Systematic Reviews Open Access
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, 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
ORCID number: Takumi Onoyama (0000-0003-0310-0720); Yohei Takeda (0000-0003-1096-5909); Taro Yamashita (0000-0003-2726-3356); Wataru Hamamoto (0000-0003-2220-9916); Yuri Sakamoto (0000-0001-9682-6410); Hiroki Koda (0000-0003-4000-6899); Soichiro Kawata (0000-0002-2194-0582); Kazuya Matsumoto (0000-0002-5680-4791); Hajime Isomoto (0000-0001-8998-7865).
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.

Key Words: 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.



INTRODUCTION

The programmed cell death-1 (PD-1) receptor is expressed on activated T cells, whereas the programmed cell death-ligand 1 (PD-L1) is overexpressed on specific types of cancer cells. When bound by PD-L1, PD-1 causes the suppression of T cell cytotoxic immune responses. This repression pathway is an essential immune prevention mechanism from host immunity and is upregulated in many malignant tumors and their surrounding microenvironment[1]. Recently, developments in immunotherapy have demonstrated efficacy for the treatment of various malignancies. PD-1 inhibitors were also indicated for many types of malignancies, such as non-small cell lung cancer, melanoma, Hodgkin lymphoma, renal cell cancer, bladder cancer, gastric cancer, and esophageal cancer[2-12]. Moreover, pembrolizumab has been indicated for solid carcinoma with mismatch repair deficiency[13,14]. Therefore, many patients with malignant disease will be treated with a PD-1 inhibitor. Although PD-1 inhibitors are beneficial for the treatment of malignancies, it has been noted that immune-related adverse events (irAEs) result from dysregulation of the host immune system[15]. Hepatobiliary disorders are irAEs that affect 0%–4.5% of patients treated with PD-1 inhibitors[16-18]. Recently, PD-1 inhibitor-related sclerosing cholangitis (SC) and its clinical features have been reported[19,20]. However, the diagnostic criteria for PD-1 inhibitor-related SC have not been clarified. We also have experience of six cases of suspected of PD-1 inhibitor-related SC.

The objective of this work was to perform a systematic review of cases of PD-1 inhibitor-related SC, and to evaluate the clinical and imaging features of PD-1 inhibitor-related SC.

MATERIALS AND METHODS
Literature search strategy

We identified relevant studies in the literature by searching the databases of PubMed. The review was restricted to the period from January 2014 to September 2019 and focused on case reports or case series with PD-1 inhibitor-related SC that were published in English. The search terms consisted of the words [“Programmed cell death 1” (All Fields) and “cholangitis” (All Fields)], [“Programmed cell death ligand 1” [All Fields] AND “cholangitis” (All Fields)], [“Nivolumab”(All Fields) and “cholangitis” (All Fields)], [“Pembrolizumab” (All Fields) and “cholangitis” (All Fields)], [“Cemplimab” (All Fields) and “cholangitis” (All Fields)], [“Atezolizumab” (All Fields) and “cholangitis” (All Fields)], [“Avelumab” (All Fields) and “cholangitis” (All Fields)], and [“Durvalumab” (All Fields) and “cholangitis” (All Fields)]. We also read the reference lists of the selected studies to manually identify further relevant studies.

Articles were excluded from this review if: (1) The article was a review, basic research, commentary, or clinical study; (2) The study had insufficient information and descriptions; and (3) The full text was unavailable.

We have also investigated six cases of PD-1 inhibitor-related SC, three of which have not yet been published. We have included these three cases in this case review.

RESULTS

The process of the literature selection is presented in Figure 1. The literature search of the databases of PubMed identified 70 studies that met the search terms. We found an additional three relevant articles in the references of those studies. After the removal of duplicate studies, we evaluated 56 studies by screening the titles and abstracts to check that they met the search criteria. Consequently, we excluded 20 basic research studies, 3 review articles, 3 editorial letters, and 10 clinical studies. Moreover, two studies were case reports about same patient with PD-1 inhibitor-related SC; therefore, one of these studies was excluded. Finally, 19 studies, which included 5 case series and 14 case reports, were assessed in this review[19-37]. One case series reported 10 patients with hepatobiliary disorder caused by PD-1 inhibitors, which included two patients with PD-1 inhibitor-related SC[37]. With the inclusion of our three cases, a total of 31 cases of PD-1 inhibitor-related SC were evaluated.

