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Anwar MT, Shahzil M, Arif TB, Khaqan MA, Co EL, Hasan F, Tarar R, Naeem H, Farooq S, Jaan A, Chaudhary AJ, Jahagirdar V, Salgia R. MMF Is an Effective and Safer Treatment Options for Treatment-Naïve Patients With Autoimmune Hepatitis Compared to Azathioprine: A Systematic Review and Meta-Analysis. J Dig Dis 2025. [PMID: 40386905 DOI: 10.1111/1751-2980.13348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Revised: 04/27/2025] [Accepted: 05/05/2025] [Indexed: 05/20/2025]
Abstract
OBJECTIVES Autoimmune Hepatitis (AIH) is a chronic inflammatory liver disease with significant morbidity and mortality if untreated. Current first-line treatment involves corticosteroids and azathioprine (AZA), which are effective but are associated with significant adverse effects and treatment intolerance. Mycophenolate mofetil (MMF), an immunosuppressive agent with a potentially better safety profile, has emerged as an alternative. This meta-analysis evaluated the efficacy and safety of MMF compared to AZA in treatment-naïve AIH patients. METHODS We conducted a systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Databases were searched for articles published up to May 2024. Statistical analysis was performed using RevMan, employing a random-effects model. RESULTS Five studies involving 621 patients were included. MMF showed significantly higher rates of complete biochemical response compared to AZA (odds ratio [OR] 3.64, 95% confidence interval [CI] 2.07-6.40, p < 0.00001) and lower non-response rates (OR 0.45, 95% CI 0.24-0.85, p = 0.01). Corticosteroid withdrawal rates were also higher in the MMF group (OR 2.89, 95% CI 1.69-4.94, p = 0.0001). Relapse rate and cumulative prednisolone dose were comparable between the two groups. MMF demonstrated a better safety profile, with significantly lower rates of gastrointestinal symptoms (OR 0.46, 95% CI 0.27-0.79, p = 0.005). CONCLUSIONS MMF shows superior efficacy and tolerability compared to AZA in treatment-naïve AIH patients and may serve as a preferred first-line therapy, offering improved patient adherence and clinical outcomes. Further randomized controlled trials are warranted to confirm these findings.
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Affiliation(s)
- Muhammad Tayyab Anwar
- Department of Internal Medicine, John H. Stroger Jr. Hospital of Cook County, Chicago, Illinois, USA
| | - Muhammad Shahzil
- Department of Internal Medicine, Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pennsylvania, USA
| | - Taha Bin Arif
- Department of Internal Medicine, Sinai Hospital of Baltimore, Baltimore, Maryland, USA
| | - Muhammad Ali Khaqan
- Department of Gastroenterology and Hepatology, University of Kentucky, Lexington, Kentucky, USA
| | - Edzel Lorraine Co
- Department of Internal Medicine, University of Santo Tomas Faculty of Medicine and Surgery, Sampaloc, Manila, Philippines
| | - Fariha Hasan
- Department of Internal Medicine, Cooper University Hospital, Camden, New Jersey, USA
| | - Rameez Tarar
- Department of Medicine, King Edward Medical University, Lahore, Pakistan
| | - Hamza Naeem
- Department of Medicine, King Edward Medical University, Lahore, Pakistan
| | - Sibgha Farooq
- Department of Medicine, Avicenna Medical College, Lahore, Pakistan
| | - Ali Jaan
- Department of Internal Medicine, Rochester General Hospital, Rochester, New York, USA
| | | | - Vinay Jahagirdar
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Reena Salgia
- Department of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, Michigan, USA
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Flatley S, Dixon S, Pilsworth E, Dube A, Hoeroldt B, Harrison L, Gleeson D. Diabetes Mellitus in Patients With Autoimmune Hepatitis: Frequency, Risk Factors and Effect on Outcome. Aliment Pharmacol Ther 2025. [PMID: 40342076 DOI: 10.1111/apt.70188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 09/02/2024] [Accepted: 04/30/2025] [Indexed: 05/11/2025]
Abstract
BACKGROUND Treatment for autoimmune hepatitis (AIH) includes corticosteroids, which are associated with the development of diabetes mellitus (DM). Reported new-onset DM rates in patients with AIH have varied, and predisposing factors and prognostic implications are inadequately characterised. AIM To identify the frequency and predisposing factors for DM in AIH and its association with disease progression and mortality. METHODS Retrospective/prospective single-centre study of 494 patients with AIH presenting 1987-2023, 466 receiving corticosteroids (454 prednisolone, 12 budesonide) and followed for (median (range) 9 (0-36) years). RESULTS Forty-seven patients (10%) already had DM at AIH diagnosis. New-onset DM subsequently developed in another 59 (13%). In those receiving prednisolone, new-onset DM incidence was 8% ± 1% after 1 year and 14% ± 2% after 10 years (14- and 3-fold higher than expected population rate), and was independently associated with older age, non-Caucasian ethnicity, higher initial prednisolone dose, higher BMI at diagnosis and more weight gain after 2 years of follow-up. New-onset DM usually persisted despite stopping prednisolone. New-onset DM and DM at any time were independently associated with all-cause death/transplantation rate, along with previously established risk factors (older age, cirrhosis, lower ALT at diagnosis and failure of early ALT normalisation). New-onset DM and DM at any time were also independently associated with cirrhosis development. Similar associations of new-onset DM and DM at any time with liver-related death/transplantation were significant on univariate but not multivariate analysis. CONCLUSION New-onset DM occurred in 13% of patients with AIH, was related to older age, non-Caucasian ethnicity, higher prednisolone dose, higher BMI at diagnosis and weight gain; and was an independent predictor of all-cause death/transplantation and of cirrhosis development, underlining the need to minimise steroid burden in AIH.
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Affiliation(s)
- Sarah Flatley
- Liver Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
- Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, University of Sheffield Medical School, Sheffield, UK
| | - Selena Dixon
- Liver Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Eleanor Pilsworth
- Liver Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Asha Dube
- Department of Histopathology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Barbara Hoeroldt
- Liver Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Laura Harrison
- Liver Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Dermot Gleeson
- Liver Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
- Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, University of Sheffield Medical School, Sheffield, UK
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Dalekos G, Gatselis N, Drenth JP, Heneghan M, Jørgensen M, Lohse AW, Londoño M, Muratori L, Papp M, Samyn M, Tiniakos D, Lleo A. EASL Clinical Practice Guidelines on the management of autoimmune hepatitis. J Hepatol 2025:S0168-8278(25)00173-4. [PMID: 40348684 DOI: 10.1016/j.jhep.2025.03.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Accepted: 03/20/2025] [Indexed: 05/14/2025]
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disease of unknown aetiology which may affect any patient irrespective of age, sex, and ethnicity. At baseline, the clinical spectrum of the disease varies largely from asymptomatic cases to acute liver failure with massive hepatocyte necrosis. The aim of these EASL guidelines is to provide updated guidance on the diagnosis and management of AIH both in adults and children. Updated guidance on the management of patients with variants and specific forms of AIH is also provided, as is detailed guidance on the management of AIH-associated cirrhosis, including surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.
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4
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Habibi MA, Aghayee F, Mirjani MS, Karimifar MR, Ahmadi MR, Eazi SM, Minaee P, Pashaei MR, Hormati A, Akbari Aleagha MM, Ahmadpour S. The safety and efficacy of rituximab in autoimmune hepatitis: a systematic review and quality assessment. Eur J Gastroenterol Hepatol 2025:00042737-990000000-00532. [PMID: 40359300 DOI: 10.1097/meg.0000000000002981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/15/2025]
Abstract
Up now, several medications were proposed for the treatment of autoimmune hepatitis (AIH); however, because of the unclear pathophysiology of AIH, the most optimal treatment option needs to be elucidated. This systematic review sought to investigate the safety and efficacy of rituxiamb (RTX) in patients with AIH. A total of 27 studies were included in the present study. A total of 80 patients had the eligibility criteria, of which the majority of them were female (63 female and 17 male). Of the 80 patients, nine patients were pediatrics. The induction of remission and maintenance therapy were the most common indications for RTX in AIH. Of the 80 patients, we found complete remission in 55% of patients (n = 44) and partial remission in 11% of patients (n = 11). Of the nine pediatric patients, we found complete remission in 77% of patients (n = 7) and partial remission in 22% of patients (n = 2). Unclear response was also reported in 31% of patients (n = 25), which included four studies. 375 mg/m2 × 4 followed by 1000 mg × 2 was the most commonly applied RTX dosage used for treatment of AIH. RTX therapy was associated with infectious complications in six patients; however, one episode of cancer, death, mild conjunctivitis, and large bowel perforation were also reported. RTX is an anti-CD20 mAb and was shown to be effective for the treatment of AIH, but there is no consensus regarding the therapeutic role of RTX in AIH.
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Affiliation(s)
- Mohammad Amin Habibi
- Department of Neurosurgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran
| | - Fatemeh Aghayee
- Student Research Committee, Qom University of Medical Sciences
| | | | | | | | | | - Poriya Minaee
- Student Research Committee, Qom University of Medical Sciences
| | - Mohammad Reza Pashaei
- Department of Internal Medicine, School of Medicine, Urmia University of Medical Sciences, Urmia
| | - Ahmad Hormati
- Department of Internal Medicine, School of Medicine, Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran
| | | | - Sajjad Ahmadpour
- Patient Safety Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran
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Gleeson D, Bornand R, Brownlee A, Dhaliwal H, Dyson JK, Hails J, Henderson P, Kelly D, Mells GF, Miquel R, Oo YH, Sutton A, Yeoman A, Heneghan MA. British Society of Gastroenterology guidelines for diagnosis and management of autoimmune hepatitis. Gut 2025:gutjnl-2024-333171. [PMID: 40169244 DOI: 10.1136/gutjnl-2024-333171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 10/22/2024] [Indexed: 04/03/2025]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which, if untreated, often leads to cirrhosis, liver failure and death. The last British Society of Gastroenterology (BSG) guideline for the management of AIH was published in 2011. Since then, our understanding of AIH has advanced in many areas. This update to the previous guideline was commissioned by the BSG and developed by a multidisciplinary group. The aim of this guideline is to review and summarise the current evidence, in order to inform and guide diagnosis and management of patients with AIH and its variant syndromes. The main focus is on AIH in adults, but the guidelines should also be relevant to older children and adolescents.
