|
1
|
Anwar MT, Shahzil M, Arif TB, Khaqan MA, Co EL, Hasan F, Tarar R, Naeem H, Farooq S, Jaan A, Chaudhary AJ, Jahagirdar V, Salgia R. MMF Is an Effective and Safer Treatment Options for Treatment-Naïve Patients With Autoimmune Hepatitis Compared to Azathioprine: A Systematic Review and Meta-Analysis. J Dig Dis 2025. [PMID: 40386905 DOI: 10.1111/1751-2980.13348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Revised: 04/27/2025] [Accepted: 05/05/2025] [Indexed: 05/20/2025]
Abstract
OBJECTIVES Autoimmune Hepatitis (AIH) is a chronic inflammatory liver disease with significant morbidity and mortality if untreated. Current first-line treatment involves corticosteroids and azathioprine (AZA), which are effective but are associated with significant adverse effects and treatment intolerance. Mycophenolate mofetil (MMF), an immunosuppressive agent with a potentially better safety profile, has emerged as an alternative. This meta-analysis evaluated the efficacy and safety of MMF compared to AZA in treatment-naïve AIH patients. METHODS We conducted a systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Databases were searched for articles published up to May 2024. Statistical analysis was performed using RevMan, employing a random-effects model. RESULTS Five studies involving 621 patients were included. MMF showed significantly higher rates of complete biochemical response compared to AZA (odds ratio [OR] 3.64, 95% confidence interval [CI] 2.07-6.40, p < 0.00001) and lower non-response rates (OR 0.45, 95% CI 0.24-0.85, p = 0.01). Corticosteroid withdrawal rates were also higher in the MMF group (OR 2.89, 95% CI 1.69-4.94, p = 0.0001). Relapse rate and cumulative prednisolone dose were comparable between the two groups. MMF demonstrated a better safety profile, with significantly lower rates of gastrointestinal symptoms (OR 0.46, 95% CI 0.27-0.79, p = 0.005). CONCLUSIONS MMF shows superior efficacy and tolerability compared to AZA in treatment-naïve AIH patients and may serve as a preferred first-line therapy, offering improved patient adherence and clinical outcomes. Further randomized controlled trials are warranted to confirm these findings.
Collapse
Affiliation(s)
- Muhammad Tayyab Anwar
- Department of Internal Medicine, John H. Stroger Jr. Hospital of Cook County, Chicago, Illinois, USA
| | - Muhammad Shahzil
- Department of Internal Medicine, Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pennsylvania, USA
| | - Taha Bin Arif
- Department of Internal Medicine, Sinai Hospital of Baltimore, Baltimore, Maryland, USA
| | - Muhammad Ali Khaqan
- Department of Gastroenterology and Hepatology, University of Kentucky, Lexington, Kentucky, USA
| | - Edzel Lorraine Co
- Department of Internal Medicine, University of Santo Tomas Faculty of Medicine and Surgery, Sampaloc, Manila, Philippines
| | - Fariha Hasan
- Department of Internal Medicine, Cooper University Hospital, Camden, New Jersey, USA
| | - Rameez Tarar
- Department of Medicine, King Edward Medical University, Lahore, Pakistan
| | - Hamza Naeem
- Department of Medicine, King Edward Medical University, Lahore, Pakistan
| | - Sibgha Farooq
- Department of Medicine, Avicenna Medical College, Lahore, Pakistan
| | - Ali Jaan
- Department of Internal Medicine, Rochester General Hospital, Rochester, New York, USA
| | | | - Vinay Jahagirdar
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Reena Salgia
- Department of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, Michigan, USA
| |
Collapse
|
|
2
|
Habibi MA, Aghayee F, Mirjani MS, Karimifar MR, Ahmadi MR, Eazi SM, Minaee P, Pashaei MR, Hormati A, Akbari Aleagha MM, Ahmadpour S. The safety and efficacy of rituximab in autoimmune hepatitis: a systematic review and quality assessment. Eur J Gastroenterol Hepatol 2025:00042737-990000000-00532. [PMID: 40359300 DOI: 10.1097/meg.0000000000002981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/15/2025]
Abstract
Up now, several medications were proposed for the treatment of autoimmune hepatitis (AIH); however, because of the unclear pathophysiology of AIH, the most optimal treatment option needs to be elucidated. This systematic review sought to investigate the safety and efficacy of rituxiamb (RTX) in patients with AIH. A total of 27 studies were included in the present study. A total of 80 patients had the eligibility criteria, of which the majority of them were female (63 female and 17 male). Of the 80 patients, nine patients were pediatrics. The induction of remission and maintenance therapy were the most common indications for RTX in AIH. Of the 80 patients, we found complete remission in 55% of patients (n = 44) and partial remission in 11% of patients (n = 11). Of the nine pediatric patients, we found complete remission in 77% of patients (n = 7) and partial remission in 22% of patients (n = 2). Unclear response was also reported in 31% of patients (n = 25), which included four studies. 375 mg/m2 × 4 followed by 1000 mg × 2 was the most commonly applied RTX dosage used for treatment of AIH. RTX therapy was associated with infectious complications in six patients; however, one episode of cancer, death, mild conjunctivitis, and large bowel perforation were also reported. RTX is an anti-CD20 mAb and was shown to be effective for the treatment of AIH, but there is no consensus regarding the therapeutic role of RTX in AIH.
Collapse
Affiliation(s)
- Mohammad Amin Habibi
- Department of Neurosurgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran
| | - Fatemeh Aghayee
- Student Research Committee, Qom University of Medical Sciences
| | | | | | | | | | - Poriya Minaee
- Student Research Committee, Qom University of Medical Sciences
| | - Mohammad Reza Pashaei
- Department of Internal Medicine, School of Medicine, Urmia University of Medical Sciences, Urmia
| | - Ahmad Hormati
- Department of Internal Medicine, School of Medicine, Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran
| | | | - Sajjad Ahmadpour
- Patient Safety Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| |
Collapse
|
|
3
|
Gleeson D, Bornand R, Brownlee A, Dhaliwal H, Dyson JK, Hails J, Henderson P, Kelly D, Mells GF, Miquel R, Oo YH, Sutton A, Yeoman A, Heneghan MA. British Society of Gastroenterology guidelines for diagnosis and management of autoimmune hepatitis. Gut 2025:gutjnl-2024-333171. [PMID: 40169244 DOI: 10.1136/gutjnl-2024-333171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 10/22/2024] [Indexed: 04/03/2025]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which, if untreated, often leads to cirrhosis, liver failure and death. The last British Society of Gastroenterology (BSG) guideline for the management of AIH was published in 2011. Since then, our understanding of AIH has advanced in many areas. This update to the previous guideline was commissioned by the BSG and developed by a multidisciplinary group. The aim of this guideline is to review and summarise the current evidence, in order to inform and guide diagnosis and management of patients with AIH and its variant syndromes. The main focus is on AIH in adults, but the guidelines should also be relevant to older children and adolescents.
Collapse
Affiliation(s)
- Dermot Gleeson
- Liver Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
- Division of Clinical Medicine, School of Medicine and Population Science, University of Sheffield, Sheffield, UK
| | | | | | - Harpreet Dhaliwal
- Department of Gastroenterology, Manchester Royal Infirmary, Manchester, UK
| | - Jessica K Dyson
- Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Janeane Hails
- Division of Gastroenterology and Hepatology, Addenbrooke's Hospital, Cambridge, UK
| | - Paul Henderson
- Royal Hospital for Children and Young People, Edinburgh, UK
| | - Deirdre Kelly
- Birmingham Women's & Children's Hospital, Birmingham, UK
- University of Birmingham, Birmingham, UK
| | - George F Mells
- Division of Gastroenterology and Hepatology, Addenbrooke's Hospital, Cambridge, UK
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - Rosa Miquel
- Liver Histopathology Laboratory, Institute of Liver Studies, King's College London, London, UK
| | - Ye H Oo
- Centre for Liver and Gastroenterology research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- NIHR Biomedical Research Centre, University of Birmingham and University Hospital Birmingham NHS Foundation Trust, Birmingham, UK
- Centre for Rare Diseases, European Reference Network on Hepatological Diseases (ERN-RARE-LIVER) centre, Birmingham, UK
| | - Anthea Sutton
- Sheffield Centre for Health and Related Research, The University of Sheffield, Sheffield, UK
| | | | | |
Collapse
|
|
4
|
Broekaert IJ, Assa A, Borrelli O, Saccomani MD, Homan M, Martin‐de‐Carpi J, Mas E, Miele E, Misak Z, Sila S, Thomson M, Tzivinikos C, Dolinsek J. Approach to anaemia in gastrointestinal disease: A position paper by the ESPGHAN Gastroenterology Committee. J Pediatr Gastroenterol Nutr 2025; 80:510-532. [PMID: 39783775 PMCID: PMC11874238 DOI: 10.1002/jpn3.12454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 10/31/2024] [Accepted: 12/10/2024] [Indexed: 01/12/2025]
Abstract
Anaemia is a frequent consequence of many gastrointestinal (GI) diseases in children and it can even be the initial presenting symptom of underlying chronic GI disease. The definition of anaemia is age and gender-dependent and it can be classified based on pathophysiology, red cell morphology, and clinical presentation. Although nutritional deficiencies, including GI malabsorption of nutrients and GI bleeding, play a major role, other pathophysiologic mechanisms seen in chronic GI diseases, whether inflammatory (e.g., inflammatory bowel disease) or not (e.g., coeliac disease and dysmotility), are causing anaemia. Drugs, such as proton pump inhibitors, mesalamine, methotrexate and sulfasalazine, are also a potential cause of anaemia. Not uncommonly, due to a combination of factors, such as iron deficiency and a chronic inflammatory state, the underlying pathophysiology may be difficult to decipher and a broad diagnostic work-up is required. The goal of treatment is correction of anaemia by supplementation of iron and vitamins. The first therapeutic step is to treat the underlying cause of anaemia including bleeding control, restoration of intestinal integrity and reduction of inflammatory burden. The route of iron and vitamin supplementation is guided by the severity of anaemia.
