|
1
|
Dalekos G, Gatselis N, Drenth JP, Heneghan M, Jørgensen M, Lohse AW, Londoño M, Muratori L, Papp M, Samyn M, Tiniakos D, Lleo A. EASL Clinical Practice Guidelines on the management of autoimmune hepatitis. J Hepatol 2025:S0168-8278(25)00173-4. [PMID: 40348684 DOI: 10.1016/j.jhep.2025.03.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Accepted: 03/20/2025] [Indexed: 05/14/2025]
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disease of unknown aetiology which may affect any patient irrespective of age, sex, and ethnicity. At baseline, the clinical spectrum of the disease varies largely from asymptomatic cases to acute liver failure with massive hepatocyte necrosis. The aim of these EASL guidelines is to provide updated guidance on the diagnosis and management of AIH both in adults and children. Updated guidance on the management of patients with variants and specific forms of AIH is also provided, as is detailed guidance on the management of AIH-associated cirrhosis, including surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.
Collapse
|
|
2
|
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.
Collapse
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
| |
Collapse
|
|
3
|
Stoelinga AEC, Tushuizen ME, van den Hout WB, Girondo MDMR, de Vries ES, Levens AD, Moes DJAR, Gevers TJG, van der Meer S, Brouwer HT, de Jonge HJM, de Boer YS, Beuers UHW, van der Meer AJ, van den Berg AP, Guichelaar MMJ, Drenth JPH, van Hoek B. Tacrolimus versus mycophenolate for AutoImmune hepatitis patients with incompLete response On first-line therapy (TAILOR study): a study protocol for a phase III, open-label, multicentre, randomised controlled trial. Trials 2024; 25:61. [PMID: 38233878 PMCID: PMC10792789 DOI: 10.1186/s13063-023-07832-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 11/24/2023] [Indexed: 01/19/2024] Open
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical response is the most important risk factor for liver transplantation or liver-related mortality. First-line treatment consists of a combination of azathioprine and prednisolone. If CR is not reached, tacrolimus (TAC) or mycophenolate mofetil (MMF) can be used as second-line therapy. Both products are registered for the prevention of graft rejection in solid organ transplant recipients. The aim of this study is to compare the effectiveness and safety of TAC and MMF as second-line treatment for AIH. METHODS The TAILOR study is a phase IIIB, multicentre, open-label, parallel-group, randomised (1:1) controlled trial performed in large teaching and university hospitals in the Netherlands. We will enrol 86 patients with AIH who have not reached CR after at least 6 months of treatment with first-line therapy. Patients are randomised to TAC (0.07 mg/kg/day initially and adjusted by trough levels) or MMF (max 2000 mg/day), stratified by the presence of cirrhosis at inclusion. The primary endpoint is the difference in the proportion of patients reaching CR after 12 months. Secondary endpoints include the difference in the proportion of patients reaching CR after 6 months, adverse effects, difference in fibrogenesis, quality of life and cost-effectiveness. DISCUSSION This is the first randomised controlled trial comparing two second-line therapies for AIH. Currently, second-line treatment is based on retrospective cohort studies. The rarity of AIH is the main issue in clinical research for alternative treatment options. The results of this trial can be implemented in existing international clinical guidelines. TRIAL REGISTRATION ClinicalTrials.gov NCT05221411 . Retrospectively registered on 3 February 2022; EudraCT number 2021-003420-33. Prospectively registered on 16 June 2021.
Collapse
Affiliation(s)
- Anna E C Stoelinga
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
| | - Maarten E Tushuizen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Wilbert B van den Hout
- Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Elsemieke S de Vries
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
- Department of Gastroenterology and Hepatology, Isala Hospital, Zwolle, The Netherlands
| | - Amar D Levens
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Dirk-Jan A R Moes
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Tom J G Gevers
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- European Reference Network RARE-LIVER, Hamburg, Germany
| | - Suzanne van der Meer
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Hans T Brouwer
- Department of Gastroenterology and Hepatology, Reinier de Graaf Gasthuis, Delft, The Netherlands
| | - Hendrik J M de Jonge
- Department of Gastroenterology and Hepatology, Jeroen Bosch Hospital, 'S-Hertogenbosch, The Netherlands
| | - Ynte S de Boer
- European Reference Network RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Location VU University Medical Center, Amsterdam, The Netherlands
| | - Ulrich H W Beuers
- European Reference Network RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Location Academic Medical Center, Amsterdam, The Netherlands
| | - Adriaan J van der Meer
- European Reference Network RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Aad P van den Berg
- European Reference Network RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Maureen M J Guichelaar
- Department of Gastroenterology and Hepatology, Medisch Spectrum Twente, Enschede, The Netherlands
| | - Joost P H Drenth
- European Reference Network RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| |
Collapse
|
|
4
|
Baven-Pronk MAMC, Hew JM, Biewenga M, Tushuizen ME, van den Berg AP, Bouma G, Brouwer JT, van Hoek B, Dutch Autoimmune Hepatitis Study Group. Calcineurin Inhibitors in the Treatment of Adult Autoimmune Hepatitis: A Systematic Review. J Clin Transl Hepatol 2022; 10:1155-1166. [PMID: 36381101 PMCID: PMC9634779 DOI: 10.14218/jcth.2021.00535] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 02/05/2022] [Accepted: 02/27/2022] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND AND AIMS A considerable number of autoimmune hepatitis (AIH) patients completely or partially fail on first-line treatment. Several studies on the use of calcineurin inhibitors (CNIs) in the treatment of AIH have been published without focusing on indication. The aim was to assess the efficacy of CNIs in the treatment of adult AIH patients, specifically focusing on indication: first-line intolerant and with first-line insufficient response (failure to achieve or maintain remission), and with second versus third-line treatment. METHODS A literature search included studies on the use of CNIs in adult AIH. Patients with past or present use of CNIs from the Dutch AIH group cohort were added. The primary endpoint was biochemical remission while using CNIs. Secondary endpoints were biochemical response, treatment failure, and adverse effects. RESULTS Twenty studies from the literature and nine Dutch patients were included describing the use of cyclosporine in 59 and tacrolimus in 219 adult AIH patients. The CNI remission rate was 53% in patients with insufficient response to first-line treatment and 67% in patients intolerant to first-line treatment. CNIs were used as second-line treatment in 73% with a remission rate of 52% and as third-line treatment in 22% with a remission rate of 26%. Cyclosporine was discontinued in 13% and tacrolimus in 11% of patients because of adverse events. CONCLUSIONS CNIs as rescue treatment in adult AIH patients are reasonably effective and safe both with insufficient response or intolerance to previous treatment. Prospective studies are needed.
Collapse
Affiliation(s)
- Martine AMC Baven-Pronk
- Department of Gastroenterology and Hepatology, Groene Hart Hospital, Gouda, Netherlands
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands
| | - Joffre M. Hew
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands
| | - Maaike Biewenga
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands
| | - Maarten E. Tushuizen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands
| | - Aad P. van den Berg
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, Netherlands
| | - Gerd Bouma
- Department of Gastroenterology and Hepatology Amsterdam University Medical Center, Location VU, Amsterdam, Netherlands
| | | | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands
- Correspondence to: Bart van Hoek, Department of Gastroenterology and Hepatology. C4-P Leiden University Medical Center, Albinusdreef 2, 2300 ZC Leiden, Netherlands. ORCID: https://orcid.org/0000-0001-6527-764X. Tel: +31-71-5269111, E-mail:
| | | |
Collapse
|
|
5
|
Olivas I, Rodríguez-Tajes S, Londoño MC. Hepatitis autoinmune: retos y novedades. Med Clin (Barc) 2022; 159:289-298. [DOI: 10.1016/j.medcli.2022.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 04/04/2022] [Accepted: 04/06/2022] [Indexed: 10/18/2022]
|
|
6
|
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.
Collapse
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.
| |
Collapse
|
|
7
|
Ferre-Aracil C, Riveiro-Barciela M, Trapero-Marugán M, Rodríguez-Perálvarez M, Llovet LP, Téllez L, Sánchez-Torrijos Y, Díaz-Fontenla F, Salcedo-Plaza M, Álvarez-López P, de la Mata M, Londoño MC, Bañares-Cañizares R, Calleja JL. Tacrolimus as an Effective and Durable Second-Line Treatment for Chronic Autoimmune Hepatitis: A Multicentric Study. Dig Dis Sci 2021; 66:2826-2832. [PMID: 32860579 DOI: 10.1007/s10620-020-06569-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 08/19/2020] [Indexed: 12/09/2022]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a chronic liver disease able to progress to acute liver failure, cirrhosis, and liver cancer. A significant proportion of patients fail to first-line therapy or develop severe toxicity. AIMS To assess safety and effectiveness of tacrolimus as a second-line therapy in AIH patients. METHODS Multicentric retrospective study of AIH patients treated with tacrolimus for at least 3 months as a second-line therapy. Effectiveness was defined as complete normalization of transaminases and IgG. RESULTS A total of 23 AIH patients were included in the final analysis. In 13% of patients tacrolimus was initiated because of toxicity to previous first-line treatments and the rest were switched because of previous non-efficacy. Tacrolimus was effective in 18 patients (78%; 95%CI: 55.20-91.92%). The median time receiving tacrolimus was 16 months (IQR 20). There was a sustained response with a significant improvement in all liver enzymes and IgG on last follow-up. Only one patient discontinued tacrolimus at the third month because of severe neuropathy, and ototoxicity. Responders were significantly older at diagnosis of AIH (41 ± 13 vs. 27 ± 10 years old; p = 0.0496). CONCLUSION Tacrolimus is effective and well tolerated as a second-line therapy in patients with AIH.