Figure 1
Figure 1 PRISMA 2009 Flow diagram describing the selection of the studies reporting programmed cell death-1 inhibitor-related cholangitis for our review.

The characteristics of patients with PD-1 inhibitor-related SC are shown in Tables 1-3. The median age at the onset of PD-1 inhibitor-related SC was 67 years (range, 43–89). PD-1 inhibitor-related SC appeared to be more prevalent in men, with a male-to-female ratio of 21:10. The patients’ primary diseases that were an adaptation disease for the treatment of PD-1 inhibitor were non-small cell lung cancer (20 cases), melanoma (4 cases), gastric cancer (3 cases), bladder cancer (2 cases), small cell lung cancer (1 case), and epithelioid mesothelioma (1 case). The 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 onset of PD-1 inhibitor-related SC was 5.5 (range, 1–27). Abdominal pain or discomfort (35.5%, 11/31) was the most frequent symptom, followed by fever (19.4%, 6/31) and jaundice (12.9%, 4/31). Eight patients did not have any symptoms, but did have liver dysfunction (25.8%, 8/31). The median levels of total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase were 0.75 mg/dL (range, 0.3–15.9), 129.0 U/L (range, 49–961), 125.0 U/L (range, 31–1536), 1543.0 U/L (range, 237–5066), and 452.0 U/L (range, 114–2094), respectively. Of the 13 patients tested for immunoglobulin G4 (IgG4), almost all patients were negative (92.3%, 12/13).

