based on well described efficacy and safety studies , tocilizumab , a recombinant humanized anti - interleukin-6 monoclonal antibody , and anakinra , an interleukin-1 receptor antagonist , have been approved for the treatment of refractory rheumatoid arthritis in adults.13 both agents suppress the inflammation and cartilage degradation associated with rheumatoid arthritis , and both have been reported as safe and well tolerated for up to three years of continuous use in patients with the disease.14 tocilizumab is given intravenously on a monthly schedule and anakinra is given subcutaneously once a day.4,5 common infusion reactions include headache , nausea , flu - like symptoms , and local injection site reactions.1,2 the most severe adverse events are infections ( mainly pneumonia and upper respiratory tract infections ) , sinusitis , and diarrhea.14 sepsis and opportunistic infections , including mycobacterial infection and histoplasmosis , have occasionally been reported.13 in a large study involving 1346 patients treated with anakinra or tocilizumab , a total of 15 fatalities occurred during a three - year period . these were due to cardiac arrest , myocardial infarction , cerebro - vascular accident , ventricular fibrillation , sepsis , upper gastrointestinal hemorrhage , malignant melanoma , lymphoma , and suicide.14 liver injury in patients treated with tocilizumab and anakinra is now well recognized.13,6 increased serum transaminase and bilirubin levels are common , requiring dose adjustments or discontinuation.1,7 liver injury was resolved or alleviated in most cases following reduction of the dose of tocilizumab.7,3 in general , neither alanine transaminase elevations nor increases in bilirubin are associated with clinical evidence of hepatic decompensation.1,6,7 indeed , other etiologies are suspected in such cases , including autoimmune hepatitis , steroid - induced steatohepatitis , and other drug - induced hepatotoxicity , in particular , methotrexate.1,2,7 although adverse effects of anakinra and tocilizumab on the liver have been reported , histological evaluation of this pathology has not been reported . here we describe two patients with rheumatoid arthritis who developed hepatotoxicity on tocilizumab and anakinra . a 46-year - old woman , initially diagnosed as having rheumatoid arthritis in may 2000 , was treated with methotrexate 12.5 mg weekly for 10 years . due to progressive arthralgia and severe morning stiffness , despite lack of bony erosions , treatment with methotrexate was discontinued , and tocilizumab 8 mg / kg ( total dose 640 mg ) once monthly was instituted intravenously in january 2010 , with a good clinical response . before administration of tocilizumab , her white blood cell count was normal , hemoglobin was 14 g / dl , and platelet count was 178,000 mcl . biochemical data were within the normal range , including all liver and renal function tests . on february 12 , 2010 , a few days after the second infusion , the patient complained of extreme general weakness and fatigue . laboratory examinations at that time remained within normal limits , including liver function tests and hematological parameters . the patient consumed no alcohol and had no other risk factors , including medications for liver disease . due to ongoing severe fatigue , weakness , and findings of fatty liver and splenomegaly on initial ultrasound , a liver biopsy was performed in july 2010 . histological examination revealed focal hemorrhagic necrosis of hepatocytes , with areas of macrovesicular steatosis ( figure 1 ) . we could not find any evidence of hepatitis or other cause of hepatotoxicity to explain the findings in this patient . this case was a 49-year - old woman with a 12-year history of rheumatoid arthritis , and hypertension treated with beta- blockers , and moderate obesity ( body mass index 31 ) . she had been treated with methotrexate for five years and intermittent nonsteroidal anti - inflammatory drugs . she had been known to have nonalcoholic fatty liver disease , with consistently normal liver function tests . other than obesity , she had no other risk factors for chronic liver disease and was taking no other hepatotoxic medications . due to worsening of her rheumatoid symptoms , in particular morning stiffness and joint pain , anakinra 100 mg / day subcutaneously was instituted in november 2009 . before administration of anakinra , her complete blood count and biochemical data , including liver function tests , were all within the normal range . two months later , she developed severe fatigue , and