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Affiliation(s)
- Dermot Gleeson
- Liver Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
- Division of Clinical Medicine, School of Medicine and Population Science, University of Sheffield, Sheffield, UK
| | | | | | - Harpreet Dhaliwal
- Department of Gastroenterology, Manchester Royal Infirmary, Manchester, UK
| | - Jessica K Dyson
- Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Janeane Hails
- Division of Gastroenterology and Hepatology, Addenbrooke's Hospital, Cambridge, UK
| | - Paul Henderson
- Royal Hospital for Children and Young People, Edinburgh, UK
| | - Deirdre Kelly
- Birmingham Women's & Children's Hospital, Birmingham, UK
- University of Birmingham, Birmingham, UK
| | - George F Mells
- Division of Gastroenterology and Hepatology, Addenbrooke's Hospital, Cambridge, UK
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - Rosa Miquel
- Liver Histopathology Laboratory, Institute of Liver Studies, King's College London, London, UK
| | - Ye H Oo
- Centre for Liver and Gastroenterology research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- NIHR Biomedical Research Centre, University of Birmingham and University Hospital Birmingham NHS Foundation Trust, Birmingham, UK
- Centre for Rare Diseases, European Reference Network on Hepatological Diseases (ERN-RARE-LIVER) centre, Birmingham, UK
| | - Anthea Sutton
- Sheffield Centre for Health and Related Research, The University of Sheffield, Sheffield, UK
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Gleeson D, Martyn-StJames M, Oo Y, Flatley S. What is the optimal first-line treatment of autoimmune hepatitis? A systematic review with meta-analysis of randomised trials and comparative cohort studies. BMJ Open Gastroenterol 2025; 12:e001549. [PMID: 40154965 PMCID: PMC11956290 DOI: 10.1136/bmjgast-2024-001549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 10/09/2024] [Indexed: 04/01/2025] Open
Abstract
OBJECTIVES Uncertainty remains about many aspects of first-line treatment of autoimmune hepatitis (AIH). DESIGN Systemic review with meta-analysis (MA). DATA SOURCES Bespoke AIH Endnote Library, updated to 30 June 2024. ELIGIBILITY CRITERIA Randomised controlled trials (RCTs) and comparative cohort studies including adult patients with AIH, reporting death/transplantation, biochemical response (BR) and/or adverse effects (AEs). DATA EXTRACTION AND SYNTHESIS Data pooled in MA as relative risk (RR) under random effects. Risk of bias (ROB) assessed using Cochrane ROB-2 and ROBINS-1 tools. RESULTS From seven RCTs (five with low and two with some ROB) and 18 cohort studies (12 moderate ROB, six high for death/transplant), we found lower death/transplantation rates in (a) patients receiving pred+/-aza (vs no pred): overall (RR 0.38 (95% CI 0.20 to 0.74)), in patients without symptoms (0.38 (0.19-0.75)), without cirrhosis (0.30 (0.14-0.65)), and with decompensated cirrhosis (RR 0.38 (0.23-0.61)), and (b) patients receiving pred+aza (vs pred alone) (0.38 (0.22-0.65)). Patients receiving higher (vs lower) initial pred doses had similar BR rates (RR 1.07 (0.92-1.24)) and mortality (0.71 (0.25-2.05)) but more AEs (1.73 (1.17-2.55)). Patients receiving bud (vs pred) had similar BR rates (RR 0.99 (0.71-1.39)), with fewer cosmetic AEs (0.46 (0.34-0.62)). Patients receiving mycophenolate mofetil (MMF) (vs aza) had similar BR rates (RR 1.32 (0.73-2.38)) and fewer AEs requiring drug cessation (0.20 (0.09-0.43)). CONCLUSIONS Mortality is lower in pred-treated (vs untreated) patients, overall and in several subgroups, and in those receiving pred+aza (vs pred). Higher initial pred doses confer no clear benefit and cause more AEs. Bud (vs pred) achieves similar BR rates, with fewer cosmetic AEs. MMF (vs aza) achieves similar BR rates, with fewer serious AEs.
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Affiliation(s)
- Dermot Gleeson
- Liver Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Marrissa Martyn-StJames
- School of Medicine and Population Health, University of Sheffield, Sheffield School of, Sheffield, UK
| | - Ye Oo
- Centre for Liver Research and National Institute of Health Research Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Liver Transplant Unit, Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK
| | - Sarah Flatley
- Liver Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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7
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Hirschfield GM, Lohse AW. Treating autoimmune hepatitis - More science, more progress, better therapy. J Hepatol 2024; 80:534-536. [PMID: 38309440 DOI: 10.1016/j.jhep.2024.01.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 01/15/2024] [Indexed: 02/05/2024]
Affiliation(s)
- Gideon M Hirschfield
- Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, Toronto General Hospital, Toronto, Canada.
| | - Ansgar W Lohse
- Division of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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8
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SORRENTINO MC, a nome del GdS-AI SIPMeL, CARBONE T, CINQUANTA L, ALESSIO MG, INFANTINO M, DELEONARDI G, TREVISAN MT, PORCELLI B, TERZUOLI L, PLATZGUMMER S, BRUSCA I, ANTICO A, TAMPOIA M, PESCE G, VILLALTA D, BIZZARO N. Linee guida SIPMeL per la determinazione degli autoanticorpi nella diagnosi delle malattie autoimmuni del fegato. LA RIVISTA ITALIANA DELLA MEDICINA DI LABORATORIO 2024; 20. [DOI: 10.23736/s1825-859x.24.00226-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Mucenic M. Advancements in autoimmune hepatitis management: Perspectives for future guidelines. World J Hepatol 2024; 16:135-139. [PMID: 38495280 PMCID: PMC10941753 DOI: 10.4254/wjh.v16.i2.135] [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: 12/03/2023] [Revised: 01/04/2024] [Accepted: 01/23/2024] [Indexed: 02/27/2024] Open
Abstract
The first-line treatment for autoimmune hepatitis involves the use of prednisone or prednisolone either as monotherapy or in combination with azathioprine (AZA). Budesonide has shown promise in inducing a complete biochemical response (CBR) with fewer adverse effects and is considered an optional first-line treatment, particularly for patients without cirrhosis; however, it is worth noting that the design of that study favored budesonide. A recent real-life study revealed higher CBR rates with prednisone when equivalent initial doses were administered. Current guidelines recommend mycophenolate mofetil (MMF) for patients who are intolerant to AZA. It is important to mention that the evidence supporting this recommendation is weak, primarily consisting of case series. Nevertheless, MMF has demonstrated superiority to AZA in the context of renal transplant. Recent comparative studies have shown higher CBR rates, lower therapeutic failure rates, and reduced intolerance in the MMF group. These findings may influence future guidelines, potentially leading to a significant modification in the first-line treatment of autoimmune hepatitis. Until recently, the only alternative to corticosteroids was lifelong maintenance treatment with AZA, which comes with notable risks, such as skin cancer and lymphoma. Prospective trials are essential for a more comprehensive assessment of treatment suspension strategies, whether relying on histological criteria, strict biochemical criteria, or a combination of both. Single-center studies using chloroquine diphosphate have shown promising results in significantly reducing relapse rates compared to placebo. However, these interesting findings have yet to be replicated by other research groups. Additionally, second-line drugs, such as tacrolimus, rituximab, and infliximab, should be subjected to controlled trials for further evaluation.
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Affiliation(s)
- Marcos Mucenic
- Liver Transplantation Group, Santa Casa de Porto Alegre, Porto Alegre 90035-070, RS, Brazil.
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10
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Abstract
The goal of autoimmune hepatitis treatment is to achieve clinical and biochemical remission, which is associated with significantly improved outcomes. Induction treatment with corticosteroids and the subsequent addition of steroid-sparing therapy with gradual tapering of corticosteroids remains the standard of care. Several alternatives to azathioprine and second-line agents, such as mycophenolate mofetil, tacrolimus, cyclosporine, sirolimus, or rituximab, have been evaluated in those with intolerance or inadequate response to standard-of-care therapy. Treatment withdrawal is achievable in less than 20% of patients after 2 years of sustained remission. Liver transplantation should be considered in those with progressive liver disease or those with complications such as hepatocellular carcinoma.
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Affiliation(s)
- Aparna Goel
- Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, CA 94043, USA.
| | - Paul Kwo
- Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, CA 94043, USA
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11
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Abstract
Clinical trials have been a central driver of change and have provided the evidence base necessary to advance new therapies for liver diseases. This review provides a perspective on the status of trials in hepatology and a vantage point into the emerging capabilities and external forces that will shape the conduct of clinical trials in the future. The adaptations to clinical trial operations in response to the disruptions by the COVID-19 pandemic and opportunities for innovation in hepatology trials are emphasized. Future trials in hepatology will be driven by unmet therapeutic needs and fueled by technological advances incorporating digital capabilities with expanded participant-derived data collection, computing, and analytics. Their design will embrace innovative trial designs adapted to these advances and that emphasize broader and more inclusive participant engagement. Their conduct will be further shaped by evolving regulatory needs and the emergence of new stakeholders in the clinical trials ecosystem. The evolution of clinical trials will offer unique opportunities to advance new therapeutics that will ultimately improve the lives of patients with liver diseases.
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Affiliation(s)
- Paul Y Kwo
- Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA
| | - Tushar Patel
- Department of Transplantation, Mayo Clinic, Jacksonville, Florida, USA
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12
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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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13
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Gerussi A, Halliday N, Carbone M, Invernizzi P, Thorburn D. Open challenges in the management of autoimmune hepatitis. Minerva Gastroenterol (Torino) 2023; 69:61-83. [PMID: 33267568 DOI: 10.23736/s2724-5895.20.02805-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
Autoimmune hepatitis (AIH) is a rare autoimmune disease of the liver with many open questions as regards its etiopathogenesis, natural history and clinical management. The classical picture of AIH is chronic hepatitis with fluctuating elevation of serum transaminases and Immunoglobulin G levels, the presence of circulating autoantibodies and typical histological features. However, atypical presentations do occur and are not well captured by current diagnostic scores, with important consequences in terms of missed diagnoses and delayed treatments. AIH is treated with corticosteroids and immunosuppressive drugs but up to 40% of patients do not achieve full biochemical response and are at risk of progressing to cirrhosis and liver failure. Moreover, standard therapies are associated by significant side-effects which may impair the quality of life of patients living with AIH. However, advances in the understanding of the underlying immunology of AIH is raising the prospect of novel therapies and optimization of existing therapeutic approaches to reduce side-effect burdens and potentially restore immunological tolerance. In this review we outlined the clinical characteristics, etiopathogenesis and management of AIH and current challenges in the diagnosis and management of AIH and provided evidence underlying the evolution of diagnostic and clinical management protocols.
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Affiliation(s)
- Alessio Gerussi
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milano-Bicocca, Monza, Monza-Brianza, Italy - .,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Monza-Brianza, Italy - .,Ancient DNA Lab Dan David Center for Human Evolution and Biohistory Research, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel -
| | - Neil Halliday
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Marco Carbone
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milano-Bicocca, Monza, Monza-Brianza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Monza-Brianza, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milano-Bicocca, Monza, Monza-Brianza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Monza-Brianza, Italy
| | - Douglas Thorburn
- Institute for Liver and Digestive Health, University College London, London, UK
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14
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Kim JK. [Treatment of Autoimmune Hepatitis]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2023; 81:72-85. [PMID: 36824035 DOI: 10.4166/kjg.2023.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/13/2023] [Accepted: 02/13/2023] [Indexed: 02/25/2023]
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disease, characterized by elevated levels of transaminases, immunoglobulin G, and positive autoantibodies. The disease course is dynamic and presents heterogeneous disease manifestations at diagnosis. This review summarizes the issues regarding the treatment and monitoring of AIH in adult patients. Glucocorticoids and azathioprine are the first line of treatment. Alternative first-line treatments include budesonide or mycophenolate mofetil (MMF). Although no randomized controlled trials have been performed, MMF, cyclosporine, tacrolimus, 6-mercaptopurine, 6-thioguanine, allopurinol, sirolimus, everolimus, infliximab, or rituximab have been attempted in patients not responding to or intolerant to first-line treatments. Most patients require life-long special monitoring, with or without maintenance treatment.