Collapse
Affiliation(s)
- Carlos Ferre-Aracil
- Gastroenterology and Hepatology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Joaquin Rodrigo 1, Majadahonda, 28888, Madrid, Spain.
| | - Mar Riveiro-Barciela
- Hepatology - Internal Medicine Unit, Hospital Universitario Vall d'Hebrón, Barcelona, Spain
- CIBERehd, Barcelona, Spain
| | - María Trapero-Marugán
- Gastroenterology and Hepatology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Joaquin Rodrigo 1, Majadahonda, 28888, Madrid, Spain
| | - Manuel Rodríguez-Perálvarez
- Hepatology and Liver Transplantation Unit, Hospital Universitario Reina Sofía, IMBIC, CIBERehd, Córdoba, Spain
| | | | - Luis Téllez
- Gastroenterology and Hepatology Unit, Hospital Universitario Ramón y Cajal, IRYCIS, CIBERehd, Universidad de Alcalá, Madrid, Spain
| | | | - Fernando Díaz-Fontenla
- Gastroenterology and Hepatology Unit, Hospital Universitario Gregorio Marañón, Madrid, Spain
| | - Magdalena Salcedo-Plaza
- Gastroenterology and Hepatology Unit, Hospital Universitario Gregorio Marañón, Madrid, Spain
| | - Patricia Álvarez-López
- Hepatology - Internal Medicine Unit, Hospital Universitario Vall d'Hebrón, Barcelona, Spain
| | - Manuel de la Mata
- Hepatology and Liver Transplantation Unit, Hospital Universitario Reina Sofía, IMBIC, CIBERehd, Córdoba, Spain
| | | | | | - José Luis Calleja
- Gastroenterology and Hepatology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Joaquin Rodrigo 1, Majadahonda, 28888, Madrid, Spain
| |
Collapse
|
|
8
|
Ronca V, Bozward AG, Oo YH. Use of immunosuppression in non-transplant hepatology. Best Pract Res Clin Gastroenterol 2021; 54-55:101760. [PMID: 34874849 DOI: 10.1016/j.bpg.2021.101760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 06/29/2021] [Accepted: 07/01/2021] [Indexed: 01/31/2023]
Abstract
Human liver possesses a persistent and tightly regulated immune response. Maintaining this homeostatic state is the key to prevent pathological processes, as a failure in clearing dangerous stimuli, is associated with tissue damage. A dysregulation of the liver immune homeostasis is involved in many disease processes and the use of the immunosuppression aims to control the inflammatory response, where the physiologic mechanisms failed. The use of steroids which targets broadly the inflammatory cascade and the immune system activation have been extensively employed in both acute and chronic liver diseases. They currently are the backbone of the treatment of autoimmune diseases such as autoimmune hepatitis or IgG4 sclerosing cholangitis. The steroid use in acute liver injury, especially alcohol mediated and drug induced liver injury (DILI), have been debated, despite the biological rationale. The immunosuppression molecules currently employed in liver diseases target the immune system broadly, causing multiple side effects either intrinsic in the mechanisms of the drug or secondary to off-target toxicity. The future of immunosuppressant treatment is moving towards more selective strategies, targeting disease specific pathways. This review aims to explore the rationale of use of immunosuppression in non-transplant hepatology. A broad summary of the immune biology of liver immune mediated diseases will be provided to the readers in order to highlight the potential therapeutic targets. An extensive description of the molecules employed in liver diseases will follow and the clinical evidences in AIH, IgG4 related cholangitis, alcoholic hepatitis and DILI will be reviewed.
Collapse
Affiliation(s)
- Vincenzo Ronca
- Centre for Liver and Gastro Research and NIHR Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, UK; Centre for Rare Diseases, European Reference Network Centre- Rare Liver, Birmingham, UK; Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, UK.
| | - Amber G Bozward
- Centre for Liver and Gastro Research and NIHR Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, UK; Centre for Rare Diseases, European Reference Network Centre- Rare Liver, Birmingham, UK
| | - Ye Htun Oo
- Centre for Liver and Gastro Research and NIHR Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, UK; Centre for Rare Diseases, European Reference Network Centre- Rare Liver, Birmingham, UK; Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, UK.
| |
Collapse
|
|
9
|
Liberal R, de Boer YS, Heneghan MA. Established and novel therapeutic options for autoimmune hepatitis. Lancet Gastroenterol Hepatol 2021; 6:315-326. [DOI: 10.1016/s2468-1253(20)30328-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 08/14/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023]
|
|
10
|
Chung Y, Rahim MN, Graham JJ, Zen Y, Heneghan MA. An update on the pharmacological management of autoimmune hepatitis. Expert Opin Pharmacother 2021; 22:1475-1488. [PMID: 33624559 DOI: 10.1080/14656566.2021.1895747] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Introduction: Autoimmune hepatitis (AIH) is an immune mediated, inflammatory disease affecting the liver as a result of environmental triggers in susceptible individuals leading to loss of self-tolerance. The immunopathogenesis of AIH is not fully understood, which limits targeted therapeutic options.Areas covered: In this review, the authors provide an overview of current practice in the management of AIH, which include induction therapy with corticosteroids (± thiopurines), followed by maintenance therapy. Lack of early response to treatment may serve as a predictor of those at risk of requiring treatment escalation to second- and third-line agents such as mycophenolate mofetil (MMF), calcineurin inhibitors or biologics. Evidence for third-line agents from small retrospective studies or individual centers are reviewed. The nuances of AIH treatment in pregnancy, overlap syndromes, and drug induced liver injury (DILI) warrant further consideration.Expert opinion: Augmenting the balance of regulatory T cells (Treg) and effector T cells is an appealing therapeutic target with a multitude of agents in development. Many of the challenges in AIH research are due to its rarity and lack of randomized data. Management of AIH should strive towards individualized care through risk stratification and use of the best therapeutic modality for each patient.
Collapse
Affiliation(s)
- Yooyun Chung
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom
| | - Mussarat N Rahim
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom
| | - Jonathon J Graham
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom
| | - Yoh Zen
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom
| | - Michael A Heneghan
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom
| |
Collapse
|
|
11
|
Roberts SK, Strasser SI, Nicoll AJ, Kemp W, Majeed A, Mitchell J, Stuart K, Gow P, Sood S, MacQuillan G, George J, Mitchell J, McCaughan GW. Efficacy and safety profile of calcineurin inhibitor salvage therapy in autoimmune hepatitis. Scand J Gastroenterol 2020; 55:1309-1317. [PMID: 33070650 DOI: 10.1080/00365521.2020.1821764] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND As data is limited on the outcomes of calcineurin inhibitors (CNI) in autoimmune hepatitis (AIH), we evaluated the efficacy and safety of CNI in AIH patients who failed prior treatment(s). METHODS A retrospective study was performed of AIH patients who received cyclosporine A (CsA) and/or tacrolimus (TAC) after prior treatment(s) failure. Records were reviewed for baseline demographic and clinical characteristics, and treatment outcomes. The primary outcome was biochemical remission. UNLABELLED Results: Thirty-three AIH patients received CNI across seven liver centers:17 received CsA, 21 TAC and 5 TAC after CsA failure/intolerance. 82% received CNI for an insufficient response to treatment(s). Overall, 48% of CNI treated patients achieved biochemical remission including 41% in prior non-responders and 83% in treatment intolerant patients. Remission rates with CNI as second-line and third-line therapy were 63% and 29% respectively. There were no baseline predictors of response to CNI on multivariate analysis. Eighteen (55%) patients developed significant side effects and 8 (24%) discontinued due to intolerance. Three patients required liver transplantation for decompensated cirrhosis and 6 patients died including one from malignancy possibly related to CNI. CONCLUSION CNI salvage therapy is well tolerated and moderately effective achieving remission in around 50% of AIH who failed standard therapy.
Collapse
Affiliation(s)
- Stuart K Roberts
- The Alfred Hospital, Melbourne, Australia.,Monash University, Melbourne, Australia
| | - Simone I Strasser
- Royal Prince Alfred Hospital, Sydney, Australia.,University of Sydney, Sydney, Australia
| | - Amanda J Nicoll
- Monash University, Melbourne, Australia.,Eastern Health, Melbourne, Australia
| | - William Kemp
- The Alfred Hospital, Melbourne, Australia.,Monash University, Melbourne, Australia
| | - Ammar Majeed
- The Alfred Hospital, Melbourne, Australia.,Monash University, Melbourne, Australia
| | | | | | - Paul Gow
- Austin Hospital, Melbourne, Australia
| | | | | | - Jacob George
- University of Sydney, Sydney, Australia.,Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital, Sydney, Australia
| | | | - Geoffrey W McCaughan
- Royal Prince Alfred Hospital, Sydney, Australia.,Centenary Research Institute, Sydney, Australia
| | | |
Collapse
|
|
12
|
Abdollahi M, Ekrami NK, Ghojazadeh M, Boezen HM, Somi M, Alizadeh BZ. Tacrolimus and mycophenolate mofetil as second-line treatment in autoimmune hepatitis: Is the evidence of sufficient quality to develop recommendations? World J Gastroenterol 2020; 26:5896-5910. [PMID: 33132643 PMCID: PMC7579758 DOI: 10.3748/wjg.v26.i38.5896] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 08/11/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The standard management of autoimmune hepatitis (AIH) is based on corticosteroids, alone or in combination with azathioprine. Second-line treatments are needed for patients who have refractory disease. However, high-quality data on the alternative management of AIH are scarce.
AIM To evaluate the efficacy and safety of tacrolimus and mycophenolate mofetil (MMF) and the quality of evidence by using the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE).
METHODS A systematic review and meta-analysis of the available data were performed. We calculated pooled event rates for three outcome measures: Biochemical remission, adverse events, and mortality, with their corresponding 95% confidence intervals (CI).
RESULTS The pooled biochemical remission rate was 68.9% (95%CI: 60.4-76.2) for tacrolimus, and 59.6% (95%CI: 54.8-64.2) for MMF, and rates of adverse events were 25.5% (95%CI: 12.4-45.3) for tacrolimus and 24.1% (95%CI: 15.4-35.7) for MMF. The pooled mortality rate was estimated at 11.5% (95%CI: 7.1-18.1) for tacrolimus and 9.01% (95%CI: 6.2-12.8) for MMF. Pooled biochemical remission rates for tacrolimus and MMF in patients with intolerance to standard therapy were 56.6% (CI: 43.4-56.6) vs 73.5% (CI: 58.1-84.7), and among non-responders were 59.1% (CI: 48.7-68.8) vs 40.8% (CI: 32.3-50.0), respectively. Moreover, the overall quality assessments using GRADE proved to be very low for all our outcomes in both treatment groups.
