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

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Abstract

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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Most cited references 85

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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.

Ferdinand C Breedveld, Michael Weisman, Arthur F Kavanaugh … (2006)

To compare the efficacy and safety of adalimumab plus methotrexate (MTX) versus MTX monotherapy or adalimumab monotherapy in patients with early, aggressive rheumatoid arthritis (RA) who had not previously received MTX treatment. This was a 2-year, multicenter, double-blind, active comparator-controlled study of 799 RA patients with active disease of < 3 years' duration who had never been treated with MTX. Treatments included adalimumab 40 mg subcutaneously every other week plus oral MTX, adalimumab 40 mg subcutaneously every other week, or weekly oral MTX. Co-primary end points at year 1 were American College of Rheumatology 50% improvement (ACR50) and mean change from baseline in the modified total Sharp score. Combination therapy was superior to both MTX and adalimumab monotherapy in all outcomes measured. At year 1, more patients receiving combination therapy exhibited an ACR50 response (62%) than did patients who received MTX or adalimumab monotherapy (46% and 41%, respectively; both P < 0.001). Similar superiority of combination therapy was seen in ACR20, ACR70, and ACR90 response rates at 1 and 2 years. There was significantly less radiographic progression (P < or = 0.002) among patients in the combination treatment arm at both year 1 and year 2 (1.3 and 1.9 Sharp units, respectively) than in patients in the MTX arm (5.7 and 10.4 Sharp units) or the adalimumab arm (3.0 and 5.5 Sharp units). After 2 years of treatment, 49% of patients receiving combination therapy exhibited disease remission (28-joint Disease Activity Score <2.6), and 49% exhibited a major clinical response (ACR70 response for at least 6 continuous months), rates approximately twice those found among patients receiving either monotherapy. The adverse event profiles were comparable in all 3 groups. In this population of patients with early, aggressive RA, combination therapy with adalimumab plus MTX was significantly superior to either MTX alone or adalimumab alone in improving signs and symptoms of disease, inhibiting radiographic progression, and effecting clinical remission.

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Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study.

Hyon K Choi, Miguel A. Hernán, John Seeger … (2002)

Methotrexate is the most frequent choice of disease-modifying antirheumatic therapy for rheumatoid arthritis. Although results of studies have shown the efficacy of such drugs, including methotrexate, on rheumatoid arthritis morbidity measures, their effect on mortality in patients with the disease remains unknown. Our aim was to prospectively assess the effect on mortality of methotrexate in a cohort of patients with rheumatoid arthritis. Our cohort included 1240 patients with rheumatoid arthritis seen at the Wichita Arthritis Center, an outpatient rheumatology facility. Patients' details were entered into a computerised database at the time of their first clinic visit. We also obtained and recorded demographic, clinical, laboratory, and self-reported data at each follow-up visit (average interval 3.5 months). We estimated the mortality hazard ratio of methotrexate with a marginal structural Cox proportional hazards model. 191 individuals died during follow-up. Patients who began treatment with methotrexate (n=588) had worse prognostic factors for mortality. After adjustment for this confounding by indication, the mortality hazard ratio for methotrexate use compared with no methotrexate use was 0.4 (95% CI 0.2-0.8). Other conventional disease-modifying antirheumatic drugs did not have a significant effect on mortality. The hazard ratio of methotrexate use for cardiovascular death was 0.3 (0.2-0.7), whereas that for non-cardiovascular deaths was 0.6 (0.2-1.2). Our data indicate that methotrexate may provide a substantial survival benefit, largely by reducing cardiovascular mortality. This survival benefit of methotrexate would set a standard against which new disease-modifying antirheumatic drugs could be compared.

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Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis.

Harrie Verhoeven, Pieter Jacobs, H Schouten … (1997)

