A case series analysis of serious exacerbations of viral hepatitis and non‐viral hepatic injuries in tocilizumab‐treated patients

Abstract

Background and Aims Reports of moderate to severe liver injury associated with tocilizumab, an interleukin‐6 (IL‐6) receptor antagonist, have been reported in the post‐marketing setting. This case series aims to characterize cases of tocilizumab‐associated clinically significant hepatic injury. Methods We analysed cases of severe acute liver injury associated with tocilizumab reported in the FDA Adverse Event Reporting System and the medical literature. Results We identified 12 cases in which tocilizumab was a suspected primary cause of liver injury and eight cases in which serious sequelae of underlying or coincident viral hepatitis were temporally associated with its use. Using the Drug‐Induced Liver Injury Network (DILIN) severity scale, five of 12 cases were Grade 5 (two liver transplants, three deaths), one was Grade 4 (liver failure) and six were Grade 3 (serious events with elevated bilirubin). Two cases reported liver atrophy with low hepatocellular expression of Ki‐67, a marker of cellular proliferation. Among the eight cases of tocilizumab‐associated viral hepatitis exacerbation, three were scored as DILIN severity Grade 5 (one liver transplant, two deaths), one was Grade 4 (liver failure), and four were Grade 3. The reported viral hepatitis events were hepatitis B virus (HBV) reactivation (n = 3), hepatitis C virus (HCV) flare (n = 1), cytomegalovirus (CMV)‐induced liver failure (n = 1), Epstein‐Barr virus hepatitis (n = 1), acute hepatitis E (HEV, n = 1) and HEV‐induced macrophage activation syndrome (n = 1). Conclusion Tocilizumab may be a primary cause of severe liver injury, as well as exacerbate underlying viral hepatitis. The disruption by tocilizumab of IL‐6‐mediated immune protection and hepatocyte regeneration may aggravate clinical outcomes in some cases.

The Risk of Hepatitis B Virus Reactivation in Rheumatoid Arthritis Patients Receiving Tocilizumab: A Systematic Review and Meta-Analysis

“…As a result, the reporting of HBV reactivation in HBsAg + patients was limited. Nonetheless, cases of HBV flares, including fatal ones, have been reported in RA patients who are HBsAg + following treatment with tocilizumab [ 36 , 37 ]. In our systematic review, only three studies involving HBsAg + patients receiving TCZ were identified, with a total sample size of 25 individuals [ 17 , 23 , 35 ].…”

Successful Treatment of SARS-CoV-2 Vaccination-related Activation of Rheumatoid Arthritis with Positive Findings for Epstein-Barr Virus

“…If similar studies are conducted on EBV in the future, it may be possible to prove the direct impact of TCZ. At present, there is only one reported case of TCZ reactivation of EBV ( 24 ) in a patient with viral hepatitis. TCZ should thus be administered with caution, with consideration for its potential effects on other viruses.…”

Management of hepatitis B virus reactivation due to treatment of COVID-19

“…More data on HBVr following tocilizumab therapy exist from its established use in RA. Case reports of serious and even fatal HBV flares in HBsAg-positive patients with RA after tocilizumab have been described [ 46 , 47 ]. As such antivirals are often commenced in these patients prior to treatment, thus limiting their representation in the literature.…”