CONCLUSION Tacrolimus and MMF are in practice considered effective for patients with AIH who are non-responders or intolerant to first-line treatment, but we found no high-quality evidence to support this statement.
Collapse
Affiliation(s)
| | | | - Morteza Ghojazadeh
- Research Center for Evidence Based Medicine, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran
| | - H Marike Boezen
- Department of Epidemiology, University of Groningen, Groningen 9700 RB, Netherlands
| | - Mohammadhossein Somi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran
| | - Behrooz Z Alizadeh
- Department of Epidemiology, University of Groningen, Groningen 9700 RB, Netherlands
| |
Collapse
|
|
13
|
Autoimmune Hepatitis in Children: Prednisone Plus Azathioprine Versus Cyclosporine: A Randomized Trial. J Pediatr Gastroenterol Nutr 2020; 71:376-380. [PMID: 32520828 DOI: 10.1097/mpg.0000000000002776] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE The aim of this study was to find the outcome and adverse effects of 2 initial treatments in children with autoimmune hepatitis, prednisone (PRED) plus azathioprine (AZA) versus cyclosporine (CsA). STUDY DESIGN Between December 2008 and February 2012, 50 consecutive patients were centrally randomized to 1 of 2 treatment arms. Group 1: PRED was indicated at a dose of 1 to 2 mg · kg · day (up to 60 mg/day) and AZA at a dose of 1 to 2 mg · kg · day. Group 2: CsA was administered at a dose of 4 mg · kg · day orally divided into 2 doses. After remission, all patients were given a combination of PRED at 0.3 to 0.5 mg · kg · day and AZA at 1 to 2 mg · kg · day. Children presenting liver failure were placed on a triple immunosuppressive regimen if this condition persisted after 1 week of treatment, after liver function normalization they were switched back to their initial scheme. RESULTS A total of 26 patients received PRED-AZA and 24 CsA. Both treatments showed similar initial results in effectiveness and safety, although remission was achieved earlier with PRED-AZA: 8.6 versus CsA: 13.6 weeks (P < 0.0081). All children recovered liver function in a mean time of 32 ± 26 days. Cushingoid syndrome was more frequently observed with PRED-AZA (P < 0.001) and gingival hypertrophy with CsA (P < 0.001). A significant increase in body mass index was observed in all patients from initial treatment to remission, being greater with PRED-AZA. CONCLUSIONS Similar outcomes were obtained with PRED plus AZA or CsA treatments. Either therapeutic strategy could be used according to the particular characteristics of each patient. Triple immunosuppression was beneficial in patients with liver failure at onset.
Collapse
|
|
14
|
Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, Vierling JM, Alsawas M, Murad MH, Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology 2020; 72:671-722. [PMID: 31863477 DOI: 10.1002/hep.31065] [Citation(s) in RCA: 548] [Impact Index Per Article: 109.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Cara L Mack
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - David Adams
- Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - David N Assis
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT
| | - Nanda Kerkar
- Golisano Children's Hospital at Strong, University of Rochester Medical Center, New York, NY
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marlyn J Mayo
- Division of Digestive and Liver Diseases, University of Texas SW Medical Center, Dallas, TX
| | - John M Vierling
- Medicine and Surgery, Baylor College of Medicine, Houston, TX
| | | | - Mohammad H Murad
- Mayo Knowledge and Encounter Research Unit, Mayo Clinic College of Medicine, Rochester, MN
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
| |
Collapse
|
|
15
|
Abstract
OBJECTIVE Therapy for autoimmune hepatitis (AIH) consists of steroid induction therapy, followed by maintenance therapy with azathioprine. However, up to 20% of patients experience either insufficient response or intolerance on first-line therapy. Calcineurin inhibitors (CNIs) are frequently used when first-line therapy fails. Although a number of studies report on efficacy, less is known on the patient trajectory before switch to CNIs. Our aim was to describe the road toward CNI therapy in AIH patients. METHODS Patients with an AIH diagnosis who used CNIs as either second- or third-line treatment were included in the study. Reason for switch to CNI was assessed as either an insufficient response or intolerance to prior therapy. Efficacy was assessed by normalization of transaminases at last moment of follow-up. RESULTS Final analysis included 20 patients who were treated with CNIs. Ten patients were treated with tacrolimus and ten patients received cyclosporine. In patients who used CNI treatment as third-line therapy (n = 13), duration of first-line therapy was almost twice as long as duration of second-line therapy (2.58 years vs. 1.33 years; P = 0.67). Patients treated with tacrolimus had relatively high trough levels (7.6 ng/mL) and more (minor) adverse events. Fifty-five percent of patients had normalization of transaminases at last moment of follow-up. CONCLUSION CNI treatment in AIH as second- or third-line therapy is effective in ~50% of patients. The trajectory before switch varies considerably between patients.
Collapse
|
|
16
|
Than NN, Hodson J, Schmidt-Martin D, Taubert R, Wawman RE, Botter M, Gautam N, Bock K, Jones R, Appanna GD, Godkin A, Montano-Loza AJ, Lammert F, Schramm C, Manns MP, Swain M, Burak KW, Adams DH, Hirschfield GM, Oo YH. Efficacy of rituximab in difficult-to-manage autoimmune hepatitis: Results from the International Autoimmune Hepatitis Group. JHEP Rep 2019; 1:437-445. [PMID: 32039395 PMCID: PMC7005655 DOI: 10.1016/j.jhepr.2019.10.005] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 10/21/2019] [Accepted: 10/25/2019] [Indexed: 02/07/2023] Open
Abstract
Treatment options remain limited for patients with autoimmune hepatitis (AIH), while there are still concerns over the consequences of long-term corticosteroid use. A few studies have suggested a role for B cell-driven autoimmune liver injury in AIH. This multicentre, international retrospective cohort study from the International Autoimmune Hepatitis Group aims to evaluate the clinical efficacy and safety of rituximab in difficult-to-manage AIH. METHODS Clinical data from 22 patients who received rituximab between 2007 and 2017 were collected from centres in the United Kingdom, Germany and Canada. Clinical response was assessed using changes in biochemical and immunological parameters up to 24 months post-rituximab infusion. In addition, we compared the doses of prednisolone used 3 months before and 12 months after treatment, and assessed freedom from AIH flares over the post-treatment period. RESULTS Twenty-two patients with type-1 AIH were included, with a median age of 40 years at diagnosis (range 19-79); 15/22 (68%) were female and 18/22 (82%) were Caucasian. The median period from diagnosis to the end of follow-up in these patients was 11 years (range 3-28). Values of alanine aminotransferase, aspartate aminotransferase and albumin improved significantly following rituximab therapy, and were sustained for up to 2 years (all p ≪0.001). Prednisolone doses were significantly reduced by 12 months post-treatment (p = 0.003), with 13/21 (62%) patients having a dose reduction. Over a median post-treatment follow-up period of 6 years (range 1-10), 5 patients developed AIH flares at a median of 22 months post-treatment, giving an estimated 71% freedom from AIH flare at 2 years. Four of these patients received a second course of treatment, of whom 2 had subsequent further flares. No serious adverse events attributable to rituximab were recorded. CONCLUSION In patients with difficult-to-manage AIH, rituximab appears to be clinically effective and well tolerated. Rituximab was associated with sustained improvements in serum liver tests, an absence of clinical disease flares, and a reduction in prednisolone dose. Controlled trials are warranted to further evaluate B cell-targeting therapies in patients with AIH. LAY SUMMARY Autoimmune hepatitis is an autoimmune condition of the liver, usually treated with medications that suppress the immune system, such as steroids. However, some patients do not respond to this treatment. We analysed the safety and efficacy of rituximab in patients who were not responding to first- or second-line therapies. Rituximab was safe and improved liver blood tests in 70% of patients over a 2-year follow-up period, while enabling steroid doses to be reduced in two-thirds of patients, which is a very positive clinical outcome.
Collapse
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
| |
Collapse
|
|
17
|
Abstract
Autoreactive B cells can promote autoimmunity through antigen presentation to autoreactive T cells, production of autoantibodies, generation of cytokines promoting T cell activation and differentiation, and inhibition of regulatory T cells and B cells. Here, the authors highlight studies pertaining to B cell mechanisms associated with disease pathogenesis and outcomes in autoimmune hepatitis and the immune-mediated cholangiopathies (primary biliary cholangitis, primary sclerosing cholangitis, and biliary atresia). The vast majority of investigations focus on autoantibodies and future research endeavors should include deciphering the role of the B cell in T cell activation (through antigen presentation, cytokine/chemokine production, and inhibition of regulation). Targeting B cell mechanisms in the treatment of autoimmune liver diseases is also highlighted.
Collapse
Affiliation(s)
- Sarah A. Taylor
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - David N. Assis
- Section of Digestive Diseases, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Cara L. Mack
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Digestive Health Institute, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado
| |
Collapse
|
|
18
|
Doycheva I, Watt KD, Gulamhusein AF. Autoimmune hepatitis: Current and future therapeutic options. Liver Int 2019; 39:1002-1013. [PMID: 30716203 DOI: 10.1111/liv.14062] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 01/13/2019] [Accepted: 01/17/2019] [Indexed: 02/13/2023]
Abstract
Autoimmune hepatitis (AIH) is a rare immune-mediated liver disease with few major advances in treatment options over the last several decades. Available options are effective in most patients albeit are imprecise in their mechanisms. Novel and more tolerable induction regimens and alternative options for management of patients intolerant or with suboptimal response to traditional therapies including in the post-transplant setting remain an important unmet need. This review aims to summarize recent data on pharmacological options and investigational drugs in development for patients with AIH. Standard therapy using prednisone with or without azathioprine remains the mainstay of therapy and is effective in most patients. Budesonide may be considered for induction in early disease and in those with mild fibrosis, but has not been approved for maintenance therapy. Mycophenolate mofetil (MMF) in combination with steroids might be an alternative first-line therapy, but results from a randomized trial are awaited. MMF as a second-line maintenance agent has moderate efficacy though more frequent adverse events in patients with cirrhosis may be seen. Tacrolimus may be an equally effective second-line option particularly in non-responders, but data remain limited. Management of recurrent AIH post-liver transplantation remains controversial with insufficient data to support long-term steroid use. Moving forward, expanding the scope of therapeutic options to include biologics including B-cell depleting agents may be a promising step. Recent insights in understanding the pathogenesis of AIH could serve as a basis for future therapies, including the elucidation of different immunoregulatory pathways and the potential role of the intestinal microbiome.