Collapse
Affiliation(s)
- Ilse Julia Broekaert
- Department of Paediatrics, Faculty of Medicine and University Hospital CologneUniversity of CologneCologneGermany
| | - Amit Assa
- The Juliet Keidan Institute of Paediatric Gastroenterology and Nutrition, Shaare Zedek Medical CentreThe Hebrew UniversityJerusalemIsrael
| | - Osvaldo Borrelli
- Division of Neurogastroenterology & Motility, Department of Paediatric GastroenterologyGreat Ormond Street HospitalLondonUK
| | | | - Matjaž Homan
- Department of Gastroenterology, Hepatology and Nutrition, University Children's HospitalFaculty of MedicineUniversity of LjubljanaLjubljanaSlovenia
| | - Javier Martin‐de‐Carpi
- Department of Paediatric Gastroenterology, Hepatology and NutritionHospital Sant Joan de DéuBarcelonaSpain
| | - Emmanuel Mas
- Service de Gastroentérologie, Hépatologie, Nutrition et Maladies Héréditaires du Métabolisme, Hôpital des Enfants, and IRSDUniversité de Toulouse, INSERM, INRAE, ENVT, UPSToulouseFrance
| | - Erasmo Miele
- Department of Translational Medical Science, Section of PediatricsUniversity of Naples “Federico II”NaplesItaly
| | - Zrinjka Misak
- Referral Centre for Paediatric Gastroenterology and NutritionChildren's Hospital ZagrebZagrebCroatia
| | - Sara Sila
- Referral Centre for Paediatric Gastroenterology and NutritionChildren's Hospital ZagrebZagrebCroatia
| | - Mike Thomson
- Centre for Paediatric GastroenterologySheffield Children's Hospital NHS Foundation TrustSheffieldUK
| | - Christos Tzivinikos
- Paediatric Gastroenterology Department, Al Jalila Children's Specialty HospitalMohammed Bin Rashid University, Dubai Medical CollegeDubaiUnited Arab Emirates
| | - Jernej Dolinsek
- Department of PaediatricsUniversity Medical Centre MariborMariborSlovenia
| |
Collapse
|
|
5
|
Rahmat AK, Irmasari, Nafiah Z, Ikawati Z. Pharmacogenetics to optimize immunosuppressant therapy in systemic lupus erythematosus: a scoping review. Pharmacogenomics 2025; 26:129-142. [PMID: 40208755 DOI: 10.1080/14622416.2025.2490464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 04/04/2025] [Indexed: 04/12/2025] Open
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease requiring immunosuppressive medications to control symptoms and prevent organ damage. This review explores the influence of genetic polymorphisms on the pharmacokinetics and therapeutic responses of immunosuppressants in SLE. A total of 37 studies were reviewed, focusing on mycophenolic acid, tacrolimus, azathioprine, glucocorticoids, and cyclophosphamide. Genetic variants in UGT1A9, UGT2B7, CYP3A5, ABCB1,ABCC2 and TPMT significantly affect drug metabolism, efficacy, and toxicity. For instance, ABCB1 polymorphisms influence drug transport and bioavailability, impacting tacrolimus and glucocorticoid response, while ABCC2 variants alter MPA clearance, potentially affecting therapeutic outcomes, UGT1A9 and UGT2B7 variants influence mycophenolic acid metabolism, CYP3A5 impacts tacrolimus dosing, TPMT determines azathioprine metabolism, and CYP2C19 and CYP2B6 affect cyclophosphamide processing. These genetic differences can alter treatment effectiveness and risk of adverse effects. However, most pharmacogenetic studies focus on organ transplantation, leaving a critical gap in SLE-specific research, particularly among diverse populations. Addressing this gap is essential to optimizing personalized treatment for SLE. Integrating pharmacogenetics into clinical practice holds great potential to enhance the safety, efficacy, and outcomes of immunosuppressive therapy in SLE. This review highlights the urgent need for further studies to advance precision medicine for SLE patients.
Collapse
Affiliation(s)
- Alim Khodimul Rahmat
- Doctor's Program in Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia
- Master's Program in Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Irmasari
- Master's Program in Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Zahrotun Nafiah
- Master's Program in Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Zullies Ikawati
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia
| |
Collapse
|
|
6
|
Weltzsch JP, Bartel CF, Waldmann M, Renné T, Schulze S, Terziroli Beretta-Piccoli B, Papp M, Oo YH, Ronca V, Sebode M, Lohse AW, Schramm C, Hartl J. Optimizing thiopurine therapy in autoimmune hepatitis: A multicenter study on monitoring metabolite profiles and co-therapy with allopurinol. Hepatology 2024; 80:1026-1040. [PMID: 39162583 DOI: 10.1097/hep.0000000000000940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 04/09/2024] [Indexed: 08/21/2024]
Abstract
BACKGROUND AND AIMS In autoimmune hepatitis, achieving complete biochemical remission (CBR) with current weight-based thiopurine dosing is challenging. We investigated whether patients could be stratified regarding CBR according to a target range of thiopurine metabolites. Moreover, we explored the effects of azathioprine dosage increases and co-therapy of allopurinol with low-dose thiopurines on metabolite profiles and treatment response. APPROACH AND RESULTS The relation between metabolites and treatment response was assessed in 337 individuals from 4 European centers. In a global, cross-sectional analysis, active metabolites 6-thioguanine nucleotides (6TGN) were similar in those with and without CBR. However, analyzing patients with sequential measurements over 4 years (N = 146) revealed higher average 6TGN levels in those with stable CBR (260 pmol/0.2 mL) compared to those failing to maintain CBR (181 pmol/0.2 mL; p = 0.0014) or never achieving CBR (153 pmol/0.2 mL; p < 0.0001), with an optimal 6TGN cutoff of ≥223 pmol/0.2 mL (sensitivity: 76% and specificity: 78%). Only 42% exhibited 6TGN ≥223 pmol/0.2 mL following weight-based dosing, as doses weakly correlated with 6TGN but with 6-methylmercaptopurine (6MMP), a metabolite associated with toxicity. Azathioprine dose increases led to preferential 6MMP formation (+127% vs. 6TGN +34%; p < 0.0001). Conversely, adding allopurinol to thiopurines in difficult-to-treat patients (N = 36) raised 6TGN (168→321 pmol/0.2 mL; p < 0.0001) and lowered 6MMP (2125→184 pmol/0.2 mL; p < 0.0001), resulting in improved transaminases in all patients and long-term CBR in 75%. CONCLUSIONS Maintaining CBR in autoimmune hepatitis was associated with 6TGN ≥223 pmol/0.2 mL. For patients who fail to achieve CBR and therapeutic 6TGN levels despite thiopurine dose increase due to preferential 6MMP formation, comedication of allopurinol alongside low-dose thiopurines represents an efficient alternative.
Collapse
Affiliation(s)
- Jan Philipp Weltzsch
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Claudius F Bartel
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
| | - Moritz Waldmann
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
| | - Thomas Renné
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Stephanie Schulze
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
| | - Benedetta Terziroli Beretta-Piccoli
- Epatocentro Ticino, Lugano, Switzerland
- Faculty of Biochemical Sciences, Università della Svizzera Italiana, Lugano, Switzerland
- Mowat Labs, Faculty of Life Sciences & Medicine, King's College London, King's College Hospital, London, UK
| | - Maria Papp
- Department of Gastroenterology, Institute of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Ye H Oo
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
- Centre for Liver Research and National Institute of Health Research Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham
- Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust
| | - Vincenzo Ronca
- Centre for Liver Research and National Institute of Health Research Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham
| | - Marcial Sebode
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Ansgar W Lohse
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Christoph Schramm
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
- Hamburg Centre for Translational Immunology (HCTI), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Johannes Hartl
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| |
Collapse
|
|
7
|
Xu Y, Yu X, Guo Y. From the experimental to the clinical: Deepening the understanding of mycophenolate mofetil combined with prednisolone therapy. J Hepatol 2024; 81:e37. [PMID: 38346578 DOI: 10.1016/j.jhep.2024.02.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 02/01/2024] [Accepted: 02/08/2024] [Indexed: 04/12/2024]
Affiliation(s)
- Yixuan Xu
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xiaofei Yu
- Department of Neurology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Yongmei Guo
- Department of Neurology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| |
Collapse
|
|
8
|
Snijders RJALM, Stoelinga AEC, Gevers TJG, Pape S, Biewenga M, Tushuizen ME, Verdonk RC, de Jonge HJM, Vrolijk JM, Bakker SF, Vanwolleghem T, de Boer YS, Baven Pronk MAMC, Beuers U, van der Meer AJ, Gerven NMFV, Sijtsma MGM, van Eijck BC, van IJzendoorn MC, van Herwaarden M, van den Brand FF, Korkmaz KS, van den Berg AP, Guichelaar MMJ, Levens AD, van Hoek B, Drenth JPH. An open-label randomised-controlled trial of azathioprine vs. mycophenolate mofetil for the induction of remission in treatment-naive autoimmune hepatitis. J Hepatol 2024; 80:576-585. [PMID: 38101756 DOI: 10.1016/j.jhep.2023.11.032] [Citation(s) in RCA: 35] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 11/15/2023] [Accepted: 11/21/2023] [Indexed: 12/17/2023]
Abstract
BACKGROUND & AIMS Patients with autoimmune hepatitis (AIH) almost invariably require lifelong immunosuppressive treatment. There is genuine concern about the efficacy and tolerability of the current standard combination therapy of prednisolone and azathioprine. Mycophenolate mofetil (MMF) has emerged as an alternative option. The aim of this study was to compare MMF to azathioprine as induction therapy for AIH. METHODS In this 24-week, prospective, randomised, open-label, multicentre superiority trial, 70 patients with treatment-naive AIH received either MMF or azathioprine, both in combination with prednisolone. The primary endpoint was biochemical remission defined as normalisation of serum levels of alanine aminotransferase and IgG after 24 weeks of treatment. Secondary endpoints included safety and tolerability. RESULTS Seventy patients (mean 57.9 years [SD 14.0]; 72.9% female) were randomly assigned to the MMF plus prednisolone (n = 39) or azathioprine plus prednisolone (n = 31) group. The primary endpoint was met in 56.4% and 29.0% of patients assigned to the MMF group and the azathioprine group, respectively (difference, 27.4 percentage points; 95% CI 4.0 to 46.7; p = 0.022). The MMF group exhibited higher complete biochemical response rates at 6 months (72.2% vs. 32.3%; p = 0.004). No serious adverse events occurred in patients who received MMF (0%) but serious adverse events were reported in four patients who received azathioprine (12.9%) (p = 0.034). Two patients in the MMF group (5.1%) and eight patients in the azathioprine group (25.8%) discontinued treatment owing to adverse events or serious adverse events (p = 0.018). CONCLUSIONS In patients with treatment-naive AIH, MMF with prednisolone led to a significantly higher rate of biochemical remission at 24 weeks compared to azathioprine combined with prednisolone. Azathioprine use was associated with more (serious) adverse events leading to cessation of treatment, suggesting superior tolerability of MMF. IMPACT AND IMPLICATIONS This randomised-controlled trial directly compares azathioprine and mycophenolate mofetil, both in combination with prednisolone, for the induction of biochemical remission in treatment-naive patients with autoimmune hepatitis. Achieving complete remission is desirable to prevent disease progression. Patients assigned to the mycophenolate mofetil group reached biochemical remission more often and experienced fewer adverse events. The findings in this trial may contribute to the re-evaluation of international guidelines for the standard of care in treatment-naive patients with autoimmune hepatitis. TRIAL REGISTRATION NUMBER #NCT02900443.
