|
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
|
Dalekos G, Gatselis N, Drenth JP, Heneghan M, Jørgensen M, Lohse AW, Londoño M, Muratori L, Papp M, Samyn M, Tiniakos D, Lleo A. EASL Clinical Practice Guidelines on the management of autoimmune hepatitis. J Hepatol 2025:S0168-8278(25)00173-4. [PMID: 40348684 DOI: 10.1016/j.jhep.2025.03.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Accepted: 03/20/2025] [Indexed: 05/14/2025]
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disease of unknown aetiology which may affect any patient irrespective of age, sex, and ethnicity. At baseline, the clinical spectrum of the disease varies largely from asymptomatic cases to acute liver failure with massive hepatocyte necrosis. The aim of these EASL guidelines is to provide updated guidance on the diagnosis and management of AIH both in adults and children. Updated guidance on the management of patients with variants and specific forms of AIH is also provided, as is detailed guidance on the management of AIH-associated cirrhosis, including surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.
Collapse
|
|
3
|
Chen Y, Chen R, Li H, Shuai Z. Clinical management of autoimmune liver diseases: juncture, opportunities, and challenges ahead. Immunol Res 2025; 73:67. [PMID: 40195209 PMCID: PMC11976385 DOI: 10.1007/s12026-025-09622-9] [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: 11/27/2024] [Accepted: 03/14/2025] [Indexed: 04/09/2025]
Abstract
The three major autoimmune liver diseases are autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC).These conditions are assumed to result from a breakdown in immunological tolerance, which leads to an inflammatory process that causes liver damage.The self-attack is started by T-helper cell-mediated identification of liver autoantigens and B-cell production of autoantibodies,and it is maintained by a reduction in the number and activity of regulatory T-cells.Infections and environmental factors have been explored as triggering factors for these conditions, in addition to a genetic predisposition.Allelic mutations in the HLA locus have been linked to vulnerability, as have relationships with single nucleotide polymorphisms in non-HLA genes.Despite the advances in the management of these diseases, there is no curative treatment for these disorders, and a significant number of patients eventually progress to an end-stage liver disease requiring liver transplantation.In this line, tailored immune-therapeutics have emerged as possible treatments to control the disease.In addition, early diagnosis and treatment are pivotal for reducing the long-lasting effects of these conditions and their burden on quality of life.Herein we present a review of the etiology, clinical presentation, diagnosis, and challenges on ALDs and the feasible solutions for these complex diseases.
Collapse
MESH Headings
- Humans
- Hepatitis, Autoimmune/therapy
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/immunology
- Hepatitis, Autoimmune/etiology
- Cholangitis, Sclerosing/therapy
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/immunology
- Liver Cirrhosis, Biliary/therapy
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/immunology
- Animals
- Immunotherapy/methods
- Autoimmune Diseases/therapy
- Autoimmune Diseases/diagnosis
- Disease Management
- Genetic Predisposition to Disease
Collapse
Affiliation(s)
- Yangfan Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Ruofei Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Haiyan Li
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Zongwen Shuai
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, China.
| |
Collapse
|
|
4
|
Hu Y, Liu M, Li S, Ji Y, Su Y, Yang J, Zhang X, Zhou S, Guo L, Li Y, Ran Y, Zhao X, Chu H, Dong S, Yang H, Zhang Q, Zheng Z, Zhou L. Co-occurrence of autoimmune liver disease and gallstones: a clinically overlooked phenomenon. Eur J Gastroenterol Hepatol 2025:00042737-990000000-00515. [PMID: 40359288 DOI: 10.1097/meg.0000000000002978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/15/2025]
Abstract
BACKGROUND Gallstone disease is a relatively common complicating condition in patients with autoimmune liver disease (AILD) in clinical practice, yet this phenomenon has not been reported previously. Thus, we investigated the prevalence and the clinical characteristics of gallstones in patients with AILD. METHODS We retrospectively analyzed 560 patients with AILD, comprising 207 with primary biliary cholangitis (PBC), 289 with autoimmune hepatitis (AIH), and 64 with PBC-AIH overlap syndrome (PBC-AIH), who attended the General Hospital of Tianjin Medical University from November 2012 to October 2022. In addition, 937 control (CTRL) individuals matched for age and sex were included. RESULTS The proportion of patients with AILD, PBC, AIH, and PBC-AIH complicated by gallstones was 32.5, 35.7, 28.4, and 40.6%, significantly higher than in the CTRL (14.3%). Types of gallstones are predominantly multiple stones (43.4%), followed by single stones (32.4%) and sludge stones (6%). Patients with AILD with gallstones exhibited significantly higher age at the first visit (P = 0.007) and serum biochemical markers associated with bile duct injury, such as gamma-glutamyl transpeptidase (P = 0.003) and alkaline phosphatase (P = 0.001). Patients with AILD aged 61.5 and older were significantly more prone to gallstones (P = 0.003). CONCLUSION Gallstones are a common comorbidity in patients with AILD, predominantly multiple stones. Patients with gallstones should be aware of the early diagnosis of AILD to prevent delayed treatment. Older patients with AILD should be alerted and prevented from developing stones. Our findings provide new ideas for clinical diagnosis and etiologic investigation.
Collapse
Affiliation(s)
- Yujie Hu
- Department of Gastroenterology and Hepatology, General Hospital
| | - Man Liu
- Department of Gastroenterology and Hepatology, General Hospital
| | - Shuqian Li
- Health Management Center, Tianjin Medical University General Hospital
| | - Yinglan Ji
- Department of Gastroenterology and Hepatology, General Hospital
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Yingxi Su
- Department of Gastroenterology and Hepatology, General Hospital
| | - Jie Yang
- Department of Gastroenterology and Hepatology, General Hospital
| | - Xue Zhang
- Department of Gastroenterology and Hepatology, General Hospital
| | - Simin Zhou
- Department of Gastroenterology and Hepatology, General Hospital
| | - Liping Guo
- Department of Gastroenterology and Hepatology, General Hospital
| | - Yanni Li
- Department of Gastroenterology and Hepatology, General Hospital
| | - Ying Ran
- Department of Gastroenterology and Hepatology, General Hospital
| | - Xingliang Zhao
- Department of Gastroenterology and Hepatology, General Hospital
| | - Hongyu Chu
- Department of Gastroenterology and Hepatology, General Hospital
| | - Shijing Dong
- Department of Gastroenterology and Hepatology, General Hospital
| | - Hui Yang
- Department of Gastroenterology and Hepatology, General Hospital
| | - Qing Zhang
- Health Management Center, Tianjin Medical University General Hospital
| | - Zhongqing Zheng
- Department of Gastroenterology and Hepatology, General Hospital
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, General Hospital
| |
Collapse
|
|
5
|
Paulina B, Kuczkowska J, Areshchanka Y, Banach W, Rzepka J, Kudliński B, Rzepka R. Acute Liver Failure During Early Pregnancy-Case Report and Review of Literature. J Clin Med 2025; 14:2028. [PMID: 40142836 PMCID: PMC11942626 DOI: 10.3390/jcm14062028] [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: 01/12/2025] [Revised: 03/07/2025] [Accepted: 03/14/2025] [Indexed: 03/28/2025] Open
Abstract
Background/Objectives: This article presents the case of a 31-year-old primigravida who experienced acute liver failure in the 23rd week of pregnancy, along with a review of the literature on this rare condition during pregnancy. The purpose of this publication is to highlight the diagnostic and therapeutic challenges associated with acute liver failure in pregnant women. Methods: The patient presented with jaundice, pruritus, and dark-colored urine. Laboratory tests revealed a significant increase in aminotransferase, bilirubin, and bile acid levels, suggesting liver problems; however, due to the patient's rapidly deteriorating condition and test results, autoimmune hepatitis was considered. Viral infections and other causes of liver damage were excluded. No clear diagnosis was established. The patient was administered ursodeoxycholic acid and due to her worsening condition, a cesarean section was performed at 23 weeks of gestation. After delivery, the patient's condition improved, although she did experience cardiac arrest during hospitalization. The patient was discharged with a diagnosis of acute liver failure in the course of an overlap syndrome of autoimmune hepatitis and primary cholangitis or intrahepatic cholestasis of pregnancy. No abnormalities were noted during a follow-up visit 6 weeks after delivery. Despite a detailed case analysis, a final diagnosis was not established, which complicates planning for future pregnancies. Discussion: Several liver conditions can occur during pregnancy, including intrahepatic cholestasis of pregnancy, primary biliary cholangitis, and autoimmune hepatitis. Diagnosing these conditions can be challenging due to overlapping symptoms and metabolic and immunological adaptations during pregnancy that can affect the course of liver diseases. Rapid intervention is crucial to protect the health of both the mother and the fetus. Conclusions: In summary, this article aims to increase awareness of the complexities surrounding acute liver failure during pregnancy, highlighting the diagnostic challenges and importance of prompt medical intervention for the well-being of both the mother and the child. This paper aims to provide a comprehensive overview of the complexities surrounding acute liver failure during pregnancy, aiming to improve the understanding, diagnosis, and management of this condition.
Collapse
Affiliation(s)
- Banach Paulina
- Department of Gynecology and Obstetrics, Collegium Medicum, University of Zielona Góra, 65417 Zielona Góra, Poland; (B.P.); (J.K.); (Y.A.)
| | - Justyna Kuczkowska
- Department of Gynecology and Obstetrics, Collegium Medicum, University of Zielona Góra, 65417 Zielona Góra, Poland; (B.P.); (J.K.); (Y.A.)
| | - Yulia Areshchanka
- Department of Gynecology and Obstetrics, Collegium Medicum, University of Zielona Góra, 65417 Zielona Góra, Poland; (B.P.); (J.K.); (Y.A.)
| | - Weronika Banach
- Poznan University of Medical Sciences, 61701 Poznań, Poland;
| | - Jakub Rzepka
- Poznan University of Medical Sciences, 61701 Poznań, Poland;
| | - Bartosz Kudliński
- Department of Anesthesiology, Intensive Care and Emergency Medicine, Collegium Medicum, University of Zielona Góra, 65417 Zielona Góra, Poland;
| | - Rafał Rzepka
- Department of Gynecology and Obstetrics, Collegium Medicum, University of Zielona Góra, 65417 Zielona Góra, Poland; (B.P.); (J.K.); (Y.A.)
| |
Collapse
|
|
6
|
Azariadis K, Gatselis NK, Lyberopoulou A, Arvaniti P, Zachou K, Gabeta S, Dalekos GN. PNPLA3 I148 M genetic variant in autoimmune hepatitis characterises advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related mortality. J Transl Autoimmun 2024; 9:100243. [PMID: 38974691 PMCID: PMC11225017 DOI: 10.1016/j.jtauto.2024.100243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 05/22/2024] [Accepted: 06/02/2024] [Indexed: 07/09/2024] Open
Abstract
Background Autoimmune hepatitis (AIH) is a relatively rare autoimmune disease with a strong genetic background. The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148 M (rs738409 C/G) variant has been associated with hepatic inflammation and fibrosis in chronic hepatic diseases beyond metabolic dysfunction-associated steatotic liver disease (MASLD). Aim Our aim was to investigate the significance of PNPLA3 I148 M variant in AIH. Method Two hundred AIH patients, followed in our centre, were evaluated while 100 healthy subjects served as controls. Genotyping was performed with allelic discrimination end-point polymerase chain reaction (PCR). Results The I148 M variant was present in 95/200 (47.5 %) AIH patients compared to 47/100 (47 %) healthy controls (p = 1.000). Patients with GG/CG genotypes were more likely to present with decompensated cirrhosis at diagnosis (GG/CG 6.3 % vs. CC 1 %, p = 0.039). Comorbidity with cardiometabolic risk factors and concurrence of MASLD was similar across genotypes. Simple steatosis was present in 37/186 (19.9 %) and steatohepatitis in 14/186 (7.5 %) patients with available liver biopsy without correlation with PNPLA3 genotype. Fibrosis stage and grade of inflammation were not correlated with any genotype. Response to treatment was also independent of the presence of the I148 M variant, even though a longer time was needed to achieve complete biochemical response in those carrying the GG/CG genotypes (p = 0.07). On Kaplan Meier analysis homozygosity for the G allele corelated with reduced survival free of decompensation (p = 0.006), cirrhotic events (decompensation, liver transplantation, hepatocellular carcinoma; p = 0.001) and liver-related death or liver transplantation (p = 0.011) in treated patients. Conclusions The PNPLA3 I148 M variant in AIH patients is associated with increased risk of advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related death or liver transplantation, regardless of the presence of MASLD. This signifies a potential role for the PNPLA3 I148 M variant as a new AIH biomarker allowing to identify patients at increased risk of disease progression.
