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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
  1. K Visser1,
  2. W Katchamart2,
  3. E Loza3,
  4. J A Martinez-Lopez4,
  5. C Salliot5,
  6. J Trudeau6,
  7. C Bombardier2,7,
  8. L Carmona4,
  9. D van der Heijde1,
  10. J W J Bijlsma8,
  11. D T Boumpas9,
  12. H Canhao10,
  13. C J Edwards11,
  14. V Hamuryudan12,
  15. T K Kvien13,
  16. B F Leeb14,
  17. E M Martín-Mola15,
  18. H Mielants16,
  19. U Müller-Ladner17,
  20. G Murphy18,
  21. M Østergaard19,
  22. I A Pereira20,
  23. C Ramos-Remus21,
  24. G Valentini22,
  25. J Zochling23,
  26. M Dougados5
  1. 1
    Leiden University Medical Center, Leiden, The Netherlands
  2. 2
    Rheumatology Division, Department of Medicine, University of Toronto, Ontario, Canada
  3. 3
    Department of Rheumatology, Hospital Clinico San Carlos, Madrid, Spain
  4. 4
    Research Unit, Fundación Española de Reumatología, Madrid, Spain
  5. 5
    Paris Descartes University, Medicine Faculty; UPRES-EA 4058; APHP, Rheumatology B Department, Cochin Hospital, Paris, France
  6. 6
    CHUM-Hôpital Notre-Dame, Université de Montréal, Montréal, Canada
  7. 7
    Division of Clinical Decision Making and Health Care Research, Health Network Research Institute, Toronto, Ontario, Canada
  8. 8
    Department of Rheumatology and Clinical Immunology, University Medical Center, Utrecht, The Netherlands
  9. 9
    Division of Rheumatology, University of Crete, Heraklion, Greece
  10. 10
    Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa; Serviço de Reumatologia e Doenças Ósseas Metabólicas, Hospital de Santa Maria, Lisbon, Portugal
  11. 11
    Southampton University Hospital, Southampton, UK
  12. 12
    Istanbul University, Cerrahpasa Medical Faculty, Department of Internal Medicine, Division of Rheumatology, Istanbul, Turkey
  13. 13
    Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway
  14. 14
    State Hospital Stockerau, Center for Rheumatology, Lower Austria, Stockerau, Austria
  15. 15
    Hospital Universitario La Paz, Department of Rheumatology, Universidad Autónoma, Madrid, Spain
  16. 16
    Department of Rheumatology, University of Gent, Gent, Belgium
  17. 17
    Department of Rheumatology and Clinical Immunology, Justus-Liebig-University Giessen, Kerckhoff Clinic, Bad Nauheim, Germany
  18. 18
    Cork University Hospital, Wilton, Cork, Ireland
  19. 19
    Departments of Rheumatology, Copenhagen University Hospitals at Hvidovre and Herlev, Denmark
  20. 20
    University Hospital of Santa Catarina, UFSC, Division of Rheumatology, Florianopolis, Brazil
  21. 21
    Unidad de Investigación en Enf Cronico-Degenerativas, Guadalajara, Mexico
  22. 22
    University of Naples, Department of Internal Medicine, Rheumatology Unit, Naples, Italy
  23. 23
    Menzies Research Institute, University of Tasmania, Hobart, Australia
  1. Dr K Visser, Leiden University Medical Center, Department of Rheumatology, PO Box 9600, 2300 RC Leiden, The Netherlands; k.visser{at}


Objectives: 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.

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  • WK, EL, JAM-L, CS and JT contributed equally to the work

  • Funding: This work was supported by Abbott with an unrestricted educational grant.

  • Competing interests: None.

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