Collapse
Affiliation(s)
- Iliana Doycheva
- Division of Gastroenterology and Hepatology, Medical University, Sofia, Bulgaria
| | - Kymberly D Watt
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Aliya F Gulamhusein
- Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University Health Network, Toronto, ON, Canada
| |
Collapse
|
|
19
|
Giannakopoulos G, Verbaan H, Friis-Liby IL, Sangfelt P, Nyhlin N, Almer S. Mycophenolate mofetil treatment in patients with autoimmune hepatitis failing standard therapy with prednisolone and azathioprine. Dig Liver Dis 2019; 51:253-257. [PMID: 30389427 DOI: 10.1016/j.dld.2018.10.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 09/19/2018] [Accepted: 10/03/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Data on rescue treatment of autoimmune hepatitis in patients that fail standard treatment are sparse. AIMS To report our long-term experience with mycophenolate mofetil. METHODS Retrospective study in 22 patients with autoimmune hepatitis who failed azathioprine and prednisolone due to adverse events (n = 14, 64%), lack of remission (n = 5, 23%) or a combination (n = 3, 13%). RESULTS Mycophenolate mofetil was started at a dose of 20 mg/kg/day and increased to a maximum of 3 g/day. Follow-up was 0-6 months in 7 patients; more than 12 months in 15 (68%) and more than 24 months in 10. Normal aminotransferase levels were obtained (n = 3) or maintained (n = 7) in 10 patients (45%) after three to 30 weeks. 12 patients (55%) were withdrawn during the first 6 months, due to adverse events. Three patients were switched to cyclosporine and one underwent liver transplantation. Successful treatment with mycophenolate mofetil continued in 10 patients (45%) for a median of 71 months (range 20-124). Of these, one stopped prednisolone, five have a prednisolone dose <5 mg daily and four patients 5-10 mg. CONCLUSION Approximately one of two patients with autoimmune hepatitis that fail standard treatment benefit from long-term maintenance with mycophenolate mofetil, especially those with previous intolerance to thiopurines, where mycophenolate mofetil is effective in two thirds.
Collapse
Affiliation(s)
- Georgios Giannakopoulos
- Division of Gastroenterology, Department of Gastroenterology, Dermatology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - Hans Verbaan
- Department of Medicine, Skåne University Hospital, Malmö, Sweden
| | | | - Per Sangfelt
- Department of Medicine, Akademiska Hospital, Uppsala, Sweden
| | - Nils Nyhlin
- Department of Medicine, Örebro University Hospital, Örebro, Sweden
| | - Sven Almer
- Division of Gastroenterology, Department of Gastroenterology, Dermatology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
| | | |
Collapse
|
|
20
|
Hanouneh M, Ritchie MM, Ascha M, Ascha MS, Chedid A, Sanguankeo A, Zein NN, Hanouneh IA. A review of the utility of tacrolimus in the management of adults with autoimmune hepatitis. Scand J Gastroenterol 2019; 54:76-80. [PMID: 30650311 DOI: 10.1080/00365521.2018.1551498] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND There is paucity of data on alternative drug therapies for patients with autoimmune hepatitis (AIH). Tacrolimus (TAC) is a promising salvage agent. We present a review of TAC therapy in AIH patients. METHODS A search for studies with keywords 'autoimmune hepatitis' and 'tacrolimus' was performed. Reviews, studies of AIH post-transplant and AIH in children were excluded. Diagnosis of AIH was based on criteria established by the International Autoimmune Hepatitis Group. Complete biochemical response was defined as normalisation of aspartate aminotransferase (AST <45) and alanine aminotransferase (ALT <50). No biochemical response was defined as failure to return to normalisation at the end of follow-up. Demographic information and details of pre- and post-treatment liver biopsy were collected. RESULTS Seven articles achieved the inclusion criteria and reported data for a total of 162 adult patients. The majority of studies reported average ages approximately 35 years old. Treatment duration ranged from 1 to 136 months. Indications for therapy were mostly AIH refractory to steroid treatment or inability to tolerate standard steroid treatment. Eighty-three patients (51.2%) were reported to have pre-therapy liver biopsy. Of 49 patients for whom stage was reported, 6 patients were stage 1, 16 were stage 2, 14 were stage 3 and 13 were stage 4. Of 40 patients for whom grade was reported, 1 patient was grade 0, 3 were grade 1, 9 were grade 2, 14 were grade 3 and 13 were grade 4. Dosing regimens were between 1 and 8 mg/day. Target trough TAC serum concentrations ranged from 0.5 to 10.7 ng/mL TAC was discontinued in 28 (17.3%) patients for various reasons. Renal function remained stable in most patients. One hundred and twenty-one patients (74.7%) demonstrated complete biochemical response to treatment. Post-therapy liver biopsy was obtained for 30 (18.5%) patients, and 25 (15.4%) of these patients were noted to have histological remission according to the grade of inflammation or stage of fibrosis. CONCLUSION TAC is relatively effective in the treatment of AIH refractory to traditional therapy. It appears that liver function can be enhanced at a minimal cost to renal function. Key Points There is a cohort of patients with autoimmune hepatitis (AIH) who do not respond to standard therapy. Alternative treatment options for these patients have been explored, but outcomes have not been comprehensively examined. We report the use and efficacy of tacrolimus (TAC) in patients with AIH. We found that TAC can be safely and effectively used in patients with AIH with minimal side effects. TAC can be a potential treatment option for patients with AIH refractory to standard therapy.
Collapse
Affiliation(s)
- Mohamad Hanouneh
- a Department of Internal Medicine, Division of Nephrology , Johns Hopkins University Hospital , Baltimore , MD, USA
| | | | - Mona Ascha
- c School of Medicine , Case Western Reserve University , Cleveland , OH, USA
| | - Mustafa S Ascha
- d Center for Clinical Investigation, Department of Epidemiology and Biostatistics , Case Western Reserve University , Cleveland , OH, USA
| | - Alice Chedid
- a Department of Internal Medicine, Division of Nephrology , Johns Hopkins University Hospital , Baltimore , MD, USA
| | - Anawin Sanguankeo
- a Department of Internal Medicine, Division of Nephrology , Johns Hopkins University Hospital , Baltimore , MD, USA
| | - Nizar N Zein
- e Department of Gastroenterology and Hepatology , Digestive Disease Institute, Cleveland Clinic , Cleveland , OH, USA
| | - Ibrahim A Hanouneh
- b Abbott Northwestern Hospital , Minneapolis , MN, USA.,f Minnesota Gastroenterology , Minneapolis , MN, USA
| |
Collapse
|
|
21
|
Abstract
BACKGROUND Azathioprine (AZA) is the mainstay of maintenance therapy in pediatric autoimmune hepatitis (AIH). The use of thiopurines metabolites to individualize therapy and avoid toxicity has not, however, been clearly defined. METHODS Retrospective analysis of children ≤18 years diagnosed with AIH between January 2001 and 2016. Standard definitions were used for treatment response and disease flare. Thiopurine metabolite levels were correlated with the corresponding liver function test. RESULTS A total of 56 children (32 girls) were diagnosed with AIH at a median age of 11 years (interquartile range [IQR] 9). No difference in 6-thioguanine-nucleotide (6-TG) levels (271[IQR 251] pmol/8 × 10 red blood cell vs 224 [IQR 147] pmol/8 × 10 red blood cell, P = 0.06) was observed in children in remission when compared with those who were not in remission. No correlation was observed between the 6-TG and alanine aminotransferase levels (r = -0.179, P = 0.109) or between 6-methyl-mercaptopurine (6-MMP) and alanine aminotransferase levels (r = 0.139, P = 0.213). The 6-MMP/6-TG ratio was significantly lower in patients who were in remission (2[7] vs 5 (10), P = 0.04). Using a quartile analysis, we found that having a ratio of <4 was significantly associated with being in remission with OR 2.50 (95% confidence interval 1.02-6.10), P = 0.047. Use of allopurinol with low-dose AZA in 6 children with preferential 6-MMP production brought about remission in 5/6 (83.3%). CONCLUSIONS Thiopurine metabolite levels should be measured in patients with AIH who have experienced a loss of remission. A 6-MMP/6-TG ratio of <4 with the addition of allopurinol could be considered in these patients.
