Background/Purpose

There is good evidence that folic acid 5-10mg per week leads to reduction in methotrexate (MTX) toxicity in rheumatoid arthritis (RA). However, this data comes from old studies using a lower dose of MTX. There is limited data of folic acid doses with contemporary usage of MTX, i.e., when MTX is started at a high dose and rapidly escalated. We wondered whether a higher dose of folic acid i.e. 30mg per week (approx. 1:1 MTX) would be better, in this context, in reducing toxicity than 10 mg per week.

Methods

This was a single-center double-blind randomized controlled trial of 24 weeks duration. Included patients 18-75 years of age, who fulfilled 1987 ACR criteria for RA and had active disease (DAS28(3)>3.2). MTX was started at 15mg/week and escalated by 8 weeks to 25 mg/week. At 16 weeks, a new DMARD could be added on the physician’s discretion. Folic acid was given at a dose of 10 mg (FA-10) or 30 mg per week (FA-30), as 6 identical tablets for every day of the week except the day of taking MTX. Patients were seen every 8 weeks. Co-primary endpoints were incidence of toxicity and change in disease activity by 24 weeks. Toxicity included undesirable symptoms (evaluated by questionnaire) and laboratory abnormalities (cytopenias: WBC<4000 or platelet<100x10³/ul or transaminitis: >2ULN). Disease activity was evaluated using modified disease activity score using 3 variables (DAS28(3)). In addition, HAQ, serum and RBC folate and MMP-3 were done at 0 and 24 weeks. Intention-to-treat and per-protocol analyses were performed. Trial # NCT01583959

Results

This study included 100 patients, having a mean±SD age of 44.3±10.9 years, disease duration of 4.8±4.7 years and DAS28(3) of 5.8±0.9. At enrolment 13 patients were on steroids and 4 on other DMARDs. FA-10 and FA-30 groups had 51 and 49 patients respectively, with similar baseline characteristics. Similar numbers of patients were lost to follow up (6,6). At 24 weeks, the mean±SD dose of MTX in both groups (22.8±4.4, 21.4±4.6mg/week) was similar (p=0.1). Leflunomide was added in 18 and 10 patients at 16 weeks and SSZ in 1 patient. Among patients with at least 1 follow up, there were no significant differences between groups in the frequency of undesirable symptoms or laboratory abnormalities. Lung toxicity was suspected in 2 patients in the FA10 group (Table 1). DAS28(3) declined similarly from baseline to 24 weeks (p=0.2) in FA10 (-1.1±1.0) and FA30 (-1.3±1.0) groups. At 24 weeks, serum folic acid was significantly (p<0.001) higher in FA30 (45.1±39.7) compared to FA10 group (20.4±17.1ng/ml), but there was no difference in RBC folate, HAQ and MMP-3.

Conclusion We did not find any significant difference in toxicity or efficacy of MTX with higher dose of folic acid even when starting MTX at a high dose and escalating rapidly. The finding of 2 cases of suspected lung toxicity with folic acid 10 mg/week warrants larger studies.

Table 1:Frequency of MTX related toxicity in patients who had at least one follow up visit

	Folic acid 10 mg per week (N=47) N(%)	Folic acid 30 mg per week (N=46) N(%)	P value
Laboratory abnormalities
Cytopenias	2 (4.3)	2 (4.3)	0.99
Transaminitis	20 (42.6)	21 (45.7)	0.76
Undesirable symptoms
Nausea	10 (21.3)	17 (37)	0.10
Dizziness	6 (12.8)	1 (2.2)	0.11
Fatigue	2(4.3)	3(6.5)	0.98
Loss of appetite	2 (4.3)	3 (6.5)	0.98
Uneasiness	4 (8.5)	3 (6.5)	0.99
Headache	0 (0)	4(8.7)	0.11
Oral ulcers	0 (0)	2 (4.3)	0.99
Altered taste	1(2.1)	1 (2.2)	0.99
Other adverse effects
Herpes Zoster	2 (4.3)	1 (2.2)	0.99
Suspected lung toxicity	2 (4.3)	0 (0)	0.25

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/does-a-higher-dose-of-folic-acid-reduce-adverse-effects-of-methotrexate-in-rheumatoid-arthritis-a-randomized-controlled-trial/