Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide.
BACKGROUND
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 (>1x 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 >2x 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 > or =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 (> or =10 mg/day) + LEF. These findings should help inform monitoring for potential hepatotoxicity in these patient populations.
Curtis
J R
JR
Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 510 20 Street South, FOT 840, Birmingham, AL 35294, USA. jcurtis@uab.edu
Beukelman
T
T
Onofrei
A
A
Cassell
S
S
Greenberg
J D
JD
Kavanaugh
A
A
Reed
G
G
Strand
V
V
Kremer
J M
JM
D000293:Adolescent; D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015535:Arthritis, Psoriatic / Q000188:drug therapy* / Q000201:enzymology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis* / Q000209:etiology; D004796:Clinical Enzyme Tests / Q000379:methods; D015331:Cohort Studies; D016903:Drug Monitoring / Q000379:methods; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use; D007555:Isoxazoles / Q000009:adverse effects* / Q000627:therapeutic use; D000077339:Leflunomide; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged; D055815:Young Adult
D018501:Antirheumatic Agents; D015415:Biomarkers; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000077339:Leflunomide; D008727:Methotrexate