Table 1 Demographic characteristics of patients with programmed cell death-1 inhibitor-related sclerosing cholangitis.
Patient characteristicsValue
Age, median (range, yr)67.0 (43–89)
Sex, male/female21/10
Primary disease
NSCLC20
Melanoma4
GC3
BC2
SCLC1
Epithelioid mesothelioma1
Drugs
Nivolumab19
Pembrolizumab10
Avelumab1
Durvalumab1
Atezolizumab0
Treatment cycles until onset5.5 (1–27)
Symptoms
Abdominal pain or discomfort11
Fever6
Jaundice4
Vomiting2
Appetite loss2
Diarrhea or soft stool2
Skin disorder2
General fatigue1
Backache1
None (liver dysfunction)8
Liver functional test
T-Bil, median (range, mg/dL)0.75 (0.3–15.9)
AST, median (range, U/L)129.0 (49–961)
ALT, median (range, U/L)125.0 (31–1536)
ALP, median (range, U/L)1543.0 (237–5066)
GGT, median (range, U/L)452.0 (114–2094)
Serological test
IgG, median (range, U/L)1230.0 (1050-1789)
IgA, median (range, U/L)297.5 (199-474.4)
IgM, median (range, U/L)64.0 (38-94)
IgG4, ≥ 135 U/L / < 135 U/L1/12
Antinuclear antibody, ≥ 40 / < 407/12
Imaging findings
Biliary stenosis8
Intrahepatic bile duct3
Extrahepatic bile duct1
Multiple4
Absence15
Biliary dilation
Presence/Absence20 / 6
Hypertrophy of the biliary tract20
Diffuse19
Gallbladder1
Absence1
Pathological findings
Liver15
Inflammation15
Biliary or peribiliary tract14
-CD 8+ T cells dominant8
Lobular hepatitis2
Bile duct8
Inflammation8
-CD 8+ T cells dominant2
Gallbladder2
Inflammation2
-CD 8+ T cells dominant1
Therapy
Corticosteroid26
UDCA13
MMF6
Tacrolimus1
Bezafibrate1
Response to steroid therapy
Good3
Moderate15
Poor8
Table 2 Baseline characteristics of cases of programmed cell death-1 inhibitor-related sclerosing cholangitis.
CaseRef.AgeSexPrimary diseaseDrugCycles until onsetSymptoms
1Gelsomino et al[21]79MNSCLCNivolumab4Itching, jaundice
2Kawakami et al[19]64MNSCLCNivolumab9Fever, abdominal discomfort
3Kawakami et al[19]73FNSCLCNivolumab6Fever, vomiting, abdominal discomfort, diarrhea
4Kawakami et al[19]82FNSCLCNivolumab12Fever, general fatigue
5Kashima et al[22]63MNSCLCNivolumab24Epigastric pain, soft stool
6Doherty et al[23]49FMelanomaPembrolizumab1Jaundice
7Doherty et al[23]59FMelanomaNivolumab3None (liver dysfunction)
8Doherty et al[23]76Mepithelioid mesotheliomaPembrolizumab1Jaundice
9Cho et al[24]69MNSCLCAvelumab21Right upper abdominal discomfort
10Hamoir et al[25]71MNSCLCNivolumabNA (11 mo)None (liver dysfunction)
11Kuraoka et al[26]69MNSCLCNivolumab3Pruritic rash, liver dysfunction
12Ogawa et al[27]73MMelanomaPembrolizumabNA (3 mo)None (liver dysfunction)
13Kono et al[28]69FGCNivolumab2Jaundice
14Noda-Narita et al[29]57FNSCLCNivolumabNA (12 mo)Abdominal pain
15Sawada et al[30]76MGCNivolumab4None (liver dysfunction)
16Tallec et al[31]56FNSCLCNivolumab16 (9 mo)Myalgia, skin thickening
17Oda et al[32]43MGCNivolumab1Fever, tachycardia, appetite loss, malaise
18Koya et al[33]66MSCLCPembrolizumab5Epigastric pain
19Fouchard et al[34]52MNSCLCNivolumab8Abdominal pain
20Fouchard et al[34]NAMNSCLCDurvalumab (+ tremelimumab)4Fever, abdominal pain
21Fouchard et al[34]61MNSCLCPembrolizumab17None (liver dysfunction)
22Cǎlugǎreanu et al[35]43FMelanomaNivolumab27Epigastralgia, anorexia,
23Anderson et al[36]67MNSCLCNivolumab8Right upper abdominal pain
24Zen et al[37]68MNSCLCPembrolizumabNA (5.5 mo)Abdominal pain, vomiting
25Zen et al[40]67MNSCLCPembrolizumabNA (1 mo)Fever, malaise
26Our case61MBCPembrolizumab5Fever
27Our case89MBCPembrolizumab4None (liver dysfunction)
28Our case63MNSCLCPembrolizumab7None (liver dysfunction)
29Our case55MNSCLCNivolumab11Abdominal pain
30Our case81FNSCLCNivolumab25Backache
31Our case82FNSCLCNivolumab2None (liver dysfunction)
Table 3 Clinical, imaging, and pathological findings of cases of programmed cell death-1 inhibitor-related sclerosing cholangitis.
CaseT-Bil/AST/ALT/ALP/GGT/IgG4Biliary stenosis /dilationHypertrophy of biliary tractPathological findingsTreatment (Dosage)Steroid response
1Grade 4/NA/Grade 3; Grade 3/Grade 4/NANANALiver: CD8+ T cells infiltration in bile ductmPSL (1 mg/kg), + UDCA (15 mg/kg)Moderate
