Immune-related adverse events in hepatitis treated with thiopurine-based immunosuppressants: A case report

Our plain-English summary of Immune-related adverse events in hepatitis treated with thiopurine-based immunosuppressants: A case report, by K. Kawakado, K. Nakashima, H. Tobita, et al (Thoracic Cancer, 2023).

The study

• Authors: K. Kawakado, K. Nakashima, H. Tobita, M. Nagase, K. Yoshihara, M. Horie, M. Hamaguchi, T. Okimoto, Y. Tsubata, T. Isobe
• Journal: Thoracic Cancer
• Published: 2023;14(13):1208-1211
• Type of article: Case report
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

An 82-year-old man was treated with ipilimumab and nivolumab for malignant pleural mesothelioma. Although he was previously treated with prednisolone (1 mg/kg/day) for immune-related adverse event (irAE) hepatitis by a previous doctor, he still had worsening liver function and was transferred to our hospital. Blood tests and imaging findings were negative for autoimmune and infectious hepatitis, and liver biopsy results were consistent with irAE hepatitis. Steroid pulse therapy improved liver function, but tapering to prednisolone (1 mg/kg/day) again worsened his liver function. Concomitant use of mycophenolate mofetil was initiated, but no improvement in liver function was observed, therefore azathioprine, a thiopurine immunosuppressant, was administered in combination with steroids. During the course of treatment, hepatic dysfunction due to azathioprine was suspected, and the concomitant use of mercaptopurine and prednisolone was started. Afterward, the liver function improved, and the prednisolone dose was gradually reduced to 10 mg/day. This is a rare case in which a thiopurine-based immunosuppressant was effective against irAE hepatitis, therefore thiopurine-based immunosuppressants may be effective against steroid-refractory hepatitis.

© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

In plain English

This article was a case report about one 82-year-old man in Japan with malignant pleural mesothelioma. He developed hepatitis (liver inflammation) as an immune-related side effect of the cancer drugs ipilimumab and nivolumab. On day 15 of treatment his liver tests were severely abnormal (AST 529 U/L, ALT 499 U/L). Prednisolone 60 mg/day did not help, and jaundice developed. Tests for viral and autoimmune hepatitis were negative, and a liver biopsy was consistent with immune-related hepatitis. High-dose steroid pulses improved his liver tests, but they worsened again as steroids were lowered. Adding mycophenolate mofetil did not bring improvement. Adding azathioprine was followed by improvement. Because of concern that azathioprine itself might injure the liver, the doctors switched to mercaptopurine. His liver tests kept improving (AST 26 U/L, ALT 44 U/L), and prednisolone was reduced to 10 mg/day. The authors concluded that thiopurine-based drugs may be effective against steroid-resistant hepatitis of this kind. They said the exact mechanism was unknown. The report did not discuss asbestos.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: case report (one patient)
• Who was studied: One 82-year-old man with malignant pleural mesothelioma (cT1N1M0, cStage II), treated at Shimane University Faculty of Medicine, Izumo, Japan
• Exposure: Not an asbestos exposure study. The exposure was cancer immunotherapy with ipilimumab plus nivolumab, which was followed by immune-related hepatitis. Treatments for the hepatitis were prednisolone, methylprednisolone pulses, mycophenolate mofetil, azathioprine and mercaptopurine.
• Main results:
  • On the 15th day after starting ipilimumab and nivolumab, the patient had grade 4 liver dysfunction (AST 529 U/L, ALT 499 U/L).
  • After 1 week of prednisolone 60 mg/day, liver function had not improved (AST 434 U/L, ALT 727 U/L), and grade 3 jaundice developed.
  • Tests for viral hepatitis and autoantibodies suggesting autoimmune hepatitis were negative.
  • The liver biopsy findings were consistent with immune-related hepatitis.
  • After steroid pulse therapy and reduction of prednisolone to 60 mg, transaminase levels rose again (AST 293 U/L, ALT 1115 U/L).
  • Mycophenolate mofetil 2000 mg/day was added, but liver function did not improve, so steroid pulse therapy was repeated.
  • Azathioprine 100 mg/day was added, and liver function then improved.
  • Because of concern about liver injury from azathioprine, the doctors switched to mercaptopurine 30 mg/day.
  • Afterward, liver function continued to improve (AST 26 U/L, ALT 44 U/L), and prednisolone was tapered to 10 mg/day.
• The authors' conclusion: The authors concluded that thiopurine-based immunosuppressants may be effective against steroid-refractory immune-related hepatitis. They described this as, to their knowledge, the first report of such improvement using mercaptopurine together with prednisolone.
• Limitations the authors state:
  • The authors stated that the exact mechanism by which the thiopurine drugs worked was unknown.

Topics

Medical terms in this study, explained in our Lexicon: Immune-Related Adverse Events, Ipilimumab (Yervoy), Nivolumab (Opdivo), Pleural Mesothelioma, Biopsy.

Related studies

• Correlation between immune-related adverse events and therapeutic effects of nivolumab in patients with malignant pleural mesothelioma — H. Yoneda, H. Nokihara, et al. (2021)
• Early severe immune-related pneumonitis, hepatitis, and agranulocytosis with radiographic response in sarcomatoid malignant pleural mesothelioma treated with nivolumab and ipilimumab: a case report highlighting dual liver biopsies and rechallenge decision-making — T. Oba, K. Itogawa, et al. (2025)
• The association between aspirin use and immune-related adverse events in specific cancer patients receiving ICIs therapy: analysis of the FAERS database — H. Yang, Z. Liu, et al. (2023)
• Registry study of immune-related adverse events using electronic patient-reported outcome in patients with cancer receiving immune checkpoint inhibitors: protocol for a multicentre cohort study — T. Hirata, T. Kawaguchi, et al. (2023)
• Thrombocytopenia as an Immune-Related Adverse Event in Malignant Pleural Mesothelioma: A Case Report — T. Tanaka, S. Asakura, et al. (2022)
• Remarkable Antitumor Effects and Serious Multiple Immune-Related Adverse Events in Malignant Pleural Mesothelioma: Two Case Reports — K. Harada, H. Irie, et al. (2025)

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