Collapse
|
|
22
|
Bao J, Gao S, Weng Y, Zhu J, Ye H, Zhang X. Clinical efficacy of tacrolimus for treating myasthenia gravis and its influence on lymphocyte subsets. Rev Neurol (Paris) 2018; 175:65-72. [PMID: 30293884 DOI: 10.1016/j.neurol.2018.01.377] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 12/26/2017] [Accepted: 01/22/2018] [Indexed: 01/01/2023]
Abstract
BACKGROUND This study aimed to determine the clinical efficacy and effects of tacrolimus in treating myasthenia gravis (MG). METHODS A total of 45 outpatients and inpatients were divided into a tacrolimus group (n=15) and non-tacrolimus group (n=30): those in the former group were treated with 3mg/day of tacrolimus for 24 weeks, while those in the latter (control) group took other immunosuppressants (prednisone, azathioprine combined with prednisone). Each group was evaluated at weeks 4, 8, 12, 16, 20 and 24 by Myasthenia Gravis Foundation of America Quantitative Myasthenia Gravis (MGFA-QMG) Test, activities of daily living (ADL) profiles, and manual muscle (MMT) and fatigue tests. Dynamic changes in CD4+CD25+high cells were tested by flow cytometry. Inflammatory cytokines were also evaluated in the tacrolimus group. RESULTS Efficacy index scores decreased significantly compared with baseline at every test week in both groups (P<0.01), although improvements were more evident with than without tacrolimus treatment (F=9.312, P<0.01 vs. F=24.551, P<0.01 and F=10.710, P<0.01). At week 24, peripheral blood CD4+CD25+high T cells with tacrolimus decreased significantly (P<0.01), but increased significantly without tacrolimus (P<0.01). During treatment, CD19+BAFF-R B cells in peripheral blood decreased in both groups (P<0.05). Interferon (IFN)-γ concentrations in peripheral blood also diminished significantly with tacrolimus (P<0.01). CONCLUSION A relatively low dose of tacrolimus can affect multiple immune-system targets and, thus, can treat MG effectively in terms of both clinical symptoms and immunological responses.
Collapse
Affiliation(s)
- J Bao
- Department of Neurology, the First Affiliated Hospital of Wenzhou Medical College, 325000 Wenzhou, China
| | - S Gao
- Department of Hematology, the First Affiliated Hospital of Wenzhou Medical College, 325000 Wenzhou, China
| | - Y Weng
- Department of Neurology, the First Affiliated Hospital of Wenzhou Medical College, 325000 Wenzhou, China
| | - J Zhu
- Department of Mental Health, the First Affiliated Hospital of Wenzhou Medical College, 325000 Wenzhou, China
| | - H Ye
- Neuroimmune Laboratory, the First Affiliated Hospital of Wenzhou Medical College, 325000 Wenzhou, China
| | - X Zhang
- Department of Neurology, the First Affiliated Hospital of Wenzhou Medical College, 325000 Wenzhou, China.
| |
Collapse
|
|
23
|
Bossen L, Gerussi A, Lygoura V, Mells GF, Carbone M, Invernizzi P. Support of precision medicine through risk-stratification in autoimmune liver diseases – histology, scoring systems, and non-invasive markers. Autoimmun Rev 2018; 17:854-865. [DOI: 10.1016/j.autrev.2018.02.013] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 02/26/2018] [Indexed: 02/07/2023]
|
|
24
|
de Boer YS, Liberal R, Heneghan MA. Letter: tacrolimus may be hazardous in decompensated autoimmune liver disease with hyperbilirubinemia-authors' reply. Aliment Pharmacol Ther 2018; 47:1568-1569. [PMID: 29878432 DOI: 10.1111/apt.14651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Affiliation(s)
- Y S de Boer
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - R Liberal
- Institute of Liver Studies, King's College Hospital, London, UK
| | - M A Heneghan
- Institute of Liver Studies, King's College Hospital, London, UK
| |
Collapse
|
|
25
|
A systematic review and meta-analysis of second-line immunosuppressants for autoimmune hepatitis treatment. Eur J Gastroenterol Hepatol 2018; 30:212-216. [PMID: 29227329 DOI: 10.1097/meg.0000000000001019] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
INTRODUCTION The gold-standard treatment for autoimmune hepatitis (AIH) is a prednisone/azathioprine combination. However, subgroups of patients may be unresponsive to this treatment. The aim of this study is to evaluate the efficacy of second-line immunosuppressive therapies for AIH through a systematic review and meta-analysis in adult patients. PATIENTS AND METHODS The systematic review was registered at the PROSPERO platform under number 42015019831. Databases MEDLINE (PubMed), Lilacs, Cochrane, and Scielo were searched. The keywords used were 'Hepatitis, Autoimmune' and descriptors terms (MeSH and DeCS). These terms were linked with each immunosuppressant of interest. RESULTS A total of 1532 studies were identified. Of these, 1492 were excluded on the basis of title and abstract reading. Among the 40 studies retrieved for detailed full-text analysis, a total of 15 fulfilled the inclusion criteria for the analysis. The most studied second-line immunosuppressive was mycophenolate mofetil (MM). The mean reduction of aminotransferases was observed in 94.3% with tacrolimus/prednisone, 91.3% for cyclosporine/prednisone, 85.5% for budesonide, and 78.7% MM/prednisone. For MM/prednisone, the mean rate of histological remission was 88.6%, liver transplantation was indicated in 11.4%, and the mortality rate was 7.2%. Limitations were also present, such as the lack of randomized-controlled trials and prospective studies, the small number of patients, and the heterogeneity between remission criteria. CONCLUSION This is the first systematic review and meta-analysis to compare the second-line imunossupressant therapy for AIH. The most studied second-line immunosuppressive is the MM, with a reasonable histological remission. The use of combined tacrolimus/prednisone was the most effective for the normalization of aminotransferases.
Collapse
|
|
26
|
[Autoimmune hepatitis in the pediatric age]. BOLETIN MEDICO DEL HOSPITAL INFANTIL DE MEXICO 2018; 74:324-333. [PMID: 29382475 DOI: 10.1016/j.bmhimx.2017.05.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 04/25/2017] [Accepted: 05/11/2017] [Indexed: 11/23/2022] Open
Abstract
In pediatrics, autoimmune hepatitis and sclerosing cholangitis are liver disorders with an immunological damage mechanism. Autoimmune hepatitis is a disease of unknown etiology characterized by interface hepatitis, hypergammaglobulinemia, circulating autoantibodies and a favorable response to immunosuppression. It is an eminently pediatric disease with a prevalent condition in young women. Therapy should be instituted promptly to prevent rapid deterioration, promote remission of disease and long-term survival. The persistent lack of response or lack of adherence to treatment results in terminal liver failure; these patients, and those with fulminant hepatic insufficiency at the time of diagnosis, will require liver transplantation.
Collapse
|
|
27
|
Efe C, Hagström H, Ytting H, Bhanji RA, Müller NF, Wang Q, Purnak T, Muratori L, Werner M, Marschall HU, Muratori P, Gunşar F, Klintman D, Parés A, Heurgué-Berlot A, Schiano TD, Cengiz M, May-Sien Tana M, Ma X, Montano-Loza AJ, Berg T, Verma S, Larsen FS, Ozaslan E, Heneghan MA, Yoshida EM, Wahlin S. Efficacy and Safety of Mycophenolate Mofetil and Tacrolimus as Second-line Therapy for Patients With Autoimmune Hepatitis. Clin Gastroenterol Hepatol 2017; 15:1950-1956.e1. [PMID: 28603052 DOI: 10.1016/j.cgh.2017.06.001] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 05/24/2017] [Accepted: 06/02/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Predniso(lo)ne, alone or in combination with azathioprine, is the standard-of-care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH. METHODS We performed a retrospective study of data (from 19 centers in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6-190 mo). Patients were categorized according to their response to SOC. Patients in group 1 (n = 108) had a complete response to the SOC, but were switched to second-line therapy as a result of side effects of predniso(lo)ne or azathioprine, whereas patients in group 2 (n = 93) had not responded to SOC. RESULTS There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P = .639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P = .682). Significantly more group 2 patients given tacrolimus compared with MMF had a complete response (56.5% vs 34%, respectively; P = .029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P = .472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal. CONCLUSIONS Long-term therapy with MMF or tacrolimus generally was well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous nonresponder patients compared with MMF.
Collapse
Affiliation(s)
- Cumali Efe
- Department of Gastroenterology, Hacettepe University, Ankara, Turkey.
| | - Hannes Hagström
- Hepatology Division, Centre for Digestive Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Henriette Ytting
- Department of Hepatology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Rahima A Bhanji
- Division of Gastroenterology and Liver Unit, University of Alberta, Alberta, Canada
| | - Niklas F Müller
- Sektion Hepatologie, Klinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig, Germany
| | - Qixia Wang
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Tugrul Purnak
- Department of Gastroenterology, Hacettepe University, Ankara, Turkey
| | - Luigi Muratori
- Centro per lo Studio e la Cura delle Malattie Autoimmuni del Fegato e delle Vie Biliari, Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum, Università di Bologna, Bologna, Italy
| | - Mårten Werner
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Paolo Muratori
- Centro per lo Studio e la Cura delle Malattie Autoimmuni del Fegato e delle Vie Biliari, Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum, Università di Bologna, Bologna, Italy
| | - Fulya Gunşar
- Department of Gastroenterology, Ege University, Bornova, Izmir, Turkey
| | - Daniel Klintman
- Department of Molecular and Clinical Medicine, Skåne University Hospital, Lund, Sweden; Division of Gastroenterology University of British Columbia, Vancouver General Hospital, Vancouver, Canada
| | - Albert Parés
- Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | | | - Thomas D Schiano
- Division of Liver Diseases, The Mount Sinai Medical Center, New York, New York
| | - Mustafa Cengiz
- Department of Gastroenterology, Dr A.Y. Oncology Training and Research Hospital, Ankara, Turkey
| | - Michele May-Sien Tana
- The Liver Center at University of California, San Francisco, Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, California
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Alberta, Canada
| | - Thomas Berg
- Sektion Hepatologie, Klinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig, Germany
| | - Sumita Verma
- Department of Medicine, Brighton and Sussex Medical School, Department of Gastroenterology and Hepatology, Brighton and Sussex University Hospital, Brighton, United Kingdom
| | - Fin Stolze Larsen
- Department of Hepatology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Ersan Ozaslan
- Department of Gastroenterology, Numune Research and Education Hospital, Ankara, Turkey
| | - Michael A Heneghan
- Institute of Liver Studies, King's College Hospital National Health Service Foundation Trust, London, United Kingdom
| | - Eric M Yoshida
- Division of Gastroenterology University of British Columbia, Vancouver General Hospital, Vancouver, Canada
| | - Staffan Wahlin
- Hepatology Division, Centre for Digestive Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| |
Collapse
|
|
28
|
Alashkar F, Föhring D, Dührsen U, Baba HA, Röth A. Cytopenia first - hepatitis second: an unusual sequence in aplastic anemia. Clin Case Rep 2017; 5:778-781. [PMID: 28588809 PMCID: PMC5458037 DOI: 10.1002/ccr3.917] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 01/06/2017] [Accepted: 02/28/2017] [Indexed: 11/25/2022] Open
Abstract
To the best of our knowledge, this is the first report of aplastic anemia (AA) preceding autoantibody‐negative autoimmune hepatitis (AIH) with successful treatment of both conditions with the same immunosuppressive regimen, resulting in hematopoietic reconstitution and remission of AIH.
