MADRID – A low versus high starting dose of methotrexate given as monotherapy or in combination with glucocorticoids or conventional synthetic disease-modifying antirheumatic drugs to newly diagnosed rheumatoid arthritis patients doesn’t seem to make a difference in short-term disease activity and physical functioning responses, but a higher starting dose of at least 15 mg/week may provide a better chance at achieving a good response at 6 months, according to two separate observational studies presented at the European Congress of Rheumatology.

One of the studies looked at 3- to 6-month disease activity and physical functioning responses to methotrexate used as mono- or combination therapy and the other assessed EULAR clinical responses at 6 months in mostly monotherapy-treated patients.

Low vs. high dose in combination treatments

“Methotrexate is the anchor drug in the treatment of rheumatoid arthritis patients. Current guidelines for methotrexate monotherapy recommend initiating 15 mg/week orally then escalating to 25-30 mg/week or the highest tolerable dose, but no recommendations exist for the drug’s use in combination therapy,” said Sytske Anne Bergstra, first author of a study using the international, observational METEOR database, a cohort with real-world clinical data.

“Our study questioned whether a higher initial methotrexate dose in combination with other effective medication would be more effective than a lower initial dose in the short term,” said Ms. Bergstra, a PhD student at Leiden (the Netherlands) University Medical Center.

The investigators selected 1,404 RA patients from the METEOR database who had a symptom duration of less than 5 years, had less than 2 months between diagnosis and first visit, and did not change medications (only dose adjustments were allowed). They were divided into three groups: methotrexate monotherapy, methotrexate plus conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and methotrexate plus glucocorticoids (and possibly csDMARDs). The investigators defined initial starting doses of methotrexate as low (10 mg/week or less) or high (15 mg/week or more) based on the last reported dose of methotrexate at no later than 8 weeks of follow-up.

In each group, females comprised about 80% of patients, and the mean age was 45-48 years. The group that received methotrexate plus csDMARDs had a median symptom duration nearly twice that of the other groups (730 days vs. 365 for monotherapy and 458 for methotrexate plus glucocorticoids). Rheumatoid factor positivity ranged from 77% to 84% and anticitrullinated peptide autoantibody positivity from 72% to 85%.

The use of a high methotrexate starting dose generally trended upward in patients enrolled in the database through 2015, whereas the high point for use of a low dose was 2010 and declined thereafter. Overall, a high starting dose was used in 28% of monotherapy patients, 14% with methotrexate plus csDMARDs, and 46% with methotrexate plus glucocorticoids.

In propensity score–adjusted analyses that helped to control for confounding by indication, there were no differences in the effectiveness of low or high methotrexate starting doses for all three groups after follow-up between 3 and 6 months on Disease Activity Score (DAS), 28-joint DAS, or the Health Assessment Questionnaire (HAQ).

“Our findings seem to contradict the general trend of starting with high methotrexate doses. They indicate that higher doses did not provide better short-term clinical outcome in either monotherapy or combination therapy,” Ms. Bergstra observed.

She continued: “For the moment, we suggest that rheumatologists consider starting with a lower initial methotrexate dose, especially when prescribing in combination with other synthetic DMARDS or glucocorticoids.”

Effect of initial dose on EULAR response

Rebecca Davies of the Centre for Musculoskeletal Research at the University of Manchester (England) presented data from a separate study that examined the effect of giving a low versus a high dose of methotrexate on patients’ rate of response to EULAR criteria at 6 months.

“Methotrexate is the recommended first line treatment for rheumatoid arthritis; however, we have not yet established [a] clear optimal strategy for the starting dose of this therapy,” Ms. Davies said.

International, evidence-based recommendations advise starting oral methotrexate at 10-15 mg/week with escalation of 5 mg every 2-4 weeks up to 20-30 mg/week, she explained, but practice varies regarding the starting dose of methotrexate in the United Kingdom. This is most likely a result of the lack of published evidence on the importance of the initial methotrexate dose on its efficacy and safety, she suggested.

The aim of the study was therefore to assess the two most commonly used methotrexate starting doses used in the United Kingdom (7.5 mg/week or less vs. 15 mg/week or more) and how they affected the DAS28 of patients.

A total of 810 patients with rheumatoid arthritis who were starting methotrexate were recruited from the U.K. national, multicenter, longitudinal, observational Rheumatoid Arthritis Medication Study. For inclusion in the study, patients had to have complete DAS28 data at baseline and at 6 months.

The median age of patients was similar among the low- and high-dose groups, at 58 and 61 years, respectively. Most of the participants were female (70% vs. 60%), with a median disease duration of 6 years. Median baseline DAS28 scores were 4.2 in low- and 4.1 in high-dose groups, and baseline HAQ scores were 1.3 and 0.9, respectively.

Ms. Davies noted that 627 (77%) of the patients newly initiated on methotrexate received 15 mg/week, 10 received 20 mg, and 2 received 25 mg. The low dose of 7.5 mg/week was started by 165 patients (20%), 4 started on 5 mg, and 2 started on 2.5 mg. In more than 90% of patients, methotrexate was given orally in both the low- and high-dose groups.

Patients who were initiated on the lower methotrexate dose were more often prescribed concomitant nonbiologic DMARDs (17% vs. 10% of those in the high-dose group). Half of patients in both high- and low-dose groups used oral steroids, and a quarter used intramuscular steroids.

According to the EULAR response criteria, a good response is seen if the final DAS28 drops to 3.2 or below and there is also an improvement of 1.2 or more from baseline values. This was achieved in 23% of patients in the low-dose group and in 33% of patients in the high-dose group. Moderate EULAR clinical responses were seen in 32% and 25%, and nonresponses seen in a respective 45% and 42%.

However, findings on a multinomial logistic regression model “showed that RA patients starting methotrexate on a higher dose have a higher probability of having a good EULAR clinical response, as opposed to nonresponse, at 6 months,” Ms. Davies said.

The unadjusted relative risk ratio in patients starting a high versus low dose was 0.8 for a moderate EULAR response and 1.5 for a good EULAR response. The respective adjusted RRR was 1.0 and 2.7, suggesting that there is no difference between the doses in achieving a moderate response, but the higher dose has the edge at helping patients achieve a good EULAR response by 6 months.

During the discussion following Ms. Davies’ presentation, Roy Fleischmann, MD, of the department of internal medicine at the University of Texas Southwestern Medical Center, Dallas, asked whether a high dose had actually been used at all in the study. Dr. Fleischmann observed that both 7.5 mg/week and 15 mg/week could be considered low doses.

However, one of the chairs of the session, Peter Taylor, PhD , of the University of Oxford (England) noted that the bioavailability of methotrexate does not change much when the dose is above 15 mg via the oral route.

Kimme Hyrich, MD, of the University of Manchester (England) and senior author on the study, pointed out that the point of the analysis was to compare the starting doses of methotrexate among patients, and there might have been patients who received higher doses (25 mg or more) during the 6-month follow-up period. It is expected that future work will look at the change in the dose response over the 6-month time period, she said.

Ms. Bergstra and Ms. Davies reported that they had no relevant financial disclosures. Several coauthors for the METEOR database study disclosed financial relationships with numerous companies that market drugs for RA.

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Studies examine methotrexate starting dose for RA in monotherapy and combinations