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Eldew H, Soldera J. Evaluation of biological therapies in autoimmune hepatitis: A case-based systematic review. World J Gastrointest Pathophysiol 2025; 16:101481. [DOI: 10.4291/wjgp.v16.i1.101481] [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: 09/15/2024] [Revised: 02/17/2025] [Accepted: 02/25/2025] [Indexed: 03/18/2025] Open
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is typically treated with immunomodulators and steroids. However, some patients are refractory to these treatments, necessitating alternative approaches. Biological therapies have recently been explored for these difficult cases.
AIM To assess the efficacy and safety of biologics in AIH, focusing on patients unresponsive to standard treatments and evaluating outcomes such as serological markers and histological remission.
METHODS A case-based systematic review was performed following the PRISMA protocol to evaluate the efficacy and safety of biological therapies in AIH. The primary focus was on serological improvement and histological remission. The secondary focus was on assessing therapy safety and additional outcomes. A standardized search command was applied to MEDLINE, EMBASE, and Cochrane Library databases to identify relevant studies. Inclusion criteria encompassed adult AIH patients treated with biologics. Data were analyzed based on demographics, prior treatments, and therapy-related outcomes. A narrative synthesis was employed to address biases and provide a comprehensive overview of the evidence.
RESULTS A total of 352 studies were reviewed, with 30 selected for detailed analysis. Key findings revealed that Belimumab led to a favourable response in five out of eight AIH patients across two studies. Rituximab demonstrated high efficacy, with 41 out of 45 patients showing significant improvement across six studies. Basiliximab was assessed in a single study, where the sole patient treated experienced a beneficial outcome. Additionally, a notable number of AIH cases were induced by anti-tumor necrosis factor (TNF) medications, including 16 cases associated with infliximab and four cases with adalimumab. All these cases showed improvement upon withdrawal of the biologic agent.
CONCLUSION Belimumab and Rituximab show promise as effective alternatives for managing refractory AIH, demonstrating significant improvements in clinical outcomes and liver function. However, the variability in patient responses to different therapies highlights the need for personalized treatment strategies. The risk of AIH induced by anti-TNF therapies underscores the need for vigilant monitoring and prompt symptom recognition. These findings support the incorporation of biologic agents into AIH treatment protocols, particularly for patients who do not respond to conventional therapies.
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Affiliation(s)
- Haifa Eldew
- Consultant in Acute Internal Medicine with Specialist Interest in Hepatology, Princess Royal University Hospital, Kings College Hospital Foundation Trust, Orpington Kent BR6 8ND, United Kingdom
| | - Jonathan Soldera
- Acute Medicine and Gastroenterology, University of South Wales, Cardiff CF37 1DL, United Kingdom
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Cananzi M, Jørgensen MH, Buescher G, De Bruyne R, Samyn M. Current practice in the management of paediatric autoimmune liver disease in Europe. J Pediatr Gastroenterol Nutr 2025; 80:260-270. [PMID: 39618087 DOI: 10.1002/jpn3.12424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 11/10/2024] [Accepted: 11/13/2024] [Indexed: 02/04/2025]
Abstract
OBJECTIVE Paediatric autoimmune liver disease (pAILD) is a rare condition with serious health implications. Notwithstanding treatment advancements, areas of uncertainty and knowledge gaps still exist. We here investigated the real-life approach to pAILD management in Europe. METHODS A survey was distributed to members of the European Rare Liver Disease Reference Network (ERN RARE-LIVER) and the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) Hepatology Interest Group. Information was gathered regarding clinical activity, medications used, and access to paediatric drug formulations at each site. RESULTS Thirty-six centres from 22 European countries responded to the survey. The majority are exclusively paediatric units (86%). Among participants, 80% follow <50 children with pAILD, of which 25%-50% are <10 years old in 44% of centres. All centres use predniso(lo)ne as first-line therapy, alone (15/36) or with azathioprine (21/36). Azathioprine and mycophenolate are the preferred second-line options in centres using first-line steroid monotherapy (11/15) or combined steroid-azathioprine (19/21), respectively. Tacrolimus is used as third-line agent in 15/36 centres. Proactive measurement of drug metabolites and target levels vary widely among centres. Paediatric predniso(lo)ne formulations are commercially available in 7/22 European countries, azathioprine in 3, mycophenolate in 14, tacrolimus in 15 and ursodeoxycholic acid in 14. When paediatric formulations are unavailable, children are treated with magisterial preparations or 'solid' formulations (crushed or intact). CONCLUSIONS Treatment of pAILD in Europe varies widely in terms of medications used and treatment monitoring. Availability of paediatric drug formulations across Europe is limited. Collaborative initiatives are needed to define evidence-based strategies for management of pAILD and to promote an equal, age-appropriate treatment for affected children.
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Affiliation(s)
- Mara Cananzi
- Unit of Paediatric Gastroenterology, Digestive Endoscopy, Hepatology and Care of the Child with Liver Transplantation, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy
| | | | - Gustav Buescher
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Ruth De Bruyne
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Ghent University Hospital, Belgium
| | - Marianne Samyn
- Paediatric Liver, GI and Nutrition Centre, King's College Hospital NHS Trust, London, UK
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Zhao L, Tang H, Cheng Z. Pharmacotherapy of Liver Fibrosis and Hepatitis: Recent Advances. Pharmaceuticals (Basel) 2024; 17:1724. [PMID: 39770566 PMCID: PMC11677259 DOI: 10.3390/ph17121724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 12/05/2024] [Accepted: 12/17/2024] [Indexed: 01/03/2025] Open
Abstract
Liver fibrosis is a progressive scarring process primarily caused by chronic inflammation and injury, often closely associated with viral hepatitis, alcoholic liver disease, metabolic dysfunction-associated steatotic liver disease (MASLD), drug-induced liver injury, and autoimmune liver disease (AILD). Currently, there are very few clinical antifibrotic drugs available, and effective targeted therapy is lacking. Recently, emerging antifibrotic drugs and immunomodulators have shown promising results in animal studies, and some have entered clinical research phases. This review aims to systematically review the molecular mechanisms underlying liver fibrosis, focusing on advancements in drug treatments for hepatic fibrosis. Furthermore, since liver fibrosis is a progression or endpoint of many diseases, it is crucial to address the etiological treatment and secondary prevention for liver fibrosis. We will also review the pharmacological treatments available for common hepatitis leading to liver fibrosis.
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Affiliation(s)
- Liangtao Zhao
- Hepato-Pancreato-Biliary Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China;
| | - Haolan Tang
- School of Medicine, Southeast University, Nanjing 210009, China;
| | - Zhangjun Cheng
- Hepato-Pancreato-Biliary Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China;
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Costaguta A, Costaguta G, Álvarez F. Autoimmune hepatitis: Towards a personalized treatment. World J Hepatol 2024; 16:1225-1242. [PMID: 39606175 PMCID: PMC11586748 DOI: 10.4254/wjh.v16.i11.1225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 09/02/2024] [Accepted: 10/11/2024] [Indexed: 11/06/2024] Open
Abstract
Autoimmune hepatitis is an uncommon condition that affects both adults and children and is characterized by chronic and recurrent inflammatory activity in the liver. This inflammation is accompanied by elevated IgG and autoantibody levels. Historically, treatment consists of steroids with the addition of azathioprine, which results in remission in approximately 80% of patients. Despite significant advancements in our understanding of the immune system over the past two decades, few modifications have been made to treatment algorithms, which have remained largely unchanged since they were first proposed more than 40 years ago. This review summarized the various treatment options currently available as well as our experiences using them. Although steroids are the standard treatment for induction therapy, other medications may be considered. Cyclosporin A, a calcineurin inhibitor that decreases T cell activation, has proven effective for induction of remission, but its long-term side effects limit its appeal for maintenance. Tacrolimus, a drug belonging to the same family, has been used in patients with refractory diseases with fewer side effects. Sirolimus and everolimus have interesting effects on regulatory T cell populations and may become viable options in the future. Mycophenolate mofetil is not effective for induction but is a valid alternative for patients who are intolerant to azathioprine. B cell-depleting drugs, such as rituximab and belimumab, have been successfully used in refractory cases and are useful in both the short and long term. Other promising treatments include anti-tumor necrosis factors, Janus kinases inhibitors, and chimeric antigen receptor T cell therapy. This growing armamentarium allows us to imagine a more tailored approach to the treatment of autoimmune hepatitis in the near future.
