Methotrexate use more than doubled the risk of liver enzyme abnormalities but was not tied to serious hepatic outcomes among patients with rheumatic diseases, according to a meta-analysis of 32 randomized, controlled trials.

“Serious liver events were rare, with a suggestion of a trend towards fewer poor liver outcomes,” wrote Dr. Richard Conway of Galway (Ireland) University Hospitals. “The short duration of the included studies and the lack of liver biopsies are limitations, but the available data provide robust evidence for short-term safety” of methotrexate, wrote Dr. Conway and his associates.

Methotrexate is a first-line RA therapy with efficacy in several other inflammatory diseases, but concerns about toxicity have limited its use, the researchers noted. Clinicians have particularly debated its hepatic effects, in part because it can be “exceedingly difficult” to determine if liver disease is preexisting, methotrexate related, or caused by other medications or comorbidities, they said. To better assess the issue, they searched PubMed and the Cochrane Central Register of Controlled Trials for relevant double-blind, randomized, controlled trials published between 1990 and 2014. They found 32 such trials that included 13,177 patients with rheumatoid arthritis, psoriasis, psoriatic arthritis or inflammatory bowel disease ( Semin Arthritis Rheum. 2015;45:156-62 ). Methotrexate use approximately doubled the risk of any adverse hepatic event (relative risk, 2.19; 95% confidence interval, 1.73-2.77) and of major and minor liver enzyme abnormalities (RR, 2.16; 95% CI, 1.67-2.79), but did not increase the risk of liver failure, cirrhosis, or liver-related mortality (RR, 0.12; 95% CI, 0.01-1.09), the investigators reported. “Clinical trials have inherent limitations, including short duration, selection bias, failure to collect information or reports that are not part of a prespecified protocol, and limited power to evaluate rare or unusual reports,” they cautioned. “While meta-analyses help overcome the last of these, the others raise some concern.”

But several other reports align with their results, the researchers noted. In an analysis of methotrexate studies lasting at least 2 years, about 10% of patients developed at least one minor liver enzyme abnormality, but less than 4% stopped methotrexate because of liver toxicity. Other controlled studies did not link methotrexate to severe fibrosis or cirrhosis – even after 4 years of treatment, they added. “It appears likely that serious liver-related complications due to methotrexate may take many years of treatment to manifest,” the investigators concluded.

The researchers reported no funding sources or conflicts of interest.