Prospective study of patients with immune checkpoint inhibitor-induced hepatitis; characterization of liver injury, outcome of therapy, and management of steroid-unresponsive and steroid-dependent hepatitis
(2026) In Journal for ImmunoTherapy of Cancer 14(3).- Abstract
BackgroundImmune-related hepatitis (ir-hepatitis) ranks among the most frequent adverse events of immune checkpoint inhibitors (ICIs). Limited knowledge exists regarding the incidence, characteristics, and treatment of patients having an inadequate response to initial therapy with steroids. Characterizing ir-hepatitis phenotypes and treatment responses can provide valuable insights for guiding treatment decisions and prognosis.MethodsThis is a prospective study including patients treated with ICIs experiencing grade 3–4 ir-hepatitis. All patients received methylprednisolone 2 mg/kg for at least 72 hours and underwent liver biopsy. Ursodeoxycholic acid was added in mixed and cholestatic drug-induced liver injury (DILI) phenotypes, and... (More)
BackgroundImmune-related hepatitis (ir-hepatitis) ranks among the most frequent adverse events of immune checkpoint inhibitors (ICIs). Limited knowledge exists regarding the incidence, characteristics, and treatment of patients having an inadequate response to initial therapy with steroids. Characterizing ir-hepatitis phenotypes and treatment responses can provide valuable insights for guiding treatment decisions and prognosis.MethodsThis is a prospective study including patients treated with ICIs experiencing grade 3–4 ir-hepatitis. All patients received methylprednisolone 2 mg/kg for at least 72 hours and underwent liver biopsy. Ursodeoxycholic acid was added in mixed and cholestatic drug-induced liver injury (DILI) phenotypes, and mycophenolate mofetil (MMF) was added in patients with inadequate response to steroids. Multiplex immunohistochemistry (mIHC) for CD3, CD8, FoxP3, CD20, and CD56/NKp46 was used on liver biopsies, and single-cell RNA sequencing of peripheral blood samples was employed to characterize the immunological response.ResultsA total of 34 patients with ir-hepatitis were included, of which 20 patients (59%) responded to steroids. Six patients (18%) were steroid-unresponsive and needed MMF. Eight patients (23%) had steroid-dependent ir-hepatitis; they had an initial response to steroids but relapsed during tapering. Patients with steroid-unresponsive and steroid-dependent ir-hepatitis were treated with significantly higher accumulated steroid doses. Alcohol consumption and male sex were significantly related to inadequate response to steroids. Patients with mixed DILI had the highest steroid response rates (72%), while only half of the patients with hepatocellular and cholestatic DILI responded. Patients with cholestatic DILI had the worst prognosis concerning management of ir-hepatitis, risk of cancer progression and death.MIHC of liver biopsies revealed significantly increased T cell infiltration in ir-hepatitis, including cytotoxic, helper and regulatory T cells. Single-cell RNA sequencing of blood samples showed CD8+ effector T cell clonal expansion in a patient with steroid-unresponsive ir-hepatitis than in a steroid responder.ConclusionNearly half of patients developing ir-hepatitis had an inadequate response to steroids and needed MMF as a secondary immunosuppressant. Patients with mixed DILI were more likely to respond to steroids, while alcohol consumption was associated with inadequate steroid response. Immune analyses showed high T cell infiltration in the liver among patients with ir-hepatitis.Trial registration numberClinicalTrials.gov ID number NCT04810156 and EudraCT no. 2020-004483-26.
(Less)
- author
- organization
- publishing date
- 2026-03
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Hepatoxicity, Immune Checkpoint Inhibitor, Immune related adverse event - irAE, Immunosuppression, Immunotherapy
- in
- Journal for ImmunoTherapy of Cancer
- volume
- 14
- issue
- 3
- publisher
- BMJ Publishing Group
- external identifiers
-
- scopus:105032342174
- pmid:41786454
- ISSN
- 2051-1426
- DOI
- 10.1136/jitc-2025-013861
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © Author(s) (or their employer(s)) 2026. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See https://creativecommons.org/licenses/by-nc/4.0/.
