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Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature
  1. K Visser (k.visser{at}
  1. Leiden University Medical Center, Netherlands
    1. D van der Heijde (d.vanderheijde{at}
    1. Leiden University Medical Center, Netherlands


      Objectives: To systematically review the available literature on the optimal dosage and route of administration of methotrexate (MTX) in patients with rheumatoid arthritis (RA), as an evidence base for generating clinical practice recommendations.

      Methods: A systematic literature search was carried out in MEDLINE, EMBASE, Cochrane Library and ACR/EULAR meeting abstracts, searching for randomized controlled trials evaluating various dosages or routes of administration of MTX in RA. Articles that fulfilled predefined inclusion criteria were systematically reviewed and the quality was appraised. Effect sizes (ES) and odds ratios (OR) for clinical, radiological and toxicity outcomes were calculated and directly or indirectly compared between study groups using MTX in different dosages or via different routes.

      Results: A total of 38 publications out of 1748 identified references were included in the review. Start doses of 25mg/wk or fast escalation with 5mg/month to 25-30mg/wk were associated with higher clinical ES and more (gastrointestinal) adverse events in comparison with doses of 5-15mg/wk or slow escalation. Starting with 15mg/wk subcutaneous versus oral MTX was associated with higher clinical efficacy, but more withdrawal due to toxicity in early RA. In longstanding RA, however, after failure on 15-20mg/wk orally, a switch to 15mg/wk intramuscular with subsequent dose escalation did not result in increased efficacy.

      Conclusions Starting on MTX 15mg/wk orally, escalating with 5mg/month to 25-30mg/wk, or the highest tolerable dose, with a subsequent switch to subcutaneous in case of an insufficient response, seems to be the optimal evidence-based dosing and routing recommendation for MTX in RA.

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