The value of intensive combination therapy in early rheumatoid arthritis is unproven. In a multicentre, double-blind, randomised trial (COBRA), we compared the combination of sulphasalazine (2 g/day), methotrexate (7.5 mg/week), and prednisolone (initially 60 mg/day, tapered in 6 weekly steps to 7.5 mg/day) with sulphasalazine alone. 155 patients with early rheumatoid arthritis (median duration 4 months) were randomly assigned combined treatment (76) or sulphasalazine alone (79). Prednisolone and methotrexate were tapered and stopped after 28 and 40 weeks, respectively. The main outcomes were the pooled index (a weighted change score of five disease activity measures) and the Sharp/Van der Heijde radiographic damage score in hands and feet. Independent health-care professionals assessed the main outcomes without knowledge of treatment allocation. At week 28, the mean pooled index was 1.4 (95% CI 1.2-1.6) in the combined treatment group and 0.8 (0.6-1.0) in the sulphasalazine group (p < 0.0001). At this time, 55 (72%) and 39 (49%) patients, respectively, were improved according to American College of Rheumatology criteria. The clinical difference between the groups decreased and was no longer significant after prednisolone was stopped, and there were no further changes after methotrexate was stopped. At 28 weeks, the radiographic damage score had increased by a median of 1 (range 0-28) in the combined-therapy group and 4 (0-44) in the sulphasalazine group (p < 0.0001). The increases at week 56 (2 [0-43] vs 6 [0-54], p = 0.004), and at week 80 (4 [0-80] vs 12 [0-72], p = 0.01) were also significant. Further analysis suggests that combined therapy immediately suppressed damage progression, whereas sulphasalazine did so less effectively and with a lag of 6 to 12 months. There were fewer withdrawals in the combined therapy than the sulphasalazine group (6 [8%] vs 23 [29%]), and they occurred later. This combined-therapy regimen offers additional disease control over and above that of sulphasalazine alone that persists for up to a year after corticosteroids are stopped. Although confirmatory studies and long-term follow-up are needed, this approach may prove useful in the treatment of early rheumatoid arthritis.

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Author and article information

Journal

Journal ID (nlm-ta): Ann Rheum Dis

Journal ID (publisher-id): ard

Title: Annals of the Rheumatic Diseases

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Print): 0003-4967

ISSN (Electronic): 1468-2060

Publication date Collection: July 2009

Publication date (Electronic): 24 November 2008

Volume: 68

Issue: 7

Pages: 1086-1093

Affiliations

[1 ]Leiden University Medical Center, Leiden, The 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; UPRES-EA 4058; APHP, Rheumatology B Department, Cochin Hospital, Paris, France

[6 ]CHUM-Hôpital Notre-Dame, Université de Montréal, Montréal, Canada

[7 ]Division of Clinical Decision Making and Health Care Research, Health Network Research Institute, Toronto, Ontario, Canada

[8 ]Department of Rheumatology and Clinical Immunology, University Medical Center, Utrecht, The Netherlands

[9 ]Division of Rheumatology, University of Crete, Heraklion, Greece

[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 ]Southampton University Hospital, Southampton, UK

[12 ]Istanbul University, Cerrahpasa Medical Faculty, Department of Internal Medicine, Division of Rheumatology, Istanbul, Turkey

[13 ]Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway

[14 ]State Hospital Stockerau, Center for Rheumatology, Lower Austria, Stockerau, Austria

[15 ]Hospital Universitario La Paz, Department of Rheumatology, Universidad Autónoma, Madrid, Spain

[16 ]Department of Rheumatology, University of Gent, Gent, Belgium

[17 ]Department of Rheumatology and Clinical Immunology, Justus-Liebig-University Giessen, Kerckhoff Clinic, Bad Nauheim, Germany

[18 ]Cork University Hospital, Wilton, Cork, Ireland

[19 ]Departments of Rheumatology, Copenhagen University Hospitals at Hvidovre and Herlev, Denmark

[20 ]University Hospital of Santa Catarina, UFSC, Division of Rheumatology, Florianopolis, Brazil

[21 ]Unidad de Investigación en Enf Cronico-Degenerativas, Guadalajara, Mexico

[22 ]University of Naples, Department of Internal Medicine, Rheumatology Unit, Naples, Italy

[23 ]Menzies Research Institute, University of Tasmania, Hobart, Australia

Author notes

Correspondence to: Dr K Visser, Leiden University Medical Center, Department of Rheumatology, PO Box 9600, 2300 RC Leiden, The Netherlands; k.visser@ 123456lumc.nl

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

Article

Publisher ID: ar94474

DOI: 10.1136/ard.2008.094474

PMC ID: 2689523

PubMed ID: 19033291

SO-VID: 3d804544-b577-4095-95c5-e9c9f2d75674

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

History

Date accepted : 16 November 2008

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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

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Abstract

Objectives:

Methods:

Results:

Conclusions:

Related collections

Gamma Delta T cells

Most cited references 85

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.

Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study.

Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis.

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Cited by 98

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