Collapse
Affiliation(s)
- Kalliopi Azariadis
- 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
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), 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
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece
| | - Aggeliki Lyberopoulou
- 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
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), 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
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, 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
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), 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
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece
| | - 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
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece
| |
Collapse
|
|
7
|
Schregel I, Papp M, Sipeki N, Kovats PJ, Taubert R, Engel B, Campos-Murguia A, Dalekos GN, Gatselis N, Zachou K, Milkiewicz P, Janik MK, Raszeja-Wyszomirska J, Ytting H, Braun F, Casar C, Sebode M, Lohse AW, Schramm C. Unmet needs in autoimmune hepatitis: Results of the prospective multicentre European Reference Network Registry (R-LIVER). Liver Int 2024; 44:2687-2699. [PMID: 39037185 DOI: 10.1111/liv.16035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 06/04/2024] [Accepted: 06/26/2024] [Indexed: 07/23/2024]
Abstract
BACKGROUND AND AIMS The European Reference Network on Hepatological Diseases (ERN RARE-LIVER) launched the prospective, multicentre, quality-controlled R-LIVER registry on rare liver diseases. The aim of this study was to assess the presentation and outcome of autoimmune hepatitis (AIH) after 1 year of treatment. METHODS Data were prospectively collected at the time of diagnosis and after 6 and 12 months follow-up. Complete biochemical response (CBR) was defined as normalization of alanine aminotransferase (ALT) and immunoglobulin G (IgG) serum levels. RESULTS A total of 231 patients from six European centres were included in the analysis. After 6 months of treatment 50% (106/212), and after 12 months 63% (131/210) of patients reached CBR with only 27% (56/211) achieving a steroid-free CBR within the first year. Overall, 16 different treatment regimens were administered. Change of treatment, mostly due to intolerance, occurred in 30.4% within the first 6 months. In multivariate analysis, younger age at diagnosis (odds ratio [OR] = 1.03 [95% confidence interval (CI) 1.01-1.05]; p = .007), severe fibrosis (OR .38 [95% .16-.89], p = .026) and change of treatment within the first 6 months (OR .40 [95% CI .2-.86]; p = .018) were associated with a lesser chance of ALT normalization at 12 months follow-up. CONCLUSION The landscape of AIH treatment in Europe is highly heterogeneous, even between expert centres. The results from this first European multicentre prospective registry reveal several unmet needs, highlighted by the overall low rates of CBR and the frequent failure to withdraw corticosteroids.
Collapse
Affiliation(s)
- Ida Schregel
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
| | - Maria Papp
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Hungary, Germany
| | - Nora Sipeki
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Hungary, Germany
| | - Patricia J Kovats
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Hungary, Germany
- Faculty of Medicine, Kálmán Laki Doctoral School, University of Debrecen, Hungary, Germany
| | - Richard Taubert
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Bastian Engel
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Alejandro Campos-Murguia
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - George N Dalekos
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- 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 Gatselis
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- 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
| | - Kalliopi Zachou
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- 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
| | - Piotr Milkiewicz
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Department of Hepatology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
- Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland
| | - Maciej K Janik
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Department of Hepatology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Joanna Raszeja-Wyszomirska
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Department of Hepatology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Henriette Ytting
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Department of Clinical Medicine, Hvidovre University Hospital of Copenhagen, Copenhagen, Denmark
| | - Felix Braun
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
| | - Christian Casar
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
| | - Marcial Sebode
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
| | - Ansgar W Lohse
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
| | - Christoph Schramm
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Martin Zeitz Center for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| |
Collapse
|
|
8
|
Reau NS, Lammert CS, Weinberg EM. Autoimmune hepatitis: Current and future therapies. Hepatol Commun 2024; 8:e0458. [PMID: 38836863 PMCID: PMC11155538 DOI: 10.1097/hc9.0000000000000458] [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: 02/16/2024] [Accepted: 04/09/2024] [Indexed: 06/06/2024] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that can lead to cirrhosis and liver failure. AIH can present in all ages, races, and ethnicities, but it predominantly affects women. As a heterogeneous disease, AIH presents variably in different patients, making diagnosis and treatment a challenge. Currently, the standard treatment for AIH comprises immunosuppressants; however, their long-term use is associated with adverse effects. The pathogenesis of AIH is complex, involving T cells, macrophages, and plasma cells that invade the periportal parenchyma and lead to an inflammatory cascade that can result in liver damage. Due to the complexity of AIH pathogenesis, treatment targets several inflammatory pathways. However, unlike other autoimmune diseases in which targeted treatments have been approved, there has been little progress made in advancing the treatment paradigm for AIH. Major obstacles to progress include challenges in conducting clinical trials, particularly patient recruitment and ensuring a diverse range of backgrounds; poorly defined outcomes to assess treatment response and improved quality of life; and a lack of study designs that account for the stage of disease and variations in treatment. A focus on individualized and steroid-free treatment approaches is needed to improve AIH prognosis and minimize steroid-associated adverse effects.
Collapse
Affiliation(s)
- Nancy S. Reau
- Section of Hepatology, Hepatology Services, Rush University Medical Center, Chicago, Illinois, USA
| | - Craig S. Lammert
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Ethan M. Weinberg
- Division of Gastroenterology & Hepatology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| |
Collapse
|
|
9
|
Ruf T, Kramer R, Forschner A, Leiter U, Meier F, Reinhardt L, Dücker P, Ertl C, Tomsitz D, Tietze JK, Gutzmer R, Dabrowski E, Zimmer L, Gesierich A, Zierold S, French LE, Eigentler T, Amaral T, Heinzerling L. Second-line therapies for steroid-refractory immune-related adverse events in patients treated with immune checkpoint inhibitors. Eur J Cancer 2024; 203:114028. [PMID: 38652976 DOI: 10.1016/j.ejca.2024.114028] [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: 01/10/2024] [Revised: 03/03/2024] [Accepted: 03/12/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICI) induce adverse events (irAEs) that do not respond to steroids, i.e. steroid-refractory (sr) irAEs, and irAEs in which steroids cannot be tapered, i.e. steroid-dependent (sd) irAEs, in about 10% of cases. An evidence-based analysis of the effectiveness of second-line immunosuppressive agents with regard to irAE and tumor control is lacking. METHODS The international web-based Side Effect Registry Immuno-Oncology (SERIO; http://serio-registry.org) is a collaborative initiative with the Paul-Ehrlich-Institute to document rare, severe, complex or therapy-refractory immunotherapy-induced side effects. The registry was queried on August 1, 2023 for cases of irAEs which were treated with second-line therapies. RESULTS From a total of 1330 cases, 217 patients (16.3%) received 249 second-line therapies. A total of 19 different second-line therapies were employed, including TNF-alpha antagonists (46.5%), intravenous immunoglobulins (IVIG; 19.1%), mycophenolate mofetil (15.9%), and methotrexate (3.6%). Therapy choices were determined by the type of irAE. The time to onset of sr-/sd-irAEs after ICI initiation did not consistently differ from steroid-responsive irAEs. While 74.3% of sr-/sd-irAEs resolved and 13.1% had improved, 4.3% persisted, 3.9% resulted in permanent sequelae, and 4.3% in death with ongoing symptoms. Infliximab exhibited potential for earlier symptom improvement compared to mycophenolate mofetil or IVIG. Tumor response in patients with second-line treated sd-/sr-irAE was similar to patients with irAEs treated with steroids only. CONCLUSION Several second-line therapies are effective against sr-/sd-irAEs, the second-line therapies show no clear negative impact on tumor response, and infliximab shows potential for faster improvement of symptoms. However, prospective comparative data are needed.
Collapse
Affiliation(s)
- Theresa Ruf
- Department of Dermatology and Allergology, University Hospital, LMU Munich, Munich, Germany; SERIO registry
| | - Rafaela Kramer
- Department of Dermatology, University Clinic Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; SERIO registry
| | - Andrea Forschner
- Department of Dermatology, Eberhard-Karls-University of Tübingen, Tübingen, Germany
| | - Ulrike Leiter
- Department of Dermatology, Eberhard-Karls-University of Tübingen, Tübingen, Germany
| | - Friedegund Meier
- Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden, Germany
| | - Lydia Reinhardt
- Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden, Germany
| | - Pia Dücker
- Department of Dermatology, Hospital Dortmund, Dortmund, Germany
| | - Carolin Ertl
- Department of Dermatology and Allergology, University Hospital, LMU Munich, Munich, Germany; SERIO registry
| | - Dirk Tomsitz
- Department of Dermatology and Allergology, University Hospital, LMU Munich, Munich, Germany
| | - Julia K Tietze
- Clinic for Dermatology and Venerology, University Medical Center Rostock, Rostock, Germany
| | - Ralf Gutzmer
- Department of Dermatology, Johannes Wesling Medical Center, Ruhr-University Bochum, Minden, Germany
| | | | - Lisa Zimmer
- Department of Dermatology, Essen University Hospital, West German Cancer Center, University of Duisburg-Essen and the German Cancer Consortium (DKTK), Partner site Essen/Düsseldorf, Germany
| | - Anja Gesierich
- Department of Dermatology, University Hospital Würzburg, Germany
| | - Sarah Zierold
- Department of Dermatology and Allergology, University Hospital, LMU Munich, Munich, Germany; SERIO registry
| | - Lars E French
- Department of Dermatology and Allergology, University Hospital, LMU Munich, Munich, Germany; Dr. Philip Frost Department of Dermatology & Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Thomas Eigentler
- Department of Dermatology, Charité University Medicine Berlin, Berlin, Germany
| | - Teresa Amaral
- Department of Dermatology, Eberhard-Karls-University of Tübingen, Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180), Tübingen, Germany
| | - Lucie Heinzerling
- Department of Dermatology and Allergology, University Hospital, LMU Munich, Munich, Germany; Department of Dermatology, University Clinic Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; SERIO registry.
| |
Collapse
|
|
10
|
Rashad E, Moazam MM, Chaudhry R, El Eraky N, Mirza MSS, Nazmin F. Efficacy of Combination Therapies for Autoimmune Hepatitis: A Systematic Review and Meta-Analysis. Cureus 2024; 16:e60049. [PMID: 38854256 PMCID: PMC11162748 DOI: 10.7759/cureus.60049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/10/2024] [Indexed: 06/11/2024] Open
Abstract
Autoimmune hepatitis (AIH) is a hepatocellular disorder thought to be caused by an immune system that cannot tolerate autoantigens specific to hepatocytes. This study aims to evaluate the efficacy of using corticosteroids (prednisolone and azathioprine) as a combination therapy in treating AIH. This study aims to synthesize and analyze existing evidence to inform clinical practices concerning the overall clinical efficacy of this treatment approach in managing AIH. A comprehensive search was conducted across multiple online databases and search engines, including PubMed, Google Scholar, ScienceDirect, Medline, and Embase. RevMan 5.4 software was used for meta-analysis, with forest plots created for each outcome. Thirteen studies were included in this systematic review and meta-analysis. The results indicate that the combination of prednisolone and azathioprine for treating AIH leads to less recurrence and better disease control.
Collapse
Affiliation(s)
- Essam Rashad
- Hospital Medicine, Parkview Regional Medical Center, Fort Wayne, USA
| | - Mustafa M Moazam
- Psychiatry, Texas Tech University Health Sciences Center El Paso, El Paso, USA
| | | | - Noha El Eraky
- Radiology, St Vincent's University Hospital, Dublin, IRL
| | | | | |
Collapse
|
|
11
|
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
|
|
12
|
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
|
|
13
|
Abstract
The goal of autoimmune hepatitis treatment is to achieve clinical and biochemical remission, which is associated with significantly improved outcomes. Induction treatment with corticosteroids and the subsequent addition of steroid-sparing therapy with gradual tapering of corticosteroids remains the standard of care. Several alternatives to azathioprine and second-line agents, such as mycophenolate mofetil, tacrolimus, cyclosporine, sirolimus, or rituximab, have been evaluated in those with intolerance or inadequate response to standard-of-care therapy. Treatment withdrawal is achievable in less than 20% of patients after 2 years of sustained remission. Liver transplantation should be considered in those with progressive liver disease or those with complications such as hepatocellular carcinoma.
