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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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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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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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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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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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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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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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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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Czaja AJ. Immune inhibitory proteins and their pathogenic and therapeutic implications in autoimmunity and autoimmune hepatitis. Autoimmunity 2019; 52:144-160. [PMID: 31298041 DOI: 10.1080/08916934.2019.1641200] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Key inhibitory proteins can blunt immune responses to self-antigens, and deficiencies in this repertoire may promote autoimmunity. The goals of this review are to describe the key immune inhibitory proteins, indicate their possible impact on the development of autoimmune disease, especially autoimmune hepatitis, and encourage studies to clarify their pathogenic role and candidacy as therapeutic targets. English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed. Cytotoxic T lymphocyte antigen-4 impairs ligation of CD28 to B7 ligands on antigen presenting cells and inhibits the adaptive immune response by increasing anti-inflammatory cytokines, generating regulatory T cells, and reducing T cell activation and proliferation. Programed cell death antigen-1 inhibits T cell selection, activation, and proliferation by binding with two ligands at different phases and locations of the immune response. A soluble alternatively spliced variant of this protein can dampen the inhibitory signal. Autoimmune hepatitis has been associated with polymorphisms of the cytotoxic T lymphocyte antigen-4 gene, reduced hepatic expression of a ligand of programed cell death antigen-1, an interfering soluble variant of this key inhibitory protein, and antibodies against it. Findings have been associated with laboratory indices of liver injury and suboptimal treatment response. Abatacept, belatacept, CD28 blockade, and induction of T cell exhaustion are management considerations that require scrutiny. In conclusion, deficiencies in key immune inhibitory proteins may promote the occurrence of autoimmune diseases, such as autoimmune hepatitis, and emerging interventions may overcome these deficiencies. Investigations should define the nature, impact and management of these inhibitory disturbances in autoimmune hepatitis.
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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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Autoimmune Hepatitis with Concomitant Idiopathic Thrombocytopenic Purpura Diagnosed by Transjugular Liver Biopsy. Case Reports Hepatol 2019; 2018:5305691. [PMID: 30631611 PMCID: PMC6304620 DOI: 10.1155/2018/5305691] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 10/14/2018] [Accepted: 11/29/2018] [Indexed: 01/20/2023] Open
Abstract
Patients with autoimmune hepatitis (AIH) may sometimes have concomitant idiopathic thrombocytopenic purpura (ITP). Severe thrombocytopenia in ITP interferes with percutaneous liver biopsy for pathological diagnosis of AIH. Here, we report a case of AIH with ITP in a 63-year-old woman. The patient presented to our hospital with liver dysfunction and thrombocytopenia. For histological examination, transjugular liver biopsy (TJLB) was performed, leading to a diagnosis of AIH. Corticosteroids treatment led to an improvement in her liver enzyme levels and platelet count. In conclusion, patients with AIH may sometimes have concomitant ITP. TJLB was effective for making the diagnosis of AIH with severe thrombocytopenia due to ITP.
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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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Abstract
Autoimmune hepatitis (AIH) is an inflammatory liver disease that is characterized by circulating autoantibodies, hypergammaglobulinemia, and a lymphoplasmocytic infiltration with interface hepatitis on liver biopsy. Treatment with corticosteroids and other immunosuppressive agents is effective and early diagnosis can result in near-normal life expectancy. Untreated patients, however, can progress to cirrhosis and liver failure. The clinical presentation is heterogeneous and may pose diagnostic and therapeutic dilemmas. This case-based review will address the diagnosis and management of this disease, in addition to difficult but commonly encountered clinical scenarios.
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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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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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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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Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis: Current Status and Future Directions. Gut Liver 2016; 10:177-203. [PMID: 26934884 PMCID: PMC4780448 DOI: 10.5009/gnl15352] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 11/04/2015] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis is characterized by autoantibodies, hypergammaglobulinemia, and interface hepatitis on histological examination. The features lack diagnostic specificity, and other diseases that may resemble autoimmune hepatitis must be excluded. The clinical presentation may be acute, acute severe (fulminant), or asymptomatic; conventional autoantibodies may be absent; centrilobular necrosis and bile duct changes may be present; and the disease may occur after liver transplantation or with features that suggest overlapping disorders. The diagnostic criteria have been codified, and diagnostic scoring systems can support clinical judgment. Nonstandard autoantibodies, including antibodies to actin, α-actinin, soluble liver antigen, perinuclear antineutrophil antigen, asialoglycoprotein receptor, and liver cytosol type 1, are tools that can support the diagnosis, especially in patients with atypical features. Prednisone or prednisolone in combination with azathioprine is the preferred treatment, and strategies using these medications in various doses can ameliorate treatment failure, incomplete response, drug intolerance, and relapse after drug withdrawal. Budesonide, mycophenolate mofetil, and calcineurin inhibitors can be considered in selected patients as frontline or salvage therapies. Molecular (recombinant proteins and monoclonal antibodies), cellular (adoptive transfer and antigenic manipulation), and pharmacological (antioxidants, antifibrotics, and antiapoptotic agents) interventions constitute future directions in management. The evolving knowledge of the pathogenic pathways and the advances in technology promise new management algorithms.
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Affiliation(s)
- Albert J. Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN,
USA
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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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Abstract
A 59-year-old female received a matched related donor stem cell transplant for chronic myelogenous leukemia. After being successfully treated with prednisone for chronic graft versus host disease that initially started 50 days posttransplant, she developed hepatic dysfunction during the steroid taper on day 531, as evidenced by jaundice, elevated liver enzymes, and increased bilirubin. Liver biopsy showed histology suggestive of autoimmune-like hepatitis, which is a rare manifestation of chronic “hepatitic” graft versus host disease.
