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Costaguta A, Costaguta G, Álvarez F. Autoimmune hepatitis: Towards a personalized treatment. World J Hepatol 2024; 16:1225-1242. [PMID: 39606175 PMCID: PMC11586748 DOI: 10.4254/wjh.v16.i11.1225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 09/02/2024] [Accepted: 10/11/2024] [Indexed: 11/06/2024] Open
Abstract
Autoimmune hepatitis is an uncommon condition that affects both adults and children and is characterized by chronic and recurrent inflammatory activity in the liver. This inflammation is accompanied by elevated IgG and autoantibody levels. Historically, treatment consists of steroids with the addition of azathioprine, which results in remission in approximately 80% of patients. Despite significant advancements in our understanding of the immune system over the past two decades, few modifications have been made to treatment algorithms, which have remained largely unchanged since they were first proposed more than 40 years ago. This review summarized the various treatment options currently available as well as our experiences using them. Although steroids are the standard treatment for induction therapy, other medications may be considered. Cyclosporin A, a calcineurin inhibitor that decreases T cell activation, has proven effective for induction of remission, but its long-term side effects limit its appeal for maintenance. Tacrolimus, a drug belonging to the same family, has been used in patients with refractory diseases with fewer side effects. Sirolimus and everolimus have interesting effects on regulatory T cell populations and may become viable options in the future. Mycophenolate mofetil is not effective for induction but is a valid alternative for patients who are intolerant to azathioprine. B cell-depleting drugs, such as rituximab and belimumab, have been successfully used in refractory cases and are useful in both the short and long term. Other promising treatments include anti-tumor necrosis factors, Janus kinases inhibitors, and chimeric antigen receptor T cell therapy. This growing armamentarium allows us to imagine a more tailored approach to the treatment of autoimmune hepatitis in the near future.
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Affiliation(s)
- Alejandro Costaguta
- Department of Hepatology and Liver Transplant Unit, Sanatorio de Niños de Rosario, Rosario 2000, Santa Fe, Argentina.
| | - Guillermo Costaguta
- Department of Gastroenterology, Hepatology, and Nutrition, CHU Sainte-Justine, Montreal H3T 1C5, Quebec, Canada
| | - Fernando Álvarez
- Department of Pediatrics, CHU Sainte-Justine, Montreal H3T 1C5, Quebec, Canada
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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: 20] [Impact Index Per Article: 20.0] [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.
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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.
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Autoimmune Hepatitis and Fibrosis. J Clin Med 2023; 12:jcm12051979. [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.
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Hassoun J, Goossens N, Restellini S, Ramer L, Ongaro M, Giostra E, Hadengue A, Rubbia‐Brandt L, Spahr L. Discontinuation of immunosuppression in patients with immune-mediated drug-induced liver injury or idiopathic autoimmune hepatitis: A case-control study. JGH Open 2023; 7:135-140. [PMID: 36852147 PMCID: PMC9958343 DOI: 10.1002/jgh3.12862] [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: 08/29/2022] [Revised: 12/22/2022] [Accepted: 01/01/2023] [Indexed: 01/13/2023]
Abstract
Background and Aim Drug-induced liver injury (DILI) may present with autoimmune features and require immunosuppressive therapy (IST) to reach biochemical response. Discontinuation of IST without hepatitis relapse may be more frequent in these patients as compared to patients with classical autoimmune hepatitis (AIH). We aimed to determine baseline characteristics and outcome of patients with immune-mediated drug induced liver injury (IMDILI) with particular emphasis on IST during follow-up. Methods We performed a single-center retrospective study of consecutive patients presenting at a tertiary care center between January 2005 and December 2019 either with IMDILI or with classical AIH, for whom full baseline characteristics and a close follow-up were available over a 12-month period. Results Overall, 31 patients (IMDILI n = 16, mean age 59 [34-74] years; AIH n = 15, mean age 47 [15-61] years) were included, showing similar biochemical, serological, and histological characteristics. Incriminating drugs in IMDILI patients were mostly represented by nonsteroidal antiinflammatory drugs and sartans. Initial corticosteroids combined with IST led to biochemical response in all patients. Compared to idiopathic AIH, more patients with IMDILI were weaned off corticosteroids at the end of follow-up (11/16 [68.7%] vs 4/15 [26.6%], P < 0.02). At 1 year of follow-up, more patients in the IMDILI group compared to the classical AIH group were off any type of IST (13/16 [81%] vs 15/15 [100%], P = 0.08). Conclusions Although presenting with similar baseline biochemical and histological characteristics as idiopathic AIH, patients with IMDILI may not require long-term IST.
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Affiliation(s)
- Jeremy Hassoun
- Department of Gastroenterology and HepatologyUniversity Hospitals of Geneva and Faculty of MedicineGenevaSwitzerland
| | - Nicolas Goossens
- Department of Gastroenterology and HepatologyUniversity Hospitals of Geneva and Faculty of MedicineGenevaSwitzerland
| | - Sophie Restellini
- Department of Gastroenterology and HepatologyUniversity Hospitals of Geneva and Faculty of MedicineGenevaSwitzerland
| | - Lucas Ramer
- Department of Gastroenterology and HepatologyUniversity Hospitals of Geneva and Faculty of MedicineGenevaSwitzerland
| | - Marie Ongaro
- Department of Gastroenterology and HepatologyUniversity Hospitals of Geneva and Faculty of MedicineGenevaSwitzerland
| | - Emiliano Giostra
- Department of Gastroenterology and HepatologyUniversity Hospitals of Geneva and Faculty of MedicineGenevaSwitzerland
| | - Antoine Hadengue
- Department of Gastroenterology and HepatologyUniversity Hospitals of Geneva and Faculty of MedicineGenevaSwitzerland
| | - Laura Rubbia‐Brandt
- Department of Clinical PathologyUniversity Hospitals of Geneva and Faculty of MedicineGenevaSwitzerland
| | - Laurent Spahr
- Department of Gastroenterology and HepatologyUniversity Hospitals of Geneva and Faculty of MedicineGenevaSwitzerland
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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] [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.
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Affiliation(s)
- Romée J. A. L. M. Snijders
- grid.10417.330000 0004 0444 9382Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands ,European Reference Network RARE-LIVER, Hamburg, Germany
| | - Anna E. C. Stoelinga
- grid.10419.3d0000000089452978Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Tom J. G. Gevers
- grid.10417.330000 0004 0444 9382Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands ,European Reference Network RARE-LIVER, Hamburg, Germany ,grid.412966.e0000 0004 0480 1382Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands ,grid.5012.60000 0001 0481 6099Nutrim School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Simon Pape
- grid.10417.330000 0004 0444 9382Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands ,European Reference Network RARE-LIVER, Hamburg, Germany
| | - Maaike Biewenga
- grid.10419.3d0000000089452978Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Robert C. Verdonk
- grid.415960.f0000 0004 0622 1269Department of Gastroenterology and Hepatology, St. Antonius Hospital, Nieuwegein, The Netherlands
| | - Hendrik J. M. de Jonge
- grid.413508.b0000 0004 0501 9798Department of Gastroenterology and Hepatology, Jeroen Bosch Hospital, ‘s Hertogenbosch, The Netherlands
| | - Jan Maarten Vrolijk
- grid.415930.aDepartment of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, The Netherlands
| | - Sjoerd F. Bakker
- grid.416373.40000 0004 0472 8381Department of Gastroenterology and Hepatology, Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands
| | - Thomas Vanwolleghem
- grid.411414.50000 0004 0626 3418Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium
| | - Ynto S. de Boer
- European Reference Network RARE-LIVER, Hamburg, Germany ,grid.509540.d0000 0004 6880 3010Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, location VU University Medical Center, Amsterdam, The Netherlands
| | - Martine A. M. C. Baven Pronk
- grid.413370.20000 0004 0405 8883Department of Gastroenterology and Hepatology, Groene Hart Hospital, Gouda, The Netherlands
| | - Ulrich H. W. Beuers
- European Reference Network RARE-LIVER, Hamburg, Germany ,grid.509540.d0000 0004 6880 3010Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, The Netherlands
| | - Adriaan J. van der Meer
- grid.5645.2000000040459992XDepartment 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
- grid.416219.90000 0004 0568 6419Department 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
- grid.413649.d0000 0004 0396 5908Department of Gastroenterology and Hepatology, Deventer Hospital, Deventer, The Netherlands
| | - Floris F. van den Brand
- grid.440209.b0000 0004 0501 8269Department of Gastroenterology and Hepatology, OLVG Oost, Amsterdam, The Netherlands
| | - Kerem Sebib Korkmaz
- Department of Gastroenterology and Hepatology, IJselland Hospital, Capelle aan den Ijssel, The Netherlands
| | - Aad P. van den Berg
- grid.4494.d0000 0000 9558 4598Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Maureen M. J. Guichelaar
- grid.415214.70000 0004 0399 8347Department of Gastroenterology and Hepatology, Medisch Spectrum Twente, Enschede, The Netherlands
| | - Khalida Soufidi
- grid.416905.fDepartment of Gastroenterology and Hepatology, Zuyderland, Heerlen, The Netherlands
| | - Amar D. Levens
- grid.10419.3d0000000089452978Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Bart van Hoek
- grid.10419.3d0000000089452978Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Joost P. H. Drenth
- grid.10417.330000 0004 0444 9382Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands ,European Reference Network RARE-LIVER, Hamburg, Germany
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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
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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
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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: 1] [Impact Index Per Article: 0.3] [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.
