Immune-mediated cholangitis: is it always nivolumab’s fault? (2024)

Dear Editors,

We read with much interest the article published by Kashima and colleagues on “Bile duct obstruction in a patient treated with nivolumab as second-line chemotherapy for advanced non-small cell lung cancer: a case report” [1].

Immune-related AEs (irAEs) affecting the biliary system on treatment with immune-oncology (I-O) agents, such PD-1/PD-L1 mAbs, are considered rare and their management remains unclear.

Recently, four cases of nivolumab-related cholangitis have been reported in the literature, including three cases of “large-duct cholangitis” [2] and one case of “small-duct cholangitis” [3]. None of the patients had a history of autoimmune disorders or IgG4-related disease and all showed a predominant elevation of alkaline phosphatase and gamma-glutamyltranspeptidase enzymes.

The three Japanese patients with “large-duct cholangitis” developed an extensive extrahepatic biliary tract dilation without obstruction that progressed during drug administration. However, a diagnosis of primitive sclerosing cholangitis could not be definitively ruled out due to lack of data on perinuclear antineutrophil cytoplasmic antibodies (pANCA).

Our case referred to as “small-duct cholangitis” did not show either intrahepatic or extrahepatic bile duct dilation and a complete serological autoimmune panel excluded any other diagnosis. However, histological findings on liver biopsies were similar in all four cases reporting a significant T cell infiltrate with a predominant CD8-positive cluster.

We first speculated on the presence of different patterns of nivolumab-related cholangitis. In our opinion, the case described by Kashima and colleagues presents several aspects that differ from those previously reported (Table1) and make a diagnosis of nivolumab-related cholangitis unlikely.

Table 1

Nivolumab-related cholangitis: case series

PatientClinical featuresLaboratory abnormality (Grade)aAutoimmune panelImagingHistological patternResponse to steroidResumption of treatment
#1 [1]

Epigastric pain

Soft stool

Fever

ALP (G4)

AST/ALT (G2)

Amylase (G2)

ND

CT: wall thickening of the gallbladder without gallstones; obstruction of the lower portion of the common bile duct

MRCP: narrowing of the common bile duct

US: wall thickening of the gallbladder

Interstitial fibrosis

Neutrophil-infiltrated atypical mucosa

GoodNo
#2 [2]

Fever

Abdominal discomfort

ALP (G3)

GGT (G3)

AST/ALT (G2)

IgG4 (−)

AMA (−)

ANA (−)

US: no obstruction; diffuse hypertrophy of gallbladder and extrahepatic bile duct

CT: extrahepatic bile duct dilation; hypertrophy of gallbladder and extrahepatic bile duct

T cell infiltration with CD8 + clusterGoodYes (with flare of biliary enzymes)
#3 [2]

Fever

Abdominal discomfort

Vomiting

Diarrhea

ALP (G3)

GGT (G3)

AST/ALT (G1)

Total bilirubin (G3)

IgG4 (−)

AMA (−)

ANA (+)

US: no obstruction; diffuse hypertrophy of extrahepatic bile duct

CT: extrahepatic bile duct dilation

ERCP/MRCP: no obstructive lesions; extrahepatic bile duct dilation

NDGoodYes (with flare of biliary enzymes)
#4 [2]

Fever

Fatigue

ALP (G4)

GGT (G3)

AST/ALT (G1)

IgG4 (−)

AMA (−)

ANA (−)

US: no obstruction; diffuse hypertrophy of extrahepatic bile duct

CT: extrahepatic bile duct dilation

ERCP: no obstruction; extrahepatic bile duct dilation

T cell infiltration with CD8 + clusterNANo
#5 [3]

Itch

Jaundice

Total bilirubin (G4)

GGT (G4)

ALP (G3)

ALT (G3)

Normal gamma-globulins

pANCA (−)

ANA (+)

SMA (−)

LKM (−)

SLA/LP (−)

LC1 (−)

Anti-MPO (−)

Anti-PR-3 (−)

US and CT: no liver metastases, no biliary tree distension, no portal thrombosis

T-lymphoid infiltrate (CD3+)

Prevalence of CD8 + infiltrates

Ductular proliferation

Bile duct aggression

Mild sinusoidal expansion without fibrosis

Mild periportal necrosis

Intraductal microabscesses

PoorNo

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GGT gamma-glutamyltranspeptidase, ALP alkaline phosphatase, ALT alanine aminotransferase, IgG4 Immunoglobulin G4, AMA anti-mitochondrial antibodies, pANCA perinuclear antineutrophil cytoplasmic antibodies, ANA antinuclear antibodies, SMA anti-smooth muscle antibodies, LKM1 liver kidney microsomal type 1 antibodies, SLA/LP soluble liver antigen/liver pancreas antibodies, LC1 liver cytosol antigen type 1 antibodies, MPO myeloperoxidase antibodies, PR-3 proteinase-3 antibodies, US ultrasound, CT computed tomography, AST aspartate aminotransferase, ERCP endoscopic cholangiopancreatography, MRCP magnetic resonance cholangiopancreatography, NA not available

aNCI-CTCAE version 4.03: National Cancer Institute Common Terminology Criteria for Adverse Events

