Efficacy of rituximab in difficult-to-manage autoimmune hepatitis: Results from the International Autoimmune Hepatitis Group
Nwe Ni Than,
James Hodson,
Daniel Schmidt-Martin,
Richard Taubert,
Rebecca E. Wawman,
Meemee Botter,
Nishant Gautam,
Kilian Bock,
Rebecca Jones,
Gautham D Appanna,
Andrew Godkin,
Aldo J. Montano-Loza,
Frank Lammert,
Christoph Schramm,
Michael P. Manns,
Mark Swain,
Kelly W. Burak,
David H. Adams,
Gideon M Hirschfield,
Ye Htun Oo
Affiliations
Nwe Ni Than
Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom; Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
James Hodson
Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
Daniel Schmidt-Martin
Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
Richard Taubert
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; European Reference Network (ERN) Rare Liver
Rebecca E. Wawman
Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom; Imperial College, London
Meemee Botter
Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom; University of Amsterdam, Netherland
Nishant Gautam
Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
Kilian Bock
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; European Reference Network (ERN) Rare Liver
Rebecca Jones
Leeds Liver Transplant Unit, St James University Hospital, Leeds, United Kingdom
Gautham D Appanna
University Hospital of Wales, Cardiff, United Kingdom
Andrew Godkin
University Hospital of Wales, Cardiff, United Kingdom
Aldo J. Montano-Loza
Division of Gastroenterology and Liver Unit, University of Alberta, Canada
Frank Lammert
Department of Medicine II, Saarland University Medical Centre, Homburg
Christoph Schramm
University Medical Centre Hamburg-Eppendorf, Hamburg, I. Department of Medicine and Martin Zeitz Centre for Rare Diseases, Germany
Michael P. Manns
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany; Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany; European Reference Network (ERN) Rare Liver
Mark Swain
Department of Medicine, Division of Gastroenterology and Hepatology, University of Calgary, Canada
Kelly W. Burak
Department of Medicine, Division of Gastroenterology and Hepatology, University of Calgary, Canada
David H. Adams
Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom; Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom; Autoimmune Liver Diseases Clinic, Centre for Rare Diseases, Institute of Translational Medicine, University of Birmingham, Birmingham, United Kingdom
Gideon M Hirschfield
University of Toronto, Canada; Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Canada
Ye Htun Oo
Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom; Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom; Autoimmune Liver Diseases Clinic, Centre for Rare Diseases, Institute of Translational Medicine, University of Birmingham, Birmingham, United Kingdom; European Reference Network (ERN) Rare Liver; Corresponding author. Address: Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, Vincent Drive, B15 2TT, Birmingham, United Kingdom. Tel: +44 121 415 8700, fax: +44 121 415 8701.
Background & Aims: Treatment options remain limited for patients with autoimmune hepatitis (AIH), while there are still concerns over the consequences of long-term corticosteroid use. A few studies have suggested a role for B cell-driven autoimmune liver injury in AIH. This multicentre, international retrospective cohort study from the International Autoimmune Hepatitis Group aims to evaluate the clinical efficacy and safety of rituximab in difficult-to-manage AIH. Methods: Clinical data from 22 patients who received rituximab between 2007 and 2017 were collected from centres in the United Kingdom, Germany and Canada. Clinical response was assessed using changes in biochemical and immunological parameters up to 24 months post-rituximab infusion. In addition, we compared the doses of prednisolone used 3 months before and 12 months after treatment, and assessed freedom from AIH flares over the post-treatment period. Results: Twenty-two patients with type-1 AIH were included, with a median age of 40 years at diagnosis (range 19–79); 15/22 (68%) were female and 18/22 (82%) were Caucasian. The median period from diagnosis to the end of follow-up in these patients was 11 years (range 3–28). Values of alanine aminotransferase, aspartate aminotransferase and albumin improved significantly following rituximab therapy, and were sustained for up to 2 years (all p ≪0.001). Prednisolone doses were significantly reduced by 12 months post-treatment (p = 0.003), with 13/21 (62%) patients having a dose reduction. Over a median post-treatment follow-up period of 6 years (range 1–10), 5 patients developed AIH flares at a median of 22 months post-treatment, giving an estimated 71% freedom from AIH flare at 2 years. Four of these patients received a second course of treatment, of whom 2 had subsequent further flares. No serious adverse events attributable to rituximab were recorded. Conclusion: In patients with difficult-to-manage AIH, rituximab appears to be clinically effective and well tolerated. Rituximab was associated with sustained improvements in serum liver tests, an absence of clinical disease flares, and a reduction in prednisolone dose. Controlled trials are warranted to further evaluate B cell-targeting therapies in patients with AIH. Lay summary: Autoimmune hepatitis is an autoimmune condition of the liver, usually treated with medications that suppress the immune system, such as steroids. However, some patients do not respond to this treatment. We analysed the safety and efficacy of rituximab in patients who were not responding to first- or second-line therapies. Rituximab was safe and improved liver blood tests in 70% of patients over a 2-year follow-up period, while enabling steroid doses to be reduced in two-thirds of patients, which is a very positive clinical outcome. Keywords: Autoimmune hepatitis, Prednisolone, Difficult-to-manage, B cell depletion therapy, Rituximab