diyarbakır, Turkey
| | - Nazım Ekin
- Department of Gastroenterology, Diyarbakir Health Science University Training and Research Hospital, Diyarbakır, Turkey
| | - Murat Torgutalp
- Department of Rheumatology, Ankara University and Ibni-Sina Hospital, Ankara, Turkey
| | - Staffan Wahlin
- Division of Hepatology, Centre for Digestive Diseases, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Cumali Efe
- Department of Gastroenterology, Harran University School of Medicine, Şanlıurfa, Turkey
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16
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Second-line and third-line therapy for autoimmune hepatitis: A position statement from the European Reference Network on Hepatological Diseases and the International Autoimmune Hepatitis Group. J Hepatol 2020; 73:1496-1506. [PMID: 32707224 DOI: 10.1016/j.jhep.2020.07.023] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/08/2020] [Accepted: 07/11/2020] [Indexed: 02/06/2023]
Abstract
Most patients with autoimmune hepatitis respond well to standard immunosuppressive therapy with steroids and azathioprine, and while untreated disease is usually fatal, patients who respond well to therapy have an excellent prognosis. However, insufficient response to standard therapy or intolerable side effects requiring dose adaptions or treatment changes occur in 10-20% of patients. While there is fairly good agreement on second-line treatment options, there is very wide variation in the indication and use of possible third-line therapies. Herein, the European Reference Network on Hepatological Diseases (ERN RARE-LIVER) and the International Autoimmune Hepatitis Group (IAIHG) outline a treatment algorithm for both children and adults that should help to standardise treatment approaches, in order to improve patient care and to enable the comparison of treatment results between scientific publications.
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17
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Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, Vierling JM, Alsawas M, Murad MH, Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology 2020; 72:671-722. [PMID: 31863477 DOI: 10.1002/hep.31065] [Citation(s) in RCA: 548] [Impact Index Per Article: 109.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Cara L Mack
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - David Adams
- Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - David N Assis
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT
| | - Nanda Kerkar
- Golisano Children's Hospital at Strong, University of Rochester Medical Center, New York, NY
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marlyn J Mayo
- Division of Digestive and Liver Diseases, University of Texas SW Medical Center, Dallas, TX
| | - John M Vierling
- Medicine and Surgery, Baylor College of Medicine, Houston, TX
| | | | - Mohammad H Murad
- Mayo Knowledge and Encounter Research Unit, Mayo Clinic College of Medicine, Rochester, MN
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
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18
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Vierling JM, Kerkar N, Czaja AJ, Mack CL, Adams D, Assis DN, Manns MP, Mayo MJ, Nayfeh T, Majzoub AMM, Alzuabi MA, Ding J, Haffar S, Murad MH, Alsawas M. Immunosuppressive Treatment Regimens in Autoimmune Hepatitis: Systematic Reviews and Meta-Analyses Supporting American Association for the Study of Liver Diseases Guidelines. Hepatology 2020; 72:753-769. [PMID: 32500593 DOI: 10.1002/hep.31407] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/30/2020] [Accepted: 05/26/2020] [Indexed: 12/13/2022]
Affiliation(s)
- John M Vierling
- Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Nanda Kerkar
- Department of Pediatrics, University of Rochester School of Medicine, Rochester, NY, USA
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Cara L Mack
- Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA
| | - David Adams
- College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - David N Assis
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marlyn J Mayo
- University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Tarek Nayfeh
- Mayo Clinic Evidence-Based Practice Research Program, Rochester, MN, USA
| | | | - Muayad A Alzuabi
- Mayo Clinic Evidence-Based Practice Research Program, Rochester, MN, USA
| | - Jingyi Ding
- Mayo Clinic Evidence-Based Practice Research Program, Rochester, MN, USA
| | - Samir Haffar
- Mayo Clinic Evidence-Based Practice Research Program, Rochester, MN, USA
| | - M Hassan Murad
- Mayo Clinic Evidence-Based Practice Research Program, Rochester, MN, USA
| | - Mouaz Alsawas
- Mayo Clinic Evidence-Based Practice Research Program, Rochester, MN, USA
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Czaja AJ. Review article: opportunities to improve and expand thiopurine therapy for autoimmune hepatitis. Aliment Pharmacol Ther 2020; 51:1286-1304. [PMID: 32363674 DOI: 10.1111/apt.15743] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 03/07/2020] [Accepted: 03/31/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use. AIMS To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response. METHODS English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. RESULTS Thiopurine methyltransferase activity and 6-tioguanine (6-thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre-treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose-restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6-tioguanine nucleotides and ameliorating thiopurine intolerance or resistance. CONCLUSIONS The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