Collapse
Affiliation(s)
- Romée J A L M Snijders
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands; European Reference Network RARE-LIVER, Germany
| | - Anna E C Stoelinga
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Tom J G Gevers
- Nutrim School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands; European Reference Network RARE-LIVER, Germany
| | - Simon Pape
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands; European Reference Network RARE-LIVER, Germany
| | - Maaike Biewenga
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Maarten E Tushuizen
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Robert C Verdonk
- Department of Gastroenterology and Hepatology, St. Antonius Hospital, Nieuwegein, The Netherlands
| | - Hendrik J M de Jonge
- Department of Gastroenterology and Hepatology, Jeroen Bosch Hospital, 's Hertogenbosch, The Netherlands
| | - Jan Maarten Vrolijk
- Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, The Netherlands
| | - Sjoerd F Bakker
- Department of Gastroenterology and Hepatology, Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands
| | - Thomas Vanwolleghem
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium; European Reference Network RARE-LIVER, Germany
| | - Ynto S de Boer
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centres, location VU Medical Centre, Amsterdam, The Netherlands; European Reference Network RARE-LIVER, Germany
| | | | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centres, location Academic Medical Centre, Amsterdam, The Netherlands; European Reference Network RARE-LIVER, Germany
| | - Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, The Netherlands
| | - Nicole M F van Gerven
- Department of Gastroenterology and Hepatology, Rode Kruis Hospital, Beverwijk, The Netherlands
| | - Marijn G M Sijtsma
- Department of Gastroenterology and Hepatology, St. Jansdal Hospital, Harderwijk, The Netherlands
| | - Brechje C van Eijck
- Department of Gastroenterology and Hepatology, Spaarne Gasthuis, Haarlem, The Netherlands
| | - Manon C van IJzendoorn
- Department of Gastroenterology and Hepatology, Hospital Bernhoven, Uden, The Netherlands
| | - Margot van Herwaarden
- Department of Gastroenterology and Hepatology, Deventer Hospital, Deventer, The Netherlands
| | | | - Kerem Sebib Korkmaz
- Department of Gastroenterology and Hepatology, IJselland Hospital, Capelle aan den Ijssel, the Netherlands
| | - Aad P van den Berg
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands; European Reference Network RARE-LIVER, Germany
| | - Maureen M J Guichelaar
- Department of Gastroenterology and Hepatology, Medisch Spectrum Twente, Enschede, The Netherlands
| | - Amar D Levens
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands; European Reference Network RARE-LIVER, Germany.
| |
Collapse
|
|
9
|
Mercado LA, Gil-Lopez F, Chirila RM, Harnois DM. Autoimmune Hepatitis: A Diagnostic and Therapeutic Overview. Diagnostics (Basel) 2024; 14:382. [PMID: 38396421 PMCID: PMC10887775 DOI: 10.3390/diagnostics14040382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/02/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Autoimmune hepatitis is an immune-mediated inflammatory condition of the liver of undetermined cause that affects both sexes, all ages, races, and ethnicities. Its clinical presentation can be very broad, from having an asymptomatic and silent course to presenting as acute hepatitis, cirrhosis, and acute liver failure potentially requiring liver transplantation. The diagnosis is based on histological abnormalities (interface hepatitis), characteristic clinical and laboratory findings (increased aspartate aminotransferase, alanine aminotransferase, and serum IgG concentration), and the presence of one or more characteristic autoantibodies. The large heterogeneity of these clinical, biochemical, and histological findings can sometimes make a timely and proper diagnosis a difficult task. Treatment seeks to achieve remission of the disease and prevent further progression of liver disease. First-line therapy includes high-dose corticosteroids, which are later tapered to decrease side effects, and azathioprine. In the presence of azathioprine intolerance or a poor response to the standard of care, second-line therapy needs to be considered, including mycophenolate mofetil. AIH remains a diagnostic and therapeutic challenge, and a further understanding of the pathophysiological pathways of the disease and the implementation of randomized controlled trials are needed.
Collapse
Affiliation(s)
- Lydia A. Mercado
- Department of Liver Transplant, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Fernando Gil-Lopez
- Department of Liver Transplant, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Razvan M. Chirila
- Department of General Internal Medicine, Mayo Clinic Florida, Jacksonville, FL 32224, USA;
| | - Denise M. Harnois
- Department of Liver Transplant, Mayo Clinic Florida, Jacksonville, FL 32224, USA
- Department of Gastroenterology and Hepatology, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| |
Collapse
|
|
10
|
The Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines for management of autoimmune hepatitis 2022. Clin Mol Hepatol 2023; 29:542-592. [PMID: 37137334 PMCID: PMC10366804 DOI: 10.3350/cmh.2023.0087] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/27/2023] [Accepted: 04/03/2023] [Indexed: 05/05/2023] Open
|
|
11
|
Kim JK. [Treatment of Autoimmune Hepatitis]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2023; 81:72-85. [PMID: 36824035 DOI: 10.4166/kjg.2023.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/13/2023] [Accepted: 02/13/2023] [Indexed: 02/25/2023]
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disease, characterized by elevated levels of transaminases, immunoglobulin G, and positive autoantibodies. The disease course is dynamic and presents heterogeneous disease manifestations at diagnosis. This review summarizes the issues regarding the treatment and monitoring of AIH in adult patients. Glucocorticoids and azathioprine are the first line of treatment. Alternative first-line treatments include budesonide or mycophenolate mofetil (MMF). Although no randomized controlled trials have been performed, MMF, cyclosporine, tacrolimus, 6-mercaptopurine, 6-thioguanine, allopurinol, sirolimus, everolimus, infliximab, or rituximab have been attempted in patients not responding to or intolerant to first-line treatments. Most patients require life-long special monitoring, with or without maintenance treatment.
Collapse
Affiliation(s)
- Ja Kyung Kim
- Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea
| |
Collapse
|
|
12
|
Harrington C, Krishnan S, Mack CL, Cravedi P, Assis DN, Levitsky J. Noninvasive biomarkers for the diagnosis and management of autoimmune hepatitis. Hepatology 2022; 76:1862-1879. [PMID: 35611859 PMCID: PMC9796683 DOI: 10.1002/hep.32591] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 01/07/2023]
Abstract
Autoimmune hepatitis (AIH) is a rare disease of unclear etiology characterized by loss of self-tolerance that can lead to liver injury, cirrhosis, and acute liver failure. First-line treatment consists of systemic corticosteroids, or budesonide, and azathioprine, to which most patients are initially responsive, although predictors of response are lacking. Relapses are very common, correlate with histological activity despite normal serum transaminases, and increase hepatic fibrosis. Furthermore, current regimens lead to adverse effects and reduced quality of life, whereas medication titration is imprecise. Biomarkers that can predict the clinical course of disease, identify patients at elevated risk for relapse, and improve monitoring and medication dosing beyond current practice would have high clinical value. Herein, we review novel candidate biomarkers in adult and pediatric AIH based on prespecified criteria, including gene expression profiles, proteins, metabolites, and immune cell phenotypes in different stages of AIH. We also discuss biomarkers relevant to AIH from other immune diseases. We conclude with proposed future directions in which biomarker implementation into clinical practice could lead to advances in personalized therapeutic management of AIH.
Collapse
Affiliation(s)
- Claire Harrington
- Division of Gastroenterology & HepatologyNorthwestern University Feinberg School of MedicineChicagoIllinoisUSA
| | - Swathi Krishnan
- Medicine DepartmentYale School of MedicineNew HavenConnecticutUSA
| | - Cara L. Mack
- Section of Pediatric Gastroenterology, Hepatology & Nutrition, Children's Hospital ColoradoUniversity of Colorado School of MedicineAuroraColoradoUSA
| | - Paolo Cravedi
- Division of NephrologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - David N. Assis
- Section of Digestive DiseasesYale School of MedicineNew HavenConnecticutUSA
| | - Josh Levitsky
- Division of Gastroenterology & HepatologyNorthwestern University Feinberg School of MedicineChicagoIllinoisUSA
| |
Collapse
|
|
13
|
Heneghan MA, Shumbayawonda E, Dennis A, Ahmed RZ, Rahim MN, Ney M, Smith L, Kelly M, Banerjee R, Culver EL. Quantitative magnetic resonance imaging to aid clinical decision making in autoimmune hepatitis. EClinicalMedicine 2022; 46:101325. [PMID: 35340625 PMCID: PMC8943410 DOI: 10.1016/j.eclinm.2022.101325] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 01/14/2022] [Accepted: 02/11/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND In autoimmune hepatitis (AIH), clinical practice and treatment guidelines frequently diverge as a reflection of disease heterogeneity and challenges in achieving standardised care. We sought to explore the utility of multiparametric (mp) MR in patients with AIH, and the impact of this technology on physicians' decision making and intended patient management. METHODS 82 AIH patients, recruited from two sites between June and November 2019 as part of an observational cohort study, underwent non-contrast MRI alongside their standard clinical investigations. Correlations between iron-corrected T1 (cT1) and other markers of disease were investigated alongside the utility of imaging markers to risk stratify patients in biochemical remission. The impact of mpMR on clinical decision making was evaluated using pairwise t-tests. The discriminatory ability of the imaging markers was assessed using area under the receiver operating characteristic curves (AUCs). FINDINGS cT1 had a significant impact on clinician intended patient management (p<0.0001). cT1 correlated with ALT (p = 0.0005), AST (p<0.001), IgG (p = 0.0005), and liver stiffness (p<0.0001). Patients in deep biochemical remission (N = 11; AST/ALT <50% upper limit of normal [ULN] and IgG <12 g/L) had low cT1, while 7/34 in normal biochemical remission (AST/ALT between 50 and 100% of ULN) had high cT1 and were at risk of disease flare. cT1 measures of disease heterogeneity, ALP and bilirubin made the best predictor of those not in biochemical remission (AUC:0.85). INTERPRETATION This study investigates the impact of mpMR results on intended clinical management in a real world setting. Findings showed that mpMR demonstrated a significant impact on clinical management of AIH and has the potential to inform patient risk stratification. FUNDING This paper presents independent research supported by the Innovate UK grant (104,915).
Collapse
Affiliation(s)
- Michael A. Heneghan
- Institute of Liver Studies, King's College Hospital, NHS Foundation Trust, Denmark Hill, London, United Kingdom
- Corresponding author.
| | | | | | - Refah Z. Ahmed
- Institute of Liver Studies, King's College Hospital, NHS Foundation Trust, Denmark Hill, London, United Kingdom
| | - Mussarat N. Rahim
- Institute of Liver Studies, King's College Hospital, NHS Foundation Trust, Denmark Hill, London, United Kingdom
| | - Michael Ney
- Institute of Liver Studies, King's College Hospital, NHS Foundation Trust, Denmark Hill, London, United Kingdom
| | - Loren Smith
- John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | | | | | - Emma L. Culver
- John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| |
Collapse
|
|
14
|
Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. Autoimmmune hepatitis. Cell Mol Immunol 2022; 19:158-176. [PMID: 34580437 PMCID: PMC8475398 DOI: 10.1038/s41423-021-00768-8] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 08/29/2021] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a T-cell mediated, inflammatory liver disease affecting all ages and characterized by female preponderance, elevated serum transaminase and immunoglobulin G levels, positive circulating autoantibodies, and presence of interface hepatitis at liver histology. AIH type 1, affecting both adults and children, is defined by positive anti-nuclear and/or anti-smooth muscle antibodies, while type 2 AIH, affecting mostly children, is defined by positive anti-liver-kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody. While the autoantigens of type 2 AIH are well defined, being the cytochrome P4502D6 (CYP2D6) and the formiminotransferase cyclodeaminase (FTCD), in type 1 AIH they remain to be identified. AIH-1 predisposition is conferred by possession of the MHC class II HLA DRB1*03 at all ages, while DRB1*04 predisposes to late onset disease; AIH-2 is associated with possession of DRB1*07 and DRB1*03. The majority of patients responds well to standard immunosuppressive treatment, based on steroid and azathioprine; second- and third-line drugs should be considered in case of intolerance or insufficient response. This review offers a comprehensive overview of pathophysiological and clinical aspects of AIH.
Collapse
Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- Epatocentro Ticino & Facoltà di Scienze Biomediche, Università della Svizzera Italiana, Lugano, Switzerland.
- Institute for Research in Biomedicine, Bellinzona, Switzerland.
