Objective: To perform a systematic literature review regarding the long term safety of methotrexate (MTX) monotherapy in rheumatoid arthritis (RA).
Methods: The search was performed in MEDLINE, COCHRANE and EMBASE. The population studied was adults with RA who received MTX monotherapy for more than 2 years.
Results: 88 published studies were included. Over 12 years of treatment, the termination rate of MTX for toxicity is less than for Sulfasalazine, Gold, D-penicillamine and higher than for HCQ (level of evidence 2a-2b). Long term use of MTX treatment does not appear as a risk factor for serious infections including herpes zoster (2b-4) and could provide a survival benefit by reduction of cardiovascular mortality (2b). The prevalence of elevated liver enzymes (more than twice upper limit of normal) is close to 13% of the patients and 3.7% of them stopped MTX permanently for liver toxicity (2b). Data on the risk for liver fibrosis/cirrhosis are conflicting: a meta-analysis shows an incidence of fibrosis of 2.7% after 4 years of MTX (2a). However, 2 other studies on sequential liver biopsies do not show evidence for developing severe damage (2b). Insufficient data are available to fully assess the risk of lymphoma and malignancies, although there is no strong evidence of increased risk (2b-4).
Conclusion: This systematic literature search on MTX monotherapy with relatively low dose use during at least 2 years shows a favourable long-term safety.