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Background <p>Mycophenolate mofetil (MMF) is a second-line agent for steroid-refractory immune checkpoint inhibitor-induced immune-mediated hepatotoxicity (IMH). However, the clinicopathologic characteristics and the efficacy and safety of MMF for steroid-refractory IMH are not fully understood.</p> Methods <p>This retrospective study enrolled 33 patients with pathologically diagnosed IMH by liver biopsy at Kyushu University Hospital between 2017 and 2023.</p> Results <p>Prednisolone (PSL) was administered as steroid monotherapy in 13 patients who were steroid-responsive or in combination with MMF in 10 patients who were steroid-refractory. Of the 10 steroid-refractory IMH cases, 9 eventually improved, but 1 was refractory to PSL + MMF. There were no adverse events related to MMF. Pathological evaluation revealed significantly more frequent cholangitis in the steroid-refractory group than in the steroid-responsive group [70.0% vs. 27.8%, <i>p</i> = 0.042]. The steroid-refractory IMH cases were further categorized into the MMF responder and MMF non-responder groups, according to the decreased level of alanine aminotransferase (ALT) 1&#xa0;week before and after MMF initiation. Compared with the MMF responder group, the MMF non-responder group had significantly higher number of patients with cholestatic and mixed patterns and significantly longer interval from PSL initiation to MMF initiation [29&#xa0;days (range: 21–60&#xa0;days) vs. 20&#xa0;days (range: 10–20&#xa0;days), <i>p</i> = 0.0048].</p> Conclusions <p>This study is the first to demonstrate that cholangitis is more prominent in steroid-refractory IMH. MMF is a safe and effective second-line treatment, and its early induction should be considered in patients with histological evidence of cholangitis.</p>

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Clinicopathological features of steroid-refractory immune-mediated hepatotoxicity induced by immune checkpoint inhibitors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月17日

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  • Tomonobu Hioki,
  • Koji Imoto,
  • Takeshi Goya,
  • Yuki Azuma,
  • Atsushi Horiuchi,
  • Tomomi Aoyagi,
  • Motoi Takahashi,
  • Yoshinao Oda,
  • Masaki Kato,
  • Motoyuki Kohjima,
  • Masatake Tanaka,
  • Yoshihiro Ogawa

摘要

Background

Mycophenolate mofetil (MMF) is a second-line agent for steroid-refractory immune checkpoint inhibitor-induced immune-mediated hepatotoxicity (IMH). However, the clinicopathologic characteristics and the efficacy and safety of MMF for steroid-refractory IMH are not fully understood.

Methods

This retrospective study enrolled 33 patients with pathologically diagnosed IMH by liver biopsy at Kyushu University Hospital between 2017 and 2023.

Results

Prednisolone (PSL) was administered as steroid monotherapy in 13 patients who were steroid-responsive or in combination with MMF in 10 patients who were steroid-refractory. Of the 10 steroid-refractory IMH cases, 9 eventually improved, but 1 was refractory to PSL + MMF. There were no adverse events related to MMF. Pathological evaluation revealed significantly more frequent cholangitis in the steroid-refractory group than in the steroid-responsive group [70.0% vs. 27.8%, p = 0.042]. The steroid-refractory IMH cases were further categorized into the MMF responder and MMF non-responder groups, according to the decreased level of alanine aminotransferase (ALT) 1 week before and after MMF initiation. Compared with the MMF responder group, the MMF non-responder group had significantly higher number of patients with cholestatic and mixed patterns and significantly longer interval from PSL initiation to MMF initiation [29 days (range: 21–60 days) vs. 20 days (range: 10–20 days), p = 0.0048].

Conclusions

This study is the first to demonstrate that cholangitis is more prominent in steroid-refractory IMH. MMF is a safe and effective second-line treatment, and its early induction should be considered in patients with histological evidence of cholangitis.