- King's College London Faculty of Life Sciences & Medicine at King's College Hospital, London, UK.
| | - Giorgina Mieli-Vergani
- King's College London Faculty of Life Sciences & Medicine at King's College Hospital, London, UK
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, London, UK
| | - Diego Vergani
- King's College London Faculty of Life Sciences & Medicine at King's College Hospital, London, UK
- Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK
| |
Collapse
|
|
15
|
Dalekos GN, Arvaniti P, Gatselis NK, Samakidou A, Gabeta S, Rigopoulou E, Koukoulis GK, Zachou K. First Results From a Propensity Matching Trial of Mycophenolate Mofetil vs. Azathioprine in Treatment-Naive AIH Patients. Front Immunol 2022; 12:798602. [PMID: 35087524 PMCID: PMC8787111 DOI: 10.3389/fimmu.2021.798602] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 12/15/2021] [Indexed: 12/12/2022] Open
Abstract
Background/Aims As previous real-world studies and meta-analyses have shown that mycophenolate mofetil (MMF) might have better efficacy than azathioprine (AZA) in autoimmune hepatitis (AIH), we conducted a propensity matching study to assess the efficacy and safety of MMF vs. AZA. Methods All 126 consecutive treatment-naive adult AIH patients, diagnosed and followed in our department since 2016, were included. Patients received prednisolone 0.5-1 mg/kg/day plus either AZA 1-2 mg/kg/day or 1.5-2 g/day MMF. The tapering of prednisolone was identical between groups. Results After propensity matching score and adjustment for known factors affecting response to treatment and outcome, 64 patients were included in the study (MMF = 32 and AZA = 32). Rates of non-response, complete biochemical response (CBR) at 6 and 12 months, and prednisolone withdrawal (6 months, 12 months, and end of follow-up) were identical between groups. However, MMF treatment was significantly associated with CBR at the end of follow-up [odds ratio (OR) 11.259; 95% CI: 1.3-97.4, p = 0.028]. AZA patients were more prone to stop treatment due to AZA intolerance/insufficient response (p = 0.0001). At the end of follow-up, the overall efficacy of each schedule was also significantly higher in the MMF group compared to the AZA group (p = 0.0001). Conclusion We showed for the first time in a propensity matching study that MMF can be used as first-line therapy in AIH as attested by the significantly higher CBR at end of follow-up compared to AZA. Whether this better efficacy is also associated with higher histological remission rates and sustained CBR off immunosuppression needs further evaluation.
Collapse
Affiliation(s)
- George N. Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Pinelopi Arvaniti
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Nikolaos K. Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Anna Samakidou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Stella Gabeta
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Eirini Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - George K. Koukoulis
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| |
Collapse
|
|
16
|
Vergani D, Terziroli Beretta-Piccoli B, Mieli-Vergani G. A reasoned approach to the treatment of autoimmune hepatitis. Dig Liver Dis 2021; 53:1381-1393. [PMID: 34162505 DOI: 10.1016/j.dld.2021.05.033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/15/2021] [Accepted: 05/27/2021] [Indexed: 12/11/2022]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease affecting all ages, characterised by elevated transaminase and immunoglobulin G levels, positive autoantibodies, interface hepatitis on histology and good response to immunosuppressive treatment. If untreated, it has a poor prognosis. The aim of this review is to analyse AIH therapeutic interventions with reference to our knowledge of the pathogenesis of AIH. Standard treatment, based on steroids and azathioprine, leads to disease remission in 80-90% of patients. Alternative first-line treatment with budesonide is effective in adults, but less so in the juvenile form of AIH; first-line treatment with ciclosporin does not provide convincing advantages compared to standard treatment. Second-line treatments are needed for patients not responding or intolerant to first-line standard management. Mycophenolate mofetil is the most widely used second-line drug, and has good efficacy particularly for patients intolerant to azathioprine, but is teratogenic. Only few and heterogeneous data on calcineurin inhibitors and m-TOR inhibitors are available. Biologicals, including anti-tumour necrosis factor- α and anti-CD20 monoclonal antibodies, have given ambivalent results and may have severe side-effects. Clinical trials with new therapeutic options aiming at targeting B lymphocytes and proinflammatory cytokines, or expanding regulatory T cells to restore tolerance are ongoing.
Collapse
Affiliation(s)
- Diego Vergani
- King's College London Faculty of Life Sciences & Medicine, London, UK; Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK; Epatocentro Ticino, Lugano, Switzerland
| | - Benedetta Terziroli Beretta-Piccoli
- Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK; Epatocentro Ticino, Lugano, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Switzerland
| | - Giorgina Mieli-Vergani
- King's College London Faculty of Life Sciences & Medicine, London, UK; Epatocentro Ticino, Lugano, Switzerland; Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, London, UK.
| |
Collapse
|
|
17
|
Bolia R, Goel A, Srivastava A. Systematic Review and Meta-Analysis of Thiopurine Metabolite Levels and Biochemical Remission in Autoimmune Hepatitis. Ther Drug Monit 2021; 43:609-616. [PMID: 33346628 DOI: 10.1097/ftd.0000000000000848] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 11/17/2020] [Indexed: 11/25/2022]
Abstract
BACKGROUND The utility of measuring thiopurine metabolites (TM) to individualize therapy in autoimmune hepatitis (AIH) has not been defined, and the evidence regarding its use in clinical practice is heterogeneous. This systematic review and meta-analysis aimed to compare the mean concentration of TM between patients in biochemical remission and those not in remission. METHODS A systematic literature search was conducted using PubMed, Scopus, the Cochrane Library, and Google Scholar for keywords related to TM and AIH. Two reviewers independently searched and selected studies comparing the levels of 6-methyl mercaptopurine (6-MMP) and 6-thioguanine nucleotide (6-TGN) and their ratio in cases of AIH in remission and otherwise. Meta-analysis was performed by calculating the weighted mean difference using the inverse variance heterogeneity model. RESULTS A total of 1066 records were identified through systematic search; of which, 7 (n = 3 pediatric, n = 4 adults) were considered for inclusion, and 442 TM measurements (n = 128 in children) were analyzed. Mean 6-TGN levels were significantly higher among patients in remission than in those who were not, with a pooled weighted mean difference (WMD) of 15.67 [95% confidence interval (CI), 6.68-24.66] pmol/8 × 108 red blood cells (RBC). The difference was higher in the pediatric age group (WMD, 56.11; 95% CI, 13.60-98.62) than in adults (WMD, 13.77; 95% CI, 4.58-22.97). There was no significant difference in the 6-MMP levels (WMD, -431.7; 95% CI, -1237.4 to 373.9 pmol/8 × 108 RBC; I2 = 82%; n = 3 studies) or 6-MMP/6-TGN ratio among the patients who were in biochemical remission and those who were not (WMD, -0.97; 95% CI, -5.77 to 3.84; I2 = 82%; n = 3 studies). CONCLUSIONS This meta-analysis suggests a link between 6-TGN levels and biochemical remission in AIH. Further high-quality studies are required to determine the therapeutic cutoff of 6-TGN.
Collapse
Affiliation(s)
- Rishi Bolia
- Division of Pediatric Gastroenterology, Department of Pediatrics, All India Institute of Medical Sciences, Rishikesh
| | - Akhil Goel
- Department of Community and Family Medicine, All India Institute of Medical Sciences, Jodhpur; and
| | - Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| |
Collapse
|
|
18
|
Dorsey YC, Oloruntoba O, Pendse AA, King LY. More Than Meets the Eye? Clin Liver Dis (Hoboken) 2021; 18:173-178. [PMID: 34745573 PMCID: PMC8549717 DOI: 10.1002/cld.1107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 02/12/2021] [Indexed: 02/04/2023] Open
Abstract
Content available: Author Audio Recording.
Collapse
Affiliation(s)
- Ying Claire Dorsey
- Division of Gastroenterology and HepatologyDuke University School of MedicineDurhamNC
| | - Omobonike Oloruntoba
- Division of Gastroenterology and HepatologyDuke University School of MedicineDurhamNC
| | - Avani A. Pendse
- Department of PathologyDuke University School of MedicineDurhamNC
| | - Lindsay Y. King
- Division of Gastroenterology and HepatologyDuke University School of MedicineDurhamNC
| |
Collapse
|
|
19
|
Candels LS, Rahim MN, Shah S, Heneghan MA. Towards personalised medicine in autoimmune hepatitis: Measurement of thiopurine metabolites results in higher biochemical response rates. J Hepatol 2021; 75:324-332. [PMID: 33872691 DOI: 10.1016/j.jhep.2021.03.023] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 03/17/2021] [Accepted: 03/18/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Patients with autoimmune hepatitis (AIH) usually receive maintenance therapy with thiopurines, such as azathioprine (AZA) or mercaptopurine. Genetic polymorphisms in AZA metabolism can lead to variations in thioguanine nucleotide (TGN) and 6-methylmercaptopurine, both of which can cause adverse drug reactions (ADRs). In inflammatory bowel disease, a therapeutic TGN range (225-450 pmol/8x108 erythrocytes) has been identified to optimise effectiveness. We evaluated the benefits of a personalised medicine approach to thiopurine dosing, in comparison to standard weight-based dosing. METHODS A retrospective matched cohort study of 214 patients with AIH who were seen at King's College between 1999-2019 was performed. Metabolite levels were measured in 109 patients. The control group included 105 patients on weight-based thiopurine dosing with no metabolite monitoring. RESULTS Biochemical response (BR) occurred more frequently at 6-month follow-up in patients with metabolite monitoring compared to those on a weight-based regimen (77% vs. 60%, p = 0.008). This remained true with data analysis based on clinicians who measure metabolites and those who do not (BR at 6 months: 84% vs. 64%, p = 0.016). Patients with BR had TGN levels within the therapeutic range of 225-450 pmol/8x108 erythrocytes significantly more often than those who failed to achieve or lost BR (40% vs. 13%, p <0.0001). Moreover, TGN levels within the pre-defined therapeutic range predicted more stable disease within 6 months of testing compared to levels outside the range (p <0.0001). A high proportion of patients with sub-therapeutic TGN levels (75-225 pmol/8x108 erythrocytes) remained in BR (75% vs. 81%, p = 0.589) with fewer ADRs (44% vs. 86%, p = 0.0002) when compared to patients with therapeutic TGN levels. CONCLUSION A strategy of personalised medicine using metabolite levels can optimise treatment regimens in AIH, resulting in fewer ADRs whilst maintaining BR. LAY SUMMARY This study looked to see if measuring the breakdown products of a medication used in autoimmune hepatitis increases the chances of gaining good control of the disease, when compared to a group of patients who were on a dose of this medication based on their weight. A group of 214 patients with autoimmune hepatitis were split into 2 groups: roughly half had their medication dose adjusted according to measurements of breakdown products in the blood, whilst the other half received their weight-based dose as normal. The results confirmed that using a personalised approach and checking drug breakdown products resulted in fewer side effects and potentially improved control of disease.
Collapse
Affiliation(s)
- Lena S Candels
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK; Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Mussarat N Rahim
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK; School of Transplantation, Immunology and Mucosal Biology, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Sital Shah
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK
| | - Michael A Heneghan
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK; School of Transplantation, Immunology and Mucosal Biology, Faculty of Life Sciences and Medicine, King's College London, London, UK; European Reference Network - Hepatological Diseases (ERN RARE-LIVER).
| |
Collapse
|
|
20
|
Wang G, Tanaka A, Zhao H, Jia J, Ma X, Harada K, Wang FS, Wei L, Wang Q, Sun Y, Hong Y, Rao H, Efe C, Lau G, Payawal D, Gani R, Lindor K, Jafri W, Omata M, Sarin SK. The Asian Pacific Association for the Study of the Liver clinical practice guidance: the diagnosis and management of patients with autoimmune hepatitis. Hepatol Int 2021; 15:223-257. [PMID: 33942203 PMCID: PMC8144150 DOI: 10.1007/s12072-021-10170-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 02/27/2021] [Indexed: 02/06/2023]
Affiliation(s)
- Guiqiang Wang
- Peking University First Hospital, Beijing, China.