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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
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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.
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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
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10
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Vergani D, Terziroli Beretta-Piccoli B, Mieli-Vergani G. A reasoned approach to the treatment of autoimmune hepatitis. Dig Liver Dis 2021; 53:1381-1393. [PMID: 34162505 DOI: 10.1016/j.dld.2021.05.033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/15/2021] [Accepted: 05/27/2021] [Indexed: 12/11/2022]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease affecting all ages, characterised by elevated transaminase and immunoglobulin G levels, positive autoantibodies, interface hepatitis on histology and good response to immunosuppressive treatment. If untreated, it has a poor prognosis. The aim of this review is to analyse AIH therapeutic interventions with reference to our knowledge of the pathogenesis of AIH. Standard treatment, based on steroids and azathioprine, leads to disease remission in 80-90% of patients. Alternative first-line treatment with budesonide is effective in adults, but less so in the juvenile form of AIH; first-line treatment with ciclosporin does not provide convincing advantages compared to standard treatment. Second-line treatments are needed for patients not responding or intolerant to first-line standard management. Mycophenolate mofetil is the most widely used second-line drug, and has good efficacy particularly for patients intolerant to azathioprine, but is teratogenic. Only few and heterogeneous data on calcineurin inhibitors and m-TOR inhibitors are available. Biologicals, including anti-tumour necrosis factor- α and anti-CD20 monoclonal antibodies, have given ambivalent results and may have severe side-effects. Clinical trials with new therapeutic options aiming at targeting B lymphocytes and proinflammatory cytokines, or expanding regulatory T cells to restore tolerance are ongoing.
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Affiliation(s)
- Diego Vergani
- King's College London Faculty of Life Sciences & Medicine, London, UK; Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK; Epatocentro Ticino, Lugano, Switzerland
| | - Benedetta Terziroli Beretta-Piccoli
- Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK; Epatocentro Ticino, Lugano, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Switzerland
| | - Giorgina Mieli-Vergani
- King's College London Faculty of Life Sciences & Medicine, London, UK; Epatocentro Ticino, Lugano, Switzerland; Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, London, UK.
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11
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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.
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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
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12
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Liberal R, Gaspar R, Lopes S, Macedo G. Long-term outcome of patients with difficult-to-treat autoimmune hepatitis receiving mycophenolate mofetil. Clin Res Hepatol Gastroenterol 2021; 45:101487. [PMID: 32651078 DOI: 10.1016/j.clinre.2020.06.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 05/22/2020] [Accepted: 06/15/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Most patients with autoimmune hepatitis (AIH) respond to a combination of prednisolone and azathioprine. For patients who are intolerant or refractory to azathioprine, proposed alternative therapies are based on scarce data, limited to transplant centres and with short-term follow-up periods. OBJECTIVE To evaluate the long-term efficacy and safety of MMF as a second-line therapy in patients with AIH managed at a tertiary non-transplant centre. METHODS Retrospective analysis of a prospectively collated database identified AIH patients who received MMF from 2006 to 2015. Clinical, biochemical and immunological parameters were assessed at 3-, 6- and 12-months, and at last follow-up. Biochemical response (BR) was defined as improvement of transaminases, complete remission (CR) as normalisation of transaminases and IgG, while others were considered non-responders (NR). RESULTS Eighteen out of 151 (12%) AIH patients received MMF. Nine received MMF due to azathioprine-intolerance (group 1), while nine due to refractory disease (group 2). In group 1, CR and BR was achieved in six (67%) and two (22%) patients respectively. In group 2, CR and BR was achieved in one (11%) and five (56%) patients respectively. Adverse events occurred in eight patients (44%), with one patient requiring drug discontinuation. After a medium follow-up of 78 (31-116) months, there was a significant decrease in transaminase levels, mirrored by decrease in prednisolone dose from 25 to 6.25 mg/day (P<0.05). CONCLUSION Long-term therapy with MMF is safe and effective in AIH patients requiring second-line therapies, and these patients can be effectively managed at tertiary non-liver transplant centres.
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Affiliation(s)
- Rodrigo Liberal
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal; World Gastroenterology Organization (WGO) Porto Training Center, Portugal.
| | - Rui Gaspar
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal; World Gastroenterology Organization (WGO) Porto Training Center, Portugal
| | - Susana Lopes
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal; World Gastroenterology Organization (WGO) Porto Training Center, Portugal
| | - Guilherme Macedo
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal; World Gastroenterology Organization (WGO) Porto Training Center, Portugal
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13
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Second-line and third-line therapy for autoimmune hepatitis: A position statement from the European Reference Network on Hepatological Diseases and the International Autoimmune Hepatitis Group. J Hepatol 2020; 73:1496-1506. [PMID: 32707224 DOI: 10.1016/j.jhep.2020.07.023] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/08/2020] [Accepted: 07/11/2020] [Indexed: 02/06/2023]
Abstract
Most patients with autoimmune hepatitis respond well to standard immunosuppressive therapy with steroids and azathioprine, and while untreated disease is usually fatal, patients who respond well to therapy have an excellent prognosis. However, insufficient response to standard therapy or intolerable side effects requiring dose adaptions or treatment changes occur in 10-20% of patients. While there is fairly good agreement on second-line treatment options, there is very wide variation in the indication and use of possible third-line therapies. Herein, the European Reference Network on Hepatological Diseases (ERN RARE-LIVER) and the International Autoimmune Hepatitis Group (IAIHG) outline a treatment algorithm for both children and adults that should help to standardise treatment approaches, in order to improve patient care and to enable the comparison of treatment results between scientific publications.
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14
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Abdollahi M, Ekrami NK, Ghojazadeh M, Boezen HM, Somi M, Alizadeh BZ. Tacrolimus and mycophenolate mofetil as second-line treatment in autoimmune hepatitis: Is the evidence of sufficient quality to develop recommendations? World J Gastroenterol 2020; 26:5896-5910. [PMID: 33132643 PMCID: PMC7579758 DOI: 10.3748/wjg.v26.i38.5896] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 08/11/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The standard management of autoimmune hepatitis (AIH) is based on corticosteroids, alone or in combination with azathioprine. Second-line treatments are needed for patients who have refractory disease. However, high-quality data on the alternative management of AIH are scarce.
AIM To evaluate the efficacy and safety of tacrolimus and mycophenolate mofetil (MMF) and the quality of evidence by using the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE).
METHODS A systematic review and meta-analysis of the available data were performed. We calculated pooled event rates for three outcome measures: Biochemical remission, adverse events, and mortality, with their corresponding 95% confidence intervals (CI).
RESULTS The pooled biochemical remission rate was 68.9% (95%CI: 60.4-76.2) for tacrolimus, and 59.6% (95%CI: 54.8-64.2) for MMF, and rates of adverse events were 25.5% (95%CI: 12.4-45.3) for tacrolimus and 24.1% (95%CI: 15.4-35.7) for MMF. The pooled mortality rate was estimated at 11.5% (95%CI: 7.1-18.1) for tacrolimus and 9.01% (95%CI: 6.2-12.8) for MMF. Pooled biochemical remission rates for tacrolimus and MMF in patients with intolerance to standard therapy were 56.6% (CI: 43.4-56.6) vs 73.5% (CI: 58.1-84.7), and among non-responders were 59.1% (CI: 48.7-68.8) vs 40.8% (CI: 32.3-50.0), respectively. Moreover, the overall quality assessments using GRADE proved to be very low for all our outcomes in both treatment groups.
CONCLUSION Tacrolimus and MMF are in practice considered effective for patients with AIH who are non-responders or intolerant to first-line treatment, but we found no high-quality evidence to support this statement.
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Affiliation(s)
| | | | - Morteza Ghojazadeh
- Research Center for Evidence Based Medicine, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran
| | - H Marike Boezen
- Department of Epidemiology, University of Groningen, Groningen 9700 RB, Netherlands
| | - Mohammadhossein Somi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran
| | - Behrooz Z Alizadeh
- Department of Epidemiology, University of Groningen, Groningen 9700 RB, Netherlands
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15
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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.