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Affiliation(s)
- Ja Kyung Kim
- Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea
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15
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Abstract
Autoimmune hepatitis is an inflammatory disease of the liver of unknown cause that may progress to liver cirrhosis and end stage liver failure if diagnosis is overlooked and treatment delayed. The clinical presentation is often that of acute hepatitis, sometimes very severe; less frequently, it can be insidious or completely asymptomatic. The disease can affect people of any age and is more common in women; its incidence and prevalence seem to be on the rise worldwide. An abnormal immune response targeting liver autoantigens and inducing persistent and self-perpetuating liver inflammation is the pathogenic mechanism of the disease. A specific set of autoantibodies, increased IgG concentrations, and histological demonstration of interface hepatitis and periportal necrosis are the diagnostic hallmarks of autoimmune hepatitis. Prompt response to treatment with corticosteroids and other immunomodulatory drugs is almost universal and supports the diagnosis. The aims of treatment are to induce and maintain long term remission of liver inflammation. Treatment can often even reverse liver fibrosis, thus preventing progression to advanced cirrhosis and its complications. Most patients need lifelong maintenance therapy, and repeated follow-up in experienced hands improves the quality of care and quality of life for affected patients.
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Affiliation(s)
- Luigi Muratori
- DIMEC, Università di Bologna and IRCCS Policlinico di Sant'Orsola, Bologna, Italy
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
| | - Ansgar W Lohse
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
| | - Marco Lenzi
- DIMEC, Università di Bologna and IRCCS Policlinico di Sant'Orsola, Bologna, Italy
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
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16
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Lloyd C, Leighton J, Wong LL, Goulding A, Brownlee A, Gray P, Culver E, Halliday N, Thorburn D, Heneghan MA, Jones DEJ, Exley C, Dyson JK. Patient Priorities in Autoimmune Hepatitis: The Need for Better Treatments, More Education and Challenging Stigma. Dig Dis Sci 2023; 68:87-97. [PMID: 35579795 PMCID: PMC9112273 DOI: 10.1007/s10620-022-07525-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 04/18/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND Data show that patients with autoimmune hepatitis have significantly reduced quality-of-life and that corticosteroids carry marked side effects. AIMS This study explored patients' experiences of autoimmune hepatitis and its treatments; key aspects for developing safe and effective new approaches to therapy. METHODS An anonymised, internet-based survey collected data including patient demographics, treatments, side-effects, impact on day-to-day life, sources of support and attitudes towards autoimmune hepatitis between December 2019-January 2020. Semi-structured interviews were conducted with 13 patients to further explore their support networks, treatment experiences and health priorities. Descriptive and quantitative analyses were undertaken using R and free text responses were subject to thematic analysis. RESULTS In total, 270 survey responses were received (median age 55 years and 94% female). Perceived medication side-effects were reported by 66% (169/257) and 73% responded negatively about their experience of corticosteroids. The majority (62·3% [(109/175]) would 'definitely' or 'probably' consider clinical trial participation to improve their care. Only 18·7% (31/166) reported access to a specialist liver nurse and nearly half were involved in support groups. Interview and survey data suggested that major issues were stigma, loss of control and fatigue. CONCLUSIONS This study provides insights into the realities of living with autoimmune hepatitis with clear issues around lack of support networks, need for patient empowerment and stigma surrounding liver disease. Patient priorities are better therapies to slow disease progression, avoiding corticosteroids and minimising side-effects. Patient willingness to participate in trials suggests that they are achievable provided they have the right design and clinical endpoints.
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Affiliation(s)
- Charlotte Lloyd
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Jessica Leighton
- Translational and Clinical Research Institute, Newcastle University and Liver Unit, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE7 7DN UK
| | | | - Anna Goulding
- School of Medical Education, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | | | | | | | - Neil Halliday
- Institute for Liver and Digestive Health, University College London and Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK
| | - Doug Thorburn
- Institute for Liver and Digestive Health, University College London and Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK
| | | | - David E. J. Jones
- Translational and Clinical Research Institute, Newcastle University and Liver Unit, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE7 7DN UK
| | - Catherine Exley
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Jessica K. Dyson
- Translational and Clinical Research Institute, Newcastle University and Liver Unit, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE7 7DN UK
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17
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Reyes A, Mohanty A, Pharaon R, Massarelli E. Association between Immunosuppressive Therapy Utilized in the Treatment of Autoimmune Disease or Transplant and Cancer Progression. Biomedicines 2022; 11:biomedicines11010099. [PMID: 36672607 PMCID: PMC9856025 DOI: 10.3390/biomedicines11010099] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 12/28/2022] [Accepted: 12/28/2022] [Indexed: 01/01/2023] Open
Abstract
Autoimmunity and cancer rates have both been on the rise in Western civilization prompting many to investigate the link between the two entities. This review will investigate the complex interactions between the activation and deactivation of the immune system and the development of malignancy. Additional focus will be placed on the main classes of immune inhibitor therapy utilized in transplant patients and in autoimmune disease including TNF-alpha, Calcineurin, mTOR, purine synthesis antagonists and IMPDH inhibitors.
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18
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Snijders RJALM, Stoelinga AEC, Gevers TJG, Pape S, Biewenga M, Verdonk RC, de Jonge HJM, Vrolijk JM, Bakker SF, Vanwolleghem T, de Boer YS, Pronk MAMCB, Beuers UHW, van der Meer AJ, van Gerven NMF, Sijtsma MGM, Verwer BJ, Gisbertz IAM, Bartelink M, van den Brand FF, Sebib Korkmaz K, van den Berg AP, Guichelaar MMJ, Soufidi K, Levens AD, van Hoek B, Drenth JPH. Assessing the efficacy and safety of mycophenolate mofetil versus azathioprine in patients with autoimmune hepatitis (CAMARO trial): study protocol for a randomised controlled trial. Trials 2022; 23:1012. [PMID: 36514163 PMCID: PMC9745715 DOI: 10.1186/s13063-022-06890-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 11/05/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which necessitates cessation of azathioprine or changes in therapy. In addition, not all patients achieve complete biochemical response (CR). Uncontrolled data indicate that mycophenolate mofetil (MMF) can induce CR in a majority of patients. Better understanding of first-line treatment and robust evidence from randomised clinical trials are needed. The aim of this study was to explore the potential benefits of MMF as compared to azathioprine, both combined with prednisolone, as induction therapy in a randomised controlled trial in patients with treatment-naive AIH. METHODS CAMARO is a randomised (1:1), open-label, parallel-group, multicentre superiority trial. All patients with AIH are screened for eligibility. Seventy adult patients with AIH from fourteen centres in the Netherlands and Belgium will be randomised to receive MMF or azathioprine. Both treatment arms will start with prednisolone as induction therapy. The primary outcome is biochemical remission, defined as serum levels of alanine aminotransferase and immunoglobulin G below the upper limit of normal. Secondary outcomes include safety and tolerability of MMF and azathioprine, time to remission, changes in Model For End-Stage Liver Disease (MELD)-score, adverse events, and aspects of quality of life. The study period will last for 24 weeks. DISCUSSION The CAMARO trial investigates whether treatment with MMF and prednisolone increases the proportion of patients in remission compared with azathioprine and prednisolone as the current standard treatment strategy. In addition, we reflect on the challenges of conducting a randomized trial in rare diseases. TRIAL REGISTRATION EudraCT 2016-001038-91 . Prospectively registered on 18 April 2016.
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Affiliation(s)
- Romée J A L M Snijders
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands.
- European Reference Network RARE-LIVER, Hamburg, Germany.
| | - Anna E C Stoelinga
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Tom J G Gevers
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
- European Reference Network RARE-LIVER, Hamburg, Germany
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- Nutrim School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Simon Pape
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
- European Reference Network RARE-LIVER, Hamburg, Germany
| | - Maaike Biewenga
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Robert C Verdonk
- Department of Gastroenterology and Hepatology, St. Antonius Hospital, Nieuwegein, The Netherlands
| | - Hendrik J M de Jonge
- Department of Gastroenterology and Hepatology, Jeroen Bosch Hospital, 's Hertogenbosch, The Netherlands
| | - Jan Maarten Vrolijk
- Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, The Netherlands
| | - Sjoerd F Bakker
- Department of Gastroenterology and Hepatology, Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands
| | - Thomas Vanwolleghem
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium
| | - Ynto S de Boer
- European Reference Network RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, location VU University Medical Center, Amsterdam, The Netherlands
| | | | - Ulrich H W Beuers
- European Reference Network RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, The Netherlands
| | - Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Nicole M F van Gerven
- Department of Gastroenterology and Hepatology, Rode Kruis Hospital, Beverwijk, The Netherlands
| | - Marijn G M Sijtsma
- Department of Gastroenterology and Hepatology, St. Jansdal Hospital, Harderwijk, The Netherlands
| | - Bart J Verwer
- Department of Gastroenterology and Hepatology, Spaarne Gasthuis, Haarlem, The Netherlands
| | - Ingrid A M Gisbertz
- Department of Gastroenterology and Hepatology, Hospital Bernhoven, Uden, The Netherlands
| | - Maartje Bartelink
- Department of Gastroenterology and Hepatology, Deventer Hospital, Deventer, The Netherlands
| | | | - Kerem Sebib Korkmaz
- Department of Gastroenterology and Hepatology, IJselland Hospital, Capelle aan den Ijssel, The Netherlands
| | - Aad P van den Berg
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Maureen M J Guichelaar
- Department of Gastroenterology and Hepatology, Medisch Spectrum Twente, Enschede, The Netherlands
| | - Khalida Soufidi
- Department of Gastroenterology and Hepatology, Zuyderland, Heerlen, The Netherlands
| | - Amar D Levens
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
- European Reference Network RARE-LIVER, Hamburg, Germany
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19
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Harrington C, Krishnan S, Mack CL, Cravedi P, Assis DN, Levitsky J. Noninvasive biomarkers for the diagnosis and management of autoimmune hepatitis. Hepatology 2022; 76:1862-1879. [PMID: 35611859 PMCID: PMC9796683 DOI: 10.1002/hep.32591] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 01/07/2023]
Abstract
Autoimmune hepatitis (AIH) is a rare disease of unclear etiology characterized by loss of self-tolerance that can lead to liver injury, cirrhosis, and acute liver failure. First-line treatment consists of systemic corticosteroids, or budesonide, and azathioprine, to which most patients are initially responsive, although predictors of response are lacking. Relapses are very common, correlate with histological activity despite normal serum transaminases, and increase hepatic fibrosis. Furthermore, current regimens lead to adverse effects and reduced quality of life, whereas medication titration is imprecise. Biomarkers that can predict the clinical course of disease, identify patients at elevated risk for relapse, and improve monitoring and medication dosing beyond current practice would have high clinical value. Herein, we review novel candidate biomarkers in adult and pediatric AIH based on prespecified criteria, including gene expression profiles, proteins, metabolites, and immune cell phenotypes in different stages of AIH. We also discuss biomarkers relevant to AIH from other immune diseases. We conclude with proposed future directions in which biomarker implementation into clinical practice could lead to advances in personalized therapeutic management of AIH.
