Ann Rheum Dis doi:10.1136/ard.2008.101378

Elevated liver enzyme tests among rheumatoid arthritis and psoriatic arthritis patients treated with methotrexate and/or leflunomide

  1. Jeffrey R Curtis (jcurtis{at}
  1. University of Alabama at Birmingham, United States
    1. Timothy Beukelman (tbeukelman{at}
    1. University of Alabama at Birmingham, United States
      1. Alina Onofrei (aonofrei{at}
      1. University of Massachusetts, United States
        1. Sarah Cassell
        1. Los Alamos Medical Center, United States
          1. Jeffrey Greenberg (jgreenberg{at}
          1. NYU, United States
            1. Arthur Kavanaugh
            1. University of California, United States
              1. George Reed (george.reed{at}
              1. University of Massachusetts, United States
                1. Vibeke Strand
                1. Stanford University, United States
                  1. Joel M Kremer (jkremer{at}
                  1. The Center for Rheumatology, Albany, United States
                    • Published Online First 15 January 2009


                    Introduction: Potential hepatotoxicity associated with disease modifying anti-rheumatic drugs [DMARDs] requires laboratory monitoring. In rheumatoid and psoriatic arthritis [RA, PsA] patients, we examined the incidence of elevated alanine/aspartate aminotransferase (ALT/AST) enzymes associated with methotrexate (MTX), leflunomide (LEF), and MTX+LEF vs. other DMARDs.

                    Methods: RA and PsA patients enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) initiating DMARDs were identified. Abnormalities were identified when either was 1 or 2-fold time above the upper limits of normal (ULN). Odds ratios [OR] between MTX/LEF dose and elevated ALT/AST enzymes were estimated using generalized estimating equations. Interaction terms for use of MTX+LEF quantified the incremental risk of the combination compared to each individually.

                    Results: Elevated ALT/AST levels (>1x ULN) occurred in 22, 17, 31, and 14% RA patients receiving MTX, LEF, MTX+LEF, or neither, respectively; elevations were 2.76 fold (95% CI 1.84 - 4.15) more likely in PsA patients. Elevations > 2x ULN occurred in 1-2% of patients on MTX or LEF monotherapy compared to 5% with the combination. After multivariable adjustment and compared with either monotherapy, combination MTX + LEF was associated with greater risk according to MTX dose used as part of the combination: MTX 10-17.5mg/week, OR=2.91 (95% confidence interval [CI] 1.23-6.90) and MTX ≥20 mg/week, OR=3.98 (95% CI: 1.72-9.24).

                    Conclusions: 14-35% of RA and PsA patients initiating DMARD therapy developed abnormal ALT/AST levels. Risks were incrementally greater in those with PsA and in those receiving MTX (≥ 10mg/day) + LEF. These findings should help inform monitoring for potential hepatotoxicity in these patient populations.