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Methotrexate in early rheumatoid arthritis: Are higher doses not superior to low-dose therapies?

Recent data questions high dose usage in the early therapy phases for rheumatoid arthritis (RA) with oral methotrexate (MTX).

Meta-analysis questions first-line treatments

Recent data questions high dose usage in the early therapy phases for rheumatoid arthritis (RA) with oral methotrexate (MTX).

In the treatment of early rheumatoid arthritis (RA) with oral methotrexate (MTX), doses should be gradually increased to 20-30 mg per week or until the maximum tolerated dose is reached. However, recently published data casts doubts over the clinical benefit of high doses in therapy-oriented patients during early therapies phases.

The aim of patients’ treatment with newly diagnosed RA is the rapid control of disease activity. According to current recommendations, MTX monotherapy should start at 15 mg per week and then be increased in cumulative steps from around 5 mg per month to 25-30 mg per week or up to the maximum tolerated dose. There are no specific recommendations for the dosage of MTX in combination with other antirheumatic drugs.

However, it is questionable whether higher MTX doses in first-line therapies are actually more effective than lower doses. Thus, authors of a meta-analyses conclude that higher MTX doses in patients with recently diagnosed RA are not associated with a better clinical outcome than lower doses, at least in the first months after the start of therapy, neither in the context of monotherapy nor in combination with glucocorticoids or biological disease-modifying antirheumatic drugs (bDMARDs).

An evaluation of the international METEOR database

This is now supported by the evaluation of data from the international METEOR (Measurement of Efficacy of Treatment in the "Era of Outcome" in Rheumatology) register of RA patients from 20 countries. Included in the analysis were DMARD-naïve patients with early RA who had initially received MTX therapy.

Combinations of MTX with bDMARDs were not considered due to their low numbers (only eleven patients). 94% of patients were from India, South Africa, Portugal, the Netherlands, the USA, Ireland, and Mexico.

Differences in efficacy are minor and clinically irrelevant

Therapeutic effectiveness was evaluated using the changes in the Disease Activity Score (DAS), the Disease Activity Score based on 28 points (DAS28) and the Health Assessment Questionnaire (HAQ) - in the first three to six months after the start of therapy. MTX dosages ≥ mg per week were considered low and dosages ≥ mg per week were considered high.

Measured by the three endpoints, the differences between high and low MTX doses in all groups (mono- and combination therapies) were small and clinically irrelevant even after adjustment for various influencing factors.

As the data also show, there has been a trend towards higher MTX doses since the beginning of the METEOR register over the years. This concerns particularly the combination with glucocorticoids - possibly because rheumatologists have found RA to be especially severe in these patients.

According to the authors, the lack of MTX’s dose dependence effect can very probably be explained by its pharmacokinetics. The availability of active MTX polyglutamates seems to be independent of the weekly dose.

Like many other studies, this study is not without its weak points - for example, such as those raised by the arbitrary division into high and low doses. Previously published clinical studies have also shown, however, that different combinations and dosages of drugs in RA therapy can lead to comparable clinical results.

First, aim for a low MTX dosage

Results may not be applicable to subcutaneous MTX administration as most of the patients included in the evaluation took it orally. However, they contradict the general trend towards the use of higher MTX doses in patients with early RA. As the publication authors admit, a low MTX dosage could delay the control of disease activity.

Nevertheless, they argue that rheumatologists should first consider a low rather than a high MTX dose in patients with early RA. This applies in particular to the combination of MTX with csDMARDs or glucocorticoids. Even if adverse drug reactions have not been recorded in the METEOR database, it can be assumed that higher doses are associated with more side effects - and they can endanger patients’ compliance. Further along, nonetheless, the therapy can still be intensified as part of a treat-to-target strategy.

Bergstra SA, Allaart CF, van den Berg R, et al. Similar short-term clinical response to high-dose versus low-dose methotrexate in monotherapy and combination therapy in patients with rheumatoid arthritis. Arthritis Res Ther 2017; 19: 258