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Affiliation(s)
- Claire Harrington
- Division of Gastroenterology & HepatologyNorthwestern University Feinberg School of MedicineChicagoIllinoisUSA
| | - Swathi Krishnan
- Medicine DepartmentYale School of MedicineNew HavenConnecticutUSA
| | - Cara L. Mack
- Section of Pediatric Gastroenterology, Hepatology & Nutrition, Children's Hospital ColoradoUniversity of Colorado School of MedicineAuroraColoradoUSA
| | - Paolo Cravedi
- Division of NephrologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - David N. Assis
- Section of Digestive DiseasesYale School of MedicineNew HavenConnecticutUSA
| | - Josh Levitsky
- Division of Gastroenterology & HepatologyNorthwestern University Feinberg School of MedicineChicagoIllinoisUSA
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20
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Mycophenolate mofetil as second line treatment in autoimmune hepatitis – A retrospective single center analysis. J Transl Autoimmun 2022; 5:100172. [DOI: 10.1016/j.jtauto.2022.100172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 11/16/2022] [Indexed: 11/21/2022] Open
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21
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Advancing Biologic Therapy for Refractory Autoimmune Hepatitis. Dig Dis Sci 2022; 67:4979-5005. [PMID: 35147819 DOI: 10.1007/s10620-021-07378-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/27/2021] [Indexed: 01/05/2023]
Abstract
Biologic agents may satisfy an unmet clinical need for treatment of refractory autoimmune hepatitis. The goals of this review are to present the types and results of biologic therapy for refractory autoimmune hepatitis, indicate opportunities to improve and expand biologic treatment, and encourage comparative clinical trials. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Rituximab (monoclonal antibodies against CD20 on B cells), infliximab (monoclonal antibodies against tumor necrosis factor-alpha), low-dose recombinant interleukin 2 (regulatory T cell promoter), and belimumab (monoclonal antibodies against B cell activating factor) have induced laboratory improvement in small cohorts with refractory autoimmune hepatitis. Ianalumab (monoclonal antibodies against the receptor for B cell activating factor) is in clinical trial. These agents target critical pathogenic pathways, but they may also have serious side effects. Blockade of the B cell activating factor or its receptors may disrupt pivotal B and T cell responses, and recombinant interleukin 2 complexed with certain interleukin 2 antibodies may selectively expand the regulatory T cell population. A proliferation-inducing ligand that enhances T cell proliferation and survival is an unevaluated, potentially pivotal, therapeutic target. Fully human antibodies, expanded target options, improved targeting precision, more effective delivery systems, and biosimilar agents promise to improve efficacy, safety, and accessibility. In conclusion, biologic agents target key pathogenic pathways in autoimmune hepatitis, and early experiences in refractory disease encourage clarification of the preferred target, rigorous clinical trial, and comparative evaluations.
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22
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Dalekos GN, Arvaniti P, Gatselis NK, Gabeta S, Samakidou A, Giannoulis G, Rigopoulou E, Koukoulis GK, Zachou K. Long-term results of mycophenolate mofetil vs. azathioprine use in patients with autoimmune hepatitis. JHEP Rep 2022; 4:100601. [DOI: 10.1016/j.jhepr.2022.100601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 09/17/2022] [Accepted: 09/21/2022] [Indexed: 12/15/2022] Open
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23
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Pape S, Snijders RJALM, Gevers TJG, Chazouilleres O, Dalekos GN, Hirschfield GM, Lenzi M, Trauner M, Manns MP, Vierling JM, Montano-Loza AJ, Lohse AW, Schramm C, Drenth JPH, Heneghan MA. Systematic review of response criteria and endpoints in autoimmune hepatitis by the International Autoimmune Hepatitis Group. J Hepatol 2022; 76:841-849. [PMID: 35066089 DOI: 10.1016/j.jhep.2021.12.041] [Citation(s) in RCA: 97] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 11/18/2021] [Accepted: 12/11/2021] [Indexed: 12/12/2022]
Abstract
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 statement on 5 agreed response criteria and endpoints: complete biochemical response, insufficient response, non-response, remission, and intolerance to treatment, which can be used to guide future reporting.
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Affiliation(s)
- Simon Pape
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Romée J A L M Snijders
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Tom J G Gevers
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands; Division of Gastroenterology and Hepatology, Maastricht University Medical Center, Maastricht 6229HX, The Netherlands; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Oliver Chazouilleres
- Hepatology Department, Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Saint-Antoine Hospital Assistance Publique-Hôpitaux de Paris, Paris, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, University of Thessaly Medical School, Larissa, Greece
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Canada
| | - Marco Lenzi
- Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi, University of Bologna, Bologna, Italy
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - John M Vierling
- Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Aldo J Montano-Loza
- Division of Gastroenterology and Hepatology, University of Alberta Hospital, Edmonton, Canada
| | - Ansgar W Lohse
- 1(st) Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Christoph Schramm
- 1(st) Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Michael A Heneghan
- Institute of Liver Studies, King's College Hospital, London, United Kingdom; European Reference Network on Hepatological Diseases (ERN RARE-LIVER).
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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: 88] [Impact Index Per Article: 29.3] [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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25
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Dalekos GN, Arvaniti P, Gatselis NK, Samakidou A, Gabeta S, Rigopoulou E, Koukoulis GK, Zachou K. First Results From a Propensity Matching Trial of Mycophenolate Mofetil vs. Azathioprine in Treatment-Naive AIH Patients. Front Immunol 2022; 12:798602. [PMID: 35087524 PMCID: PMC8787111 DOI: 10.3389/fimmu.2021.798602] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 12/15/2021] [Indexed: 12/12/2022] Open
Abstract
Background/Aims As previous real-world studies and meta-analyses have shown that mycophenolate mofetil (MMF) might have better efficacy than azathioprine (AZA) in autoimmune hepatitis (AIH), we conducted a propensity matching study to assess the efficacy and safety of MMF vs. AZA. Methods All 126 consecutive treatment-naive adult AIH patients, diagnosed and followed in our department since 2016, were included. Patients received prednisolone 0.5-1 mg/kg/day plus either AZA 1-2 mg/kg/day or 1.5-2 g/day MMF. The tapering of prednisolone was identical between groups. Results After propensity matching score and adjustment for known factors affecting response to treatment and outcome, 64 patients were included in the study (MMF = 32 and AZA = 32). Rates of non-response, complete biochemical response (CBR) at 6 and 12 months, and prednisolone withdrawal (6 months, 12 months, and end of follow-up) were identical between groups. However, MMF treatment was significantly associated with CBR at the end of follow-up [odds ratio (OR) 11.259; 95% CI: 1.3-97.4, p = 0.028]. AZA patients were more prone to stop treatment due to AZA intolerance/insufficient response (p = 0.0001). At the end of follow-up, the overall efficacy of each schedule was also significantly higher in the MMF group compared to the AZA group (p = 0.0001). Conclusion We showed for the first time in a propensity matching study that MMF can be used as first-line therapy in AIH as attested by the significantly higher CBR at end of follow-up compared to AZA. Whether this better efficacy is also associated with higher histological remission rates and sustained CBR off immunosuppression needs further evaluation.
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Affiliation(s)
- George N. Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Pinelopi Arvaniti
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Nikolaos K. Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Anna Samakidou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Stella Gabeta
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Eirini Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - George K. Koukoulis
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. Autoimmune Hepatitis: Serum Autoantibodies in Clinical Practice. Clin Rev Allergy Immunol 2022; 63:124-137. [PMID: 34491531 PMCID: PMC9464171 DOI: 10.1007/s12016-021-08888-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/24/2021] [Indexed: 01/13/2023]
Abstract
Circulating autoantibodies are a key diagnostic tool in autoimmune hepatitis (AIH), being positive in 95% of the cases if tested according to dedicated guidelines issued by the International Autoimmune Hepatitis Group. They also allow the distinction between type 1 AIH, characterized by positive anti-nuclear and/or anti-smooth muscle antibody, and type 2 AIH, characterized by positive anti-liver kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody. Anti-soluble liver antigen is the only AIH-specific autoantibody, and is found in 20-30% of both type 1 and type 2 AIH. Anti-neutrophil cytoplasmic antibody is frequently positive in type 1 AIH, being associated also with inflammatory bowel disease and with primary/autoimmune sclerosing cholangitis. The reference method for autoantibody testing remains indirect immunofluorescence on triple tissue (rodent liver, kidney and stomach), allowing both the detection of the majority of liver-relevant reactivities, including those autoantibodies whose molecular target antigens are unknown. Of note, the current knowledge of the clinical significance of autoantibodies relies on studies based on this technique. However, immunofluorescence requires trained laboratory personnel, is observer-dependent, and lacks standardization, leading to ongoing attempts at replacing this method with automated assays, the sensitivity, and specificity of which, however, require further studies before they can be used as a reliable alternative to immunofluorescence; currently, they may be used as complementary to immunofluorescence.
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Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- grid.29078.340000 0001 2203 2861Epatocentro Ticino & Facoltà Di Scienze Biomediche, Università Della Svizzera Italiana, Lugano, Switzerland ,grid.29078.340000 0001 2203 2861Institute for Research in Biomedicine, Bellinzona, Switzerland ,grid.46699.340000 0004 0391 9020King’s College London Faculty of Life Sciences &, Medicine At King’s College Hospital, London, UK
| | - Giorgina Mieli-Vergani
- grid.46699.340000 0004 0391 9020King’s College London Faculty of Life Sciences &, Medicine At King’s College Hospital, London, UK ,grid.46699.340000 0004 0391 9020Paediatric Liver, GI and Nutrition Centre, MowatLabs, King’s College Hospital, London, UK
| | - Diego Vergani
- grid.46699.340000 0004 0391 9020King’s College London Faculty of Life Sciences &, Medicine At King’s College Hospital, London, UK ,grid.46699.340000 0004 0391 9020Institute of Liver Studies, MowatLabs, King’s College Hospital, London, UK
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Olivas I, Cobreros M, Londoño MC, Díaz-González Á. Budesonide in the first line treatment of patients with autoimmune hepatitis. GASTROENTEROLOGIA Y HEPATOLOGIA 2021; 45:561-570. [PMID: 34923033 DOI: 10.1016/j.gastrohep.2021.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 11/12/2021] [Accepted: 11/29/2021] [Indexed: 10/19/2022]
Abstract
Budesonide is a glucocorticoid characterized by its local action, with a low systemic bioavailability. Since the original trial comparing budesonide with prednisone in 2010, it is recommended as an effective alternative for the treatment of non-severe acute or chronic autoimmune hepatitis. In this document, we review the general pharmacologic properties of glucocorticoids, the available evidence for the use of budesonide as first line option for autoimmune hepatitis as well as the safety profile of the drug.
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Affiliation(s)
- Ignasi Olivas
- Liver Unit. Hospital Clínic of Barcelona. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS). CIBERehd. Universitat de Barcelona, Barcelona, Spain
| | - Marina Cobreros
- Digestive Diseases Department. Marqués de Valdecilla University Hospital. Instituto de investigación sanitaria Valdecilla (IDIVAL), Santander, Spain
| | - María-Carlota Londoño
- Liver Unit. Hospital Clínic of Barcelona. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS). CIBERehd. Universitat de Barcelona, Barcelona, Spain
| | - Álvaro Díaz-González
- Digestive Diseases Department. Marqués de Valdecilla University Hospital. Instituto de investigación sanitaria Valdecilla (IDIVAL), Santander, Spain
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A Collaborative Integrative and Ayurvedic Approach to Cirrhosis in the setting of Autoantibody Negative Autoimmune Hepatitis. ADVANCES IN INTEGRATIVE MEDICINE 2021. [DOI: 10.1016/j.aimed.2021.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Madhu D, Sharma S, Agarwal A, Saraya A. Special Considerations in the Management of Autoimmune Hepatitis in COVID-19 Hotspots: A Review. J Clin Transl Hepatol 2021; 9:568-575. [PMID: 34447687 PMCID: PMC8369025 DOI: 10.14218/jcth.2021.00001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 04/22/2021] [Accepted: 04/27/2021] [Indexed: 02/06/2023] Open
Abstract
The ongoing coronavirus disease-2019 (COVID-19) pandemic has necessitated special considerations in the management of diseases. The way presence of pre-existing diseases or treatment for it predisposes to, alters course of, and changes the management of COVID-19, is of relevance and is being extensively studied. Autoimmune hepatitis (AIH) is unique in that it is an autoimmune disease mandating treatment with immunosuppressive drugs, as well as a liver disease with potential for varying degrees of underlying fibrosis. The use of immunosuppressive drugs could alter the risk of acquiring COVID-19, the clinical course and severity of COVID-19 and the degree of underlying liver fibrosis could alter the clinical outcomes of patients with COVID-19. In this review, we try to summarize key areas relevant in understanding and improving the clinical care of patients with AIH in the current pandemic. Special considerations required in the management of patients with AIH in COVID-19 hotspots have been outlined based on the current evidence.
