Elsevier

Joint Bone Spine

Volume 73, Issue 4, July 2006, Pages 388-395
Joint Bone Spine

Original article
Methotrexate therapy for rheumatoid arthritis: clinical practice guidelines based on published evidence and expert opinion

https://doi.org/10.1016/j.jbspin.2006.01.007Get rights and content

Abstract

Objectives

To develop clinical practice guidelines for the use of methotrexate in rheumatoid arthritis (RA), using the evidence-based approach and expert opinion.

Methods

A scientific committee used a Delphi procedure to select five questions, which formed the basis for developing recommendations. Evidence providing answers to the five questions was sought in the Cochrane databases, PubMed, and proceedings of meetings of the French Society for Rheumatology, European League Against Rheumatism, and American College of Rheumatology. Using this evidence, a group of rheumatologists developed and validated the recommendations. For each recommendation, the level of evidence and the extent of agreement among experts were specified.

Results

The recommendations were as follows: 1: The starting dosage for methotrexate in patients with RA should not be less than 10 mg/week and should be determined based on disease severity and patient-related factors; 2: When a patient with RA shows an inadequate response to methotrexate, the dosage should be increased at intervals of 6 weeks, up to 20 mg/week, according to tolerance and patient-related factors; 3: When starting methotrexate treatment in a patient with RA, preference should be given to the oral route. A switch to the intramuscular or subcutaneous route should be considered in patients with poor compliance, inadequate effectiveness, or gastrointestinal side effects; 4: At present, there is no evidence indicating that a change in methotrexate dosage is in order when a TNF antagonist is given concomitantly; 5: The investigations that are mandatory before starting methotrexate therapy in a patient with RA consist of a full blood cell count, serum transaminase levels, serum creatinine with computation of creatinine clearance, and a chest radiograph. In addition, serological tests for the hepatitis viruses B and C and a serum albumin assay are recommended. In patients with a history of respiratory disease or current respiratory symptoms, lung function tests with determination of the diffusing capacity for carbon monoxide are recommended; 6: Investigations that are mandatory for monitoring methotrexate therapy in patients with RA consist of full blood cell counts and serum transaminase and creatinine assays. These tests should be obtained at least once a month for the first 3 months then every 4–12 weeks; 7: Folate supplementation can be given routinely to patients treated with methotrexate for RA. In practice, a minimal dosage of 5 mg of folic acid once a week, at a distance from the methotrexate dose, is appropriate; 8: In the event of respiratory symptoms possibly related to methotrexate toxicity, the drug must be stopped and symptom severity evaluated. Should evidence of serious disease be found, the patient should be admitted immediately or advice from a pulmonologist should be obtained immediately.

Conclusion

Recommendations about methotrexate therapy for RA were developed. These recommendations should help to improve practice uniformity and, ultimately, to improve the management of RA.

Introduction

Methotrexate is used by most rheumatologists as the first-line disease-modifying antirheumatic drug for patients with rheumatoid arthritis (RA). This choice rests on the good effectiveness and safety profile of the drug, its low cost, and the availability of long-term follow-up data on RA patients given methotrexate [1], [2]. In addition, recent data indicate that methotrexate can produce substantial survival benefits by reducing cardiovascular mortality in patients with RA [3].

However, 20 years after the first randomized controlled trials (RCTs) demonstrated that methotrexate as monotherapy was effective in decreasing disease activity in RA [4], [5], 15 years after the first RCTs established its ability to slow the progression of structural joint damage [6], [7], and nearly 10 years after the first RCTs of the efficacy and safety of methotrexate combined with other conventional disease-modifying antirheumatic drugs [8], [9] or biotherapies [10], [11], [12], considerable variability continues to exist in the modalities of methotrexate use in RA, most notably regarding starting and maximal dosages, dosage adjustment, criteria used to monitor patients in daily practice, and the use of folate supplementation.

The objective of this work was to develop clinical practice guidelines for the use of methotrexate in patients with RA, using evidence from the international literature and expert opinion, with the goal of optimizing everyday clinical practice [13].

Section snippets

Methods

The procedure for developing the recommendations involved several steps, as detailed in the article by Pham et al. [14], [15].

Results and discussion

Eight recommendations about using methotrexate in patients with RA were developed during the 2005 Meeting of Rheumatology Experts. The wording and strength of the recommendations are shown in Table 1, as well as the extent of agreement of the experts with each recommendation.

Acknowledgments

We are grateful to Catherine Mazzacco, Gérard Goldfarb, and Fabrice Michiels at Abbott France for their support; Janine de Palmas and Fabien Moll-François at Margaux Orange for their help; and the 75 experts who used their knowledge and their experience of rheumatoid arthritis to develop the recommendations [15].

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    This project was supported by a grant from Abbott France.

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