- Peking University International Hospital, Beijing, China.
| | | | - Hong Zhao
- Peking University First Hospital, Beijing, China
- Peking University International Hospital, Beijing, China
| | - Jidong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiong Ma
- Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine Kanazawa, Kanazawa, Japan
| | - Fu-Sheng Wang
- Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Lai Wei
- Beijing Tsinghua Changgung Hospital, Beijing, China
| | - Qixia Wang
- Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Sun
- Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yuan Hong
- Peking University First Hospital, Beijing, China
| | - Huiying Rao
- Peking University People's Hospital, Beijing, China
| | - Cumali Efe
- Department of Gastroenterology, Harran University, Şanlıurfa, Turkey
| | - George Lau
- Humanity and Health Medical Group, Hong Kong Special Administrative Region, China
| | - Diana Payawal
- Department of Hepatology, Cardinal Santos Medical Center, Manila, Philippines
| | - Rino Gani
- Department of Internal Medicine, Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia
| | - Keith Lindor
- College of Health Solutions, Arizona State University, Phoenix, AZ, USA
| | | | - Masao Omata
- Department of Gastroenterology, Yamanashi Prefectural Central Hospital, Kofu-City, Yamanashi, Japan
- The University of Tokyo, Tokyo, Japan
| | | |
Collapse
|
|
21
|
Behairy BES, El-Said HH, Konswa HAA, El-Deen AESN, Adawy NM, Sira AM. Predictors of azathioprine toxicity in children with autoimmune hepatitis. Clin Exp Hepatol 2021; 7:47-54. [PMID: 34027115 PMCID: PMC8122100 DOI: 10.5114/ceh.2021.104634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 11/02/2020] [Indexed: 11/17/2022] Open
Abstract
AIM OF THE STUDY Azathioprine (AZA) is an important steroid-sparing drug in the management of autoimmune hepatitis (AIH). Avoidance of its adverse events that could be severe and carry a risk of mortality in a few cases is important, preferably with cheap and easy assessments that could be feasible in developing countries with the unavailability of molecular assays. Assessment of thiopurine methyltransferase (TPMT), the key enzyme for the inactivation of AZA, as a predictor of AZA toxicity had been a matter of conflict. This work aimed to study the role of TPMT serum level assessment and other host-, disease-, and treatment-related factors in predicting AZA toxicity. MATERIAL AND METHODS Sixty-six children with AIH, divided into two groups, were recruited. Group 1 included twelve children with AZA toxicity and group 2 included fifty-four children without AZA toxicities. Both groups were compared for demographic, clinical, laboratory, histopathological, and treatment-related factors, and serum TPMT level, measured by ELISA. RESULTS TPMT serum level was comparable in both groups (p = 0.363). Duration of treatment until enzyme normalization and duration of AZA therapy were significantly associated with AZA toxicity (p = 0.007 and p = 0.01, respectively). At the first follow-up treatment with AZA, total leucocyte count (TLC) and neutrophil counts were significantly lower in group 1 (p = 0.005 and p = 0.002, respectively). Moreover, the percentage reduction of TLC and neutrophil counts were significantly higher in group 1 (p < 0.001, for both). CONCLUSIONS Monitoring for AZA adverse events in those with the defined predictors of AZA-related adverse events is more important than TPMT assessment.
Collapse
Affiliation(s)
- Behairy El-Sayed Behairy
- Department of Pediatric Hepatology, Gastroenterology, and Nutrition, National Liver Institute, Menoufia University, Egypt
| | - Hala Hany El-Said
- Department of Clinical Biochemistry, National Liver Institute, Menoufia University, Egypt
| | - Hatem Abd-Alsattar Konswa
- Department of Pediatric Hepatology, Gastroenterology, and Nutrition, National Liver Institute, Menoufia University, Egypt
| | | | - Nermin Mohamed Adawy
- Department of Pediatric Hepatology, Gastroenterology, and Nutrition, National Liver Institute, Menoufia University, Egypt
| | - Ahmad Mohamed Sira
- Department of Pediatric Hepatology, Gastroenterology, and Nutrition, National Liver Institute, Menoufia University, Egypt
| |
Collapse
|
|
22
|
Affiliation(s)
| | - Simon Pape
- Department of Gastroenterology and Hepatology, Radboudumc, Nijmegen, The Netherlands
| | - Tom J G Gevers
- Department of Gastroenterology and Hepatology, Radboudumc, Nijmegen, The Netherlands
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboudumc, Nijmegen, The Netherlands
| |
Collapse
|
|
23
|
Halliday N, Dyson JK, Thorburn D, Lohse AW, Heneghan MA. Review article: experimental therapies in autoimmune hepatitis. Aliment Pharmacol Ther 2020; 52:1134-1149. [PMID: 32794592 DOI: 10.1111/apt.16035] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 03/02/2020] [Accepted: 07/22/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Current therapeutic options for autoimmune hepatitis (AIH) are limited by adverse events associated with corticosteroids and thiopurines and the limited evidence base for second- and third-line treatment options. Furthermore, current treatment approaches require long-term exposure of patients to pharmacological agents. There have been significant advances in the understanding of the mechanisms underpinning autoimmunity and an expansion in the available therapeutic agents for suppressing autoimmune responses or potentially restoring self-tolerance. AIM To review the mechanisms and evidence for experimental therapies that are being actively explored in the management of AIH. METHODS We have reviewed the literature relating to a range of novel therapeutic immunomodulatory treatment strategies and drugs. RESULTS Drugs which block B cell-activating factor of the tumour necrosis factor family (BAFF) and tumour necrosis factor α are currently in clinical trials for the treatment of AIH. Experimental therapies and technologies to increase immune tolerance, such as pre-implantation factor and regulatory T cell therapies, are undergoing development for application in autoimmune disorders. There is also evidence for targeting inflammatory pathways to control other autoimmune conditions, such as blockade of IL1 and IL6 and Janus-associated kinase (JAK) inhibitors. CONCLUSIONS With the range of tools available to clinicians and patients increasing, it is likely that the therapeutic landscape of AIH will change over the coming years and treatment approaches offering lower corticosteroid use and aiming to restore immune self-tolerance should be sought.
Collapse
Affiliation(s)
- Neil Halliday
- Institute of Liver and Digestive Health, University College London, London, UK.,The Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK
| | - Jessica Katharine Dyson
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK.,Hepatology Department, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Douglas Thorburn
- Institute of Liver and Digestive Health, University College London, London, UK.,The Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | |
Collapse
|
|
24
|
Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, Vierling JM, Alsawas M, Murad MH, Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology 2020; 72:671-722. [PMID: 31863477 DOI: 10.1002/hep.31065] [Citation(s) in RCA: 548] [Impact Index Per Article: 109.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Cara L Mack
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - David Adams
- Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - David N Assis
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT
| | - Nanda Kerkar
- Golisano Children's Hospital at Strong, University of Rochester Medical Center, New York, NY
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marlyn J Mayo
- Division of Digestive and Liver Diseases, University of Texas SW Medical Center, Dallas, TX
| | - John M Vierling
- Medicine and Surgery, Baylor College of Medicine, Houston, TX
| | | | - Mohammad H Murad
- Mayo Knowledge and Encounter Research Unit, Mayo Clinic College of Medicine, Rochester, MN
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
| |
Collapse
|
|
25
|
Czaja AJ. Review article: opportunities to improve and expand thiopurine therapy for autoimmune hepatitis. Aliment Pharmacol Ther 2020; 51:1286-1304. [PMID: 32363674 DOI: 10.1111/apt.15743] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 03/07/2020] [Accepted: 03/31/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use. AIMS To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response. METHODS English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. RESULTS Thiopurine methyltransferase activity and 6-tioguanine (6-thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre-treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose-restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6-tioguanine nucleotides and ameliorating thiopurine intolerance or resistance. CONCLUSIONS The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.
Collapse
Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| |
Collapse
|
|
26
|
Weersink RA, Burger DM, Hayward KL, Taxis K, Drenth JP, Borgsteede SD. Safe use of medication in patients with cirrhosis: pharmacokinetic and pharmacodynamic considerations. Expert Opin Drug Metab Toxicol 2019; 16:45-57. [DOI: 10.1080/17425255.2020.1702022] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Rianne A. Weersink
- Department of Pharmacy, Unit of Pharmacotherapy, -Epidemiology and -Economics, University of Groningen, Groningen, The Netherlands
- Department of Clinical Decision Support, Health Base Foundation, Houten, The Netherlands
| | - David M. Burger
- Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Kelly L. Hayward
- Centre for Liver Disease Research, Translational Research Institute, Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Pharmacy Department, Princess Alexandra Hospital, Brisbane, Australia
| | - Katja Taxis
- Department of Pharmacy, Unit of Pharmacotherapy, -Epidemiology and -Economics, University of Groningen, Groningen, The Netherlands
| | - Joost P.H. Drenth
- Department of Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Sander D. Borgsteede
- Department of Clinical Decision Support, Health Base Foundation, Houten, The Netherlands
| |
Collapse
|
|
27
|
Doycheva I, Watt KD, Gulamhusein AF. Autoimmune hepatitis: Current and future therapeutic options. Liver Int 2019; 39:1002-1013. [PMID: 30716203 DOI: 10.1111/liv.14062] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 01/13/2019] [Accepted: 01/17/2019] [Indexed: 02/13/2023]
Abstract
Autoimmune hepatitis (AIH) is a rare immune-mediated liver disease with few major advances in treatment options over the last several decades. Available options are effective in most patients albeit are imprecise in their mechanisms. Novel and more tolerable induction regimens and alternative options for management of patients intolerant or with suboptimal response to traditional therapies including in the post-transplant setting remain an important unmet need. This review aims to summarize recent data on pharmacological options and investigational drugs in development for patients with AIH. Standard therapy using prednisone with or without azathioprine remains the mainstay of therapy and is effective in most patients. Budesonide may be considered for induction in early disease and in those with mild fibrosis, but has not been approved for maintenance therapy. Mycophenolate mofetil (MMF) in combination with steroids might be an alternative first-line therapy, but results from a randomized trial are awaited. MMF as a second-line maintenance agent has moderate efficacy though more frequent adverse events in patients with cirrhosis may be seen. Tacrolimus may be an equally effective second-line option particularly in non-responders, but data remain limited. Management of recurrent AIH post-liver transplantation remains controversial with insufficient data to support long-term steroid use. Moving forward, expanding the scope of therapeutic options to include biologics including B-cell depleting agents may be a promising step. Recent insights in understanding the pathogenesis of AIH could serve as a basis for future therapies, including the elucidation of different immunoregulatory pathways and the potential role of the intestinal microbiome.
