Effect of Methotrexate and Folic Acid Co-Administration in Arthritis

BackgroundMethotrexate (MTX) is the recommended first-line treatment for rheumatoid arthritis. Adjuvant-induced arthritis (AIA) rat is a robust model with a high prevalence of arthritis used to investigate arthritis. MTX reduces inflammation, but associated with adverse events, such as gastrointestinal, hepatic, and hematology toxicity (1). To reduce these side effects, folic acid (FA) is administrated at distance to MTX with no defined recommendation for its dosing (5-25mg/week) or time point of administration (2) (1-3 days after MTX application). Whether the complicated therapeutic regimen with MTX once a week and FA at another time point affects compliance is an open question. MTX is metabolized in polyglutamates derivates (MTX-PG), which is a biomarker of MTX efficacy as its half-life (1-4 weeks) is longer than MTX (4h) (3).ObjectivesThe aim of this study was to assess efficacy and tolerance of co-administration of MTX and FA compared to MTX with FA applied one day after MTX in the AIA.MethodsFemale Lewis rat were randomly divided in three groups and received an injection of Mycobacterium butyricum defining day (D) 0 to induce arthritis. An historic AIA group was used as control. Treatment began on D9, one day before arthritis onset in this model. The first group rats were treated with MTX only (n=13), the second group received MTX and FA at the same day (n=14), and the third group received FA one day after MTX administration (n=14). MTX was administrated intraperitoneally (IP) at 1 mg/kg every 3 days (4) and FA was delivered IP at 0.17 mg/kg. Arthritic index (AI) and ankle circumference (AC) were monitored to assess arthritis. Microcomputed tomography of the ankle was performed to assess bone loss. Moreover, complete blood count, transaminases, and MTX-PG were assessed.ResultsArthritis developed at D10 in all groups. AI and AC were similar in MTX groups at the various time points. At D17, arthritis severity was lower in MTX groups (AI (mean and standard deviation): 1.4 ± 1.6; AC: 35 ± 7 mm) compared to AIA historical group (AI: 3.3 ± 0.6; AC: 42 ± 4 mm). Bone erosion and bone loss parameters were similar in all groups. Cortical porosity was around 0.40% ± 0.15 and bone volume / total volume was around 0.22% ± 0.13. MTX-PG1 was found at similar levels in MTX groups and correlated negatively with AI in MTX alone or MTX and FA at the same day groups (p<0.05 and p<0.01, respectively). Finally, white and red blood cells, platelets, hemoglobin, mean corpuscular volume, transaminases, and creatinine were found at a similar level in MTX groups.ConclusionCo-administration of MTX with FA on the same day is effective compared to FA application one day after MTX. MTX metabolism was not affected, as demonstrated by the MTX-PG concentrations. The biological tolerance between the protocols was comparable. Thus, co-administration of MTX and FA seems to be possible and may be more convenient to the patients and improve compliance at the end.References[1]Albrecht K, Müller-Ladner U. Side effects and management of side effects of methotrexate in rheumatoid arthritis. Clin Exp Rheumatol 2010;28:S95-101.[2]Gaujoux-Viala C, et al. Recommendations of the French Society for Rheumatology for managing rheumatoid arthritis. Joint Bone Spine 2014;81:287–297.[3]Angelis-Stoforidis P, et al. Methotrexate polyglutamate levels in circulating erythrocytes and polymorphs correlate with clinical efficacy in rheumatoid arthritis. Clin Exp Rheumatol 1999;17:313–320.[4]Le Goff B, et al. A combination of methotrexate and zoledronic acid prevents bone erosions and systemic bone mass loss in collagen induced arthritis. Arthritis Res Ther 2009;11:R185.AcknowledgementsWe thank Ghislaine Roux, Diane Denis and Valentine Berrucas for their support in animal experiments. We thank Xavier Delavenne for MTX-PG dosage. We thank Nadia Boutahar for transaminases and creatinine dosage.Disclosure of InterestsElisa Dalix Grant/research support from: GEBRO, Mathieu Maalouf Grant/research support from: GEBRO, Sylvie Peyroche Grant/research support from: GEBRO, Arnaud Vanden-Bossche Grant/research support from: GEBRO, Charles-Antoine Arthaud Grant/research support from: GEBRO, Sophie Hodin Grant/research support from: GEBRO, Hubert MAROTTE Grant/research support from: GEBRO, Nordic Pharma, Rüdiger Müller Grant/research support from: GEBRO, Nordic Pharma