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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
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16
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Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, Vierling JM, Alsawas M, Murad MH, Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology 2020; 72:671-722. [PMID: 31863477 DOI: 10.1002/hep.31065] [Citation(s) in RCA: 515] [Impact Index Per Article: 103.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Cara L Mack
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - David Adams
- Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - David N Assis
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT
| | - Nanda Kerkar
- Golisano Children's Hospital at Strong, University of Rochester Medical Center, New York, NY
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marlyn J Mayo
- Division of Digestive and Liver Diseases, University of Texas SW Medical Center, Dallas, TX
| | - John M Vierling
- Medicine and Surgery, Baylor College of Medicine, Houston, TX
| | | | - Mohammad H Murad
- Mayo Knowledge and Encounter Research Unit, Mayo Clinic College of Medicine, Rochester, MN
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
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17
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Vierling JM, Kerkar N, Czaja AJ, Mack CL, Adams D, Assis DN, Manns MP, Mayo MJ, Nayfeh T, Majzoub AMM, Alzuabi MA, Ding J, Haffar S, Murad MH, Alsawas M. Immunosuppressive Treatment Regimens in Autoimmune Hepatitis: Systematic Reviews and Meta-Analyses Supporting American Association for the Study of Liver Diseases Guidelines. Hepatology 2020; 72:753-769. [PMID: 32500593 DOI: 10.1002/hep.31407] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/30/2020] [Accepted: 05/26/2020] [Indexed: 12/13/2022]
Affiliation(s)
- John M Vierling
- Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Nanda Kerkar
- Department of Pediatrics, University of Rochester School of Medicine, Rochester, NY, USA
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Cara L Mack
- Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA
| | - David Adams
- College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - David N Assis
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marlyn J Mayo
- University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Tarek Nayfeh
- Mayo Clinic Evidence-Based Practice Research Program, Rochester, MN, USA
| | | | - Muayad A Alzuabi
- Mayo Clinic Evidence-Based Practice Research Program, Rochester, MN, USA
| | - Jingyi Ding
- Mayo Clinic Evidence-Based Practice Research Program, Rochester, MN, USA
| | - Samir Haffar
- Mayo Clinic Evidence-Based Practice Research Program, Rochester, MN, USA
| | - M Hassan Murad
- Mayo Clinic Evidence-Based Practice Research Program, Rochester, MN, USA
| | - Mouaz Alsawas
- Mayo Clinic Evidence-Based Practice Research Program, Rochester, MN, USA
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18
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Czaja AJ. Review article: opportunities to improve and expand thiopurine therapy for autoimmune hepatitis. Aliment Pharmacol Ther 2020; 51:1286-1304. [PMID: 32363674 DOI: 10.1111/apt.15743] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 03/07/2020] [Accepted: 03/31/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use. AIMS To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response. METHODS English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. RESULTS Thiopurine methyltransferase activity and 6-tioguanine (6-thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre-treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose-restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6-tioguanine nucleotides and ameliorating thiopurine intolerance or resistance. CONCLUSIONS The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
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19
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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.
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20
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Doycheva I, Watt KD, Gulamhusein AF. Autoimmune hepatitis: Current and future therapeutic options. Liver Int 2019; 39:1002-1013. [PMID: 30716203 DOI: 10.1111/liv.14062] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 01/13/2019] [Accepted: 01/17/2019] [Indexed: 02/13/2023]
Abstract
Autoimmune hepatitis (AIH) is a rare immune-mediated liver disease with few major advances in treatment options over the last several decades. Available options are effective in most patients albeit are imprecise in their mechanisms. Novel and more tolerable induction regimens and alternative options for management of patients intolerant or with suboptimal response to traditional therapies including in the post-transplant setting remain an important unmet need. This review aims to summarize recent data on pharmacological options and investigational drugs in development for patients with AIH. Standard therapy using prednisone with or without azathioprine remains the mainstay of therapy and is effective in most patients. Budesonide may be considered for induction in early disease and in those with mild fibrosis, but has not been approved for maintenance therapy. Mycophenolate mofetil (MMF) in combination with steroids might be an alternative first-line therapy, but results from a randomized trial are awaited. MMF as a second-line maintenance agent has moderate efficacy though more frequent adverse events in patients with cirrhosis may be seen. Tacrolimus may be an equally effective second-line option particularly in non-responders, but data remain limited. Management of recurrent AIH post-liver transplantation remains controversial with insufficient data to support long-term steroid use. Moving forward, expanding the scope of therapeutic options to include biologics including B-cell depleting agents may be a promising step. Recent insights in understanding the pathogenesis of AIH could serve as a basis for future therapies, including the elucidation of different immunoregulatory pathways and the potential role of the intestinal microbiome.
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Affiliation(s)
- Iliana Doycheva
- Division of Gastroenterology and Hepatology, Medical University, Sofia, Bulgaria
| | - Kymberly D Watt
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Aliya F Gulamhusein
- Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University Health Network, Toronto, ON, Canada
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21
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Zipprich A. Rheumatologie und Hepatologie: Diagnostik und Therapie von
autoimmunen Lebererkrankungen. AKTUEL RHEUMATOL 2019. [DOI: 10.1055/a-0885-9314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
ZusammenfassungUnter autoimmunen Lebererkrankungen werden im klassischen Sinne 3 verschiedene
Entitäten, die Autoimmune Hepatitis (AIH), die Primär biliäre Cholangitis (PBC)
und die Primär sklerosierende Cholangitis (PSC) verstanden. Der nachfolgende
Übersichtartikel fokusiert auf die Diagnostik und die Therapie dieser 3
autoimmunen Lebererkrankungen und gibt eine Übersicht zu möglichen zusätzlich
assoziierten Autoimmunerkrankungen.
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22
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Santiago P, Schwartz I, Tamariz L, Levy C. Systematic review with meta-analysis: mycophenolate mofetil as a second-line therapy for autoimmune hepatitis. Aliment Pharmacol Ther 2019; 49:830-839. [PMID: 30761563 DOI: 10.1111/apt.15157] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 11/05/2018] [Accepted: 01/01/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND First-line treatment for autoimmune hepatitis (AIH) typically includes corticosteroids in combination with azathioprine. Mycophenolate mofetil (MMF) is often used as a rescue therapy in patients who are intolerant of, or nonresponsive to, standard therapy. AIM To systematically review studies and perform a meta-analysis on the efficacy and safety of MMF as a second-line therapy for AIH patients. METHODS MEDLINE, EMBASE and Cochrane Central were searched for studies that reported data on efficacy and safety of MMF as a second-line therapy in AIH. We calculated the pooled response rate, adverse events rate and discontinuation rate due to side effects, with their corresponding 95% confidence intervals. RESULTS Twelve studies comprising 397 patients, followed for a median of 34 months (range, 12-47 months), were included. MMF doses ranged from 0.5-4.0 g/d. Pooled response rate was 0.58 (95% CI 0.54-0.63). Pooled adverse events rate was 0.14 (95% CI 0.11-0.17), and pooled discontinuation rate due to side effects was 0.08 (95% CI 0.06-0.11). Five studies (n = 309) specified response rates according to reason for using MMF. Pooled response rate in the subgroup with intolerance to standard therapy was 0.82 (95% CI 0.77-0.87) and pooled response rate among nonresponders was 0.32 (95% CI 0.24-0.39). CONCLUSIONS The overall efficacy of MMF as second-line therapy in AIH was high. Response rate was greater in patients who started the medication due to intolerance to standard therapy as opposed to nonresponse. Overall, MMF was well tolerated, with a low discontinuation rate due to side effects.
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Affiliation(s)
| | | | | | - Cynthia Levy
- Division of Hepatology, Department of Medicine, University of Miami, Miami, Florida
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23
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Giannakopoulos G, Verbaan H, Friis-Liby IL, Sangfelt P, Nyhlin N, Almer S. Mycophenolate mofetil treatment in patients with autoimmune hepatitis failing standard therapy with prednisolone and azathioprine. Dig Liver Dis 2019; 51:253-257. [PMID: 30389427 DOI: 10.1016/j.dld.2018.10.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 09/19/2018] [Accepted: 10/03/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Data on rescue treatment of autoimmune hepatitis in patients that fail standard treatment are sparse. AIMS To report our long-term experience with mycophenolate mofetil. METHODS Retrospective study in 22 patients with autoimmune hepatitis who failed azathioprine and prednisolone due to adverse events (n = 14, 64%), lack of remission (n = 5, 23%) or a combination (n = 3, 13%). RESULTS Mycophenolate mofetil was started at a dose of 20 mg/kg/day and increased to a maximum of 3 g/day. Follow-up was 0-6 months in 7 patients; more than 12 months in 15 (68%) and more than 24 months in 10. Normal aminotransferase levels were obtained (n = 3) or maintained (n = 7) in 10 patients (45%) after three to 30 weeks. 12 patients (55%) were withdrawn during the first 6 months, due to adverse events. Three patients were switched to cyclosporine and one underwent liver transplantation. Successful treatment with mycophenolate mofetil continued in 10 patients (45%) for a median of 71 months (range 20-124). Of these, one stopped prednisolone, five have a prednisolone dose <5 mg daily and four patients 5-10 mg. CONCLUSION Approximately one of two patients with autoimmune hepatitis that fail standard treatment benefit from long-term maintenance with mycophenolate mofetil, especially those with previous intolerance to thiopurines, where mycophenolate mofetil is effective in two thirds.
