Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.

Leflunomide and the Risk of Hepatotoxicity: A Review of Post-Marketing Data.

Gilbert1,  Jane L., Gelperin2,  Kate, Lee2,  Joann, Mishra2,  Poonam, Choi2,  Lauren, Brinker2,  Allen, Graham2,  David

FDA, Washington, DC


This abstract summarizes a review undertaken by FDA to evaluate the risk of hepatotoxicity in patients receiving leflunomide (LEF). LEF is an oral, disease-modifying, antirheumatic drug (DMARD), approved in the US for the treatment of rheumatoid arthritis (RA) in 1998. ACR guidelines (2008) recommend "leflunomide monotherapy for [RA] patients with all disease durations and for all degrees of disease activity...." Combination therapy with methotrexate (MTX) is "recommended for patients with intermediate or longer disease duration... as long as disease activity [is] high." The potential for LEF hepatotoxicity was noted at the time of product approval and a bolded warning describing severe liver injury with LEF as well as a recommendation to monitor serum transaminase levels every 6–8 weeks was added to the U.S. label in 2003.


Using pre-specified criteria, a comprehensive search of FDA's Adverse Event Reporting System (AERS) database was undertaken to identify post-marketing cases (US and foreign) of serious liver injury and acute liver failure (ALF) from 8/25/2002 through 5/1/2009. Additional cases reported to the Drug-Induced Liver Injury Network (DILIN), a multicentre network established to assess liver injury due to medications, were also retrieved. A multidisciplinary group of experts from the FDA, including hepatologists, adjudicated these cases based on DILIN criteria. Cases involving death and ALF were further analyzed for common features.


A total of 111 reports were identified (106 from AERS and 5 from DILIN). Many of these reports (62) were either duplicates, had insufficient information or were clearly unrelated to LEF. The remaining 49 reports (including 27 describing ALF) met criteria for the DILIN definition of severe liver injury, formed the case series, and were adjudicated. Based upon DILIN causality criteria, adjudicators classified all 27 cases of ALF (including 12 deaths and 5 liver transplants) as at least possibly associated with leflunomide. Case series analysis revealed that LEF hepatotoxicity may be rapid in onset and progress to ALF. This contrasts with MTX hepatotoxicity which usually involves chronic fibrosis or cirrhosis. Among the cases resulting in death or transplant, 88% (15 of 17) of patients were using concomitant hepatotoxic medications such as MTX, TNF inhibitors or statins. In the same group, 24% (4 of 17) had evidence of hepatitis B (active or chronic) or previous hepatitis A.


Leflunomide is approved in the US (for RA) and Europe (RA and psoriatic arthritis). It is recommended by the ACR for mono- or combination therapy. Our review shows a LEF risk for hepatoxicity which may present with rapid onset. The review further points to specific risk factors: concomitant hepatotoxic medication and pre-existing liver disease. Appropriate patient selection and careful monitoring may mitigate this risk.

To cite this abstract, please use the following information:
Gilbert, Jane L., Gelperin, Kate, Lee, Joann, Mishra, Poonam, Choi, Lauren, Brinker, Allen, et al; Leflunomide and the Risk of Hepatotoxicity: A Review of Post-Marketing Data. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :75
DOI: 10.1002/art.27844

Abstract Supplement

Meeting Menu