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Affiliation(s)
- Alejandro Costaguta
- Department of Hepatology and Liver Transplant Unit, Sanatorio de Niños de Rosario, Rosario 2000, Santa Fe, Argentina.
| | - Guillermo Costaguta
- Department of Gastroenterology, Hepatology, and Nutrition, CHU Sainte-Justine, Montreal H3T 1C5, Quebec, Canada
| | - Fernando Álvarez
- Department of Pediatrics, CHU Sainte-Justine, Montreal H3T 1C5, Quebec, Canada
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Riveiro-Barciela M, Barreira-Díaz A, Esteban P, Rota R, Álvarez-Navascúes C, Pérez-Medrano I, Mateos B, Gómez E, De-la-Cruz G, Ferre-Aracil C, Horta D, Díaz-González Á, Ampuero J, Díaz-Fontenla F, Salcedo M, Ruiz-Cobo JC, Londoño MC. Rituximab is a safe and effective alternative treatment for patients with autoimmune hepatitis: Results from the ColHai registry. Liver Int 2024; 44:2303-2314. [PMID: 38809086 DOI: 10.1111/liv.15970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 04/23/2024] [Accepted: 04/30/2024] [Indexed: 05/30/2024]
Abstract
BACKGROUND AND AIMS Small series suggest that rituximab could be effective as treatment for autoimmune hepatitis (AIH), although data are scarce. We aimed to evaluate the efficacy and safety of rituximab in different cohorts of patients with AIH. METHODS Multicentre retrospective analysis of the 35 patients with AIH and its variant forms treated with rituximab and included in the ColHai registry between 2015 and 2023. RESULTS Most patients were female (83%), 10 (29%) had cirrhosis and four (11.4%) variant forms of AIH. Indication for rituximab were as follows: 14(40%) refractory AIH, 19(54%) concomitant autoimmune or haematological disorder, 2(6%) intolerance to prior treatments. In three (9%) subjects with a concomitant disorder, rituximab was the first therapy for AIH. Overall, 31 (89%) patients achieved or maintained complete biochemical response (CBR), including the three in first-line therapy. No difference in CBR was observed according to rituximab indication (refractory AIH 86% vs. concomitant disorders 90%, p = .824) or cirrhosis (80% vs. 92%, p = .319). Rituximab was associated with a significant reduction in corticosteroids (median dose: prior 20 vs. post 5 mg, p < .001) and the discontinuation of ≥1 immunosuppressant in 47% of patients. Flare-free rate at 1st, 2nd and 3rd year was 86%, 73% and 62% respectively. Flares were not associated with the development of liver failure and were successfully managed with repeated doses of rituximab and/or increased corticosteroids. Three (9%) patients experienced infusion-related adverse events (1 anaphylaxis and 2 flu-like symptoms) and five (14%) infections. CONCLUSION Rituximab is safe and effective in patients with refractory AIH and those treated due to concomitant autoimmune or haematological disorders.
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Affiliation(s)
- Mar Riveiro-Barciela
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Eppendorf, Germany
| | - Ana Barreira-Díaz
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Paula Esteban
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Rosa Rota
- Liver Unit, Gastroenterology Department, Hospital Universitario de Bellvitge, IDIBELL, L'hospitalet, Spain
| | | | - Indhira Pérez-Medrano
- Gastroenterology Department, Complejo Hospitalario Universitario de Pontevedra, Pontevedra, Spain
| | - Beatriz Mateos
- Gastroenterology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Elena Gómez
- Gastroenterology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Gema De-la-Cruz
- Gastroenterology Department, Complejo Hospitalario Universitario de Toledo, Toledo, Spain
| | - Carlos Ferre-Aracil
- Gastroenterology and Hepatology Department, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Diana Horta
- Gastroenterology Department, Hospital Universitari Mutua de Terrassa, Terrassa, Spain
| | - Álvaro Díaz-González
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, Santander, Spain
| | - Javier Ampuero
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Gastroenterology Department, Hospital Universitario Virgen del Rocio, Institute of Biomedicine of Sevilla (IBIS), Sevilla, Spain
- Department of Medicine, University of Sevilla, Sevilla, Spain
| | - Fernando Díaz-Fontenla
- Gastroenterology Department, Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid, Madrid, Spain
| | - Magdalena Salcedo
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Gastroenterology Department, Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid, Madrid, Spain
| | - Juan-Carlos Ruiz-Cobo
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - María-Carlota Londoño
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Eppendorf, Germany
- Liver Unit, Hospital Clínic de Barcelona, Barcelona, Spain
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Costaguta GA, Álvarez F. B cell depletion for autoimmune liver diseases: A retrospective review of indications and outcomes. JPGN REPORTS 2024; 5:326-333. [PMID: 39149184 PMCID: PMC11322033 DOI: 10.1002/jpr3.12098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 04/08/2024] [Accepted: 05/19/2024] [Indexed: 08/17/2024]
Abstract
Objectives Pediatric autoimmune hepatitis has an incidence of 0.23/100.000 children in North America, with a bleak prognosis if left untreated. Steroids are the therapy of choice but are not always effective. B cell depletion is a safe and effective therapy that allows for a steroid-sparing protocol, especially in patients who do not tolerate side effects. Methods We retrospectively reviewed rituximab-treated patients between 2017 and 2022. Demographics, previous treatments, reasons for B cell depletion, response, and adverse effects were noted. Results Six patients with a mean age of 10.2 years were included. All patients had comorbidities that rendered treatment with steroids unsuccessful or undesirable. Rituximab was started at a mean follow-up of 8 months. After 6 months, the mean alanine transaminase and aspartate transaminase levels decreased from 575 IU/L and 342 IU/L, respectively, to 28 IU/L (p = 0.02) and 36 IU/L (p = 0.008), respectively. Mean γ-glutamyl transpeptidase decreased from 105 to 25 IU/L (p = 0.01). Immunoglobulin G levels were normalized in all patients (p = 0.01). No severe adverse events were observed. One patient had persistent hypogammaglobulinemia, and another had lymphopenia. Conclusion B-cell depletion is an effective and safe treatment for autoimmune liver diseases and should be included as an option, particularly for relapsing patients in whom steroids are undesirable or have shown nonadherence.
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Affiliation(s)
| | - Fernando Álvarez
- Gastroenterology, Hepatology and NutritionCHU Sainte‐JustineMontrealQuebecCanada
- Department of PediatricsUniversity of MontrealMontrealQuebecCanada
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Fujimori S, Chu PS, Teratani T, Harada Y, Suzuki T, Amiya T, Taniki N, Kasuga R, Mikami Y, Koda Y, Ichikawa M, Tabuchi T, Morikawa R, Yamataka K, Noguchi F, Tsujikawa H, Kurebayashi Y, Sakamoto M, Kanai T, Nakamoto N. IL-15-producing splenic B cells play pathogenic roles in the development of autoimmune hepatitis. JHEP Rep 2023; 5:100757. [PMID: 37305442 PMCID: PMC10251155 DOI: 10.1016/j.jhepr.2023.100757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 03/02/2023] [Accepted: 03/21/2023] [Indexed: 06/13/2023] Open
Abstract
Background & Aims B-cell depletion therapy with an anti-CD20 is an effective treatment strategy for patients with refractory autoimmune hepatitis (AIH). However, the mechanisms underlying B-cell action are unclear. Methods Herein, we used the adeno-associated virus IL-12 model, in which hepatic IL-12 expression triggers liver injuries characteristic of AIH. We also analysed the clinical samples of patients with AIH. Results B-cell depletion using anti-CD20 or splenectomy was found to improve liver functions and decrease the cytotoxic CD8+ T-cell (cytotoxic T lymphocyte [CTL]) count in the liver. This improvement was reversed by the adoptive transfer of splenic B cells derived from AAV IL-12-treated mice to splenectomised mice as it caused the hepatic CTL count to increase. RNA-sequencing analysis identified IL-15 as a key factor in pathogenic B cells, which promotes CTL expansion and subsequent migration to the liver via the CXCL9/CXCR3 axis. Indeed, IL-15 neutralisation ameliorated hepatitis by suppressing splenic and hepatic CTLs in vivo. The close distribution of B220+ B cells and CD8+ T cells in the spleen of AIH mice suggested mutual interactions. Mechanistically, IFNγ and CD40L/CD40 signalling were indispensable for the expression of IL-15 in B cells, and in vitro co-culture experiments revealed that splenic CD40L+CD8+ T cells promoted IL-15 production in B cells, which led to CTL expansion. In patients with AIH, high serum IL-15 concentration and IL-15+ B-cell counts, positively correlating with serum alanine aminotransferase levels, support translation and potential therapeutic targeting in human AIH. Conclusions This investigation elucidated the roles of IL-15-producing splenic B cells that occur in concert with pathogenic CD8+ T cells during the development of AIH. Impact and Implications IL-15-producing B cells were shown to exacerbate experimental AIH via cytotoxic T lymphocyte expansion. CD40L+CD8+ T cells promoted IL-15 expression in B cells, indicating the mutual interaction of both cells. High serum IL-15 concentrations, IL-15+ B-cell counts, and CD40L+IL-15Rα+CD8+ T-cell counts were confirmed in the blood of patients with AIH.
