Journal Article

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

Kavanaugh, A, Reed, G, Beukelman, T, Greenberg, J D, Kremer, J M, Onofrei, A, Strand, V, Curtis, J R, Cassell, S

2010

Overview

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.

• Publisher: BMJ Publishing Group Ltd and European League Against Rheumatism,Elsevier Limited
• Subject: Adolescent / Adult / Aged / Alanine Transaminase - blood / Alcohol / Antirheumatic Agents - adverse effects / Antirheumatic Agents - therapeutic use / Arthritis / Arthritis, Psoriatic - drug therapy / Arthritis, Psoriatic - enzymology / Arthritis, Rheumatoid - drug therapy / Aspartate Aminotransferases - blood / Biomarkers - blood / Biopsy / Chemical and Drug Induced Liver Injury - diagnosis / Chemical and Drug Induced Liver Injury - etiology / Clinical Enzyme Tests - methods / Clinical medicine / Clinical trials / Cohort Studies / Drug dosages / Drug Monitoring - methods / Drug Therapy, Combination / Enzymes / Female / Health risk assessment / Humans / Immunosuppressive Agents - adverse effects / Immunosuppressive Agents - therapeutic use / Isoxazoles - adverse effects / Isoxazoles - therapeutic use / Laboratories / Leflunomide / Male / Methotrexate / Methotrexate - adverse effects / Methotrexate - therapeutic use / Middle Aged / Studies / TNF inhibitors / Tumor necrosis factor-TNF / Young Adult