Folate’s protective benefits confirmed

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While upping the dose of folate to compensate for an increased dose of methotrexate might seem logical, there is little in the medical literature on this

It’s well-known that folate supplements reduce methotrexate’s side effects, but Chinese researchers have questioned whether the dose needs to be higher.

Today’s patients with rheumatoid arthritis are taking a higher dose of methotrexate than in the past but the recommended dose of folate has remained steady at around 5-10mg per week, the researchers said.

“As the methotrexate dosage used currently is much higher than before, the optimum dosage of folate may be higher,” the researchers from Zhengzhou University hospital wrote in a study published in the Journal of Clinical Rheumatology in August.

While upping the dose of folate to compensate for the increased dose of methotrexate might seem logical, there was little in the medical literature on this subject, they said.

After a literature search of 6,000 papers, the researchers could only find two papers that compared low and high doses of folate, and the papers (published in 2015 and 1994) weren’t conclusive.

The 2015 study included in the systematic review compared doses of 10mg versus 30 mg of folic acid per week and demonstrated that there was no difference in effect between the two doses.

“It is still uncertain whether a higher dosage of folate is necessary,” the researchers said.

“The issue of folate supplementation in methotrexate has long been a vexed one,” said Dr Susanna Proudman, a rheumatologist at the Royal Adelaide Hospital.

“The prevailing view is that it is a good idea to use folate to minimise methotrexate toxicity, especially mucositis and GI toxicity. Much of the dogma about dose, timing … has not been evidence-based.”

Clinical guidelines currently recommend that folic acid supplementation be used with methotrexate, with some guidelines specifying a minimum dose of 5mg a week.

Dr Sabina Ciciriello, a rheumatologist at Melbourne Health, agreed that there was currently no evidence that higher doses of folic acid were more protective.

However, she increases the folic acid dose in patients experiencing methotrexate side effects.

Also commenting on the study, Dr Patrick Hanrahan, a Perth-based rheumatologist agreed the evidence to date was equivocal in terms of the optimal folate dose relative to the dose of methotrexate.

A 2018 study of 40 people by a New Zealand team (not cited in the paper) showed that there was no difference between a 5mg a week dose of folate and an even lower dose of 0.8mg a week in terms of RA disease activity or methotrexate-related adverse effects, he told Rheumatology Republic.

Dr Hanrahan prescribes 5 mg of folate twice a week, not given on the same day as the methotrexate for his RA patients.

Regardless of the dose, a major issue was that folate “remains underused”, Dr Hanrahan claims.

He cited a 2016 US studywhere it was found 50% of patients were no longer taking folate with their methotrexate at 20 months. In addition, 27% were not prescribed it within a month of methotrexate initiation.

The Chinese study also confirmed the protective effects of folate, mirroring the findings of a 2013 Cochrane systematic review.

The Chinese researchers examined five studies with over 700 RA patients. Each study was a double-blind RCT that ran for 12-48 weeks.

In the studies, patients who took folate (at any dose) had a 29% lower chance of gastrointestinal side-effects such as nausea and vomiting than patients who did not take folate.

Patients on folate had an 85% reduced chance of having elevated transaminase (a sign of liver damage).

They were also 71% more likely to adhere to their methotrexate treatment, probably because the side effects were less severe.

Folate supplementation was thought to offset the side effects from methotrexate because methotrexate had an antagonistic effect on folic acid metabolism and caused folate depletion, said Dr Ciciriello.


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