Collapse
Affiliation(s)
- Aparna Goel
- Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, CA 94043, USA.
| | - Paul Kwo
- Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, CA 94043, USA
| |
Collapse
|
|
14
|
Stoelinga AEC, Tushuizen ME, van den Hout WB, Girondo MDMR, de Vries ES, Levens AD, Moes DJAR, Gevers TJG, van der Meer S, Brouwer HT, de Jonge HJM, de Boer YS, Beuers UHW, van der Meer AJ, van den Berg AP, Guichelaar MMJ, Drenth JPH, van Hoek B. Tacrolimus versus mycophenolate for AutoImmune hepatitis patients with incompLete response On first-line therapy (TAILOR study): a study protocol for a phase III, open-label, multicentre, randomised controlled trial. Trials 2024; 25:61. [PMID: 38233878 PMCID: PMC10792789 DOI: 10.1186/s13063-023-07832-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 11/24/2023] [Indexed: 01/19/2024] Open
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical response is the most important risk factor for liver transplantation or liver-related mortality. First-line treatment consists of a combination of azathioprine and prednisolone. If CR is not reached, tacrolimus (TAC) or mycophenolate mofetil (MMF) can be used as second-line therapy. Both products are registered for the prevention of graft rejection in solid organ transplant recipients. The aim of this study is to compare the effectiveness and safety of TAC and MMF as second-line treatment for AIH. METHODS The TAILOR study is a phase IIIB, multicentre, open-label, parallel-group, randomised (1:1) controlled trial performed in large teaching and university hospitals in the Netherlands. We will enrol 86 patients with AIH who have not reached CR after at least 6 months of treatment with first-line therapy. Patients are randomised to TAC (0.07 mg/kg/day initially and adjusted by trough levels) or MMF (max 2000 mg/day), stratified by the presence of cirrhosis at inclusion. The primary endpoint is the difference in the proportion of patients reaching CR after 12 months. Secondary endpoints include the difference in the proportion of patients reaching CR after 6 months, adverse effects, difference in fibrogenesis, quality of life and cost-effectiveness. DISCUSSION This is the first randomised controlled trial comparing two second-line therapies for AIH. Currently, second-line treatment is based on retrospective cohort studies. The rarity of AIH is the main issue in clinical research for alternative treatment options. The results of this trial can be implemented in existing international clinical guidelines. TRIAL REGISTRATION ClinicalTrials.gov NCT05221411 . Retrospectively registered on 3 February 2022; EudraCT number 2021-003420-33. Prospectively registered on 16 June 2021.
Collapse
Affiliation(s)
- Anna E C Stoelinga
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
| | - Maarten E Tushuizen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Wilbert B van den Hout
- Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Elsemieke S de Vries
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
- Department of Gastroenterology and Hepatology, Isala Hospital, Zwolle, The Netherlands
| | - Amar D Levens
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Dirk-Jan A R Moes
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Tom J G Gevers
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- European Reference Network RARE-LIVER, Hamburg, Germany
| | - Suzanne van der Meer
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Hans T Brouwer
- Department of Gastroenterology and Hepatology, Reinier de Graaf Gasthuis, Delft, The Netherlands
| | - Hendrik J M de Jonge
- Department of Gastroenterology and Hepatology, Jeroen Bosch Hospital, 'S-Hertogenbosch, The Netherlands
| | - Ynte S de Boer
- European Reference Network RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Location VU University Medical Center, Amsterdam, The Netherlands
| | - Ulrich H W Beuers
- European Reference Network RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Location Academic Medical Center, Amsterdam, The Netherlands
| | - Adriaan J van der Meer
- European Reference Network RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Aad P van den Berg
- European Reference Network RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Maureen M J Guichelaar
- Department of Gastroenterology and Hepatology, Medisch Spectrum Twente, Enschede, The Netherlands
| | - Joost P H Drenth
- European Reference Network RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| |
Collapse
|
|
15
|
Beehler MK, Kearns SA, Crouse ZJ. Mycophenolate mofetil as a treatment for presumed idiopathic chronic hepatitis in dogs: Six cases (2010-2022). Vet Med Sci 2023; 9:2527-2533. [PMID: 37659075 PMCID: PMC10650243 DOI: 10.1002/vms3.1261] [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: 05/29/2023] [Revised: 07/17/2023] [Accepted: 08/18/2023] [Indexed: 09/04/2023] Open
Abstract
OBJECTIVES The objectives of this study were to describe the clinical findings, treatment and outcomes of six dogs with presumed idiopathic chronic hepatitis treated with mycophenolate mofetil (MMF). MATERIALS AND METHODS Medical records were retrospectively searched to identify dogs in which idiopathic chronic hepatitis was diagnosed on histopathology between January 2010 and June 2022 that were treated with MMF for at least two weeks with >2 follow-up examinations. Data recorded from each dog included signalment, clinical signs, diagnostic test results and treatment. RESULTS Six dogs were treated with MMF at a median initial dosage of 9.6 mg/kg PO q 12 h. Reported adverse effects from MMF included decreased appetite, vomiting and diarrhoea. In all six dogs, MMF was used successfully long term for the treatment of idiopathic chronic hepatitis as determined by 46% or greater improvement of alanine aminotransferase (ALT) between 4 and 18 weeks of starting MMF. Three dogs were also temporarily treated for 4-6 months on a tapering dose of prednisone. In two dogs, ALT remained within the reference interval, and in one dog, it was very mildly elevated when on MMF alone. In all six dogs, owners reported that the medication was well tolerated. CLINICAL SIGNIFICANCE To the authors' knowledge, this is the first report describing the use of MMF with and without a tapering dose of prednisone for the treatment of idiopathic chronic hepatitis in six dogs. Based on the outcomes of the dogs in this report, MMF can be effective for the long-term treatment of idiopathic chronic hepatitis as measured by reduction in ALT and improvement of clinical signs.
Collapse
Affiliation(s)
- Michelle K. Beehler
- Department of Internal MedicineAngell Animal Medical CenterBostonMassachusettsUSA
| | - Shawn A. Kearns
- Department of Internal MedicineAngell Animal Medical CenterBostonMassachusettsUSA
| | - Zachary J. Crouse
- Department of Internal MedicineAngell Animal Medical CenterBostonMassachusettsUSA
| |
Collapse
|
|
16
|
Zhu J, Chen H, Cui J, Zhang X, Liu G. Oroxylin A inhibited autoimmune hepatitis-induced liver injury and shifted Treg/Th17 balance to Treg differentiation. Exp Anim 2023; 72:367-378. [PMID: 36927981 PMCID: PMC10435359 DOI: 10.1538/expanim.22-0171] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 03/06/2023] [Indexed: 03/16/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a kind of autoimmune disease mediated by T cells, and its incidence is gradually increasing in the world. Oroxylin A (OA) is one of the major bioactive flavonoids that has been reported to inhibit inflammatory. Here, an AIH model of mouse was induced by Concanavalin A (Con A). It found that serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were decreased in mice with the treatment of OA. Hematoxylin-eosin staining showed that the liver injury was attenuated by OA, and TUNEL staining indicated that the cells apoptosis of liver was weakened in mice with OA treatment. ELISA analysis of cytokines and chemokines suggested that OA reduced the expression of IL-6, IL-17A, chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 1 (CXCL1) and CXCL10, but promoted the expression of IL-10 and TGF-β in mice. The mRNA levels of Il-17a in liver and spleen tissues were also significantly decreased, on the contrary, the mRNA levels of Il-10 in liver and spleen tissues were increased. The proportion of Treg/Th17 detected by flow cytometry revealed that OA promoted the differentiation of Treg and inhibited the differentiation of Th17 both in the liver and spleen. The results of this study demonstrated the inhibitory effects of OA on AIH-induced liver injury and the inflammatory response of AIH, and revealed that OA affected the balance of Treg/Th17 and shifted the balance toward Treg differentiation. It provided new potential drugs for the prevention of AIH.
Collapse
Affiliation(s)
- Jinxia Zhu
- The First Clinical Medical College, Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou, Henan, 450046, P.R. China
| | - Hongxiu Chen
- The First Clinical Medical College, Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou, Henan, 450046, P.R. China
| | - Jianjiao Cui
- Spleen, Stomach and Hepatobiliary Department, The First Affiliated Hospital of Henan University of Chinese Medicine, No. 19, Renmin Road, Zhengzhou, Henan, 450003, P.R. China
| | - Xiaorui Zhang
- Spleen, Stomach and Hepatobiliary Department, The First Affiliated Hospital of Henan University of Chinese Medicine, No. 19, Renmin Road, Zhengzhou, Henan, 450003, P.R. China
| | - Guangwei Liu
- Spleen, Stomach and Hepatobiliary Department, The First Affiliated Hospital of Henan University of Chinese Medicine, No. 19, Renmin Road, Zhengzhou, Henan, 450003, P.R. China
| |
Collapse
|
|
17
|
Yi Q, Yang J, Wu Y, Wang Y, Cao Q, Wen W. Immune microenvironment changes of liver cirrhosis: emerging role of mesenchymal stromal cells. Front Immunol 2023; 14:1204524. [PMID: 37539053 PMCID: PMC10395751 DOI: 10.3389/fimmu.2023.1204524] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 06/21/2023] [Indexed: 08/05/2023] Open
Abstract
Cirrhosis is a progressive and diffuse liver disease characterized by liver tissue fibrosis and impaired liver function. This condition is brought about by several factors, including chronic hepatitis, hepatic steatosis, alcohol abuse, and other immunological injuries. The pathogenesis of liver cirrhosis is a complex process that involves the interaction of various immune cells and cytokines, which work together to create the hepatic homeostasis imbalance in the liver. Some studies have indicated that alterations in the immune microenvironment of liver cirrhosis are closely linked to the development and prognosis of the disease. The noteworthy function of mesenchymal stem cells and their paracrine secretion lies in their ability to promote the production of cytokines, which in turn enhance the self-repairing capabilities of tissues. The objective of this review is to provide a summary of the alterations in liver homeostasis and to discuss intercellular communication within the organ. Recent research on MSCs is yielding a blueprint for cell typing and biomarker immunoregulation. Hopefully, as MSCs researches continue to progress, novel therapeutic approaches will emerge to address cirrhosis.
Collapse
Affiliation(s)
- Qiuyun Yi
- National Center for Liver Cancer, Third Affiliated Hospital of Naval Medical University, Shanghai, China
- International Cooperation Laboratory on Signal Transduction, Third Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai, China
| | - Jinxian Yang
- National Center for Liver Cancer, Third Affiliated Hospital of Naval Medical University, Shanghai, China
- International Cooperation Laboratory on Signal Transduction, Third Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai, China
| | - Ying Wu
- Department of Breast and Thyroid Surgery, Changhai Hospital, Naval Military Medical University, Shanghai, China
| | - Ying Wang
- Department of Laboratory Diagnosis, Third Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai, China
| | - Qiqi Cao
- National Center for Liver Cancer, Third Affiliated Hospital of Naval Medical University, Shanghai, China
- International Cooperation Laboratory on Signal Transduction, Third Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai, China
| | - Wen Wen
- National Center for Liver Cancer, Third Affiliated Hospital of Naval Medical University, Shanghai, China
- Department of Laboratory Diagnosis, Third Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai, China
| |
Collapse
|
|
18
|
Buechter M, Dorn D, Möhlendick B, Siffert W, Baba HA, Gerken G, Kahraman A. Characteristics and Long-Term Outcome of 535 Patients with Autoimmune Hepatitis-The 20-Year Experience of a High-Volume Tertiary Center. J Clin Med 2023; 12:4192. [PMID: 37445225 DOI: 10.3390/jcm12134192] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 06/12/2023] [Accepted: 06/16/2023] [Indexed: 07/15/2023] Open
Abstract
Background and aims: Autoimmune hepatitis (AIH) is a complex and progressive inflammatory liver disease characterized by immune-mediated destruction of the liver parenchyma, hypergammaglobulinemia, the presence of circulating autoantibodies, and good response to immunosuppressive therapy. Since the prevalence of AIH is relatively rare, data on the clinical course and the long-term outcome are scarce. Patients and methods: We retrospectively analyzed the data of 535 well-documented AIH patients treated at the University Hospital Essen between 2000 and 2020. Results: The majority of patients were middle-aged females (75% women, mean age 45 years) with AIH type 1 (97%). Approximately 32% of patients were diagnosed with cirrhosis due to AIH, 29% had concomitant autoimmune (predominantly autoimmune thyroiditis), and 10% had psychiatric diseases, respectively. Skin tumors were the most common malignant diseases (47% of all tumors), while hepatocellular carcinoma rarely occurred (only six cases). Overall long-term mortality and liver-associated mortality were 9.16% and 4.67%, respectively. However, long-term survival was strongly associated with disease remission. Conclusions: Although AIH is a silent disease and cirrhosis is present in many cases, a favorable long-term prognosis can be achieved by consequent immunosuppressive therapy. The incidence of (liver-associated) complications seems to be lower in comparison to other etiologies, such as viral hepatitis or NASH, and mainly depends on the long-term side effects of immunosuppressive therapy.
