Systematic Reviews
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 21, 2020; 26(3): 353-365
Published online Jan 21, 2020. doi: 10.3748/wjg.v26.i3.353
Programmed cell death-1 inhibitor-related sclerosing cholangitis: A systematic review
Takumi Onoyama, Yohei Takeda, Taro Yamashita, Wataru Hamamoto, Yuri Sakamoto, Hiroki Koda, Soichiro Kawata, Kazuya Matsumoto, Hajime Isomoto
Takumi Onoyama, Yohei Takeda, Taro Yamashita, Wataru Hamamoto, Yuri Sakamoto, Hiroki Koda, Soichiro Kawata, Hajime Isomoto, Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori prefecture 683-8504, Japan
Kazuya Matsumoto, Internal Medicine, Irisawa Medical Clinic, Shimane prefecture 690-0025, Japan
Author contributions: Onoyama T and Takeda Y contributed equally to the work; Matsumoto K and Isomoto H conceptualized and designed the review together with Onoyama T; Onoyama T, Yamashita T, Koda H, Hamamoto W, Sakamoto Y and Kawata S carried out the analysis; Onoyama T drafted the initial manuscript; all authors reviewed and approved the final manuscript as submitted.
Conflict-of-interest statement: All the authors declare that they have no competing interests.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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 and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Takumi Onoyama, MD, PhD, Doctor, Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago, Tottori prefecture 683-8504, Japan. golf4to@yahoo.co.jp
Received: November 23, 2019
Peer-review started: November 23, 2019
First decision: December 23, 2019
Revised: January 7, 2020
Accepted: January 11, 2020
Article in press: January 11, 2020
Published online: January 21, 2020
Processing time: 54 Days and 0.7 Hours
Abstract
BACKGROUND

Programmed cell death-1 (PD-1) inhibitor has been indicated for many types of malignancies. However, these inhibitors also cause immune-related adverse events. Hepatobiliary disorder is a phenotype of immune-related adverse event affecting 0%–4.5% of patients treated with PD-1 inhibitors. Recent studies have reported PD-1 inhibitor-related sclerosing cholangitis (SC); however, the associated clinical and pathological features are unclear.

AIM

To evaluate the clinical and pathological features of PD-1 inhibitor-related SC through a systematic review of the literature.

METHODS

The review, conducted using electronic databases in PubMed, was restricted to the period from January 2014 to September 2019 and focused on case reports/series on PD-1 inhibitor-related SC published in English. We scanned the references of the selected literature to identify any further relevant studies. Six cases previously studied by us, including three that have not yet been published, were included in this review.

RESULTS

Thirty-one PD-1 inhibitor-related SC cases were evaluated. Median age of patients was 67 years (range, 43–89), with a male to female ratio of 21:10. The main disease requiring PD-1 inhibitor treatment was non-small cell lung cancer. Agents that caused PD-1 inhibitor-related SC were nivolumab (19 cases), pembrolizumab (10 cases), avelumab (1 case), and durvalumab (1 case). The median number of cycles until PD-1 inhibitor-related SC onset was 5.5 (range, 1–27). Abdominal pain or discomfort (35.5%, 11/31) was the most frequent symptom. Blood serum tests identified liver dysfunction with a notable increase in biliary tract enzymes relative to hepatic enzymes, and a normal level of serum immunoglobulin G4. Biliary dilation without obstruction (76.9%, 20/26), diffuse hypertrophy of the extrahepatic biliary tract (90.5%, 19/21), and multiple strictures of the intrahepatic biliary tract (30.4%, 7/23) were noted. In 11/23 (47.8%) cases, pathological examination indicated that CD8+ T cells were the dominant inflammatory cells in the bile duct or peribiliary tract. Although corticosteroids were mainly used for PD inhibitor-related SC treatment, the response rate was 11.5% (3/26).

CONCLUSION

Some clinical and pathological features of PD-1 inhibitor-related SC were revealed. To establish diagnostic criteria for PD-1 inhibitor-related SC, more cases need to be evaluated.

Keywords: Nivolumab; Pembrolizumab; Avelumab; Durvalumab; Atezolizumab; Programmed cell death-1 inhibitor; Immune-related adverse events; Cholangitis

Core tip: This study systematically reviewed the literature on the programmed cell death-1 inhibitor-related sclerosing cholangitis. Biliary dilation without obstruction, diffuse hypertrophy of the extrahepatic biliary tract and/or multiple strictures of intrahepatic biliary tract, liver dysfunction with a notable increase in biliary tract enzymes relative to hepatic enzymes, normal level of the serum immunoglobulin G4, and a moderate to poor response to steroid therapy, and CD8+ T cell infiltration in the biliary tract were clinical and pathological features of programmed cell death-1 inhibitor-related sclerosing cholangitis.