Collapse
Affiliation(s)
- Ferras Alashkar
- Department of Hematology West German Cancer Centre University Hospital Essen University of Duisburg-Essen Essen Germany
| | - Daniel Föhring
- Department of Hematology West German Cancer Centre University Hospital Essen University of Duisburg-Essen Essen Germany
| | - Ulrich Dührsen
- Department of Hematology West German Cancer Centre University Hospital Essen University of Duisburg-Essen Essen Germany
| | - Hideo Andreas Baba
- Institute of Pathology University Hospital Essen University of Duisburg-Essen Essen Germany
| | - Alexander Röth
- Department of Hematology West German Cancer Centre University Hospital Essen University of Duisburg-Essen Essen Germany
| |
Collapse
|
|
29
|
Affiliation(s)
- Albert J. Czaja
- Professor Emeritus of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
| |
Collapse
|
|
30
|
Liberal R, de Boer YS, Andrade RJ, Bouma G, Dalekos GN, Floreani A, Gleeson D, Hirschfield GM, Invernizzi P, Lenzi M, Lohse AW, Macedo G, Milkiewicz P, Terziroli B, van Hoek B, Vierling JM, Heneghan MA. Expert clinical management of autoimmune hepatitis in the real world. Aliment Pharmacol Ther 2017; 45:723-732. [PMID: 28004405 DOI: 10.1111/apt.13907] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 10/12/2016] [Accepted: 11/27/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND High-quality data on the management of autoimmune hepatitis (AIH) are scarce. Despite published guidelines, management of AIH is still expert based rather than evidence based. AIM To survey expert hepatologists, asking each to describe their practices in the management of patients with AIH. METHODS A survey questionnaire was distributed to members of the International AIH Group. The questionnaire consisted of four clinical scenarios on different presentations of AIH. RESULTS Sixty surveys were sent, out of which 37 were returned. None reported budesonide as a first line induction agent for the acute presentation of AIH. Five (14%) participants reported using thiopurine S-methyltransferase measurements before commencement of thiopurine maintenance therapy. Thirteen (35%) routinely perform liver biopsy at 2 years of biochemical remission. If histological inflammatory activity is absent, four (11%) participants reduced azathioprine, whereas 10 (27%) attempted withdrawal altogether. Regarding the management of difficult-to-treat patients, mycophenolate mofetil is the most widely used second-line agent (n = ~450 in 28 centres), whereas tacrolimus (n = ~115 in 21 centres) and ciclosporin (n = ~112 in 18 centres) are less often reported. One centre reported considerable experience with infliximab, while rescue therapy with rituximab has been tried in seven centres. CONCLUSIONS There is a wide variation in the management of patients with autoimmune hepatitis even among the most expert in the field. Although good quality evidence is lacking, there is considerable experience with second-line therapies. Future prospective studies should address these issues, so that we move from an expert- to an evidence- and personalised-based care in autoimmune hepatitis.
Collapse
|
|
31
|
Joshi D, Gupta N, Samyn M, Deheragoda M, Dobbels F, Heneghan MA. The management of childhood liver diseases in adulthood. J Hepatol 2017; 66:631-644. [PMID: 27914924 DOI: 10.1016/j.jhep.2016.11.013] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 11/20/2016] [Accepted: 11/21/2016] [Indexed: 12/12/2022]
Abstract
An increasing number of patients with childhood liver disease survive into adulthood. These young adults are now entering adult services and require ongoing management. Aetiologies can be divided into liver diseases that develop in young adults which present to adult hepatologists i.e., biliary atresia and Alagille syndrome or liver diseases that occur in children/adolescents and adults i.e., autoimmune hepatitis or Wilson's disease. To successfully manage these young adults, a dynamic and responsive transition service is essential. In this review, we aim to describe the successful components of a transition service highlighting the importance of self-management support and a multi-disciplinary approach. We will also review some of the liver specific aetiologies which are unique to young adults, offering an update on pathogenesis, management and outcomes.
Collapse
Affiliation(s)
- Deepak Joshi
- Institute of Liver Studies, King's College Hospital, London, UK.
| | - Nitika Gupta
- Division of Paediatric Gastroenterology, Emory University School of Medicine, Atlanta, USA
| | - Marianne Samyn
- Institute of Liver Studies, King's College Hospital, London, UK
| | | | - Fabienne Dobbels
- Academic Centre for Nursing and Midwifery, Katholieke Universiteit Leuven, Belgium
| | | |
Collapse
|
|
32
|
Abstract
Autoimmune hepatitis (AIH) is a chronic progressive liver disease characterized by high levels of aminotransferases and autoantibodies, hypergammaglobulinemia, and interface hepatitis. AIH affects all races and all ages worldwide, regardless of sex, although a preponderance of females is a constant finding. The etiology of AIH has not been completely elucidated, but immunogenetic background and environmental parameters may contribute to its development. The most important genetic factor is human leukocyte antigens (HLAs), especially HLA-DR, whereas the role of environmental factors is not completely understood. Immunologically, disruption of the immune tolerance to autologous liver antigens may be a trigger of AIH. The diagnosis of classical AIH is fairly easy, though not without pitfalls. In contrast, the diagnosis of atypical AIH poses great challenges. There is confusion as to the definition of the disease entity and its boundaries in the diagnosis of overlap syndrome, drug-induced autoimmune hepatitis, and AIH with concomitant nonalcoholic fatty liver disease (NAFLD) or chronic hepatitis C. Centrilobular zonal necrosis is now included in the histological spectrum of AIH. However, the definition and the significance of AIH presenting with centrilobular zonal necrosis have not been examined extensively. In ~20% of AIH patients who are treated for the first time with standard therapy, remission is not achieved. The development of more effective and better tolerated novel therapies is an urgent need. In this review, we discuss the current challenges and the future prospects in relation to the diagnosis and treatment of AIH, which have been attracting considerable recent attention.
Collapse
Affiliation(s)
- Yoshio Aizawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University Katsushika Medical Center, Katsushika-ku, Tokyo, Japan
| | - Atsushi Hokari
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University Katsushika Medical Center, Katsushika-ku, Tokyo, Japan
| |
Collapse
|
|
33
|
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.
Collapse
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.
| |
Collapse
|
|
34
|
van Gerven NMF, de Boer YS, Mulder CJJ, van Nieuwkerk CMJ, Bouma G. Auto immune hepatitis. World J Gastroenterol 2016; 22:4651-4661. [PMID: 27217697 PMCID: PMC4870072 DOI: 10.3748/wjg.v22.i19.4651] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Revised: 03/29/2016] [Accepted: 04/20/2016] [Indexed: 02/06/2023] Open
Abstract
To provide an update of the latest trends in epidemiology, clinical course, diagnostics, complications and treatment of auto immune hepatitis (AIH). A search of the MEDLINE database was performed using the search terms: “auto immune hepatitis”, “clinical presentation”, “symptoms”, “signs”, “diagnosis”, “auto antibodies”, “laboratory values”, “serology”, “histopathology”, “histology”, “genetics”, “HLA genes”, “non-HLA genes”, “environment”, “epidemiology”, “prevalence”, “incidence”, “demographics”, “complications”, “HCC”, “PBC”, “PSC”, “corticosteroid”, “therapy”, “treatment”, “alternative treatment”. English-language full-text articles and abstracts were considered. Articles included reviews, meta-analysis, prospective retrospective studies. No publication date restrictions were applied. AIH is an immune meditated progressive inflammatory liver disease that predominantly affects middle-aged females but may affect people of all ages. The clinical spectrum of AIH is wide, ranging from absent or mild symptoms to fulminant hepatic failure. The aetiology of AIH is still unknown, but is believed to occur as the consequence of an aberrant immune response towards an un-known trigger in a genetically susceptible host. In the absence of a gold standard, diagnosis is based on the combination of clinical, biochemical and histopathological criteria. Immunosuppressive treatment has been the cornerstone of treatment since the earliest description of the disease in 1950 by Waldenström. Such treatment is often successful at inducing remission and generally leads to normal life expectancy. Nevertheless, there remain significant areas of unmet aetiological a clinical needs including fundamental insight in disease pathogenesis, optimal therapy, duration of treatment and treatment alternatives in those patients unresponsive to standard treatment regimens.
Collapse
|
|
35
|
Than NN, Wiegard C, Weiler-Normann C, Füssel K, Mann J, Hodson J, Hirschfield GM, Lohse AW, Adams DH, Schramm C, Oo YH. Long-term follow-up of patients with difficult to treat type 1 autoimmune hepatitis on Tacrolimus therapy. Scand J Gastroenterol 2016; 51:329-36. [PMID: 26458216 DOI: 10.3109/00365521.2015.1095351] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Autoimmune hepatitis (AIH) is an immune-mediated liver disease, which requires long-term immunosuppression. Ten to fifteen percent of patients experience insufficient/intolerance response to standard therapy. Although alternate immunosuppression has been applied, there is little long-term data reported on safety, efficacy, steroid-dose reduction and disease evolution in patients with difficult AIH who were on Tacrolimus therapy. MATERIALS AND METHODS Clinical, biochemical, immunological profiles, treatment response and side effects of 17 AIH patients treated with Tacrolimus between 2003 and 2014 were analyzed from two tertiary referral liver centers. RESULTS Tacrolimus was started on 16/17 (94%) patients due to insufficient response to standard therapy. The median duration of treatment was 24 months and patients were followed up for median of 60 months. Tacrolimus dosage was 2 mg/day (median). During first year of therapy, there was a significant improvement in immunoglobulin G and Aspartate transaminase level. 9/17 (52%) compliant and definite AIH patients remained on Tacrolimus at end of follow-up and prednisolone dose reduction was achieved from 10 to 5 mg. All patients are alive and one patient underwent liver transplantation. 4/17 (24%) patients developed overlap with primary sclerosing cholangitis over follow-up period. No significant side effects were observed with Tacrolimus therapy. CONCLUSION Tacrolimus could be used in compliant patients with difficult to treat AIH in experienced centers. Its use is safe and can improve liver biochemistry, IgG and reduce steroid requirement. However, due to the lack of immunomodulatory effect, unmet need for effective immune-regulatory therapies still remain for AIH patients.
