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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.

[1]  K. Tolman,et al.  Methotrexate and the liver. , 1985, The Journal of rheumatology. Supplement.

[2]  Robert S. Pinals,et al.  A double‐blind, placebo‐controlled trial , 1986 .

[3]  A. Russell,et al.  Concurrent use of folinic acid and methotrexate in rheumatoid arthritis. , 1988, The Journal of rheumatology.

[4]  D. Pisetsky,et al.  Methotrexate-associated hepatotoxicity: retrospective analysis of 210 patients with rheumatoid arthritis. , 1988, The American journal of medicine.

[5]  J. Kremer,et al.  Methotrexate for Rheumatoid Arthritis , 1994 .

[6]  J. Kremer,et al.  Liver histology in rheumatoid arthritis patients receiving long-term methotrexate therapy. A prospective study with baseline and sequential biopsy samples. , 1989, Arthritis and rheumatism.

[7]  H. Frenzel,et al.  Liver biopsy findings in patients with rheumatoid arthritis undergoing longterm treatment with methotrexate. , 1989, The Journal of rheumatology.

[8]  D. Furst,et al.  Increasing methotrexate effect with increasing dose in the treatment of resistant rheumatoid arthritis. , 1989, The Journal of rheumatology.

[9]  A. Mackenzie,et al.  Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheumatic disease. , 1990, The American journal of medicine.

[10]  P. A. Leonard,et al.  Liver histology in patients receiving low dose pulse methotrexate for the treatment of rheumatoid arthritis. , 1990, Annals of the rheumatic diseases.

[11]  G. Alarcón,et al.  The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. , 1990, Arthritis and rheumatism.

[12]  P. Vacek,et al.  Administration of folinic acid after low dose methotrexate in patients with rheumatoid arthritis. , 1990, The Journal of rheumatology.

[13]  D. M. Hoffman,et al.  Exacerbation of rheumatoid arthritis in patients treated with methotrexate after administration of folinic acid. , 1991, Annals of the rheumatic diseases.

[14]  L. Espinoza,et al.  Psoriatic arthritis: clinical response and side effects to methotrexate therapy. , 1992, The Journal of rheumatology.

[15]  C. A. Phillips,et al.  Clinical liver disease in patients with rheumatoid arthritis taking methotrexate. , 1992, The Journal of rheumatology.

[16]  Randall G. Lee,et al.  Determinants of serious liver disease among patients receiving low-dose methotrexate for rheumatoid arthritis. , 1993, Arthritis and rheumatism.

[17]  F. Canovas,et al.  Influence of methotrexate on the frequency of postoperative infectious complications in patients with rheumatoid arthritis. , 1993, The Journal of rheumatology.

[18]  D. Mock,et al.  A comparison of low dose methotrexate bioavailability: oral solution, oral tablet, subcutaneous and intramuscular dosing. , 1993, The Journal of rheumatology.

[19]  J. Esdaile,et al.  Low-dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis. Results of a multicenter randomized, double-blind, placebo-controlled trial. , 1993, Arthritis and rheumatism.

[20]  M. Weinblatt,et al.  Low dose leucovorin does not interfere with the efficacy of methotrexate in rheumatoid arthritis: an 8 week randomized placebo controlled trial. , 1993, The Journal of rheumatology.

[21]  H. A. Dean,et al.  Liver cirrhosis in rheumatoid arthritis patients treated with long-term methotrexate. , 1993, Veterinary and human toxicology.

[22]  R. Warnke,et al.  Lymphoid neoplasms in patients with rheumatoid arthritis and dermatomyositis: frequency of Epstein-Barr virus and other features associated with immunosuppression. , 1994, Human pathology.

[23]  J. Kremer,et al.  Methotrexate for rheumatoid arthritis : suggested guidelines for monitoring liver toxicity , 1994 .

[24]  G. Alarcón,et al.  Supplementation with Folic Acid during Methotrexate Therapy for Rheumatoid Arthritis: A Double-Blind, Placebo-Controlled Trial , 1994, Annals of Internal Medicine.

[25]  G. Koren,et al.  Methotrexate exposure prior to and during pregnancy. , 1994, Teratology.

[26]  J. Kremer,et al.  Light and electron microscopic analysis of sequential liver biopsy samples from rheumatoid arthritis patients receiving long-term methotrexate therapy. Followup over long treatment intervals and correlation with clinical and laboratory variables. , 1995, Arthritis and rheumatism.

