Background/Purpose: Low-dose weekly methotrexate (MTX) is the first-choice second-line drug in the treatment of juvenile idiopathic arthritis (JIA). Folate (as either Folic acid (FA) or Folinic acid (FLA)) effectively ameliorates or prevents some of MTX’s adverse events (AE) in adults with RA.  Folate supplementation in JIA, therefore, has become the standard of care in many medical centers. Although widely used in JIA patients, including in research studies, the evidence for folate-use in JIA to prevent AEs is based on only one-43 patient, non-randomized retrospective case series. To begin defining the most commonly used folate regimens, we examined the methods of folate supplementation in MTX-treated JIA patients among pediatric rheumatologists around the globe, using an electronic survey. 

Methods: An Internet-based survey was distributed among the registrants of the pediatric rheumatology list serve, an electronic forum and mailing list, which hosts 1040 subscribers worldwide. The survey was initiated between March and April 2011 and followed up with 3 subsequent electronic reminders. Chi-square tests of proportions were used to compare the distribution of responses between US and Non-US populations. A Bonferroni corrected significance level of 0.0125 was used to account for repeated testing.

Results: 214 pediatric rheumatologists from 25 countries responded to the survey (table 1). 11.7% of respondents do not routinely use ANY folate supplementation unless the patient experiences AEs during the course of treatment; 72.5% prescribe only FA; 5.1% prescribe only FLA; and 10.7% use both forms of folate supplementation.

An extremely wide spectrum of prescribing regimens (71 unique regimens) for folate supplementation was reported:

1)     Folic acid (FA): Some physicians used multivitamin supplements as the source of their FA. Others used FA in doses between 400 mcgs and 10 mg daily, 6 days per week or only 24-48 hours after MTX intake. 

2)     Folinic Acid (FLA): FLA was generally used in dose ranges of 5-10 mg once a week (24 hours after MTX intake).

A majority of the responders (53.6%) agreed with the statement that they did not know which supplementation regimen was superior.

Conclusion: We found a high degree of variability among pediatric rheumatologists in how and whether folate supplementation is used in JIA. This variability, often arising from a lack of evidence and certainly true in this case, emphasizes the need for a well-designed clinical trial to support a rational regimen of either FA or FLA supplementation in MTX-treated JIA patients.

Table 1. Folate supplementation in MTX-treated JIA

Regimen	Total (%, n=214)	US (%, n=128)	Non-US (%, n=86)	p-value
Folic acid	72.5	62.5	87.2	0.0001
Folinic acid	5.1	5.5	4.7	0.9600
Both	10.7	16.4	2.3	0.0024
None*	11.7	15.6	5.8	0.0484
* Only if the patient experiences adverse events during the course of treatment

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/folate-usage-in-methotrexate-treated-juvenile-idiopathic-arthritis-patients-is-inconsistent-and-highly-variable/