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Vergani D, Terziroli Beretta-Piccoli B, Mieli-Vergani G. A reasoned approach to the treatment of autoimmune hepatitis. Dig Liver Dis 2021; 53:1381-1393. [PMID: 34162505 DOI: 10.1016/j.dld.2021.05.033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/15/2021] [Accepted: 05/27/2021] [Indexed: 12/11/2022]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease affecting all ages, characterised by elevated transaminase and immunoglobulin G levels, positive autoantibodies, interface hepatitis on histology and good response to immunosuppressive treatment. If untreated, it has a poor prognosis. The aim of this review is to analyse AIH therapeutic interventions with reference to our knowledge of the pathogenesis of AIH. Standard treatment, based on steroids and azathioprine, leads to disease remission in 80-90% of patients. Alternative first-line treatment with budesonide is effective in adults, but less so in the juvenile form of AIH; first-line treatment with ciclosporin does not provide convincing advantages compared to standard treatment. Second-line treatments are needed for patients not responding or intolerant to first-line standard management. Mycophenolate mofetil is the most widely used second-line drug, and has good efficacy particularly for patients intolerant to azathioprine, but is teratogenic. Only few and heterogeneous data on calcineurin inhibitors and m-TOR inhibitors are available. Biologicals, including anti-tumour necrosis factor- α and anti-CD20 monoclonal antibodies, have given ambivalent results and may have severe side-effects. Clinical trials with new therapeutic options aiming at targeting B lymphocytes and proinflammatory cytokines, or expanding regulatory T cells to restore tolerance are ongoing.
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Affiliation(s)
- Diego Vergani
- King's College London Faculty of Life Sciences & Medicine, London, UK; Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK; Epatocentro Ticino, Lugano, Switzerland
| | - Benedetta Terziroli Beretta-Piccoli
- Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK; Epatocentro Ticino, Lugano, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Switzerland
| | - Giorgina Mieli-Vergani
- King's College London Faculty of Life Sciences & Medicine, London, UK; Epatocentro Ticino, Lugano, Switzerland; Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, London, UK.
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2
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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.
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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
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3
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Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, Vierling JM, Alsawas M, Murad MH, Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology 2020; 72:671-722. [PMID: 31863477 DOI: 10.1002/hep.31065] [Citation(s) in RCA: 548] [Impact Index Per Article: 109.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Cara L Mack
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - David Adams
- Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - David N Assis
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT
| | - Nanda Kerkar
- Golisano Children's Hospital at Strong, University of Rochester Medical Center, New York, NY
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marlyn J Mayo
- Division of Digestive and Liver Diseases, University of Texas SW Medical Center, Dallas, TX
| | - John M Vierling
- Medicine and Surgery, Baylor College of Medicine, Houston, TX
| | | | - Mohammad H Murad
- Mayo Knowledge and Encounter Research Unit, Mayo Clinic College of Medicine, Rochester, MN
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: Standard treatment and systematic review of alternative treatments. World J Gastroenterol 2017; 23:6030-6048. [PMID: 28970719 PMCID: PMC5597495 DOI: 10.3748/wjg.v23.i33.6030] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 07/18/2017] [Accepted: 08/02/2017] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis is a rare chronic inflammatory liver disease, affecting all ages, characterised by elevated transaminase and immunoglobulin G levels, positive autoantibodies, interface hepatitis at liver histology and good response to immunosuppressive treatment. If untreated, it has a poor prognosis. The aim of this review is to summarize the evidence for standard treatment and to provide a systematic review on alternative treatments for adults and children. Standard treatment is based on steroids and azathioprine, and leads to disease remission in 80%-90% of patients. Alternative first line treatment has been attempted with budesonide or cyclosporine, but their superiority compared to standard treatment remains to be demonstrated. Second-line treatments are needed for patients not responding or intolerant to standard treatment. No randomized controlled trials have been performed for second-line options. Mycophenolate mofetil is the most widely used second-line drug, and has good efficacy particularly for patients intolerant to azathioprine, but has the major disadvantage of being teratogenic. Only few and heterogeneous data on cyclosporine, tacrolimus, everolimus and sirolimus are available. More recently, experience with the anti-tumour necrosis factor-alpha infliximab and the anti-CD20 rituximab has been published, with ambivalent results; these agents may have severe side-effects and their use should be restricted to specialized centres. Clinical trials with new therapeutic options are ongoing.
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Affiliation(s)
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom
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5
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Cropley A, Weltman M. The use of immunosuppression in autoimmune hepatitis: A current literature review. Clin Mol Hepatol 2017; 23:22-26. [PMID: 28288505 PMCID: PMC5381833 DOI: 10.3350/cmh.2016.0089] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2016] [Accepted: 02/10/2017] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis (AIH) is an organ specific autoimmune condition which can manifest at any age of life. The heterogeneous nature of this condition means that great variation can be seen in severity, progression of disease and response to treatment within this patient group. Since the 1980s prednisolone and azathioprine have been used for induction and remission of the disease and remain the mainstay of treatment. Other immunosuppressive agents have been employed in difficult to treat cases. While there is less published data regarding these agents compared with the conventional treatments of steroid and azathioprine, there is mounting evidence to support the use of mycophenolate mofetil as a second-line agent. The calcineurin inhibitors, though less studied, additionally show promise. More data is needed on the use of biological agents in refractory disease. This review focuses on our centre’s approach to treatment of AIH in the context of a contemporary review of the literature.
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Affiliation(s)
- Angela Cropley
- Department of Gastroenterology and Hepatology, Nepean Hospital, New South Wales, Sydney, Australia
| | - Martin Weltman
- Department of Gastroenterology and Hepatology, Nepean Hospital, New South Wales, Sydney, Australia
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Systematic Review of the Toxicity of Long-Course Oral Corticosteroids in Children. PLoS One 2017; 12:e0170259. [PMID: 28125632 PMCID: PMC5268779 DOI: 10.1371/journal.pone.0170259] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 01/01/2017] [Indexed: 02/05/2023] Open
Abstract
Background Long courses of oral corticosteroids are commonly used in children in the management of chronic conditions. Various adverse drug reactions (ADRs) are known to occur with their use. This systematic review aimed to identify the most common and serious ADRs and to determine their relative risk levels. Methods A literature search of Embase, Medline, International Pharmaceutical Abstracts, CINAHL, Cochrane Library and PubMed was performed with no language restrictions in order to identify studies where oral corticosteroids were administered to patients aged 28 days to 18 years of age for at least 15 days of treatment. Each database was searched from their earliest dates to January 2016. All studies providing clear information on ADRs were included. Results One hundred and one studies including 33 prospective cohort studies; 21 randomised controlled trials; 21 case series and 26 case reports met the inclusion criteria. These involved 6817 children and reported 4321 ADRs. The three ADRs experienced by the highest number of patients were weight gain, growth retardation and Cushingoid features with respective incidence rates of 21.1%, 18.1% and 19.4% of patients assessed for these ADRs. 21.5% of patients measured showed decreased bone density and 0.8% of patients showed osteoporosis. Biochemical HPA axis suppression was detected in 269 of 487 patients where it was measured. Infection was the most serious ADR, with twenty one deaths. Varicella zoster was the most frequent infection (9 deaths). Conclusions Weight gain, growth retardation and Cushingoid features were the most frequent ADRs seen when long-course oral corticosteroids were given to children. Increased susceptibility to infection was the most serious ADR.
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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.
