No Added Benefit to High Methotrexate Starting Dose in DMARD-Naive RA

Clinical outcomes with higher starting doses of methotrexate were examined in disease-modifying antirheumatic drug-naive patients with early rheumatoid arthritis.

More does not appear to be better when it comes to the use of methotrexate (MTX) in early rheumatoid arthritis (RA). Although a number of trials have shown that starting dosages of 20 to 30 mg/wk are more effective than the standard recommended starting dosage of 15 mg/wk, this may not hold true for patients who have yet to be exposed to disease-modifying antirheumatic drugs (DMARDs), according to a systematic literature review emerging from Leiden University in the Netherlands.1,2

The rationale for early MTX therapy has been the prevention of progressive joint damage. Researchers continue to up the ante in search of ways to tamp down disease activity at the outset to minimize later functional disability.

High Yield Data Summary

  • No clinical benefit was found with starting high-dose MTX as opposed to low-dose MTX in newly diagnosed RA.

High-dose MTX monotherapy has been one strategy, but it reportedly fails to result in low disease activity within 3 to 6 months for up to 75% of patients who are DMARD-naive. Combination regimens, particularly with biologic DMARDs, are increasingly being studied, but efficacy and safety issues have yet to be fleshed out. The aim of the Dutch literature review was to examine the short-term dose-response relationships of MTX monotherapy and combination therapy in recent-onset RA in patients who are DMARD-naive.

Studies eligible for inclusion had to be focused on patients with a clinical diagnosis or suspicion of recent-onset RA who were DMARD-naive. MTX had to be part of the first treatment strategy, either as monotherapy or combination therapy, and the studies had to include exact dosages of all study medications mentioned, measures of treatment effects, and overall results at 6 months.

Measures to be included were the Health Assessment Questionnaire (HAQ), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), and/or disease activity scores (DAS or DAS28). Treatment groups to be examined were patients receiving MTX monotherapy and patients receiving MTX in combination with either synthetic DMARDs, biologic DMARDs, or glucocorticoids.

Of 1518 articles and 398 meeting abstracts, 31 studies met inclusion criteria. Of the total 5589 patients represented, 2029 had received MTX monotherapy, 403 combination therapy with a synthetic DMARD, 2496 MTX plus a glucocorticoid, and 661 MTX plus a biologic DMARD. MTX dosages ranged from 7.5 to 30 mg/wk.

Improvement within 3 to 6 months was seen with mostly large effect sizes, especially in relation to DAS, for all outcomes for all treatment groups except in 1 small study that showed small positive effect sizes for the HAQ and CRP measures.

Otherwise, large effect sizes were mostly seen for MTX and biologic DMARD combinations (large effect sizes in 89% of groups), followed by combination therapy with glucocorticoids (87%), synthetic DMARDs (70%), and MTX monotherapy (63%). However, none of the groups showed a clear increase or decrease in effect size relative to increasing MTX dosage.

No appreciable difference was seen in outcomes between patients receiving MTX in the range of 10 mg/wk and patients receiving the agent in the range of 20 mg/wk. Thus, the authors concluded that little short-term gain can be expected from starting MTX at high rather than standard dosages in the DMARD-naive patient.

Summary & Clinical Applicability

Although a number of trials have shown that starting MTX at dosages of 20 to 30 mg/wk are more effective than the standard recommended starting dosage of 15 mg/wk in patients with RA, no difference in short-term outcomes are being seen in DMARD-naive patients receiving low-dose or high-dose MTX monotherapy or combination therapy.

Thus, in terms of safety and cost concerns, high starting doses of MTX may not be appropriate in DMARD-naive patients; however, safety and dosing issues regarding high-dose MTX in combination with DMARDs or glucocorticoids have yet to be identified.

Study Limitations

  • Although baseline disease activity was controlled for in the systemic literature review, patients included in the studies with the highest starting doses may have had more severe disease, resulting in higher HAQ and DAS28/DAS outcomes compared with patients in studies in which the MTX starting dose was lower.

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  1. Bergstra SA, Allaart CF, Stijnen T, Landewé R. Meta-regression of a dose-response relationship of methotrexate in mono- and combination therapy in DMARD naive early rheumatoid arthritis patients [published online December 29, 2016]. Arthritis Care Res (Hoboken). doi:10.1002/acr.23164
  2. Quinn MA, Conaghan PG, O’Connor PJ, et al. Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;52:27-35. 

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