To date, this is the first review that specifically deals with the long-term safety of MTX monotherapy in patients with RA. According to the cohort and case–control studies, there is no evidence of an increased risk of CVD, mortality and infections in patients receiving MTX. Overall, although many patients experience adverse events during MTX treatment, they are generally mild and withdrawals of MTX for toxicity are less common than for most other DMARDs. The results remain inconclusive for the risk of cirrhosis and malignancies, including lymphoma.
There are challenges to the interpretation of the data as several weaknesses were apparent in the results of the systematic literature search. First, the studies were heterogeneous in their study design, the level of evidence, the type of adverse events reported, the presentation of the results as prevalence, incidence rate, RR, etc. Moreover, the control groups were not always well defined and described. Also, information on relevant data such as comorbidity, concomitant use of other drugs and folic acid supplementation were often not available. Consequently, we could only pool the results for the adverse events in general and elevation of liver enzymes from uncontrolled prospective studies. But even here, we were unable to present the occurrence of adverse events per patient per year of exposure.
Second, the focus of the systematic literature search is on use of MTX as monotherapy. This is valid but does limit the interpretation on the long-term safety of MTX in combination with other DMARDs and/or biological agents which is often the case in modern treatment of RA.
Third, the average dose of 10.7 mg/week overall in all studies, with a maximum dose of 18 mg/week in one study, is low compared with the currently recommended dose. We tried to evaluate a time trend in the dosage of MTX use but the mean dose in the studies published before 1995 was similar to the dose used in the studies published after 1995. Recent publications do include data on the use of MTX in higher dosages, but there is only information on long-term safety in one of these studies.39
However, this study shows no difference in frequency and type of adverse events from those in the studies with lower dosages. But in general, the data provided in this systematic literature search relate to the long-term safety of relatively low doses of MTX.
Fourth, nowadays concomitant use of folic acid and MTX is standard treatment. Most of the studies did not report or insufficiently reported the use of folic acid. Therefore, we do not know what the role of folic acid is in the long-term safety of MTX. However, within the 3E Initiative there is a specific systematic literature search on the usefulness of adding folic acid to MTX.40
Although the data on cirrhosis and malignancies are inconclusive, the findings of this review do not suggest serious problems of toxicity with the long-term use of MTX as monotherapy with an average dose of 10.7 mg/week in patients with RA. Many patients experience adverse events, but these are usually of mild. Whether these conclusions are valid for higher doses and in combination with other DMARDs and biological agents needs to be investigated by future research. The data from this systematic literature search were used as one of the evidence-based pieces of information forming the basis for the recommendations on the use of MTX in rheumatic diseases.3