Objectives: To systematically review the literature on liver toxicity in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients treated with methotrexate (MTX), as an evidence base for generating clinical practice recommendations for the management of MTX and the indication for a liver biopsy (LB) in case of elevated liver enzymes (LE).
Methods: A systematic literature search was carried out in MEDLINE, EMBASE, Cochrane Library and ACR/EULAR meeting abstracts. Data on the incidence of elevated LE, subsequent adjustments in MTX therapy and the prevalence of fibrosis/cirrhosis in pre-MTX and post-MTX LB were pooled.
Results: Forty-seven out of 426 identified references were included in the systematic review. For RA, the incidence rate of elevated LE in the first three years of MTX use was 13/100 patient-years with a cumulative incidence of 31%. MTX was permanently discontinued in 7%, paused or reduced in 26% and continued without any adjustment in 67% of patients with an abnormal test. After 4 years of MTX use, LB showed in 15.3% of the (unrelated) cases mild fibrosis, in 1.3% severe fibrosis and in 0.5% cirrhosis, while pre-MTX biopsies showed 9%, 0.3% and 0.3% abnormalities, respectively. For PsA, evidence is limited. Additional studies suggest that cumulative MTX dose and serial LE elevations among other risk factors are related to liver pathology.
Conclusions: This review suggests that LE elevations during MTX therapy are a frequent but transient problem, that serial abnormal LE tests might be associated with liver pathology, but that cirrhosis is relatively rare. It is, however, not clear from the literature how therapy should be adjusted in case of elevated LE and to what extent MTX independently attributes to liver toxicity.