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Affiliation(s)
- Georgios Giannakopoulos
- Division of Gastroenterology, Department of Gastroenterology, Dermatology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - Hans Verbaan
- Department of Medicine, Skåne University Hospital, Malmö, Sweden
| | | | - Per Sangfelt
- Department of Medicine, Akademiska Hospital, Uppsala, Sweden
| | - Nils Nyhlin
- Department of Medicine, Örebro University Hospital, Örebro, Sweden
| | - Sven Almer
- Division of Gastroenterology, Department of Gastroenterology, Dermatology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
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24
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Dalekos GN, Koskinas J, Papatheodoridis GV. Hellenic Association for the Study of the Liver Clinical Practice Guidelines: Autoimmune hepatitis. Ann Gastroenterol 2019; 32:1-23. [PMID: 30598587 PMCID: PMC6302199 DOI: 10.20524/aog.2018.0330] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Accepted: 10/29/2018] [Indexed: 02/07/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a relatively rare acute or chronic liver disease of unknown etiology characterized by large heterogeneity. Its distribution is global, covering all ages, both sexes and all ethnic groups. The aim of the present Clinical Practice Guidelines (CPG) of the Hellenic Association for the Study of the Liver was to provide updated guidance and help to gastroenterologists, hepatologists, internists and general practitioners for AIH diagnosis and management. AIH diagnosis is based on clinicopathological characteristics: namely, polyclonal hypergammaglobulinemia, particularly of immunoglobulin G (IgG), circulating autoantibodies, interface hepatitis on liver histology, absence of viral hepatitis, and a favorable response to immunosuppression. Clinical manifestations at disease onset are variable, ranging from asymptomatic to the acute/severe form. Aminotransferase and bilirubin levels vary, while the presence of hepatitis at the histological level is a prerequisite for diagnosis. Autoantibodies are the hallmark for AIH diagnosis; therefore, the CPG describe the appropriate serological algorithm for their detection. AIH therapy should aim to achieve complete biochemical (normalization of IgG and aminotransferases) and histological remission. All patients who have active disease, even those with cirrhosis, should be treated with individualized and response-guided induction therapy using prednisolone in combination with azathioprine or mycophenolate mofetil as first-line therapy. Immunosuppression should be given for at least 3 years and for at least 2 years after the achievement of complete biochemical response, while a liver biopsy should be recommended before treatment discontinuation. Current CPG are also provided for several specific conditions and difficult-to-treat patients.
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Affiliation(s)
- George N. Dalekos
- Institute of Internal Medicine and Hepatology, Larissa (George N. Dalekos)
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa (George N. Dalekos)
| | - John Koskinas
- Second Department of Internal Medicine, National and Kapodistrian University of Athens, “Hippokratio” General Hospital of Athens, Athens (John Koskinas)
| | - George V. Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, “Laiko” General Hospital of Athens, Athens (George V. Papatheodoridis), Greece
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25
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Roberts SK, Lim R, Strasser S, Nicoll A, Gazzola A, Mitchell J, Siow W, Khoo T, Hamarneh Z, Weltman M, Gow P, Janko N, Tse E, Mishra G, Cheng EH, Levy M, Cheng W, Sood S, Skoien R, Mitchell J, Zekry A, George J, MacQuillan G, Wigg A, Stuart K, Sievert W, McCaughan G. Efficacy and Safety of Mycophenolate Mofetil in Patients With Autoimmune Hepatitis and Suboptimal Outcomes After Standard Therapy. Clin Gastroenterol Hepatol 2018; 16:268-277. [PMID: 29050991 DOI: 10.1016/j.cgh.2017.09.063] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 08/18/2017] [Accepted: 09/25/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Little is known about outcomes of patients with autoimmune hepatitis (AIH) who have a suboptimal outcome to standard therapy and are then given mycophenolate mofetil as rescue therapy. We evaluated the efficacy and safety of mycophenolate mofetil in patients failed by or intolerant to corticosteroids, with or without azathioprine. METHODS We performed a retrospective study of 105 patients with AIH who received mycophenolate mofetil therapy after an inadequate response or intolerance to standard therapy (98% received combination therapy with corticosteroids plus thiopurines). Patients were recruited from 17 liver clinics via the Australian Liver Association Clinical Research Network. We reviewed records for baseline demographic features and characteristics of liver disease, initial therapy, mycophenolate mofetil indications, treatment outcome, and side effects. The primary outcome was biochemical remission, defined as levels of alanine and aspartate transferase and IgG level within the normal reference range, with or without normal liver histology within the first 2 years of treatment. RESULTS The indication for mycophenolate mofetil therapy was non-response to treatment for 40% of cases and intolerance to therapy for 60%. Overall, 63 patients (60%) achieved biochemical remission following a median 12 weeks treatment with mycophenolate mofetil. The proportion of patients who achieved biochemical remission was similar between patients receiving mycophenolate mofetil for non-response to standard therapy (57%) and patients with intolerance to standard therapy (62%). However, a lower proportion of patients with cirrhosis achieved biochemical remission (47%) than patients without cirrhosis (6%) (P = .07). Serious adverse events occurred in 3 patients (2.7%) including 1 death, and 10 patients (9.2%) discontinued mycophenolate mofetil because of adverse events. CONCLUSION In this retrospective study of patients with AIH who received mycophenolate mofetil as a rescue therapy, we found the drug to be well tolerated and moderately effective, inducing biochemical remission in 60% of subjects. Rates of response are lower and rates of infection are higher in patients with AIH and cirrhosis. Prospective studies of mycophenolate mofetil are warranted for this population.
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Affiliation(s)
| | - Ricky Lim
- Royal Prince Alfred Hospital, Sydney
| | - Simone Strasser
- Royal Prince Alfred Hospital, Sydney; Centenary Research Institute, Sydney
| | - Amanda Nicoll
- Eastern Health, Box Hill Hospital, and Monash University, Box Hill
| | | | | | - Way Siow
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney
| | | | | | | | | | - Natasha Janko
- The Alfred, Melbourne; Eastern Health, Box Hill Hospital, and Monash University, Box Hill
| | | | - Gauri Mishra
- Monash Medical Centre and Monash University, Melbourne
| | | | | | | | | | | | | | | | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney
| | | | | | | | | | - Geoffrey McCaughan
- Royal Prince Alfred Hospital, Sydney; Centenary Research Institute, Sydney
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26
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Efe C, Hagström H, Ytting H, Bhanji RA, Müller NF, Wang Q, Purnak T, Muratori L, Werner M, Marschall HU, Muratori P, Gunşar F, Klintman D, Parés A, Heurgué-Berlot A, Schiano TD, Cengiz M, May-Sien Tana M, Ma X, Montano-Loza AJ, Berg T, Verma S, Larsen FS, Ozaslan E, Heneghan MA, Yoshida EM, Wahlin S. Efficacy and Safety of Mycophenolate Mofetil and Tacrolimus as Second-line Therapy for Patients With Autoimmune Hepatitis. Clin Gastroenterol Hepatol 2017; 15:1950-1956.e1. [PMID: 28603052 DOI: 10.1016/j.cgh.2017.06.001] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 05/24/2017] [Accepted: 06/02/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Predniso(lo)ne, alone or in combination with azathioprine, is the standard-of-care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH. METHODS We performed a retrospective study of data (from 19 centers in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6-190 mo). Patients were categorized according to their response to SOC. Patients in group 1 (n = 108) had a complete response to the SOC, but were switched to second-line therapy as a result of side effects of predniso(lo)ne or azathioprine, whereas patients in group 2 (n = 93) had not responded to SOC. RESULTS There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P = .639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P = .682). Significantly more group 2 patients given tacrolimus compared with MMF had a complete response (56.5% vs 34%, respectively; P = .029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P = .472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal. CONCLUSIONS Long-term therapy with MMF or tacrolimus generally was well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous nonresponder patients compared with MMF.