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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
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8
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Casal Moura M, Liberal R, Cardoso H, Horta e Vale AM, Macedo G. Management of autoimmune hepatitis: Focus on pharmacologic treatments beyond corticosteroids. World J Hepatol 2014; 6:410-418. [PMID: 25018851 PMCID: PMC4081615 DOI: 10.4254/wjh.v6.i6.410] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 05/08/2014] [Indexed: 02/06/2023] Open
Abstract
In autoimmune hepatitis, patients who are intolerant or with toxicity experience, non-responders, relapsers or refractory are challenging. Non-standard drugs are being tried to preemptively avoid corticosteroid-related side effects. Prognosis and quality of life of life rely on treatment optimization. Recently, emergence of powerful immunosuppressive agents, mainly from liver transplantation, challenged the supremacy of the corticosteroid regime and promise greater immunosuppression than conventional medications, offer site-specific actions and satisfactory patient tolerance. Successes in experimental models of related diseases have primed these molecular interventions. We performed a literature review on alternative treatments. Azatioprine intolerance is the principal indication for mycophenolate use but it can be used as a front-line therapy. Cyclosporine A and tacrolimus have been tested for non-responders or relapsers. Rituximab may be used as salvage therapy. Anti-tumor necrosis factor-alpha agents may be used for incomplete responses or non-responders. Methotrexate is possibly an alternative for induction of remission and maintenance in refractory patients. Cyclophosphamide has been included in the induction regimen with corticosteroids. Ursodeoxycholic acid action is mainly immunomodulatory. Non-standard treatments are coming slowly to the attention, but its use should be cautious performed by experienced centers.
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9
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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.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
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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.
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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
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Nasseri-Moghaddam S, Nikfam S, Karimian S, Khashayar P, Malekzadeh R. Cyclosporine-A Versus Prednisolone for Induction of Remission in Auto-immune Hepatitis: Interim Analysis Report of a Randomized Controlled Trial. Middle East J Dig Dis 2013; 5:193-200. [PMID: 24829691 PMCID: PMC3990153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2013] [Accepted: 09/18/2013] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Corticosteroids are used to induce remission in auto-immune hepatitis.They are not universally effective; therefore, alternative treatments are needed.In this study Cysclosporine-A has been compared with prednisolone as an alternativetreatment in a randomized controlled trial. This paper is an interimanalysis of an ongoing clinical trial. METHODS Sixteen years and older consenting patients were enrolled. Group-A receivedprednisolone and group-B cyclosporine-A according to a preset protocoland followed at regular intervals for 48 weeks. Final assessment was doneat week 48. Primary outcome was response rate as defined below. "Completeresponse" was defined as achieving AST and ALT in the normal range andabsence of any clinical signs of deterioration, and partial response was definedas a decrease in AST and ALT by less than half of their original values but notto within normal limit. Non-responding ones at week eight were switched tothe other arm. RESULTS Thirty-nine patients were enrolled (24 group-A, 9 male). Mean AST andALT at baseline were higher in group-B, but other variables were comparable.At week 12, 34.8% and 64.3% of group-A and B had achieved AST and ALTin the normal range (less than 40 IU/L) respectively (p=0.081). Correspondingfigures at week 48 were 50.0% and 47.6% (p=0.62 & 0.48 respectively).At week 12, 86.9% and 85.7% of patients had AST and ALT levels less thantwice upper normal limit in groups-A and B respectively (p=0.54 & 0.42).Corresponding figures at week 48 were 90.0% for both groups. There was onetreatment failure in group-B which did not respond to prednisolone either.Serious adverse events (death and liver transplantation) occurred in group-Aonly. Serum creatinine did not change during the study period in either group. CONCLUSION According to our data, Cyclosporine-A is as effective as prednisolone forinduction of remission in AIH. Adverse events and serious adverse events weremore common with prednisolone.
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Affiliation(s)
- Siavosh Nasseri-Moghaddam
- 1Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
,Corresponding Author: Siavosh Nasseri-Moghaddam, MD, MPH Digestive Disease Research Center, Shariati Hospital, North Amirabad Ave, Tehran 14117, Iran Tel: + 98 21 82415113 Fax: +98 21 82415400
| | - Sepideh Nikfam
- 1Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Saied Karimian
- 1Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Patricia Khashayar
- 2Endocrinology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Malekzadeh
- 1Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Czaja AJ. Review article: the management of autoimmune hepatitis beyond consensus guidelines. Aliment Pharmacol Ther 2013; 38:343-64. [PMID: 23808490 DOI: 10.1111/apt.12381] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2013] [Revised: 05/30/2013] [Accepted: 06/03/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND Consensus guidelines aid in the diagnosis and management of autoimmune hepatitis, but they are frequently based on low-quality clinical evidence, conflicting experiences and divergent opinions. Recommendations may be weak, discrepant or non-existent at critical decision points. AIMS To identify the decision points where guidelines are weak or non-existent and review the evidence essential in the decision process. METHODS Full-text articles published in English using the keyword 'autoimmune hepatitis' were identified by PubMed from 1972 to 2013. Personal experience and investigations in autoimmune hepatitis also identified important contributions. RESULTS Seventy per cent of the guidelines developed by the American Association for the Study of Liver Diseases and 48% of those proposed by the British Society of Gastroenterology are based on low-quality evidence, conflicting experiences or divergent opinions. The key uncertainties in diagnosis relate to the timing of liver biopsy, recognising acute severe (fulminant) disease, interpreting coincidental nonclassical histological changes, accommodating atypical or deficient features in non-White patients, differentiating drug-induced from classical disease and identifying overlap syndromes. The key uncertainties in management relate to pre-treatment testing for thiopurine methyltransferase activity, treating asymptomatic mild disease, determining treatment end points, managing suboptimal responses, incorporating nonstandard medications as front-line and salvage agents, using azathioprine in pregnancy and instituting surveillance for hepatocellular carcinoma. CONCLUSIONS Consensus guidelines are fraught with uncertainties in the diagnosis and management of autoimmune hepatitis. Each decision point must counterbalance the current available evidence and tailor the application of this evidence to the individual patient.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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13
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Trivedi PJ, Hirschfield GM. Treatment of autoimmune liver disease: current and future therapeutic options. Ther Adv Chronic Dis 2013; 4:119-41. [PMID: 23634279 DOI: 10.1177/2040622313478646] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Autoimmune liver disease spans three predominant processes, from the interface hepatitis of autoimmune hepatitis to the lymphocytic cholangitis of primary biliary cirrhosis, and finally the obstructive fibrosing sclerotic cholangiopathy of primary sclerosing cholangitis. Although all autoimmune in origin, they differ in their epidemiology, presentation and response to immunosuppressive therapy and bile acid based treatments. With an ongoing better appreciation of disease aetiology and pathogenesis, treatment is set ultimately to become more rational. We provide an overview of current and future therapies for patients with autoimmune liver disease, with an emphasis placed on some of the evidence that drives current practice.
