Programmed cell death-1 inhibitor-related sclerosing cholangitis: A systematic review

Table 1 Demographic characteristics of patients with programmed cell death-1 inhibitor-related sclerosing cholangitis

Patient characteristics	Value
Age, median (range, yr)	67.0 (43–89)
Sex, male/female	21/10
Primary disease
NSCLC	20
Melanoma	4
GC	3
BC	2
SCLC	1
Epithelioid mesothelioma	1
Drugs
Nivolumab	19
Pembrolizumab	10
Avelumab	1
Durvalumab	1
Atezolizumab	0
Treatment cycles until onset	5.5 (1–27)
Symptoms
Abdominal pain or discomfort	11
Fever	6
Jaundice	4
Vomiting	2
Appetite loss	2
Diarrhea or soft stool	2
Skin disorder	2
General fatigue	1
Backache	1
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/L	1/12
Antinuclear antibody, ≥ 40 / < 40	7/12
Imaging findings
Biliary stenosis	8
Intrahepatic bile duct	3
Extrahepatic bile duct	1
Multiple	4
Absence	15
Biliary dilation
Presence/Absence	20 / 6
Hypertrophy of the biliary tract	20
Diffuse	19
Gallbladder	1
Absence	1
Pathological findings
Liver	15
Inflammation	15
Biliary or peribiliary tract	14
-CD 8+ T cells dominant	8
Lobular hepatitis	2
Bile duct	8
Inflammation	8
-CD 8+ T cells dominant	2
Gallbladder	2
Inflammation	2
-CD 8+ T cells dominant	1
Therapy
Corticosteroid	26
UDCA	13
MMF	6
Tacrolimus	1
Bezafibrate	1
Response to steroid therapy
Good	3
Moderate	15
Poor	8

NSCLC: Non-small cell lung cancer; SCLC: Small cell lung cancer; GC: Gastric cancer; BC: Bladder cancer; MCC: Merkel cell carcinoma; RPC: Renal pelvis cancer; T-Bil: Total bilirubin; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyl transpeptidase; IgG: Immunoglobulin G; IgA: Immunoglobulin A; IgM: Immunoglobulin M; IgG4: Immunoglobulin G4; Mpsl: Methylprednisolone; PSL: Prednisolone; UDCA: Ursodeoxycholic acid; MMF: Mycophenolate mofetil.

Table 2 Baseline characteristics of cases of programmed cell death-1 inhibitor-related sclerosing cholangitis

Case	Ref.	Age	Sex	Primary disease	Drug	Cycles until onset	Symptoms
1	Gelsomino et al[21]	79	M	NSCLC	Nivolumab	4	Itching, jaundice
2	Kawakami et al[19]	64	M	NSCLC	Nivolumab	9	Fever, abdominal discomfort
3	Kawakami et al[19]	73	F	NSCLC	Nivolumab	6	Fever, vomiting, abdominal discomfort, diarrhea
4	Kawakami et al[19]	82	F	NSCLC	Nivolumab	12	Fever, general fatigue
5	Kashima et al[22]	63	M	NSCLC	Nivolumab	24	Epigastric pain, soft stool
6	Doherty et al[23]	49	F	Melanoma	Pembrolizumab	1	Jaundice
7	Doherty et al[23]	59	F	Melanoma	Nivolumab	3	None (liver dysfunction)
8	Doherty et al[23]	76	M	epithelioid mesothelioma	Pembrolizumab	1	Jaundice
9	Cho et al[24]	69	M	NSCLC	Avelumab	21	Right upper abdominal discomfort
10	Hamoir et al[25]	71	M	NSCLC	Nivolumab	NA (11 mo)	None (liver dysfunction)
11	Kuraoka et al[26]	69	M	NSCLC	Nivolumab	3	Pruritic rash, liver dysfunction
12	Ogawa et al[27]	73	M	Melanoma	Pembrolizumab	NA (3 mo)	None (liver dysfunction)
13	Kono et al[28]	69	F	GC	Nivolumab	2	Jaundice
14	Noda-Narita et al[29]	57	F	NSCLC	Nivolumab	NA (12 mo)	Abdominal pain
15	Sawada et al[30]	76	M	GC	Nivolumab	4	None (liver dysfunction)
16	Tallec et al[31]	56	F	NSCLC	Nivolumab	16 (9 mo)	Myalgia, skin thickening
17	Oda et al[32]	43	M	GC	Nivolumab	1	Fever, tachycardia, appetite loss, malaise
18	Koya et al[33]	66	M	SCLC	Pembrolizumab	5	Epigastric pain
19	Fouchard et al[34]	52	M	NSCLC	Nivolumab	8	Abdominal pain
20	Fouchard et al[34]	NA	M	NSCLC	Durvalumab (+ tremelimumab)	4	Fever, abdominal pain
21	Fouchard et al[34]	61	M	NSCLC	Pembrolizumab	17	None (liver dysfunction)
22	Cǎlugǎreanu et al[35]	43	F	Melanoma	Nivolumab	27	Epigastralgia, anorexia,
23	Anderson et al[36]	67	M	NSCLC	Nivolumab	8	Right upper abdominal pain
24	Zen et al[37]	68	M	NSCLC	Pembrolizumab	NA (5.5 mo)	Abdominal pain, vomiting
25	Zen et al[40]	67	M	NSCLC	Pembrolizumab	NA (1 mo)	Fever, malaise
26	Our case	61	M	BC	Pembrolizumab	5	Fever
27	Our case	89	M	BC	Pembrolizumab	4	None (liver dysfunction)
28	Our case	63	M	NSCLC	Pembrolizumab	7	None (liver dysfunction)
29	Our case	55	M	NSCLC	Nivolumab	11	Abdominal pain
30	Our case	81	F	NSCLC	Nivolumab	25	Backache
31	Our case	82	F	NSCLC	Nivolumab	2	None (liver dysfunction)

