Case of severe liver damage after the induction of tocilizumab therapy for rheumatoid vasculitis

Abstract

A 71-year-old male patient was diagnosed with rheumatoid arthritis (RA) in 2000. Various disease-modifying anti-rheumatic drugs (DMARDs) and an anti-tumor necrosis factor biologic etanercept were administrated, but were unable to control the disease activity of RA. He was then diagnosed with rheumatoid vasculitis and received a total of 3 courses of an anti-interleukin-6 receptor antibody, tocilizumab. After the 3 courses of tocilizumab therapy, ascites and renal dysfunction gradually appeared and he was admitted to our hospital. Biochemical data suggested that he had developed decompensated liver cirrhosis. His renal function deteriorated rapidly, and he died 9 days after the admission. Serum aminotransferase levels had been relatively low during the treatment with tocilizumab, however, autopsy showed marked atrophy of the liver. Immunohistochemical analysis revealed that the hepatocytes had fallen into apoptosis and that hepatic regeneration had been extremely suppressed. Although molecular target drugs such as tocilizumab are being widely used and are important emerging treatment options in adult patients with moderate to severe RA, these drugs could induce liver failure by inhibiting liver regeneration as in this case. Physicians need to stay alert to the impact of these drugs on liver regeneration and should follow up with ultrasonography or computed tomography.

Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2012: Table 1

“…Liver test abnormalities have been documented within the TCZ clinical trials (category A/D evidence156 163 165 174 176 181 182 199 203 204 220–222). Cases have been reported of TCZ-induced hepatic failure (category D evidence223). …”

Tocilizumab-Induced Acute Liver Injury in Adult Onset Still’s Disease

“…Mahamid et al and Hiura et al reported each a case with rather sub acute evolution over months leading in the first case to histological focal pericentral vein hepatocellular necrosis and steatosis [ 14 ]. In the second one, of note a lethal case, marked liver atrophy and ascites were observed with no focal necrosis but mild inflammatory cell infiltration and little periportal fibrosis at histology [ 15 ]. Interestingly, liver enzymes were normal or only slightly elevated, and supplementary immunohistochemical analysis in the second case revealed a high amount of cleaved caspase 3 antigen positive hepatocytes, suggesting rather apoptosis than necrosis at the origin of liver injury [ 15 ].…”

“…In the second one, of note a lethal case, marked liver atrophy and ascites were observed with no focal necrosis but mild inflammatory cell infiltration and little periportal fibrosis at histology [ 15 ]. Interestingly, liver enzymes were normal or only slightly elevated, and supplementary immunohistochemical analysis in the second case revealed a high amount of cleaved caspase 3 antigen positive hepatocytes, suggesting rather apoptosis than necrosis at the origin of liver injury [ 15 ]. The authors hypothesized that the poor outcome could be due to IL-6 inhibition, a cytokine involved with liver regeneration [ 4 ].…”

Erhöhte Leberwerte bei einem Rheumapatienten. Was nun?

“…Bei einer großen Untersuchung ist dies in 0,06 von 100 Patientenjahren der Fall [21]. Leichte Transaminasenanstiege sind häufig, aber auch schwere Hepatitiden sind unter den berichteten Zwischenfällen [22,23]. Für den B-Zelldepletor Rituximab und den T-Zell-Kostimulationshemmer Abatacept wurden bisher keine schweren Leberreaktionen publiziert, das letztere wurde sogar als Ausweichpräparat bei Adalimumab-induzierter Hepatitis vorgeschlagen [24].…”