Collapse
Affiliation(s)
- Matthias Buechter
- Department of Gastroenterology and Hepatology, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
- Department of Gastroenterology and Hepatology, Elisabeth Hospital, 58638 Iserlohn, Germany
| | - Dominik Dorn
- Department of Gastroenterology and Hepatology, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Birte Möhlendick
- Institute of Pharmacogenetics, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Winfried Siffert
- Institute of Pharmacogenetics, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Hideo A Baba
- Institute of Pathology, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Guido Gerken
- Department of Gastroenterology and Hepatology, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
- Department of Gastroenterology and Hepatology, Helios Clinic, 42549 Velbert, Germany
| | - Alisan Kahraman
- Department of Gastroenterology and Hepatology, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
- Department of Gastroenterology and Hepatology, Max Grundig Clinic, 77815 Bühl, Germany
| |
Collapse
|
|
19
|
Bhat R, Tonutti A, Timilsina S, Selmi C, Gershwin ME. Perspectives on Mycophenolate Mofetil in the Management of Autoimmunity. Clin Rev Allergy Immunol 2023:10.1007/s12016-023-08963-3. [PMID: 37338709 DOI: 10.1007/s12016-023-08963-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2023] [Indexed: 06/21/2023]
Abstract
Before becoming a cornerstone in the treatment of numerous immune-mediated diseases, mycophenolate mofetil (MMF) was first introduced as an immunosuppressive agent in transplant immunology and later received the attention of rheumatologists and clinicians involved in the management of autoimmune diseases. MMF is now a widespread immunosuppressive drug for the treatment of several conditions, including lupus nephritis, interstitial lung disease associated with systemic sclerosis, and anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis while being efficacious also as rescue therapy in various orphan diseases, including dermatomyositis and IgA-associated nephropathy. Similarly, case reports or series support a possible use of MMF in other rare autoimmune diseases. Beyond modulating lymphocyte activation, MMF acts on other immune and non-immune cells and these effects may explain the therapeutic profile of this medication. The effects of MMF are broadly characterized by the impact on the immune system and the antiproliferative and antifibrotic changes induced. In this latter case, mechanistic data on fibroblasts may in the future allow to reevaluate the use of MMF in selected patients with inflammatory arthritis or systemic sclerosis. Attention must be paid towards the possible occurrence of adverse events, such as gastrointestinal complaints and teratogenicity, while the risk of infections and cancer related to MMF needs to be further investigated.
Collapse
Affiliation(s)
- Rithika Bhat
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, USA
| | - Antonio Tonutti
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Suraj Timilsina
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, USA
| | - Carlo Selmi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
- Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
| | - M Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, USA.
| |
Collapse
|
|
20
|
Pellicano R, Ferro A, Cicerchia F, Mattivi S, Fagoonee S, Durazzo M. Autoimmune Hepatitis and Fibrosis. J Clin Med 2023; 12:1979. [PMID: 36902767 PMCID: PMC10004701 DOI: 10.3390/jcm12051979] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/16/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic immune-inflammatory disease of the liver, generally considered a rare condition. The clinical manifestation is extremely varied and can range from paucisymptomatic forms to severe hepatitis. Chronic liver damage causes activation of hepatic and inflammatory cells leading to inflammation and oxidative stress through the production of mediators. This results in increased collagen production and extracellular matrix deposition leading to fibrosis and even cirrhosis. The gold standard for the diagnosis of fibrosis is liver biopsy; however, there are serum biomarkers, scoring systems, and radiological methods useful for diagnosis and staging. The goal of AIH treatment is to suppress fibrotic and inflammatory activities in the liver to prevent disease progression and achieve complete remission. Therapy involves the use of classic steroidal anti-inflammatory drugs and immunosuppressants, but in recent years scientific research has focused on several new alternative drugs for AIH that will be discussed in the review.
Collapse
Affiliation(s)
- Rinaldo Pellicano
- Unit of Gastroenterology, Città della Salute e della Scienza Hospital, C.so Bramante 88, 10126 Turin, Italy
| | - Arianna Ferro
- Department of Medical Sciences, University of Turin, C.so A.M. Dogliotti 14, 10126 Turin, Italy
| | - Francesca Cicerchia
- Department of Medical Sciences, University of Turin, C.so A.M. Dogliotti 14, 10126 Turin, Italy
| | - Simone Mattivi
- Department of Medical Sciences, University of Turin, C.so A.M. Dogliotti 14, 10126 Turin, Italy
| | - Sharmila Fagoonee
- Institute for Biostructure and Bioimaging, National Research Council, Molecular Biotechnology Centre, 10126 Turin, Italy
| | - Marilena Durazzo
- Department of Medical Sciences, University of Turin, C.so A.M. Dogliotti 14, 10126 Turin, Italy
| |
Collapse
|
|
21
|
Lloyd C, Leighton J, Wong LL, Goulding A, Brownlee A, Gray P, Culver E, Halliday N, Thorburn D, Heneghan MA, Jones DEJ, Exley C, Dyson JK. Patient Priorities in Autoimmune Hepatitis: The Need for Better Treatments, More Education and Challenging Stigma. Dig Dis Sci 2023; 68:87-97. [PMID: 35579795 PMCID: PMC9112273 DOI: 10.1007/s10620-022-07525-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 04/18/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND Data show that patients with autoimmune hepatitis have significantly reduced quality-of-life and that corticosteroids carry marked side effects. AIMS This study explored patients' experiences of autoimmune hepatitis and its treatments; key aspects for developing safe and effective new approaches to therapy. METHODS An anonymised, internet-based survey collected data including patient demographics, treatments, side-effects, impact on day-to-day life, sources of support and attitudes towards autoimmune hepatitis between December 2019-January 2020. Semi-structured interviews were conducted with 13 patients to further explore their support networks, treatment experiences and health priorities. Descriptive and quantitative analyses were undertaken using R and free text responses were subject to thematic analysis. RESULTS In total, 270 survey responses were received (median age 55 years and 94% female). Perceived medication side-effects were reported by 66% (169/257) and 73% responded negatively about their experience of corticosteroids. The majority (62·3% [(109/175]) would 'definitely' or 'probably' consider clinical trial participation to improve their care. Only 18·7% (31/166) reported access to a specialist liver nurse and nearly half were involved in support groups. Interview and survey data suggested that major issues were stigma, loss of control and fatigue. CONCLUSIONS This study provides insights into the realities of living with autoimmune hepatitis with clear issues around lack of support networks, need for patient empowerment and stigma surrounding liver disease. Patient priorities are better therapies to slow disease progression, avoiding corticosteroids and minimising side-effects. Patient willingness to participate in trials suggests that they are achievable provided they have the right design and clinical endpoints.
Collapse
Affiliation(s)
- Charlotte Lloyd
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Jessica Leighton
- Translational and Clinical Research Institute, Newcastle University and Liver Unit, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE7 7DN UK
| | | | - Anna Goulding
- School of Medical Education, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | | | | | | | - Neil Halliday
- Institute for Liver and Digestive Health, University College London and Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK
| | - Doug Thorburn
- Institute for Liver and Digestive Health, University College London and Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK
| | | | - David E. J. Jones
- Translational and Clinical Research Institute, Newcastle University and Liver Unit, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE7 7DN UK
| | - Catherine Exley
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Jessica K. Dyson
- Translational and Clinical Research Institute, Newcastle University and Liver Unit, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE7 7DN UK
| |
Collapse
|
|
22
|
Snijders RJALM, Stoelinga AEC, Gevers TJG, Pape S, Biewenga M, Verdonk RC, de Jonge HJM, Vrolijk JM, Bakker SF, Vanwolleghem T, de Boer YS, Pronk MAMCB, Beuers UHW, van der Meer AJ, van Gerven NMF, Sijtsma MGM, Verwer BJ, Gisbertz IAM, Bartelink M, van den Brand FF, Sebib Korkmaz K, van den Berg AP, Guichelaar MMJ, Soufidi K, Levens AD, van Hoek B, Drenth JPH. Assessing the efficacy and safety of mycophenolate mofetil versus azathioprine in patients with autoimmune hepatitis (CAMARO trial): study protocol for a randomised controlled trial. Trials 2022; 23:1012. [PMID: 36514163 PMCID: PMC9745715 DOI: 10.1186/s13063-022-06890-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 11/05/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which necessitates cessation of azathioprine or changes in therapy. In addition, not all patients achieve complete biochemical response (CR). Uncontrolled data indicate that mycophenolate mofetil (MMF) can induce CR in a majority of patients. Better understanding of first-line treatment and robust evidence from randomised clinical trials are needed. The aim of this study was to explore the potential benefits of MMF as compared to azathioprine, both combined with prednisolone, as induction therapy in a randomised controlled trial in patients with treatment-naive AIH. METHODS CAMARO is a randomised (1:1), open-label, parallel-group, multicentre superiority trial. All patients with AIH are screened for eligibility. Seventy adult patients with AIH from fourteen centres in the Netherlands and Belgium will be randomised to receive MMF or azathioprine. Both treatment arms will start with prednisolone as induction therapy. The primary outcome is biochemical remission, defined as serum levels of alanine aminotransferase and immunoglobulin G below the upper limit of normal. Secondary outcomes include safety and tolerability of MMF and azathioprine, time to remission, changes in Model For End-Stage Liver Disease (MELD)-score, adverse events, and aspects of quality of life. The study period will last for 24 weeks. DISCUSSION The CAMARO trial investigates whether treatment with MMF and prednisolone increases the proportion of patients in remission compared with azathioprine and prednisolone as the current standard treatment strategy. In addition, we reflect on the challenges of conducting a randomized trial in rare diseases. TRIAL REGISTRATION EudraCT 2016-001038-91 . Prospectively registered on 18 April 2016.
Collapse
Affiliation(s)
- Romée J A L M Snijders
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands.
- European Reference Network RARE-LIVER, Hamburg, Germany.
| | - Anna E C Stoelinga
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Tom J G Gevers
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
- European Reference Network RARE-LIVER, Hamburg, Germany
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- Nutrim School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Simon Pape
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
- European Reference Network RARE-LIVER, Hamburg, Germany
| | - Maaike Biewenga
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, 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
| | - Ynto S de Boer
- European Reference Network RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, location VU University Medical Center, Amsterdam, The Netherlands
| | | | - Ulrich H W Beuers
- European Reference Network RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, The Netherlands
| | - Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, 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
| | - Bart J Verwer
- Department of Gastroenterology and Hepatology, Spaarne Gasthuis, Haarlem, The Netherlands
| | - Ingrid A M Gisbertz
- Department of Gastroenterology and Hepatology, Hospital Bernhoven, Uden, The Netherlands
| | - Maartje Bartelink
- 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
| | - Maureen M J Guichelaar
- Department of Gastroenterology and Hepatology, Medisch Spectrum Twente, Enschede, The Netherlands
| | - Khalida Soufidi
- Department of Gastroenterology and Hepatology, Zuyderland, Heerlen, The Netherlands
| | - Amar D Levens
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
- European Reference Network RARE-LIVER, Hamburg, Germany
| |
Collapse
|
|
23
|
Mycophenolate mofetil as second line treatment in autoimmune hepatitis – A retrospective single center analysis. J Transl Autoimmun 2022; 5:100172. [DOI: 10.1016/j.jtauto.2022.100172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 11/16/2022] [Indexed: 11/21/2022] Open
|
|
24
|
Zhang F, Fan L, Liu Q, Tang S, Zhang S, Xiao L, Zhang L, Li Q, Maihemuti N, Li L. Comprehensive immune cell analysis of human menstrual-blood-derived stem cells therapy to concanavalin A hepatitis. Front Immunol 2022; 13:974387. [PMID: 36248904 PMCID: PMC9559565 DOI: 10.3389/fimmu.2022.974387] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 09/02/2022] [Indexed: 11/13/2022] Open
Abstract
Autoimmune hepatitis is an autoimmune disease with increasing occurrence worldwide. The most common and convenient mouse model is the concanavalin A (ConA) mouse model. Human menstrual-blood-derived stem cells (MenSCs) have shown great potential as a type of mesenchymal stem cell for treating various diseases. Time-of-flight mass cytometry was performed in phosphate-buffered saline control (NC) group and ConA injection with or without MenSCs treatment groups, and conventional flow cytometry was used for further validation. The serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and H&E staining depicted that MenSCs treatment could significantly alleviate ConA-induced hepatitis. The t-distributed stochastic neighbor embedding (t-SNE) analysis of nine liver samples displayed favorable cell clustering, and the NC group was significantly different from the other two groups. The proportions of CD69+ T cells, NKT cells, and PD-L1+ macrophages were notably increased by ConA injection, while MenSCs could decrease ConA-induced macrophage percentage and M1 polarization in the liver tissue. The analysis of proinflammatory factors carried out by cytometric bead array demonstrated that tumor necrosis factor alpha (TNF-α), interleukin (IL)-17A, IL-12p70, IL-6, IL-2, IL-1b, and interferon gamma (IFN-γ) were upregulated after ConA injection and then rapidly decreased at 12 h. MenSCs also played an important role in downregulating these cytokines. Here, we described the comprehensive changes in leukocytes in the liver tissue of ConA-induced hepatitis at 12 h after ConA injection and found that MenSCs rescued ConA-induced hepatitis mostly by inhibiting macrophages and M1 polarization in mouse liver.