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Affiliation(s)
- Nick M. Baniak
- University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Rani Kanthan
- University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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Montano-Loza AJ, Czaja AJ. Cell mediators of autoimmune hepatitis and their therapeutic implications. Dig Dis Sci 2015; 60:1528-42. [PMID: 25487192 DOI: 10.1007/s10620-014-3473-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Accepted: 11/27/2014] [Indexed: 12/12/2022]
Abstract
Autoimmune hepatitis is associated with interactive cell populations of the innate and adaptive immune systems, and these populations are amenable to therapeutic manipulation. The goals of this review are to describe the key cell populations implicated in autoimmune hepatitis and to identify investigational opportunities to develop cell-directed therapies for this disease. Studies cited in PubMed from 1972 to 2014 for autoimmune hepatitis, innate and adaptive immune systems, and therapeutic interventions were examined. Dendritic cells can promote immune tolerance to self-antigens, present neo-antigens that enhance the immune response, and expand the regulatory T cell population. Natural killer cells can secrete pro-inflammatory and anti-inflammatory cytokines and modulate the activity of dendritic cells and antigen-specific T lymphocytes. T helper 2 lymphocytes can inhibit the cytotoxic activities of T helper 1 lymphocytes and limit the expansion of T helper 17 lymphocytes. T helper 17 lymphocytes can promote inflammatory activity, and they can also up-regulate genes that protect against oxidative stress and hepatocyte apoptosis. Natural killer T cells can expand the regulatory T cell population; gamma delta lymphocytes can secrete interleukin-10, stimulate hepatic regeneration, and induce the apoptosis of hepatic stellate cells; and antigen-specific regulatory T cells can dampen immune cell proliferation and function. Pharmacological agents, neutralizing antibodies, and especially the adoptive transfer of antigen-specific regulatory T cells that have been freshly generated ex vivo are evolving as management strategies. The cells within the innate and adaptive immune systems are key contributors to the occurrence of autoimmune hepatitis, and they are attractive therapeutic targets.
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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
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Koyamada R, Higuchi T, Kitada A, Nakagawa T, Ikeya T, Okada S, Fujita Y. Association of Primary Biliary Cirrhosis-autoimmune Hepatitis Overlap Syndrome with Immune Thrombocytopenia and Graves' Disease. Intern Med 2015; 54:2013-6. [PMID: 26278293 DOI: 10.2169/internalmedicine.54.4405] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
A 54-year-old woman suffering from pruritus for five years was diagnosed to have Graves' disease and immune thrombocytopenia (ITP) associated with primary biliary cirrhosis (PBC)-autoimmune hepatitis (AIH) overlap syndrome, which was confirmed histologically after a prompt recovery in the platelet count number following steroid therapy. The association between PBC-AIH overlap syndrome and ITP has been rarely reported and the additional association with Graves' disease has not yet been reported. An underlying global derangement of autoimmunity or shared genetic susceptibility was suspected.
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MESH Headings
- Autoimmunity
- Female
- Genetic Predisposition to Disease
- Graves Disease/complications
- Graves Disease/diagnosis
- Graves Disease/drug therapy
- Hepatitis, Autoimmune/complications
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/drug therapy
- Humans
- Liver Cirrhosis, Biliary/complications
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/drug therapy
- Middle Aged
- Purpura, Thrombocytopenic, Idiopathic/complications
- Purpura, Thrombocytopenic, Idiopathic/pathology
- Syndrome
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Affiliation(s)
- Ryosuke Koyamada
- Division of Hematology, St. Luke's International Hospital, Japan
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Abstract
INTRODUCTION Corticosteroids alone or in combination with azathioprine are the mainstay therapies of autoimmune hepatitis. Suboptimal responses (treatment failure, partial response, drug toxicity), frequent relapse after drug withdrawal, and the emergence of alternative immunosuppressive medications have fueled the pursuit of new treatments. The goals of this review are to present current management strategies and evolving interventions. AREAS COVERED PubMed searches from 1970 - 2014 provide the bases for this review. Corticosteroid regimens should be administered until resolution of symptoms, laboratory tests, and liver tissue abnormalities. Treatment failure warrants high doses of the original regimen, and relapse warrants re-treatment followed by long-term maintenance with azathioprine. The calcineurin inhibitors, budesonide, and mycophenolate mofetil are evolving as frontline therapies, and they may be considered as salvage therapies with the exception of budesonide. Rapamycin, rituximab, and infliximab have also rescued refractory patients but experiences are limited. Anti-oxidants, recombinant molecules, mAbs, and modulators of critical cell populations are key prospects. EXPERT OPINION Autoimmune hepatitis must be managed by multiple medications that supplement or supplant current regimens depending on the clinical situation. Rescue therapies will emerge as adjunctive interventions to minimize tissue damage (prevent fibrosis and hepatocyte apoptosis) and improve immune tolerance (regulatory T cell manipulations).