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Affiliation(s)
- Sota Fujimori
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
- Mitsubishi Tanabe Pharma Corporation, Kanagawa, Japan
| | - Po-Sung Chu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Toshiaki Teratani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yosuke Harada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Takahiro Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Takeru Amiya
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
- Mitsubishi Tanabe Pharma Corporation, Kanagawa, Japan
| | - Nobuhito Taniki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Ryosuke Kasuga
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yohei Mikami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yuzo Koda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
- Mitsubishi Tanabe Pharma Corporation, Kanagawa, Japan
| | - Masataka Ichikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Takaya Tabuchi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, 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
| | - Hanako Tsujikawa
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Yutaka Kurebayashi
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Michiie Sakamoto
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
- Japan Agency for Medical Research and Development, AMED, Tokyo, Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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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: 1] [Impact Index Per Article: 0.5] [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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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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Amendt T, Tybulewicz VLJ. Antidepressants cheer up hepatic B1 B cells: Hope for the treatment of autoimmune liver diseases? Front Immunol 2023; 13:1083173. [PMID: 36733387 PMCID: PMC9887017 DOI: 10.3389/fimmu.2022.1083173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 12/16/2022] [Indexed: 01/18/2023] Open
Affiliation(s)
- Timm Amendt
- Institute of Immunology, Ulm University, Ulm, Germany,*Correspondence: Timm Amendt,
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11
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Harsini S, Rezaei N. Autoimmune diseases. Clin Immunol 2023. [DOI: 10.1016/b978-0-12-818006-8.00001-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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12
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Giovannini D, Belbezier A, Baillet A, Bouillet L, Kawano M, Dumestre-Perard C, Clavarino G, Noble J, Pers JO, Sturm N, Huard B. Heterogeneity of antibody-secreting cells infiltrating autoimmune tissues. Front Immunol 2023; 14:1111366. [PMID: 36895558 PMCID: PMC9989216 DOI: 10.3389/fimmu.2023.1111366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 01/27/2023] [Indexed: 02/23/2023] Open
Abstract
The humoral response is frequently dysfunctioning in autoimmunity with a frequent rise in total serum immunoglobulins, among which are found autoantibodies that may be pathogenic by themselves and/or propagate the inflammatory reaction. The infiltration of autoimmune tissues by antibody-secreting cells (ASCs) constitutes another dysfunction. The known high dependency of ASCs on the microenvironment to survive combined to the high diversity of infiltrated tissues implies that ASCs must adapt. Some tissues even within a single clinical autoimmune entity are devoid of infiltration. The latter means that either the tissue is not permissive or ASCs fail to adapt. The origin of infiltrated ASCs is also variable. Indeed, ASCs may be commonly generated in the secondary lymphoid organ draining the autoimmune tissue, and home at the inflammation site under the guidance of specific chemokines. Alternatively, ASCs may be generated locally, when ectopic germinal centers are formed in the autoimmune tissue. Alloimmune tissues with the example of kidney transplantation will also be discussed own to their high similarity with autoimmune tissues. It should also be noted that antibody production is not the only function of ASCs, since cells with regulatory functions have also been described. This article will review all the phenotypic variations indicative of tissue adaptation described so for at the level of ASC-infiltrating auto/alloimmune tissues. The aim is to potentially define tissue-specific molecular targets in ASCs to improve the specificity of future autoimmune treatments.
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Affiliation(s)
- Diane Giovannini
- Department of Pathology, Grenoble University Hospital, Grenoble, France.,Translational Research in Autoimmunity and Inflammation Group (TRAIG), Translational Innovation in Medicine and Complexity (TIMC), University Grenoble-Alpes, CNRS Unité mixte de recherche (UMR) 5525, Grenoble, France
| | - Aude Belbezier
- Translational Research in Autoimmunity and Inflammation Group (TRAIG), Translational Innovation in Medicine and Complexity (TIMC), University Grenoble-Alpes, CNRS Unité mixte de recherche (UMR) 5525, Grenoble, France.,Department of Internal Medicine, Grenoble University Hospital, Grenoble, France
| | - Athan Baillet
- Translational Research in Autoimmunity and Inflammation Group (TRAIG), Translational Innovation in Medicine and Complexity (TIMC), University Grenoble-Alpes, CNRS Unité mixte de recherche (UMR) 5525, Grenoble, France.,Department of Rheumatology, Grenoble University Hospital, Grenoble, France
| | - Laurence Bouillet
- Translational Research in Autoimmunity and Inflammation Group (TRAIG), Translational Innovation in Medicine and Complexity (TIMC), University Grenoble-Alpes, CNRS Unité mixte de recherche (UMR) 5525, Grenoble, France.,Department of Internal Medicine, Grenoble University Hospital, Grenoble, France
| | - Mitsuhiro Kawano
- Department of Rheumatology, Kanazawa University Hospital, Kanazawa, Japan
| | | | | | - Johan Noble
- Department of Nephrology, Grenoble University Hospital, Grenoble, France
| | - Jacques-Olivier Pers
- B Lymphocytes, Autoimmunity and Immunotherapies, Brest University, INSERM, UMR1227, Brest, France.,Odontology Unit, Brest University Hospital, Brest, France
| | - Nathalie Sturm
- Department of Pathology, Grenoble University Hospital, Grenoble, France.,Translational Research in Autoimmunity and Inflammation Group (TRAIG), Translational Innovation in Medicine and Complexity (TIMC), University Grenoble-Alpes, CNRS Unité mixte de recherche (UMR) 5525, Grenoble, France
| | - Bertrand Huard
- Translational Research in Autoimmunity and Inflammation Group (TRAIG), Translational Innovation in Medicine and Complexity (TIMC), University Grenoble-Alpes, CNRS Unité mixte de recherche (UMR) 5525, Grenoble, France
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13
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Hepatitis-associated Aplastic Anemia. J Pediatr Gastroenterol Nutr 2022; 75:553-555. [PMID: 36070526 DOI: 10.1097/mpg.0000000000003603] [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: 02/04/2023]
Abstract
Hepatitis-associated aplastic anemia (HAAA) accounts for 4% of autoimmune hepatitis in children. An episode of seronegative autoimmune hepatitis is followed a few days or months later by aplastic anemia or full aplasia. This autoimmune disease could be due to a regulation defect in the immune response to a viral trigger, in a genetically predisposed individual. Other causes of hepatitis or aplastic anemia have to be ruled out. Steroids and azathioprine usually control the liver damage but do not prevent the development of aplastic anemia. Aplastic anemia is treated with either hematopoietic stem cell transplantation in patients with a sibling donor or anti-thymocyte globulins and cyclosporine. We propose guidelines to explore and treat this rare disease. We emphasize on the necessary close collaboration between hepatologists and hematologists.
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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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15
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Whitehead B, Kriegermeier A. Natural history and management of refractory autoimmune hepatitis. Clin Liver Dis (Hoboken) 2022; 20:120-123. [PMID: 36245680 PMCID: PMC9549313 DOI: 10.1002/cld.1231] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 04/22/2022] [Accepted: 04/26/2022] [Indexed: 02/04/2023] Open
Abstract
Content available: Author Interview and Audio Recording.
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Affiliation(s)
- Bridget Whitehead
- Division of Gastroenterology, Hepatology and NutritionNorthwestern UniversityFeinberg School of MedicineAnn & Robert H. Lurie Children's Hospital of ChicagoChicagoIllinoisUSA
| | - Alyssa Kriegermeier
- Division of Gastroenterology, Hepatology and NutritionNorthwestern UniversityFeinberg School of MedicineAnn & Robert H. Lurie Children's Hospital of ChicagoChicagoIllinoisUSA
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16
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Shin E, Schwarz KB, Jones-Brando LV, Florea LD, Sabunciyan S, Wood LD, Yolken RH. Expression of HLA and Autoimmune Pathway Genes in Liver Biopsies of Young Subjects With Autoimmune Hepatitis Type 1. J Pediatr Gastroenterol Nutr 2022; 75:269-275. [PMID: 35759748 PMCID: PMC9365252 DOI: 10.1097/mpg.0000000000003538] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 05/18/2022] [Indexed: 12/10/2022]
Abstract
OBJECTIVES To test the hypothesis that autoimmune hepatitis (AIH type I) in young subjects is due to genetic differences in proinflammatory genes responding to viral triggers in patients and controls. METHODS Intrahepatic gene expression was compared between AIH type I (n = 24, age 9-30 years) patients (hereafter referred to as the AIH group) and controls (n = 21, age 4-25 years). RNA sequencing was performed on complementary DNA (cDNA) libraries made from total RNA extracted from formalin-fixed paraffin-embedded (FFPE) liver biopsy samples. Gene expression levels were quantified, and differentially expressed genes were functionally analyzed. Pathway analysis was performed using the databases Kyoto Encyclopedia of Genes and Genomes (KEGG) and PANTHER. The remaining sequences were mapped to the RefSeq complete set of viral genomes. RESULTS Differential gene analysis identified 181 genes that were significantly differentially expressed (136 upregulated in the AIH group). Autoimmune pathway genes such as CD19 and CD20 which are important in B cell regulation and maturation as well as, CD8 and LY9 , which are T-cell related, were upregulated in our AIH group. Genes implicated in AIH pathogenesis including CXCL10 , which is thought to be associated with AIH severity and progression, complement genes ( C1QA, C1QB , and C1QC ), and human leucocyte antigen ( HLA ) genes ( HLA-DRB1, HLA-DRA, HLA-B , and HLA-C ) were upregulated in samples from the AIH group. Specific viral etiologies were not found. CONCLUSIONS Unbiased next-generation sequencing and differential gene expression analysis of the AIH group has not only added support for the role of B cells in the pathogenesis and treatment of AIH but also has introduced potential new therapeutic targets: CXCL10 (anti- CXCL10 ) and several complement system-related genes.