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Affiliation(s)
- Cumali Efe
- Department of Gastroenterology, Hacettepe University, Ankara, Turkey.
| | - Hannes Hagström
- Hepatology Division, Centre for Digestive Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Henriette Ytting
- Department of Hepatology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Rahima A Bhanji
- Division of Gastroenterology and Liver Unit, University of Alberta, Alberta, Canada
| | - Niklas F Müller
- Sektion Hepatologie, Klinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig, Germany
| | - Qixia Wang
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Tugrul Purnak
- Department of Gastroenterology, Hacettepe University, Ankara, Turkey
| | - Luigi Muratori
- Centro per lo Studio e la Cura delle Malattie Autoimmuni del Fegato e delle Vie Biliari, Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum, Università di Bologna, Bologna, Italy
| | - Mårten Werner
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Paolo Muratori
- Centro per lo Studio e la Cura delle Malattie Autoimmuni del Fegato e delle Vie Biliari, Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum, Università di Bologna, Bologna, Italy
| | - Fulya Gunşar
- Department of Gastroenterology, Ege University, Bornova, Izmir, Turkey
| | - Daniel Klintman
- Department of Molecular and Clinical Medicine, Skåne University Hospital, Lund, Sweden; Division of Gastroenterology University of British Columbia, Vancouver General Hospital, Vancouver, Canada
| | - Albert Parés
- Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | | | - Thomas D Schiano
- Division of Liver Diseases, The Mount Sinai Medical Center, New York, New York
| | - Mustafa Cengiz
- Department of Gastroenterology, Dr A.Y. Oncology Training and Research Hospital, Ankara, Turkey
| | - Michele May-Sien Tana
- The Liver Center at University of California, San Francisco, Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, California
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Alberta, Canada
| | - Thomas Berg
- Sektion Hepatologie, Klinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig, Germany
| | - Sumita Verma
- Department of Medicine, Brighton and Sussex Medical School, Department of Gastroenterology and Hepatology, Brighton and Sussex University Hospital, Brighton, United Kingdom
| | - Fin Stolze Larsen
- Department of Hepatology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Ersan Ozaslan
- Department of Gastroenterology, Numune Research and Education Hospital, Ankara, Turkey
| | - Michael A Heneghan
- Institute of Liver Studies, King's College Hospital National Health Service Foundation Trust, London, United Kingdom
| | - Eric M Yoshida
- Division of Gastroenterology University of British Columbia, Vancouver General Hospital, Vancouver, Canada
| | - Staffan Wahlin
- Hepatology Division, Centre for Digestive Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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27
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: Standard treatment and systematic review of alternative treatments. World J Gastroenterol 2017; 23:6030-6048. [PMID: 28970719 PMCID: PMC5597495 DOI: 10.3748/wjg.v23.i33.6030] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 07/18/2017] [Accepted: 08/02/2017] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis is a rare chronic inflammatory liver disease, affecting all ages, characterised by elevated transaminase and immunoglobulin G levels, positive autoantibodies, interface hepatitis at liver histology and good response to immunosuppressive treatment. If untreated, it has a poor prognosis. The aim of this review is to summarize the evidence for standard treatment and to provide a systematic review on alternative treatments for adults and children. Standard treatment is based on steroids and azathioprine, and leads to disease remission in 80%-90% of patients. Alternative first line treatment has been attempted with budesonide or cyclosporine, but their superiority compared to standard treatment remains to be demonstrated. Second-line treatments are needed for patients not responding or intolerant to standard treatment. No randomized controlled trials have been performed for second-line options. Mycophenolate mofetil is the most widely used second-line drug, and has good efficacy particularly for patients intolerant to azathioprine, but has the major disadvantage of being teratogenic. Only few and heterogeneous data on cyclosporine, tacrolimus, everolimus and sirolimus are available. More recently, experience with the anti-tumour necrosis factor-alpha infliximab and the anti-CD20 rituximab has been published, with ambivalent results; these agents may have severe side-effects and their use should be restricted to specialized centres. Clinical trials with new therapeutic options are ongoing.
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Affiliation(s)
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom
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28
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Affiliation(s)
- Albert J. Czaja
- Professor Emeritus of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
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29
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Grant CR, Holder BS, Liberal R, Heneghan MA, Ma Y, Mieli-Vergani G, Vergani D, Longhi MS. Immunosuppressive drugs affect interferon (IFN)-γ and programmed cell death 1 (PD-1) kinetics in patients with newly diagnosed autoimmune hepatitis. Clin Exp Immunol 2017; 189:71-82. [PMID: 28257599 DOI: 10.1111/cei.12956] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/28/2017] [Indexed: 01/20/2023] Open
Abstract
Autoimmune hepatitis (AIH) is characterized by overwhelming effector immune responses associated with defective regulatory T cells (Tregs ). Several lines of evidence indicate CD4 as the main effectors involved in autoimmune liver damage. Herein we investigate the in-vitro effects of prednisolone, 6-mercaptopurine, cyclosporin, tacrolimus, mycophenolic acid (MPA) and rapamycin, immunosuppressive drugs (ISDs) used in AIH treatment, on the expression of proinflammatory cytokines, co-inhibitory molecules and ability to proliferate of CD4+ CD25- cells, isolated from the peripheral blood of treatment-naive patients with AIH. We note that in healthy subjects (HS) following polyclonal stimulation and in the absence of ISDs, the expression of interferon (IFN)-γ, interleukin (IL)-17 and tumour necrosis factor (TNF)-α by CD4 effectors peaks at 48 h and decreases at 96 h to reach baseline levels. In contrast, in AIH the expression of all these proinflammatory cytokines continue rising between 48 and 96 h. Levels of programmed cell death-1 (PD-1), T cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) and cytotoxic T lymphocyte antigen-4 (CTLA-4) increase over 96-h culture both in HS and AIH, although with faster kinetics in the latter. Exposure to ISDs contains IFN-γ and PD-1 expression in AIH, where control over CD4+ CD25- cell proliferation is also noted upon exposure to MPA. Treatment with tacrolimus and cyclosporin render CD4+ CD25- cells more susceptible to Treg control. Collectively, our data indicate that in treatment-naive patients with AIH, all ISDs restrain T helper type 1 (Th1) cells and modulate PD-1 expression. Furthermore, they suggest that tacrolimus and cyclosporin may ameliorate effector cell responsiveness to Tregs .
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Affiliation(s)
- C R Grant
- Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK
| | - B S Holder
- Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK.,Department of Paediatrics, Imperial College, London
| | - R Liberal
- Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK.,Gastroenterology Department, Centro Hospitalar São João, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - M A Heneghan
- Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK
| | - Y Ma
- Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK
| | - G Mieli-Vergani
- Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK.,MowatLabs Paediatric Liver, GI and Nutrition Centre, King's College London, Faculty of Life Sciences and Medicine, London, UK
| | | | - M S Longhi
- Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK.,Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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30
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Liberal R, de Boer YS, Andrade RJ, Bouma G, Dalekos GN, Floreani A, Gleeson D, Hirschfield GM, Invernizzi P, Lenzi M, Lohse AW, Macedo G, Milkiewicz P, Terziroli B, van Hoek B, Vierling JM, Heneghan MA. Expert clinical management of autoimmune hepatitis in the real world. Aliment Pharmacol Ther 2017; 45:723-732. [PMID: 28004405 DOI: 10.1111/apt.13907] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 10/12/2016] [Accepted: 11/27/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND High-quality data on the management of autoimmune hepatitis (AIH) are scarce. Despite published guidelines, management of AIH is still expert based rather than evidence based. AIM To survey expert hepatologists, asking each to describe their practices in the management of patients with AIH. METHODS A survey questionnaire was distributed to members of the International AIH Group. The questionnaire consisted of four clinical scenarios on different presentations of AIH. RESULTS Sixty surveys were sent, out of which 37 were returned. None reported budesonide as a first line induction agent for the acute presentation of AIH. Five (14%) participants reported using thiopurine S-methyltransferase measurements before commencement of thiopurine maintenance therapy. Thirteen (35%) routinely perform liver biopsy at 2 years of biochemical remission. If histological inflammatory activity is absent, four (11%) participants reduced azathioprine, whereas 10 (27%) attempted withdrawal altogether. Regarding the management of difficult-to-treat patients, mycophenolate mofetil is the most widely used second-line agent (n = ~450 in 28 centres), whereas tacrolimus (n = ~115 in 21 centres) and ciclosporin (n = ~112 in 18 centres) are less often reported. One centre reported considerable experience with infliximab, while rescue therapy with rituximab has been tried in seven centres. CONCLUSIONS There is a wide variation in the management of patients with autoimmune hepatitis even among the most expert in the field. Although good quality evidence is lacking, there is considerable experience with second-line therapies. Future prospective studies should address these issues, so that we move from an expert- to an evidence- and personalised-based care in autoimmune hepatitis.