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20
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Czaja AJ. Autoimmune Hepatitis: Surviving Crises of Doubt and Elimination. Clin Liver Dis (Hoboken) 2020; 15:S72-S81. [PMID: 32140216 PMCID: PMC7050953 DOI: 10.1002/cld.917] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 12/05/2019] [Indexed: 02/04/2023] Open
Affiliation(s)
- Albert J. Czaja
- Division of Gastroenterology and HepatologyMayo Clinic College of Medicine and ScienceRochesterMN
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21
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Comparison of mycophenolate mofetil with standard treatment for autoimmune hepatitis: a meta-analysis. Eur J Gastroenterol Hepatol 2019; 31:873-877. [PMID: 31150366 DOI: 10.1097/meg.0000000000001367] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To systematically evaluate the efficacy of mycophenolate mofetil (MMF) compared with the standard treatment for autoimmune hepatitis. METHODS Medline (PubMed), Embase, and Cochrane Library databases were searched between 1966 and June 2018 for studies on prednisone and/or azathioprine/mycophenolate mofetil in autoimmune hepatitis. The keywords and descriptor terms used were 'hepatitis', 'autoimmunity', 'prednisone', 'prednisolone', 'azathioprine', and 'mycophenolate mofetil'. The Z test and Cochrane Q test were used in the statistical analysis. RESULTS Seven hundred and eighty-eight related articles were found; 779 studies were excluded after further review. Ultimately, seven studies (583 participants) were included. The remission rate of aminotransferase and immunoglobulin (Ig)-G levels with standard treatment was 33.33-86.67%, and the nonresponse rate was 15.15-66.67%. Although the remission rate of the aminotransferase level with prednisone and MMF was 55.17-88.89% and that of the IgG level was 61.16-88.89%, the nonresponse rate was 6.42-33.33%. Remission rates of the aminotransferase level (P<0.05, I=49%) and IgG level (P<0.01, I=0) with MMF were superior to those of standard treatment, and the nonresponse rate was lower (P<0.01, I=0). For those with no response to the standard treatment who were switched to MMF, the remission rates were 0, 13.33, 22.22, 25, and 34.04%. Sequential treatment with MMF was effective (P<0.01, I=90%). CONCLUSION Compared with the standard treatment, the combination of prednisone and MMF as a first-line treatment enables patients with autoimmune hepatitis to obtain higher remission rates of aminotransferase and IgG levels and a lower nonresponse rate. The validity and safety of long-term MMF use needs investigated further.
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Giannakopoulos G, Verbaan H, Friis-Liby IL, Sangfelt P, Nyhlin N, Almer S. Mycophenolate mofetil treatment in patients with autoimmune hepatitis failing standard therapy with prednisolone and azathioprine. Dig Liver Dis 2019; 51:253-257. [PMID: 30389427 DOI: 10.1016/j.dld.2018.10.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 09/19/2018] [Accepted: 10/03/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Data on rescue treatment of autoimmune hepatitis in patients that fail standard treatment are sparse. AIMS To report our long-term experience with mycophenolate mofetil. METHODS Retrospective study in 22 patients with autoimmune hepatitis who failed azathioprine and prednisolone due to adverse events (n = 14, 64%), lack of remission (n = 5, 23%) or a combination (n = 3, 13%). RESULTS Mycophenolate mofetil was started at a dose of 20 mg/kg/day and increased to a maximum of 3 g/day. Follow-up was 0-6 months in 7 patients; more than 12 months in 15 (68%) and more than 24 months in 10. Normal aminotransferase levels were obtained (n = 3) or maintained (n = 7) in 10 patients (45%) after three to 30 weeks. 12 patients (55%) were withdrawn during the first 6 months, due to adverse events. Three patients were switched to cyclosporine and one underwent liver transplantation. Successful treatment with mycophenolate mofetil continued in 10 patients (45%) for a median of 71 months (range 20-124). Of these, one stopped prednisolone, five have a prednisolone dose <5 mg daily and four patients 5-10 mg. CONCLUSION Approximately one of two patients with autoimmune hepatitis that fail standard treatment benefit from long-term maintenance with mycophenolate mofetil, especially those with previous intolerance to thiopurines, where mycophenolate mofetil is effective in two thirds.
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Affiliation(s)
- Georgios Giannakopoulos
- Division of Gastroenterology, Department of Gastroenterology, Dermatology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - Hans Verbaan
- Department of Medicine, Skåne University Hospital, Malmö, Sweden
| | | | - Per Sangfelt
- Department of Medicine, Akademiska Hospital, Uppsala, Sweden
| | - Nils Nyhlin
- Department of Medicine, Örebro University Hospital, Örebro, Sweden
| | - Sven Almer
- Division of Gastroenterology, Department of Gastroenterology, Dermatology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
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23
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Juvenile autoimmune hepatitis: A comprehensive review. J Autoimmun 2018; 95:69-76. [DOI: 10.1016/j.jaut.2018.10.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Accepted: 10/13/2018] [Indexed: 12/12/2022]
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