Background/Purpose: It
is recommended that all patients receiving MTX also receive at least 5mg/week
of folic acid in an effort to reduce occurrence of MTX associated adverse
effects. Previous research has suggested that supplemental folic acid has no
detrimental effects on control of RA. However, we have shown that patients with
higher red blood cell (RBC) folate have more active RA compared to those with
lower RBC folate concentrations. The aim of this study was to determine whether
reducing the amount of supplemental folic acid patients receive improves
disease control in RA patients receiving MTX Methods: A randomized double blind controlled trial of the effect of
reducing folic acid supplementation was undertaken in patients with RA as
defined by ARA 1987 criteria. Patients were on MTX for at least 3 months at a
stable dose for at least one month. All patients had active disease as defined
by DAS28≥3.2 or required a change in therapy as determined by the
treating clinician. Patients were randomized to receive supplemental folic acid
5mg/week (high dose or 0.8mg/week low dose. Patients were seen at weeks 4, 8,
16 and 24. Disease activity, full blood count, liver function tests, RBC folate
and RBC methotrexate polyglutamates (MTXPGs) were collected at each visit along
with reports of adverse events.

Results:
Forty patients were recruited. Demographics are outlined in the table. The mean
(SD) change in RBC folate between baseline and 24 weeks was +87.9 (57.4) nmol/l
in the high dose group and -113.3 (65.7) nmol/l in the low dose group
(p<0.05). There was no significant difference in the change in DAS28CRP
between the high and low dose groups at 24 weeks (-0.14 (SEM 0.30) vs -0.31
(0.37) respectively (p=0.72)). One patient in the high dose group and one in
the low dose group had a transient reduction in neutrophils (1.7 and 1.5×10⁹/l
respectively). Three patients in the low dose and one in the higher dose group had
an increase in ALT (all <1.5x upper limit normal). One patient in the low
dose group had an increase in AST (<1.5x upper limit normal).

There was no relationship
between change in RBC folate and change in DAS28 irrespective of randomisation
(r=0.05, p=0.80).  There was no significant association between change in RBC folate
and change in RBC MTX polyglutamate concentrations (p>0.05 for all).

Conclusion: We
have shown that a reduction in RBC folate resulting from a reduction in oral supplemental
folic acid was not associated with a change in RA disease activity and there
was no change in RBC methotrexate polyglutamate concentrations or adverse
effects. The relatively low DAS28 at entry may have made it difficult for a
difference to be observed.

Table: Demographics