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Affiliation(s)
- Deepak Madhu
- Department of Gastroenterology, Aster MIMS Calicut, Kerala, India
- Department of Gastroenterology, Caritas Hospital, Kottayam, Kerala, India
| | - Sanchit Sharma
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Ashish Agarwal
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
- Department of Gastroenterology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
- Correspondence to: Anoop Saraya, Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Ansari Nagar; New Delhi 110029, India. ORCID: https://orcid.org/0000-0002-3921-6752. Tel: +91-9868397203, E-mail:
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Laschtowitz A, Zachou K, Lygoura V, Pape S, Derben F, Jaeckel E, Oller-Moreno S, Weidemann S, Krech T, Piecha F, Schön G, Liebhoff AM, Al Tarrah M, Heneghan M, Drenth JP, Dalekos G, Taubert R, Lohse AW, Schramm C. Histological activity despite normal ALT and IgG serum levels in patients with autoimmune hepatitis and cirrhosis. JHEP Rep 2021; 3:100321. [PMID: 34381983 PMCID: PMC8333110 DOI: 10.1016/j.jhepr.2021.100321] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 05/14/2021] [Accepted: 05/31/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND & AIMS In autoimmune hepatitis (AIH), normal levels of transaminases and IgG define biochemical remission and are considered the best surrogate markers for histological remission. This study assessed whether this also applies to patients with AIH cirrhosis. METHODS In this European multicentric study, we included 125 biopsies from 113 patients with AIH and histologically proven cirrhosis; 105 biopsies from 104 patients with AIH without cirrhosis served as controls. Biochemical parameters were available within 4 weeks of biopsy. AIH activity was graded according to the modified Hepatitis Activity Index (mHAI), with mHAI ≥4/18 considered to indicate risk of disease progression. RESULTS In total, 47 out of 125 liver biopsies were obtained from patients with AIH cirrhosis and normal ALT levels at time of biopsy. Only 26% (12/47) of those livers showed histological remission (mHAI <4/18), whereas 36% (17/47) showed moderate to high histological activity (mHAI ≥6/18). In patients with noncirrhotic AIH, 88% (46/52 biopsies) of cases with normal ALT levels had histological remission and only 4% (2/52) had an mHAI ≥6/18 (p <0.001). The addition of IgG to define complete biochemical remission only slightly improved the association with histological remission in the limited number of patients with AIH cirrhosis available for analysis [29% (5/17) of biopsies with mHAI <4/18]. ALT correlated closely with mHAI in AIH without cirrhosis but poorly in AIH with cirrhosis. CONCLUSIONS In contrast to patients with noncirrhotic AIH, in patients with AIH cirrhosis, who are at risk of disease progression, normal ALT levels and potentially also complete biochemical remission are poor surrogate markers of histological remission. Thus, new biomarkers are needed to monitor disease activity and progression in patients with AIH cirrhosis. LAY SUMMARY Autoimmune hepatitis (AIH) is an inflammatory disease of the liver that usually responds to immunosuppressive therapy. Serum transaminases and IgG levels within the normal ranges define complete biochemical remission and are considered as surrogate markers for histological disease activity. Here, we show that those biochemical markers are not sufficient to indicate low disease activity in patients with AIH and already established cirrhosis. Consequently, until better biomarkers for disease activity are found, only liver biopsy can reliably indicate disease activity in the presence of cirrhosis. Additional investigations, such as measurements of liver stiffness, should be undertaken to monitor non-invasively for disease progression in patients with AIH and established cirrhosis.
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Key Words
- AIH, autoimmune hepatitis
- ALD, alcoholic liver disease
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- Autoimmune hepatitis
- Biochemical remission
- Cirrhosis
- EASL, European Association for the Study of the Liver
- Histological activity
- ICC, intraclass correlation coefficient
- INR, international normalised ratio
- LLN, lower limit of normal
- Liver biopsy
- MELD, model for end-stage liver disease
- NAFLD, non-alcoholic fatty liver disease
- TE, transient elastography
- TIPS, transjugular intrahepatic portosystemic shunt
- ULN, upper limit of normal
- gamma-GT, gamma glutamyl transferase
- mHAI
- mHAI, modified Hepatitis Activity Index
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Affiliation(s)
- Alena Laschtowitz
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- European Reference Network for Hepatological Diseases (ERN-RARE LIVER)
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Centre of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Vasiliki Lygoura
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Centre of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Simon Pape
- European Reference Network for Hepatological Diseases (ERN-RARE LIVER)
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Finn Derben
- European Reference Network for Hepatological Diseases (ERN-RARE LIVER)
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Elmar Jaeckel
- European Reference Network for Hepatological Diseases (ERN-RARE LIVER)
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Sergio Oller-Moreno
- Institute of Medical Systems Biology, Centre for Molecular Neurobiology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Sören Weidemann
- European Reference Network for Hepatological Diseases (ERN-RARE LIVER)
- Department of Pathology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Till Krech
- Department of Pathology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Felix Piecha
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- German Centre for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Gerhard Schön
- Institute of Medical Biometry and Epidemiology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Anna-Maria Liebhoff
- Institute of Medical Systems Biology, Centre for Molecular Neurobiology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Munira Al Tarrah
- Institute of Liver Studies and Transplantation, King´s College Hospital, London, UK
| | - Michael Heneghan
- Institute of Liver Studies and Transplantation, King´s College Hospital, London, UK
| | - Joost P.H. Drenth
- European Reference Network for Hepatological Diseases (ERN-RARE LIVER)
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - George Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Centre of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Richard Taubert
- European Reference Network for Hepatological Diseases (ERN-RARE LIVER)
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Ansgar Wilhelm Lohse
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- European Reference Network for Hepatological Diseases (ERN-RARE LIVER)
- German Centre for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
- Hamburg Centre for Translational Immunology (HCTI), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- European Reference Network for Hepatological Diseases (ERN-RARE LIVER)
- Hamburg Centre for Translational Immunology (HCTI), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
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Biewenga M, Verhelst XPDMJ, Baven-Pronk MAMC, Putter H, van den Berg AP, van Nieuwkerk KCMJ, van Buuren HR, Bouma G, de Boer YS, Simoen C, Colle I, Schouten J, Sermon F, van Steenkiste C, van Vlierberghe H, van der Meer AJ, Nevens F, van Hoek B. Development and validation of a prognostic score for long-term transplant-free survival in autoimmune hepatitis type 1. United European Gastroenterol J 2021; 9:662-671. [PMID: 34165262 PMCID: PMC8281048 DOI: 10.1002/ueg2.12112] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/26/2021] [Accepted: 03/28/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND No prognostic score is currently available for long-term survival in autoimmune hepatitis (AIH) patients. OBJECTIVE The aim of this study was to develop and validate such a prognostic score for AIH patients at diagnosis. METHODS The prognostic score was developed using uni- & multivariate Cox regression in a 4-center Dutch cohort and validated in an independent 6-center Belgian cohort. RESULTS In the derivation cohort of 396 patients 19 liver transplantations (LTs) and 51 deaths occurred (median follow-up 118 months; interquartile range 60-202 months). In multivariate analysis age (hazard ratio [HR] 1.045; p < 0.001), non-caucasian ethnicity (HR 1.897; p = 0.045), cirrhosis (HR 3.266; p < 0.001) and alanine aminotransferase level (HR 0.725; p = 0.003) were significant independent predictors for mortality or LT (C-statistic 0.827; 95% CI 0.790-0.864). In the validation cohort of 408 patients death or LT occurred in 78 patients during a median follow-up of 74 months (interquartile range: 25-142 months). Predicted 5-year event rate did not differ from observed event rate (high risk group 21.5% vs. 15.7% (95% CI: 6.3%-24.2%); moderate risk group 5.8% versus 4.3% (95% CI: 0.0%-9.1%); low risk group 1.9% versus 5.4% (95% CI: 0.0%-11.4%); C-statistic 0.744 [95% CI 0.644-0.844]). CONCLUSIONS A Dutch-Belgian prognostic score for long-term transplant-free survival in AIH patients at diagnosis was developed and validated.
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Affiliation(s)
- Maaike Biewenga
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | | | | | - Hein Putter
- Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands
| | - Aad P van den Berg
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, the Netherlands
| | - Karin C M J van Nieuwkerk
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, location VUmc, Amsterdam, the Netherlands
| | - Henk R van Buuren
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, the Netherlands
| | - Gerd Bouma
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, location VUmc, Amsterdam, the Netherlands
| | - Ynte S de Boer
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, location VUmc, Amsterdam, the Netherlands
| | - Cedric Simoen
- Department of Gastroenterology and Hepatology, UZ Ghent, Ghent, Belgium
| | - Isabelle Colle
- Department of Gastroenterology and Hepatology, ASZ Aalst, Aalst, Belgium
| | - Jeoffrey Schouten
- Department of Gastroenterology and Hepatology, AZ Nikolaas, Sint-Niklaas, Belgium
| | - Filip Sermon
- Department of Gastroenterology and Hepatology, OLV Aalst, Aalst, Belgium
| | - Christophe van Steenkiste
- Department of Gastroenterology and Hepatology, AZ Maria Middelares Ghent, Ghent, Belgium.,Department of Gastroenterology and Hepatology, University Hospital Antwerp, Antwerp, Belgium
| | | | | | - Frederik Nevens
- Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
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Wang G, Tanaka A, Zhao H, Jia J, Ma X, Harada K, Wang FS, Wei L, Wang Q, Sun Y, Hong Y, Rao H, Efe C, Lau G, Payawal D, Gani R, Lindor K, Jafri W, Omata M, Sarin SK. The Asian Pacific Association for the Study of the Liver clinical practice guidance: the diagnosis and management of patients with autoimmune hepatitis. Hepatol Int 2021; 15:223-257. [PMID: 33942203 PMCID: PMC8144150 DOI: 10.1007/s12072-021-10170-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 02/27/2021] [Indexed: 02/06/2023]
Affiliation(s)
- Guiqiang Wang
- Peking University First Hospital, Beijing, China.