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic College of Medicine, From the Division of Gastroenterology and Hepatology , 200 First Street S.W, Rochester, MN 55905 , USA +1 507 284 2691 ; +1 507 284 0538 ;
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Abstract
Autoimmune hepatitis is a disease of the hepatic parenchyma that can present in acute or chronic forms. In common with many autoimmune diseases, autoimmune hepatitis is associated with non-organ-specific antibodies in the context of hepatic autoimmunity. This dichotomy has made definition of a unifying hypothesis in the pathophysiology of the disease difficult, although data from the past 8 years have drawn attention to the role of regulatory T cells. Several triggers have been identified, and the disease arises in genetically susceptible individuals. Clinical and biochemical remission is achievable in up to 85% of cases. For the remaining patients, alternative immunosuppression strategies are an option. Liver transplantation provides an excellent outcome for patients with acute liver failure or complications of end-stage liver disease, including hepatocellular carcinoma. Variant or overlapping syndromes are worthy of consideration when unexpected disease features arise.
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Affiliation(s)
- Michael A Heneghan
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK.
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Rituximab for refractory autoimmune hepatitis: a case report. Arab J Gastroenterol 2013; 14:135-8. [PMID: 24206745 DOI: 10.1016/j.ajg.2013.08.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2012] [Revised: 06/05/2013] [Accepted: 06/13/2013] [Indexed: 12/14/2022]
Abstract
Auto-immune hepatitis (AIH) is a chronic progressive hepatitis of unknown aetiology whose clinical presentation ranges from asymptomatic to fulminant hepatic failure. Corticosteroids and azathioprine, which are considered standard therapy for AIH, may, however, be associated with treatment failures and toxicities. Among the alternative medications under investigation, rituximab, used to treat successfully various auto-immune disorders, has fewer side effects. We report herein the case of a 68-year-old woman who developed AIH with worsening clinical, laboratory and histological features despite high-dose prednisone. On rituximab, the patient showed rapid and dramatic clinical improvement, suggesting a therapeutic role for this medication in severe AIH. Indeed, prospective controlled studies are needed to assess and validate this role.
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Floreani A, Liberal R, Vergani D, Mieli-Vergani G. Autoimmune hepatitis: Contrasts and comparisons in children and adults - a comprehensive review. J Autoimmun 2013; 46:7-16. [PMID: 24035197 DOI: 10.1016/j.jaut.2013.08.004] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Revised: 08/13/2013] [Accepted: 08/14/2013] [Indexed: 12/24/2022]
Abstract
This review concentrates on autoimmune hepatitis (AIH), a liver disorder affecting both children and adults, characterized by inflammatory liver histology, elevated transaminase levels, circulating non-organ-specific autoantibodies, and increased levels of immunoglobulin G, in the absence of a known aetiology. Two types of AIH are recognized according to seropositivity: smooth muscle antibody and/or antinuclear antibody define AIH type 1, while antibodies to liver-kidney microsome type 1 and/or liver cytosol type 1 define AIH type 2. AIH type 1 affects both adults and children, while AIH type 2 is mainly a paediatric disease, though it does occasionally affects young adults. There is a female predominance in both types. AIH is particularly aggressive in children/adolescents, progressing rapidly unless immunosuppressive treatment is started promptly. With appropriate treatment 80% of patients achieve remission and long-term survival. In childhood/adolescence, sclerosing cholangitis with strong autoimmune features, including interface hepatitis and serological features identical to AIH type 1, is as prevalent as AIH, but it affects boys and girls equally. The differential diagnosis relies on cholangiographic studies. In autoimmune sclerosing cholangitis, liver parenchymal damage responds satisfactorily to immunosuppressive treatment, whereas bile duct disease progresses in 50% of cases, leading to a worse prognosis and higher transplantation requirement; it has a higher recurrence rate after transplant than AIH. AIH can arise de novo in patients transplanted for non-autoimmune liver disease. Post transplant de novo AIH affects children and adults and responds well to the same treatment schedule used for classical AIH, but not to that used for acute rejection.
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Affiliation(s)
- Annarosa Floreani
- Dept. of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Italy.
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D'Agostino D, Costaguta A, Álvarez F. Successful treatment of refractory autoimmune hepatitis with rituximab. Pediatrics 2013; 132:e526-30. [PMID: 23821693 DOI: 10.1542/peds.2011-1900] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Autoimmune hepatitis is a severe liver disease in which ~10% of patients do not respond to standard treatment. We describe a new rescue therapy using anti-CD20 monoclonal antibodies (rituximab). Complete remission was obtained and maintained by using low doses of immunosuppressive drugs with repeated anti-CD20 infusions.
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Affiliation(s)
- Daniel D'Agostino
- Pediatric Gastroenterology-Hepatology Division, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
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Trivedi PJ, Hirschfield GM. Treatment of autoimmune liver disease: current and future therapeutic options. Ther Adv Chronic Dis 2013; 4:119-41. [PMID: 23634279 DOI: 10.1177/2040622313478646] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Autoimmune liver disease spans three predominant processes, from the interface hepatitis of autoimmune hepatitis to the lymphocytic cholangitis of primary biliary cirrhosis, and finally the obstructive fibrosing sclerotic cholangiopathy of primary sclerosing cholangitis. Although all autoimmune in origin, they differ in their epidemiology, presentation and response to immunosuppressive therapy and bile acid based treatments. With an ongoing better appreciation of disease aetiology and pathogenesis, treatment is set ultimately to become more rational. We provide an overview of current and future therapies for patients with autoimmune liver disease, with an emphasis placed on some of the evidence that drives current practice.
