Outcomes related to methotrexate dose and route of administration in patients with rheumatoid arthritis: a systematic literature review.

OBJECTIVES: Methotrexate (MTX) is considered the 'anchor drug' in the therapy of rheumatoid arthritis (RA), yet many physicians do not optimise MTX regimens in spite of high RA disease activity. The recent development of an auto-injector for the subcutaneous (subQ) administration of MTX has prompted re-evaluation of MTX utilisation. The purpose of this systematic literature review is to determine the optimal dose, drug level, and route of administration for MTX in the context of relevant pharmacokinetics and pharmacogenomics.

METHODS: A systematic literature review was performed in Medline searching specifically for randomised controlled trials, systematic reviews, case control and cohort studies evaluating outcomes related to MTX dose and route of administration. Articles fulfilling these inclusion criteria were reviewed. Data on MTX dose, route of administration, clinical response, drug levels and adverse events were evaluated.

RESULTS: Our search identified 420 articles of which 6 were eligible for inclusion using the above criteria. These included 2 systematic reviews, 2 randomised open label trials, one longitudinal study and one retrospective cohort study.

CONCLUSIONS: Efficacy and toxicity for MTX appear related to absorbed dose of MTX, not to route of administration. While bioavailability is greater for parenteral MTX, there is no evidence yet that splitting the oral dose of MTX is less advantageous, less safe or less tolerable than administering parenteral MTX. However, there appear to be modest benefits in beginning with higher doses of MTX, and switching to parenteral MTX when the clinical response to an oral dose is inadequate.