NSCLC: Non-small cell lung cancer; SCLC: Small cell lung cancer; GC: Gastric cancer; BC: Bladder cancer; NA: Not available.

Table 3 Clinical, imaging, and pathological findings of cases of programmed cell death-1 inhibitor-related sclerosing cholangitis

Case	T-Bil/AST/ALT/ALP/GGT/IgG4	Biliary stenosis /dilation	Hypertrophy of biliary tract	Pathological findings	Treatment (Dosage)	Steroid response
1	Grade 4/NA/Grade 3; Grade 3/Grade 4/NA	NA	NA	Liver: CD8+ T cells infiltration in bile duct	mPSL (1 mg/kg), + UDCA (15 mg/kg)	Moderate
2	0.7/142/144; 1769/902/normal	-/+	Diffuse	Liver: CD8+ and CD4+ T cells infiltration in Glisson’s capsule	PSL (0.5 mg/kg)	Poor
3	3.8/89/101; 1947/804/normal	-/+	Diffuse	NA	PSL (0.5 mg/kg), Biliary drainage	Moderate
4	0.8/108/70; 2996/813/normal	-/+	Diffuse	Liver: CD8+ and CD4+ T cells infiltration in Glisson’s capsule	Biliary drainage	-
5	NA/88/92; 1543/NA/NA	Distal bile duct/+	Diffuse	Bile duct: Interstitial fibrosis, neutrophils infiltration in mucosa	PSL (2 mg/kg) Biliary drainage	Moderate
6	NA/961/1536; 237/2094/NA	NA/-	NA	Liver: Severe steatohepatitis, absence of bile ducts	1st PSL (1 mg/kg), 2nd PSL + UDCA (NA) + MMF (2 g)	Poor
7	NA/NA/>300; >1000/NA/NA	NA	NA	Liver: Degenerative bile duct atypia and periductal fibrosis	1st PSL (1 mg/kg), 2nd PSL + UDCA (NA)	Poor
8	NA/NA/>500; >700/NA/NA	NA	NA	Liver: Attenuated bile duct, cellular and canalicular cholestasis in parenchyma	mPSL (2 mg/kg) + cholestyramine (NA) + MMF (1 g) + UDCA (NA)	Poor
9	0.6/Grade 1/Grade 1; Grade 2/Grade 2/NA	-/+	Diffuse	NA	mPSL (1 mg/kg)	Moderate
10	Normal/129/135; 558/984/NA	Multiple/-	None	Liver: CD8+ T cell infiltration in the periportal zone and cholangitis	mPSL (0.5 mg/kg), + UDCA (10 mg/kg)	Good
11	NA/NA/NA; NA/NA/NA	-/+	Diffuse	Bile duct: Inflammatory cells and lymphocytes infiltration in epithelium	1st PSL (60 mg), 2nd mPSL (500 mg)	Poor
12	NA/58/77; 1111/461/NA	Multiple/+	Diffuse	Bile duct: Destruction of epithelium, fibrosis with CD8+ T cell infiltration in submucosa	Discontinuation of Pembrolizumab	-
13	15.9/454/NA; 5066/NA/20.2	Intrahepatic bile duct/-	Gall bladder	NA	Biliary drainage	-
14	NA/NA/NA; 1065/304/normal	-/+	Diffuse	NA	UDCA (300 mg)	-
15	0.8/69/68; 2427/252/41.0	-/+	NA	Liver: Eosinophil, CD8+, and CD4+ T cell infiltration in the portal tract. Eosinophil infiltration in the epithelial linings of the bile duct	PSL (0.5 mg/kg), + UDCA (NA)	Good
16	Normal/272/516; 615/442/NA	NA	Diffuse	NA	Corticosteroid (NA)	Good