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Affiliation(s)
- Palak J Trivedi
- Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK
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Burak KW, Swain MG, Santodomingo-Garzon T, Santodomino-Garzon T, Lee SS, Urbanski SJ, Aspinall AI, Coffin CS, Myers RP. Rituximab for the treatment of patients with autoimmune hepatitis who are refractory or intolerant to standard therapy. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2013; 27:273-80. [PMID: 23712302 PMCID: PMC3735730 DOI: 10.1155/2013/512624] [Citation(s) in RCA: 118] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2012] [Accepted: 12/09/2012] [Indexed: 12/22/2022]
Abstract
BACKGROUND Although most patients with autoimmune hepatitis (AIH) respond to treatment with prednisone and⁄or azathioprine, some patients are intolerant or refractory to standard therapy. Rituximab is an anti-CD20 monoclonal antibody that depletes B cells and has demonstrated efficacy in other autoimmune conditions. AIMS To evaluate the safety and efficacy of rituximab in patients with refractory AIH in an open-label, single-centre pilot study. METHODS Six patients with definite, biopsy-proven AIH who failed prednisone and azathioprine treatment received two infusions of rituximab 1000 mg two weeks apart and were followed for 72 weeks. RESULTS Rituximab was well tolerated with no serious adverse events. By week 24, mean (± SD) aspartate aminotransferase (AST) levels had significantly improved (90.0±23.3 U⁄L versus 31.3±4.2 U⁄L; P=0.03) and mean immunoglobulin G levels had fallen (16.4±2.0 g⁄L versus 11.5±1.1 g⁄L; P=0.056). The prednisone dose was weaned in three of four subjects, with one subject flaring after steroid withdrawal. Inflammation grade improved in all four subjects who underwent repeat liver biopsy at week 48. Regulatory T cell levels examined by FoxP3 immunohistochemistry paralleled inflammatory activity and did not increase on follow-up biopsies. There was no significant change in serum chemokine or cytokine levels from baseline to week 24 (n=5), although interferon-gamma-induced protein 10 levels improved in three of five subjects. CONCLUSIONS Rituximab was safe, well tolerated and resulted in biochemical improvement in subjects with refractory AIH. These results support further investigation of rituximab as a treatment for AIH.
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Affiliation(s)
- Kelly W Burak
- Liver Unit, Division of Gastroenterologyand Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
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Fallatah HI, Akbar HO. Autoimmune hepatitis as a unique form of an autoimmune liver disease: immunological aspects and clinical overview. Autoimmune Dis 2012; 2012:312817. [PMID: 23304455 PMCID: PMC3530748 DOI: 10.1155/2012/312817] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2012] [Revised: 09/09/2012] [Accepted: 10/12/2012] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a unique form of immune-mediated disease that attacks the liver through a variety of immune mechanisms. The outcomes of AIH are either acute liver disease, which can be fatal, or, more commonly, chronic progressive liver disease, which can lead to decompensated liver cirrhosis if left untreated. AIH has characteristic immunological, and pathological, features that are important for the establishment of the diagnosis. More importantly, most patients with AIH have a favorable response to treatment with prednisolone and azathioprine, although some patients with refractory AIH or more aggressive disease require more potent immune-suppressant agents, such as cyclosporine or Mycophenolate Mofetil. In this paper, we discuss the immunological, pathological and clinical features of AIH, as well as the standard and alternative treatments for AIH.
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Affiliation(s)
- Hind I. Fallatah
- Medical Department, Arab Board and Saudi Board of Internal Medicine, MACP, King Abdul Aziz University Hospital, P.O. Box 9714, Jeddah 21423, Saudi Arabia
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Abstract
Autoimmune hepatitis (AIH) is characterized by a T-cell rich infiltrate associated with lobular and interface hepatitis, hypergammaglobulinemia and production of autoantibodies. Genetic risk is linked to the HLA particularly DRB1*0301 and DRB1*0401 alleles in North American and European Caucasian populations. It has recently been suggested that functional deficiencies in CD4(+)CD25(+)CD127(low)FOXP3(+) regulatory T cells contribute to the breakdown of immune tolerance that results in AIH. Most patients respond to immunosuppressive therapy with corticosteroids and can be maintained in remission by low-dose corticosteroid treatment and/or azathioprine. For those who progress to end-stage disease liver transplantation is an effective treatment although it is associated with recurrence. In the future it is likely that biological therapies will allow more targeted therapy designed to switch the balance to immune regulation and thereby restore immune homeostasis. Although treatment for many cases is relatively straightforward and successful problems are encountered in those who fail to respond to standard treatment, are unable to tolerate it or relapse. In such cases alternative therapies should be considered. In addition treatment is complicated in some patients by comorbidity and special care is required during and after pregnancy. We will discuss the current and future therapeutic options for patients with difficult to treat AIH.