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Affiliation(s)
- Palak J Trivedi
- Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK
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Abstract
Autoimmune hepatitis frequently has an abrupt onset of symptoms, and it can present with acute liver failure. The abrupt presentation can indicate spontaneous exacerbation of a pre-existent chronic disease, newly created disease, a superimposed infectious or toxic injury, or new disease after viral infection, drug therapy, or liver transplantation. Deficiencies in the classical phenotype may include a low serum immunoglobulin G level and low or absent titers of the conventional autoantibodies. The original revised diagnostic scoring system of the International Autoimmune Hepatitis Group can guide the diagnostic evaluation, but low scores do not preclude the diagnosis. Liver tissue examination is valuable to exclude viral-related or drug-induced liver injury and support the diagnosis by demonstrating centrilobular necrosis (usually with interface hepatitis), lymphoplasmacytic infiltration, hepatocyte rosettes, and fibrosis. Conventional therapy with prednisone and azathioprine induces clinical and laboratory improvement in 68-75 % of patients with acute presentations, and high dose prednisone or prednisolone (preferred drug) is effective in 20-100 % of patients with acute severe (fulminant) presentations. Failure to improve or worsening of any clinical or laboratory feature within 2 weeks of treatment or worsening of a mathematical model of end-stage liver disease within 7 days justifies liver transplantation in acute liver failure. Liver transplantation for acute severe (fulminant) autoimmune hepatitis is as successful as liver transplantation for autoimmune hepatitis with a chronic presentation and other types of acute liver failure (patient survival >1 year, 80-94 %). Liver transplantation should not be delayed or superseded by protracted corticosteroid therapy or the empiric institution of nonstandard medications.
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Autoimmune hepatitis: focusing on treatments other than steroids. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2013; 26:615-20. [PMID: 22993733 DOI: 10.1155/2012/512132] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Corticosteroid therapy has been the time-honoured treatment for autoimmune hepatitis; however, the emergence of new immunosuppressive agents has afforded opportunities to improve or replace the standard regimens. OBJECTIVE To describe technological advances and feasible treatment interventions that promise to supplant the current generation of corticosteroids. METHODS A review of the MEDLINE database for published experiences from 1984 to 2011 was conducted. RESULTS Cyclosporine and tacrolimus have been uniformly successful as salvage therapies for steroid-refractory autoimmune hepatitis. Ten reports of cyclosporine therapy involving 133 patients had positive outcomes in 93%, whereas therapy with tacrolimus in three reports involving 41 patients had positive outcomes in 98%. Salvage therapy with mycophenolate mofetil had a favourable outcome in 47%, especially in patients with azathioprine intolerance. Front-line therapy with mycophenolate mofetil normalized liver parameters in 88% and allowed corticosteroid tapering in 58%. Front-line therapy with budesonide combined with azathioprine for six months normalized liver parameters more frequently (47% versus 18%) and with fewer side effects (28% versus 53%) than prednisone combined with azathioprine. Monoclonal antibodies to CD3 and recombinant cytotoxic T lymphocyte antigen 4 fused with immunoglobulin represent feasible molecular interventions for study in autoimmune hepatitis. DISCUSSION Nonstandard drug therapies must be used in highly selected clinical situations including steroid failure (calcineurin inhibitors), azathioprine intolerance (mycophenolate mofetil), and mild disease or fragile patients (budesonide combined with azathioprine). Molecular interventions for autoimmune hepatitis are feasible for study because of their use in other immune-mediated diseases. CONCLUSION Opportunities to improve or replace standard corticosteroid regimens have emerged.
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Selvarajah V, Montano-Loza AJ, Czaja AJ. Systematic review: managing suboptimal treatment responses in autoimmune hepatitis with conventional and nonstandard drugs. Aliment Pharmacol Ther 2012; 36:691-707. [PMID: 22973822 DOI: 10.1111/apt.12042] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2012] [Revised: 07/17/2012] [Accepted: 08/21/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND Corticosteroid treatment for autoimmune hepatitis has been shown by randomised controlled clinical trials to ameliorate symptoms, normalise liver tests, improve histological findings and extend survival. Nevertheless, suboptimal responses to corticosteroid treatment still occur. AIM To describe the current definitions, frequencies, clinical relevance and treatment options for suboptimal responses, and to discuss alternative medications that have been used off-label for these occurrences. METHODS Literature search was made for full-text papers published in English using the keyword 'autoimmune hepatitis'. Authors' personal experience and investigational studies also helped to identify important contributions to the literature. RESULTS Suboptimal responses to standard therapy include treatment failure (7%), incomplete response (14%), drug toxicity (13%) and relapse after drug withdrawal (50-86%). The probability of a suboptimal response prior to treatment is higher in young patients and in patients with a severe presentation, jaundice, high MELD score at diagnosis, multilobular necrosis or cirrhosis, antibodies to soluble liver antigen, or inability to improve by clinical indices within two weeks or by MELD score within 7 days of conventional corticosteroid treatment. Management strategies have been developed for the adverse responses and nonstandard drugs, including mycophenolate mofetil, budesonide, ciclosporin, tacrolimus, sirolimus and rituximab, are emerging as rescue therapies or alternative frontline agents. CONCLUSIONS Once diagnosed, the suboptimal response should be treated by a highly individualised and well-monitored regimen, preferentially using first-line therapy. Nonstandard drugs warrant consideration as salvage or second-line therapies.
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Affiliation(s)
- V Selvarajah
- Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
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Abstract
Nonsteroidal medications, previously unfamiliar in the management of autoimmune hepatitis, can supplement or replace conventional corticosteroid regimens, especially in problematic patients. Mycophenolate mofetil is a next-generation purine antagonist that has been useful in treating patients with azathioprine intolerance. It has been less effective in salvaging patients with steroid-refractory disease. Azathioprine is the choice as a corticosteroid-sparing agent in treatment-naive patients and in individuals with corticosteroid intolerance, incomplete response and relapse after drug withdrawal. Tacrolimus is preferred over cyclosporine for recalcitrant disease because of its established preference in organ transplantation, but replacement with cyclosporine should be considered if the disease worsens on treatment. Rapamycin has antiproliferative and proapoptotic actions that warrant further study in autoimmune hepatitis. The nonstandard, nonsteroidal medications are mainly salvage therapies with off-label indications that must be used in highly individualized and well-monitored clinical situations.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905 USA.
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Trivedi PJ, Hirschfield GM. Review article: overlap syndromes and autoimmune liver disease. Aliment Pharmacol Ther 2012; 36:517-33. [PMID: 22817525 DOI: 10.1111/j.1365-2036.2012.05223.x] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Revised: 03/30/2012] [Accepted: 07/01/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) all nestle within the family of autoimmune liver diseases, whereby the result of immune-mediated liver injury gives rise to varied clinical presentations. Some patients demonstrate a phenotype whereby there is evidence of either PBC or PSC together with overlapping features of AIH. Due to an absence of well-validated diagnostic criteria and a lack of large therapeutic trials, treatment of overlap conditions is empiric and extrapolated from data derived from the primary autoimmune liver diseases. AIMS To review overlaps in the context of autoimmune liver diseases. METHODS General and specific review of published articles using PubMed, Medline and Ovid search engines, alongside pre-existing clinical management protocols, guidelines, and the authors' own knowledge of the published literature. RESULTS The challenges in diagnosis, clinical presentation, determining natural history and outcome of overlaps are presented, as well as present-day management suggestions, some based on evidence, others on consensus and opinion. CONCLUSIONS Overlapping autoimmune features, be they clinical, serological, histological or radiological are not infrequent, but appropriate diagnosis remains hindered by a lack of standardised diagnostic criteria. Optimum care for those with suspected overlap should thus focus on attention to detail over the fundamental aspects of timely secure diagnosis of the dominant disease entity. Clinicians should counsel patients carefully with regard to the risks and benefits of treatment, bearing in mind the paucity of randomised and controlled outcome data for medical interventions.
