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

K Visser ^1*, W Katchamart ², E Loza ³, J A Martinez-Lopez ⁴, C Salliot ⁵, J Trudeau ⁶, C Bombardier ², L Carmona ⁴, D van der Heijde ¹, J W J Bijlsma ⁷, D T Boumpas ⁸, H Canhao ⁹, C J Edwards ¹⁰, V Hamuryudan ¹¹, T K Kvien ¹², B F Leeb ¹³, E M Martín-Mola ¹⁴, H Mielants ¹⁵, U Müller-Ladner ¹⁶, G Murphy ¹⁷, M stergaard ¹⁸, I A Pereira ¹⁹, C Ramos-Remus ²⁰, G Valentini ²¹, J Zochling ²² and M Dougados ⁵

¹ Leiden University Medical Center, Netherlands
² Rheumatology Division, Department of Medicine, University of Toronto, Ontario, Canada
³ Department of Rheumatology, Hospital Clinico San Carlos, Madrid, Spain
⁴ Research Unit, Fundación Española de Reumatología, Madrid, Spain
⁵ Paris Descartes University, Medicine Faculty, Rheumatology B Dept, Cochin Hospital, Paris, France
⁶ CHUM-Hôpital Notre-Dame, Université de Montréal, Montréal, Canada
⁷ Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Netherlands
⁸ Division of Rheumatology, University of Crete, Heraklion, Greece
⁹ Rheumatology Research Unit, Faculdade de Medicina da Universidade de Lisboa; Hospital de Santa Maria, Portugal
¹⁰ Southampton University Hospital, Southampton, United Kingdom
¹¹ Istanbul University, Cerrahpasa Medical Faculty, Dept of Internal Medicine, Division of Rheumatology, Turkey
¹² Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway
¹³ State Hospital Stockerau, Center for Rheumatology, Lower Austria, Stockerau, Austria
¹⁴ Hospital Universitario La Paz, Department of Rheumatology, Universidad Autónoma, Madrid, Spain
¹⁵ Department of Rheumatology, University of Gent, Belgium
¹⁶ Dept of Rheumatology and Clinical Immunology, Justus-Liebig-University Gießen, Kerckhoff Clinic, Germany
¹⁷ Cork University Hospital, Wilton, Cork, Ireland, United Kingdom
¹⁸ Departments of Rheumatology, Copenhagen University Hospitals at Hvidovre and Herlev, Denmark
¹⁹ University Hospital of Santa Catarina, UFSC, Division of Rheumatology, Florianopolis, Brazil
²⁰ Unidad de Investigación en Enf. Cronico-Degenerativas, Guadalajara, Mexico
²¹ University of Naples, Department of Internal Medicine, Rheumatology Unit, Naples, Italy
²² Menzies Research Institute, University of Tasmania, Hobart, Australia

^* To whom correspondence should be addressed. E-mail: k.visser{at}lumc.nl.

Accepted 16 November 2008

Abstract

Objectives: To develop evidence-based recommendations for the use of methotrexate (MTX) in daily clinical practice in rheumatic disorders.

Methods: A total of 751 rheumatologists from 17 countries participated in the 3E (Evidence Expertise Exchange) Initiative of 2007-2008 consisting of 3 separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of MTX in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005-2007 ACR/EULAR 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 16979 references were identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of MTX were formulated. Nine recommendations were specific for rheumatoid arthritis, including the work-up before initiating MTX, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the peri-operative period and before/during pregnancy. One recommendation concerned MTX as a steroid-sparing agent in other rheumatic diseases.

Conclusions: Ten recommendations for the use of MTX 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.