- Peking University International Hospital, Beijing, China.
| | | | - Hong Zhao
- Peking University First Hospital, Beijing, China
- Peking University International Hospital, Beijing, China
| | - Jidong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiong Ma
- Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine Kanazawa, Kanazawa, Japan
| | - Fu-Sheng Wang
- Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Lai Wei
- Beijing Tsinghua Changgung Hospital, Beijing, China
| | - Qixia Wang
- Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Sun
- Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yuan Hong
- Peking University First Hospital, Beijing, China
| | - Huiying Rao
- Peking University People's Hospital, Beijing, China
| | - Cumali Efe
- Department of Gastroenterology, Harran University, Şanlıurfa, Turkey
| | - George Lau
- Humanity and Health Medical Group, Hong Kong Special Administrative Region, China
| | - Diana Payawal
- Department of Hepatology, Cardinal Santos Medical Center, Manila, Philippines
| | - Rino Gani
- Department of Internal Medicine, Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia
| | - Keith Lindor
- College of Health Solutions, Arizona State University, Phoenix, AZ, USA
| | | | - Masao Omata
- Department of Gastroenterology, Yamanashi Prefectural Central Hospital, Kofu-City, Yamanashi, Japan
- The University of Tokyo, Tokyo, Japan
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Chung Y, Rahim MN, Graham JJ, Zen Y, Heneghan MA. An update on the pharmacological management of autoimmune hepatitis. Expert Opin Pharmacother 2021; 22:1475-1488. [PMID: 33624559 DOI: 10.1080/14656566.2021.1895747] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Introduction: Autoimmune hepatitis (AIH) is an immune mediated, inflammatory disease affecting the liver as a result of environmental triggers in susceptible individuals leading to loss of self-tolerance. The immunopathogenesis of AIH is not fully understood, which limits targeted therapeutic options.Areas covered: In this review, the authors provide an overview of current practice in the management of AIH, which include induction therapy with corticosteroids (± thiopurines), followed by maintenance therapy. Lack of early response to treatment may serve as a predictor of those at risk of requiring treatment escalation to second- and third-line agents such as mycophenolate mofetil (MMF), calcineurin inhibitors or biologics. Evidence for third-line agents from small retrospective studies or individual centers are reviewed. The nuances of AIH treatment in pregnancy, overlap syndromes, and drug induced liver injury (DILI) warrant further consideration.Expert opinion: Augmenting the balance of regulatory T cells (Treg) and effector T cells is an appealing therapeutic target with a multitude of agents in development. Many of the challenges in AIH research are due to its rarity and lack of randomized data. Management of AIH should strive towards individualized care through risk stratification and use of the best therapeutic modality for each patient.
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Affiliation(s)
- Yooyun Chung
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom
| | - Mussarat N Rahim
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom
| | - Jonathon J Graham
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom
| | - Yoh Zen
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom
| | - Michael A Heneghan
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom
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Liberal R, Gaspar R, Lopes S, Macedo G. Long-term outcome of patients with difficult-to-treat autoimmune hepatitis receiving mycophenolate mofetil. Clin Res Hepatol Gastroenterol 2021; 45:101487. [PMID: 32651078 DOI: 10.1016/j.clinre.2020.06.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 05/22/2020] [Accepted: 06/15/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Most patients with autoimmune hepatitis (AIH) respond to a combination of prednisolone and azathioprine. For patients who are intolerant or refractory to azathioprine, proposed alternative therapies are based on scarce data, limited to transplant centres and with short-term follow-up periods. OBJECTIVE To evaluate the long-term efficacy and safety of MMF as a second-line therapy in patients with AIH managed at a tertiary non-transplant centre. METHODS Retrospective analysis of a prospectively collated database identified AIH patients who received MMF from 2006 to 2015. Clinical, biochemical and immunological parameters were assessed at 3-, 6- and 12-months, and at last follow-up. Biochemical response (BR) was defined as improvement of transaminases, complete remission (CR) as normalisation of transaminases and IgG, while others were considered non-responders (NR). RESULTS Eighteen out of 151 (12%) AIH patients received MMF. Nine received MMF due to azathioprine-intolerance (group 1), while nine due to refractory disease (group 2). In group 1, CR and BR was achieved in six (67%) and two (22%) patients respectively. In group 2, CR and BR was achieved in one (11%) and five (56%) patients respectively. Adverse events occurred in eight patients (44%), with one patient requiring drug discontinuation. After a medium follow-up of 78 (31-116) months, there was a significant decrease in transaminase levels, mirrored by decrease in prednisolone dose from 25 to 6.25 mg/day (P<0.05). CONCLUSION Long-term therapy with MMF is safe and effective in AIH patients requiring second-line therapies, and these patients can be effectively managed at tertiary non-liver transplant centres.
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Affiliation(s)
- Rodrigo Liberal
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal; World Gastroenterology Organization (WGO) Porto Training Center, Portugal.
| | - Rui Gaspar
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal; World Gastroenterology Organization (WGO) Porto Training Center, Portugal
| | - Susana Lopes
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal; World Gastroenterology Organization (WGO) Porto Training Center, Portugal
| | - Guilherme Macedo
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal; World Gastroenterology Organization (WGO) Porto Training Center, Portugal
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Rigopoulou EI, Dalekos GN. Current Trends and Characteristics of Hepatocellular Carcinoma in Patients with Autoimmune Liver Diseases. Cancers (Basel) 2021; 13:1023. [PMID: 33804480 PMCID: PMC7957658 DOI: 10.3390/cancers13051023] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/17/2021] [Accepted: 02/24/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC), the commonest among liver cancers, is one of the leading causes of mortality among malignancies worldwide. Several reports demonstrate autoimmune liver diseases (AILDs), including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) to confer increased risk of hepatobiliary malignancies, albeit at lower frequencies compared to other liver diseases. Several parameters have been recognized as risk factors for HCC development in AIH and PBC, including demographics such as older age and male sex, clinical features, the most decisive being cirrhosis and other co-existing factors, such as alcohol consumption. Moreover, biochemical activity and treatment response have been increasingly recognized as prognostic factors for HCC development in AIH and PBC. As available treatment modalities are effective only when HCC diagnosis is established early, surveillance has been proven essential for HCC prognosis. Considering that the risk for HCC is not uniform between and within disease groups, refinement of screening strategies according to prevailing demographic, clinical, and molecular risk factors is mandated in AILDs patients, as personalized HCC risk prediction will offer significant advantage in patients at high and/or medium risk. Furthermore, future investigations should draw attention to whether modification of immunosuppression could benefit AIH patients after HCC diagnosis.
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Affiliation(s)
| | - George N. Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110 Larissa, Greece;
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Biewenga M, Inderson A, Tushuizen ME, Crobach ASL, van Hoek B. Early Predictors of Short-Term Prognosis in Acute and Acute Severe Autoimmune Hepatitis. Liver Transpl 2020; 26:1573-1581. [PMID: 32997870 PMCID: PMC7756691 DOI: 10.1002/lt.25906] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/22/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022]
Abstract
Presentation of autoimmune hepatitis (AIH) can differ from nonacute to acute autoimmune hepatitis (A-AIH) with jaundice and acute severe autoimmune hepatitis (AS-AIH) with jaundice and coagulopathy. The aim of the study was to evaluate the short-term prognosis of different presentations of AIH and the influence of liver function improvement on short-term prognosis. In this single-center retrospective cohort study, AIH patients with repeatedly tested liver function at diagnosis and during at least 1 year of follow-up were included. A-AIH was defined as bilirubin >45 µmol and international normalized ratio (INR) <1.5. AS-AIH was defined as bilirubin level >45 µmol/L and INR ≥1.5. Of the 81 included patients, 17 (21%) presented with A-AIH, and 14 (17%) presented with AS-AIH. After the start of immunosuppressive therapy, bilirubin, albumin, and INR normalized in 70%, 77%, and 69%, respectively, in a median of 2.6 months, 3 months, and 4 weeks, respectively, in patients with A-AIH and AS-AIH. Liver transplantation (LT)-free survival rate was 100% in nonacute AIH, 94% in A-AIH, and 57% in AS-AIH at 12 months after diagnosis. An increase of INR or bilirubin at 2 weeks was the best predictive factor for the need of LT within 12 months with a Youden's index of 0.85. A-AIH was present in 21%, and AS-AIH was present in 17% of AIH patients. In the majority of patients, bilirubin, albumin, and INR normalized in the first months of treatment. Deterioration of liver function after 2 weeks of treatment should lead to rapid evaluation for LT and consideration of second-line medication.
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Affiliation(s)
- Maaike Biewenga
- Department of Gastroenterology and HepatologyLeiden University Medical CenterLeiden2300 RCthe Netherlands
| | - Akin Inderson
- Department of Gastroenterology and HepatologyLeiden University Medical CenterLeiden2300 RCthe Netherlands
| | - Maarten E. Tushuizen
- Department of Gastroenterology and HepatologyLeiden University Medical CenterLeiden2300 RCthe Netherlands
| | | | - Bart van Hoek
- Department of Gastroenterology and HepatologyLeiden University Medical CenterLeiden2300 RCthe Netherlands
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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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38
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Sherman M. Reminiscences of a soon-to-be ex-hepatologist. CANADIAN LIVER JOURNAL 2020; 3:305-308. [DOI: 10.3138/canlivj-2020-0021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 07/09/2020] [Indexed: 11/20/2022]
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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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40
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Richardson N, Ng STH, Wraith DC. Antigen-Specific Immunotherapy for Treatment of Autoimmune Liver Diseases. Front Immunol 2020; 11:1586. [PMID: 32793226 PMCID: PMC7385233 DOI: 10.3389/fimmu.2020.01586] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 06/15/2020] [Indexed: 12/11/2022] Open
Abstract
The liver is a critical organ in controlling immune tolerance. In particular, it is now clear that targeting antigens for presentation by antigen presenting cells in the liver can induce immune tolerance to either autoantigens from the liver itself or tissues outside of the liver. Here we review immune mechanisms active within the liver that contribute both to the control of infectious diseases and tolerance to self-antigens. Despite its extraordinary capacity for tolerance induction, the liver remains a target organ for autoimmune diseases. In this review, we compare and contrast known autoimmune diseases of the liver. Currently patients tend to receive strong immunosuppressive treatments and, in many cases, these treatments are associated with deleterious side effects, including a significantly higher risk of infection and associated health complications. We propose that, in future, antigen-specific immunotherapies are adopted for treatment of liver autoimmune diseases in order to avoid such adverse effects. We describe various therapeutic approaches that either are in or close to the clinic, highlight their mechanism of action and assess their suitability for treatment of autoimmune liver diseases.
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Affiliation(s)
| | | | - David C. Wraith
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
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41
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Normalization of serum immunoglobulin G levels is associated with improved transplant-free survival in patients with autoimmune hepatitis. Dig Liver Dis 2020; 52:761-767. [PMID: 32473882 DOI: 10.1016/j.dld.2020.04.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 04/09/2020] [Accepted: 04/15/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND There is limited evidence linking achievement of biochemical response with outcomes in Autoimmune Hepatitis (AIH), and it is unclear whether normalization of serum immunoglobulin G (IgG) levels influences prognosis. AIMS We aimed to investigate factors associated with death or liver transplantation in patients affected by AIH. METHODS We undertook a retrospective analysis of all AIH patients attending a tertiary liver unit since 1980. Patients not meeting established diagnostic criteria for AIH or with a follow-up shorter than 18 months were excluded. RESULTS 107 patients meeting inclusion criteria were included in the study. Mean age at diagnosis was 44 years, 29 patients (27.1%) had cirrhosis at baseline. Median follow-up was 79 months, and 70 patients (79.5%) reached biochemical response. Biochemical response was associated with reduced hazard of liver transplant or death (HR 0.07, 95% CI 0.01-0.46), whereas cirrhosis at diagnosis was an independent predictor of liver transplantation or death (Hazard ratio (HR) 11.8, 95%, confidence interval (CI) 1.18-117.4). Lack of normalization of serum IgG levels was associated with reduced 5-year transplant-free survival (95% in patients normalizing, compared to 86%, p = 0.02). CONCLUSION Normalization of serum IgG levels alone translates in better transplant-free survival in patients with AIH and should be a treatment target along with transaminases.