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Affiliation(s)
- Emilia Shin
- From the Pediatrics, Johns Hopkins Medical Institutions, Baltimore, MD
| | | | | | - Liliana D. Florea
- the Genetic Medicine, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Sarven Sabunciyan
- From the Pediatrics, Johns Hopkins Medical Institutions, Baltimore, MD
| | | | - Robert H. Yolken
- From the Pediatrics, Johns Hopkins Medical Institutions, Baltimore, MD
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Czaja AJ. Immune Inhibitory Properties and Therapeutic Prospects of Transforming Growth Factor-Beta and Interleukin 10 in Autoimmune Hepatitis. Dig Dis Sci 2022; 67:1163-1186. [PMID: 33835375 DOI: 10.1007/s10620-021-06968-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 03/22/2021] [Indexed: 12/14/2022]
Abstract
Transforming growth factor-beta and interleukin 10 have diverse immune inhibitory properties that have restored homeostatic defense mechanisms in experimental models of autoimmune disease. The goals of this review are to describe the actions of each cytokine, review their investigational use in animal models and patients, and indicate their prospects as interventions in autoimmune hepatitis. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Transforming growth factor-beta expands the natural and inducible populations of regulatory T cells, limits the proliferation of natural killer cells, suppresses the activation of naïve CD8+ T cells, decreases the production of interferon-gamma, and stimulates fibrotic repair. Interleukin 10 selectively inhibits the CD28 co-stimulatory signal for antigen recognition and impairs antigen-specific activation of uncommitted CD4+ and CD8+ T cells. It also inhibits maturation of dendritic cells, suppresses Th17 cells, supports regulatory T cells, and limits production of diverse pro-inflammatory cytokines. Contradictory immune stimulatory effects have been associated with each cytokine and may relate to the dose and accompanying cytokine milieu. Experimental findings have not translated into successful early clinical trials. The recombinant preparation of each agent in low dosage has been safe in human studies. In conclusion, transforming growth factor-beta and interleukin 10 have powerful immune inhibitory actions of potential therapeutic value in autoimmune hepatitis. The keys to their therapeutic application will be to match their predominant non-redundant function with the pivotal pathogenic mechanism or cytokine deficiency and to avoid contradictory immune stimulatory actions.
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Affiliation(s)
- Albert J Czaja
- Professor Emeritus of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, 200 First Street S.W., Rochester, MN, 55905, USA.
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18
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Vitale G, Gitto S, Campani C, Turco L, Baldan A, Marra F, Morelli MC. Biological therapies in patients with liver disease: are they really lifesavers? Expert Opin Biol Ther 2021; 22:473-490. [PMID: 34860629 DOI: 10.1080/14712598.2022.2013799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION The liver plays a key role in the setting of immune tolerance. Targeting antigens for presentation by antigen-presenting cells in the liver can induce immune tolerance to either autoantigens from the liver itself or organs outside of the liver. Despite its non-conventional capacity for tolerance induction, the liver remains a target organ for autoimmune diseases. Whereas chronic inflammation and intra-hepatic immuno-suppressive microenvironment occurring during liver fibrosis lead to hepatocellular carcinoma. Monoclonal antibodies have revolutionized the therapeutic strategies of many autoimmune diseases and some cancers. AREAS COVERED We review data from literature regarding the safety and efficacy of biologics in treating hepatobiliary autoimmune diseases and primary liver cancers. Furthermore, we describe their potential use in the setting of liver transplants and their main immune-related liver adverse events. EXPERT OPINION Biological therapies have changed the natural history of main autoimmune diseases and solid cancers. Compared to other organs and disease settings, the liver lags behind in biologics and their applications. The development of novel diagnostic and therapeutic strategies based on the immunological and antigenic characteristics of the hepatobiliary system could reduce mortality and transplant rates linked to chronic liver diseases.
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Affiliation(s)
- Giovanni Vitale
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Claudia Campani
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Laura Turco
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Anna Baldan
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Maria Cristina Morelli
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
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Vergani D, Terziroli Beretta-Piccoli B, Mieli-Vergani G. A reasoned approach to the treatment of autoimmune hepatitis. Dig Liver Dis 2021; 53:1381-1393. [PMID: 34162505 DOI: 10.1016/j.dld.2021.05.033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/15/2021] [Accepted: 05/27/2021] [Indexed: 12/11/2022]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease affecting all ages, characterised by elevated transaminase and immunoglobulin G levels, positive autoantibodies, interface hepatitis on histology and good response to immunosuppressive treatment. If untreated, it has a poor prognosis. The aim of this review is to analyse AIH therapeutic interventions with reference to our knowledge of the pathogenesis of AIH. Standard treatment, based on steroids and azathioprine, leads to disease remission in 80-90% of patients. Alternative first-line treatment with budesonide is effective in adults, but less so in the juvenile form of AIH; first-line treatment with ciclosporin does not provide convincing advantages compared to standard treatment. Second-line treatments are needed for patients not responding or intolerant to first-line standard management. Mycophenolate mofetil is the most widely used second-line drug, and has good efficacy particularly for patients intolerant to azathioprine, but is teratogenic. Only few and heterogeneous data on calcineurin inhibitors and m-TOR inhibitors are available. Biologicals, including anti-tumour necrosis factor- α and anti-CD20 monoclonal antibodies, have given ambivalent results and may have severe side-effects. Clinical trials with new therapeutic options aiming at targeting B lymphocytes and proinflammatory cytokines, or expanding regulatory T cells to restore tolerance are ongoing.
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Affiliation(s)
- Diego Vergani
- King's College London Faculty of Life Sciences & Medicine, London, UK; Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK; Epatocentro Ticino, Lugano, Switzerland
| | - Benedetta Terziroli Beretta-Piccoli
- Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK; Epatocentro Ticino, Lugano, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Switzerland
| | - Giorgina Mieli-Vergani
- King's College London Faculty of Life Sciences & Medicine, London, UK; Epatocentro Ticino, Lugano, Switzerland; Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, London, UK.
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20
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Czaja AJ. Review article: targeting the B cell activation system in autoimmune hepatitis. Aliment Pharmacol Ther 2021; 54:902-922. [PMID: 34506662 DOI: 10.1111/apt.16574] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/30/2021] [Accepted: 08/05/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND The B cell activation system, consisting of B cell activating factor and a proliferation-inducing ligand, may have pathogenic effects in autoimmune hepatitis. AIMS To describe the biological actions of the B cell activation system, indicate its possible role in autoimmune diseases, and evaluate its prospects as a therapeutic target in autoimmune hepatitis 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 The B cell activating factor is crucial for the maturation and survival of B cells, and it can co-stimulate T cell activation, proliferation, and survival. It can also modulate the immune response by inducing interleukin 10 production by regulatory B cells. A proliferation-inducing ligand modulates and diversifies the antibody response by inducing class-switch recombination in B cells. It can also increase the proliferation, survival, and antigen activation of T cells. These immune stimulatory actions can be modulated by inducing proliferation of regulatory T cells. The B cell activation system has been implicated in diverse autoimmune diseases, and therapeutic blockade is a management strategy now being evaluated in autoimmune hepatitis. CONCLUSIONS The B cell activation system has profound effects on B and T cell function in autoimmune diseases. Blockade therapy is being actively evaluated in autoimmune hepatitis. Clarification of the critical pathogenic components of the B cell activation system will improve the targeting, efficacy, and safety of blockade therapy in this disease.
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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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21
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Patel AM, Liu YS, Davies SP, Brown RM, Kelly DA, Scheel-Toellner D, Reynolds GM, Stamataki Z. The Role of B Cells in Adult and Paediatric Liver Injury. Front Immunol 2021; 12:729143. [PMID: 34630404 PMCID: PMC8495195 DOI: 10.3389/fimmu.2021.729143] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/16/2021] [Indexed: 12/16/2022] Open
Abstract
B lymphocytes are multitasking cells that direct the immune response by producing pro- or anti-inflammatory cytokines, by presenting processed antigen for T cell activation and co-stimulation, and by turning into antibody-secreting cells. These functions are important to control infection in the liver but can also exacerbate tissue damage and fibrosis as part of persistent inflammation that can lead to end stage disease requiring a transplant. In transplantation, immunosuppression increases the incidence of lymphoma and often this is of B cell origin. In this review we bring together information on liver B cell biology from different liver diseases, including alcohol-related and metabolic fatty liver disease, autoimmune hepatitis, primary biliary and primary sclerosing cholangitis, viral hepatitis and, in infants, biliary atresia. We also discuss the impact of B cell depletion therapy in the liver setting. Taken together, our analysis shows that B cells are important in the pathogenesis of liver diseases and that further research is necessary to fully characterise the human liver B cell compartment.