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Abstract
Autoimmune hepatitis (AIH) is a chronic progressive liver disease characterized by high levels of aminotransferases and autoantibodies, hypergammaglobulinemia, and interface hepatitis. AIH affects all races and all ages worldwide, regardless of sex, although a preponderance of females is a constant finding. The etiology of AIH has not been completely elucidated, but immunogenetic background and environmental parameters may contribute to its development. The most important genetic factor is human leukocyte antigens (HLAs), especially HLA-DR, whereas the role of environmental factors is not completely understood. Immunologically, disruption of the immune tolerance to autologous liver antigens may be a trigger of AIH. The diagnosis of classical AIH is fairly easy, though not without pitfalls. In contrast, the diagnosis of atypical AIH poses great challenges. There is confusion as to the definition of the disease entity and its boundaries in the diagnosis of overlap syndrome, drug-induced autoimmune hepatitis, and AIH with concomitant nonalcoholic fatty liver disease (NAFLD) or chronic hepatitis C. Centrilobular zonal necrosis is now included in the histological spectrum of AIH. However, the definition and the significance of AIH presenting with centrilobular zonal necrosis have not been examined extensively. In ~20% of AIH patients who are treated for the first time with standard therapy, remission is not achieved. The development of more effective and better tolerated novel therapies is an urgent need. In this review, we discuss the current challenges and the future prospects in relation to the diagnosis and treatment of AIH, which have been attracting considerable recent attention.
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Affiliation(s)
- Yoshio Aizawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University Katsushika Medical Center, Katsushika-ku, Tokyo, Japan
| | - Atsushi Hokari
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University Katsushika Medical Center, Katsushika-ku, Tokyo, Japan
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Liberal R, Krawitt EL, Vierling JM, Manns MP, Mieli-Vergani G, Vergani D. Cutting edge issues in autoimmune hepatitis. J Autoimmun 2016; 75:6-19. [PMID: 27502148 DOI: 10.1016/j.jaut.2016.07.005] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 07/06/2016] [Accepted: 07/10/2016] [Indexed: 12/14/2022]
Abstract
Autoimmune hepatitis (AIH) is a severe liver disease affecting all age groups worldwide. Novel basic and clinical aspects of AIH, addressed at a Monothematic Conference in London in September 2015, are highlighted in this review. The diagnosis of AIH relies upon detection of characteristic autoantibodies, hypergammaglobulinemia, and interface hepatitis on liver histology. The International Autoimmune Hepatitis Group (IAIHG) has devised diagnostic scoring systems to help in comparative studies and clinical practice. AIH arises in a genetically predisposed host, when yet unknown triggers - such an encounter with a pathogen - lead to a T cell-mediated immune response targeting liver autoantigens. This immune response is inadequately controlled because regulatory mechanisms are impaired. The mainstay of treatment for AIH is immunosuppression, which should be instituted as soon as the diagnosis is made. Standard treatment regimens include relatively high doses of predniso(lo)ne, which are tapered gradually as azathioprine is introduced. Recent guidelines have described newer treatment regimens and have tightened the goal of therapy to complete normalization of biochemical, serological and histological parameters. Mycophenolate mofetil, calcineurin inhibitors, mTOR inhibitors and biological agents are potential salvage therapies, but should be reserved for selected non-responsive patients and administered only in experienced centers. Liver transplantation is a life-saving option for those patients who progress to end-stage liver disease. Further dissection of cellular and molecular pathways involved in AIH pathogenesis is likely to lead to the discovery of novel, tailored and better tolerated therapies.
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Affiliation(s)
- Rodrigo Liberal
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Edward L Krawitt
- Department of Medicine, Dartmouth College, Hanover, NH, USA; Department of Medicine, University of Vermont, Burlington, VT, USA
| | - John M Vierling
- Departments of Medicine and Surgery, Baylor College of Medicine, Baylor-St Luke's Medical Center, Houston, TX, USA
| | | | - Giorgina Mieli-Vergani
- Institute of Liver Studies, King's College Hospital, London, UK; Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK
| | - Diego Vergani
- Institute of Liver Studies, King's College Hospital, London, UK.
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33
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Dalekos GN, Zachou K. Editorial: autoimmune hepatitis - identifying options for treatment. Authors' reply. Aliment Pharmacol Ther 2016; 43:1237-8. [PMID: 27137726 DOI: 10.1111/apt.13626] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- G N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece.
| | - K Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
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34
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Janmohamed A, Hirschfield GM. Editorial: autoimmune hepatitis - identifying options for treatment. Aliment Pharmacol Ther 2016; 43:1236-7. [PMID: 27137725 DOI: 10.1111/apt.13607] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- A Janmohamed
- Centre for Liver Research, NIHR Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK
| | - G M Hirschfield
- Centre for Liver Research, NIHR Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK.
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Hübener S, Oo YH, Than NN, Hübener P, Weiler-Normann C, Lohse AW, Schramm C. Efficacy of 6-Mercaptopurine as Second-Line Treatment for Patients With Autoimmune Hepatitis and Azathioprine Intolerance. Clin Gastroenterol Hepatol 2016; 14:445-53. [PMID: 26492846 DOI: 10.1016/j.cgh.2015.09.037] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 09/01/2015] [Accepted: 09/30/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that requires long-term immunosuppressive therapy. Although most patients have an excellent response to standard therapy (azathioprine in combination with corticosteroids), approximately 10%-15% have intolerance or an insufficient response to azathioprine treatment. We investigated whether 6-mercaptopurine (6-MP) is an effective second-line therapy for patients with AIH. METHODS We performed a retrospective study of 22 patients with AIH who were switched to 6-MP therapy after treatment with the combination of azathioprine and prednisolone at 2 tertiary care institutions in Europe (Germany and the United Kingdom) before November 15, 2014. We performed statistical analyses of data on clinical and biochemical responses collected 4 weeks after 6-MP treatment and then at regular physician visits. RESULTS A total of 15 of 20 patients with prior azathioprine intolerance (75%) responded to 6-MP treatment; 8 of these patients had a complete response and 7 had partial remission, based on biochemical features. In these 15 patients, 6-MP was well tolerated, whereas the 5 remaining patients had to be switched to different immunosuppressive regimes because of 6-MP intolerance. The 2 patients with insufficient response to azathioprine treatment also showed no response to 6-MP. CONCLUSIONS In patients with AIH and azathioprine intolerance, 6-MP seems to be an effective and well-tolerated second-line treatment. 6-MP might be ineffective in patients with insufficient response to azathioprine.
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Affiliation(s)
- Sina Hübener
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ye Htun Oo
- Centre for Liver Research, University of Birmingham Liver Unit, Birmingham, United Kingdom
| | - Nwe Ni Than
- Centre for Liver Research, University of Birmingham Liver Unit, Birmingham, United Kingdom
| | - Peter Hübener
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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36
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Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis: Current Status and Future Directions. Gut Liver 2016; 10:177-203. [PMID: 26934884 PMCID: PMC4780448 DOI: 10.5009/gnl15352] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 11/04/2015] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis is characterized by autoantibodies, hypergammaglobulinemia, and interface hepatitis on histological examination. The features lack diagnostic specificity, and other diseases that may resemble autoimmune hepatitis must be excluded. The clinical presentation may be acute, acute severe (fulminant), or asymptomatic; conventional autoantibodies may be absent; centrilobular necrosis and bile duct changes may be present; and the disease may occur after liver transplantation or with features that suggest overlapping disorders. The diagnostic criteria have been codified, and diagnostic scoring systems can support clinical judgment. Nonstandard autoantibodies, including antibodies to actin, α-actinin, soluble liver antigen, perinuclear antineutrophil antigen, asialoglycoprotein receptor, and liver cytosol type 1, are tools that can support the diagnosis, especially in patients with atypical features. Prednisone or prednisolone in combination with azathioprine is the preferred treatment, and strategies using these medications in various doses can ameliorate treatment failure, incomplete response, drug intolerance, and relapse after drug withdrawal. Budesonide, mycophenolate mofetil, and calcineurin inhibitors can be considered in selected patients as frontline or salvage therapies. Molecular (recombinant proteins and monoclonal antibodies), cellular (adoptive transfer and antigenic manipulation), and pharmacological (antioxidants, antifibrotics, and antiapoptotic agents) interventions constitute future directions in management. The evolving knowledge of the pathogenic pathways and the advances in technology promise new management algorithms.
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Affiliation(s)
- Albert J. Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN,
USA
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37
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Vierling JM. Autoimmune Hepatitis and Overlap Syndromes: Diagnosis and Management. Clin Gastroenterol Hepatol 2015; 13:2088-108. [PMID: 26284592 DOI: 10.1016/j.cgh.2015.08.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 08/11/2015] [Accepted: 08/11/2015] [Indexed: 12/14/2022]
Affiliation(s)
- John M Vierling
- Departments of Medicine and Surgery, Baylor College of Medicine, Baylor-St Luke's Medical Center, Houston, Texas.