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Affiliation(s)
- Richard Parker
- Centre for Liver Research & Birmingham NIHR Biomedical Research Liver Centre, School of Infection and Immunity, MRC Centre for Immune Regulation, Institute for Biomedical Research, Medical School, University of Birmingham, Birmingham, UK
| | - Ye Htun Oo
- Centre for Liver Research & Birmingham NIHR Biomedical Research Liver Centre, School of Infection and Immunity, MRC Centre for Immune Regulation, Institute for Biomedical Research, Medical School, University of Birmingham, Birmingham, UK
| | - David H. Adams
- Centre for Liver Research & Birmingham NIHR Biomedical Research Liver Centre, School of Infection and Immunity, MRC Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TT, UK
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Selvarajah V, Montano-Loza AJ, Czaja AJ. Systematic review: managing suboptimal treatment responses in autoimmune hepatitis with conventional and nonstandard drugs. Aliment Pharmacol Ther 2012; 36:691-707. [PMID: 22973822 DOI: 10.1111/apt.12042] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2012] [Revised: 07/17/2012] [Accepted: 08/21/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND Corticosteroid treatment for autoimmune hepatitis has been shown by randomised controlled clinical trials to ameliorate symptoms, normalise liver tests, improve histological findings and extend survival. Nevertheless, suboptimal responses to corticosteroid treatment still occur. AIM To describe the current definitions, frequencies, clinical relevance and treatment options for suboptimal responses, and to discuss alternative medications that have been used off-label for these occurrences. METHODS Literature search was made for full-text papers published in English using the keyword 'autoimmune hepatitis'. Authors' personal experience and investigational studies also helped to identify important contributions to the literature. RESULTS Suboptimal responses to standard therapy include treatment failure (7%), incomplete response (14%), drug toxicity (13%) and relapse after drug withdrawal (50-86%). The probability of a suboptimal response prior to treatment is higher in young patients and in patients with a severe presentation, jaundice, high MELD score at diagnosis, multilobular necrosis or cirrhosis, antibodies to soluble liver antigen, or inability to improve by clinical indices within two weeks or by MELD score within 7 days of conventional corticosteroid treatment. Management strategies have been developed for the adverse responses and nonstandard drugs, including mycophenolate mofetil, budesonide, ciclosporin, tacrolimus, sirolimus and rituximab, are emerging as rescue therapies or alternative frontline agents. CONCLUSIONS Once diagnosed, the suboptimal response should be treated by a highly individualised and well-monitored regimen, preferentially using first-line therapy. Nonstandard drugs warrant consideration as salvage or second-line therapies.
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Affiliation(s)
- V Selvarajah
- Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
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Narita A, Muramatsu H, Takahashi Y, Sakaguchi H, Doisaki S, Nishio N, Hama A, Shimada A, Ito M, Kojima S. Autoimmune-like hepatitis following unrelated BMT successfully treated with rituximab. Bone Marrow Transplant 2011; 47:600-2. [PMID: 21666737 DOI: 10.1038/bmt.2011.124] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Jothimani D, Cramp ME, Mitchell JD, Cross TJS. Treatment of autoimmune hepatitis: a review of current and evolving therapies. J Gastroenterol Hepatol 2011; 26:619-27. [PMID: 21073674 DOI: 10.1111/j.1440-1746.2010.06579.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Autoimmune hepatitis (AIH) is an immune-mediated necroinflammatory condition of the liver. Presentation can vary from the asymptomatic individual with abnormal liver function test to fulminant liver failure. The diagnosis is based on the combination of biochemical, autoimmune, and histological parameters, and exclusion of other liver diseases. Standard therapy consists of a combination of corticosteroids and azathioprine, which is efficacious in 80% of patients. Alternative therapies are increasingly being explored in patients who do not respond to the standard treatment and/or have unacceptable adverse effects. This review examines the role of alternative drugs (second-line agents) available for AIH treatment non-responders. These agents include budesonide, mycophenolate mofetil, cyclosporin, tacrolimus, 6-mercaptopurine, 6-thioguanine, rituximab, ursodeoxycholic acid, rapamycin, and methotrexate. In addition, the risk of opportunistic infections and malignancies are discussed. A treatment algorithm is proposed for the management of patients with AIH treatment non-responders.
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Affiliation(s)
- Dinesh Jothimani
- The Southwest Liver Unit, Derriford Hospital, Plymouth, Devon, UK
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36
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Muratori L, Muratori P, Granito A, Pappas G, Cassani F, Lenzi M. Current topics in autoimmune hepatitis. Dig Liver Dis 2010; 42:757-64. [PMID: 20615766 DOI: 10.1016/j.dld.2010.05.019] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2010] [Revised: 05/23/2010] [Accepted: 05/31/2010] [Indexed: 12/11/2022]
Abstract
Autoimmune hepatitis is a chronic liver disease of unknown aetiology characterized by interface hepatitis, hypergammaglobulinaemia and circulating autoantibodies. In the last decade a number of advancements have been made in the field of clinical and basic research: the simplified diagnostic criteria, the complete response defined as normalization of transaminase levels, the molecular identification of the antigenic targets of anti-liver cytosol antibody type 1 and anti-soluble liver antigen, the detection of anti-actin antibodies, the description of de novo autoimmune hepatitis after liver transplantation for non-autoimmune liver diseases, the characterization of autoimmune hepatitis with overlapping features of primary biliary cirrhosis or primary sclerosing cholangitis, the preliminary experience with novel treatment strategies based on cyclosporine, mycophenolate mofetil and budesonide, the role played by "impaired" regulatory T cells and the development of novel animal models of autoimmune hepatitis.
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Affiliation(s)
- Luigi Muratori
- Department of Clinical Medicine, Alma Mater Studiorum - University of Bologna, Policlinico Sant'Orsola-Malpighi, Padiglione 11, Bologna, Italy.