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Affiliation(s)
- Arzoo M. Patel
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Yuxin S. Liu
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Scott P. Davies
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Rachel M. Brown
- Department of Histopathology, Queen Elizabeth Hospital, Birmingham Women’s and Children’s National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
| | - Deirdre A. Kelly
- The Liver Unit, Birmingham Women’s and Children’s Hospital and the University of Birmingham, Birmingham, United Kingdom
| | - Dagmar Scheel-Toellner
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Gary M. Reynolds
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- The Liver Unit, Birmingham Women’s and Children’s Hospital and the University of Birmingham, Birmingham, United Kingdom
| | - Zania Stamataki
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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22
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Saul SA, Taylor SA, Mohammad S. Treatment of Refractory Pediatric Autoimmune Hepatitis With Rituximab. JPGN REPORTS 2021; 2:e069. [PMID: 37205961 PMCID: PMC10191550 DOI: 10.1097/pg9.0000000000000069] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 01/27/2021] [Indexed: 05/21/2023]
Affiliation(s)
- Samantha A. Saul
- From the Division of Gastroenterology, Hepatology, and Nutrition, Feinberg School of Medicine, Northwestern University, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL
| | - Sarah A. Taylor
- From the Division of Gastroenterology, Hepatology, and Nutrition, Feinberg School of Medicine, Northwestern University, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL
| | - Saeed Mohammad
- From the Division of Gastroenterology, Hepatology, and Nutrition, Feinberg School of Medicine, Northwestern University, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL
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Buitrago-Molina LE, Dywicki J, Noyan F, Schepergerdes L, Pietrek J, Lieber M, Schlue J, Manns MP, Wedemeyer H, Jaeckel E, Hardtke-Wolenski M. Anti-CD20 Therapy Alters the Protein Signature in Experimental Murine AIH, but Not Exclusively towards Regeneration. Cells 2021; 10:cells10061471. [PMID: 34208308 PMCID: PMC8231180 DOI: 10.3390/cells10061471] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/06/2021] [Accepted: 06/08/2021] [Indexed: 12/29/2022] Open
Abstract
Background: Autoimmune hepatitis (AIH) is a chronic autoimmune inflammatory disease that usually requires lifelong immunosuppression. Frequent recurrences after the discontinuation of therapy indicate that intrahepatic immune regulation is not restored by current treatments. Studies of other autoimmune diseases suggest that temporary depletion of B cells can improve disease progression in the long term. Methods: We tested a single administration of anti-CD20 antibodies to reduce B cells and the amount of IgG to induce intrahepatic immune tolerance. We used our experimental murine AIH (emAIH) model and treated the mice with anti-CD20 during the late stage of the disease. Results: After treatment, the mice showed the expected reductions in B cells and serum IgGs, but no improvements in pathology. However, all treated animals showed a highly altered serum protein expression pattern, which was a balance between inflammation and regeneration. Conclusions: In conclusion, anti-CD20 therapy did not produce clinically measurable results because it triggered inflammation, as well as regeneration, at the proteomic level. This finding suggests that anti-CD20 is ineffective as a sole treatment for AIH or emAIH.
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Affiliation(s)
- Laura Elisa Buitrago-Molina
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (L.E.B.-M.); (J.D.); (F.N.); (L.S.); (M.L.); (M.P.M.); (H.W.); (E.J.)
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany;
| | - Janine Dywicki
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (L.E.B.-M.); (J.D.); (F.N.); (L.S.); (M.L.); (M.P.M.); (H.W.); (E.J.)
| | - Fatih Noyan
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (L.E.B.-M.); (J.D.); (F.N.); (L.S.); (M.L.); (M.P.M.); (H.W.); (E.J.)
| | - Lena Schepergerdes
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (L.E.B.-M.); (J.D.); (F.N.); (L.S.); (M.L.); (M.P.M.); (H.W.); (E.J.)
| | - Julia Pietrek
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany;
| | - Maren Lieber
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (L.E.B.-M.); (J.D.); (F.N.); (L.S.); (M.L.); (M.P.M.); (H.W.); (E.J.)
| | - Jerome Schlue
- Institute of Pathology, Hannover Medical School, 30625 Hannover, Germany;
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (L.E.B.-M.); (J.D.); (F.N.); (L.S.); (M.L.); (M.P.M.); (H.W.); (E.J.)
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (L.E.B.-M.); (J.D.); (F.N.); (L.S.); (M.L.); (M.P.M.); (H.W.); (E.J.)
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (L.E.B.-M.); (J.D.); (F.N.); (L.S.); (M.L.); (M.P.M.); (H.W.); (E.J.)
| | - Matthias Hardtke-Wolenski
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (L.E.B.-M.); (J.D.); (F.N.); (L.S.); (M.L.); (M.P.M.); (H.W.); (E.J.)
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany;
- Correspondence: ; Tel.: +49-201-723-6081; Fax: +49-201-723-6915
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Antigen presentation, autoantibody production, and therapeutic targets in autoimmune liver disease. Cell Mol Immunol 2020; 18:92-111. [PMID: 33110250 PMCID: PMC7852534 DOI: 10.1038/s41423-020-00568-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 09/24/2020] [Indexed: 02/07/2023] Open
Abstract
The liver is an important immunological organ that controls systemic tolerance. The liver harbors professional and unconventional antigen-presenting cells that are crucial for tolerance induction and maintenance. Orchestrating the immune response in homeostasis depends on a healthy and well-toned immunological liver microenvironment, which is maintained by the crosstalk of liver-resident antigen-presenting cells and intrahepatic and liver-infiltrating leukocytes. In response to pathogens or autoantigens, tolerance is disrupted by unknown mechanisms. Intrahepatic parenchymal and nonparenchymal cells exhibit unique antigen-presenting properties. The presentation of microbial and endogenous lipid-, metabolite- and peptide-derived antigens from the gut via conventional and nonconventional mechanisms can educate intrahepatic immune cells and elicit effector responses or tolerance. Perturbation of this balance results in autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. Although the exact etiologies of these autoimmune liver diseases are unknown, it is thought that the disruption of tolerance towards self-antigens and microbial metabolites and lipids, as well as alterations in bile acid composition, may result in changes in effector cell activation and polarization and may reduce or impair protective anti-inflammatory regulatory T and B cell responses. Additionally, the canonical and noncanonical transmission of antigens and antigen:MHC complexes via trogocytosis or extracellular vesicles between different (non) immune cells in the liver may play a role in the induction of hepatic inflammation and tolerance. Here, we summarize emerging aspects of antigen presentation, autoantibody production, and the application of novel therapeutic approaches in the characterization and treatment of autoimmune liver diseases.
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Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, Vierling JM, Alsawas M, Murad MH, Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology 2020; 72:671-722. [PMID: 31863477 DOI: 10.1002/hep.31065] [Citation(s) in RCA: 507] [Impact Index Per Article: 101.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Cara L Mack
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - David Adams
- Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - David N Assis
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT
| | - Nanda Kerkar
- Golisano Children's Hospital at Strong, University of Rochester Medical Center, New York, NY
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marlyn J Mayo
- Division of Digestive and Liver Diseases, University of Texas SW Medical Center, Dallas, TX
| | - John M Vierling
- Medicine and Surgery, Baylor College of Medicine, Houston, TX
| | | | - Mohammad H Murad
- Mayo Knowledge and Encounter Research Unit, Mayo Clinic College of Medicine, Rochester, MN
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
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Assis DN. Immunopathogenesis of Autoimmune Hepatitis. Clin Liver Dis (Hoboken) 2020; 15:129-132. [PMID: 32257125 PMCID: PMC7128031 DOI: 10.1002/cld.873] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 08/12/2019] [Indexed: 02/04/2023] Open
Abstract
http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-3-reading-assis a video presentation of this article http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-3-interview-assis the interview with the author.
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Affiliation(s)
- David N. Assis
- Department of Medicine, Section of Digestive DiseasesYale School of MedicineNew HavenCT
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Chang C, Tanaka A, Bowlus C, Gershwin ME. The use of biologics in the treatment of autoimmune liver disease. Expert Opin Investig Drugs 2020; 29:385-398. [PMID: 32102572 DOI: 10.1080/13543784.2020.1733527] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Autoimmune liver diseases include autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and juvenile autoimmune hepatitis (JAIH). The pathophysiologic features of each disease vary, but generally include presence of autoantibodies, cytokine abnormalities, and/or T and B cell autoreactivity.Areas covered: This article compares conventional therapy with newer biologics available for treatment of autoimmune liver diseases. Conventional therapy involves the use of immunosuppressive agents, or other treatment modalities for specific autoimmune liver diseases such as ursodeoxycholic acid and fibrates for PBC. Biologics were developed to target the production of autoantibodies by B cells, the presence of proinflammatory cytokines, adhesion molecules or T and B cell activation.Expert opinion: Despite the promise of biologics being able to target specific cellular and humoral pathways, results have been generally poor, and safety has not been as expected. Cases of autoimmune hepatitis have also developed with the use of these biologicals. Reasons for the lack of success of biologics in treating autoimmune liver disease has led to a reevaluation of our understanding of underlying pathogenesis, demonstrating that while our knowledge of the immunity has improved over the past two decades, it is far from complete.