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Affiliation(s)
- P J Trivedi
- Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK
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Advances in the current treatment of autoimmune hepatitis. Dig Dis Sci 2012; 57:1996-2010. [PMID: 22476586 DOI: 10.1007/s10620-012-2151-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2011] [Accepted: 03/16/2012] [Indexed: 12/17/2022]
Abstract
Current treatment strategies for autoimmune hepatitis are complicated by frequent relapse after drug withdrawal, medication intolerance, and refractory disease. The objective of this review is to describe advances that have improved treatment outcomes by defining the optimum objectives of initial therapy, managing relapse more effectively, identifying problematic patients early, and incorporating the new pharmacological interventions that have emerged as frontline and salvage therapies. Initial corticosteroid treatment should be continued until serum aminotransferase, γ-globulin, and immunoglobulin G levels are normal, and maintenance of this improvement for 3-8 months before liver tissue assessment. Improvement to normal liver tissue is the ideal histological result that justifies drug withdrawal, but it is achievable in only 22 % of patients. Minimum portal hepatitis, inactive cirrhosis, or minimally active cirrhosis is the most common treatment end point. Relapse after drug withdrawal warrants institution of a long-term maintenance regimen, preferably with azathioprine. Mathematical models can identify problematic adult patients early, as also can clinical phenotype (age ≤ 30 years and HLA DRB1 03), rapidity of treatment response (≤ 24 months), presence of antibodies to soluble liver antigen, and non-white ethnicity. The calcineurin inhibitors (cyclosporine and tacrolimus) can be effective in steroid-refractory disease; mycophenolate mofetil can be corticosteroid-sparing and effective for azathioprine intolerance; budesonide combined with azathioprine can be effective for treatment-naïve, non-cirrhotic patients. Standard treatment regimens for autoimmune hepatitis can be upgraded without adjustments that require major new expertise.
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Shafiei M, Alavian SM. Autoimmune hepatitis in Iran: what we know, what we don't know and requirements for better management. HEPATITIS MONTHLY 2012; 12:73-6. [PMID: 22509182 PMCID: PMC3321324 DOI: 10.5812/hepatmon.840] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/29/2012] [Revised: 02/05/2012] [Accepted: 02/15/2012] [Indexed: 12/11/2022]
Affiliation(s)
- Mostafa Shafiei
- Baqiyatallah Research Center for Gastroenterology and Liver diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Sayed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
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Autoimmune Hepatitis in Iran: What We Know, What We Don’t Know and Requirements for Better Management. HEPATITIS MONTHLY 2012. [DOI: 10.5812/hepatmon.4847] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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Snider KR, Potter TG. Budesonide for the treatment of autoimmune hepatitis. Ann Pharmacother 2011; 45:1144-50. [PMID: 21878659 DOI: 10.1345/aph.1q244] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE To evaluate the use of budesonide for the treatment of autoimmune hepatitis (AIH). DATA SOURCES Literature was accessed through PubMed/MEDLINE (1966-June 2011) and Web of Science (1965-June 2011) using the terms autoimmune hepatitis and budesonide. Literature was limited to English-language publications. In addition, references from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION All articles in English identified from the data sources were evaluated. DATA SYNTHESIS The initial treatment of choice for AIH is prednisone alone or with azathioprine. However, a significant number of patients do not respond adequately or have adverse reactions to this regimen; therefore, alternative treatments are required. Budesonide is an orally administered synthetic corticosteroid with high affinity for the glucocorticoid receptor that undergoes extensive first-pass metabolism. It has Food and Drug Administration-approved labeling for the treatment and maintenance of remission of mild-to-moderate Crohn disease involving the ileum and/or ascending colon. One prospective, active-controlled study of budesonide in the treatment of AIH was identified, as well as 5 small open-label studies and 1 retrospective chart review. Budesonide appears to have efficacy in the treatment of AIH, including in patients intolerant to standard therapy with prednisone alone or with azathioprine, with a reduced incidence of corticosteroid-related adverse reactions. However, in patients with AIH and cirrhosis, the efficacy of budesonide may be reduced and the incidence of corticosteroid-related adverse reactions may be increased. CONCLUSIONS Budesonide may be an additional treatment option for patients with AIH but without cirrhosis who are intolerant to standard therapy with prednisone or prednisone with azathioprine.
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Affiliation(s)
- Kenneth R Snider
- Internal Medicine, Virginia Commonwealth University Health System/Medical College of Virginia Hospitals, Richmond, VA, USA.
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Abstract
Treatment decisions in autoimmune hepatitis are complicated by the diversity of its clinical presentations, uncertainties about its natural history, evolving opinions regarding treatment end points, varied nature of refractory disease, and plethora of alternative immunosuppressive agents. The goals of this article are to review the difficult treatment decisions and to provide the bases for making sound therapeutic judgments. The English literature on the treatment problems in autoimmune hepatitis were identified by Medline search up to October 2009 and 32 years of personal experience. Autoimmune hepatitis may have an acute severe presentation, mild inflammatory activity, lack autoantibodies, exhibit atypical histological changes (centrilobular zone 3 necrosis or bile duct injury), or have variant features reminiscent of another disease (overlap syndrome). Corticosteroid therapy must be instituted early, applied despite the absence of symptoms, or modified in an individualized fashion. Pursuit of normal liver tests and tissue is the ideal treatment end point, but this objective must be tempered against the risk of side effects. Relapse after treatment withdrawal requires long-term maintenance therapy, preferably with azathioprine. Treatment failure or an incomplete response warrants salvage therapy that can include conventional medications in modified dose or empirical therapies with calcineurin inhibitors or mycophenolate mofetil. Liver transplantation supersedes empirical drug therapy in decompensated patients. Elderly and pregnant patients warrant treatment modifications. Difficult treatment decisions in autoimmune hepatitis can be simplified by recognizing its diverse manifestations and individualizing treatment, pursuing realistic goals, applying appropriate salvage regimens, and identifying problematic patients early.
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Czaja AJ, Bayraktar Y. Non-classical phenotypes of autoimmune hepatitis and advances in diagnosis and treatment. World J Gastroenterol 2009; 15:2314-28. [PMID: 19452572 PMCID: PMC2684596 DOI: 10.3748/wjg.15.2314] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Non-classical manifestations of autoimmune hepatitis can delay diagnosis and treatment. Our aims were to describe the clinical phenotypes that can confound the diagnosis, detail scoring systems that can ensure their recognition, and outline advances in treatment that can improve their outcome. Prime source and review articles in English were selected through Medline from 1970-2008 and assimilated into personal libraries spanning 32 years. Acute severe or asymptomatic presentations and atypical histological findings, including centrilobular zone 3 necrosis and concurrent bile duct changes, are compatible with the diagnosis. Cholangiographic abnormalities may be present in children and adults with the disease, and autoimmune hepatitis must be considered in patients without autoantibodies or with antimitochondrial antibodies and no other cholestatic features. Asymptomatic patients frequently become symptomatic; mild disease can progress; and there are no confident indices that justify withholding treatment. Two diagnostic scoring systems with complementary virtues have been developed to evaluate patients with confusing features. Normal liver tests and tissue constitute the optimal end point of treatment, and the first relapse is an indication for long-term azathioprine therapy. Cyclosporine, tacrolimus and mycophenolate mofetil are promising salvage therapies, and budesonide with azathioprine may be a superior frontline treatment. We conclude that the non-classical phenotypes of autoimmune hepatitis can be recognized promptly, diagnosed accurately, and treated effectively.