laboratory examination at that time revealed elevated liver function tests , with aspartate aminotransferase 30 u / l , alanine aminotransferase 50 u / l , lactate dehydrogenase 584 u / l , alkaline phosphatase 161 u / l , gamma glutamyltranspeptidase 85 u / l , and normal total bilirubin and amylase . anakinra was discontinued , fatigue resolved , and liver function tests returned to normal within three weeks . a liver biopsy ( figure 2 ) revealed extensive macrovesicular steatosis ( 80% of the biopsy volume ) with focal necrosis of hepatocytes and mild infiltrate of lymphocytes around the areas of necrosis and sinusoids of the liver . we present here for the first time histological liver changes in two female patients due to biological treatment for rheumatoid arthritis . unique to the first patient treated with tocilizumab was focal hemorrhagic necrosis without cellular infiltrates . she had well documented fatty liver disease , although her liver function tests were always within normal limits . it is reasonable to assume that development of steatosis was induced by tocilizumab in the first patient , and progression from nonalcoholic fatty liver disease to nonalcoholic steatohepatitis was due to anakinra in the second patient . interesting to note was that despite the remarkable histological findings , the clinical manifestations were nonspecific , and the liver enzymes were normal in the first case and only slightly elevated in the second case . although one patient had an increased body mass index and both were exposed to steroid treatment , steatosis and steatohepatitis could also be a manifestation of hepatotoxicity . 8 the mechanism by which tocilizumab and anakinra is implicated in the pathogenesis of the fatty infiltrate formation is unclear . leptin , plasminogen activator inhibitor-1 , and insulin resistance are suggested to provide an etiopathological link.6,9,10,11 however , more studies are needed to confirm this complex mechanism . the liver is unique amongst the body organs in its ability to regenerate fully after extensive liver damage.9 hepatocyte activation requires priming by inflammatory cytokines , such as interleukin-1 , interleukin-6 , and tumor necrosis factor alpha.7,10,11 once primed , the hepatocytes respond to a number of growth factors , including hepatocyte growth factor released by stellate cells.6,12 in mice deficient in interleukin-1 and interleukin-6 , regeneration of the liver was suppressed after partial hepatectomy.9,8 therefore , interleukin-6 signaling is currently the best characterized pathway thought to be associated with hepatoprotection.10,11 tocilizumab and anakinra are anti - interleukin-6 and anti - interleukin-1 receptors that inhibit interleukin-6 and interleukin-1 signal transduction , respectively . the pathological findings suggest acute liver injury.6,12 one strange phenomenon was the absence of marked elevation of the serum aminotransferase level , suggesting that the hepatocytes had gone into apoptosis rather than necrosis or autophagic cell death , and that hepatic regeneration had been markedly suppressed by blockade of the interleukin-1 and interleukin-6 pathways.1,6,7,10,11 here we describe , for the first time , histological changes in two cases of acute liver injury due to tocilizumab and anakinra , two biological agents commonly used in the treatment of rheumatoid arthritis . drugs targeting interleukin-6 and interleukin-1 are being widely used for various other autoimmune diseases as well , and could induce severe liver injury by promoting apoptosis and inhibiting liver regeneration , as in our two cases .
elevation of liver enzymes in patients with rheumatoid arthritis treated with the biological agents , tocilizumab and anakinra , is now well documented . 
 however , histological characterization of these effects and outcomes has not been defined . here 
 we report toxic liver effects in two women with rheumatoid arthritis , refractory to all nonbiological therapies , following treatment with anakinra and tocilizumab . 
 liver biopsy in both cases showed focal necrosis of hepatocytes as a hallmark of drug toxicity , along with steatosis and early fibrosis . 
 in addition , the patient treated with anakinra demonstrated inflammatory changes . 
 tocilizumab was continued with no further deterioration in liver function . 
 withdrawal of anakinra led to rapid normalization of liver function . 
 the biological agents , tocilizumab and anakinra , may result in significant histological hepatic changes , including necrosis , but despite this , the outcome appears to be good .