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Affiliation(s)
- Christopher Chang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.,Division of Pediatric Immunology and Allergy, Joe DiMaggio Children's Hospital, Hollywood, FL, USA
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Christopher Bowlus
- Division of Gastroenterology, University of California at Davis, Davis, CA, USA
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
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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: 46] [Impact Index Per Article: 7.7] [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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Autoimmune Hepatitis-Immunologically Triggered Liver Pathogenesis-Diagnostic and Therapeutic Strategies. J Immunol Res 2019; 2019:9437043. [PMID: 31886312 PMCID: PMC6899271 DOI: 10.1155/2019/9437043] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 09/15/2019] [Accepted: 09/21/2019] [Indexed: 12/20/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a severe liver disease that arises in genetically predisposed male and female individuals worldwide. Diagnosis of AIH is made clinically applying diagnostic scores; however, the heterotopic disease phenotype often makes a rapid determination of disease challenging. AIH responds favorably to steroids and pharmacologic immunosuppression, and liver transplantation is only necessary in cases with acute liver failure or end-stage liver cirrhosis. Recurrence or development of de novo AIH after transplantation is possible, and treatment is similar to standard AIH therapy. Current experimental investigations of T cell-mediated autoimmune pathways and analysis of changes within the intestinal microbiome might advance our knowledge on the pathogenesis of AIH and trigger a spark of hope for novel therapeutic strategies.
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Abstract
Autoreactive B cells can promote autoimmunity through antigen presentation to autoreactive T cells, production of autoantibodies, generation of cytokines promoting T cell activation and differentiation, and inhibition of regulatory T cells and B cells. Here, the authors highlight studies pertaining to B cell mechanisms associated with disease pathogenesis and outcomes in autoimmune hepatitis and the immune-mediated cholangiopathies (primary biliary cholangitis, primary sclerosing cholangitis, and biliary atresia). The vast majority of investigations focus on autoantibodies and future research endeavors should include deciphering the role of the B cell in T cell activation (through antigen presentation, cytokine/chemokine production, and inhibition of regulation). Targeting B cell mechanisms in the treatment of autoimmune liver diseases is also highlighted.
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Affiliation(s)
- Sarah A. Taylor
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - David N. Assis
- Section of Digestive Diseases, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Cara L. Mack
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Digestive Health Institute, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado
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Doycheva I, Watt KD, Gulamhusein AF. Autoimmune hepatitis: Current and future therapeutic options. Liver Int 2019; 39:1002-1013. [PMID: 30716203 DOI: 10.1111/liv.14062] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 01/13/2019] [Accepted: 01/17/2019] [Indexed: 02/13/2023]
Abstract
Autoimmune hepatitis (AIH) is a rare immune-mediated liver disease with few major advances in treatment options over the last several decades. Available options are effective in most patients albeit are imprecise in their mechanisms. Novel and more tolerable induction regimens and alternative options for management of patients intolerant or with suboptimal response to traditional therapies including in the post-transplant setting remain an important unmet need. This review aims to summarize recent data on pharmacological options and investigational drugs in development for patients with AIH. Standard therapy using prednisone with or without azathioprine remains the mainstay of therapy and is effective in most patients. Budesonide may be considered for induction in early disease and in those with mild fibrosis, but has not been approved for maintenance therapy. Mycophenolate mofetil (MMF) in combination with steroids might be an alternative first-line therapy, but results from a randomized trial are awaited. MMF as a second-line maintenance agent has moderate efficacy though more frequent adverse events in patients with cirrhosis may be seen. Tacrolimus may be an equally effective second-line option particularly in non-responders, but data remain limited. Management of recurrent AIH post-liver transplantation remains controversial with insufficient data to support long-term steroid use. Moving forward, expanding the scope of therapeutic options to include biologics including B-cell depleting agents may be a promising step. Recent insights in understanding the pathogenesis of AIH could serve as a basis for future therapies, including the elucidation of different immunoregulatory pathways and the potential role of the intestinal microbiome.
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Affiliation(s)
- Iliana Doycheva
- Division of Gastroenterology and Hepatology, Medical University, Sofia, Bulgaria
| | - Kymberly D Watt
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Aliya F Gulamhusein
- Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University Health Network, Toronto, ON, Canada
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Sciveres M, Nastasio S, Maggiore G. Novel Diagnostic and Therapeutic Strategies in Juvenile Autoimmune Hepatitis. Front Pediatr 2019; 7:382. [PMID: 31616649 PMCID: PMC6763601 DOI: 10.3389/fped.2019.00382] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 09/04/2019] [Indexed: 12/12/2022] Open
Abstract
Juvenile autoimmune hepatitis (JAIH) is a rare, chronic, inflammatory disease of the liver characterized by a complex interaction between genetic, immunological, and environmental factors leading to loss of immunotolerance to hepatic antigens. It affects both children and adolescents, most commonly females, and its clinical manifestations are quite variable. JAIH is progressive in nature and if left untreated may lead to cirrhosis and terminal liver failure. Although JAIH was first described almost 50 years ago, there have been few significant advances in the clinical management of these patients, both in terms of available diagnostic tools and therapeutic options. Aminotransferase activity, class G immunoglobulins and autoantibodies are the biomarkers used to diagnose AIH and monitor treatment response alongside clinical and histological findings. Despite their utility and cost-effectiveness, these biomarkers are neither an accurate expression of AIH pathogenic mechanism nor a precise measure of treatment response. Current standard of care is mainly based on the administration of steroids and azathioprine. This combination of drugs has been proven effective in inducing remission of disease in the majority of patients dramatically improving their survival; however, it not only fails to restore tolerance to hepatic autoantigens, but it also does not halt disease progression in some patients, it is often needed life-long and finally, it has deleterious side-effects. The ideal therapy should be enough selective to contrast immune-mediated live damage while preserving or potentiating the ability to develop permanent tolerance vs. pathogenic autoantigens. By reviewing the state of the art literature, this article highlights novel diagnostic and therapeutic strategies for managing pediatric AIH with a special focus on new strategies of immunotherapy. These promising tools could improve the diagnostic algorithm, more accurately predict disease prognosis, and provide targeted, individualized treatment.
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Affiliation(s)
- Marco Sciveres
- Pediatric Hepatology and Liver Transplantation, ISMETT-University of Pittsburgh Medical Center Italy, Palermo, Italy
| | - Silvia Nastasio
- Division of Gastroenterology, Hepatology, and Nutrition, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Giuseppe Maggiore
- Pediatric Hepatology and Liver Transplantation, ISMETT-University of Pittsburgh Medical Center Italy, Palermo, Italy.,Section of Pediatrics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
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The role of APRIL - A proliferation inducing ligand - In autoimmune diseases and expectations from its targeting. J Autoimmun 2018; 95:179-190. [DOI: 10.1016/j.jaut.2018.10.016] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 10/17/2018] [Indexed: 12/12/2022]
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Juvenile autoimmune hepatitis: A comprehensive review. J Autoimmun 2018; 95:69-76. [DOI: 10.1016/j.jaut.2018.10.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Accepted: 10/13/2018] [Indexed: 12/12/2022]
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Taubert R, Hupa-Breier KL, Jaeckel E, Manns MP. Novel therapeutic targets in autoimmune hepatitis. J Autoimmun 2018; 95:34-46. [DOI: 10.1016/j.jaut.2018.10.022] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 10/22/2018] [Indexed: 02/07/2023]
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Incidence and Clinical Features of Autoimmune Hepatitis in the Province of Santa Fe (Argentina). J Pediatr Gastroenterol Nutr 2018; 67:e107-e110. [PMID: 30095578 DOI: 10.1097/mpg.0000000000002122] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJETIVES The aim of the study is to investigate the incidence and clinical features of autoimmune hepatitis (AIH) in children from the province of Santa Fe, Argentina, for 10 years. METHODS From the records of all of the pediatric hepatologists in the province of Santa Fe, Argentina, we reviewed the clinical charts of patients <18 years who were diagnosed with AIH (simplified score >6 points) and followed between January 2003 and December 2013. Population data were extracted from the 2010 national census. Values were expressed as percentages and median ± interquartile range. Mann-Whitney U test was used for comparison between the groups. RESULTS Sixty-seven patients fulfilled inclusion criteria, from which 11 (16%) were later reclassified as having "autoimmune sclerosing cholangitis" according to biochemical, histological, and radiological findings. A final sample of 56 patients (39 F) with AIH was analyzed, giving an annual incidence of 0.56/100,000. Median age at presentation was 8 (5.7-11) years, and the median follow-up was 4 (2-7) years. Type 1 AIH was diagnosed in 89%. An acute presentation was observed in 53%, while 13 (23%) showed cirrhosis on initial biopsy. Prednisone (87%) and azathioprine (60%) were the most common drugs prescribed. At the end of follow-up, 53/56 (95%) were alive, including 4 patients (7%) who underwent liver transplantation. CONCLUSIONS AIH has an estimated incidence of 0.56/100,000 per year in children from the province of Santa Fe (Argentina). Overall survival rate was 95%. A subgroup of patients diagnosed as AIH develops predominant biliary disease and should be better classified as autoimmune sclerosing cholangitis.