Collapse
Affiliation(s)
- Fen Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Linxiao Fan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiuhong Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shima Tang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Sainan Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Infectious Disease, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University, Shulan International Medical College, Hangzhou, China
| | - Lanlan Xiao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lingjian Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qian Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Nueraili Maihemuti
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Lanjuan Li,
| |
Collapse
|
|
25
|
Dalekos GN, Arvaniti P, Gatselis NK, Gabeta S, Samakidou A, Giannoulis G, Rigopoulou E, Koukoulis GK, Zachou K. Long-term results of mycophenolate mofetil vs. azathioprine use in patients with autoimmune hepatitis. JHEP Rep 2022; 4:100601. [DOI: 10.1016/j.jhepr.2022.100601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 09/17/2022] [Accepted: 09/21/2022] [Indexed: 12/15/2022] Open
|
|
26
|
Zachou K, Arvaniti P, Lyberopoulou A, Sevdali E, Speletas M, Ioannou M, Koukoulis GK, Renaudineau Y, Dalekos GN. Altered DNA methylation pattern characterizes the peripheral immune cells of patients with autoimmune hepatitis. Liver Int 2022; 42:1355-1368. [PMID: 35108441 DOI: 10.1111/liv.15176] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/18/2021] [Accepted: 01/12/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Little is known about the impact of DNA methylation modifications on autoimmune hepatitis (AIH) pathogenesis and therapeutic response. We investigated the potential alterations of DNA methylation in AIH peripheral lymphocytes at diagnosis and remission. METHODS Ten AIH patients at diagnosis (time-point 1; AIH-tp1), 8/10 following biochemical response (time-point 2; AIH-tp2), 9 primary biliary cholangitis (PBC) and 10 healthy controls (HC) were investigated. Peripheral CD19(+) and CD4(+) cells were isolated. Global DNA methylation (5m C)/hydroxymethylation (5hm C) was studied by ELISAs. mRNA of DNA methylation (DNMT1/3A/3B) and their counteracting hydroxymethylation enzymes (TET1/2/3) was determined by quantitative RT-PCR. Epigenome wide association study (EWAS) was performed in CD4(+) cells (Illumina HumanMethylation 850 K array) in AIH and HC. Total 5m C/5hm C was also assessed by immunohistochemistry (IHC) on paraffin-embedded liver sections. RESULTS Reduced TET1 and increased DNMT3A mRNA levels characterized CD19(+) and CD4(+)-lymphocytes from AIH-tp1 compared to HC and PBC, respectively, without affecting global DNA 5m C/5hm C. In AIH-tp1, CD4(+) DNMT3A expression was negatively correlated with serum IgG (P = .03). In remission, DNMT3A decreased in both CD19(+) and CD4(+) cells compared to AIH-tp1 (P = .02, P = .03 respectively). EWAS in CD4(+) cells from AIH patients confirmed important modifications in genes implicated in immune responses (HLA-DP, TNF, lnRNAs and CD86). IHC showed increased 5hm C staining of periportal infiltrating lymphocytes in AIH-tp1 compared to HC and PBC. CONCLUSION Altered TET1 and DNMT3A expressions, characterize peripheral lymphocytes in AIH. DNMT3A was associated with disease activity and decreased following remission. Gene DNA methylation modifications affect immunological pathways that may play an important role in AIH pathogenesis.
Collapse
Affiliation(s)
- Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), 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, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Aggeliki Lyberopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Eirini Sevdali
- Faculty of Medicine, Department of Immunology and Histocompatibility, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Matthaios Speletas
- Faculty of Medicine, Department of Immunology and Histocompatibility, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Maria Ioannou
- Faculty of Medicine, Department of Pathology, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - George K Koukoulis
- Faculty of Medicine, Department of Pathology, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Yves Renaudineau
- INSERN U1291, CNR U5051, University Toulouse III, Toulouse Institute for infectious and inflammatory diseases, Toulouse, France.,Department of Immunology, Purpan University Hospital Toulouse, Toulouse, France
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| |
Collapse
|
|
27
|
Jiang R, Tang J, Zhang X, He Y, Yu Z, Chen S, Xia J, Lin J, Ou Q. CCN1 Promotes Inflammation by Inducing IL-6 Production via α6β1/PI3K/Akt/NF-κB Pathway in Autoimmune Hepatitis. Front Immunol 2022; 13:810671. [PMID: 35547732 PMCID: PMC9084230 DOI: 10.3389/fimmu.2022.810671] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 03/25/2022] [Indexed: 12/12/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease with unknown etiology. CCN1, an extracellular matrix-associated protein, is associated with carcinoma, inflammation, liver fibrosis, and even autoimmune diseases. However, the role that CCN1 plays in AIH has remained undetermined. In this study, expression of CCN1 in liver was detected by real-time PCR, western blot and immunohistochemistry (IHC). CCN1 level in serum was detected by ELISA. Diagnostic value of CCN1 was determined by receiver operating characteristic (ROC) curve analysis. CCN1 conditional knockout (CCN1fl/flCre+) mice were generated by mating CCN1fl/fl C57BL/6J and CAG-Cre-ERT C57BL/6J mice. Autoimmune hepatitis mice model was induced by concanavalin A (ConA). IKKα/β, IκBα, NF-κB p65 and Akt phosphorylation were determined by western blot. NF-κB p65 nuclear translocation was examined by immunofluorescence. Here, we found that CCN1 was over-expressed in hepatocytes of AIH patients. CCN1 level also increased in serum of AIH patients compared to healthy controls (HC). ROC curve analysis results showed that serum CCN1 was able to distinguish AIH patients from HD. In ConA induced hepatitis mice model, CCN1 conditional knockout (CCN1fl/flCre+) attenuated inflammation by reducing ALT/AST level and IL-6 expression. In vitro, CCN1 treatment dramatically induced IL-6 production in LO2 cells. Moreover, the production of IL-6 was attenuated by CCN1 knockdown. Furthermore, we showed that CCN1 could activate IL-6 production via the PI3K/Akt/NF-κB signaling pathway by binding to α6β1 receptor. In summary, our results reveal a novel role of CCN1 in promoting inflammation by upregulation of IL-6 production in AIH. Our study also suggests that targeting of CCN1 may represent a novel strategy in AIH treatment.
Collapse
Affiliation(s)
- Renquan Jiang
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Jifeng Tang
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Xuehao Zhang
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yujue He
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Ziqing Yu
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Shuhui Chen
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Jinfang Xia
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Jinpiao Lin
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Qishui Ou
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| |
Collapse
|
|
28
|
Ueno M, Takabatake H, Hata A, Kayahara T, Morimoto Y, Notohara K, Mizuno M. Mycophenolate mofetil for immune checkpoint inhibitor‐related hepatotoxicity relapsing during dose reduction of corticosteroid: A report of two cases and literature review. Cancer Rep (Hoboken) 2022; 5:e1624. [PMID: 35575047 PMCID: PMC9458512 DOI: 10.1002/cnr2.1624] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 03/27/2022] [Accepted: 04/17/2022] [Indexed: 11/21/2022] Open
Abstract
Background Immune checkpoint inhibitors (ICIs) sometimes cause immune‐related liver injury, which can lead to cessation of treatment, hospitalization, and even mortality. Although high‐dose corticosteroids are usually effective in treatment of ICI‐related liver injury, one fifth of affected patients require additional immunosuppressive therapy. It remains uncertain how best to treat ICI‐related liver injury that relapses under corticosteroid therapy after temporary remission. Case Here we report two cases of ICI‐related liver injury successfully treated with mycophenolate mofetil (MMF). In the first case, a 74‐year‐old man with stage IIIA lung cancer underwent curative chemoradiotherapy. After the second infusion of durvalumab, grade 3 ICI‐related liver injury (mixed pattern) developed. In the second case, a 46‐year‐old man with stage IVB lung cancer received pembrolizumab‐containing chemotherapy. After the first cycle, grade 2 ICI‐related hepatitis developed. In the both cases, liver injury improved with high‐dose prednisolone but relapsed during tapering of the drug. After liver biopsy was performed to confirm the diagnosis of ICI‐related liver injury, MMF (2000 mg/day) was added. MMF was effective for both patients and permitted discontinuation or reduction of prednisolone. Conclusion MMF appears to be an appropriate treatment option for ICI‐related liver injury that respond to high‐dose corticosteroids but relapse during steroid tapering.
Collapse
Affiliation(s)
- Masayuki Ueno
- Department of Gastroenterology and Hepatology Kurashiki Central Hospital Okayama Japan
- Department of Gastroenterology and Hepatology, Graduate School of Medicine Kyoto University Kyoto Japan
| | - Hiroyuki Takabatake
- Department of Gastroenterology and Hepatology Kurashiki Central Hospital Okayama Japan
| | - Ayako Hata
- Department of Gastroenterology and Hepatology Kurashiki Central Hospital Okayama Japan
| | - Takahisa Kayahara
- Department of Gastroenterology and Hepatology Kurashiki Central Hospital Okayama Japan
| | - Youichi Morimoto
- Department of Gastroenterology and Hepatology Kurashiki Central Hospital Okayama Japan
| | - Kenji Notohara
- Department of Anatomic Pathology Kurashiki Central Hospital Okayama Japan
| | - Motowo Mizuno
- Department of Gastroenterology and Hepatology Kurashiki Central Hospital Okayama Japan
| |
Collapse
|
|
29
|
Pape S, Snijders RJALM, Gevers TJG, Chazouilleres O, Dalekos GN, Hirschfield GM, Lenzi M, Trauner M, Manns MP, Vierling JM, Montano-Loza AJ, Lohse AW, Schramm C, Drenth JPH, Heneghan MA. Systematic review of response criteria and endpoints in autoimmune hepatitis by the International Autoimmune Hepatitis Group. J Hepatol 2022; 76:841-849. [PMID: 35066089 DOI: 10.1016/j.jhep.2021.12.041] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 11/18/2021] [Accepted: 12/11/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Autoimmune hepatitis (AIH) has been well characterised and codified through the development of diagnostic criteria. These criteria have been adapted and simplified and are widely used in clinical practice. However, there is a need to update and precisely define the criteria for both treatment response and treatment. METHODS A systematic review was performed and a modified Delphi consensus process was used to identify and redefine the response criteria in autoimmune hepatitis. RESULTS The consensus process initiated by the International Autoimmune Hepatitis Group proposes that the term 'complete biochemical response' defined as 'normalization of serum transaminases and IgG below the upper limit of normal' be adopted to include a time point at 6 months after initiation of treatment. An insufficient response by 6 months was a failure to meet the above definition. Non-response was defined as '<50% decrease of serum transaminases within 4 weeks after initiation of treatment'. Remission is defined as liver histology with a Hepatitis Activity Index <4/18. Intolerance to treatment was agreed to stand for 'any adverse event possibly related to treatment leading to potential drug discontinuation'. CONCLUSIONS These definitions provide a simple and reproducible framework to define treatment response and non-response, irrespective of the therapeutic intervention. A consensus on endpoints is urgently required to set a global standard for the reporting of study results and to enable inter-study comparisons. Future prospective database studies are needed to validate these endpoints. LAY SUMMARY Consensus among international experts on response criteria and endpoints in autoimmune hepatitis is lacking. A consensus on endpoints is urgently required to set a global standard for the reporting of study results and to enable the comparison of results between clinical trials. Therefore, the International Autoimmune Hepatitis Group (IAIHG) herein presents a statement on 5 agreed response criteria and endpoints: complete biochemical response, insufficient response, non-response, remission, and intolerance to treatment, which can be used to guide future reporting.
