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Extended report
Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide
  1. J R Curtis1,
  2. T Beukelman1,
  3. A Onofrei2,
  4. S Cassell3,
  5. J D Greenberg4,
  6. A Kavanaugh5,
  7. G Reed2,
  8. V Strand6,
  9. J M Kremer7
  1. 1
    Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA
  2. 2
    University of Massachusetts Medical School, Worcester, Massachusetts, USA
  3. 3
    Los Alamos Medical Center, Los Alamos, New Mexico, USA
  4. 4
    New York University, New York, USA
  5. 5
    University of California, San Diego, California, USA
  6. 6
    Stanford University, Palo Alto, California, USA
  7. 7
    Albany Medical College, The Center for Rheumatology, New York, USA
  1. Correspondence to Dr J Curtis, University of Alabama at Birmingham, 510 20th Street South, FOT 840, Birmingham, AL 35294, USA; jcurtis{at}


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

Methods: Patients with RA and PsA 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 times above the upper limits of normal (ULN). Odds ratios (OR) between MTX/LEF dose and elevated ALT/AST enzymes were estimated using generalised estimating equations. Interaction terms for use of MTX+LEF quantified the incremental risk of the combination compared with each individually.

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

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

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  • Funding This work was supported in part by the Doris Duke Charitable Foundation and the National Institutes of Health (AR053351).

  • Competing interests JRC: Consulting: Roche, UCB, Proctor & Gamble, CORRONA; speakers bureau: Merck, Proctor & Gamble, Eli Lilly, Roche, Novartis; research grants: Merck, Proctor & Gamble, Eli Lilly, Amgen, Novartis. JG: Consulting: Roche, Novartis, UCB, BMS, CORRONA; research grants: BMS. VS: Consulting: Abbott, Allergan, Almirall, AlPharma, Amgen, AstraZeneca, Bayhill, Bexel, BiogenIdec, CanFite, Centocor, Chelsea, Cypress Biosciences, Dianippon Sumitomo, Fibrogen, Forest Labs, Genelabs, Genentech, Human Genome Sciences, Incyte, Jazz Pharm, Lexicon Genetics, Lux Biosciences, Merck, Novartis, NovoNordisk, Noxxon Pharma, Ono Pharm, Pfizer, Procter & Gamble, Proprius, Rigel, Roche, Sanofi-Aventis, Savient, Schering Plough, Scios, SKK, UCB, VLST, Wyeth, Xdx, Zelos Therapeutics; advisory boards: Abbott, Amgen, BiogenIdec, Bioseek, BMS, CanFite, Centocor, Chelsea, Eurodiagnostica, Forest, Incyte, Novartis, Pfizer, Rigel, Rigen, Roche, Savient, Schering-Plough, UCB, Wyeth. JK: CORRONA. TB, AO, SC, AK, GR: none.

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