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25
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Gluud LL, Dahl EE, Al-Rifai A, Prince M. Medical treatments for autoimmune hepatitis. Hippokratia 2009. [DOI: 10.1002/14651858.cd004543.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Lise Lotte Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 3344, Rigshospitalet, Copenhagen University Hospital; Cochrane Hepato-Biliary Group; Blegdamsvej 9 Copenhagen Denmark DK-2100
| | | | | | - Martin Prince
- Manchester Royal Infirmary; Oxford Road Manchester UK M13 9WL
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The use of budesonide in the treatment of autoimmune hepatitis in Canada. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2008; 22:388-92. [PMID: 18414714 DOI: 10.1155/2008/509459] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a chronic inflammatory disease that is successfully treated with prednisone and/or azathioprine immunosuppressive therapy in 70% to 80% of patients. The remaining patients are intolerant or refractory to these standard medications. Budesonide, a synthetic glucocorticoid, undergoes a high degree of first-pass metabolism, reducing its systemic bioavailability, and has a 15-fold greater affinity for the glucocorticoid receptor than prednisolone. Budesonide may be a potentially useful systemic steroid-sparing immunosuppressive agent in the treatment of AIH. OBJECTIVE To review the Canadian experience using budesonide to treat AIH. METHODS Patients with AIH currently or previously treated with budesonide were identified through the Canadian Association for the Study of the Liver membership. Data were collected regarding their clinical and treatment history. RESULTS A total of nine patients were identified. All patients were female, with an average age of 39 years (range 12 to 66 years). The indications for budesonide were adverse side effects of prednisone in two patients, noncompliance with prednisone and azathioprine in one patient and intolerance to azathioprine resulting in prednisone dependence in the remaining six patients. Patients were treated in doses ranging from 9 mg daily to 3 mg every other day for 24 weeks to eight years. Seven of nine patients had a complete response, defined as sustained normalization of the aminotransferase levels. The remaining two patients were classified as nonresponders (less than a 50% reduction in pretreatment aminotransferase levels). CONCLUSIONS In Canada, budesonide has been successfully used in seven of nine patients with autoimmune hepatitis who were either intolerant to prednisone and azathioprine or prednisone-dependent. No adverse effects were reported with budesonide. Budesonide is potentially a valuable treatment option for AIH patients refractory or intolerant to standard therapy, and is deserving of further study.
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Abstract
BACKGROUND Prednisone and azathioprine are effective in the treatment of autoimmune hepatitis, but diverse side effects can diminish their net benefit. OBJECTIVES Describe the frequency and nature of these side effects and propose management strategies to minimize their impact. METHODS Pertinent articles published from 1970 to 2007 were identified by Medline search and through a personal library. RESULTS Medication is prematurely discontinued in 13% of patients mainly because of cosmetic changes, cytopenia, or osteopenia. Populations at high risk are the elderly, those with pre-existent co-morbidities, patients with near-zero thiopurine methyltransferase activity, individuals who are treatment-dependent, pregnant women, and asymptomatic patients who are over-treated. CONCLUSIONS Proper patient selection, effective pre-treatment counseling, preemptive protective measures, realistic treatment objectives, and early identification of problematic patients can reduce complications. Individualized dosing schedules and the emergence of non-steroidal medications are realistic expectations.
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic and Mayo Clinic College of Medicine, Division of Gastroenterology and Hepatology, Department of Medicine, 200 First Street SW, Rochester, Minnesota 55905, USA.
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Abstract
Autoimmune liver disease in children presents predominantly as autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). These diagnoses must be considered in patients who have acute and chronic hepatitis, particularly when an extrahepatic autoimmune disorder is present. In AIH, the timely and sustained control of liver inflammation is critical to improve the short- and long-term outcomes. No effective treatment for PSC has been identified to date, but supportive care, careful attention to complications and associated nonhepatic diseases, and liver transplantation significantly improve the long-term outcome.
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Affiliation(s)
- Fernando Alvarez
- Department of Pediatrics, Hôpital Sainte-Justine, University of Montreal, 3175 Côte Sainte-Catherine, Montreal, Québec H3T 1C5, Canada.
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Heneghan MA, Al-Chalabi T, McFarlane IG. Cost-effectiveness of pharmacotherapy for autoimmune hepatitis. Expert Opin Pharmacother 2006; 7:145-56. [PMID: 16433580 DOI: 10.1517/14656566.7.2.145] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
In > 80% of patients with autoimmune hepatitis, steroid therapy alone or in combination with azathioprine results in disease remission. Treatment response results in reversal of fibrosis and excellent long-term survival in many patients, whereas untreated patients may expect a 10-year survival of < 30%. The use of azathioprine monotherapy (2 mg/kg/day) has gained widespread acceptance in maintaining remission in clinical practice. Although all patients with autoimmune hepatitis may not need treatment, particularly those with mild disease, alternative strategies are required in patients who have failed to achieve remission on standard therapy of steroids with or without azathioprine, or patients with azathioprine-induced drug toxicity. In such circumstances, the use of salvage therapy in the form of ciclosporin, tacrolimus or mycophenolate mofetil may be warranted. Liver transplantation is the treatment of choice for patients who present with subacute liver failure or decompensated cirrhosis. Salvage therapy results in an exponential rise in cost with each increment in therapeutic escalation. As an alternative to standard therapy, it has also been suggested that novel therapies such as ciclosporin, tacrolimus or mycophenolate mofetil be initiated to achieve remission. However, a > 10-fold cost differential exists between the charges associated with more potent immunosuppression and standard therapy. Therefore, in evaluating novel immunosuppression in autoimmune hepatitis, it behoves clinicians not only to consider end points pertaining to efficacy, but also end points pertaining to cost-effectiveness. Moreover, the exact role of pharmacogenomics and genotyping of thiopurine methyltransferase in patients with autoimmune hepatitis needs to be fully defined.
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Affiliation(s)
- Michael A Heneghan
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE5 9RS, UK
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Czaja AJ, Carpenter HA. Empiric therapy of autoimmune hepatitis with mycophenolate mofetil: comparison with conventional treatment for refractory disease. J Clin Gastroenterol 2005; 39:819-25. [PMID: 16145346 DOI: 10.1097/01.mcg.0000177260.72692.e8] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
GOAL To assess the outcomes of empiric therapy with mycophenolate mofetil in patients with autoimmune hepatitis. BACKGROUND Mycophenolate mofetil is a purine antagonist that selectively inhibits immunocyte proliferation, and its empiric use in autoimmune hepatitis has been stimulated by small clinical experiences. STUDY Eight patients received mycophenolate mofetil (0.5-3 g daily) for 19 +/- 7 months as frontline therapy or after adverse responses to conventional corticosteroid treatment. Seventeen patients who had been treated with high-dose corticosteroid regimens after treatment failure constituted a historical comparison population. RESULTS Five of the 8 patients receiving mycophenolate mofetil and all 17 patients who had been treated with the conventional corticosteroid regimens for treatment failure responded to therapy. The frequency of response (62% vs. 100%, P = 0.02) was lower during longer intervals of treatment (19 +/- 7 months vs. 6 +/- 1 months, P = 0.02) in the patients receiving mycophenolate mofetil. None receiving mycophenolate mofetil resolved their laboratory abnormalities, whereas 6 patients in the comparison group improved to normal tests (0% vs. 35%, P = 0.1). Histologic resolution did not occur in 4 patients sampled during treatment, and successive specimens in 2 patients showed progressive fibrosis. Corticosteroids could not be withdrawn in the patients treated with mycophenolate mofetil, whereas discontinuation was possible in 7 patients in the comparison group (0% vs. 41%, P = 0.06). CONCLUSIONS Mycophenolate mofetil did not induce laboratory resolution, prevent progressive fibrosis, or allow corticosteroid withdrawal. Clinical trials are needed to evaluate its role and target population.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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SHARMA PRATIMA, VARGAS HUGOE, RAKELA JORGE. Monitoring and Care of the Patient Before Liver Transplantation. TRANSPLANTATION OF THE LIVER 2005:473-489. [DOI: 10.1016/b978-0-7216-0118-2.50037-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Abstract
Autoimmune hepatitis is an uncommon liver disease affecting children and adults. Early diagnosis and start of treatment improve the response and long-term outcome. Initial treatment depends on patient's age and the clinical, laboratory, and histological features that allow the prediction of the response, as well as the presence or absence of associated extrahepatic disorders. In specialized centers, short-term cyclosporine is used safely and successfully to control the liver inflammatory process. Low doses of prednisone in association with azathioprine are sufficient to sustain the response. Maintenance treatment must be administered for several years, and withdrawal can be attempted after at least 4 years of a complete and sustained response. Future research should focus on the recovery of immune homeostasis in these patients by less aggressive means.