[27]  P. Tugwell,et al.  Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The Methotrexate-Cyclosporine Combination Study Group. , 1995, The New England journal of medicine.

[28]  L. Criswell,et al.  What explains the variation among rheumatologists in their use of prednisone and second line agents for the treatment of rheumatoid arthritis? , 1995, The Journal of rheumatology.

[29]  G. Alarcón,et al.  Survival and drug discontinuation analyses in a large cohort of methotrexate treated rheumatoid arthritis patients. , 1995, Annals of the rheumatic diseases.

[30]  R. Balk,et al.  The relationship of preexisting lung disease to the development of methotrexate pneumonitis in patients with rheumatoid arthritis. , 1995, The Journal of rheumatology.

[31]  The effect of age and renal function on the efficacy and toxicity of methotrexate in rheumatoid arthritis. Rheumatoid Arthritis Clinical Trial Archive Group. , 1995, The Journal of rheumatology.

[32]  S. West,et al.  Usefulness of the American College of Rheumatology recommendations for liver biopsy in methotrexate-treated rheumatoid arthritis patients. , 1995, Arthritis and rheumatism.

[33]  C. Kwoh,et al.  Guidelines for monitoring drug therapy in rheumatoid arthritis. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. , 1996, Arthritis and rheumatism.

[34]  J. O'dell,et al.  Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. , 1996, The New England journal of medicine.

[35]  S. West,et al.  Postoperative joint infections in rheumatoid arthritis patients on methotrexate therapy. , 1996, Orthopedics.

[36]  V. Cottin,et al.  Pulmonary function in patients receiving long-term low-dose methotrexate. , 1996, Chest.

[37]  M. Rijn,et al.  Hodgkin's disease and lymphoproliferations resembling Hodgkin's disease in patients receiving long-term low-dose methotrexate therapy. , 1996, The American journal of surgical pathology.

[38]  J. Kremer,et al.  Significant changes in serum AST across hepatic histological biopsy grades: prospective analysis of 3 cohorts receiving methotrexate therapy for rheumatoid arthritis. , 1996, The Journal of rheumatology.

[39]  C. Beyeler,et al.  Pulmonary function in rheumatoid arthritis treated with low-dose methotrexate: a longitudinal study. , 1996, British journal of rheumatology.

[40]  L. Espinoza,et al.  Pancytopenia secondary to methotrexate therapy in rheumatoid arthritis. , 1996, Arthritis and rheumatism.

[41]  F. Salaffi,et al.  Methotrexate in polymyalgia rheumatica: preliminary results of an open, randomized study. , 1996, The Journal of rheumatology.

[42]  M Macaluso,et al.  Risk Factors for Methotrexate-Induced Lung Injury in Patients with Rheumatoid Arthritis: A Multicenter, Case-Control Study , 1997, Annals of Internal Medicine.

[43]  S. van der Linden,et al.  Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis , 1997, The Lancet.

[44]  L. V. D. van de Putte,et al.  Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial. , 1997, British journal of rheumatology.

[45]  S. Satya‐Murti.  Evidence-based Medicine: How to Practice and Teach EBM , 1997 .

[46]  M. Dougados,et al.  Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components , 1999, Annals of the rheumatic diseases.

[47]  E. Sato,et al.  Double blind, randomized, placebo controlled clinical trial of methotrexate in systemic lupus erythematosus. , 1999, The Journal of rheumatology.

[48]  K. Salvesen,et al.  Low dose weekly methotrexate in early pregnancy. A case series and review of the literature. , 2000, The Journal of rheumatology.

[49]  P. Jones,et al.  Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term? , 2000, Rheumatology.

[50]  L. Regan,et al.  Epidemiology and the medical causes of miscarriage. , 2000, Bailliere's best practice & research. Clinical obstetrics & gynaecology.

[51]  M. Islam,et al.  Efficacy of sulphasalazine plus methotrexate in rheumatoid arthritis. , 2000, Bangladesh Medical Research Council bulletin.

[52]  P. Tugwell,et al.  Meta-analysis of treatment termination rates among rheumatoid arthritis patients receiving disease-modifying anti-rheumatic drugs. , 2000, Rheumatology.

[53]  B. Dijkmans,et al.  Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. , 2001, Arthritis and rheumatism.

[54]  L. Grismer,et al.  Liver Biopsy in Psoriatic Arthritis to Detect Methotrexate Hepatotoxicity , 2001, Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases.

[55]  D. Grennan,et al.  Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopaedic surgery , 2001, Annals of the rheumatic diseases.