Collapse
Affiliation(s)
- Iliana Doycheva
- Division of Gastroenterology and Hepatology, Medical University, Sofia, Bulgaria
| | - Kymberly D Watt
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Aliya F Gulamhusein
- Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University Health Network, Toronto, ON, Canada
| |
Collapse
|
|
28
|
Fan X, Yin D, Men R, Xu H, Yang L. NUDT15 Polymorphism Confer Increased Susceptibility to Thiopurine-Induced Leukopenia in Patients With Autoimmune Hepatitis and Related Cirrhosis. Front Pharmacol 2019; 10:346. [PMID: 31024313 PMCID: PMC6465603 DOI: 10.3389/fphar.2019.00346] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 03/20/2019] [Indexed: 02/05/2023] Open
Abstract
The aim of this study was to investigate the influence of NUDT15 R139C and thiopurine S-methyltransferase (TPMT) on azathioprine (AZA) induced leukopenia in patients with autoimmune hepatitis (AIH) and related cirrhosis. A total of 149 Chinese AIH patients with a history of AZA treatment were retrospectively evaluated. The clinical and epidemiological characteristics of the patients were obtained from an electronic database and reviewed. NUDT15 (rs116855232) and TPMT∗3C (rs1142345) SNPs were genotyped using a PCR method. Twelve patients developed leukopenia, and this adverse drug reaction was significantly associated with the T risk allele in NUDT15 [P < 0.00001, odds ratio = 20.41; 95% confidence interval (CI) (7.84, 53.13)], with the sensitivity and specificity of 91.67 and 89.05%, respectively. The median maintenance dosages for patients with the rs116855232 CC and CT genotypes were 1.23 (0.95, 1.53) mg ⋅ kg−1 ⋅ d−1 and 0.96 (0.83, 1.19) mg ⋅ kg−1 ⋅ d−1, respectively (P = 0.028). In contrast, no significant association was observed for TPMT∗3C genotypes. Notably, subgroup analysis of the 13 patients with leukopenia before therapy, these white blood cell (WBC) counts did not show further reduction after AZA treatment and maintenance dosage was 1.13 (0.94, 1.60) mg ⋅ kg−1 ⋅ d−1. Therefore, NUDT15 polymorphism is significantly associated with thiopurine-induced leukopenia in Chinese patients with AIH and related cirrhosis. Adjusting the AZA dosage should be considered in patients according to the NUDT15 R139C genotypes.
Collapse
Affiliation(s)
- Xiaoli Fan
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
| | - Dandan Yin
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Ruoting Men
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
| | - Heng Xu
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Li Yang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
29
|
Harrison L, Gleeson D. Stopping immunosuppressive treatment in autoimmune hepatitis (AIH): Is it justified (and in whom and when)? Liver Int 2019; 39:610-620. [PMID: 30667576 DOI: 10.1111/liv.14051] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 01/07/2019] [Accepted: 01/10/2019] [Indexed: 02/13/2023]
Abstract
BACKGROUND Initial treatment of autoimmune hepatitis (AIH) with prednisolone ± azathioprine is based on randomised controlled trials. Many patients receive long-term immunosuppressive treatment to prevent disease relapse; this strategy has a weaker evidence base. AIM To consider whether immunosuppressive treatment (IST) withdrawal in AIH is justified and to develop a rationale for patient selection. METHODS We reviewed published papers between 1972 and 2018, which addressed the outcomes of IST withdrawal and/or complications of IST in AIH. RESULTS (1) AIH relapse rates after withdrawal of IST vary between 25% and 100%. There is heterogeneity in these studies regarding relapse definition, IST duration prior to withdrawal and criteria for biochemical and histological remission prior to withdrawal. (2) Factors associated with relapse following IST withdrawal include: (a) absence of an identifiable initial disease trigger, (b) presence of other autoimmune diseases, (c) longer time to biochemical remission and (d) elevated serum transaminases on treatment withdrawal. Reports of associations between relapse and age, IST duration and failure of histological remission have been inconsistent. (3) Continued IST reduces risk of AIH relapse over at least 5 years. However, there is no evidence that routine (as opposed to selective) long-term IST improves disease outcome. (4) Patients with AIH have an increased risk of extrahepatic cancer, notably non-melanoma skin cancer, to which long-term IST may contribute. Long-term corticosteroid therapy is associated with weight gain, low-trauma fractures, diabetes and possibly vascular disease. CONCLUSIONS While further studies are needed, evidence supports a strategy of IST withdrawal in some patients with AIH who have achieved remission.
Collapse
Affiliation(s)
- Laura Harrison
- Liver Unit, Northern General Hospital, Sheffield Teaching Hospital's NHS Foundation Trust, Sheffield, UK.,Department of Infection, Immunity and Cardiovascular Disease, The University of Sheffield, Medical School, Sheffield, UK
| | - Dermot Gleeson
- Liver Unit, Northern General Hospital, Sheffield Teaching Hospital's NHS Foundation Trust, Sheffield, UK
| |
Collapse
|
|
30
|
Rengasamy KR, Khan H, Gowrishankar S, Lagoa RJ, Mahomoodally FM, Khan Z, Suroowan S, Tewari D, Zengin G, Hassan ST, Pandian SK. The role of flavonoids in autoimmune diseases: Therapeutic updates. Pharmacol Ther 2019; 194:107-131. [PMID: 30268770 DOI: 10.1016/j.pharmthera.2018.09.009] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
|
|
31
|
Dalekos GN, Koskinas J, Papatheodoridis GV. Hellenic Association for the Study of the Liver Clinical Practice Guidelines: Autoimmune hepatitis. Ann Gastroenterol 2019; 32:1-23. [PMID: 30598587 PMCID: PMC6302199 DOI: 10.20524/aog.2018.0330] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Accepted: 10/29/2018] [Indexed: 02/07/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a relatively rare acute or chronic liver disease of unknown etiology characterized by large heterogeneity. Its distribution is global, covering all ages, both sexes and all ethnic groups. The aim of the present Clinical Practice Guidelines (CPG) of the Hellenic Association for the Study of the Liver was to provide updated guidance and help to gastroenterologists, hepatologists, internists and general practitioners for AIH diagnosis and management. AIH diagnosis is based on clinicopathological characteristics: namely, polyclonal hypergammaglobulinemia, particularly of immunoglobulin G (IgG), circulating autoantibodies, interface hepatitis on liver histology, absence of viral hepatitis, and a favorable response to immunosuppression. Clinical manifestations at disease onset are variable, ranging from asymptomatic to the acute/severe form. Aminotransferase and bilirubin levels vary, while the presence of hepatitis at the histological level is a prerequisite for diagnosis. Autoantibodies are the hallmark for AIH diagnosis; therefore, the CPG describe the appropriate serological algorithm for their detection. AIH therapy should aim to achieve complete biochemical (normalization of IgG and aminotransferases) and histological remission. All patients who have active disease, even those with cirrhosis, should be treated with individualized and response-guided induction therapy using prednisolone in combination with azathioprine or mycophenolate mofetil as first-line therapy. Immunosuppression should be given for at least 3 years and for at least 2 years after the achievement of complete biochemical response, while a liver biopsy should be recommended before treatment discontinuation. Current CPG are also provided for several specific conditions and difficult-to-treat patients.
Collapse
Affiliation(s)
- George N. Dalekos
- Institute of Internal Medicine and Hepatology, Larissa (George N. Dalekos)
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa (George N. Dalekos)
| | - John Koskinas
- Second Department of Internal Medicine, National and Kapodistrian University of Athens, “Hippokratio” General Hospital of Athens, Athens (John Koskinas)
| | - George V. Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, “Laiko” General Hospital of Athens, Athens (George V. Papatheodoridis), Greece
| |
Collapse
|
|
32
|
Lowe D, John S. Autoimmune hepatitis: Appraisal of current treatment guidelines. World J Hepatol 2018; 10:911-923. [PMID: 30631396 PMCID: PMC6323516 DOI: 10.4254/wjh.v10.i12.911] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 10/16/2018] [Accepted: 10/23/2018] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis affects patients of all ages and gender, across all geographic regions. Although still rare, its incidence and prevalence are increasing. Genetic predisposition conveyed by human leucocyte antigen is a strong risk factor for the disease and may be responsible in part for the wide variation in presentation in different geographic regions. Our understanding of the underlying pathogenic mechanisms is evolving and may lead to development of more targeted immunotherapies. Diagnosis is based on elevated levels of serum aminotransferases, gamma globulins, autoantibodies and characteristic findings on histology. Exclusion of other causes of chronic hepatitis is important. Although undiagnosed disease is associated with poor outcomes, it is readily treatable with timely immunosuppressive therapy in the majority of patients. International guidelines are available to guide management but there exists a disparity in the standard treatment regimens. This minireview aims to review the available guidelines and summarize the key recommendations involved in management of this complex autoimmune disease.
Collapse
Affiliation(s)
- Dhruv Lowe
- Division of Gastroenterology and Hepatology, Department of Medicine, State University of New York, Upstate Medical University, Syracuse, NY 13202, United States
| | - Savio John
- Division of Gastroenterology and Hepatology, Department of Medicine, State University of New York, Upstate Medical University, Syracuse, NY 13202, United States.
| |
Collapse
|
|
33
|
Abstract
BACKGROUND Azathioprine (AZA) is the mainstay of maintenance therapy in pediatric autoimmune hepatitis (AIH). The use of thiopurines metabolites to individualize therapy and avoid toxicity has not, however, been clearly defined. METHODS Retrospective analysis of children ≤18 years diagnosed with AIH between January 2001 and 2016. Standard definitions were used for treatment response and disease flare. Thiopurine metabolite levels were correlated with the corresponding liver function test. RESULTS A total of 56 children (32 girls) were diagnosed with AIH at a median age of 11 years (interquartile range [IQR] 9). No difference in 6-thioguanine-nucleotide (6-TG) levels (271[IQR 251] pmol/8 × 10 red blood cell vs 224 [IQR 147] pmol/8 × 10 red blood cell, P = 0.06) was observed in children in remission when compared with those who were not in remission. No correlation was observed between the 6-TG and alanine aminotransferase levels (r = -0.179, P = 0.109) or between 6-methyl-mercaptopurine (6-MMP) and alanine aminotransferase levels (r = 0.139, P = 0.213). The 6-MMP/6-TG ratio was significantly lower in patients who were in remission (2[7] vs 5 (10), P = 0.04). Using a quartile analysis, we found that having a ratio of <4 was significantly associated with being in remission with OR 2.50 (95% confidence interval 1.02-6.10), P = 0.047. Use of allopurinol with low-dose AZA in 6 children with preferential 6-MMP production brought about remission in 5/6 (83.3%). CONCLUSIONS Thiopurine metabolite levels should be measured in patients with AIH who have experienced a loss of remission. A 6-MMP/6-TG ratio of <4 with the addition of allopurinol could be considered in these patients.
