More Methotrexate Not Always Better

A higher initial dose of methotrexate is not always associated with better clinical outcomes for newly diagnosed rheumatoid arthritis patients, a study shows.

The study, published in a December issue of the Arthritis Care & Research, “suggests that there is little short term gain from starting with high compared to low methotrexate doses,” the authors wrote.

These findings are based on a systematic review of 31 studies that included a total of 5,589 newly diagnosed rheumatoid arthritis patients. Among these, 2,209 patients had received methotrexate monotherapy; 403 had received methotrexate with conventional DMARDs; 2,496 received combination therapy with glucocorticoids; and, 661 received combination therapy with biologic DMARDs.

The current trend is to start newly diagnosed patients on higher doses of methotrexate, but in this case, researchers found no benefit for patients who were treated with a high dose of methotrexate as compared to low dose -for either mono or combination therapy.

While the currently recommended starting dose for methotrexate is 15 mg/week orally, escalating with 5 mg/month to 25-30 mg/week or the highest tolerable dosage, higher initial methotrexate dosages of 20-30mg/week have been used in recent trials.

Because up to 75 percent of DMARD-naive patients do not attain low-disease activity within three or even 12 months of starting methotrexate monotherapy, methotrexate in combination with several other drugs (e.g., conventional synthetic DMARDS, corticosteroids, biologic DMARDS) has been investigated. Compared with methotrexate monotherapy, these combinations have been shown to be superior for reducing disease symptoms more rapidly and for preventing radiographic damage in more patients.

In the absence of specific recommendations regarding methotrexate dosage in combinations with other agents, a recent trend in trials of biologic DMARDS (and perhaps in daily practice, Bergstra et al. suggest) has emerged toward initiating methotrexate at the same high levels as when methotrexate is given as monotherapy, with the intent of quickly decreasing disease activity.

In Bergstra et al.’s systematic review of multiple trials and cohorts, effect size was neither increased nor decreased through increasing methotrexate dosages. In combination therapy with glucocorticoids, higher methotrexate doses were associated with increased (worse) Health Assessment Questionnaire (HAQ) outcomes (ß[beta]=0.012, 95% CI=0.0007; 0.023). Similarly, a small but statistically significant positive association was observed with methotrexate dose in combination with biologic DMARDS (ß[beta]=0.042, 95% CI=0.012; 0.073).  Methotrexate dose increases also had a small but significant worsening effect on DAS/DAS28 (Disease Activity Score/Disease Activity Score 28) in combination with biologic DMARDS (ß [beta]=0.033, 95% CI=0.0070; 0.059) but not in combination with glucocorticoids. No associations between ESR/CRP (erythrocyte sedimentation rate/C-reactive protein) and increasing methotrexate dosages were identified.

“This finding suggests that there is little short term gain from starting with high compared to low methotrexate doses,” Bergstra et al. concluded. They pointed out, as well, that in combination with glucocorticoids a higher methotrexate dose was actually associated with a worse HAQ outcome.

Commenting on the divergence of their results from some prior reports suggesting benefit with higher methotrexate dosages, Bergstra et al. speculated, “It may be possible that DMARD-naïve rheumatoid arthritis patients are more responsive to relatively low doses of methotrexate when assessed within six months than patients with a more advanced disease.”

The finding, the authors wrote, was consistent with results of the randomized, double-blind, parallel-armed CONCERTO trial in 2014 which tested methotrexate in combination with adalimumab in methotrexate-naïve early rheumatoid arthritis  patients. CONCERTO results demonstrated no differences in disease activity, radiographic progression or functional ability response between methotrexate doses of 10 or 20 mg/week in combination with adalimumab after 6 months.

References:

SA Bergstra, MSC, CF Allaart, MD, PhD, T Stijnen, PhD, et al. “Meta-regression of a dose-response relationship of methotrexate in mono- and combination therapy in DMARD naive early rheumatoid arthritis patients,” Arthritis Care & Research. Accepted online:  Dec. 19, 2016. DOI 10.1002/acr.23164