Collapse
Affiliation(s)
- Simon Pape
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Romée J A L M Snijders
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Tom J G Gevers
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands; Division of Gastroenterology and Hepatology, Maastricht University Medical Center, Maastricht 6229HX, The Netherlands; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Oliver Chazouilleres
- Hepatology Department, Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Saint-Antoine Hospital Assistance Publique-Hôpitaux de Paris, Paris, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, University of Thessaly Medical School, Larissa, Greece
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Canada
| | - Marco Lenzi
- Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi, University of Bologna, Bologna, Italy
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - John M Vierling
- Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Aldo J Montano-Loza
- Division of Gastroenterology and Hepatology, University of Alberta Hospital, Edmonton, Canada
| | - Ansgar W Lohse
- 1(st) Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Christoph Schramm
- 1(st) Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Michael A Heneghan
- Institute of Liver Studies, King's College Hospital, London, United Kingdom; European Reference Network on Hepatological Diseases (ERN RARE-LIVER).
| |
Collapse
|
|
30
|
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
|
|
31
|
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
|
|
32
|
Gatselis NK, Azariadis K, Lyberopoulou A, Dalekos GN. Programmed cell death-1 rs11568821 and interleukin-28B rs12979860 polymorphisms in autoimmune hepatitis. J Transl Autoimmun 2021; 4:100126. [PMID: 34632357 PMCID: PMC8488593 DOI: 10.1016/j.jtauto.2021.100126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 09/27/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a relatively rare chronic liver disease of unknown etiology. The genetic background affects susceptibility, clinical phenotype, and prognosis. The programmed cell death-1 rs11568821 polymorphism (PD1.3) has been associated with susceptibility to autoimmune diseases. The interleukin-28B (IL28B) rs12979860 polymorphism has been associated with steatosis, inflammation, and fibrosis in liver diseases. AIM Our aim was to investigate for the first time the incidence and clinical significance of PD1.3 and IL28B rs12979860 in AIH. METHODS Two hundred patients with AIH were evaluated, while 100 healthy subjects were used as controls. Genotyping was performed with in-house allelic discrimination End-Point PCR. RESULTS The SNP PD1.3/A was present in 36/200 (18%) AIH patients compared to 28/100 (28%) healthy controls (p = 0.065). The AA/GA genotypes were not associated with the mode of presentation of AIH, the histological grade or stage, the presence of cirrhosis, risk of disease progression, response to treatment and survival. The IL28B rs12979860 genotype distribution was CC 79/200 (39.5%), TT 36/200 (18%) and CT 85/200 (42.5%), in similar rates with healthy controls (p = 0.878). Inflammatory activity and fibrosis stage did not differ between CC homozygotes and CT/TT carriers. LDL cholesterol was significantly higher in CC than CT/TT patients (P = 0.027), though no differences was found regarding the presence of steatosis or steatohepatitis. On-treatment response to immunosuppressive treatment was not affected by the IL28B rs12979860 polymorphism. However, CC homozygotes AIH patients achieved treatment withdrawal in significantly higher rates (OR 2.3, 95%CI: 1.1-4.7, P = 0.02) irrespective of the presence of steatosis or steatohepatitis. CONCLUSIONS The PD1.3 and IL28B rs12979860 variants are unlikely to contribute to AIH susceptibility, disease presentation and prognosis. The IL28B rs12979860 is not associated with the presence of concurrent steatosis or steatohepatitis. However, although on-treatment response rates to immunosuppression were not affected by the IL28B rs12979860 polymorphism, AIH patients with CC homozygosity were more likely to achieve complete treatment withdrawal. This novel finding needs validation and further clarification from larger multicenter studies.
Collapse
Key Words
- AIH, Autoimmune hepatitis.
- ANA, Antinuclear antibodies.
- Anti-LC1, Liver cytosol type-1 antibodies.
- Anti-LKM1, Liver kidney microsomal type-1 antibodies
- Anti-SLA/LP, Soluble liver antigen/liver pancreas antibodies.
- Autoimmune hepatitis
- CR, Complete response.
- HCC, Hepatocellular carcinoma.
- HCV, Hepatis C virus.
- HDL, High density lipoprotein.
- HLA, Human leukocyte antigen.
- HWE, Hardy-weinberg equilibrium.
- IL28B, Interleukin 28B.
- INR, International normalized ratio.
- IQR, Interquartile range.
- IgG, Immunoglobulin class G.
- Interleukin-28B
- LDL, Low density lipoprotein
- MetS, Metabolic syndrome.
- NAFLD, Non-alcoholic fatty liver disease.
- PCR, Polymerase chain reaction.
- PD1, Programmed cell death-1.
- Polymorphisms
- Programmed cell death-1
- SD, Standard deviation.
- SLE, Systemic lupus erythematosus.
- SMA, Smooth muscle antibodies.
- SNP, Single nucleotide polymorphism.
- ULN, Upper limit of normal.
Collapse
Affiliation(s)
- 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, 41110, Larissa, Greece
| | - Kalliopi Azariadis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110, Larissa, Greece
| | - Aggeliki Lyberopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110, Larissa, Greece
| | - 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, 41110, Larissa, Greece
| |
Collapse
|
|
33
|
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
|
|
34
|
Dalekos GN, Azariadis K, Lygoura V, Arvaniti P, Gampeta S, Gatselis NK. Autoimmune hepatitis in patients aged 70 years or older: Disease characteristics, treatment response and outcome. Liver Int 2021; 41:1592-1599. [PMID: 33896089 DOI: 10.1111/liv.14900] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 03/14/2021] [Accepted: 03/31/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Autoimmune hepatitis (AIH) affects both sexes and all age groups. However, very few studies have focused specifically on the characteristics and outcome of AIH in patients aged 70 y or older. METHODS 25/234 patients with well-established AIH and disease onset at ≥70-y (median: 73-y) were analysed and compared to the rest patients (median: 47 y). Treatment response was assessed in all patients from both groups who were eligible for treatment (n = 202). RESULTS Disease presentation was mainly insidious in both groups (19/25, 76% vs. 134/209, 64.1%; P = .313). At diagnosis, older patients had lower alaninoaminotrasferase (101[433] vs. 199[441] IU/L, P < .05) but were more frequently cirrhotic (12/25, 48% vs. 57/209, 27.3%; P = .03). Importantly, similar rates of on-treatment response (16/18, 89% vs. 154/184, 84%; P = .565), corticosteroid withdrawal (10/16, 62.5% vs. 113/154, 73.4%; P = .355) and complete withdrawal of immunosuppression (1/16, 6.3% vs. 40/154, 26%; P = .122) were achieved in both groups. Treatment-related adverse events were evenly observed between groups (6/18, 33% vs. 54/184, 29%; P = .724). In treated patients, the age ≥70 y was only associated with the overall mortality (HR 8.3 [95% CI: 2.1-36.4], P = .003), but not with the liver-related mortality (HR 3.4 [95% CI: 0.4-30.0], P = .268). CONCLUSION AIH should be seriously considered in patients ≥70 y with unexplained impaired liver function tests as the disease is not infrequent in this group and seems to bear an increased risk for advanced disease stage at diagnosis. However, if immunosuppression is started promptly, it seems as safe and effective as in younger patients.
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.,Institute of Internal Medicine and Hepatology, Larissa, Greece
| | - Kalliopi Azariadis
- 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
| | - Vasiliki Lygoura
- 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
| | - Stella Gampeta
- 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.,Institute of Internal Medicine and Hepatology, Larissa, Greece
| |
Collapse
|
|
35
|
Hirasawa Y, Yoshimura K, Matsui H, Kubota Y, Ishida H, Arai J, Sakaki M, Oguro N, Shida M, Taniguchi M, Hamada K, Ariizumi H, Ishiguro T, Ohkuma R, Sambe T, Horiike A, Imamura CK, Shiozawa E, Wada S, Tsurutani J, Iwamoto S, Uchida N, Kiuchi Y, Tate G, Kobayashi S, Tsunoda T. A case report on severe nivolumab-induced adverse events similar to primary sclerosing cholangitis refractory to immunosuppressive therapy. Medicine (Baltimore) 2021; 100:e25774. [PMID: 34114983 PMCID: PMC8202549 DOI: 10.1097/md.0000000000025774] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/15/2021] [Indexed: 01/04/2023] Open
Abstract
INTRODUCTION Immune checkpoint inhibitors (ICIs), particularly anti-PD-1 antibody, have dramatically changed cancer treatment; however, fatal immune-related adverse events (irAEs) can develop. Here, we describe a severe case of sclerosing cholangitis-like irAE. We report the use of 3 immunosuppressive agents that resulted in the death of the patient due to treatment inefficacy. According to a postmarketing study of nivolumab, the frequency of ICI-related sclerosing cholangitis is 0.27% and that of ICI-related cholangitis is 0.20%. There have been 4 case reports of sclerosing cholangitis-like irAE, with imaging findings, including typical intrahepatic bile duct beaded constriction in primary sclerosing cholangitis. Treatment starts with prednisolone and is combined with an immunosuppressant in refractory cases. There are no reports of severe cases that ultimately led to death. PATIENTS CONCERNS The patient is a 64-year-old male with Stage IV squamous cell lung carcinoma; he was hospitalized with abdominal pain and elevation of aspartate transaminase and alanine transaminase, approximately 4 months after ICI administration was suspended. This occurred because the patient treated with nivolumab as the second-line chemotherapy and developed type 1 diabetes mellitus after 11 courses. DIAGNOSIS A grade 3 increase in bilirubin was observed and he was diagnosed with sclerosing cholangitis, based on magnetic resonance cholangiopancreatography imaging and pathological findings of the liver and bile duct. INTERVENTIONS Prednisolone, mycophenolate mofetil, and tacrolimus combination therapy was administered. OUTCOMES The treatment was difficult and failed. He died from liver failure 8 months after diagnosis. In this case, hepatitis and cholangitis, mainly alanine transaminase-dominant liver disorder, developed in the early stages of irAEs. Although he showed some improvement after prednisolone administration, bilirubin levels began rising again, and sclerosing cholangitis did not improve even with the use of 3 immunosuppressive agents recommended by the ESMO Clinical Practice Guidelines for immune-related hepatotoxicity management. Although the antitumor effect showed a complete response, liver failure led to death. CONCLUSION This is the first case report on the ineffectiveness of triple immunosuppressant combination therapy recommended by the guidelines for immune-related hepatotoxicity. It is necessary to develop more appropriate treatment for severe sclerosing cholangitis-like irAE based on the robust evidence.
Collapse
Affiliation(s)
- Yuya Hirasawa
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
| | - Kiyoshi Yoshimura
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
- Department of Clinical Immuno-Oncology, Clinical Research Institute of Clinical Pharmacology and Therapeutics, Showa University
| | - Hiroto Matsui
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
| | - Yutaro Kubota
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
| | - Hiroo Ishida
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
| | - Jun Arai
- Division of Gastroenterology, Department of Medicine
| | | | - Nao Oguro
- Division of Rheumatology, Department of Medicine
| | - Midori Shida
- Department of Clinical Immuno-Oncology, Clinical Research Institute of Clinical Pharmacology and Therapeutics, Showa University
| | - Makoto Taniguchi
- Department of Clinical Immuno-Oncology, Clinical Research Institute of Clinical Pharmacology and Therapeutics, Showa University
| | - Kazuyuki Hamada
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
| | - Hirotsugu Ariizumi
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
| | - Tomoyuki Ishiguro
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
| | - Ryotaro Ohkuma
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
| | - Takehiko Sambe
- Division of Clinical Pharmacology, Department of Pharmacology, Showa University School of Medicine
| | - Atsushi Horiike
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
| | - Chiyo K. Imamura
- Advanced Cancer Translational Research Institute, Showa University
| | - Eisuke Shiozawa
- Department of Pathology and Laboratory Medicine, Showa University School of Medicine
| | - Satoshi Wada
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
- Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University
| | - Junji Tsurutani
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
- Advanced Cancer Translational Research Institute, Showa University
| | - Sanju Iwamoto
- Division of Physiology and Pathology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy
| | - Naoki Uchida
- Division of Clinical Pharmacology, Department of Pharmacology, Showa University School of Medicine
| | - Yuji Kiuchi
- Division of Medical Pharmacology, Department of Pharmacology, Showa University School of Medicine
| | - Genshu Tate
- Department of Pathology and Laboratory Medicine, Showa University School of Medicine
| | - Shinichi Kobayashi
- Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo, Japan
| | - Takuya Tsunoda
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
| |
Collapse
|
|
36
|
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
|
|
37
|
Rigopoulou EI, Dalekos GN. Current Trends and Characteristics of Hepatocellular Carcinoma in Patients with Autoimmune Liver Diseases. Cancers (Basel) 2021; 13:1023. [PMID: 33804480 PMCID: PMC7957658 DOI: 10.3390/cancers13051023] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/17/2021] [Accepted: 02/24/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC), the commonest among liver cancers, is one of the leading causes of mortality among malignancies worldwide. Several reports demonstrate autoimmune liver diseases (AILDs), including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) to confer increased risk of hepatobiliary malignancies, albeit at lower frequencies compared to other liver diseases. Several parameters have been recognized as risk factors for HCC development in AIH and PBC, including demographics such as older age and male sex, clinical features, the most decisive being cirrhosis and other co-existing factors, such as alcohol consumption. Moreover, biochemical activity and treatment response have been increasingly recognized as prognostic factors for HCC development in AIH and PBC. As available treatment modalities are effective only when HCC diagnosis is established early, surveillance has been proven essential for HCC prognosis. Considering that the risk for HCC is not uniform between and within disease groups, refinement of screening strategies according to prevailing demographic, clinical, and molecular risk factors is mandated in AILDs patients, as personalized HCC risk prediction will offer significant advantage in patients at high and/or medium risk. Furthermore, future investigations should draw attention to whether modification of immunosuppression could benefit AIH patients after HCC diagnosis.