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Affiliation(s)
- Fernando Alvarez
- Department of Pediatrics, Hôpital Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, Québec, H3T 1C5, Canada.
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Sciveres M, Caprai S, Palla G, Ughi C, Maggiore G. Effectiveness and safety of ciclosporin as therapy for autoimmune diseases of the liver in children and adolescents. Aliment Pharmacol Ther 2004; 19:209-17. [PMID: 14723612 DOI: 10.1046/j.1365-2036.2003.01754.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Conventional treatment for autoimmune hepatitis results in a significant percentage of failures and several, poorly tolerated, side-effects. Therapy for autoimmune cholangitis and giant cell hepatitis associated with autoimmune haemolysis is poorly documented. Ciclosporin is a promising treatment for all of these diseases. METHODS We reviewed the records of 12 patients treated in our unit between 1987 and 2001. Eight had autoimmune hepatitis, two had autoimmune cholangitis and two had giant cell hepatitis. Indications for ciclosporin were treatment failure (four patients) and contraindications to/refusal of steroids (eight patients). Ciclosporin was administered in five untreated cases and in seven patients during relapse. The mean duration of ciclosporin administration was 35.6 months (8-89 months). The median follow-up was 6.5 years (1.5-15 years). RESULTS All patients achieved complete remission in a median period of 4.5 weeks (2-12 weeks). No treatment withdrawal due to side-effects occurred. Three patients required a combination of ciclosporin with conventional treatment due to severe liver function impairment. Tolerance to ciclosporin was excellent. A 20% transient elevation of serum creatinine occurred in one case, gingival hypertrophy in two and moderate hypertrichosis in two. CONCLUSIONS Ciclosporin may be considered as a safe treatment for all autoimmune liver diseases and as an effective alternative for front-line therapy.
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Affiliation(s)
- M Sciveres
- Gastroenterologia ed Epatologia Pediatrica, Dipartimento di Medicina della Procreazione e della Età Evolutiva, Università di Pisa, Pisa, Italy.
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Medina J, García-Buey L, Moreno-Otero R. Review article: immunopathogenetic and therapeutic aspects of autoimmune hepatitis. Aliment Pharmacol Ther 2003; 17:1-16. [PMID: 12492728 DOI: 10.1046/j.1365-2036.2003.01389.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Autoimmune hepatitis is a chronic, progressive liver disease that responds well to immunosuppressive therapy, but has a poor prognosis if untreated. Possible triggering factors include viruses, other autoimmune disorders and drugs. The molecular mechanisms contributing to the pathogenesis include: reactions of autoantibodies against their corresponding autoantigens; aberrant expression of histocompatibility antigen class I and II molecules, cell adhesion molecules and cytokines; increased oxidative stress; and the occurrence of angiogenesis. The prevalence of the disease is highest in Caucasians, Europeans and women. The natural history of autoimmune hepatitis shows a poor prognosis, with frequent progression to cirrhosis and hepatic insufficiency in untreated patients. The occurrence of hepatocellular carcinoma is rare and is found only in long-standing cirrhosis. Corticosteroids as monotherapy or in combination with azathioprine are the treatments of choice; different therapeutic schedules and particularities of treatment for pregnant women and children have been established. To avoid treatment-associated adverse effects, alternative therapies have been proposed, including ciclosporin, budesonide, tacrolimus, mycophenolate mofetil, ursodeoxycholic acid, methotrexate, cyclophosphamide, mercaptopurine and free radical scavengers. Liver transplantation is indicated for patients refractory to or intolerant of immunosuppressive therapy.
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Affiliation(s)
- J Medina
- Liver Unit, Hospital de la Princesa, Autonomous University of Madrid, Diego de León 62, E-28006 Madrid, Spain
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35
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Abstract
Autoimmune hepatitis is a well-established chronic liver disease. It primarily affects women, is characterized by circulating autoantibodies and elevated gammaglobulins and is associated with extrahepatic immune-mediated syndromes. Treatment regimens have remained unchanged for a number of years because of the high efficacy of steroid monotherapy, or combination therapy of azathioprine and steroids. In approximately 90% of patients remission of the disease is reached by medical therapy, which is usually administered lifelong because long-term remission after drug withdrawal is achieved in only 17% of patients. In 10% of patients treatment failure is observed. The challenge of remission induction involves the use of transplant immunosuppressants such as cyclosporine, mycophenolate moffetil, and tacrolimus. The challenge of maintenance therapy minimizing steroid side-effects involves the evaluation of topical steroids and the use of azathioprine monotherapy. Overlap syndromes occur in approximately 20% of autoimmune liver diseases. The diagnosis is broadly based on serological, biochemical, clinical and histological parameters. Most common are the overlap of autoimmune hepatitis and primary biliary cirrhosis, as well as autoimmune hepatitis with primary sclerosing cholangitis. These yet incompletely defined syndromes are an important differential diagnosis in the difficult-to-treat patient with autoimmune hepatitis.
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Affiliation(s)
- Arndt Vogel
- Department of Hepatology, Gastroenterology and Endocrinology, Hannover Medical School, Hannover, Germany
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36
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Abstract
Refinements in the understanding of the mechanisms of immunocyte activation and the emergence of new immunosuppressive agents with highly selective actions has created opportunities for improving the treatment of autoimmune hepatitis. Drugs, such as budesonide and deflazacort, may inhibit immunocyte activation and limit corticosteroid-related side effects. Agents, such as cyclosporine and tacrolimus, can impair calcineurin activity and restrict the generation of transcription factors necessary for T cell responses. Intravenous immunoglobulin can bind anti-idiotype antibodies and reduce interleukin-2 secretion, and monoclonal antibodies directed against critical components of the T cell activation cascade can dampen the immune reaction. Drugs, such as mycophenolate mofetil, cyclophosphamide, methotrexate, and KF20444, can inhibit T cell proliferation, and other interventions promise to deplete activated T cells, impair effector mechanisms, and induce self-tolerance.
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Affiliation(s)
- John M Vierling
- Center for Liver Diseases and Transplantation and Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, and UCLA School of Medicine, CA 90048, USA.
