title: Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative.
abstract: OBJECTIVE
  To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders.
  
  
  METHODS
  751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007-8 consisting of three separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of methotrexate in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005-7 American College of Rheumatology/European League Against Rheumatism meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford levels of evidence. Each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed.
  
  
  RESULTS
  A total of 16 979 references was identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of methotrexate were formulated. Nine recommendations were specific for rheumatoid arthritis (RA), including the work-up before initiating methotrexate, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the perioperative period and before/during pregnancy. One recommendation concerned methotrexate as a steroid-sparing agent in other rheumatic diseases.
  
  
  CONCLUSIONS
  Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use.
authors.affiliation: Leiden University Medical Center, Department of Rheumatology, Leiden, The Netherlands. k.visser@lumc.nl
authors.forename: K
authors.initials: K
authors.lastname: Visser
authors.forename: W
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authors.lastname: Canhao
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authors.lastname: Mielants
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authors.lastname: Murphy
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authors.lastname: Østergaard
authors.forename: I A
authors.initials: IA
authors.lastname: Pereira
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authors.lastname: Ramos-Remus
authors.forename: G
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authors.lastname: Dougados
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000284:Administration, Oral; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D004359:Drug Therapy, Combination; D019317:Evidence-Based Medicine; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage; D006801:Humans; D008134:Long-Term Care; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects; D016742:Preconception Care; D012216:Rheumatic Diseases / Q000188:drug therapy*; D012307:Risk Factors
chemical_list: D018501:Antirheumatic Agents; D005492:Folic Acid; D008727:Methotrexate