17	3.7/49/31; 598/151/90	-/-	NA	Liver: CD8+ T cells and macrophage infiltration in bile duct	1st PSL (1 mg/kg), 2nd m PSL (1 g), 3rd PSL + MMF (2 g)	Poor
18	1.1/313/296; 2241/868/normal	Intrahepatic bile duct/+	Diffuse	Liver: CD8+ T cell and eosinophil infiltration in the periportal zones, Bile duct: CD8+ T cell infiltration and fibrosis in submucosa	1st UDCA (900 mg) + bezafibrate (400 mg), 2nd m PSL (0.5 g) followed by PSL (1 mg/kg), Biliary drainage	Poor
19	Normal/>100/>100; >900/>500/NA	-/+	NA	Gall bladder: Inflammatory cell infiltration	PSL (0.5 mg/kg) + UDCA (NA), Cholecystectomy	Moderate
20	NA/>100/>300; >800/>1700/normal	-/+	NA	Gall bladder: CD8+ T cell infiltration	PSL (120 mg) + UDCA (NA), Cholecystectomy	Moderate
21	Normal/NA/>100; >400/>1400/NA	NA	NA	NA	PSL (1 mg/kg)	Moderate
22	Normal/52/126; 545/1007/NA	Multiple/+	NA	Liver: CD3+ and CD8 T cell infiltration in the bile duct	PSL (1 mg/kg)	Moderate
23	NA/>300/NA; 793/NA/NA	Multiple/+	Diffuse	Liver: Fibrosis and inflammation in the portal tract, lobular inflammation, mild macrovesicular steatosis	mPSL (NA) following PSL (50 mg), MMF (NA), Tacrolimu (NA)s	Poor
24	0.5/67/68; 2107/279/59	NA/-	Diffuse	Liver: Cholangiopathologic change, CD8/CD4 ratio 12:7, Bile duct: Lymphocyte, eosinophil and plasma cell infiltration	PSL (50 mg)	Moderate
25	1.2/198/233; 1540/332/78	NA/-	Diffuse	Liver: Lobular hepatitis with cholangiopathic change, CD8/CD4 ratio 17:2	PSL (40 mg)	Moderate
26	0.3/91/65; 1683/159/80.4	-/+	Diffuse	Bile duct: Inflammatory cell infiltration	PSL (1 mg/kg) + UDCA (600 mg)	Moderate
27	0.4/245/124; 1245/114/352	-/+	Diffuse	Bile duct: Neutrophil and lymphocyte infiltration	UDCA (600 mg)	-
28	0.6/184/254; 1783/452/128	-/+	Diffuse	Bile duct: Inflammatory cell infiltration	PSL (1 mg/kg) + UDCA (600 mg)	Moderate
29	0.3/64/245; 1328/448/67.3	Intrahepatic bile duct/+	Diffuse	NA	mPSL (2 mg/kg) + MMF (2 g)	Moderate
30	1.3/284/248; 3029/1070/NA	-/+	Diffuse	NA	mPSL (2 mg/kg) + MMF (2 g), Biliary drainage	Moderate
31	0.7/294/85; 4635/829/NA	-/+	Diffuse	Liver: Lymphocyte infiltration in Glisson’s capsule, hydropic degeneration of hepatocytes	mPSL (1.6 mg/kg)	Moderate

T-Bil: Total bilirubin; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyl transpeptidase; IgG4: Immunoglobulin G4; mPSL: Methylprednisolone; PSL: Prednisolone; UDCA: Ursodeoxycholic acid; MMF: Mycophenolate mofetil; AZA: Azathioprine; NA: Not available.