[56]  A. Murasawa,et al.  Development of fulminant hepatitis B (precore variant mutant type) after the discontinuation of low-dose methotrexate therapy in a rheumatoid arthritis patient. , 2001, Arthritis and rheumatism.

[57]  X. Mariette,et al.  Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France. , 2002, Blood.

[58]  E. Condom,et al.  Light and electron microscopic analysis of liver biopsy samples from rheumatoid arthritis patients receiving long-term methotrexate therapy , 2002, Scandinavian journal of rheumatology.

[59]  Richard W. Martin,et al.  Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. , 2002, Arthritis and rheumatism.

[60]  J. Pope,et al.  Prescribing trends in disease modifying antirheumatic drugs for rheumatoid arthritis: a survey of practicing Canadian rheumatologists. , 2002, The Journal of rheumatology.

[61]  Michael Weisman,et al.  Concomitant Leflunomide Therapy in Patients with Active Rheumatoid Arthritis despite Stable Doses of Methotrexate , 2002, Annals of Internal Medicine.

[62]  D. Schapira,et al.  Relapse of rheumatoid arthritis after substitution of oral for parenteral administration of methotrexate , 2002, Annals of the rheumatic diseases.

[63]  James M Robins,et al.  Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study , 2002, The Lancet.

[64]  S. Gabriel,et al.  Predictors of infection in rheumatoid arthritis. , 2002, Arthritis and rheumatism.

[65]  P. Gergely,et al.  Termination of disease-modifying antirheumatic drugs in rheumatoid arthritis and in psoriatic arthritis. , 2003, Zeitschrift für Rheumatologie.

[66]  M. Arreghini,et al.  Radiographic progression in early rheumatoid arthritis: a 12-month randomized controlled study comparing the combination of cyclosporin and methotrexate with methotrexate alone. , 2003, Rheumatology.

[67]  Andrea Furlan,et al.  Updated Method Guidelines for Systematic Reviews in the Cochrane Collaboration Back Review Group , 2003, Spine.

[68]  T. Pincus,et al.  Methotrexate as the "anchor drug" for the treatment of early rheumatoid arthritis. , 2003, Clinical and experimental rheumatology.

[69]  E. Chakravarty,et al.  The use of disease modifying antirheumatic drugs in women with rheumatoid arthritis of childbearing age: a survey of practice patterns and pregnancy outcomes. , 2003, The Journal of rheumatology.

[70]  W. Gross,et al.  Tolerability of methotrexate starting with 15 or 25 mg/week for rheumatoid arthritis , 2004, Rheumatology International.

[71]  R. Caporali,et al.  Prednisone plus Methotrexate for Polymyalgia Rheumatica , 2004, Annals of Internal Medicine.

[72]  P. Carlier,et al.  Low dose methotrexate in the first trimester of pregnancy: results of a French collaborative study. , 2004, The Journal of rheumatology.

[73]  Thomas R. Riley,et al.  A Randomized Double-blind Placebo-controlled Trial , 2004 .

[74]  M. A. van de Laar,et al.  Bioavailability of higher dose methotrexate comparing oral and subcutaneous administration in patients with rheumatoid arthritis. , 2004, The Journal of rheumatology.

[75]  M. Kurosaki,et al.  Fulminant hepatitis in an asymptomatic chronic carrier of hepatitis B virus mutant after withdrawal of low-dose methotrexate therapy for rheumatoid arthritis. , 2004, Clinical and experimental rheumatology.

[76]  V. Dhillon,et al.  Dose escalation of parenteral methotrexate in active rheumatoid arthritis that has been unresponsive to conventional doses of methotrexate: a randomized, controlled trial. , 2004, Arthritis and rheumatism.

[77]  R. Caporali,et al.  Prednisone plus methotrexate for polymyalgia rheumatica: a randomized, double-blind, placebo-controlled trial. , 2004, Annals of internal medicine.

[78]  C. Michet,et al.  Risk factors for methotrexate-induced abnormal laboratory monitoring results in patients with rheumatoid arthritis. , 2004, The Journal of rheumatology.

[79]  F. Wolfe,et al.  Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients. , 2004, Arthritis and rheumatism.

[80]  P. Adeleine,et al.  Better efficacy of methotrexate given by intramuscular injection than orally in patients with rheumatoid arthritis , 2004, Annals of the rheumatic diseases.

[81]  B. Dijkmans,et al.  Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. , 2005, Arthritis and rheumatism.

[82]  Koichi Amano,et al.  Therapeutic effects of the combination of methotrexate and bucillamine in early rheumatoid arthritis: a multicenter, double-blind, randomized controlled study , 2005, Modern rheumatology.