Collapse
Affiliation(s)
- Nwe Ni Than
- a Liver Unit , University Hospital Birmingham NHS Trust , Birmingham , UK ;,b Centre for Liver Research and NIHR Biomedical Research Unit for Liver Disease, University of Birmingham , Birmingham , UK
| | - Christiane Wiegard
- c Department of Medicine , University Medical Center Hamburg-Eppendorf , Hamburg , Germany
| | | | - Katja Füssel
- c Department of Medicine , University Medical Center Hamburg-Eppendorf , Hamburg , Germany
| | - Jake Mann
- a Liver Unit , University Hospital Birmingham NHS Trust , Birmingham , UK
| | - James Hodson
- a Liver Unit , University Hospital Birmingham NHS Trust , Birmingham , UK
| | - Gideon M Hirschfield
- a Liver Unit , University Hospital Birmingham NHS Trust , Birmingham , UK ;,b Centre for Liver Research and NIHR Biomedical Research Unit for Liver Disease, University of Birmingham , Birmingham , UK
| | - Ansgar W Lohse
- c Department of Medicine , University Medical Center Hamburg-Eppendorf , Hamburg , Germany
| | - David H Adams
- a Liver Unit , University Hospital Birmingham NHS Trust , Birmingham , UK ;,b Centre for Liver Research and NIHR Biomedical Research Unit for Liver Disease, University of Birmingham , Birmingham , UK
| | - Christoph Schramm
- c Department of Medicine , University Medical Center Hamburg-Eppendorf , Hamburg , Germany
| | - Ye Htun Oo
- a Liver Unit , University Hospital Birmingham NHS Trust , Birmingham , UK ;,b Centre for Liver Research and NIHR Biomedical Research Unit for Liver Disease, University of Birmingham , Birmingham , UK
| |
Collapse
|
|
36
|
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: 101] [Impact Index Per Article: 11.2] [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.
Collapse
Affiliation(s)
- Albert J. Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN,
USA
| |
Collapse
|
|
37
|
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: 41] [Impact Index Per Article: 4.1] [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.
| |
Collapse
|
|
38
|
Kirstein MM, Metzler F, Geiger E, Heinrich E, Hallensleben M, Manns MP, Vogel A. Prediction of short- and long-term outcome in patients with autoimmune hepatitis. Hepatology 2015; 62:1524-35. [PMID: 26178791 DOI: 10.1002/hep.27983] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 07/09/2015] [Indexed: 12/22/2022]
Abstract
UNLABELLED Autoimmune hepatitis (AIH) is a chronic inflammatory disease characterized by a loss of tolerance toward the hepatocellular epithelium. Liver transplantation (LT) represents the ultimate therapeutic option for a fulminant course or end-stage liver disease. The aim of this study was to elucidate the clinical, serological, and genetic features of remission, relapse, and overall and LT-free survival. Between 2000 and 2014, 354 AIH patients from Hannover Medical School were included. Clinical, laboratory, and histological reports were analyzed. DRB1 allele analyses were performed in 264 AIH and 399 non-AIH patients. Cox's regression analysis was performed to identify factors significantly associated with survival. Patients diagnosed in childhood were at higher risk for relapses (P=0.003), requirement for LTs (P=0.014, log rank), and had a reduced life expectancy (P<0.001, log rank). Detection of soluble liver antigen/liver pancreas antigen (SLA/LP) antibodies was significantly associated with reduced overall and LT-free survival (P=0.037; P=0.021). Cirrhosis, which was evident in 25% at first diagnosis, was found to be a predictor of poor survival and requirement for LT (P=0.003; P=0.009). DRB1*04:01-positive phenotype was associated with a higher rate of complete remissions and with a lower frequency of cirrhosis and LTs. There were no significant differences for subsequent relapses or survival in patients achieving either partial or complete remission. CONCLUSION Diagnosis<18 years, histological cirrhosis at first diagnosis and SLA/LP antibodies are major risk factors for a poor short- and long-term outcome. These patients are in need of high surveillance. Separating patients with positive SLA/LP antibodies into a third group may be reconsidered. DRB1*04:01 positivity has been identified in association with a favorable clinical outcome.
Collapse
Affiliation(s)
- Martha M Kirstein
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
| | - Frauke Metzler
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
| | - Elena Geiger
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
| | - Eyk Heinrich
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
| | | | - Michael P Manns
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
| | - Arndt Vogel
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
| |
Collapse
|
|
39
|
Furumoto Y, Asano T, Sugita T, Abe H, Chuganji Y, Fujiki K, Sakata A, Aizawa Y. Evaluation of the role of HLA-DR antigens in Japanese type 1 autoimmune hepatitis. BMC Gastroenterol 2015; 15:144. [PMID: 26489422 PMCID: PMC4618735 DOI: 10.1186/s12876-015-0360-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2014] [Accepted: 10/01/2015] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The role of HLA-DR antigens in the clinicopathological features of autoimmune hepatitis (AIH) is not clearly understood. We examined the implications of HLA-DR antigens in Japanese AIH, including the effect of HLA-DR4 on the age and pattern of AIH onset, clinicopathological features, and treatment efficacy. METHODS A total of 132 AIH patients consecutively diagnosed and treated in 2000-2014 at 2 major hepatology centers of eastern Tokyo district were the subjects of this study. The frequency of HLA-DR phenotypes was compared with that in the healthy Japanese population. AIH patients were divided into HLA-DR4-positive or HLA-DR4-negative groups and further sub-classified into elderly and young-to-middle-aged groups, and differences in clinical and histological features were examined. Clinical features associated with the response to immunosuppressive therapy were also determined. RESULTS The frequency of the HLA-DR4 phenotype was significantly higher in AIH than in control subjects (59.7 % vs. 41.8 %, P < 0.001), and the relative risk was 2.14 (95 % CI; 1.51-3.04). HLA-DR4-positive AIH patients were younger than HLA-DR4-negative patients (P = 0.034). Serum IgG and IgM levels were higher (P < 0.001 and P = 0.007, respectively) in HLA-DR4-positive patients. These differences were more prominent in elderly AIH patients. However, there was no difference in IgG and IgM levels between HLA-DR4-positive and HLA-DR4-negative patients of the young-to-middle-aged group. There were no differences in the histological features. In patients with refractory to immunosuppressive therapy, higher total bilirubin, longer prothrombin time, lower serum albumin, and lower platelet count were found. Imaging revealed splenomegaly to be more frequent in refractory patients than in non-refractory patients (60.0 % vs. 30.8 %, P = 0.038). HLA-DR phenotype distribution was similar regardless of response to immunosuppressive therapy. CONCLUSIONS HLA-DR4 was the only DR antigen significantly associated with Japanese AIH. The clinical features of HLA-DR4-positive AIH differed between elderly patients and young-to-middle-aged patients. Treatment response depended on the severity of liver dysfunction but not on HLA-DR antigens.
Collapse
Affiliation(s)
- Yohei Furumoto
- Department of Internal Medicine, Tokyo Metropolitan Bokutoh Hospital, 4-23-15 Kotobashi, Sumida, Tokyo, Japan.
| | - Toru Asano
- Department of Internal Medicine, Tokyo Metropolitan Bokutoh Hospital, 4-23-15 Kotobashi, Sumida, Tokyo, Japan.
| | - Tomonori Sugita
- Department of Gastroenterology and Hepatology, the Jikei University School of Medicine Katsushika Medical Center, Tokyo, Japan.
| | - Hiroshi Abe
- Department of Gastroenterology and Hepatology, the Jikei University School of Medicine Katsushika Medical Center, Tokyo, Japan.
| | - Yoshimichi Chuganji
- Department of Internal Medicine, Tokyo Metropolitan Bokutoh Hospital, 4-23-15 Kotobashi, Sumida, Tokyo, Japan.
| | - Kazuhiko Fujiki
- Department of Internal Medicine, Tokyo Metropolitan Bokutoh Hospital, 4-23-15 Kotobashi, Sumida, Tokyo, Japan.
| | - Akihiko Sakata
- Department of Pathology, the Jikei University School of Medicine Katsushika Medical Center, Tokyo, Japan.
| | - Yoshio Aizawa
- Department of Gastroenterology and Hepatology, the Jikei University School of Medicine Katsushika Medical Center, Tokyo, Japan.
| |
Collapse
|
|
40
|
Affiliation(s)
-
- EASL office, 7 Rue Daubin, CH 1203 Geneva, Switzerland,
| |
Collapse
|
|
41
|
Ytting H, Larsen FS. Everolimus treatment for patients with autoimmune hepatitis and poor response to standard therapy and drug alternatives in use. Scand J Gastroenterol 2015; 50:1025-31. [PMID: 25862144 DOI: 10.3109/00365521.2014.998271] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Not all patients with autoimmune hepatitis (AIH) respond to standard medical therapy with corticosteroids and azathioprine. Such patients may develop end-stage liver disease with poor prognosis unless transplantation is considered. Alternatively, the introduction of new therapeutic strategies could potentially ameliorate deterioration of liver function. Patients in our tertiary center were selected for everolimus therapy when exhibiting nonresponse or intolerance to combinations of the standard and empirical drugs in use (e.g., mycophenolate mofetil, calcineurin inhibitors [CNIs]). We here report the efficacy of everolimus treatment of patients with AIH. MATERIALS AND METHODS Seven patients (six female, mean age 47 years, range 22-62 years) in whom disease control could not be achieved with standard therapy or the alternative drugs in use were included. RESULTS Treatment with everolimus induced a clear reduction of transaminases within 2 weeks. After 3-5 months three patients had normal alanine aminotransferase (ALT) levels (10-45 IU) and four patients had ALT levels below 55 IU compared to a three- to fivefold elevated level prior to everolimus treatment. Sustained remission after 1 year of treatment was observed in three patients; in another two patients ALT was 45-68 U/L. Four patients in remission after 3 years were rebiopsied. Two showed no histological progression, and in two the fibrosis had decreased. Side effects noted were myalgias and minor bacterial infections not leading to discontinuation of the drug. CONCLUSION Our experience indicates that everolimus may be of value in selected patients with therapy-resistant AIH and comorbidity/side effects that excludes the use of CNIs.