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42
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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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43
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Mederacke YS, Kirstein MM, Großhennig A, Marhenke S, Metzler F, Manns MP, Vogel A, Mederacke I. The PNPLA3 rs738409 GG genotype is associated with poorer prognosis in 239 patients with autoimmune hepatitis. Aliment Pharmacol Ther 2020; 51:1160-1168. [PMID: 32323349 DOI: 10.1111/apt.15722] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/18/2020] [Accepted: 03/22/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Fibrosis progression in autoimmune hepatitis can be attenuated by immunosuppressive treatment; however, some patients progress despite therapy. Single nucleotide polymorphisms (SNPs) such as PNPLA3-rs738409, TM6SF2-rs58542926 and MBOAT7-rs641738 are associated with non-alcoholic fatty liver disease and fibrosis progression, whereas a splice variant in HSD17B13-rs72613567:TA has been shown to be protective. AIM To analyse the impact of different SNPs on the long-term outcome of patients with autoimmune hepatitis. METHODS We included 239 patients into this study who had been treated between 1983 and 2018 for autoimmune hepatitis. Genomic DNA was isolated from whole blood and SNPs were determined by PCR analysis. Liver biopsies were available for 215/239 patients (90%). Clinical and laboratory patient data were assessed by chart review. RESULTS Mean age at baseline was 42.1 years with 74.1% being female. The median follow-up was 9.4 years (IQR 3.5-15.0), 11.7% of the patients (n = 28) died or required liver transplantation. In the Kaplan-Meier analysis of the combined endpoint time to liver transplantation or death, we observed that patients with the PNPLA3-rs738409 GG variant met more frequently the primary endpoint (P = 0.005). In Cox regression analysis PNPLA3-rs738409 GG as well as liver cirrhosis were identified as strong predictors for time to liver transplantation or death (HR 4.5 [CI 1.48-13.72], P = 0.008 and HR 9.24 [CI 2.11-40.44], P = 0.003, respectively). Neither steatosis, diabetes mellitus nor obesity were associated with outcome. CONCLUSIONS PNPLA3-rs738409 variant GG is a predictor for time to liver transplantation or death and may help to identify autoimmune hepatitis patients at risk for disease progression.
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Affiliation(s)
- Young-Seon Mederacke
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Martha M Kirstein
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Anika Großhennig
- Institute of Biostatistics, Hannover Medical School, Hannover, Germany
| | - Silke Marhenke
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Frauke Metzler
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Ingmar Mederacke
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
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Ikura A, Chu PS, Nakamoto N, Ojiro K, Taniki N, Yoshida A, Shinoda M, Morikawa R, Yamataka K, Noguchi F, Hoshi H, Usui S, Ebinuma H, Kitagawa Y, Saito H, Kanai T. CLIF-C Organ Failure Score and Liver Volume Predict Prognosis in Steroid-Treated Severe Acute Autoimmune Hepatitis. Hepatol Commun 2020; 4:1019-1033. [PMID: 32626834 PMCID: PMC7327221 DOI: 10.1002/hep4.1521] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 03/11/2020] [Accepted: 04/02/2020] [Indexed: 12/19/2022] Open
Abstract
Controversies and debates remain regarding the best management of severe acute‐onset autoimmune hepatitis (SA‐AIH) due to the lack of useful outcome or complication prediction systems. We conducted this clinical practice‐based observational study to clarify whether Chronic Liver Failure Consortium Organ Failure scores (CLIF‐C OFs) and the computed tomography–derived liver volume to standard liver volume (CTLV/SLV) ratio at admission to a tertiary transplant center can predict outcomes and complications due to infection. Thirty‐four consecutive corticosteroid‐treated patients with SA‐AIH from 2007 to 2018 were included. Severe hepatitis was defined as an international normalized ratio (of prothrombin time) over 1.3 any time before admission. Of the 34 corticosteroid‐treated patients with SA‐AIH inclusive of 25 (73.5%) acute liver failure cases, transplant‐free survival was observed in 24 patients (70.6%). Any infection was noticed in 10 patients (29.4%). CLIF‐C OFs, at the cutoff of 9, significantly predicted survival (P = 0.0002, log‐rank test), outperformed the Model for End‐stage Liver Disease system in predicting outcome (P = 0.0325), and significantly discriminated between liver transplant and death in a competing risk analysis. SA‐AIH was characterized as having decreased CTLV/SLV, which was also predictive of survival (P < 0.0001). Interestingly, CLIF‐C OFs, especially the subscores for respiratory dysfunction, also predicted infection (P = 0.007). Conclusion: In corticosteroid‐treated patients with SA‐AIH, CLIF‐C OFs and CTLV/SLV ratios predicted both survival outcome and complications due to infection. Further investigation is warranted to determine whether making decisions based on CLIF‐C OFs or CTLV/SLV ratios is useful.
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Affiliation(s)
- Akihiko Ikura
- Division of Gastroenterology and Hepatology Department of Internal Medicine Keio University School of Medicine Tokyo Japan
| | - Po-Sung Chu
- Division of Gastroenterology and Hepatology Department of Internal Medicine Keio University School of Medicine Tokyo Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology Department of Internal Medicine Keio University School of Medicine Tokyo Japan
| | - Keisuke Ojiro
- Division of Gastroenterology and Hepatology Department of Internal Medicine Keio University School of Medicine Tokyo Japan.,Department of Gastroenterology and Hepatology Tokyo Dental College Ichikawa General Hospital Ichikawa City Japan
| | - Nobuhito Taniki
- Division of Gastroenterology and Hepatology Department of Internal Medicine Keio University School of Medicine Tokyo Japan
| | - Aya Yoshida
- Division of Gastroenterology and Hepatology Department of Internal Medicine Keio University School of Medicine Tokyo Japan
| | - Masahiro Shinoda
- Department of Surgery Keio University School of Medicine Tokyo Japan
| | - Rei Morikawa
- Division of Gastroenterology and Hepatology Department of Internal Medicine Keio University School of Medicine Tokyo Japan
| | - Karin Yamataka
- Division of Gastroenterology and Hepatology Department of Internal Medicine Keio University School of Medicine Tokyo Japan
| | - Fumie Noguchi
- Division of Gastroenterology and Hepatology Department of Internal Medicine Keio University School of Medicine Tokyo Japan
| | - Hitomi Hoshi
- Division of Gastroenterology and Hepatology Department of Internal Medicine Keio University School of Medicine Tokyo Japan
| | - Shingo Usui
- Division of Gastroenterology and Hepatology Department of Internal Medicine Keio University School of Medicine Tokyo Japan.,Department of Gastroenterology and Hepatology National Hospital Organization Saitama Hospital Wako City Japan
| | - Hirotoshi Ebinuma
- Division of Gastroenterology and Hepatology Department of Internal Medicine Keio University School of Medicine Tokyo Japan.,Department of Gastroenterology International University of Health and Welfare School of Medicine Narita City Japan
| | - Yuko Kitagawa
- Department of Surgery Keio University School of Medicine Tokyo Japan
| | - Hidetsugu Saito
- Division of Gastroenterology and Hepatology Department of Internal Medicine Keio University School of Medicine Tokyo Japan.,Division of Pharmacotherapeutics Keio University School of Pharmacy Tokyo Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology Department of Internal Medicine Keio University School of Medicine Tokyo Japan
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45
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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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46
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Hartl J, Miquel R, Zachou K, Wong GW, Asghar A, Pape S, Sebode M, Peiseler M, Zenouzi R, Ehlken H, Krech T, Weiler-Normann C, Drenth JPH, Oo YH, Dalekos GN, Heneghan M, Schramm C, Lohse AW. Features and outcome of AIH patients without elevation of IgG. JHEP Rep 2020; 2:100094. [PMID: 32280942 PMCID: PMC7139106 DOI: 10.1016/j.jhepr.2020.100094] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/28/2020] [Accepted: 01/31/2020] [Indexed: 12/27/2022] Open
Abstract
Background & Aims High IgG levels are considered a hallmark of autoimmune hepatitis (AIH). A subgroup of patients with AIH has IgG within the normal range despite evidence of clinical disease activity. The clinical significance of this biomarker has not been explored. Methods In a European multicentre study we compared biochemical, clinical and histological features from patients with AIH and normal IgG-values at diagnosis to an age- and sex-matched control group of patients with typical AIH presenting with elevated IgG. Data were assessed at diagnosis, after 12 months of therapy and at last follow-up. Results Out of 1,318 patients with AIH, 130 (10%) had normal IgG at presentation. Histological and biochemical parameters at diagnosis, as well as treatment response, showed no difference between groups. Stable remission off treatment was achieved more commonly in the normal IgG group than in the typical AIH group (24 vs. 8%; p = 0.0012). Patients of the control group not only had higher IgG levels (29.5 ± 5.8 vs. 12.5 ± 3.2 g/L; p <0.0001), but also a higher IgG/IgA ratio (9.3 ± 6.9 vs. 5.4 ± 2.4; p <0.0001) at diagnosis. The IgG/IgA ratio only declined in patients with typical AIH and was no longer different between groups after 12 months (6.3 ± 4.3 vs. 5.5 ± 2.2; p = 0.1), indicating a selective increase of IgG in typical AIH and its suppression by immunosuppression. Autoantibody titres were higher in the typical AIH group, but not when controlled for IgG levels. Conclusions Compared to AIH with typical biochemical features, patients with normal IgG levels at diagnosis (i) show similar biochemical, serological and histological features and comparable treatment response, (ii) appear to lack the selective elevation of serum IgG levels observed in typical active AIH disease, (iii) may represent a subgroup with a higher chance of successful drug withdrawal. Lay summary A characteristic feature of autoimmune hepatitis (AIH) is an elevation of immunoglobulin G (IgG), which is therefore used as a major diagnostic criterion, as well as to monitor treatment response. Nevertheless, normal IgG does not preclude the diagnosis of AIH. Therefore, we herein assessed the features of patients with AIH and normal IgG in a large multicentre study. This study demonstrates that about 10% of all patients with AIH have normal IgG; these patients are indistinguishable from other patients with AIH with respect to biochemical markers, liver histology, disease severity and treatment response, but might represent a subgroup with a higher chance of remission after drug withdrawal.
Patients with AIH and normal IgG comprise around 10% of all patients with AIH. These patients are indistinguishable from patients with typical AIH by biochemical markers or liver histology. They have no selective IgG elevation, with lower IgG and IgA levels than patients with typical AIH. These patients might represent a subgroup in whom there is a high chance of successful drug withdrawal.