20.7/142/144; 1769/902/normal-/+DiffuseLiver: CD8+ and CD4+ T cells infiltration in Glisson’s capsulePSL (0.5 mg/kg)Poor
33.8/89/101; 1947/804/normal-/+DiffuseNAPSL (0.5 mg/kg), Biliary drainageModerate
40.8/108/70; 2996/813/normal-/+DiffuseLiver: CD8+ and CD4+ T cells infiltration in Glisson’s capsuleBiliary drainage-
5NA/88/92; 1543/NA/NADistal bile duct/+DiffuseBile duct: Interstitial fibrosis, neutrophils infiltration in mucosaPSL (2 mg/kg) Biliary drainageModerate
6NA/961/1536; 237/2094/NANA/-NALiver: Severe steatohepatitis, absence of bile ducts1st PSL (1 mg/kg), 2nd PSL + UDCA (NA) + MMF (2 g)Poor
7NA/NA/>300; >1000/NA/NANANALiver: Degenerative bile duct atypia and periductal fibrosis1st PSL (1 mg/kg), 2nd PSL + UDCA (NA)Poor
8NA/NA/>500; >700/NA/NANANALiver: Attenuated bile duct, cellular and canalicular cholestasis in parenchymamPSL (2 mg/kg) + cholestyramine (NA) + MMF (1 g) + UDCA (NA)Poor
90.6/Grade 1/Grade 1; Grade 2/Grade 2/NA-/+DiffuseNAmPSL (1 mg/kg)Moderate
10Normal/129/135; 558/984/NAMultiple/-NoneLiver: CD8+ T cell infiltration in the periportal zone and cholangitismPSL (0.5 mg/kg), + UDCA (10 mg/kg)Good
11NA/NA/NA; NA/NA/NA-/+DiffuseBile duct: Inflammatory cells and lymphocytes infiltration in epithelium1st PSL (60 mg), 2nd mPSL (500 mg)Poor
12NA/58/77; 1111/461/NAMultiple/+DiffuseBile duct: Destruction of epithelium, fibrosis with CD8+ T cell infiltration in submucosaDiscontinuation of Pembrolizumab-
1315.9/454/NA; 5066/NA/20.2Intrahepatic bile duct/-Gall bladderNABiliary drainage-
14NA/NA/NA; 1065/304/normal-/+DiffuseNAUDCA (300 mg)-
150.8/69/68; 2427/252/41.0-/+NALiver: Eosinophil, CD8+, and CD4+ T cell infiltration in the portal tract. Eosinophil infiltration in the epithelial linings of the bile ductPSL (0.5 mg/kg), + UDCA (NA)Good
16Normal/272/516; 615/442/NANADiffuseNACorticosteroid (NA)Good
173.7/49/31; 598/151/90-/-NALiver: CD8+ T cells and macrophage infiltration in bile duct1st PSL (1 mg/kg), 2nd m PSL (1 g), 3rd PSL + MMF (2 g)Poor
181.1/313/296; 2241/868/normalIntrahepatic bile duct/+DiffuseLiver: CD8+ T cell and eosinophil infiltration in the periportal zones, Bile duct: CD8+ T cell infiltration and fibrosis in submucosa1st UDCA (900 mg) + bezafibrate (400 mg), 2nd m PSL (0.5 g) followed by PSL (1 mg/kg), Biliary drainagePoor
19Normal/>100/>100; >900/>500/NA-/+NAGall bladder: Inflammatory cell infiltrationPSL (0.5 mg/kg) + UDCA (NA), CholecystectomyModerate
20NA/>100/>300; >800/>1700/normal-/+NAGall bladder: CD8+ T cell infiltrationPSL (120 mg) + UDCA (NA), CholecystectomyModerate
21Normal/NA/>100; >400/>1400/NANANANAPSL (1 mg/kg)Moderate
22Normal/52/126; 545/1007/NAMultiple/+NALiver: CD3+ and CD8 T cell infiltration in the bile ductPSL (1 mg/kg)Moderate
23NA/>300/NA; 793/NA/NAMultiple/+DiffuseLiver: Fibrosis and inflammation in the portal tract, lobular inflammation, mild macrovesicular steatosismPSL (NA) following PSL (50 mg), MMF (NA), Tacrolimu (NA)sPoor
240.5/67/68; 2107/279/59NA/-DiffuseLiver: Cholangiopathologic change, CD8/CD4 ratio 12:7, Bile duct: Lymphocyte, eosinophil and plasma cell infiltrationPSL (50 mg)Moderate
251.2/198/233; 1540/332/78NA/-DiffuseLiver: Lobular hepatitis with cholangiopathic change, CD8/CD4 ratio 17:2PSL (40 mg)Moderate
260.3/91/65; 1683/159/80.4-/+DiffuseBile duct: Inflammatory cell infiltrationPSL (1 mg/kg) + UDCA (600 mg)Moderate
270.4/245/124; 1245/114/352-/+DiffuseBile duct: Neutrophil and lymphocyte infiltrationUDCA (600 mg)-
280.6/184/254; 1783/452/128-/+DiffuseBile duct: Inflammatory cell infiltrationPSL (1 mg/kg) + UDCA (600 mg)Moderate
290.3/64/245; 1328/448/67.3Intrahepatic bile duct/+DiffuseNAmPSL (2 mg/kg) + MMF (2 g)Moderate
301.3/284/248; 3029/1070/NA-/+DiffuseNAmPSL (2 mg/kg) + MMF (2 g), Biliary drainageModerate
310.7/294/85; 4635/829/NA-/+DiffuseLiver: Lymphocyte infiltration in Glisson’s capsule, hydropic degeneration of hepatocytesmPSL (1.6 mg/kg)Moderate