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37
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Czaja AJ. Emerging opportunities for site-specific molecular and cellular interventions in autoimmune hepatitis. Dig Dis Sci 2010; 55:2712-26. [PMID: 20108036 DOI: 10.1007/s10620-009-1122-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2009] [Accepted: 12/28/2009] [Indexed: 02/08/2023]
Abstract
Current corticosteroid-based treatments of autoimmune hepatitis frequently have incomplete or unsatisfactory outcomes, side effects, and excessive immune suppression. The goal of this review is to describe the advances in developing animal models of autoimmune hepatitis and in treating diverse immune-mediated diseases that make pursuit of site-specific molecular and cellular inventions in autoimmune hepatitis feasible. Prime source and review articles in English were selected by a Medline search through October 2009. A murine model infected with an adenovirus expressing human CYP2D6 is a resource for evaluating new therapies because of its histological and serological features, persistence, and progressive hepatic fibrosis. Synthetic analog peptides that block autoantigen expression, a dimeric recombinant human fusion protein of cytotoxic T lymphocyte antigen-4, monoclonal antibodies against tumor necrosis factor-alpha, recombinant interleukin 10, tolerization techniques for disease-triggering autoantigens, T regulatory cell transfer, vaccination against antigen-specific cytotoxic CD8+ T cells, and gene silencing methods using small inhibitory RNAs are feasible interventions to explore. Treatments directed at dampening immunocyte activation with soluble cytotoxic T lymphocyte antigen-4, inhibiting immunocyte differentiation with recombinant interleukin 10, and improving immunosuppressive activity with regulatory T cell modulation have the most immediate promise. Progress in the development of an animal model of autoimmune hepatitis and experiences in other immune-mediated diseases justify the evaluation of site-specific molecular and cellular interventions in this disease.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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38
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Antunes H, Rocha R, Silva N, Pontes T, Antunes A, Martins S. Immune disease expressed in liver and platelets in an adolescent: a case report. Ital J Pediatr 2010; 36:42. [PMID: 20540743 PMCID: PMC2892502 DOI: 10.1186/1824-7288-36-42] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2010] [Accepted: 06/11/2010] [Indexed: 11/10/2022] Open
Abstract
We report a case of a 15-year-old boy with autoimmune hepatitis lacking common serologic markers and normal gammaglobulinemia associated with immune thrombocytopenia and family history of psoriasis. He presented to our department with a 4-year history of a cervical posterior lymphadenopathy and recent petechiae. Previous laboratory results 6 months before already showed hepatocellular injury. After exclusion of other causes, the diagnosis of autoimmune hepatitis was made based on clinical grounds, associated immune disorder and histological features of liver biopsy. The authors alert for this atypical presentation of autoimmune hepatitis and associated immune thrombocytopenia.
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Affiliation(s)
- Henedina Antunes
- Adolescents Unit and Gastrenterology, Hepatology and Nutrition Unit, Pediatrics Department, Braga Hospital, and Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal
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39
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Oo YH, Hubscher SG, Adams DH. Autoimmune hepatitis: new paradigms in the pathogenesis, diagnosis, and management. Hepatol Int 2010; 4:475-93. [PMID: 20827405 DOI: 10.1007/s12072-010-9183-5] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2010] [Accepted: 03/13/2010] [Indexed: 02/06/2023]
Abstract
Autoimmune hepatitis (AIH), primary biliary cirrhosis, and primary sclerosing cholangitis are the three major autoimmune diseases affecting the liver, and of these three, AIH is the most typical autoimmune disease being characterized by a T-cell-rich infiltrate, raised circulating γ-globulins, autoantibodies, HLA associations, and links with other autoimmune diseases. It is the only one, of the three diseases, that responds well to immunosuppressive therapy. AIH is caused by dysregulation of immunoregulatory networks and the consequent emergence of autoreactive T cells that orchestrate a progressive destruction of hepatocytes leading untreated to liver failure. T cells play a major role in the immunopathogenesis, and both CD4(+) and CD8(+) T cells are involved together with effector responses mediated by NK cells, γδ T cells, and macrophages. A number of triggering factors have been proposed including viruses, xenobiotics, and drugs, but none have been conclusively shown to be involved in pathogenesis.
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40
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Abstract
Corticosteroid therapy induces clinical, laboratory and histological improvements in 80% of patients with autoimmune hepatitis. Prednisone, alone or at a lower dose in combination with azathioprine, increases the 20-year life expectancy to 80% and prevents or reduces hepatic fibrosis in 79% of patients. The combination regimen is preferred and treatment should be considered in all patients with active disease. The duration of therapy is finite and the medication should be discontinued after resolution of all manifestations of inflammatory activity, including the histological changes. Relapse after drug withdrawal occurs in 50-79% of patients, and it should be treated with long-term azathioprine (2 mg/kg daily). Salvage therapies for individuals intolerant of or refractory to the conventional regimens include high-dose corticosteroids, with or without high-dose azathioprine, 6-mercaptopurine, mycophenolate mofetil, tacrolimus or ciclosporin. Liver transplantation should be considered in patients with hepatic failure unresponsive to corticosteroid treatment, decompensated cirrhosis with a Model for End-Stage Liver Disease score of at least 15 points, or hepatocellular carcinoma that meets transplantation criteria. Autoimmune hepatitis recurs after transplantation in at least 17% of patients, and it typically improves after adjustments in the immunosuppressive regimen. Future therapies are likely to include mesenchymal stem cell transplantation, adoptive transfer of T regulatory cells, and cytokine manipulation. The emergence of new treatments will require the development of a collaborative network of clinical and basic investigators, as the complexity and specificity of current management problems require solutions that exceed the capabilities of single institutions.