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Shahmohammadi S, Sahraian MA, Shahmohammadi A, Doosti R, Zare-Mirzaie A, Naser Moghadasi A. A presentation of ulcerative colitis after rituximab therapy in a patient with multiple sclerosis and literature review. Mult Scler Relat Disord 2018. [PMID: 29524758 DOI: 10.1016/j.msard.2018.02.030] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Multiple sclerosis (MS) is one of the most important demyelinating diseases that affects the central nervous system. Its treatment often involves a long-term disease modifying therapy. According to some studies, the prevalence of autoimmune disorders, such as autoimmune hepatitis (AIH) and ulcerative colitis (UC) is higher in MS patients than in the normal population. There are also few studies that have reported the onset of UC after rituximab therapy. The present study presents a report of a 31-years old female patient suffering from aggressive multiple sclerosis, which developed into autoimmune hepatitis during the MS therapy. Thereafter, she received rituximab for the treating both MS and AIH. One week after the third cycle of rituximab (6 doses of 1000 mg), she experienced abdominal pain, fever, and severe bloody diarrhea; finally, she was diagnosed with ulcerative colitis (UC). It seems that the administration of certain immunomodulators or immunosuppressive drugs may have a main role in the exacerbation of some autoimmune diseases.
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Affiliation(s)
- Sareh Shahmohammadi
- MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ali Sahraian
- MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Iranian Center for Neurological Research, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Abootorab Shahmohammadi
- MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Rozita Doosti
- MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Zare-Mirzaie
- Department of Pathology, Iran University of Medical Sciences, Tehran, Iran
| | - Abdorreza Naser Moghadasi
- MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Department of Neurology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran.
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Mieli-Vergani G, Vergani D, Baumann U, Czubkowski P, Debray D, Dezsofi A, Fischler B, Gupte G, Hierro L, Indolfi G, Jahnel J, Smets F, Verkade HJ, Hadžić N. Diagnosis and Management of Pediatric Autoimmune Liver Disease: ESPGHAN Hepatology Committee Position Statement. J Pediatr Gastroenterol Nutr 2018; 66:345-360. [PMID: 29356770 DOI: 10.1097/mpg.0000000000001801] [Citation(s) in RCA: 192] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Paediatric autoimmune liver disease is characterized by inflammatory liver histology, circulating autoantibodies, and increased levels of IgG, in the absence of a known etiology. Three conditions have a likely autoimmune pathogenesis: autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis, and de novo AIH after liver transplantation. Two types of pediatric AIH are recognized according to seropositivity for smooth muscle and/or antinuclear antibody (AIH-1) or liver kidney microsomal type 1 and/or anti-liver cytosol type 1 antibodies (AIH-2).Pertinent issues addressing the diagnosis, treatment, and long-term follow-up were formulated by a core group of ESPGHAN members. They have commissioned the first authors with execution of this project. Initially, they have performed a systematic literature search on MEDLINE, ResearchGate, and Mendeley databases during the last 30 years and produced a document focusing on prospective and retrospective studies in children. The ESPGHAN core group and ESPGHAN Hepatology Committee members voted on each recommendation, using a formal voting technique.
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Affiliation(s)
| | - Diego Vergani
- MowatLabs, Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK
| | - Ulrich Baumann
- Pädiatrische Gastroenterologie und Hepatologie, Medizinische Hochschule, Hannover, Germany
| | - Piotr Czubkowski
- Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Dominique Debray
- Pediatric Hepatology Unit, AP-HP-Hôpital Necker Enfants Malades, Paris, France
| | - Antal Dezsofi
- First Department of Paediatrics, Semmelweis University, Budapest, Hungary
| | - Björn Fischler
- Department of Pediatrics, Karolinska University Hospital, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Girish Gupte
- Liver Unit (Including Small Bowel Transplantation), Department of Gastroenterology and Nutrition, Birmingham Children's Hospital, Birmingham, UK
| | - Loreto Hierro
- Hospital Infantil Universitario La Paz, Madrid, Spain
| | - Giuseppe Indolfi
- Paediatric and Liver Unit, Meyer Children's University Hospital of Florence, Firenze, Italy
| | - Jörg Jahnel
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Françoise Smets
- UCL, Cliniques Universitaires Saint-Luc, Pediatric Gastroenterology and Hepatology, Brussels, Belgium
| | - Henkjan J Verkade
- Dept of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, the Netherlands
| | - Nedim Hadžić
- MowatLabs, Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: Standard treatment and systematic review of alternative treatments. World J Gastroenterol 2017; 23:6030-6048. [PMID: 28970719 PMCID: PMC5597495 DOI: 10.3748/wjg.v23.i33.6030] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 07/18/2017] [Accepted: 08/02/2017] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis is a rare chronic inflammatory liver disease, affecting all ages, characterised by elevated transaminase and immunoglobulin G levels, positive autoantibodies, interface hepatitis at liver histology and good response to immunosuppressive treatment. If untreated, it has a poor prognosis. The aim of this review is to summarize the evidence for standard treatment and to provide a systematic review on alternative treatments for adults and children. Standard treatment is based on steroids and azathioprine, and leads to disease remission in 80%-90% of patients. Alternative first line treatment has been attempted with budesonide or cyclosporine, but their superiority compared to standard treatment remains to be demonstrated. Second-line treatments are needed for patients not responding or intolerant to standard treatment. No randomized controlled trials have been performed for second-line options. Mycophenolate mofetil is the most widely used second-line drug, and has good efficacy particularly for patients intolerant to azathioprine, but has the major disadvantage of being teratogenic. Only few and heterogeneous data on cyclosporine, tacrolimus, everolimus and sirolimus are available. More recently, experience with the anti-tumour necrosis factor-alpha infliximab and the anti-CD20 rituximab has been published, with ambivalent results; these agents may have severe side-effects and their use should be restricted to specialized centres. Clinical trials with new therapeutic options are ongoing.
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Affiliation(s)
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom
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Zizzo AN, Valentino PL, Shah PS, Kamath BM. Second-line Agents in Pediatric Patients With Autoimmune Hepatitis: A Systematic Review and Meta-analysis. J Pediatr Gastroenterol Nutr 2017; 65:6-15. [PMID: 28644343 DOI: 10.1097/mpg.0000000000001530] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Ten percent to 20% of children with autoimmune hepatitis (AIH) require second-line therapy to achieve remission. Although current guidelines exist on first-line management, evidence for second-line therapy in treatment-refractory patients is lacking. Our aim was to perform a systematic review and meta-analysis of the efficacy and safety of second-line treatments used in this population. METHODS Electronic and manual searches were used to identify potential studies for inclusion. Studies were selected based on reported response rates to second-line therapies in children who failed response to prednisone and azathioprine. Data extraction and risk of bias assessment were performed independently by 2 reviewers. Meta-analysis using weighted estimate of response rates at 6 months was performed for each treatment option. Heterogeneity was assessed. RESULTS Fifteen studies of 76 pediatric patients with AIH were included in the review. Overall response rates at 6 months were estimated as 36% for mycophenolate mofetil (MMF) (N = 34, 95% confidence interval [CI] (16-57)), and 50% for tacrolimus (N = 4, 95% CI (0-100%)) and 83% for cyclosporine (N = 15, 95% CI (66%-100%)). Adverse effects were most frequent with cyclosporine (64% experiencing at least 1 adverse effect) followed by tacrolimus (54%) and MMF (48%). Pooled estimates of adverse events were 78% for cyclosporine (95% CI (54%-100%)), 42% for tacrolimus (95% CI (0%-85%)) and 45% for MMF (95% CI (25%-68%)). Sensitivity analyses were not performed due to small sample size. CONCLUSIONS Cyclosporine had the highest response rate at 6 months in children with standard-treatment-refractory AIH; however, it also had the highest rate of adverse events. MMF was the second most efficacious option with a low adverse effect rate.
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Affiliation(s)
- Andréanne N Zizzo
- *The Hospital for Sick Children †University of Toronto, Toronto, Ontario, Canada ‡Yale University School of Medicine, New Haven, CT §Mount Sinai Hospital, Toronto ||London Health Sciences Centre, Western University, London, Ontario, Canada
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Cassim S, Bilodeau M, Vincent C, Lapierre P. Novel Immunotherapies for Autoimmune Hepatitis. Front Pediatr 2017; 5:8. [PMID: 28184367 PMCID: PMC5266689 DOI: 10.3389/fped.2017.00008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 01/10/2017] [Indexed: 12/23/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a multifactorial autoimmune disease of unknown pathogenesis, characterized by a loss of immunological tolerance against liver autoantigens resulting in the progressive destruction of the hepatic parenchyma. Current treatments are based on non-specific immunosuppressive drugs. Although tremendous progress has been made using specific biological agents in other inflammatory diseases, progress has been slow to come for AIH patients. While current treatments are successful in the majority of patients, treatment discontinuation is difficult to achieve, and relapses are frequent. Lifelong immunosuppression is not without risks, especially in the pediatric population; 4% of patient with type 1 AIH will eventually develop hepatocellular carcinoma with a 2.9% probability after 10 years of treatment. Therefore, future treatments should aim to restore tolerance to hepatic autoantigens and induce long-term remission. Promising new immunotherapies have been tested in experimental models of AIH including T and B cell depletion and regulatory CD4+ T cells infusion. Clinical studies on limited numbers of patients have also shown encouraging results using B-cell-depleting (rituximab) and anti-TNF-α (infliximab) antibodies. A better understanding of key molecular targets in AIH combined with effective site-specific immunotherapies could lead to long-term remission without blanket immunosuppression and with minimal deleterious side effects.