- id
- 397a9227-4cea-439a-a544-9fa4e5e4ce84
- date added to LUP
- 2026-05-06 14:49:11
- date last changed
- 2026-07-31 03:30:15
@article{397a9227-4cea-439a-a544-9fa4e5e4ce84,
abstract = {{<p>BackgroundImmune-related hepatitis (ir-hepatitis) ranks among the most frequent adverse events of immune checkpoint inhibitors (ICIs). Limited knowledge exists regarding the incidence, characteristics, and treatment of patients having an inadequate response to initial therapy with steroids. Characterizing ir-hepatitis phenotypes and treatment responses can provide valuable insights for guiding treatment decisions and prognosis.MethodsThis is a prospective study including patients treated with ICIs experiencing grade 3–4 ir-hepatitis. All patients received methylprednisolone 2 mg/kg for at least 72 hours and underwent liver biopsy. Ursodeoxycholic acid was added in mixed and cholestatic drug-induced liver injury (DILI) phenotypes, and mycophenolate mofetil (MMF) was added in patients with inadequate response to steroids. Multiplex immunohistochemistry (mIHC) for CD3, CD8, FoxP3, CD20, and CD56/NKp46 was used on liver biopsies, and single-cell RNA sequencing of peripheral blood samples was employed to characterize the immunological response.ResultsA total of 34 patients with ir-hepatitis were included, of which 20 patients (59%) responded to steroids. Six patients (18%) were steroid-unresponsive and needed MMF. Eight patients (23%) had steroid-dependent ir-hepatitis; they had an initial response to steroids but relapsed during tapering. Patients with steroid-unresponsive and steroid-dependent ir-hepatitis were treated with significantly higher accumulated steroid doses. Alcohol consumption and male sex were significantly related to inadequate response to steroids. Patients with mixed DILI had the highest steroid response rates (72%), while only half of the patients with hepatocellular and cholestatic DILI responded. Patients with cholestatic DILI had the worst prognosis concerning management of ir-hepatitis, risk of cancer progression and death.MIHC of liver biopsies revealed significantly increased T cell infiltration in ir-hepatitis, including cytotoxic, helper and regulatory T cells. Single-cell RNA sequencing of blood samples showed CD8+ effector T cell clonal expansion in a patient with steroid-unresponsive ir-hepatitis than in a steroid responder.ConclusionNearly half of patients developing ir-hepatitis had an inadequate response to steroids and needed MMF as a secondary immunosuppressant. Patients with mixed DILI were more likely to respond to steroids, while alcohol consumption was associated with inadequate steroid response. Immune analyses showed high T cell infiltration in the liver among patients with ir-hepatitis.Trial registration numberClinicalTrials.gov ID number NCT04810156 and EudraCT no. 2020-004483-26.</p>}},
author = {{Holmstroem, Rikke Boedker and Teisner, Ane Soegaard and Sweep, Mark Wilhelmus Dirk and Noringriis, Inge Mansfield and Khan, Shawez and Aagaard, Niels Kristian and Karlström, Jacob and Jurlander, Rebecca Schou and Sohlin, Joel E. and Monberg, Tine Juul and Vestergaard, Cecilie and Stoltenborg Granhøj, Joachim and Stenbøg, Poul and Toxvaerd, Anders and Hansen, Alastair B. and Bjerring, Peter Nissen and Lorentzen, Torben and Thielsen, Peter and Bol, Kalijn and Jonsson, Goran and Ellebaek, Eva and Svane, Inge Marie}},
issn = {{2051-1426}},
keywords = {{Hepatoxicity; Immune Checkpoint Inhibitor; Immune related adverse event - irAE; Immunosuppression; Immunotherapy}},
language = {{eng}},
number = {{3}},
publisher = {{BMJ Publishing Group}},
series = {{Journal for ImmunoTherapy of Cancer}},
title = {{Prospective study of patients with immune checkpoint inhibitor-induced hepatitis; characterization of liver injury, outcome of therapy, and management of steroid-unresponsive and steroid-dependent hepatitis}},
url = {{http://dx.doi.org/10.1136/jitc-2025-013861}},
doi = {{10.1136/jitc-2025-013861}},
volume = {{14}},
year = {{2026}},
}