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Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study.
Arthritis Rheum 2001; 44(7):1515-24AR

Abstract

OBJECTIVE

To study the effect of folates on discontinuation of methotrexate (MTX) as single-drug antirheumatic treatment due to toxicity, to determine which type of adverse events are reduced, to study the effects on the efficacy of MTX, and to compare folic with folinic acid supplementation in a 48-week, randomized, double-blind, placebo-controlled trial.

METHODS

Patients with active RA (n = 434) were randomly assigned to receive MTX plus either placebo, folic acid (1 mg/day), or folinic acid (2.5 mg/week). The initial MTX dosage was 7.5 mg/week; dosage increases were allowed up to a maximum of 25 mg/week for insufficient responses. Folate dosages were doubled once the dosage of MTX reached 15 mg/week. The primary end point was MTX withdrawal because of adverse events. Secondary end points were the MTX dosage and parameters of efficacy and toxicity of MTX.

RESULTS

Toxicity-related discontinuation of MTX occurred in 38% of the placebo group, 17% of the folic acid group, and 12% of the folinic acid group. These between-group differences were explained by a decreased incidence of elevated liver enzyme levels in the folate supplementation groups. No between-group differences were found in the frequency of other adverse events or in the duration of adverse events. Parameters of disease activity improved equally in all groups. Mean dosages of MTX at the end of the study were lower in the placebo group (14.5 mg/week) than in the folic and folinic acid groups (18.0 and 16.4 mg/week, respectively).

CONCLUSION

Both folate supplementation regimens reduced the incidence of elevated liver enzyme levels during MTX therapy, and as a consequence, MTX was discontinued less frequently in these patients. Folates seem to have no effect on the incidence, severity, and duration of other adverse events, including gastrointestinal and mucosal side effects. Slightly higher dosages of MTX were prescribed to obtain similar improvement in disease activity in the folate supplementation groups.

Authors+Show Affiliations

University Medical Center St Radboud, Nijmegen, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11465701

Citation

van Ede, A E., et al. "Effect of Folic or Folinic Acid Supplementation On the Toxicity and Efficacy of Methotrexate in Rheumatoid Arthritis: a Forty-eight Week, Multicenter, Randomized, Double-blind, Placebo-controlled Study." Arthritis and Rheumatism, vol. 44, no. 7, 2001, pp. 1515-24.
van Ede AE, Laan RF, Rood MJ, et al. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2001;44(7):1515-24.
van Ede, A. E., Laan, R. F., Rood, M. J., Huizinga, T. W., van de Laar, M. A., van Denderen, C. J., ... van de Putte, L. B. (2001). Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis and Rheumatism, 44(7), pp. 1515-24.
van Ede AE, et al. Effect of Folic or Folinic Acid Supplementation On the Toxicity and Efficacy of Methotrexate in Rheumatoid Arthritis: a Forty-eight Week, Multicenter, Randomized, Double-blind, Placebo-controlled Study. Arthritis Rheum. 2001;44(7):1515-24. PubMed PMID: 11465701.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. AU - van Ede,A E, AU - Laan,R F, AU - Rood,M J, AU - Huizinga,T W, AU - van de Laar,M A, AU - van Denderen,C J, AU - Westgeest,T A, AU - Romme,T C, AU - de Rooij,D J, AU - Jacobs,M J, AU - de Boo,T M, AU - van der Wilt,G J, AU - Severens,J L, AU - Hartman,M, AU - Krabbe,P F, AU - Dijkmans,B A, AU - Breedveld,F C, AU - van de Putte,L B, PY - 2001/7/24/pubmed PY - 2001/8/17/medline PY - 2001/7/24/entrez SP - 1515 EP - 24 JF - Arthritis and rheumatism JO - Arthritis Rheum. VL - 44 IS - 7 N2 - OBJECTIVE: To study the effect of folates on discontinuation of methotrexate (MTX) as single-drug antirheumatic treatment due to toxicity, to determine which type of adverse events are reduced, to study the effects on the efficacy of MTX, and to compare folic with folinic acid supplementation in a 48-week, randomized, double-blind, placebo-controlled trial. METHODS: Patients with active RA (n = 434) were randomly assigned to receive MTX plus either placebo, folic acid (1 mg/day), or folinic acid (2.5 mg/week). The initial MTX dosage was 7.5 mg/week; dosage increases were allowed up to a maximum of 25 mg/week for insufficient responses. Folate dosages were doubled once the dosage of MTX reached 15 mg/week. The primary end point was MTX withdrawal because of adverse events. Secondary end points were the MTX dosage and parameters of efficacy and toxicity of MTX. RESULTS: Toxicity-related discontinuation of MTX occurred in 38% of the placebo group, 17% of the folic acid group, and 12% of the folinic acid group. These between-group differences were explained by a decreased incidence of elevated liver enzyme levels in the folate supplementation groups. No between-group differences were found in the frequency of other adverse events or in the duration of adverse events. Parameters of disease activity improved equally in all groups. Mean dosages of MTX at the end of the study were lower in the placebo group (14.5 mg/week) than in the folic and folinic acid groups (18.0 and 16.4 mg/week, respectively). CONCLUSION: Both folate supplementation regimens reduced the incidence of elevated liver enzyme levels during MTX therapy, and as a consequence, MTX was discontinued less frequently in these patients. Folates seem to have no effect on the incidence, severity, and duration of other adverse events, including gastrointestinal and mucosal side effects. Slightly higher dosages of MTX were prescribed to obtain similar improvement in disease activity in the folate supplementation groups. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/11465701/Effect_of_folic_or_folinic_acid_supplementation_on_the_toxicity_and_efficacy_of_methotrexate_in_rheumatoid_arthritis:_a_forty_eight_week_multicenter_randomized_double_blind_placebo_controlled_study_ L2 - https://doi.org/10.1002/1529-0131(200107)44:7<1515::AID-ART273>3.0.CO;2-7 DB - PRIME DP - Unbound Medicine ER -