Collapse
|
|
34
|
Saiz-Rodríguez M, Ochoa D, Belmonte C, Román M, Martínez-Ingelmo C, Ortega-Ruíz L, Sarmiento-Iglesias C, Herrador C, Abad-Santos F. Influence of thiopurine S-methyltransferase polymorphisms in mercaptopurine pharmacokinetics in healthy volunteers. Basic Clin Pharmacol Toxicol 2018; 124:449-455. [PMID: 30346660 DOI: 10.1111/bcpt.13153] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Accepted: 10/14/2018] [Indexed: 12/29/2022]
Abstract
Mercaptopurine is a drug commonly used in the treatment of different types of cancer, especially acute lymphoblastic leukaemia, and autoimmune diseases such as ulcerative colitis or Crohn's disease and in patients receiving organ transplants. It is metabolized by three cytosolic enzymes. One of them, thiopurine S-methyltransferase (TPMT), is responsible for catalysing the methylation reaction of mercaptopurine to 6-methylmercaptopurine, thus inactivating the drug. Individuals with TPMT loss-of-function alleles (*2, *3A, *3B or *3C) can be extremely sensitive to the effect of mercaptopurine, since it can be accumulated, therefore producing haematological toxicity. The objective of this study was to evaluate the role of TPMT polymorphisms on the pharmacokinetics of mercaptopurine. For that purpose, we used collected pharmacokinetic data from 48 healthy volunteers (all males) who received a single oral dose of mercaptopurine 50 mg in two bioequivalence studies. The volunteers were subsequently genotyped for TPMT *2, *3A, *3B and *3C alleles by real-time PCR. There were four carriers (8.3%) of TPMT*2 and TPMT*3A alleles. Mercaptopurine elimination was affected by TPMT loss-of-function polymorphisms, since heterozygous subjects show 18% higher half-life compared to wild-type individuals. This fact is consistent with the expected since the presence of loss-of-function alleles decreases TPMT enzymatic activity and, thus, affects mercaptopurine elimination. Moreover, mercaptopurine pharmacokinetic parameters were different among races, since Latins showed higher plasma concentrations and lower clearance compared to Caucasians. This fact might be due to a different distribution of polymorphisms in genes, other than TPMT, that also influence the pharmacokinetics of mercaptopurine.
Collapse
Affiliation(s)
- Miriam Saiz-Rodríguez
- Clinical Pharmacology Department, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), Hospital Universitario de La Princesa, Madrid, Spain
| | - Dolores Ochoa
- Clinical Pharmacology Department, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), Hospital Universitario de La Princesa, Madrid, Spain.,UICEC Hospital Universitario de La Princesa, Plataforma SCReN (Spanish Clinical Research Network), Instituto de Investigación Sanitaria La Princesa (IP), Madrid, Spain
| | - Carmen Belmonte
- Clinical Pharmacology Department, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), Hospital Universitario de La Princesa, Madrid, Spain.,UICEC Hospital Universitario de La Princesa, Plataforma SCReN (Spanish Clinical Research Network), Instituto de Investigación Sanitaria La Princesa (IP), Madrid, Spain
| | - Manuel Román
- Clinical Pharmacology Department, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), Hospital Universitario de La Princesa, Madrid, Spain.,UICEC Hospital Universitario de La Princesa, Plataforma SCReN (Spanish Clinical Research Network), Instituto de Investigación Sanitaria La Princesa (IP), Madrid, Spain
| | - Cristina Martínez-Ingelmo
- Clinical Pharmacology Department, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), Hospital Universitario de La Princesa, Madrid, Spain
| | - Lucía Ortega-Ruíz
- Clinical Pharmacology Department, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), Hospital Universitario de La Princesa, Madrid, Spain
| | - Carmen Sarmiento-Iglesias
- Clinical Pharmacology Department, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), Hospital Universitario de La Princesa, Madrid, Spain
| | - Coral Herrador
- Clinical Pharmacology Department, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), Hospital Universitario de La Princesa, Madrid, Spain
| | - Francisco Abad-Santos
- Clinical Pharmacology Department, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), Hospital Universitario de La Princesa, Madrid, Spain.,UICEC Hospital Universitario de La Princesa, Plataforma SCReN (Spanish Clinical Research Network), Instituto de Investigación Sanitaria La Princesa (IP), Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| |
Collapse
|
|
35
|
Fan X, Zhu Y, Men R, Wen M, Shen Y, Lu C, Yang L. Efficacy and Safety of Immunosuppressive Therapy for PBC-AIH Overlap Syndrome Accompanied by Decompensated Cirrhosis: A Real-World Study. Can J Gastroenterol Hepatol 2018; 2018:1965492. [PMID: 30155449 PMCID: PMC6098853 DOI: 10.1155/2018/1965492] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Revised: 06/02/2018] [Accepted: 07/09/2018] [Indexed: 02/05/2023] Open
Abstract
Aim To explore the efficacy and safety of immunosuppressive therapy for the treatment of primary biliary cirrhosis-autoimmune hepatitis (PBC-AIH) overlap syndrome accompanied by decompensated cirrhosis. Methods A cohort study was performed to evaluate the usefulness of immunosuppressive therapy in this unique group. This cohort study was performed between October 2013 and June 2017 and included 28 biopsy-proven patients diagnosed according to the Paris criteria. The therapies included ursodeoxycholic acid (UDCA) alone (N=14) or in combination with immunosuppression (IS) therapy (N=14). The primary endpoints were biochemical remission, liver-related adverse events, transplant-free survival, and drug side-effects. Results The frequency of biochemical remission for the AIH features was significantly higher in the UDCA+IS group than in the UDCA-only group (60.0 versus 9.1%, P=0.024) after 12 months of therapy but not after 3 and 6 months (28.6 versus 0%, P=0.165; 35.7 versus 7.1%, P=0.098). The rates of liver-related adverse events were lower in the combined group (2/14 versus 9/14, P=0.018). The Kaplan-Meier estimate showed that the transplant-free survival was distinct between the two groups (P=0.019). In the UDCA+IS group, mild and transient leukopenia occurred in two patients receiving azathioprine (AZA), and an infection was observed in one patient receiving mycophenolate mofetil (MMF). Conclusions PBC-AIH patients with decompensated cirrhosis receiving a combination of UDCA and immunosuppressors presented with higher biochemical remission rates and experienced fewer liver-related adverse events, implying that the combined treatment might be a better therapeutic option for strictly defined decompensated PBC-AIH overlap syndrome.
Collapse
Affiliation(s)
- Xiaoli Fan
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yongjun Zhu
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Ruoting Men
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Maoyao Wen
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yi Shen
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Changli Lu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Li Yang
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| |
Collapse
|
|
36
|
Abstract
Autoimmune hepatitis (AIH) is an inflammatory liver disease that is characterized by circulating autoantibodies, hypergammaglobulinemia, and a lymphoplasmocytic infiltration with interface hepatitis on liver biopsy. Treatment with corticosteroids and other immunosuppressive agents is effective and early diagnosis can result in near-normal life expectancy. Untreated patients, however, can progress to cirrhosis and liver failure. The clinical presentation is heterogeneous and may pose diagnostic and therapeutic dilemmas. This case-based review will address the diagnosis and management of this disease, in addition to difficult but commonly encountered clinical scenarios.
Collapse
|
|
37
|
Mieli-Vergani G, Vergani D, Czaja AJ, Manns MP, Krawitt EL, Vierling JM, Lohse AW, Montano-Loza AJ. Autoimmune hepatitis. Nat Rev Dis Primers 2018; 4:18017. [PMID: 29644994 DOI: 10.1038/nrdp.2018.17] [Citation(s) in RCA: 272] [Impact Index Per Article: 38.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Autoimmune hepatitis (AIH) is a severe liver disease that affects children and adults worldwide. The diagnosis of AIH relies on increased serum transaminase and immunoglobulin G levels, presence of autoantibodies and interface hepatitis on liver histology. AIH arises in genetically predisposed individuals when a trigger, such as exposure to a virus, leads to a T cell-mediated autoimmune response directed against liver autoantigens; this immune response is permitted by inadequate regulatory immune control leading to a loss of tolerance. AIH responds favourably to immunosuppressive treatment, which should be started as soon as the diagnosis is made. Standard regimens include fairly high initial doses of corticosteroids (prednisone or prednisolone), which are tapered gradually as azathioprine is introduced. For those patients who do not respond to standard treatment, second-line drugs should be considered, including mycophenolate mofetil, calcineurin inhibitors, mechanistic target of rapamycin (mTOR) inhibitors and biologic agents, which should be administered only in specialized hepatology centres. Liver transplantation is a life-saving option for those who progress to end-stage liver disease, although AIH can recur or develop de novo after transplantation. In-depth investigation of immune pathways and analysis of changes to the intestinal microbiota should advance our knowledge of the pathogenesis of AIH and lead to novel, tailored and better tolerated therapies.
Collapse
Affiliation(s)
- Giorgina Mieli-Vergani
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, Denmark Hill, SE5 9RS London, UK
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, King's College Hospital, Denmark Hill, SE5 9RS London, UK
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Edward L Krawitt
- Department of Medicine, University of Vermont, Burlington, VT, USA.,Department of Medicine, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA
| | - John M Vierling
- Division of Abdominal Transplantation and Section of Gastroenterology and Hepatology, Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Ansgar W Lohse
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada
| |
Collapse
|
|
38
|
Wang QX, Yan L, Ma X. Autoimmune Hepatitis in the Asia-Pacific Area. J Clin Transl Hepatol 2018; 6:48-56. [PMID: 29577032 PMCID: PMC5862999 DOI: 10.14218/jcth.2017.00032] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 09/23/2017] [Accepted: 10/26/2017] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis has been considered as a relatively rare immunological liver disease, especially in the Asia-Pacific area. Although the diagnosis criteria and immunosuppressive treatment regimens have been established, there are still some challenges. According to the different presentations, the personalized management of patients who suffer from this disease, including those with chronic or acute severe onset, the autoantibody-negative phenotype and cirrhosis are necessarily descriptive. Each subgroup of patients should receive an individualized therapy. Here, we review the recent studies of autoimmune hepatitis, mainly focusing on the epidemiology and genetics, personalized diagnostics, individualized treatment strategies, special subgroups and outcomes. Most of the research in the literature is based on Japanese and Chinese populations.
Collapse
Affiliation(s)
- Qi-Xia Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Li Yan
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
- *Correspondence to: Xiong Ma, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China. Tel: +86-21-63200874, Fax: +86-21-63266027, E-mail:
| |
Collapse
|
|
39
|
Abstract
Autoimmune hepatitis occurs in genetically susceptible individuals as a result of loss of immunological tolerance to hepatic autoantigens that can be precipitated by environmental triggers. The clinical manifestation is usually insidious but can be also acute with liver failure. The diagnosis is made on the basis of antibody positivity, elevated immunoglobulin G levels and interface hepatitis on liver histology. Induction of remission is achieved with high-dose steroids in the majority of cases, and maintenance of remission with azathioprine. Treatment withdrawal is achievable only in a small proportion of patients. Patients with acute liver failure unresponsive to steroids or those with end-stage liver failure or hepatocellular carcinoma may require liver transplantation. Variant forms of overlapping autoimmune hepatitis with either primary biliary cholangitis or sclerosing cholangitis are associated with worse outcomes. New insights into the pathophysiology of the disease may provide novel therapeutic targets and a more individualized approach to treatment of autoimmune hepatitis.