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Key Words
- AIH, autoimmune hepatitis
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- AMA, anti-mitochondrial antibody
- ANA, anti-nuclear antibody
- AST, aspartate aminotransferase
- Anti-SLA/LP, anti-soluble liver antigen and anti-liver-pancreas antibodies
- INR, international normalized ratio
- LKM, liver kidney microsomal antigen
- SMA, smooth muscle antibody
- autoimmune hepatitis
- drug withdrawal
- hypergammaglobulinemia
- immunoglobulin G
- immunoglobulins
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Affiliation(s)
- Johannes Hartl
- First Department of Internal Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases
| | - Rosa Miquel
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Kalliopi Zachou
- Institute of Internal Medicine and Hepatology, Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - Guan-Wee Wong
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Asma Asghar
- Centre for Liver and Gastroenterology Research, NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, United Kingdom
| | - Simon Pape
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, the Netherlands.,European Reference Network on Hepatological Diseases
| | - Marcial Sebode
- First Department of Internal Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases
| | - Moritz Peiseler
- First Department of Internal Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases
| | - Roman Zenouzi
- First Department of Internal Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases
| | - Hanno Ehlken
- Department of Interdisciplinary Endoscopy, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases
| | - Till Krech
- Department of Pathology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Christina Weiler-Normann
- First Department of Internal Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, the Netherlands.,European Reference Network on Hepatological Diseases
| | - Ye H Oo
- Centre for Liver and Gastroenterology Research, NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, United Kingdom.,Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom.,Centre for Rare Diseases, Institute of Translational Medicine, University of Birmingham, Birmingham, United Kingdom.,European Reference Network on Hepatological Diseases
| | - George Nikolaos Dalekos
- Institute of Internal Medicine and Hepatology, Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - Michael Heneghan
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Christoph Schramm
- First Department of Internal Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases
| | - Ansgar Wilhelm Lohse
- First Department of Internal Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases
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47
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Schmidt T, Schmidt C, Strahl A, Mussawy H, Rolvien T, Jandl NM, Casar C, Oheim R, Schinke T, Lohse AW, Amling M, Schramm C, Barvencik F. A System to Determine Risk of Osteoporosis in Patients With Autoimmune Hepatitis. Clin Gastroenterol Hepatol 2020; 18:226-233.e3. [PMID: 31163277 DOI: 10.1016/j.cgh.2019.05.043] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 05/12/2019] [Accepted: 05/24/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Osteoporosis is a feared complication of autoimmune hepatitis (AIH), but bone disease has not been well studied in these patients. We aimed to identify specific risk factors for osteoporosis in patients with AIH and to develop a scoring system that could be used to identify patients with increased risk of osteoporosis. METHODS We performed a retrospective cross-sectional study of 211 patients (mean age, 56.8 years; 79.1% women) in Germany with a diagnosis of AIH from 2012 through 2017 and an indication for assessment of bone mineral status. The patients underwent bone mineral density measurements by dual energy X-ray absorptiometry. A subgroup of 99 patients underwent a second measurement. We used logistic regression to identify patient and clinical factors associated with the presence of osteoporosis. We developed a weighted sum score for estimating risk of osteoporosis and tested it in development (n = 141) and validation (n = 70) sets of patients. RESULTS According to dual energy X-ray absorptiometry measurements, 15.6% of patients had osteoporosis 42.9% were in the range for osteopenia. The prevalence of osteoporosis in patients 50 years or older was 19.2%. Univariate and logistic regression analyses showed that age older than 54 years, duration of glucocorticoid use >90 months, body mass index <23 kg/m2 and transient elastography values >8 kPA increased risk of osteoporosis 13.8-fold, 6.2-fold, 5.9-fold, and 3.0-fold, respectively. Based on these factors, we developed an index that identified patients at low-, moderate-, and high-risk of osteoporosis with an area under the curve of 0.811. Of the patients with a second osteodensitometry measurement, the rate of bone loss progression ranged from 2.7% after 1 year to 8.4% after 7 years (mean bone loss, 1.2% per year). CONCLUSIONS Almost 20% of patients with AIH older than 50 years have osteoporosis. Older age, duration of corticosteroid use, low body mass index, and liver fibrosis are independent risk factors for bone loss.
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Affiliation(s)
- Tobias Schmidt
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Constantin Schmidt
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andre Strahl
- Department of Orthopaedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Haider Mussawy
- Department of Orthopaedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tim Rolvien
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Orthopaedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nico M Jandl
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Orthopaedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Casar
- 1(st) Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ralf Oheim
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thorsten Schinke
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ansgar W Lohse
- 1(st) Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Amling
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- 1(st) Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Florian Barvencik
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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48
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Than NN, Hodson J, Schmidt-Martin D, Taubert R, Wawman RE, Botter M, Gautam N, Bock K, Jones R, Appanna GD, Godkin A, Montano-Loza AJ, Lammert F, Schramm C, Manns MP, Swain M, Burak KW, Adams DH, Hirschfield GM, Oo YH. Efficacy of rituximab in difficult-to-manage autoimmune hepatitis: Results from the International Autoimmune Hepatitis Group. JHEP Rep 2019; 1:437-445. [PMID: 32039395 PMCID: PMC7005655 DOI: 10.1016/j.jhepr.2019.10.005] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 10/21/2019] [Accepted: 10/25/2019] [Indexed: 02/07/2023] Open
Abstract
Treatment options remain limited for patients with autoimmune hepatitis (AIH), while there are still concerns over the consequences of long-term corticosteroid use. A few studies have suggested a role for B cell-driven autoimmune liver injury in AIH. This multicentre, international retrospective cohort study from the International Autoimmune Hepatitis Group aims to evaluate the clinical efficacy and safety of rituximab in difficult-to-manage AIH. METHODS Clinical data from 22 patients who received rituximab between 2007 and 2017 were collected from centres in the United Kingdom, Germany and Canada. Clinical response was assessed using changes in biochemical and immunological parameters up to 24 months post-rituximab infusion. In addition, we compared the doses of prednisolone used 3 months before and 12 months after treatment, and assessed freedom from AIH flares over the post-treatment period. RESULTS Twenty-two patients with type-1 AIH were included, with a median age of 40 years at diagnosis (range 19-79); 15/22 (68%) were female and 18/22 (82%) were Caucasian. The median period from diagnosis to the end of follow-up in these patients was 11 years (range 3-28). Values of alanine aminotransferase, aspartate aminotransferase and albumin improved significantly following rituximab therapy, and were sustained for up to 2 years (all p ≪0.001). Prednisolone doses were significantly reduced by 12 months post-treatment (p = 0.003), with 13/21 (62%) patients having a dose reduction. Over a median post-treatment follow-up period of 6 years (range 1-10), 5 patients developed AIH flares at a median of 22 months post-treatment, giving an estimated 71% freedom from AIH flare at 2 years. Four of these patients received a second course of treatment, of whom 2 had subsequent further flares. No serious adverse events attributable to rituximab were recorded. CONCLUSION In patients with difficult-to-manage AIH, rituximab appears to be clinically effective and well tolerated. Rituximab was associated with sustained improvements in serum liver tests, an absence of clinical disease flares, and a reduction in prednisolone dose. Controlled trials are warranted to further evaluate B cell-targeting therapies in patients with AIH. LAY SUMMARY Autoimmune hepatitis is an autoimmune condition of the liver, usually treated with medications that suppress the immune system, such as steroids. However, some patients do not respond to this treatment. We analysed the safety and efficacy of rituximab in patients who were not responding to first- or second-line therapies. Rituximab was safe and improved liver blood tests in 70% of patients over a 2-year follow-up period, while enabling steroid doses to be reduced in two-thirds of patients, which is a very positive clinical outcome.
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Affiliation(s)
- Nwe Ni Than
- Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
- Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
| | - James Hodson
- Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
| | - Daniel Schmidt-Martin
- Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- European Reference Network (ERN) Rare Liver
| | - Rebecca E. Wawman
- Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
- Imperial College, London
| | - Meemee Botter
- Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
- University of Amsterdam, Netherland
| | - Nishant Gautam
- Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
| | - Kilian Bock
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- European Reference Network (ERN) Rare Liver
| | - Rebecca Jones
- Leeds Liver Transplant Unit, St James University Hospital, Leeds, United Kingdom
| | | | - Andrew Godkin
- University Hospital of Wales, Cardiff, United Kingdom
| | | | - Frank Lammert
- Department of Medicine II, Saarland University Medical Centre, Homburg
| | - Christoph Schramm
- University Medical Centre Hamburg-Eppendorf, Hamburg, I. Department of Medicine and Martin Zeitz Centre for Rare Diseases, Germany
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany; Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
- European Reference Network (ERN) Rare Liver
| | - Mark Swain
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Calgary, Canada
| | - Kelly W. Burak
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Calgary, Canada
| | - David H. Adams
- Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
- Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
- Autoimmune Liver Diseases Clinic, Centre for Rare Diseases, Institute of Translational Medicine, University of Birmingham, Birmingham, United Kingdom
| | - Gideon M Hirschfield
- University of Toronto, Canada
- Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Canada
| | - Ye Htun Oo
- Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
- Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
- Autoimmune Liver Diseases Clinic, Centre for Rare Diseases, Institute of Translational Medicine, University of Birmingham, Birmingham, United Kingdom
- European Reference Network (ERN) Rare Liver
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49
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Pape S, Gevers TJG, Belias M, Mustafajev IF, Vrolijk JM, van Hoek B, Bouma G, van Nieuwkerk CMJ, Hartl J, Schramm C, Lohse AW, Taubert R, Jaeckel E, Manns MP, Papp M, Stickel F, Heneghan MA, Drenth JPH. Predniso(lo)ne Dosage and Chance of Remission in Patients With Autoimmune Hepatitis. Clin Gastroenterol Hepatol 2019; 17:2068-2075.e2. [PMID: 30625402 DOI: 10.1016/j.cgh.2018.12.035] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 11/30/2018] [Accepted: 12/23/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Patients with autoimmune hepatitis (AIH) commonly receive induction therapy with predniso(lo)ne followed by maintenance therapy with azathioprine. European Association for Study of the Liver clinical practice guidelines advise a predniso(lo)ne dose range of 0.50-1 mg/kg/day, which leaves room for practice variation. We performed a multicenter study to determine the efficacy of different dose ranges of predniso(lo)ne induction therapy in a large European cohort of patients with AIH. METHODS We performed a retrospective cohort study using a comparative effectiveness design. We collected data from 451 adults with AIH who began treatment from 1978 through 2017 at 9 centers in 5 European countries. We assigned patients to a high-dose group (initial predniso(lo)ne dose ≥0.50 mg/kg/day; n = 281) or a low-dose group (<0.50 mg/kg/day; n = 170). Logistic regression was performed to determine difference in outcomes between the groups. The primary outcome was normal serum levels of transaminases at 6 months after initiation of therapy. RESULTS There was no significant difference in rates of normalization of transaminases between the high-dose predniso(lo)ne group and the low-dose group (70.5% vs 64.7%; P = .20). After multivariable logistic regression with correction for confounders, there was no difference in the likelihood of normalization of transaminases between the groups (odds ratio, 1.21; 95% CI, 0.78-1.87; P = .38). Patients given an initial high dose of predniso(lo)ne received more predniso(lo)ne over time than patients started on a lower dose (median doses over 6 months: 3780 mg vs 2573 mg) (P < .01). CONCLUSIONS In a retrospective study of patients with AIH in Europe, we found that the dose of predniso(lo)ne to induce remission in patients with AIH is less relevant than assumed. An initial predniso(lo)ne dose below 0.50 mg/kg/day substantially decreases unnecessary exposure to predniso(lo)ne in patients with AIH.
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Affiliation(s)
- Simon Pape
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Tom J G Gevers
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Michail Belias
- Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ilyas F Mustafajev
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jan Maarten Vrolijk
- Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, The Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Gerd Bouma
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Carin M J van Nieuwkerk
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Johannes Hartl
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Christoph Schramm
- 1(st) Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Ansgar W Lohse
- 1(st) Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Maria Papp
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland
| | - Michael A Heneghan
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands.
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50
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Bhamidimarri KR, Martin P. Are High-Dose Steroids Really Necessary in Treatment of Autoimmune Hepatitis? Clin Gastroenterol Hepatol 2019; 17:1948-1949. [PMID: 30885885 DOI: 10.1016/j.cgh.2019.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 03/10/2019] [Indexed: 02/07/2023]
Affiliation(s)
| | - Paul Martin
- University of Miami, School of Medicine, Miami, Florida
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