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Affiliation(s)
- Shamir Cassim
- Laboratoire d'hépatologie cellulaire, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) , Montréal, QC , Canada
| | - Marc Bilodeau
- Laboratoire d'hépatologie cellulaire, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada; Département de médecine, Université de Montréal, Montréal, QC, Canada
| | - Catherine Vincent
- Département de médecine, Université de Montréal , Montréal, QC , Canada
| | - Pascal Lapierre
- Laboratoire d'hépatologie cellulaire, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada; Département de médecine, Université de Montréal, Montréal, QC, Canada
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Béland K, Alvarez F. Reply. Hepatology 2016; 64:996-7. [PMID: 26680002 DOI: 10.1002/hep.28407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Affiliation(s)
- Kathie Béland
- Division of Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montréal, QC, Canada
| | - Fernando Alvarez
- Division of Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montréal, QC, Canada.,Microbiology and Immunology Department, University of Montréal, Montréal, QC, Canada.,Department of Pediatrics, University of Montréal, Montréal, QC, Canada
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43
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Beland K, Alvarez F. Reply. Hepatology 2016; 64:319-20. [PMID: 26474821 DOI: 10.1002/hep.28299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Affiliation(s)
- Kathie Beland
- Division of Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montréal, QC, Canada
| | - Fernando Alvarez
- Division of Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montréal, QC, Canada.,Microbiology and Immunology Department, University of Montreal, Montreal, Canada.,Department of Pediatrics, University of Montreal, Montreal, Canada
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Rubin JN, Te HS. Refractory Autoimmune Hepatitis: Beyond Standard Therapy. Dig Dis Sci 2016; 61:1757-62. [PMID: 26725067 DOI: 10.1007/s10620-015-4022-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2015] [Accepted: 12/20/2015] [Indexed: 12/11/2022]
Abstract
Autoimmune hepatitis (AIH) can be difficult to control, particularly in some African-Americans. When standard therapy of prednisone and azathioprine is ineffective or poorly tolerated, alternative therapies are resorted to. We report two patients with AIH who were refractory to or intolerant of standard therapy. They initially responded to a combination of tacrolimus and MMF, but eventually developed acute flares of the disease that had to be managed with sirolimus, and in one case, rituximab, to achieve remission.
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Affiliation(s)
- Jonah N Rubin
- Section of Hospital Medicine, Department of Medicine, University of Chicago Medicine, 5841 S. Maryland Ave., MC 5000, Chicago, IL, 60637, USA
| | - Helen S Te
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago Medicine, 5841 S. Maryland Ave., MC 7120, Chicago, IL, 60637, USA.
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Bittencourt PL, Cançado ELR, Couto CA, Levy C, Porta G, Silva AEB, Terrabuio DRB, Carvalho Filho RJD, Chaves DM, Miura IK, Codes L, Faria LC, Evangelista AS, Farias AQ, Gonçalves LL, Harriz M, Lopes Neto EPA, Luz GO, Oliveira P, Oliveira EMGD, Schiavon JLN, Seva-Pereira T, Parise ER, Parise ER. Brazilian society of hepatology recommendations for the diagnosis and management of autoimmune diseases of the liver. ARQUIVOS DE GASTROENTEROLOGIA 2015; 52 Suppl 1:15-46. [DOI: 10.1590/s0004-28032015000500002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
ABSTRACT In order to draw evidence-based recommendations concerning the management of autoimmune diseases of the liver, the Brazilian Society of Hepatology has sponsored a single-topic meeting in October 18th, 2014 at São Paulo. An organizing committee comprised of seven investigators was previously elected by the Governing Board to organize the scientific agenda as well as to select twenty panelists to make a systematic review of the literature and to present topics related to the diagnosis and treatment of autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis and their overlap syndromes. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of those recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present paper is the final version of the reviewed manuscript organized in topics, followed by the recommendations of the Brazilian Society of Hepatology.
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Vierling JM. Autoimmune Hepatitis and Overlap Syndromes: Diagnosis and Management. Clin Gastroenterol Hepatol 2015; 13:2088-108. [PMID: 26284592 DOI: 10.1016/j.cgh.2015.08.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 08/11/2015] [Accepted: 08/11/2015] [Indexed: 12/14/2022]
Affiliation(s)
- John M Vierling
- Departments of Medicine and Surgery, Baylor College of Medicine, Baylor-St Luke's Medical Center, Houston, Texas.
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Béland K, Marceau G, Labardy A, Bourbonnais S, Alvarez F. Depletion of B cells induces remission of autoimmune hepatitis in mice through reduced antigen presentation and help to T cells. Hepatology 2015; 62:1511-23. [PMID: 26175263 DOI: 10.1002/hep.27991] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 07/13/2015] [Indexed: 12/25/2022]
Abstract
UNLABELLED Autoimmune hepatitis (AIH) is known as a T cell-mediated disease. However, AIH patients refractory to conventional treatment have been successfully treated with anti-CD20-mediated B-cell depletion. The aim of this project was to understand the immunological changes underlying the AIH remission caused by B-cell depletion in an experimental model of AIH. C57BL/6 AIH mice, xenoimmunized with DNA coding for human liver antigens, were treated with a single dose of depleting mouse anti-CD20 antibody at the peak of liver inflammation. Liver inflammation, alanine aminotransferase levels, chemokine (C-X-C) ligand 10 expression, and circulating B-cell, autoantibody, and total immunoglobulin G levels were monitored following depletion. T-cell and B-cell phenotype and function were characterized. Administration of a single dose of anti-CD20 resulted in a drastic reduction of liver inflammation accompanied by a significant reduction of alanine aminotransferase levels and of proinflammatory chemokine (C-X-C) ligand 10 expression. The treatment did not result in significant changes in total immunoglobulin G levels or autoantibodies. There were significantly more naive and less antigen-experienced CD4+ and CD8+ T cells, and T-cell proliferation was significantly reduced following anti-CD20 treatment. B cells served as antigen-presenting cells to CD4+ T cells. Anti-CD20 treatment also led to a profound reduction of T follicular helper cells. CONCLUSION B cells play an active role in the pathogenesis of AIH in antigen presentation processes and the modulation of T-cell functions and influence the T follicular helper-cell population; this active role of B cells could explain the success of B-cell depletion for remission of AIH despite its classification as a T cell-mediated autoimmune liver disease.
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Affiliation(s)
- Kathie Béland
- Division of Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montreal, QC, Canada
| | - Gabriel Marceau
- Division of Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montreal, QC, Canada
| | - Agathe Labardy
- Division of Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montreal, QC, Canada
| | - Sara Bourbonnais
- Division of Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montreal, QC, Canada
| | - Fernando Alvarez
- Division of Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montreal, QC, Canada.,Microbiology and Immunology Department.,Department of Pediatrics, University of Montreal, Montreal, QC, Canada
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Paganelli M, Patey N, Bass LM, Alvarez F. Anti-CD20 treatment of giant cell hepatitis with autoimmune hemolytic anemia. Pediatrics 2014; 134:e1206-10. [PMID: 25201797 DOI: 10.1542/peds.2014-0032] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Giant cell hepatitis with autoimmune hemolytic anemia (GCH-AHA) is a rare autoimmune disease of infancy characterized by severe liver disease associated with Coombs-positive hemolytic anemia. We recently showed that GCH-AHA is probably caused by a humoral immune mechanism. Such data support the use of rituximab, an anti-CD-20 monoclonal antibody specifically targeting B lymphocytes, as a treatment for GCH-AHA. We describe here the detailed clinical evolution of 4 children with GCH-AHA who showed a complete response to rituximab. All patients shared a severe course of the disease with poor control on standard and aggressive immunosuppression. Rituximab was well tolerated, and no side effects or infections were registered. Several doses were needed to induce remission, and 5 to 11 additional maintenance injections were necessary in the 2 more severe cases. Weaning from corticosteroids was achieved in all subjects. A steroid-sparing effect was noted in the 3 children who started rituximab early in the course of the disease. Overall, we show here that there is a strong rationale for treating GCH-AHA with rituximab. Early treatment could reduce the use of corticosteroids. Nevertheless, short-term steroids should be initially associated with rituximab to account for autoantibodies' half-life. Repeated injections are needed to treat and prevent relapses, but the best frequency and duration of treatment remain to be defined.
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Affiliation(s)
| | - Natacha Patey
- Pathology, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal (QC), Canada
| | - Lee M Bass
- Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois; and Department of Pediatrics, Feinberg Medical School of Northwestern University, Chicago, Illinois
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Gao F, Ju J, Hu MM, Yan FY, Wang XQ. Progress in pharmaceutical therapy of autoimmune liver diseases. Shijie Huaren Xiaohua Zazhi 2014; 22:4087-4093. [DOI: 10.11569/wcjd.v22.i27.4087] [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] [Indexed: 02/06/2023] Open
Abstract
Autoimmune liver diseases (AILDs) include autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and overlap syndrome (OS). AILDs are the new research hotspot in the field of liver diseases nowadays. The advances in research of AILDs have led to a new understanding of pharmaceutical treatment of this disease. This article reviews the progress in the pharmaceutical therapy of AILDs.
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