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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41
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Czaja AJ, Bayraktar Y. Non-classical phenotypes of autoimmune hepatitis and advances in diagnosis and treatment. World J Gastroenterol 2009; 15:2314-28. [PMID: 19452572 PMCID: PMC2684596 DOI: 10.3748/wjg.15.2314] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [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
Non-classical manifestations of autoimmune hepatitis can delay diagnosis and treatment. Our aims were to describe the clinical phenotypes that can confound the diagnosis, detail scoring systems that can ensure their recognition, and outline advances in treatment that can improve their outcome. Prime source and review articles in English were selected through Medline from 1970-2008 and assimilated into personal libraries spanning 32 years. Acute severe or asymptomatic presentations and atypical histological findings, including centrilobular zone 3 necrosis and concurrent bile duct changes, are compatible with the diagnosis. Cholangiographic abnormalities may be present in children and adults with the disease, and autoimmune hepatitis must be considered in patients without autoantibodies or with antimitochondrial antibodies and no other cholestatic features. Asymptomatic patients frequently become symptomatic; mild disease can progress; and there are no confident indices that justify withholding treatment. Two diagnostic scoring systems with complementary virtues have been developed to evaluate patients with confusing features. Normal liver tests and tissue constitute the optimal end point of treatment, and the first relapse is an indication for long-term azathioprine therapy. Cyclosporine, tacrolimus and mycophenolate mofetil are promising salvage therapies, and budesonide with azathioprine may be a superior frontline treatment. We conclude that the non-classical phenotypes of autoimmune hepatitis can be recognized promptly, diagnosed accurately, and treated effectively.
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Hirschfield GM, Al-Harthi N, Heathcote EJ. Current status of therapy in autoimmune liver disease. Therap Adv Gastroenterol 2009; 2:11-28. [PMID: 21180531 PMCID: PMC3002506 DOI: 10.1177/1756283x08098966] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Therapeutic strategies for autoimmune liver diseases are increasingly established. Although proportionately uncommon, specialist centers have with time refined the best approaches for each disease, based on an improved understanding of the spectrum of presentation. The major treatment aims are to prevent end-stage liver disease and its associated complications. As a result of drugs such as ursodeoxycholic acid, predniso(lo)ne and azathioprine, both primary biliary cirrhosis and autoimmune hepatitis are now less commonly indications for liver transplantation. Unfortunately, the same inroads in treatment efficacy have as yet not been made for primary sclerosing cholangitis, although the recognition that a subset of patients may have a treatable secondary sclerosing cholangitis (IgG4 related) is helping a proportion. With better biological understanding, more specific interventions are expected that will benefit all those with autoimmune liver diseases.
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43
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Abstract
Autoinflammatory liver disease represents an important aspect of global hepatological practice. The three principal disease divisions recognized are autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis. Largely, but not exclusively, these diseases are considered to be autoimmune in origin. Increased recognition of outlier and overlap syndromes, changes in presentation and natural history, as well as the increased awareness of IgG4-associated sclerosing cholangitis, all highlight the limitations of the classic terminology. New insights continue to improve the care given to patients, and have arisen from carefully conducted clinical studies, therapeutic trials, as well as genetic and laboratory investigations. The challenges remain to treat patients before liver injury becomes permanent and to prevent the development of organ failure.
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Affiliation(s)
- Teru Kumagi
- Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
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44
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Abstract
BACKGROUND Prednisone and azathioprine are effective in the treatment of autoimmune hepatitis, but diverse side effects can diminish their net benefit. OBJECTIVES Describe the frequency and nature of these side effects and propose management strategies to minimize their impact. METHODS Pertinent articles published from 1970 to 2007 were identified by Medline search and through a personal library. RESULTS Medication is prematurely discontinued in 13% of patients mainly because of cosmetic changes, cytopenia, or osteopenia. Populations at high risk are the elderly, those with pre-existent co-morbidities, patients with near-zero thiopurine methyltransferase activity, individuals who are treatment-dependent, pregnant women, and asymptomatic patients who are over-treated. CONCLUSIONS Proper patient selection, effective pre-treatment counseling, preemptive protective measures, realistic treatment objectives, and early identification of problematic patients can reduce complications. Individualized dosing schedules and the emergence of non-steroidal medications are realistic expectations.
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic and Mayo Clinic College of Medicine, Division of Gastroenterology and Hepatology, Department of Medicine, 200 First Street SW, Rochester, Minnesota 55905, USA.
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45
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Zhou Z, Yang R. Rituximab treatment for chronic refractory idiopathic thrombocytopenic purpura. Crit Rev Oncol Hematol 2008; 65:21-31. [PMID: 17681784 DOI: 10.1016/j.critrevonc.2007.06.007] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2006] [Revised: 03/16/2007] [Accepted: 06/14/2007] [Indexed: 01/19/2023] Open
Abstract
Idiopathic thrombocytopenic purpura (ITP) is characterized by mucocutaneous bleeding and a low platelet count caused by increased autoantibodies against self-antigens and T-cell mediated cytotoxicity. About 10-30% patients with ITP will become refractory ITP. Most of them will become refractory to corticosteroids and splenectomy, as well as other available agents such as intravenous immunoglobulins, danazol, or chemotherapy. B cells not only are the passive producers of immunoglobulins, but also play an important immunoregulatory role in pathophysiology of ITP. Rituximab, a chimeric anti-CD20 monoclonal antibody that specifically targets the CD20 molecule on the B-cell surface, is useful in the treatment of ITP through B cells depletion. Rituximab has multiple mechanisms of inducing cytotoxicity in vivo, including antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), direct apoptosis signaling, and possible vaccine effects. In most clinical reports, rituximab was given as an intravenous infusion at a dose of 375 mg/m(2) weekly for four doses. A total complete response (CR) of 33.2% and a total response of 52.9% were reported. Most results found that no clinical or laboratory parameters could predict treatment outcome. Though the infusion-related side effects of rituximab were common in ITP, it was well tolerated with rare severe side effects. In general, rituximab appears to be a promising immunotherapeutic agent for the treatment of refractory ITP. More controlled clinical trials are necessary to evaluate both the efficacy and long-term safety of the drug.