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, 41110 Larissa, Greece;
| |
Collapse
|
|
38
|
Rigopoulou EI, Gatselis N, Arvaniti P, Koukoulis GK, Dalekos GN. Alcoholic liver disease and autoimmune hepatitis: Sometimes a closer look under the surface is needed. Eur J Intern Med 2021; 85:86-91. [PMID: 33451888 DOI: 10.1016/j.ejim.2020.12.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 12/25/2020] [Accepted: 12/27/2020] [Indexed: 02/07/2023]
Abstract
AIMS Differential diagnosis of autoimmune hepatitis (AIH) incorporates various liver diseases, including alcoholic liver disease (ALD). We report on clinical, laboratory and outcome characteristics of AIH patients who were initially referred as ALD based on increased alcohol consumption (AIH/ALD). METHODS From 2000-2019, we retrospectively identified 12 AIH/ALD patients [9 males, age: 61 (30-73) years] in our prospective data base of 317 AIH patients. RESULTS AIH diagnosis was based on aminotransferases elevation in 10 patients, high IgG in 8, compatible autoantibody profile in all and typical/compatible histology in all 9 with available biopsy. There were no significant differences of baseline demographics, presentation, cirrhosis at diagnosis, response to treatment and simplified score compared to 45 age- and sex-matched AIH patients without alcohol consumption and 44 age- and sex-matched ALD patients. However, the AIH/ALD cohort was characterized by more frequent progression to cirrhosis, higher liver-related deaths and overall mortality compared to AIH, though similar to the ALD group. AST/ALT ratio>1 seems to bear a good positive (0.84) and negative predictive value (0.88) for ALD and AIH diagnosis, respectively, but cannot help in discriminating the AIH/ALD variant. CONCLUSIONS AIH should not be forgotten in patients with alcohol use when clinical and laboratory features hint towards the diagnosis of AIH/ALD variant as this group seems to have worse outcome compared to those with AIH alone suggesting the need for closer follow-up and surveillance. Reliable autoantibody testing and cautious interpretation of liver histology appear mandatory for AIH diagnosis in these difficult to diagnose cases.
Collapse
Affiliation(s)
- Eirini I Rigopoulou
- Institute of Internal Medicine and Hepatology, 41447 Larissa, Greece; Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110 Larissa, Greece
| | - Nikolaos Gatselis
- Institute of Internal Medicine and Hepatology, 41447 Larissa, Greece; Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110 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, 41110 Larissa, Greece
| | - George K Koukoulis
- Department of Pathology, Medical School, University of Thessaly, 41110 Larissa, Greece
| | - George N Dalekos
- Institute of Internal Medicine and Hepatology, 41447 Larissa, Greece; Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110 Larissa, Greece.
| |
Collapse
|
|
39
|
Harrington CR, Yang GY, Levitsky J. Advances in Rejection Management: Prevention and Treatment. Clin Liver Dis 2021; 25:53-72. [PMID: 33978583 DOI: 10.1016/j.cld.2020.08.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Extended survival of liver transplant recipients has brought rejection management to the forefront of liver transplant research. This article discusses T-cell-mediated rejection, antibody-mediated rejection, and chronic rejection. We focus on the prevention and then discuss treatment options. Future directions of rejection management include biomarkers of rejection, which may allow for monitoring of patients who are considered high risk for rejection and detection of rejection before there is any clinical evidence to improve graft and patient survival. With improved graft life and survival of liver transplant recipients, the new frontier of rejection management focuses on immunosuppression minimization, withdrawal, and personalization.
Collapse
Affiliation(s)
- Claire R Harrington
- Department of Medicine, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 2330, Chicago, IL 60611, USA
| | - Guang-Yu Yang
- Department of Pathology, Northwestern University Feinberg School of Medicine, 251 E Huron St. Chicago, IL 60611, USA
| | - Josh Levitsky
- Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 1400, Chicago, IL 60611, USA; Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 1900, Chicago, IL 60611, USA.
| |
Collapse
|
|
40
|
Li Y, Yan L, Wang R, Wang Q, You Z, Li B, Zhang J, Huang B, Chen Y, Li Y, Lian M, Tang R, Qiu D, Gershwin ME, Xiao X, Miao Q, Ma X. Serum Immunoglobulin G Levels Predict Biochemical and Histological Remission of Autoimmune Hepatitis Type 1: A Single-Center Experience and Literature Review. Clin Rev Allergy Immunol 2021; 62:292-300. [PMID: 33512642 DOI: 10.1007/s12016-021-08833-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/04/2021] [Indexed: 12/17/2022]
Abstract
Autoimmune hepatitis (AIH) is characterized by interface hepatitis, elevated serum alanine aminotransferase and aspartate aminotransferase levels, circulating autoantibodies, and elevated predominantly immunoglobulin G (IgG) levels. The goal in the treatment of autoimmune hepatitis (AIH) is complete disease remission. Here we took advantage of a large cohort of AIH patients to clarify predictors associated with biochemical and histological remission. Of 705 patients with complete follow-up, 569 (80.7%) patients achieved complete biochemical remission. Lower IgG levels (17.8 vs. 25 g/L, p < 0.001) and less liver cirrhosis (19.3% vs. 33.1%, p < 0.001) at diagnosis were observed in these patients. They also had lower serum IgG levels (13 vs. 18.9 g/L, p < 0.001) after 3 months of treatment. Histological remission was achieved in 69.4% of 160 patients with complete biochemical remission after 3 years of treatment. Patients with histological remission had lower IgG levels (16.2 vs. 20.1 g/L, p = 0.006) and Ishak fibrosis scores (3.4 vs. 4.1, p = 0.010) at diagnosis, and they appeared to achieve biochemical remission more rapidly (1 vs. 3 months, p < 0.001). Of note, patients with histological remission had higher frequency of fibrosis regression than those with persisting histological activity (87.5% vs. 60%, p = 0.004). In conclusion, lower serum IgG levels, less fibrosis in liver histology at diagnosis, and rapid response to immunosuppressive therapy are reliable predictors of biochemical and histological remission. Our study underscores the importance of early diagnosis and appropriate treatment.
Collapse
Affiliation(s)
- You Li
- 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, 145 Middle Shandong Road, Shanghai, 200001, 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, 145 Middle Shandong Road, Shanghai, 200001, China.,Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
| | - Rui 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, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Qixia 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, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Zhengrui You
- 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, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Bo Li
- 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, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Jun Zhang
- 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, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Bingyuan Huang
- 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, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Yong Chen
- 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, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Yikang Li
- 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, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Min Lian
- 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, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Ruqi Tang
- 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, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Dekai Qiu
- 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, 145 Middle Shandong Road, Shanghai, 200001, China
| | - M Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Xiao Xiao
- 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, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Qi Miao
- 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, 145 Middle Shandong Road, Shanghai, 200001, 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, 145 Middle Shandong Road, Shanghai, 200001, China.
| |
Collapse
|
|
41
|
Dalekos GN, Gatselis NK, Koukoulis GK. Non-alcoholic steatohepatitis or autoimmune hepatitis? Sometimes a closer look under the surface is needed. BMJ Case Rep 2020; 13:13/12/e238400. [PMID: 33370951 DOI: 10.1136/bcr-2020-238400] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is nowadays the most common liver disease worldwide. Autoimmune hepatitis (AIH) is a relatively rare disease of the liver characterised by female predominance, circulating autoantibodies, polyclonal hypergammaglobulinaemia, interface hepatitis on histology and favourable response to immunosuppression. The possibility of an additional AIH diagnosis in patients with NAFLD (NAFLD/AIH concurrence) or the presence of AIH alone instead of a supposed NAFLD diagnosis represents a challenge for clinicians. We report herein two adult patients (a 33-year-old woman and a 59-year-old man) with a previous NAFLD diagnosis who proved finally to suffer from AIH alone. These two representative cases indicate how difficult and complicated could be sometimes the diagnosis of patients with AIH highlighting the range of disease manifestations and severity while they also underline that although NAFLD is by far the most frequent chronic liver disease this could not be always the case.
Collapse
Affiliation(s)
- Georgios 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, Thessaly, 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, Thessaly, Greece
| | - George K Koukoulis
- Department of Pathology, School of Medicine, University of Thessaly, Larissa, Thessaly, Greece
| |
Collapse
|
|
42
|
Wang H, Feng X, Yan W, Tian D. Regulatory T Cells in Autoimmune Hepatitis: Unveiling Their Roles in Mouse Models and Patients. Front Immunol 2020; 11:575572. [PMID: 33117375 PMCID: PMC7575771 DOI: 10.3389/fimmu.2020.575572] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 09/07/2020] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a severe and chronic liver disease, and its incidence has increased worldwide in recent years. Research into the pathogenesis of AIH remains limited largely owing to the lack of suitable mouse models. The concanavalin A (ConA) mouse model is a typical and well-established model used to investigate T cell-dependent liver injury. However, ConA-induced hepatitis is acute and usually disappears after 48 h; thus, it does not mimic the pathogenesis of AIH in the human body. Several studies have explored various AIH mouse models, but as yet there is no widely accepted and valid mouse model for AIH. Immunosuppression is the standard clinical therapy for AIH, but patient side effects and recurrence limit its use. Regulatory T cells (Tregs) play critical roles in the maintenance of immune homeostasis and in the prevention of autoimmune diseases, which may provide a potential therapeutic target for AIH therapy. However, the role of Tregs in AIH has not yet been clarified, partly because of difficulties in diagnosing AIH and in collecting patient samples. In this review, we discuss the studies related to Treg in various AIH mouse models and patients with AIH and provide some novel insights for this research area.
Collapse
Affiliation(s)
- Han Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinxia Feng
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Yan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dean Tian
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
43
|
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
|
|
44
|
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: 543] [Impact Index Per Article: 108.6] [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
|
|
45
|
Dalekos GN, Gatselis NK, Zachou K, Koukoulis GK. NAFLD and autoimmune hepatitis: Do not judge a book by its cover. Eur J Intern Med 2020; 75:1-9. [PMID: 32051092 DOI: 10.1016/j.ejim.2020.02.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 01/31/2020] [Accepted: 02/02/2020] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease (almost 25% of the general population). Autoimmune hepatitis (AIH) is a relatively rare liver disease of unknown aetiology characterized by female predominance and large heterogeneity regarding epidemiology, clinical manifestations, genetics, serology and liver pathology. The potential NAFLD/AIH coincidence or an AIH diagnosis alone instead of NAFLD represent a challenge for clinicians, both in making a correct and timely diagnosis but also in the management of these diseases. The diagnosis of both diseases can be challenging as: (a) reliable laboratory tests to confidently diagnose or exclude NAFLD or AIH are missing; (b) physicians and pathologists are much more familiar with a very common disease like NAFLD so, they do not consider an alternative or additional diagnosis; (c) most NAFLD studies do not investigate the patients for all autoantibodies involved in AIH diagnosis, apply the diagnostic scoring systems for AIH or address the possibility of AIH features on liver histology and (d) the recent European and American practice guidelines for NAFLD do not mention clearly the importance of IgG determination and liver autoimmune serology according to the AIH guidelines. Patients with NAFLD/AIH coincidence have significantly more frequently hypertension, diabetes, obesity, older age, lower transaminases, bilirubin and simplified score for AIH diagnosis but no female predominance compared to AIH patients only. The true outcome of NAFLD/AIH patients is practically unknown while their management is quite problematic because official clinical practice guidelines for this condition are missing.
