Hepatic Transaminitis Associated with Anakinra Use

Anakinra is a subcutaneously administered biologic disease-modifying antirheumatic agent (DMARD), which exerts its effects by acting as a direct interleukin-1AI antagonist. While currently indicated for the treatment of rheumatoid arthritis (RA) in adults and for neonatal-onset multisystem inflammatory disease (NOMID), it is used off-label for a variety of other conditions, including steroid- and methotrexate-refractory systemic juvenile idiopathic arthritis (sJIA). While the product labeling warns about the risks of neutropenia, infection, malignancies, injection-site reactions and hypersensitivity, recent case reports have suggested that elevations in liver transaminases and hepatitis may be previously unrecognized adverse events associated with anakinra use; specifically in pediatric patients.1

The available adult literature in RA has not demonstrated an association between anakinra use and successive transaminitis. A 2008 systemic review of 101 trials by Donahue and colleagues evaluated the efficacy and safety of traditional versus biologic DMARDs in RA and established that anakinra had lower response rates compared to other biologic therapies, a three-fold higher incidence of injection site reactions compared to adalimumab and etanercept, and a 10% increase in the overall discontinuation rate compared to etanercept and infliximab. Elevations in liver function tests (LFTs) were not observed.2 Additionally, a prospective open-label trial conducted in 1346 adults with RA treated with anakinra (and possible concomitant adjunct therapies) by Fleischmann et al, validated the adverse event profile noted in the product labeling, but did not mention any LFT abnormalities.3 These findings have been consequently echoed by the completion of a Cochrane Review on the subject in 2009.4

However, in 2011, Mahamid published the case of a 49 year old woman with RA who received 5 years of methotrexate therapy and intermittent corticosteroid pulses and subsequently developed elevations of her AST to 30 units/L, ALT to 50 units/L, LDH to 584 units/L, ALKP to 161 units/L and GGT to 85 units/L with normal bilirubin and amylase two months after initiating anakinra therapy. A biopsy revealed extensive micro-vesicular steatosis, mild lymphocytic infiltration and some sinusoidal necrosis. Discontinuation of anakinra lead to LFT normalization within 3 weeks.5

In 2009, Canna reported three cases of acute hepatitis in pediatric patients age 13 months to 8 years old undergoing sJIA therapy with anakinra. One patient received methotrexate within a month of starting anakinra while two had been exposed to corticosteroids in the month prior anakinra therapy. All developed transaminitis and abdominal pain. This was followed by jaundice in two patients. Acute hepatitis was diagnosed between 44 to 205 days after anakinra initiation. Furthermore, two patients had direct hyperbilirubinemia without elevations in their cholestatic enzymes (lipase and amylase). Biopsies revealed a mixed infiltrative process without hemophagocytosis and no coagulopathies were present, effectively ruling out sJIA-associated macrophage activation syndrome. Discontinuation of the drug lead to resolution of each patients hepatitis and two were successfully restarted on the drug without further complications after failing other therapies.6 Currently this is the only available information suggesting anakinra may precipitate hepatic transaminitis and subsequent acute hepatitis in children.

The limited available evidence suggests that pediatric patients may be more susceptible to iatrogenic hepatic adverse events secondary to anakinra therapy. Though yet to be confirmed in a randomized trial or systematic review, current case literature suggests a possible link between anakinra and ALT, AST, and direct bilirubin elevations leading to hepatitis in the weeks following initiation of the drug. While exceedingly rare, consideration should be given to discontinue anakinra in patients who develop signs and symptoms of acute hepatitis without any other known cause or precipitous events.

References:1. SOBI. Ki erect Package Insert. Revised 12/20122. Donahue, KE. Ann Intern Med.2008;148(2):124-1343. Fleischmann, RM. Ann Rheum Dis.2006 August;65(8): 10061012.4. Mertens, M. The Journal of Rheumatology 2009; 36:65. Mahamid, M. Int J Gen Med.2011;4: 657660.6. Canna, S. Pediatr Rheumatol Online J.2009;7: 21