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Abdominal pain accompanied by elevated serum inflammatory markers and biliary enzymes for diagnosing immune checkpoint inhibitor-induced sclerosing cholangitis

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Summary

Immune-related sclerosing cholangitis (irSC) is relatively rare and its clinical characteristics are not well known. In this study, we aimed to summarize the clinical features of irSC. Clinical data were collected retrospectively from 1,393 patients with advanced malignancy treated with immune-checkpoint inhibitors (ICIs) between August 2014 and October 2021. We analyzed patients with immune-related adverse events of liver injury (liver-irAEs) and compared irSC and non-irSC groups. Sixty-seven patients (4.8%) had a liver-irAE (≥ grade 3) during the follow-up period (median, 262 days). Among these, irSC was observed in eight patients (11.9%). All patients in the irSC group were treated with anti-PD-1/PD-L1 antibodies. Compared with the non-irSC group, the irSC group showed mainly non-hepatocellular liver injury (87.5 % vs 50.8 %, P = 0.065), and had elevated serum inflammatory markers (e.g., CRP and NLR) and biliary enzymes (e.g., GGTP and ALP) at the onset of liver-irAEs. Furthermore, most patients with irSC had abdominal pain. In the non-irSC group, the liver injury of 23 patients improved only with the discontinuation of ICIs, and 22 patients improved with medication including prednisolone (PSL). Conversely, almost all patients (n=7) in the irSC group were treated with PSL, but only two patients experienced an improvement in liver injury. We found that irSC is characterized by a non-hepatocellular type of liver injury with abdominal pain and a high inflammatory response and is refractory to treatment. Further examination by imaging is recommended to detect intractable irSC in cases with these characteristics.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgments

We wish to thank all those who contributed to the collection of data for this study. We also thank H. Nikki March, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Author notes

  1. Takafumi Yamamoto and Kazuyuki Mizuno are equally contributed.

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Takafumi Yamamoto, Kazuyuki Mizuno, Takanori Ito, Shinya Yokoyama, Kenta Yamamoto, Norihiro Imai, Yoji Ishizu, Takashi Honda, Takuya Ishikawa, Masatoshi Ishigami & Hiroki Kawashima

  2. Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan

    Akira Kanamori, Satoshi Yasuda & Hidenori Toyoda

  3. Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Kenji Yokota & Masashi Akiyama

  4. Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Tetsunari Hase & Makoto Ishii

  5. Department of Otorhinolaryngology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Naoki Nishio & Michihiko Sone

  6. Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan

    Osamu Maeda & Yuichi Ando

Authors
  1. Takafumi Yamamoto
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  2. Kazuyuki Mizuno
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Contributions

Concept and study design: Takafumi Yamamoto, Kazuyuki Mizuno, Takanori Ito, Takuya Ishikawa, and Masatoshi Ishigami. Data acquisition: Takafumi Yamamoto, Kazuyuki Mizuno, and Takanori Ito. Drafting of the manuscript: Takafumi Yamamoto, Kazuyuki Mizuno, Takanori Ito, and Masatoshi Ishigami. Critical revision of the manuscript for important intellectual content: Shinya Yokoyama, Kenta Yamamoto, Norihiro Imai, Yoji Ishizu, Takashi Honda, Takuya Ishikawa, Kanamori Akira, Satoshi Yasuda, Hidenori Toyoda, Kenji Yokota, Tetsunari Hase, Naoki Nishio, Osamu Maeda, Makoto Ishii, Michihiko Sone, Yuichi Ando, Masashi Akiyama, and Hiroki Kawashima. Statistical analysis: Takafumi Yamamoto, Kazuyuki Mizuno, and Takanori Ito. All the authors approved the final version of the manuscript.

Corresponding author

Correspondence to Takanori Ito.

Ethics declarations

Approval of the research protocol

This study was conducted by the tenets of the Declaration of Helsinki and approved by the Institutional Review Board of Nagoya University Hospital (no. 2018-0438).

Informed Consent

Informed consent for this study was obtained from the website of Nagoya University Hospital.

Registry and the registration no. of the study/trial

N/A.

Animal studies

N/A.

Research involving recombinant DNA

N/A.

Conflict of interest disclosure

Takanori Ito received personal fees from Chugai Pharmaceutical Co., Ltd. outside the submitted work. Masatoshi Ishigami received grants from Chugai Pharmaceutical Co., Ltd. outside the submitted work. Tetsunari Hase received grants and personal fees from AstraZeneca, grants and personal fees from Chugai Pharmaceutical Co., Ltd., personal fees from Ono Pharmaceutical Co., Ltd., personal fees from Bristol-Myers Squibb Co., and personal fees from MSD K.K, outside the submitted work. Yuichi Ando received grants and personal fees from Chugai Pharmaceutical Co.,Ltd., grants and personal fees from Kyowa Kirin Co.,Ltd., grants and personal fees from Nippon Kayaku Co., Ltd., grants and personal fees from Yakult Honsha Co.,Ltd., personal fees from Eli Lilly Japan K.K., grants and personal fees from Ono Pharmaceutical Co.,Ltd., grants and personal fees from Taiho Pharmaceutical Co.,Ltd., grants and personal fees from Novartis Pharma K.K., personal fees from Bayer Holding Ltd., personal fees from Sawai Pharmaceutical Co., Ltd, grants and personal fees from Daiichi Sankyo Company, Ltd., grants and personal fees from Eisai Co.,Ltd., personal fees from MSD K.K, personal fees from Astellas Pharma Inc., personal fees from Otsuka Holdings Co.,Ltd., personal fees from Sanwa Kagaku Kenkyusho Co., Ltd., personal fees from Hisamitsu Pharmaceutical Co., Inc., personal fees from SymBio Pharceuticals, personal fees from Aptitude Health, grants from BeiGene, Ltd, personal fees from Alfresa Pharma Corporation, outside the submitted work; . Masashi Akiyama received research grants from Ono Pharmaceutical Co., Ltd. and Taiho Pharmaceutical Co., Ltd. outside the submitted work.

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Yamamoto, T., Mizuno, K., Ito, T. et al. Abdominal pain accompanied by elevated serum inflammatory markers and biliary enzymes for diagnosing immune checkpoint inhibitor-induced sclerosing cholangitis. Invest New Drugs 41, 512–521 (2023). https://doi.org/10.1007/s10637-023-01366-3

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