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37
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Abstract
Prednisone alone or a lower dose in combination with azathioprine is effective in improving symptoms, resolving laboratory and histologic features, and prolonging survival in patients with autoimmune hepatitis. The combination regimen of prednisone and azathioprine is preferred because of its lower frequency of corticosteroid-related side effects. Only patients with severe inflammatory activity have absolute indications for therapy. Treatment must be individualized in patients with mild-to-moderate disease. Medication should be continued at fixed daily maintenance levels until a remission, treatment failure, drug intolerance, or incomplete response has been established. Histologic examination before drug withdrawal ensures remission when symptoms and laboratory tests are normal or near normal. Treatment failure warrants high-dose therapy, whereas drug toxicity and incomplete response compel regimens that are modified individually according to response. Low-dose prednisone or indefinite azathioprine therapy are indicated in patients who have relapsed multiply. Empiric nonsteroidal treatments include ursodeoxycholic acid, cyclosporine, mycophenolate mofetil, and tacrolimus, and they have been used in limited studies to treat recalcitrant disease or corticosteroid intolerance. Investigational therapies promise to target critical pathogenic mechanisms affecting immunocyte activation, autoantigen recognition, cytokine interactions, and regenerative activity.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
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38
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
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39
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Abstract
Autoimmune hepatitis has been described as recurrent or de novo disease after transplantation. The legitimacy of these diagnoses and the bases for their occurrence are unknown. To better understand these aspects of allograft dysfunction, the purported pathogenic mechanisms of classical autoimmune hepatitis were reviewed and extrapolated to recurrent and de novo disease after transplantation. Loss of self-tolerance may relate to defects in the negative selection of autoreactive immunocytes and the clonal expansion of promiscuous lymphocytes that are cross-reactive to homologous antigens (molecular mimicry). Repopulation of the allograft with recipient antigen-presenting cells and the presence of primed promiscuous cytotoxic T cells within the recipient are likely factors for recurrent disease. Targets may be the same peptides that triggered the original disease, donor-derived class II antigens of the major histocompatibility complex, or homologous antigens associated with unidentified hepatotrophic viruses. De novo disease is probably due to similar mechanisms, but its predilection for children suggests that thymic dysfunction associated with cyclosporine treatment may be a factor. Corticosteroid therapy is effective in each condition. In conclusion, recurrent and de novo autoimmune hepatitis after transplantation are examples of self-intolerance. The mechanisms that perturb immunologic homeostasis in this human model of the classical disease must be studied more rigorously.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
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40
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Abstract
Corticosteroids alone or in conjunction with azathioprine is the treatment of choice in patients with autoimmune hepatitis (AIH) and results in remission induction in over 80% of patients. Sustained response to therapy may result in substantial regression of fibrosis even in advanced cases. The outcome of rapid withdrawal of immunosuppression is disease relapse in many patients. Consequently, the use of 2 mg/kg/d of azathioprine as a sole agent to maintain remission has been widely accepted in clinical practice. Persistent severe laboratory abnormalities or histologic abnormalities such as bridging necrosis or multilobular necrosis are absolute indications for treatment based on controlled clinical trials, but debate exists as to whether all patients with AIH need treatment. Examination of liver tissue remains the best method of evaluating both treatment response and need for treatment in patients who have little biochemical activity. Alternative strategies in patients who have failed to achieve remission on "standard therapy" of corticosteroids with or without azathioprine or patients with drug toxicity include the use of cyclosporine, tacrolimus, or mycophenolate mofetil. Liver transplantation is the treatment of choice in managing decompensated disease. In this review we examine current management strategies of AIH, and evaluate available data pertaining to the use of novel immunosuppressive agents in this condition.
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Affiliation(s)
- Michael A Heneghan
- Division of Gastroenterology, Duke University Medical Center, Durham NC 27710, USA.
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41
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Al-Khalidi JA, Czaja AJ. Current concepts in the diagnosis, pathogenesis, and treatment of autoimmune hepatitis. Mayo Clin Proc 2001; 76:1237-52. [PMID: 11761505 DOI: 10.4065/76.12.1237] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Autoimmune hepatitis has a global distribution and affects all ages. Genetic factors strongly influence susceptibility, clinical expression, and treatment response. The diagnosis of autoimmune hepatitis has been codified by an international panel. An acute or fulminant presentation is recognized but not a cholestatic form. Subclassifications by predominant autoantibody profile have been proposed, but they lack etiologic and prognostic differences. Autoantibodies continue to be characterized to improve diagnostic specificity, predict outcome, and identify pertinent antigenic targets. Cytosolic enzymes are prime candidates as autoantigens. DRB1*0301 and DRB1*0401 are the susceptibility alleles in Caucasoid Northern Europeans and North Americans, and they also affect clinical expression and treatment outcome. Other autoimmune promoters affecting cytokine production and immunocyte activation may act in synergy with the susceptibility alleles to affect disease behavior. Cell-mediated and antibody-dependent forms of cytotoxicity are probably interactive pathogenic mechanisms, and novel site-specific therapies are feasible because these mechanisms are defined. Potent new immunosuppressive agents are emerging from the transplantation arena, but prednisone alone or in combination with azathioprine remains the mainstay of treatment. Corticosteroid therapy is effective but not ideal.
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Affiliation(s)
- J A Al-Khalidi
- Department of Gastroenterology, Al Amiri Hospital, Kuwait
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42
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Malekzadeh R, Nasseri-Moghaddam S, Kaviani MJ, Taheri H, Kamalian N, Sotoudeh M. Cyclosporin A is a promising alternative to corticosteroids in autoimmune hepatitis. Dig Dis Sci 2001; 46:1321-7. [PMID: 11414311 DOI: 10.1023/a:1010683817344] [Citation(s) in RCA: 102] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Autoimmune hepatitis (AIH), a chronic T-cell-mediated liver injury, is treated with corticosteroids with or without Azathioprine. Corticosteroids are not universally effective and have serious side effects. Cyclosporin A was effective in refractory cases. To assess efficacy and safety of Cyclosporin A (Neoral) in induction of remission in AIH patients this study was performed. Nineteen consenting AIH patients (nine treatment-naive) were treated with cyclosporin A in an open label trial and followed for 26 weeks. Liver biopsy was done and hepatitis activity index (HAI) determined at the beginning and end of treatment. Four patients did not complete the study for various reasons. Mean AST and ALT levels decreased from 948.7 +/- 103.5 and 454.8 +/- 354 to 100.6 +/- 111.8 and 78.5 +/- 40.3 (P < 0.03, P < 0.001) respectively. HAI decreased from 15.2 +/- 3.16 to 7.14 +/- 4.01 (P < 0.005). Serum creatinine did not change significantly. In conclusion, low-dose cyclosporin A appears to be safe and effective even in treatment-naive autoimmune hepatitis patients. Randomized controlled trials are warranted.
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Affiliation(s)
- R Malekzadeh
- Digestive Diseases Research Center, Shariati Hospital, Tehran University of Medical Sciences, Iran
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43
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Affiliation(s)
- P A Brogan
- Department of Nephrology, Institute of Child Health, 30 Guilford Street, London WC1N 3JH, UK.
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44
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Perreaux F, Zenaty D, Capron F, Trioche P, Odièvre M, Labrune P. Azathioprine-induced lung toxicity and efficacy of cyclosporin A in a young girl with type 2 autoimmune hepatitis. J Pediatr Gastroenterol Nutr 2000; 31:190-2. [PMID: 10941975 DOI: 10.1097/00005176-200008000-00020] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- F Perreaux
- Service de Pédiatrie, Hôpital Antoine Béclère, Clamart, France
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45
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46
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Debray D, Maggiore G, Girardet JP, Mallet E, Bernard O. Efficacy of cyclosporin A in children with type 2 autoimmune hepatitis. J Pediatr 1999; 135:111-4. [PMID: 10393616 DOI: 10.1016/s0022-3476(99)70339-2] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The conventional treatment of autoimmune hepatitis (AIH) with prednisone and azathioprine induces remission in most cases but is often associated with poorly tolerated side effects. We carried out a retrospective study to evaluate the efficacy of and the tolerance to cyclosporin treatment in 15 children and adolescents with type 2 AIH. Eight children received cyclosporin as primary immunosuppression because of risk factors for poor tolerance of steroids. Five other patients with relapsing AIH refused to resume treatment with steroids and were treated with cyclosporin. In both groups alanine aminotransferase activity returned to normal within 6 months. Side effects were minimal and well tolerated. No relapse occurred in 10 patients after 1 to 6 years. Cyclosporin was withdrawn in 3 patients after 1, 2, and 3 years and replaced by low doses of prednisone in combination with azathioprine. In 2 other children with acute liver failure, which progressed despite treatment with steroids and azathioprine, the addition of cyclosporin was followed by normalization of prothrombin time.
