Background/Purpose: MTX is the first line conventional synthetic DMARD (csDMARD) for the treatment of rheumatoid arthritis (RA), and folic acid (FA) supplementation is frequently co-prescribed to prevent adverse effects¹. However, the need for FA remains controversial, given the influence on the efficacy of MTX therapy^2,3. The aim of this study was to evaluate the effects of FA supplementation on efficacy and safety of MTX monotherapy in RA patients.

Methods: We retrospectively evaluated 184 RA patients (mean disease duration 30±62 SD months, mean age 63±14 SD years), diagnosed according to ACR/EULAR 2010 criteria⁴, who started low-dose MTX treatment. No serious comorbidities other than RA were present. Two groups of patients were considered: patients supplemented with FA (96 patients, FA+) and patients not-supplemented with FA (88 patients, FA-). MTX dose, prednisone (PDN) dose, disease activity score (DAS28-CRP), and adverse events (AEs) were recorded at 0, 3, 6, 9, 12 and 24 months. At baseline, MTX mean dose was 8.9±1.6 and 8.1±1.5 mg/weekly, prednisone mean dose was 7.5±3.6 and 6.3±3.9 mg/daily, and mean DAS28 was 4.4±1.4 and 4.5±1.2, respectively for both groups. Follow-up was performed until MTX discontinuation, new cs/biologic DMARD addition or need for FA supplementation. The maximum MTX dose administered during the follow-up was 20 mg/weekly. Statistical analysis was performed by non-parametric tests.

Results: DAS28 decreased in both groups of patients. However, at three months DAS28 was found significantly lower (p < 0.05) in patients without FA supplementation, when compared with patients taking FA supplementation. Patients without FA supplementation required statistically significant lower doses of both prednisone and MTX during the follow-up (table 1). Statistically significant difference (p=0.014) was found in reported mild and not critical AEs in 16% of FA+ patients, as well as in 32% of FA- patients (mainly increase of transaminases, nausea and gastrointestinal intolerance). Management of AEs was successful in the majority of cases by either discontinuing MTX for two weeks or adding FA if required.

Conclusion: In RA patients treated with low-dose MTX, FA administration decreases the efficacy of the treatment, delaying the clinical responsiveness, and leads to the need for higher doses of both PDN and MTX. Considering the benign type of AEs usually observed during low dose MTX monotherapy, this treatment should be started without FA supplementation, deferring the FA use until potential AEs appearance.

References
[1] Shea B, et al. Cochrane Database Syst Rev. 2013May 31;(5):CD000951.
[2] Arabelovic S, et al. J Am Coll Nutr2007;26:453–5.
[3] Stamp LK et al. J Clin Rheumatol2019;25(7):284-287.
[4] Aletaha D, et al. Arthritis Rheum2010;62:2569–81.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/delayed-response-to-methotrexate-treatment-in-rheumatoid-arthritis-patients-receiving-folic-acid-supplementation/