Relative risk of and determinants for adverse events of methotrexate prescribed at a low dose: a systematic review and meta-analysis of randomized placebo-controlled trials

Low-dose (i.e. ≤ 30 mg per week) methotrexate is widely prescribed by dermatologists. However, there is limited evidence-based information regarding the relative risk of and determinants for adverse events associated with this treatment. The aims of this review were to assess the relative risk of and the determinants for adverse events associated with low-dose methotrexate exposure. A systematic review was undertaken using the MEDLINE, Embase and CENTRAL databases. Randomized controlled trials comparing low-dose methotrexate with placebo were eligible. Random effect meta-analyses were conducted to assess the risk ratios (RRs) of adverse events associated with methotrexate exposure. Subgroup analyses and random effect meta-regressions were performed to examine the determinants of adverse events. In total, 68 trials (6938 participants) were included. Compared with placebo, low-dose methotrexate slightly increased the risk of adverse events (mean number per individual: 1·78 ± 2·00 in the methotrexate group, 1·53 ± 1·89 in the placebo group; P < 0·001), including nausea/vomiting, elevated transaminase levels, mucosal ulcerations, leucopenia, thrombopenia and infectious events, but not the risk of serious adverse events or death. Low-dose methotrexate also increased the number of withdrawals from studies because of adverse events [RR 1·32 (1·13-1·53)]. The concomitant prescription of folic/folinic acid was associated with a significant lower risk of any adverse events, and methotrexate prescribed orally was associated with a higher risk of abdominal pain than when prescribed subcutaneously or by intramuscular injection. On the other hand, the risk of adverse events did not increase with the weekly dose or with duration of exposure. Similar studies comparing methotrexate with other systemic/biological treatments are needed.