Biliary stenosis occurred in 8 patients (34.8%, 8/23); 7 had stenosis in the intrahepatic biliary tract, which included 4 patients with multiple strictures in the biliary tract. Biliary dilation was observed in 20 patients (76.9%, 20/26). Twenty patients had hypertrophy of the biliary tract (95.2%, 20/21), of which 19 cases were diffuse (Figure 2).

Figure 2
Figure 2 Our cases with sclerosing cholangitis caused by nivolumab (Case 29, A–C; Case 30, D–F; Case 31, G–J). A, D: Computed tomography; G, H: Magnetic resonance imaging; B, E, I: Endoscopic ultrasonography. Revealed diffuse hypertrophy of biliary tract (yellow allows) in all cases. C, F: Endoscopic retrograde cholangiopancreatography revealed biliary stenosis of the intrahepatic bile duct (arrow-head) in Case 30. J: In Case 31, liver biopsy showed lymphocyte infiltration in Glisson’s capsule (black arrow).

Peroral cholangioscopy was performed in only 5 cases[26,33,38]. Multiple scarred lesions and band-like narrowing were found in 4 patients, and 2 patients with PD-1 inhibitor-related SC showed diverticulum-like outpouching[33,38]. Ulcerative lesions with many black spots (e.g., “burned-out” epithelium) and yellow plaque were found in 1 patient[26].

In total, 23 patients underwent pathological evaluation; of these, 15 patients underwent liver biopsy. Fourteen patients had inflammatory changes in the bile duct and/or peribiliary tract, and CD8+ T cells were dominant in the inflammatory cells in 8 of these patients (53.3%, 8/15). Lobular hepatitis was found in 2 patients (13.3%, 2/15).

Transpapillary biopsy of the biliary tract with biopsy forceps was performed for 8 patients, and these pathological findings revealed Inflammatory cells infiltration in the bile duct. In 2 patients, CD8+ T cells were the dominant inflammatory cells in the bile duct.

Of the 6 patients that underwent biliary drainage, 5 did not respond.

Corticosteroids were the main treatment for PD inhibitor-related SC (83.8%, 26/31). Only 3 patients who the levels of liver and biliary enzymes were improved to normal level with steroid therapy, so that the response rate to corticosteroids was 11.5% (3/26). Eight patients with PD-1 inhibitor-related SC had poor response, no improvement of liver and biliary enzymes, to steroid therapy. In 15 patients who received steroid therapy, the levels of liver and biliary enzymes were improved, although normalization of enzyme activities was not achieved (i.e. only a moderate response occurred).

DISCUSSION

PD-1/PD-L1 inhibitors are used widely for the treatment of many types of malignancies. However, irAEs, including cardiac, respiratory, endocrine, gastrointestinal, musculoskeletal, skin, and, importantly, hepatobiliary disorders, were also reported[15-18]. However, the reasons for the occurrence of irAEs, including cholangitis, are unclear, although it may involve the T cell, antibody, and cytokine responses[39].

