Pembrolizumab-Induced Delayed-Onset Hepatitis

Abstract

Hepatitis is one of the serious immune-related adverse events (irAEs). However, delayed-onset hepatitis induced by immune-checkpoint inhibitors (ICIs) is rare, and the histopathological features remain to be clarified. A 65-year-old woman with advanced lung adenocarcinoma in the right upper lobe (cT4N3M1c, c-stage IVB) received four courses of pembrolizumab. Her hepatic and biliary tract enzyme levels started increasing 2 months after the final administration of pembrolizumab, and the elevated levels of these enzymes prolonged. Liver biopsy revealed panlobular infiltration of inflammatory cells, and most of the infiltrating inflammatory cells were lymphocytes; however, there were a small number of neutrophils, eosinophils, and plasma cells. There was no confluent necrosis. Furthermore, immunohistochemical analyses proved that infiltrating lymphocytes were predominantly CD3-positive (CD3+) and CD8+, and few CD20+ and CD4+ lymphocytes were observed. Based on these findings, she was diagnosed with a case of hepatitis as an irAE. Administration of prednisolone (0.5 mg/kg/day) as well as the addition of azathioprine failed to suppress the deterioration. However, an increase in the dose of prednisolone (up to 1 mg/kg/day) enabled us to control hepatitis. This case showed that hepatitis can occur even after discontinuation of ICIs, and that liver biopsy may be useful in the diagnosis. Clinicians should not hesitate to perform liver biopsy for confirmation of the diagnosis.

Delayed immune-related sclerosing cholangitis after discontinuation of pembrolizumab: A case report

“…Recently, new reports of irAEs emerging after discontinuation of immunotherapy, a clinical diagnostic complex termed delayed immune-related events (DIRE), have surfaced[ 9 ]. The first case of DIRE after discontinuation of pembrolizumab was reported in 2013[ 10 ], and various late-onset irAEs have also been reported in the literature[ 11 ]. Anti-PD-1 antibodies continue to bind to lymphocytes several weeks after the last infusion of PD-1 inhibitors, which explains the development of irAEs after discontinuation of ICI therapy[ 12 ].…”

Peripheral absolute eosinophil count identifies the risk of serious immune-related adverse events in non-small cell lung cancer

“…The research from Nakamura et al in melanoma showed that the occurrence of endocrine irAEs was positively linked to baseline eosinophil counts (39). Multiple studies analyzing tissue biopsy samples from patients with hepatic irAEs have found massive infiltration of inflammatory cells, primarily CD8+ T lymphocytes and eosinophils (40)(41)(42)(43). Similarly, an autopsy analysis of a melanoma patient with multiple irAEs showed a marked increase of CD8+ T lymphocytes in involved organs such as the heart, brain, and lungs (6,44).…”

Immune checkpoint inhibitor (ICI)-induced hepatitis diagnosed by liver biopsy followed by ICI-free chemotherapy leading to therapeutic effect: A case of lung cancer treatment

“…AIH and irAE hepatitis can be distinguished by immunostaining of lymphocytes [ 6 , [9] , [10] , [11] ]. AIH has predominantly CD20 + and CD4 + lymphocytes, whereas irAE has predominantly CD3 + and CD8 + lymphocytes [ 9 , [12] , [13] , [14] , [15] , [16] ].…”