[83]  R. Schneider,et al.  The effectiveness of treating juvenile dermatomyositis with methotrexate and aggressively tapered corticosteroids. , 2005, Arthritis and rheumatism.

[84]  J. Andreu,et al.  Artritis reumatoide, metotrexato y linfoma no hodgkiniano. Estudio de 3 pacientes , 2005 .

[85]  J. Andreu,et al.  [Rheumatoid arthritis, methotrexate and non-Hodgkins lymphoma. A report of 3 patients]. , 2005, Medicina clinica.

[86]  J. Esdaile,et al.  Methotrexate in systemic lupus erythematosus , 2005, Lupus.

[87]  J. Esdaile,et al.  A 48-week, randomized, double-blind, double-observer, placebo-controlled multicenter trial of combination methotrexate and intramuscular gold therapy in rheumatoid arthritis: results of the METGO study. , 2005, Arthritis and rheumatism.

[88]  Sue Townsend,et al.  Methotrexate and Hepatic Toxicity in Rheumatoid Arthritis and Psoriatic Arthritis , 2006, Clinical drug investigation.

[89]  F. Breedveld,et al.  The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. , 2006, Arthritis and rheumatism.

[90]  J. O'dell,et al.  Treatment of early seropositive rheumatoid arthritis: doxycycline plus methotrexate versus methotrexate alone. , 2006, Arthritis and rheumatism.

[91]  F. Wolfe,et al.  Rates and predictors of herpes zoster in patients with rheumatoid arthritis and non-inflammatory musculoskeletal disorders. , 2006, Rheumatology.

[92]  B. Dijkmans,et al.  Disease-modifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study , 2006, Arthritis research & therapy.

[93]  K. Chakravarty,et al.  Evidence-based clinical guidelines: a new system to better determine true strength of recommendation. , 2006, Journal of evaluation in clinical practice.

[94]  M. Østergaard,et al.  Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: an investigator-initiated, multicenter, randomized, double-blind, parallel-group, placebo-controlled study. , 2006, Arthritis and rheumatism.

[95]  Y. Tamaki,et al.  Methtrexate-associated lymphoproliferative disorders. A clinicopathological study of 13 Japanese cases. , 2006, Pathology, research and practice.

[96]  Hiromu Ito,et al.  Lack of increase in postoperative complications with low-dose methotrexate therapy in patients with rheumatoid arthritis undergoing elective orthopedic surgery , 2006, Modern rheumatology.

[97]  C. Heneghan,et al.  Levels of Evidence , 2006 .

[98]  J. Jacobs,et al.  Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial) , 2007, Annals of the rheumatic diseases.

[99]  M. Ogrendik.  Levofloxacin Treatment in Patients with Rheumatoid Arthritis Receiving Methotrexate , 2007, Southern medical journal.

[100]  R. Madhok,et al.  Combination therapy with sulfasalazine and methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with a suboptimal response to sulfasalazine: results from the double-blind placebo-controlled MASCOT study , 2006, Annals of the rheumatic diseases.

[101]  B Combe,et al.  EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT) , 2006, Annals of the rheumatic diseases.

[102]  Y. Allanore,et al.  Cardiovascular disease in rheumatoid arthritis: single-center hospital-based cohort study in France. , 2007, Joint, bone, spine : revue du rhumatisme.

[103]  P. Villiger,et al.  Therapy with immunosuppressive drugs and biological agents and use of contraception in patients with rheumatic disease. , 2007, The Journal of rheumatology.

[104]  P. Merkel,et al.  Adjunctive methotrexate for treatment of giant cell arteritis: an individual patient data meta-analysis. , 2007, Arthritis and rheumatism.

[105]  Y. Tomita,et al.  Lymphoproliferative disorders in rheumatoid arthritis: clinicopathological analysis of 76 cases in relation to methotrexate medication. , 2007, The Journal of rheumatology.

[106]  U Pichlmeier,et al.  Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. , 2008, Arthritis and rheumatism.

[107]  M. Dougados,et al.  Evidence-based recommendations for the management of ankylosing spondylitis: systematic literature search of the 3E Initiative in Rheumatology involving a broad panel of experts and practising rheumatologists. , 2008, Rheumatology.

[108]  D. M. van der Heijde,et al.  Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research , 2008, Annals of the rheumatic diseases.

[109]  C. Bombardier,et al.  Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis , 2008, Annals of the rheumatic diseases.