Collapse
Affiliation(s)
- George N Dalekos
- Institute of Internal Medicine and Hepatology, 41447 Larissa, Greece; Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110 Larissa, Thessaly, Greece.
| | - Nikolaos K Gatselis
- Institute of Internal Medicine and Hepatology, 41447 Larissa, Greece; Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110 Larissa, Thessaly, Greece
| | - Kalliopi Zachou
- Institute of Internal Medicine and Hepatology, 41447 Larissa, Greece; Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110 Larissa, Thessaly, Greece
| | - George K Koukoulis
- Department of Pathology, School of Medicine, University of Thessaly, 41110 Larissa, Greece
| |
Collapse
|
|
46
|
Zachou K, Weiler-Normann C, Muratori L, Muratori P, Lohse AW, Dalekos GN. Permanent immunosuppression in SLA/LP-positive autoimmune hepatitis is required although overall response and survival are similar. Liver Int 2020; 40:368-376. [PMID: 31626725 DOI: 10.1111/liv.14280] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 09/16/2019] [Accepted: 10/06/2019] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS Antibodies against soluble liver antigen/liver pancreas (anti-SLA/LP) are highly specific for autoimmune hepatitis (AIH) and have been linked with a more severe clinical course of the disease, frequent relapses after treatment withdrawal and worse outcome. To address definitely the clinical significance of anti-SLA/LP, we investigated a large number of anti-SLA/LP-positive and -negative patients followed in three referral centres. METHODS Prospectively collected data from 89 anti-SLA/LP-positive AIH patients (29 from Hamburg-Germany, 20 from Bologna-Italy and 40 from Larissa-Greece) were analysed retrospectively. Age- and sex-matched anti-SLA/LP-negative patients served as disease controls (n = 230; 1:2.5 ratio). RESULTS In respect to baseline characteristics, anti-SLA/LP-positive patients were more frequently asymptomatic compared to anti-SLA/LP-negative (P < .05). However, anti-SLA/LP-positive patients did not differ from anti-SLA/LP-negative in terms of the overall response to treatment, disease progression and survival even though, they were less likely to achieve corticosteroid withdrawal (P < .05), needed longer treatment duration to achieve first complete response (P < .001) and relapsed more frequently after treatment withdrawal compared to anti-SLA/LP-negative patients (P = <.001). CONCLUSIONS We showed that anti-SLA/LP antibodies do not characterize a group of AIH patients with distinct features and cannot identify patients with a more severe form of the disease or worse survival. Most importantly, however, anti-SLA/LP-positive patients appear to require lifelong immunosuppression as they are less likely to achieve the cessation of corticosteroids and present higher relapse rates after treatment withdrawal. Therefore, close long-term monitoring should be advised in all anti-SLA/LP-positive patients after withdrawal of immunosuppressive treatment.
Collapse
Affiliation(s)
- Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | | | - Luigi Muratori
- Department of Medical and Surgical Sciences, Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, Policlinico di Sant'Orsola, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Paolo Muratori
- Department of Medical and Surgical Sciences, Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, Policlinico di Sant'Orsola, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| |
Collapse
|
|
47
|
Than NN, Hodson J, Schmidt-Martin D, Taubert R, Wawman RE, Botter M, Gautam N, Bock K, Jones R, Appanna GD, Godkin A, Montano-Loza AJ, Lammert F, Schramm C, Manns MP, Swain M, Burak KW, Adams DH, Hirschfield GM, Oo YH. Efficacy of rituximab in difficult-to-manage autoimmune hepatitis: Results from the International Autoimmune Hepatitis Group. JHEP Rep 2019; 1:437-445. [PMID: 32039395 PMCID: PMC7005655 DOI: 10.1016/j.jhepr.2019.10.005] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 10/21/2019] [Accepted: 10/25/2019] [Indexed: 02/07/2023] Open
Abstract
Treatment options remain limited for patients with autoimmune hepatitis (AIH), while there are still concerns over the consequences of long-term corticosteroid use. A few studies have suggested a role for B cell-driven autoimmune liver injury in AIH. This multicentre, international retrospective cohort study from the International Autoimmune Hepatitis Group aims to evaluate the clinical efficacy and safety of rituximab in difficult-to-manage AIH. METHODS Clinical data from 22 patients who received rituximab between 2007 and 2017 were collected from centres in the United Kingdom, Germany and Canada. Clinical response was assessed using changes in biochemical and immunological parameters up to 24 months post-rituximab infusion. In addition, we compared the doses of prednisolone used 3 months before and 12 months after treatment, and assessed freedom from AIH flares over the post-treatment period. RESULTS Twenty-two patients with type-1 AIH were included, with a median age of 40 years at diagnosis (range 19-79); 15/22 (68%) were female and 18/22 (82%) were Caucasian. The median period from diagnosis to the end of follow-up in these patients was 11 years (range 3-28). Values of alanine aminotransferase, aspartate aminotransferase and albumin improved significantly following rituximab therapy, and were sustained for up to 2 years (all p ≪0.001). Prednisolone doses were significantly reduced by 12 months post-treatment (p = 0.003), with 13/21 (62%) patients having a dose reduction. Over a median post-treatment follow-up period of 6 years (range 1-10), 5 patients developed AIH flares at a median of 22 months post-treatment, giving an estimated 71% freedom from AIH flare at 2 years. Four of these patients received a second course of treatment, of whom 2 had subsequent further flares. No serious adverse events attributable to rituximab were recorded. CONCLUSION In patients with difficult-to-manage AIH, rituximab appears to be clinically effective and well tolerated. Rituximab was associated with sustained improvements in serum liver tests, an absence of clinical disease flares, and a reduction in prednisolone dose. Controlled trials are warranted to further evaluate B cell-targeting therapies in patients with AIH. LAY SUMMARY Autoimmune hepatitis is an autoimmune condition of the liver, usually treated with medications that suppress the immune system, such as steroids. However, some patients do not respond to this treatment. We analysed the safety and efficacy of rituximab in patients who were not responding to first- or second-line therapies. Rituximab was safe and improved liver blood tests in 70% of patients over a 2-year follow-up period, while enabling steroid doses to be reduced in two-thirds of patients, which is a very positive clinical outcome.
Collapse
Affiliation(s)
- Nwe Ni Than
- Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
- Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
| | - James Hodson
- Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
| | - Daniel Schmidt-Martin
- Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- European Reference Network (ERN) Rare Liver
| | - Rebecca E. Wawman
- Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
- Imperial College, London
| | - Meemee Botter
- Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
- University of Amsterdam, Netherland
| | - Nishant Gautam
- Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
| | - Kilian Bock
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- European Reference Network (ERN) Rare Liver
| | - Rebecca Jones
- Leeds Liver Transplant Unit, St James University Hospital, Leeds, United Kingdom
| | | | - Andrew Godkin
- University Hospital of Wales, Cardiff, United Kingdom
| | | | - Frank Lammert
- Department of Medicine II, Saarland University Medical Centre, Homburg
| | - Christoph Schramm
- University Medical Centre Hamburg-Eppendorf, Hamburg, I. Department of Medicine and Martin Zeitz Centre for Rare Diseases, Germany
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany; Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
- European Reference Network (ERN) Rare Liver
| | - Mark Swain
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Calgary, Canada
| | - Kelly W. Burak
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Calgary, Canada
| | - David H. Adams
- Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
- Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
- Autoimmune Liver Diseases Clinic, Centre for Rare Diseases, Institute of Translational Medicine, University of Birmingham, Birmingham, United Kingdom
| | - Gideon M Hirschfield
- University of Toronto, Canada
- Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Canada
| | - Ye Htun Oo
- Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
- Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
- Autoimmune Liver Diseases Clinic, Centre for Rare Diseases, Institute of Translational Medicine, University of Birmingham, Birmingham, United Kingdom
- European Reference Network (ERN) Rare Liver
| |
Collapse
|
|
48
|
van den Brand FF, van der Veen KS, Lissenberg‐Witte BI, de Boer YS, van Hoek B, Drenth JPH, Verdonk RC, Vrolijk JM, van Nieuwkerk CMJ, Bouma G. Adverse events related to low dose corticosteroids in autoimmune hepatitis. Aliment Pharmacol Ther 2019; 50:1120-1126. [PMID: 31617229 PMCID: PMC6899908 DOI: 10.1111/apt.15528] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 07/20/2019] [Accepted: 09/16/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Autoimmune hepatitis requires long-term therapy, and systemic corticosteroids are the backbone of therapeutic management. Prolonged use of corticosteroids may lead to adverse events but data from long-term studies are mainly derived from studies in rheumatic diseases. AIM To assess cataract, diabetes and fractures in relation to corticosteroid doses in the long-term maintenance treatment of patients with autoimmune hepatitis. METHODS We retrospectively collected data on 476 patients (77% women) with an established diagnosis of autoimmune hepatitis. Binary logistic regression with a generalised estimating equation was used to analyse the association between current corticosteroid use and the incidence of cataract, diabetes and fractures with onset after autoimmune hepatitis diagnosis. We corrected for sex, age, cirrhosis at diagnosis and predniso(lo)ne use in the prior 3 years to account for possible ongoing effects. RESULTS A total of 6634 years, with a median of 13 (range 1-40) per patient were recorded. The median age at diagnosis was 44 years (range 2-88). Adverse events were documented in 120 (25%) patients. Low-dose predniso(lo)ne (0.1-5.0 mg/d) increased the odds of fractures whereas higher doses (>5.0 mg/d) increased the odds of cataracts and diabetes. Budesonide increased the odds of cataract and fractures; this effect was independent of predniso(lo)ne use in the prior 1, 2 or 3 years. CONCLUSIONS Even low doses of corticosteroids frequently lead to substantial adverse events refuting the assumption that adverse events are prevented by administering low doses.
Collapse
Affiliation(s)
- Floris F. van den Brand
- Department of Gastroenterology and HepatologyAmsterdam UMC, Location VUmcAmsterdamThe Netherlands
| | - Koen S. van der Veen
- Department of Gastroenterology and HepatologyAmsterdam UMC, Location VUmcAmsterdamThe Netherlands
| | | | - Ynto S. de Boer
- Department of Gastroenterology and HepatologyAmsterdam UMC, Location VUmcAmsterdamThe Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and HepatologyLeiden University Medical CenterLeidenThe Netherlands
| | - Joost P. H. Drenth
- Department of Gastroenterology and HepatologyRadboud University Medical CenterNijmegenThe Netherlands
| | - Robert C. Verdonk
- Department of Gastroenterology and HepatologySint Antonius HospitalNieuwegeinThe Netherlands
| | - Jan M. Vrolijk
- Department of Gastroenterology and HepatologyRijnstate HospitalArnhemThe Netherlands
| | | | - Gerd Bouma
- Department of Gastroenterology and HepatologyAmsterdam UMC, Location VUmcAmsterdamThe Netherlands
| | | |
Collapse
|
|
49
|
Pape S, Schramm C, Gevers TJG. Clinical management of autoimmune hepatitis. United European Gastroenterol J 2019; 7:1156-1163. [PMID: 31700628 PMCID: PMC6826525 DOI: 10.1177/2050640619872408] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 07/31/2019] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis is a rare and chronic liver disease that is characterised by increased serum transaminases and immunoglobulin G, inflammatory liver histology and presence of circulating autoantibodies. An autoimmune hepatitis diagnosis justifies life-long treatment in most patients in order to prevent development of cirrhosis and end-stage liver disease. The cornerstone of treatment is steroid induction therapy followed by maintenance therapy with azathioprine, which is effective in most cases. For patients who do not respond to standard treatment, second-line treatment with other immunosuppressants can be effective. Treatment should be aimed at biochemical remission of the disease, which is defined as normalization of transaminases and immunoglobulin G. Patients should be monitored intensively during the first months of treatment in order to monitor side-effects, assess symptoms and individualise treatment. Specialist consultation should be sought in difficult-to-treat patients. Future studies and networking initiatives should result in optimization of current treatment strategies in autoimmune hepatitis.
Collapse
Affiliation(s)
- Simon Pape
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
- European Reference Network Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Christoph Schramm
- European Reference Network Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- 1st Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Tom JG Gevers
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
- European Reference Network Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| |
Collapse
|
|
50
|
Comparison of mycophenolate mofetil with standard treatment for autoimmune hepatitis: a meta-analysis. Eur J Gastroenterol Hepatol 2019; 31:873-877. [PMID: 31150366 DOI: 10.1097/meg.0000000000001367] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To systematically evaluate the efficacy of mycophenolate mofetil (MMF) compared with the standard treatment for autoimmune hepatitis. METHODS Medline (PubMed), Embase, and Cochrane Library databases were searched between 1966 and June 2018 for studies on prednisone and/or azathioprine/mycophenolate mofetil in autoimmune hepatitis. The keywords and descriptor terms used were 'hepatitis', 'autoimmunity', 'prednisone', 'prednisolone', 'azathioprine', and 'mycophenolate mofetil'. The Z test and Cochrane Q test were used in the statistical analysis. RESULTS Seven hundred and eighty-eight related articles were found; 779 studies were excluded after further review. Ultimately, seven studies (583 participants) were included. The remission rate of aminotransferase and immunoglobulin (Ig)-G levels with standard treatment was 33.33-86.67%, and the nonresponse rate was 15.15-66.67%. Although the remission rate of the aminotransferase level with prednisone and MMF was 55.17-88.89% and that of the IgG level was 61.16-88.89%, the nonresponse rate was 6.42-33.33%. Remission rates of the aminotransferase level (P<0.05, I=49%) and IgG level (P<0.01, I=0) with MMF were superior to those of standard treatment, and the nonresponse rate was lower (P<0.01, I=0). For those with no response to the standard treatment who were switched to MMF, the remission rates were 0, 13.33, 22.22, 25, and 34.04%. Sequential treatment with MMF was effective (P<0.01, I=90%). CONCLUSION Compared with the standard treatment, the combination of prednisone and MMF as a first-line treatment enables patients with autoimmune hepatitis to obtain higher remission rates of aminotransferase and IgG levels and a lower nonresponse rate. The validity and safety of long-term MMF use needs investigated further.
Collapse
|