A Case Series Analysis of Serious Exacerbations of Viral Hepatitis and Non-viral Hepatic Injuries in Tocilizumab-treated Patients.

Biehl, Ann; Harinstein, Lisa; Brinker, Allen; Glaser, Rachel; Munoz, Monica; Avigan, Mark

Reports of moderate to severe liver injury associated with tocilizumab, an interleukin-6 (IL-6) receptor antagonist, have been reported in the postmarketing setting. This case series aims to characterize cases of tocilizumab-associated clinically significant hepatic injury. We analyzed cases of severe acute liver injury associated with tocilizumab reported in the FDA Adverse Event Reporting System (FAERS) and the medical literature. We identified 12 cases in which tocilizumab was a suspected primary cause of liver injury and 8 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, 5 of 12 cases were Grade 5 (2 liver transplants, 3 deaths), 1 was Grade 4 (liver failure), and 6 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 8 cases of tocilizumab-associated viral hepatitis exacerbation, 3 were scored as DILIN Severity Grade 5 (1 liver transplant, 2 deaths), 1 was Grade 4 (liver failure), and 4 were Grade 3. The reported viral hepatitis events were Hepatitis B virus reactivation (n=3), Hepatitis C virus flare (n=1), Cytomegalovirus-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). 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.