Gelsomino et al[20,21] reported the first case of PD-1 inhibitor-related SC; subsequently, this group and Kawakami et al[19] suggested the clinical features of PD-1 inhibitor-related SC. However, PD-1 inhibitor-related SC is still not well known. Kawakami et al[19] reported SC related to the PD-1 inhibitor nivolumab was characterized by: (1) Localized extrahepatic bile duct dilation without obstruction; (2) Diffuse hypertrophy of the extrahepatic bile duct wall; (3) A dominant increase in the biliary tract enzymes alkaline phosphatase and gamma-glutamyl transpeptidase relative to hepatic enzymes aspartate aminotransferase and alanine aminotransferase; (4) Normal or reduced levels of the serum immunological markers, such as antinuclear antibody, antimitochondrial antibody, smooth muscle antibody, and IgG4; (5) The pathological finding of biliary tract CD8+ T cell infiltration from liver biopsy; and (6) A moderate to poor response to steroid therapy. In our study, some clinical features, such as biliary dilation without obstruction, diffuse hypertrophy of the extrahepatic biliary tract, liver dysfunction with a dominant increase in the biliary tract enzymes relative to hepatic enzymes, normal level of serum IgG4, and a moderate to poor response to steroid therapy, were similar to those reported by Kawakami et al[19]. In contrast, Gelsomino et al[20] suggested that there were different types of PD-1 inhibitor-related SC, such as large duct cholangitis and small ducts cholangitis, and that those types have different clinical presentation and biochemical evolution and were associated with various outcomes. Indeed, in our case review, 15 patients had diffuse extrahepatic biliary hypertrophy without biliary stenosis (extrahepatic type). Three patients had multiple stenoses, especially in the intrahepatic bile duct, without extrahepatic biliary hypertrophy (intrahepatic type). Moreover, four patients had diffuse biliary tract hypertrophy with multiple stenoses of the intrahepatic and extrahepatic bile ducts (diffuse type). The clinical implications of these types of PD-1 inhibitor-SC is uncertain, but may be clarified by more cases in the future.

Zen et al[40] reported that CD8+ T lymphocytes were the predominant infiltrates in the bile duct of patients with PD-1 inhibitor-related SC, similar to hepatic irAEs. Moreover, they reported the clinical features and detailed pathological findings of 10 cases of hepatobiliary disorders caused by PD-1 inhibitors. In that study, the ratio of CD8+ to CD4+ cells was significantly higher than that in autoimmune hepatitis or idiosyncratic drug-induced liver injury[37]. Although CD8+ T cell infiltration is one of the clinical features of irAEs, in the pathological findings of PD-1 inhibitor-related SC, CD8+ T cells were not necessarily dominant, especially in the bile duct biopsy. Other inflammatory cells, such as eosinophils, neutrophils, plasma cells, and macrophages, were also observed in the biliary tract. Although this finding may be used for auxiliary diagnosis for PD-1 inhibitor-SC, it may not always be observable.

In general, steroid therapy was recommended for the treatment of irAEs[41,42], however, corticosteroids were not useful for the treatment of PD-1 inhibitor-related SC. Although four patients received high-dose steroid therapy (methylprednisolone, 500–1000 mg/d), a good response was not shown. Therefore, at least in our study, steroid therapy was not recommended for the treatment of PD-1 inhibitor-related SC. However, the response to steroid therapy may be dependent on the type of PD-1 inhibitor-related SC, as described above. Although 15 patients with extrahepatic and diffuse type PD-1 inhibitor-related SC received steroid therapy in our case review, a good response occurred only in one case (6.7%, 1/15). Meanwhile, only two patients with intrahepatic type PD-1 inhibitor-related SC received steroid therapy: One patient’s liver function was improved and the other had a moderate response, with a response ratio of 1:1. This finding is still uncertain in a few cases.

Ursodeoxycholic acid (UDCA) was used for treatment of PD-1 inhibitor-related SC in 13 patients. Two patients received only UDCA, with discontinuation of nivolumab, and displayed a moderate response. In contrast, no response was found in the single patient who received UDCA with bezafibrate. Seven patients received combination therapy of steroids and UDCA. The response rate to that therapy was 28.6% (2/7). Three patients received steroid therapy first; when no improvement was observed, UDCA was added and a moderate response was observed in these patients. Although the efficacy was insufficient, UDCA was considered a treatment for PD-1 inhibitor-related SC owing to the low rate of adverse events[43].