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Affiliation(s)
- D Debray
- Service d'Hépatologie Pédiatrique, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France
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47
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Chen PM, Chiou TJ, Fan FS, Liu JM, Hsieh RK, Yen CC, Wang WS, Liu JH. Fulminant hepatitis is significantly increased in hepatitis B carriers after allogeneic bone marrow transplantation. Transplantation 1999; 67:1425-33. [PMID: 10385080 DOI: 10.1097/00007890-199906150-00006] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Bone marrow transplantation (BMT) is effective treatment for many hematologic disease, but performed in a population with a high endemic hepatitis B virus carrier rate, the incidence of liver function impairment and fulminant hepatitis (FH) is expected to be raised. METHODS Forty-three hepatitis B virus carriers received high-dose chemotherapy and BMT, 32 patients received an allogeneic graft, and 11 patients autologous marrow. Acute graft-versus-host disease prophylaxis consisted of methotrexate on day 1, 3, 6, and 11 and cyclosporine for 6 months. RESULTS After a median follow-up period of 68 months (range: 1-11.5 years), 26 (81.3%) allogeneic BMT patients developed impaired liver function (LF), 5 progressed to FH on day 93, 169, 170, 180, and 468, respectively, and died after an average of 13.8 days (range: 1-45 days). Whereas only 4 (36.4%) autologous BMT patients developed impaired LF, and none FH. Impaired LF (P=0.026, chi-square), and FH (odds ratio=12.86, P=0.009 for coefficient) were significantly related to an allogeneic marrow graft, and the timing of liver function impairment coincided with cyclosporine withdrawal. Hepatitis B surface antigen (HbsAg) disappeared from the serum in 4/14 (28.6%) patients receiving a marrow graft from an HbsAg+ donor. HbsAg was not detected in the serum after BMT in 2/11 (18.2%) autologous BMT patients. CONCLUSIONS Hepatitis B virus carriers receiving a marrow graft from an HbsAg+ donor have a significantly increased risk of FH.
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Affiliation(s)
- P M Chen
- Department of Medicine, Veterans General Hospital, Taipei, Taiwan, Republic of China.
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48
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Alvarez F, Ciocca M, Cañero-Velasco C, Ramonet M, de Davila MT, Cuarterolo M, Gonzalez T, Jara-Vega P, Camarena C, Brochu P, Drut R, Alvarez E. Short-term cyclosporine induces a remission of autoimmune hepatitis in children. J Hepatol 1999; 30:222-7. [PMID: 10068099 DOI: 10.1016/s0168-8278(99)80065-8] [Citation(s) in RCA: 155] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND/AIMS The current immunosuppressive treatment of patients with autoimmune hepatitis consists of prednisone and azathioprine. High doses of prednisone used to obtain the remission of the disease are associated with serious adverse effects. To avoid harmful consequences of prednisone therapy, we proposed to treat patients with oral cyclosporine to obtain the remission of the inflammatory process. METHODS This is a pilot, multinational, multicenter, clinical trial involving children with autoimmune hepatitis. Thirty-two children were recruited, who according to international criteria were considered as having definite autoimmune hepatitis. Cyclosporine alone was administered for 6 months, followed by combined low doses of prednisone and azathioprine for 1 month, after which cyclosporine was discontinued. Biochemical remission of the disease was established by the follow-up of serum transaminase activity levels. Growth parameters and adverse effects of the treatment were recorded. RESULTS Two patients were withdrawn from the study: one for non-compliance and the other for liver failure which did not improve with cyclosporine. Of the 30 remaining patients, 25 normalized alanine aminotransferase activity levels by 6 months and all the patients by 1 year of treatment. Z-scores for height showed a trend towards improvement during treatment. Adverse effects of cyclosporine were mild and disappeared during weaning off the medication. CONCLUSIONS Cyclosporine induced the biochemical remission of the hepatic inflammatory/necrotic process in children with autoimmune hepatitis, with few and well-tolerated adverse effects.
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Affiliation(s)
- F Alvarez
- Gastroenterology Unit, Hôpital Sainte-Justine, Université de Montréal, Quebec, Canada
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49
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Fernandes NF, Redeker AG, Vierling JM, Villamil FG, Fong TL. Cyclosporine therapy in patients with steroid resistant autoimmune hepatitis. Am J Gastroenterol 1999; 94:241-8. [PMID: 9934764 DOI: 10.1111/j.1572-0241.1999.00807.x] [Citation(s) in RCA: 107] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Autoimmune hepatitis is a form of chronic liver disease characterized by progressive hepatocellular inflammation, which usually responds to treatment with corticosteroids. However, 10% of patients with autoimmune hepatitis are refractory to corticosteroids and develop progressive liver disease and cirrhosis. We describe five patients with autoimmune hepatitis who did not respond to conventional corticosteroids and azathioprine therapy who were then treated with cyclosporine A. Cyclosporine A was started at 2-3 mg/kg/day and induced biochemical remission in four of five patients within 3 months. One of the four responders relapsed within 1 month of discontinuing cyclosporine on two occasions. Each time, liver tests promptly normalized after reinitiation of cyclosporine. Two responders were managed with cyclosporine alone. The single patient who did not respond to cyclosporine developed progressive liver failure, underwent orthotopic liver transplantation, and subsequently died of disseminated cytomegalovirus infection. Cyclosporine was generally well tolerated and none of the patients developed renal insufficiency. These data and review of 11 cases in the literature show that cyclosporine can induce remission of liver disease in patients with autoimmune hepatitis who are refractory to corticosteroids.
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Affiliation(s)
- N F Fernandes
- Cedars-Sinai Medical Center, Center for Liver Disease and Transplantation, and Liver Unit, University of Southern California School of Medicine, Los Angeles 90048, USA
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50
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Abstract
Prednisone alone or in combination with azathioprine is the treatment of choice for severe type 1 autoimmune hepatitis. The combination regimen is preferred, especially in the elderly, because of a lower incidence of corticosteroid-related complications. Only patients with sustained severe laboratory abnormalities, bridging necrosis or multilobular necrosis on histological assessment, and/or incapacitating symptoms, have absolute indications for treatment based on controlled clinical trials. The institution of therapy must be individualised in other patients, based mainly on symptoms and disease behaviour. Serum aspartate aminotransferase and gamma-globulin levels are the most useful indices to monitor during therapy. Liver tissue examination is the best method of evaluating completeness of response. Most patients enter remission, but relapse occurs in 50 to 86% after drug withdrawal. Maintenance therapy with low dosages of prednisone or azathioprine can be used long term in patients who have relapsed repeatedly. Inability to achieve remission after 3 years (incomplete response), deterioration during therapy (treatment failure) and drug toxicity are unsatisfactory responses that warrant alternative strategies. Liver transplantation is effective in managing decompensated disease, but recurrence of autoimmune hepatitis after transplantation is possible. Tacrolimus and budesonide are promising new drugs.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA
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