Collapse
Affiliation(s)
- Henriette Ytting
- Department of Hepatology A-2121, Rigshospitalet, University of Copenhagen , Copenhagen , Denmark
| | | |
Collapse
|
|
42
|
Corrigan M, Hirschfield GM, Oo YH, Adams DH. Autoimmune hepatitis: an approach to disease understanding and management. Br Med Bull 2015; 114:181-91. [PMID: 25995334 DOI: 10.1093/bmb/ldv021] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/15/2015] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Autoimmune hepatitis is a chronic immune-mediated liver injury, frequently associated with progression to end-stage liver disease if untreated. Patients commonly present with hepatitis, positive immune serology, elevated immunoglobulins and compatible liver histology, in the absence of an alternative aetiology. SOURCES OF DATA Data for this review were obtained using PubMed. AREAS OF AGREEMENT Disease usually responds to steroids and azathioprine, and appears to be a manifestation of autoimmune predisposition triggered in genetically susceptible individuals exposed to likely environmental challenges. We provide an up-to-date approach to disease understanding and management along with the clinical approach to diagnosis and current treatment suggestions. AREAS OF CONTROVERSY Controversies such as second line therapies and novel markers of disease activity are introduced. GROWING POINTS Increased understanding of the immunoregulatory mechanisms behind autoimmune hepatitis has led to opportunities for new therapies. These are developed including a discussion of timely research studies relevant to future therapies for patients.
Collapse
Affiliation(s)
- Margaret Corrigan
- NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - Gideon M Hirschfield
- NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - Ye H Oo
- NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - David H Adams
- NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK
| |
Collapse
|
|
43
|
|
|
44
|
Choi SI, Chung SH. Therapeutic Effects of 0.03% Tacrolimus Eye Drops for Chronic Ocular Graft-Versus-Host Disease. JOURNAL OF THE KOREAN OPHTHALMOLOGICAL SOCIETY 2015. [DOI: 10.3341/jkos.2015.56.10.1505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- Soon Il Choi
- Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - So Hyang Chung
- Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| |
Collapse
|
|
45
|
Chatrath H, Allen L, Boyer TD. Use of sirolimus in the treatment of refractory autoimmune hepatitis. Am J Med 2014; 127:1128-1131. [PMID: 24979741 DOI: 10.1016/j.amjmed.2014.06.016] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 06/06/2014] [Accepted: 06/07/2014] [Indexed: 12/31/2022]
Abstract
BACKGROUND Corticosteroids and azathioprine are widely accepted as the initial therapy for autoimmune hepatitis. However, the disease is refractory to steroids in about 10%-20% of patients, for whom currently there is no standardized treatment. Here we describe our experience with sirolimus in treatment of steroid refractory autoimmune hepatitis. METHODS This is a longitudinal follow-up study. Between November 2007 and January 2014, 5 subjects with steroid refractory autoimmune hepatitis were treated with sirolimus at our institution. RESULTS A response, defined as a sustained >50% fall in alanine aminotransferase (ALT) levels, was achieved in 4/5 patients. A complete response, sustained normalization of ALT levels, was achieved in 2/5 patients. The need for steroids was significantly reduced in all patients (P < .05). CONCLUSIONS In this small series, sirolimus appears to be useful in the treatment of patients with steroid refractory autoimmune hepatitis.
Collapse
Affiliation(s)
- Hemant Chatrath
- Department of Medicine and Liver Research Institute, University of Arizona College of Medicine, Tucson
| | - Larissa Allen
- Department of Medicine and Liver Research Institute, University of Arizona College of Medicine, Tucson
| | - Thomas D Boyer
- Department of Medicine and Liver Research Institute, University of Arizona College of Medicine, Tucson.
| |
Collapse
|
|
46
|
Role of mycophenolate mofetil for the treatment of autoimmune hepatitis-an observational study. J Clin Exp Hepatol 2014; 4:221-5. [PMID: 25755564 PMCID: PMC4284212 DOI: 10.1016/j.jceh.2014.05.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Accepted: 05/08/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Eighty percent (80%) of patients with Autoimmune hepatitis (AIH) respond to a combination of prednisolone and Azathioprine (AZA). Choice of treatment is limited for those who do not respond to this standard therapy. We evaluated the role of Mycophenolate mofetil (MMF) as a second line therapy in AIH. METHOD A retrospective observational study was carried out on all patients who received MMF for AIH. RESULTS Twenty out of 117 patients with AIH received MMF due to AZA intolerance (18 patients) or refractory disease (2 patients). Median age of the study patients was 56 (18-79) years, Male, n = 3 (15%) and Female, n = 18 (85%). After a median follow-up period of 47 (5-83) months, 14 (73.6%) patients were still on MMF with biochemical remission, including 4 out of 5 patients with cirrhosis. One patient was lost to follow-up. Three patients were intolerant of MMF due to adverse events, and two had disease refractory to MMF. Both these patients with refractory disease to MMF were initially unresponsive to AZA therapy. CONCLUSION MMF is a safe second line agent in patients with autoimmune hepatitis including those with cirrhosis.
Collapse
|
|
47
|
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).
Collapse
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 ;
| |
Collapse
|
|
48
|
Czaja AJ. Review article: The prevention and reversal of hepatic fibrosis in autoimmune hepatitis. Aliment Pharmacol Ther 2014; 39:385-406. [PMID: 24387318 DOI: 10.1111/apt.12592] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 11/29/2013] [Accepted: 12/05/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Immunosuppressive treatment of autoimmune hepatitis can prevent or reverse hepatic fibrosis, but these anti-fibrotic effects are inconsistent secondary gains. AIM To describe the anti-fibrotic effects of current therapies for autoimmune hepatitis, discuss the pathogenic mechanisms of hepatic fibrosis that might be targeted by anti-fibrotic interventions, indicate the non-invasive diagnostic tests of hepatic fibrosis that must be validated in autoimmune hepatitis and to suggest promising treatment opportunities. METHODS Studies cited in PubMed from 1972 to 2013 for autoimmune hepatitis, hepatic fibrosis, cirrhosis, anti-fibrotic therapy and non-invasive tests of hepatic fibrosis were selected. RESULTS Hepatic fibrosis improves in 53-57% of corticosteroid-treated patients with autoimmune hepatitis; progressive fibrosis slows or is prevented in 79%; and cirrhosis may be reversed. Progressive hepatic fibrosis is associated with liver inflammation, and the inability to fully suppress inflammatory activity within 12 months is associated with progression to cirrhosis (54%) and death or need for liver transplantation (15%). Liver tissue examination remains the gold standard for assessing hepatic fibrosis, but laboratory and radiological tests may be useful non-invasive methods to measure the fibrotic response. Severe liver inflammation can confound radiological assessments, and the preferred non-invasive test in autoimmune hepatitis is uncertain. Individualised treatment adjustments and adjunctive anti-fibrotic therapies are poised for study in this disease. CONCLUSIONS The prevention and reversal of hepatic fibrosis are achievable objectives in autoimmune hepatitis. Strategies that evaluate individualised therapies adjusted to the rapidity and completeness of the inflammatory response, and the use of adjunctive anti-fibrotic interventions, must be evaluated.
Collapse
Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| |
Collapse
|
|
49
|
Kapila N, Higa JT, Longhi MS, Robson SC. Autoimmune Hepatitis: Clinical Review with Insights into the Purinergic Mechanism of Disease. J Clin Transl Hepatol 2013; 1:79-86. [PMID: 26356124 PMCID: PMC4521285 DOI: 10.14218/jcth.2013.00015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Revised: 10/04/2013] [Accepted: 10/15/2013] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis (AIH) is an important disorder that predominantly results in inflammatory liver disease in genetically predisposed women. The clinicopathological picture is characterized by symptoms associated with both systemic inflammation and hepatic dysfunction, and with increased serum aminotransferases, elevated IgG, autoantibodies, and interface hepatitis on liver biopsy. AIH usually results in liver injury as a consequence of chronic hepatitis and cirrhosis. However, rarely, patients may present with fulminant liver failure. Early diagnosis is important in all instances because the disease can be highly responsive to immunosuppressive therapeutic options. Left untreated, the disease is associated with high morbidity and mortality. Here we provide an overview of the current state of knowledge on AIH and summarize the treatment options for this serious condition in adults. We also discuss the pathogenesis of the disease as a possible consequence of autoimmunity and the breakdown of hepatic tolerance. We focus on regulatory T cell impairments as a consequence of changes in CD39 ectonucleotidase expression and altered purinergic signaling. Further understanding of hepatic tolerance may aid in the development of specific and well-tolerated therapies for AIH.
Collapse
Affiliation(s)
- Nikhil Kapila
- Department of Medicine, University of Connecticut, Farmington, CT, USA
- These authors contributed equally to this work
| | - Jennifer T. Higa
- Gastroenterology Division and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
- These authors contributed equally to this work
| | - Maria Serena Longhi
- Gastroenterology Division and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill, London, UK
| | - Simon C. Robson
- Gastroenterology Division and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
50
|
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.
Collapse
Affiliation(s)
- Annarosa Floreani
- Dept. of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Italy.
| | | | | | | |
Collapse
|