Other anti-inflammatory agents, including immunomodulators or infliximab were sometimes considered to using for treatment of irAEs[44]. Tacrolimus, an immunomodulator, was also used for one case of PD-1 inhibitor-related SC; however, the response was insufficient. Infliximab was used for some irAEs, such as colitis and pneumonitis. In our case review, infliximab was not used for the treatment of PD-1 inhibitor-related SC. More cases may be needed to evaluate the usefulness of these drugs for PD-1 inhibitor-related SC.

This study had some limitations. First, there are no current diagnostic criteria for PD-1 inhibitor-related SC. Second, some clinical cases, for which blood test data, image findings, and pathological evaluation were not presented, were included in this study. Therefore, our study may include different diseases that cause sclerosing cholangitis.

In conclusion, some clinical features of PD-1 inhibitor-related SC, such as biliary dilation without obstruction, diffuse hypertrophy of the extrahepatic biliary tract and/or multiple strictures of intrahepatic biliary tract, liver dysfunction with a dominant increase in biliary tract enzymes relative to hepatic enzymes, normal level of serum IgG4, and a moderate-to-poor response to steroid therapy, were revealed, although there were many unsolved questions in our study. To establish the diagnostic criteria for PD-1 inhibitor-related SC, more cases, for which clinical data including hepatobiliary enzymes, immunological marker, image findings, and pathological evaluation were presented clearly, need to be evaluated. Although CD8+ T cell infiltration is one of the pathological features of PD-1 inhibitor-related SC, it is not enough to exclude different diseases that cause sclerosing cholangitis. We will have to find more specific features of PD-1 inhibitor-related SC.

ARTICLE HIGHLIGHTS
Research background

Programmed cell death-1 (PD-1) inhibitor has been indicated for many types of malignancies. On the other hands, these inhibitors cause immune-related adverse events (irAEs). Hepatobiliary disorder is a phenotype of irAEs that affect 0%–4.5% of patients treated with PD-1 inhibitors.

Research motivation

Recently, PD-1 inhibitor-related sclerosing cholangitis (SC), one of the irAEs, have been reported. However, the clinical and pathological features of PD-1 inhibitor-related SC are uncertain.

Research objectives

The objective of this study to evaluate the clinical and pathological features of PD-1 inhibitor-related SC through a systematic review of the literature.

Research methods

We conducted an electronic search through databases of PubMed. The review 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. The reference lists of the identified papers were also scanned to find out further relevant studies. Six cases previously studied by us, including three that have not yet been published, were included in this review.

Research results

Thirty-one PD-1 inhibitor-related SC cases were evaluated. 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. Liver dysfunction with a notable increase in biliary tract enzymes relative to hepatic enzymes, and a normal level of serum IgG4 were shown in blood serum test. 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. CD8+ T cells were the dominant inflammatory cells in the bile duct or peribiliary tract in 11/23 (47.8%) cases. The response rate of corticosteroids for PD inhibitor-related SC was 11.5% (3/26).

Research conclusions

Some clinical features of PD-1 inhibitor-related SC, such as biliary dilation without obstruction, diffuse hypertrophy of the extrahepatic biliary tract and/or multiple strictures of intrahepatic biliary tract, liver dysfunction with a dominant increase in biliary tract enzymes relative to hepatic enzymes, normal level of serum IgG4, and a moderate-to-poor response to steroid therapy, were revealed.

Research perspectives

To establish the diagnostic criteria for PD-1 inhibitor-related SC, more cases, for which clinical data including hepatobiliary enzymes, immunological marker, image findings, and pathological evaluation were presented clearly, need to be evaluated. We will have to find more specific features of PD-1 inhibitor-related SC.

ACKNOWLEDGEMENTS

We wish to thank to our colleagues in the Departments of Gastroenterology and Hepatology, and Pathology at Tottori University Faculty of Medicine (Tottori, Japan).

Footnotes

Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: Japan

Peer-review report classification

Grade A (Excellent): 0

Grade B (Very good): B

Grade C (Good): C

Grade D (Fair): 0

Grade E (Poor): 0

P-Reviewer: Uhlmann D, Yang L S-Editor: Zhang L L-Editor: A E-Editor: Xing YX

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