Radiological imaging from a 64-year-old Japanese patient who received nivolumab for the treatment of advanced NSCLC was suggestive of cholecystitis without gallstones associated with an obstruction at the lower tract of the common bile duct. A significant rise in cholestatic enzymes and clinical symptoms also supported this diagnosis. Initially, the patient underwent several endoscopic procedures and was given empirical antibiotic therapy. Later, he presented with fever and bacteria were isolated from bile cultures. After antibiotic therapy, liver function tests initially improved, but later a new deterioration in biliary enzyme levels occurred. The authors then assumed that this event was to be considered as an immune-related toxicity and the patient was treated with high doses of corticosteroid. There was a rapid improvement in biliary enzyme levels and subsequent normalization of radiological imaging over the following months.

The patient provided several bile duct biopsies/cytological smears at three different time points. The histological findings were always consistent with the presence of interstitial fibrosis and neutrophil infiltration into the bile duct. These findings were different from those reported in the other cases of immunotherapy-related cholangitis in which a CD8-positive T cell infiltrate into the liver was predominant. Furthermore, histological evidence of fibrosis would suggest a chronic disease, while the presence of a neutrophil infiltrate, associated with the detection of positive bile cultures, could be more consistent with a diagnosis of infectious disease. Finally, the presence of fibrosis and the lack of any information on serum IgG4 and pANCA levels do not rule out other forms of classic autoimmune cholangitis, such as IgG4-related disease and primitive sclerosing cholangitis. Several reports of IgG4-related disease have been described in the Japanese population, all with an excellent response to corticosteroids, as for the reported case with regression of bile strictures.

In our opinion, the lack of a liver biopsy does not allow the possible co-existence of a small-duct cholangitis, as previously reported by Kawakami and colleagues, to be excluded. Furthermore, tissue available from biopsy/cytological smears from the biliary tract is very often either not diagnostic or of poor quality.

To date, nivolumab-related cholangitis has been reported as a form of severe and prolonged liver toxicity. The authors proposed the use of infliximab in steroid-refractory cases although this indication is not recommended for the management of autoimmune cholangiopathies [4, 5].

Recently, the Japanese Pharmaceutical and Medical Devices Agency included sclerosing cholangitis as a clinically significant adverse reaction, suggesting the need for a careful evaluation of every patient before starting anti-PD-1/PD-L1 agents.

Therefore, we think that baseline screening, including serum IgG4 and an autoimmune panel, as well as a careful collection of personal and family history and ethnicity, should be considered. If these risk factors are present, a cholangio-MRI should be performed before the start of anti-PD-1/PD-L1 drugs.

Finally, all suspected cases of autoimmune cholangitis mediated by I-O agents should be investigated by performing specific serum autoimmune panels, radiological imaging and liver biopsy. Considering its low prevalence, more studies are needed to better characterize this irAE.

Francesco Gelsomino

Giovanni Vitale

Andrea Ardizzoni

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

References

1. Kashima J, Okuma Y, Shimizuguchi R, Chiba K. Bile duct obstruction in a patient treated with nivolumab as second-line chemotherapy for advanced non-small-cell lung cancer: a case report. Cancer Immunol Immunother. 2018;67:61–65. doi:10.1007/s00262-017-2062-3. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

2. Kawakami H, Tanizaki J, Tanaka K, et al. Imaging and clinicopathological features of nivolumab-related cholangitis in patients with non-small cell lung cancer. Invest New Drugs. 2017;35:529–536. doi:10.1007/s10637-017-0453-0. [PubMed] [CrossRef] [Google Scholar]

3. Gelsomino F, Vitale G, D’Errico A, Bertuzzi C, Andreone P, Ardizzoni A. Nivolumab-induced cholangitic liver disease: a novel form of serious liver injury. Ann Oncol. 2017;28:671–672. doi:10.1093/annonc/mdx422.005. [PubMed] [CrossRef] [Google Scholar]

4. European Association for the Study of the Liver EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51:237–267. doi:10.1016/j.jhep.2009.04.009. [PubMed] [CrossRef] [Google Scholar]

5. Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, Jordan K, ESMO Guidelines Committee Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv119-iv142. doi:10.1093/annonc/mdx225. [PubMed] [CrossRef] [Google Scholar]

Immune-mediated cholangitis: is it always nivolumab’s fault? (2024)

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