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Affiliation(s)
- Zeping Zhou
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, PR China
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46
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Czaja AJ. Clinical Features, Differential Diagnosis and Treatment of Autoimmune Hepatitis in the Elderly. Drugs Aging 2008; 25:219-39. [DOI: 10.2165/00002512-200825030-00005] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Egiguren L, Minondo L, Zapata E, Castiella A. [Patient with autoimmune hepatitis and idiopathic thrombocytopenic purpura after minocycline therapy]. GASTROENTEROLOGIA Y HEPATOLOGIA 2007; 30:565-6. [PMID: 17980139 DOI: 10.1157/13111686] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Montano-Loza AJ, Carpenter HA, Czaja AJ. Features associated with treatment failure in type 1 autoimmune hepatitis and predictive value of the model of end-stage liver disease. Hepatology 2007; 46:1138-45. [PMID: 17668882 DOI: 10.1002/hep.21787] [Citation(s) in RCA: 104] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
UNLABELLED Autoimmune hepatitis may fail to respond to corticosteroid therapy, but the frequency and bases for this outcome are uncertain. We aimed to determine the frequency and nature of treatment failure in patients with type 1 autoimmune hepatitis, define features associated with its occurrence, and assess if the model for end-stage liver disease can predict this outcome. Patients failing conventional corticosteroid regimens were compared to patients who responded to similar regimens. Fourteen of 214 patients (7%) failed corticosteroid treatment. Patients who failed therapy were younger (33 +/- 3 years versus 48 +/- 1 years, P = 0.0008), had higher serum levels of bilirubin at accession (4.1 +/- 0.9 mg/dL versus 2.3 +/- 0.2 mg/dL, P = 0.02), presented acutely more frequently (43% versus 14%, P = 0.01), and had a higher frequency of HLA (human leukocyte antigen) DRB1*03 (93% versus 53%, P = 0.004) than did patients who achieved remission. An alternative disease (fatty liver disease) emerged in only 1 patient who failed therapy (7%). Scores determined by the model of end-stage liver disease at presentation of patients who failed treatment were higher than those of who achieved remission (16 +/- 1 versus 10 +/- 0.3 points, P < 0.0001), and score greater than 12 points had greater sensitivity (97%) and specificity (68%) for treatment failure than did HLA DRB1*03 or other features. CONCLUSION Onset at an early age, acute presentation, hyperbilirubinemia, and presence of HLA DRB1*03 characterize patients who fail corticosteroid treatment. The model for end-stage liver disease may be a useful instrument for identifying patients prone to this outcome.
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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
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Reale LD, Besa EC. Rituximab in autoimmune pancytopenia: a case report and review of literature. Ann Hematol 2007; 86:913-6. [PMID: 17541587 DOI: 10.1007/s00277-007-0316-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2006] [Accepted: 05/07/2007] [Indexed: 11/28/2022]
MESH Headings
- Adult
- Anemia, Hemolytic, Autoimmune/drug therapy
- Anemia, Hemolytic, Autoimmune/immunology
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal, Murine-Derived
- Autoimmune Diseases/drug therapy
- Autoimmune Diseases/immunology
- Azathioprine/administration & dosage
- Azathioprine/adverse effects
- Azathioprine/therapeutic use
- Erythrocyte Transfusion
- Female
- Filgrastim
- Granulocyte Colony-Stimulating Factor/therapeutic use
- Hepatitis, Autoimmune/complications
- Hepatitis, Autoimmune/drug therapy
- Humans
- Immunosuppressive Agents/adverse effects
- Immunosuppressive Agents/therapeutic use
- Neutropenia/drug therapy
- Neutropenia/immunology
- Pancytopenia/drug therapy
- Pancytopenia/immunology
- Polyethylene Glycols
- Prednisone/administration & dosage
- Prednisone/therapeutic use
- Purpura, Thrombocytopenic, Idiopathic/drug therapy
- Purpura, Thrombocytopenic, Idiopathic/immunology
- Recombinant Proteins
- Recurrence
- Rituximab
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Abstract
PURPOSE OF REVIEW The aim of this article is to review studies that improve the diagnosis and treatment of autoimmune hepatitis and suggest new drug and molecular interventions. RECENT FINDINGS Elderly patients have an indolent but aggressive disease that responds well to corticosteroid therapy. Variant syndromes are artificial designations that reflect uncertainties regarding the diagnostic limits of classical disease. Antibodies to cyclic citrullinated proteins and complex assays for antibodies to actin and alpha-actinin may have prognostic value. Defects in the number and function of T regulatory cells may enhance cell-mediated cytotoxicity. HLA DRB113 may be a risk factor in some North American patients, and disease outcome may be influenced by the 'dose' of alleles encoding critical residues. Screening for thiopurine methyltransferase deficiency does not predict azathioprine intolerance. Treatment until normalization of the laboratory and histological features reduces the risk of relapse by 30-50%. Adverse outcomes in pregnancy are associated with antibodies to soluble liver antigen/liver pancreas and Ro/SSA. SUMMARY Novel serological tests may have prognostic value. Defects in the suppressor activity of regulatory T cells may promote liver injury. Genetic predispositions strongly influence disease occurrence and outcome. Laboratory and histological features should be normal prior to drug withdrawal. Azathioprine toxicities cannot be predicted.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
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