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Original article
Immunotherapy-related hepatitis: real-world experience from a tertiary centre
  1. Vincent Cheung1,
  2. Tarun Gupta1,
  3. Miranda Payne2,
  4. Mark R Middleton2,
  5. Jane D Collier3,
  6. Alison Simmons1,
  7. Paul Klenerman1,
  8. Oliver Brain1,
  9. Jeremy F Cobbold3
  1. 1 Gastroenterology, Translational Gastroenterology Unit and NIHR Oxford Biomedical Research Centre, Oxford, UK
  2. 2 Oncology, Churchill Hospital, Oxford, UK
  3. 3 Hepatology, Translational Gastroenterology Unit and NIHR Oxford Biomedical Research Centre, Oxford, UK
  1. Correspondence to Dr Vincent Cheung, Gastroenterology, Translational Gastroenterology Unit and NIHR Oxford Biomedical Research Centre, Oxford OX3 9DU, UK; vincent.cheung{at}doctors.org.uk

Abstract

Objective Immune checkpoint inhibitors like anti-programmed cell death protein 1 (PD-1) drugs Nivolumab and Pembrolizumab and anti-cytotoxic T-lymphocyte associated (CTLA-4) drug Ipilimumab have become standard of care in many metastatic cancers. Immunotherapy-related hepatitis and cholangitis present a diagnostic and management challenge, being rare and incompletely characterised. We aim to report the incidence, features and treatments used for this in a real-world setting and to identify useful biomarkers, which can be used to predict effective use of steroids.

Design Retrospective review of 453 patients started on immunotherapy over 7 years.

Setting Tertiary hepatology and oncology centre.

Patients 21 patients identified with immunotherapy-related hepatotoxicity.

Results Hepatitis was most common in those receiving dual therapy (incidence 20%), with 75% of Grade 4 hepatitis cases occurring with ipilimumab-containing regimens. Corticosteroid monotherapy is first line treatment, but doses above 60 mg OD prednisolone do not demonstrate any additional benefit in time to hepatitis resolution. The alanine transaminase (ALT) reduction in steroid-responsive hepatitis is typically rapid (with a halving of ALT within 11 days). The commencement of additional immunosuppression (typically mycophenolate) appears safe and prompts a more rapid fall in ALT than corticosteroid use alone. Infliximab was safely used twice as hepatitis treatment. We also describe one patient with rare immunotherapy-induced biliary disease.

Conclusions Vigilance is required for detection of immunotherapy-associated liver disease as, other than dual immunotherapy, we can identify no predictive factors for its development. Our data suggest that corticosteroid response is not dependent on the higher dosing regimens. Early escalation of immunosuppression may be of benefit in the absence of a rapid response to corticosteroids.

  • checkpoint inhibitor
  • hepatitis
  • immunotherapy
  • drug-induced liver injury
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Footnotes

  • VC and TG are joint first authors.

  • Correction notice This article has been corrected since it published Online First. The joint first author statement has been added.

  • Contributors VC, TG and JFC devised the article. VC, TG, JDC, MP and JFC collected the data. VC and TG analysed the data and drafted the original article. MRM, MP, AS, PK, JDC, OB, VC and JFC were involved in the management of the patients, edited the original article prior to submission and all reviewed and agreed the revised version. VC, TG and JFC wrote the responses to the Editor’s and reviewers’ comments and revised the manuscript. VC and JFC are responsible for the overall content as guarantors.

  • Funding The research was supported by funds from the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) and NIHR Research Capability Funding.

  • Disclaimer The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

  • Competing interests JFC and OB have received speaker fees from BMS. OB has received a research grant from Celgene. MRM has acted as a consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, GlaxoSmithKline, Immunocore, Lilly, Merck, Millennium, Novartis, Physiomics, Rigontec and Roche; his institution has received research grants from Abbvie, Amgen, AstraZeneca, Bristol-Myers Squibb, Clovis, Eisai, GlaxoSmithKline, Immunocore, Merck, Millennium, Novartis, Pfizer, Rigontec, Roche and Vertex.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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