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38
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Affiliation(s)
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- EASL office, 7 Rue Daubin, CH 1203 Geneva, Switzerland,
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39
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Ytting H, Larsen FS. Everolimus treatment for patients with autoimmune hepatitis and poor response to standard therapy and drug alternatives in use. Scand J Gastroenterol 2015; 50:1025-31. [PMID: 25862144 DOI: 10.3109/00365521.2014.998271] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Not all patients with autoimmune hepatitis (AIH) respond to standard medical therapy with corticosteroids and azathioprine. Such patients may develop end-stage liver disease with poor prognosis unless transplantation is considered. Alternatively, the introduction of new therapeutic strategies could potentially ameliorate deterioration of liver function. Patients in our tertiary center were selected for everolimus therapy when exhibiting nonresponse or intolerance to combinations of the standard and empirical drugs in use (e.g., mycophenolate mofetil, calcineurin inhibitors [CNIs]). We here report the efficacy of everolimus treatment of patients with AIH. MATERIALS AND METHODS Seven patients (six female, mean age 47 years, range 22-62 years) in whom disease control could not be achieved with standard therapy or the alternative drugs in use were included. RESULTS Treatment with everolimus induced a clear reduction of transaminases within 2 weeks. After 3-5 months three patients had normal alanine aminotransferase (ALT) levels (10-45 IU) and four patients had ALT levels below 55 IU compared to a three- to fivefold elevated level prior to everolimus treatment. Sustained remission after 1 year of treatment was observed in three patients; in another two patients ALT was 45-68 U/L. Four patients in remission after 3 years were rebiopsied. Two showed no histological progression, and in two the fibrosis had decreased. Side effects noted were myalgias and minor bacterial infections not leading to discontinuation of the drug. CONCLUSION Our experience indicates that everolimus may be of value in selected patients with therapy-resistant AIH and comorbidity/side effects that excludes the use of CNIs.
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Affiliation(s)
- Henriette Ytting
- Department of Hepatology A-2121, Rigshospitalet, University of Copenhagen , Copenhagen , Denmark
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41
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Role of mycophenolate mofetil for the treatment of autoimmune hepatitis-an observational study. J Clin Exp Hepatol 2014; 4:221-5. [PMID: 25755564 PMCID: PMC4284212 DOI: 10.1016/j.jceh.2014.05.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Accepted: 05/08/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Eighty percent (80%) of patients with Autoimmune hepatitis (AIH) respond to a combination of prednisolone and Azathioprine (AZA). Choice of treatment is limited for those who do not respond to this standard therapy. We evaluated the role of Mycophenolate mofetil (MMF) as a second line therapy in AIH. METHOD A retrospective observational study was carried out on all patients who received MMF for AIH. RESULTS Twenty out of 117 patients with AIH received MMF due to AZA intolerance (18 patients) or refractory disease (2 patients). Median age of the study patients was 56 (18-79) years, Male, n = 3 (15%) and Female, n = 18 (85%). After a median follow-up period of 47 (5-83) months, 14 (73.6%) patients were still on MMF with biochemical remission, including 4 out of 5 patients with cirrhosis. One patient was lost to follow-up. Three patients were intolerant of MMF due to adverse events, and two had disease refractory to MMF. Both these patients with refractory disease to MMF were initially unresponsive to AZA therapy. CONCLUSION MMF is a safe second line agent in patients with autoimmune hepatitis including those with cirrhosis.
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42
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Casal Moura M, Liberal R, Cardoso H, Horta e Vale AM, Macedo G. Management of autoimmune hepatitis: Focus on pharmacologic treatments beyond corticosteroids. World J Hepatol 2014; 6:410-418. [PMID: 25018851 PMCID: PMC4081615 DOI: 10.4254/wjh.v6.i6.410] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 05/08/2014] [Indexed: 02/06/2023] Open
Abstract
In autoimmune hepatitis, patients who are intolerant or with toxicity experience, non-responders, relapsers or refractory are challenging. Non-standard drugs are being tried to preemptively avoid corticosteroid-related side effects. Prognosis and quality of life of life rely on treatment optimization. Recently, emergence of powerful immunosuppressive agents, mainly from liver transplantation, challenged the supremacy of the corticosteroid regime and promise greater immunosuppression than conventional medications, offer site-specific actions and satisfactory patient tolerance. Successes in experimental models of related diseases have primed these molecular interventions. We performed a literature review on alternative treatments. Azatioprine intolerance is the principal indication for mycophenolate use but it can be used as a front-line therapy. Cyclosporine A and tacrolimus have been tested for non-responders or relapsers. Rituximab may be used as salvage therapy. Anti-tumor necrosis factor-alpha agents may be used for incomplete responses or non-responders. Methotrexate is possibly an alternative for induction of remission and maintenance in refractory patients. Cyclophosphamide has been included in the induction regimen with corticosteroids. Ursodeoxycholic acid action is mainly immunomodulatory. Non-standard treatments are coming slowly to the attention, but its use should be cautious performed by experienced centers.
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43
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Czaja AJ. Review article: The prevention and reversal of hepatic fibrosis in autoimmune hepatitis. Aliment Pharmacol Ther 2014; 39:385-406. [PMID: 24387318 DOI: 10.1111/apt.12592] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 11/29/2013] [Accepted: 12/05/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Immunosuppressive treatment of autoimmune hepatitis can prevent or reverse hepatic fibrosis, but these anti-fibrotic effects are inconsistent secondary gains. AIM To describe the anti-fibrotic effects of current therapies for autoimmune hepatitis, discuss the pathogenic mechanisms of hepatic fibrosis that might be targeted by anti-fibrotic interventions, indicate the non-invasive diagnostic tests of hepatic fibrosis that must be validated in autoimmune hepatitis and to suggest promising treatment opportunities. METHODS Studies cited in PubMed from 1972 to 2013 for autoimmune hepatitis, hepatic fibrosis, cirrhosis, anti-fibrotic therapy and non-invasive tests of hepatic fibrosis were selected. RESULTS Hepatic fibrosis improves in 53-57% of corticosteroid-treated patients with autoimmune hepatitis; progressive fibrosis slows or is prevented in 79%; and cirrhosis may be reversed. Progressive hepatic fibrosis is associated with liver inflammation, and the inability to fully suppress inflammatory activity within 12 months is associated with progression to cirrhosis (54%) and death or need for liver transplantation (15%). Liver tissue examination remains the gold standard for assessing hepatic fibrosis, but laboratory and radiological tests may be useful non-invasive methods to measure the fibrotic response. Severe liver inflammation can confound radiological assessments, and the preferred non-invasive test in autoimmune hepatitis is uncertain. Individualised treatment adjustments and adjunctive anti-fibrotic therapies are poised for study in this disease. CONCLUSIONS The prevention and reversal of hepatic fibrosis are achievable objectives in autoimmune hepatitis. Strategies that evaluate individualised therapies adjusted to the rapidity and completeness of the inflammatory response, and the use of adjunctive anti-fibrotic interventions, must be evaluated.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
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44
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Abhyankar A, Tapper E, Bonder A. Immunosuppressive therapy in immune-mediated liver disease in the non-transplanted patient. Pharmaceuticals (Basel) 2013; 7:18-28. [PMID: 24380894 PMCID: PMC3915192 DOI: 10.3390/ph7010018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2013] [Revised: 12/16/2013] [Accepted: 12/24/2013] [Indexed: 02/06/2023] Open
Abstract
Autoimmune liver disease management goals are primarily slowing disease progression and symptomatic treatment. There are few options for curative medical management other than transplant for a spectrum of autoimmune liver disease that encompasses autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis as well as their overlap syndromes. These diseases are managed primarily with immunosuppressive therapy. Herein, we review the current literature, detailing the promise and pitfalls of the recommended immunosuppressive therapy for these challenging diseases.
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Affiliation(s)
- Anita Abhyankar
- Department of Medicine, St. Elizabeth's Medical Center, Tufts University School of Medicine, 736 Cambridge Street, Brighton, MA 02135, USA.
| | - Elliot Tapper
- Department of Medicine, St. Elizabeth's Medical Center, Tufts University School of Medicine, 736 Cambridge Street, Brighton, MA 02135, USA.
| | - Alan Bonder
- Department of Medicine, St. Elizabeth's Medical Center, Tufts University School of Medicine, 736 Cambridge Street, Brighton, MA 02135, USA.
