title: Leflunomide increases the risk of silent liver fibrosis in patients with rheumatoid arthritis receiving methotrexate.
abstract: BACKGROUND
  We identified silent liver fibrosis in patients with rheumatoid arthritis (RA) using transient elastography, and investigated medication that correlated with abnormal liver stiffness measurement (LSM) values.
  
  
  METHODS
  We consecutively enrolled 105 patients with RA taking methotrexate over 24 weeks with normal liver functions and no history of underlying chronic liver disease. Blood tests were performed, and body mass index and metabolic syndrome were assessed. We checked LSM values, and adopted 5.3 kPa as the cutoff for abnormal LSM values. The cumulative doses of medications including methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, prednisolone, meloxicam, and celecoxib were calculated.
  
  
  RESULTS
  The median age of patients (20 men and 85 women) was 52.4 years. The median LSM value was 4.7 kPa and 24 (22.9%) patients had abnormal LSM values. Gamma-glutamyltranspeptidase levels and the cumulative doses of leflunomide and prednisolone significantly correlated with LSM values (P<0.05). The cumulative dose of leflunomide, but not methotrexate, was significantly higher in patients with abnormal LSM values than that in patients with normal LSM values (P = 0.008). When RA patients receiving leflunomide plus methotrexate were classified into two groups according to the optimal cutoff cumulative dose of leflunomide (19,170 mg), abnormal LSM values were more frequently identified in patients with high cumulative dose of leflunomide (odds ratio, 12.750; P<0.001).
  
  
  CONCLUSIONS
  The cumulative dose of leflunomide was the only independent predictor of abnormal LSM values in patients with RA who had received methotrexate for more than six months.
authors.forename: Sang-Won
authors.initials: SW
authors.lastname: Lee
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Park
authors.forename: Beom Kyung
authors.initials: BK
authors.lastname: Kim
authors.forename: Kwang-Hyub
authors.initials: KH
authors.lastname: Han
authors.forename: Soo-Kon
authors.initials: SK
authors.lastname: Lee
authors.forename: Seung Up
authors.initials: SU
authors.lastname: Kim
authors.forename: Yong-Beom
authors.initials: YB
authors.lastname: Park
mesh_terms: D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D003430:Cross-Sectional Studies; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D054459:Elasticity Imaging Techniques; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000009:adverse effects* / Q000627:therapeutic use*; D000077339:Leflunomide; D008099:Liver / Q000000981:diagnostic imaging / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000175:diagnosis / Q000453:epidemiology* / Q000503:physiopathology; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D015999:Multivariate Analysis; D012307:Risk Factors
chemical_list: D018501:Antirheumatic Agents; D007555:Isoxazoles; D000077339:Leflunomide; D008727:Methotrexate