Collapse
Affiliation(s)
- Eleni Theocharidou
- Senior Clinical Fellow, Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London
| | - Michael A Heneghan
- Consultant Hepatologist, Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London SE5 9RS
| |
Collapse
|
|
40
|
Mieli-Vergani G, Vergani D, Baumann U, Czubkowski P, Debray D, Dezsofi A, Fischler B, Gupte G, Hierro L, Indolfi G, Jahnel J, Smets F, Verkade HJ, Hadžić N. Diagnosis and Management of Pediatric Autoimmune Liver Disease: ESPGHAN Hepatology Committee Position Statement. J Pediatr Gastroenterol Nutr 2018; 66:345-360. [PMID: 29356770 DOI: 10.1097/mpg.0000000000001801] [Citation(s) in RCA: 192] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Paediatric autoimmune liver disease is characterized by inflammatory liver histology, circulating autoantibodies, and increased levels of IgG, in the absence of a known etiology. Three conditions have a likely autoimmune pathogenesis: autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis, and de novo AIH after liver transplantation. Two types of pediatric AIH are recognized according to seropositivity for smooth muscle and/or antinuclear antibody (AIH-1) or liver kidney microsomal type 1 and/or anti-liver cytosol type 1 antibodies (AIH-2).Pertinent issues addressing the diagnosis, treatment, and long-term follow-up were formulated by a core group of ESPGHAN members. They have commissioned the first authors with execution of this project. Initially, they have performed a systematic literature search on MEDLINE, ResearchGate, and Mendeley databases during the last 30 years and produced a document focusing on prospective and retrospective studies in children. The ESPGHAN core group and ESPGHAN Hepatology Committee members voted on each recommendation, using a formal voting technique.
Collapse
Affiliation(s)
| | - Diego Vergani
- MowatLabs, Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK
| | - Ulrich Baumann
- Pädiatrische Gastroenterologie und Hepatologie, Medizinische Hochschule, Hannover, Germany
| | - Piotr Czubkowski
- Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Dominique Debray
- Pediatric Hepatology Unit, AP-HP-Hôpital Necker Enfants Malades, Paris, France
| | - Antal Dezsofi
- First Department of Paediatrics, Semmelweis University, Budapest, Hungary
| | - Björn Fischler
- Department of Pediatrics, Karolinska University Hospital, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Girish Gupte
- Liver Unit (Including Small Bowel Transplantation), Department of Gastroenterology and Nutrition, Birmingham Children's Hospital, Birmingham, UK
| | - Loreto Hierro
- Hospital Infantil Universitario La Paz, Madrid, Spain
| | - Giuseppe Indolfi
- Paediatric and Liver Unit, Meyer Children's University Hospital of Florence, Firenze, Italy
| | - Jörg Jahnel
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Françoise Smets
- UCL, Cliniques Universitaires Saint-Luc, Pediatric Gastroenterology and Hepatology, Brussels, Belgium
| | - Henkjan J Verkade
- Dept of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, the Netherlands
| | - Nedim Hadžić
- MowatLabs, Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK
| |
Collapse
|
|
41
|
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.
Collapse
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
| |
Collapse
|
|
42
|
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.
Collapse
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
| |
Collapse
|
|
43
|
Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis: Current Status and Future Directions. Gut Liver 2016; 10:177-203. [PMID: 26934884 PMCID: PMC4780448 DOI: 10.5009/gnl15352] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 11/04/2015] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis is characterized by autoantibodies, hypergammaglobulinemia, and interface hepatitis on histological examination. The features lack diagnostic specificity, and other diseases that may resemble autoimmune hepatitis must be excluded. The clinical presentation may be acute, acute severe (fulminant), or asymptomatic; conventional autoantibodies may be absent; centrilobular necrosis and bile duct changes may be present; and the disease may occur after liver transplantation or with features that suggest overlapping disorders. The diagnostic criteria have been codified, and diagnostic scoring systems can support clinical judgment. Nonstandard autoantibodies, including antibodies to actin, α-actinin, soluble liver antigen, perinuclear antineutrophil antigen, asialoglycoprotein receptor, and liver cytosol type 1, are tools that can support the diagnosis, especially in patients with atypical features. Prednisone or prednisolone in combination with azathioprine is the preferred treatment, and strategies using these medications in various doses can ameliorate treatment failure, incomplete response, drug intolerance, and relapse after drug withdrawal. Budesonide, mycophenolate mofetil, and calcineurin inhibitors can be considered in selected patients as frontline or salvage therapies. Molecular (recombinant proteins and monoclonal antibodies), cellular (adoptive transfer and antigenic manipulation), and pharmacological (antioxidants, antifibrotics, and antiapoptotic agents) interventions constitute future directions in management. The evolving knowledge of the pathogenic pathways and the advances in technology promise new management algorithms.
Collapse
Affiliation(s)
- Albert J. Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN,
USA
| |
Collapse
|
|
44
|
Association between Thiopurine S-Methyltransferase Polymorphisms and Azathioprine-Induced Adverse Drug Reactions in Patients with Autoimmune Diseases: A Meta-Analysis. PLoS One 2015; 10:e0144234. [PMID: 26633017 PMCID: PMC4669175 DOI: 10.1371/journal.pone.0144234] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 11/16/2015] [Indexed: 01/27/2023] Open
Abstract
Purpose Azathioprine (AZA) is widely used as an immunosuppressive drug in autoimmune diseases, but its use is limited by significant adverse drug reactions (ADRs). Thiopurine S-methyltransferase (TPMT) is an important enzyme involved in AZA metabolism. Several clinical guidelines recommend determining TPMT genotype or phenotype before initiating AZA therapy. Although several studies have investigated the association between TPMT polymorphisms and AZA-induced ADRs, the results are inconsistent. The purpose of this study is to evaluate whether there is an association between TPMT polymorphisms and AZA-induced ADRs using meta-analysis. Methods We explored PubMed, Web of Science and Embase for articles on TPMT polymorphisms and AZA-induced ADRs. Studies that compared TPMT polymorphisms with-ADRs and without-ADRs in patients with autoimmune diseases were included. Relevant outcome data from all the included articles were extracted and the pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated using Revman 5.3 software. Results Eleven published studies, with a total of 651 patients with autoimmune diseases, investigated associations between TPMT polymorphisms and AZA-induced ADRs, were included in this meta-analysis. Our meta-analysis demonstrated that TPMT polymorphisms were significantly associated with AZA-induced overall ADRs, bone marrow toxicity and gastric intolerance; pooled ORs were 3.12 (1.48–6.56), 3.76 (1.97–7.17) and 6.43 (2.04–20.25), respectively. TPMT polymorphisms were not associated with the development of hepatotoxicity; the corresponding pooled OR was 2.86 (95%CI: 0.32–25.86). However, the association in GI subset could be driven by one single study. After this study was excluded, the OR was 2.11 (95%CI: 0.36–12.42); namely, the association became negative. Conclusions Our meta-analysis demonstrated an association of TPMT polymorphisms with overall AZA-induced ADRs, bone marrow toxicity and gastric intolerance, but not with hepatotoxicity. The presence of the normal TPMT genotypes cannot preclude the development of ADRs during AZA treatment, TPMT genotyping prior to commencing AZA therapy cannot replace, may augment, the current practice of regular monitoring of the white blood cell. Because of small sample sizes, large and extensive exploration was required to validate our findings.
Collapse
|
|
45
|
Wang Q, Yang F, Miao Q, Krawitt EL, Gershwin ME, Ma X. The clinical phenotypes of autoimmune hepatitis: A comprehensive review. J Autoimmun 2015; 66:98-107. [PMID: 26614611 DOI: 10.1016/j.jaut.2015.10.006] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Revised: 10/28/2015] [Accepted: 10/29/2015] [Indexed: 02/08/2023]
Abstract
Autoimmune hepatitis (AIH) fulfills the generally accepted contemporary criteria of an autoimmune liver disease: the presence of autoantibodies and autoreactive T cells, a female gender bias, association with other autoimmune diseases, response to immunosuppressive therapy and strong associations with the major histocompatibility complex HLA loci. It occurs worldwide in both children and adults and is marked by both etiopathogenic and clinical heterogeneity, differing from the other putative autoimmune liver diseases, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), albeit occasionally presenting with overlapping features of PBC or PSC. Although diagnostic criteria have been established and validated, there are still major issues to be clarified due to its variability, such as autoantibody-negative AIH, drug-induced AIH, AIH sharing features with PBC or PSC, and post-transplant de novo AIH. In view of the diverse presentations and courses, including classical chronic onset, acute and acute severe onset, cirrhosis and decompensated cirrhosis, individualized management of patients is indicated. Each patient should receive a personalized analysis of the benefits and side effect risks of drugs. Herein we describe a comprehensive review of the clinical phenotypes of AIH underscoring its clinical heterogeneity.
Collapse
Affiliation(s)
- Qixia Wang
- State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Shandong Road, Shanghai 200001, China
| | - Fan Yang
- State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Shandong Road, Shanghai 200001, China
| | - Qi Miao
- State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Shandong Road, Shanghai 200001, China
| | | | - M Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Xiong Ma
- State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Shandong Road, Shanghai 200001, China.
| |
Collapse
|
|
46
|
Vierling JM. Autoimmune Hepatitis and Overlap Syndromes: Diagnosis and Management. Clin Gastroenterol Hepatol 2015; 13:2088-108. [PMID: 26284592 DOI: 10.1016/j.cgh.2015.08.012] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 08/11/2015] [Accepted: 08/11/2015] [Indexed: 12/14/2022]
Affiliation(s)
- John M Vierling
- Departments of Medicine and Surgery, Baylor College of Medicine, Baylor-St Luke's Medical Center, Houston, Texas.
| |
Collapse
|
|
47
|
Affiliation(s)
-
- EASL office, 7 Rue Daubin, CH 1203 Geneva, Switzerland,
| |
Collapse
|
|
48
|
|
|
49
|
Abstract
Autoimmune hepatitis is characterized by increased serum aminotransferase levels, autoantibodies, hypergammaglobulinemia, and interface hepatitis. Presentation can be acute, severe (fulminant), asymptomatic, or chronic. Diagnosis requires multiple findings and exclusion of similar diseases. Treatment with prednisone or prednisolone with azathioprine is recommended. Budesonide with azathioprine has normalized laboratory test with few side effects, but histologic resolution, durability of response, and target population are uncertain. Progressive worsening, incomplete improvement, drug intolerance, and relapse after drug withdrawal are suboptimal outcomes. Calcineurin inhibitors and mycophenolate mofetil are salvage agents in small series and liver transplantation is effective for liver failure.
Collapse
|
|
50
|
Abstract
INTRODUCTION Corticosteroids alone or in combination with azathioprine are the mainstay therapies of autoimmune hepatitis. Suboptimal responses (treatment failure, partial response, drug toxicity), frequent relapse after drug withdrawal, and the emergence of alternative immunosuppressive medications have fueled the pursuit of new treatments. The goals of this review are to present current management strategies and evolving interventions. AREAS COVERED PubMed searches from 1970 - 2014 provide the bases for this review. Corticosteroid regimens should be administered until resolution of symptoms, laboratory tests, and liver tissue abnormalities. Treatment failure warrants high doses of the original regimen, and relapse warrants re-treatment followed by long-term maintenance with azathioprine. The calcineurin inhibitors, budesonide, and mycophenolate mofetil are evolving as frontline therapies, and they may be considered as salvage therapies with the exception of budesonide. Rapamycin, rituximab, and infliximab have also rescued refractory patients but experiences are limited. Anti-oxidants, recombinant molecules, mAbs, and modulators of critical cell populations are key prospects. EXPERT OPINION Autoimmune hepatitis must be managed by multiple medications that supplement or supplant current regimens depending on the clinical situation. Rescue therapies will emerge as adjunctive interventions to minimize tissue damage (prevent fibrosis and hepatocyte apoptosis) and improve immune tolerance (regulatory T cell manipulations).
Collapse
Affiliation(s)
- Albert J Czaja
- Mayo Clinic College of Medicine, From the Division of Gastroenterology and Hepatology , 200 First Street S.W, Rochester, MN 55905 , USA +1 507 284 2691 ; +1 507 284 0538 ;
| |
Collapse
|