Elsevier

Joint Bone Spine

Volume 78, Issue 6, December 2011, Pages 587-592
Joint Bone Spine

Original article
Optimizing methotrexate therapy in rheumatoid arthritis: A systematic literature review

https://doi.org/10.1016/j.jbspin.2011.01.010Get rights and content

Abstract

Objective

To describe the means of optimizing methotrexate therapy for rheumatoid arthritis in daily clinical practice, based on a systematic literature review.

Methods

We systematically reviewed the literature by searching the PubMed, Embase, and Cochrane databases and reviewing communications to ACR and EULAR meetings for studies on methotrexate starting dosages, dosage increment sizes and intervals, maximum dosages, and routes of administration in patients with rheumatoid arthritis. We used an appropriate scoring system to assess the methodological quality of each selected study.

Results

We identified 519 studies of which 11 were selected based on the titles and abstracts then on the full-length articles. Methotrexate was optimally effective when started in a high dosage (more than 10 mg/week orally) that was subsequently increased by 5 mg/month up to 25–30 mg/week,1 with appropriate adjustments based on clinical disease activity and tolerance of each patient. For a given methotrexate dosage, parenteral administration was more effective and produced fewer gastrointestinal adverse effects than oral administration.

Conclusion

The information supplied by this systematic review support higher starting dosage, an intensive dosage increase schedule and recourse to parenteral administration in case of unresponsiveness or intolerance to oral methotrexate. They should improve the management of patients given methotrexate therapy for rheumatoid arthritis.

Introduction

The introduction of biotherapies over the last few years is perceived as a breakthrough in the treatment of inflammatory joint diseases. Nevertheless, methotrexate (MTX) remains the cornerstone of disease-modifying treatment in patients with rheumatoid arthritis (RA) [1], [2]. Recent national and international recommendations support the use of MTX as the first-line disease-modifying antirheumatic drug (DMARD) for RA, based on its substantial effectiveness, good safety profile, and low cost [3], [4], [5], [6], [7]. MTX is also widely used in combination with other medications, most notably biotherapies, to increase their therapeutic effect [8], [9], [10]. However, considerable variability exists across rheumatologists regarding the MTX starting dosage, dosage increment size, interval between increments, and route of administration. The recommendations issued by the French High Health Authority for the management of established RA suggest a number of gray areas regarding the modalities of MTX use. In published studies of first-line biologic therapy for RA, over one-third of patients achieved a clinical remission in the control groups treated with MTX alone but another third had no treatment response [8], [9], [10], [11]. The absence of a response may indicate either a primary lack of efficacy or a suboptimal MTX regimen [12]. The objective of this work was to describe the means of optimizing MTX therapy in RA in daily clinical practice, based on a systematic literature review.

Section snippets

Definitions of topics of interest

A scientific committee composed of French rheumatologists working in teaching hospitals used a Delphi procedure to select topics of interest. Four topics were selected: the MTX starting dosage, the size of the dosage increments and interval between increments, the maximum dosage, and the route of administration at treatment initiation and during maintenance therapy.

Literature search

We searched the Medline, Embase, and Cochrane Central databases for articles published until May 2009, with no date limits. The

Results

Fig. 1 shows the flowchart of the articles. Our literature search retrieved 519 articles, among which 26 were preselected based on the titles and abstracts. Of these, nine were selected based on the full-length text [16], [17], [18], [19], [20], [21], [22], [23], [24]. In addition, we included two abstracts from recent meetings, of which one reported an a posteriori analysis of a previously published study [25] and the other supplied additional information on the dosage increase schedule [26].

Discussion

This systematic revue deals with the optimization of MTX use for patients with RA in daily clinical practice. An intensive strategy (consisting in high starting dosage [18], [21] followed by monthly increments of 5 mg [23]) is associated with a higher rate of minor adverse events, most notably involving the gastrointestinal tract, compared to the traditional use of MTX [18], [21], [23]. The intensive strategy is warranted in patients with early RA to take advantage of the window of opportunity

Disclosure of interest

This work was done as part of the 6th Rheumatology Expert Meetings organized with institutional support from Abbott France. Abbott was not involved in any way in the project. The authors have no financial interest related to the topic of the study. Thus, the authors have no conflict of interest to declare.

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