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Kapila N, Higa JT, Longhi MS, Robson SC. Autoimmune Hepatitis: Clinical Review with Insights into the Purinergic Mechanism of Disease. J Clin Transl Hepatol 2013; 1:79-86. [PMID: 26356124 PMCID: PMC4521285 DOI: 10.14218/jcth.2013.00015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Revised: 10/04/2013] [Accepted: 10/15/2013] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis (AIH) is an important disorder that predominantly results in inflammatory liver disease in genetically predisposed women. The clinicopathological picture is characterized by symptoms associated with both systemic inflammation and hepatic dysfunction, and with increased serum aminotransferases, elevated IgG, autoantibodies, and interface hepatitis on liver biopsy. AIH usually results in liver injury as a consequence of chronic hepatitis and cirrhosis. However, rarely, patients may present with fulminant liver failure. Early diagnosis is important in all instances because the disease can be highly responsive to immunosuppressive therapeutic options. Left untreated, the disease is associated with high morbidity and mortality. Here we provide an overview of the current state of knowledge on AIH and summarize the treatment options for this serious condition in adults. We also discuss the pathogenesis of the disease as a possible consequence of autoimmunity and the breakdown of hepatic tolerance. We focus on regulatory T cell impairments as a consequence of changes in CD39 ectonucleotidase expression and altered purinergic signaling. Further understanding of hepatic tolerance may aid in the development of specific and well-tolerated therapies for AIH.
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Affiliation(s)
- Nikhil Kapila
- Department of Medicine, University of Connecticut, Farmington, CT, USA
- These authors contributed equally to this work
| | - Jennifer T. Higa
- Gastroenterology Division and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
- These authors contributed equally to this work
| | - Maria Serena Longhi
- Gastroenterology Division and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill, London, UK
| | - Simon C. Robson
- Gastroenterology Division and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
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Abstract
Autoimmune hepatitis is a disease of the hepatic parenchyma that can present in acute or chronic forms. In common with many autoimmune diseases, autoimmune hepatitis is associated with non-organ-specific antibodies in the context of hepatic autoimmunity. This dichotomy has made definition of a unifying hypothesis in the pathophysiology of the disease difficult, although data from the past 8 years have drawn attention to the role of regulatory T cells. Several triggers have been identified, and the disease arises in genetically susceptible individuals. Clinical and biochemical remission is achievable in up to 85% of cases. For the remaining patients, alternative immunosuppression strategies are an option. Liver transplantation provides an excellent outcome for patients with acute liver failure or complications of end-stage liver disease, including hepatocellular carcinoma. Variant or overlapping syndromes are worthy of consideration when unexpected disease features arise.
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Affiliation(s)
- Michael A Heneghan
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK.
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47
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Zachou K, Muratori P, Koukoulis GK, Granito A, Gatselis N, Fabbri A, Dalekos GN, Muratori L. Review article: autoimmune hepatitis -- current management and challenges. Aliment Pharmacol Ther 2013; 38:887-913. [PMID: 24010812 DOI: 10.1111/apt.12470] [Citation(s) in RCA: 113] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Revised: 03/22/2013] [Accepted: 08/12/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a disease of unknown aetiology characterised by interface hepatitis, hypergammaglobulinaemia, circulating autoantibodies and a favourable response to immunosuppression. AIM To review recent advancements in understanding aetiopathogenesis, clinical, serological and histological features, diagnostic criteria and treatment strategies of AIH. METHODS Published studies on AIH extracted mainly from PubMed during the last 15 years. RESULTS Autoimmune hepatitis has a global distribution affecting any age, both sexes and all ethnic groups. Clinical manifestations are variable ranging from no symptoms to severe acute hepatitis and only seldom to fulminant hepatic failure. Autoimmune attack is perpetuated, possibly via molecular mimicry mechanisms, and favoured by the impaired control of regulatory T-cells. A typical laboratory finding is hypergammaglobulinaemia with selective elevation of IgG, although in 15-25% of patients - particularly children, elderly and acute cases - IgG levels are normal. Liver histology and autoantibodies, although not pathognomonic, still remain the hallmark for diagnosis. Immunosuppressive treatment is mandatory and life-saving; however, to meet strict response criteria, the conventional therapy with prednisolone with or without azathioprine is far from ideal. CONCLUSIONS Autoimmune hepatitis remains a major diagnostic and therapeutic challenge. The clinician, the hepato-pathologist and the laboratory personnel need to become more familiar with different expressions of the disease, interpretation of liver histology and autoimmune serology. According to the strict definition of treatment response issued by the 2010 AASLD guidelines, many patients are nonresponders to conventional treatment. Newer immunosuppressive agents targeting pathogenetic mechanisms can improve patient management, which needs to be tailored on a case-by-case basis.
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Affiliation(s)
- K Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, Thessaly University, Larissa, Greece
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48
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Floreani A, Liberal R, Vergani D, Mieli-Vergani G. Autoimmune hepatitis: Contrasts and comparisons in children and adults - a comprehensive review. J Autoimmun 2013; 46:7-16. [PMID: 24035197 DOI: 10.1016/j.jaut.2013.08.004] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Revised: 08/13/2013] [Accepted: 08/14/2013] [Indexed: 12/24/2022]
Abstract
This review concentrates on autoimmune hepatitis (AIH), a liver disorder affecting both children and adults, characterized by inflammatory liver histology, elevated transaminase levels, circulating non-organ-specific autoantibodies, and increased levels of immunoglobulin G, in the absence of a known aetiology. Two types of AIH are recognized according to seropositivity: smooth muscle antibody and/or antinuclear antibody define AIH type 1, while antibodies to liver-kidney microsome type 1 and/or liver cytosol type 1 define AIH type 2. AIH type 1 affects both adults and children, while AIH type 2 is mainly a paediatric disease, though it does occasionally affects young adults. There is a female predominance in both types. AIH is particularly aggressive in children/adolescents, progressing rapidly unless immunosuppressive treatment is started promptly. With appropriate treatment 80% of patients achieve remission and long-term survival. In childhood/adolescence, sclerosing cholangitis with strong autoimmune features, including interface hepatitis and serological features identical to AIH type 1, is as prevalent as AIH, but it affects boys and girls equally. The differential diagnosis relies on cholangiographic studies. In autoimmune sclerosing cholangitis, liver parenchymal damage responds satisfactorily to immunosuppressive treatment, whereas bile duct disease progresses in 50% of cases, leading to a worse prognosis and higher transplantation requirement; it has a higher recurrence rate after transplant than AIH. AIH can arise de novo in patients transplanted for non-autoimmune liver disease. Post transplant de novo AIH affects children and adults and responds well to the same treatment schedule used for classical AIH, but not to that used for acute rejection.
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Affiliation(s)
- Annarosa Floreani
- Dept. of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Italy.
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Czaja AJ. Review article: the management of autoimmune hepatitis beyond consensus guidelines. Aliment Pharmacol Ther 2013; 38:343-64. [PMID: 23808490 DOI: 10.1111/apt.12381] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2013] [Revised: 05/30/2013] [Accepted: 06/03/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND Consensus guidelines aid in the diagnosis and management of autoimmune hepatitis, but they are frequently based on low-quality clinical evidence, conflicting experiences and divergent opinions. Recommendations may be weak, discrepant or non-existent at critical decision points. AIMS To identify the decision points where guidelines are weak or non-existent and review the evidence essential in the decision process. METHODS Full-text articles published in English using the keyword 'autoimmune hepatitis' were identified by PubMed from 1972 to 2013. Personal experience and investigations in autoimmune hepatitis also identified important contributions. RESULTS Seventy per cent of the guidelines developed by the American Association for the Study of Liver Diseases and 48% of those proposed by the British Society of Gastroenterology are based on low-quality evidence, conflicting experiences or divergent opinions. The key uncertainties in diagnosis relate to the timing of liver biopsy, recognising acute severe (fulminant) disease, interpreting coincidental nonclassical histological changes, accommodating atypical or deficient features in non-White patients, differentiating drug-induced from classical disease and identifying overlap syndromes. The key uncertainties in management relate to pre-treatment testing for thiopurine methyltransferase activity, treating asymptomatic mild disease, determining treatment end points, managing suboptimal responses, incorporating nonstandard medications as front-line and salvage agents, using azathioprine in pregnancy and instituting surveillance for hepatocellular carcinoma. CONCLUSIONS Consensus guidelines are fraught with uncertainties in the diagnosis and management of autoimmune hepatitis. Each decision point must counterbalance the current available evidence and tailor the application of this evidence to the individual patient.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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Trivedi PJ, Hirschfield GM. Treatment of autoimmune liver disease: current and future therapeutic options. Ther Adv Chronic Dis 2013; 4:119-41. [PMID: 23634279 DOI: 10.1177/2040622313478646] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Autoimmune liver disease spans three predominant processes, from the interface hepatitis of autoimmune hepatitis to the lymphocytic cholangitis of primary biliary cirrhosis, and finally the obstructive fibrosing sclerotic cholangiopathy of primary sclerosing cholangitis. Although all autoimmune in origin, they differ in their epidemiology, presentation and response to immunosuppressive therapy and bile acid based treatments. With an ongoing better appreciation of disease aetiology and pathogenesis, treatment is set ultimately to become more rational. We provide an overview of current and future therapies for patients with autoimmune liver disease, with an emphasis placed on some of the evidence that drives current practice.
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Affiliation(s)
- Palak J Trivedi
- Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK
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