Low-dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis. results of a multicenter randomized, double-blind, placebo-controlled trial

Authors

  • Jeffrey B. Shiroky MD,

    Corresponding author
    1. Montreal General Hospital, McGill University, and the Hǒpital Notre-Dame, the Hǒpital Maisonneuve-Rosemont, and the Hǒpital St-Luc, Université de Montréal; the Credit Valley Hospital, Mississauga, Ontario; and the Hǒpital Charles Lemoyne, Greenfield Park, Quebec, Canada.
    • Division of Rheumatology, Montreal General Hospital, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada
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  • Carolyn Neville RN,

    1. Montreal General Hospital, McGill University, and the Hǒpital Notre-Dame, the Hǒpital Maisonneuve-Rosemont, and the Hǒpital St-Luc, Université de Montréal; the Credit Valley Hospital, Mississauga, Ontario; and the Hǒpital Charles Lemoyne, Greenfield Park, Quebec, Canada.
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  • John M. Esdaile MD, MPH,

    1. Montreal General Hospital, McGill University, and the Hǒpital Notre-Dame, the Hǒpital Maisonneuve-Rosemont, and the Hǒpital St-Luc, Université de Montréal; the Credit Valley Hospital, Mississauga, Ontario; and the Hǒpital Charles Lemoyne, Greenfield Park, Quebec, Canada.
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  • Denis Choquette MD,

    1. Montreal General Hospital, McGill University, and the Hǒpital Notre-Dame, the Hǒpital Maisonneuve-Rosemont, and the Hǒpital St-Luc, Université de Montréal; the Credit Valley Hospital, Mississauga, Ontario; and the Hǒpital Charles Lemoyne, Greenfield Park, Quebec, Canada.
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  • Michel Zummer MD,

    1. Montreal General Hospital, McGill University, and the Hǒpital Notre-Dame, the Hǒpital Maisonneuve-Rosemont, and the Hǒpital St-Luc, Université de Montréal; the Credit Valley Hospital, Mississauga, Ontario; and the Hǒpital Charles Lemoyne, Greenfield Park, Quebec, Canada.
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  • Mark Hazeltine MD,

    1. Montreal General Hospital, McGill University, and the Hǒpital Notre-Dame, the Hǒpital Maisonneuve-Rosemont, and the Hǒpital St-Luc, Université de Montréal; the Credit Valley Hospital, Mississauga, Ontario; and the Hǒpital Charles Lemoyne, Greenfield Park, Quebec, Canada.
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  • Vivian Bykerk MD,

    1. Montreal General Hospital, McGill University, and the Hǒpital Notre-Dame, the Hǒpital Maisonneuve-Rosemont, and the Hǒpital St-Luc, Université de Montréal; the Credit Valley Hospital, Mississauga, Ontario; and the Hǒpital Charles Lemoyne, Greenfield Park, Quebec, Canada.
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  • Mohamed Kanji MD,

    1. Montreal General Hospital, McGill University, and the Hǒpital Notre-Dame, the Hǒpital Maisonneuve-Rosemont, and the Hǒpital St-Luc, Université de Montréal; the Credit Valley Hospital, Mississauga, Ontario; and the Hǒpital Charles Lemoyne, Greenfield Park, Quebec, Canada.
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  • Anne St-Pierre MD,

    1. Montreal General Hospital, McGill University, and the Hǒpital Notre-Dame, the Hǒpital Maisonneuve-Rosemont, and the Hǒpital St-Luc, Université de Montréal; the Credit Valley Hospital, Mississauga, Ontario; and the Hǒpital Charles Lemoyne, Greenfield Park, Quebec, Canada.
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  • Lise Robidoux RN,

    1. Montreal General Hospital, McGill University, and the Hǒpital Notre-Dame, the Hǒpital Maisonneuve-Rosemont, and the Hǒpital St-Luc, Université de Montréal; the Credit Valley Hospital, Mississauga, Ontario; and the Hǒpital Charles Lemoyne, Greenfield Park, Quebec, Canada.
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  • Lucienne Bourque RN

    1. Montreal General Hospital, McGill University, and the Hǒpital Notre-Dame, the Hǒpital Maisonneuve-Rosemont, and the Hǒpital St-Luc, Université de Montréal; the Credit Valley Hospital, Mississauga, Ontario; and the Hǒpital Charles Lemoyne, Greenfield Park, Quebec, Canada.
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Abstract

Objective. To determine whether the side effects of methotrexate can be decreased by the concurrent use of leucovorin, without affecting the efficacy of the methotrexate.

Methods. We conducted a multicenter randomized, double-blind, placebo-controlled trial of leucovorin administration, 2.5–5.0 mg orally, to be given 24 hours after the single, weekly, oral dose of methotrexate. Every 3 weeks for 52 weeks, patients were evaluated for rheumatic disease activity and side effects. Dosage adjustments for both methotrexate and leucovorin were made as needed, according to a defined protocol. The primary outcome evaluated was the frequency of study withdrawals because of side effects and/or inefficacy. Secondary outcomes evaluated included the frequency of side effects and the relative efficacy of methotrexate in the leucovorin and placebo treatment groups.

Results. Ninety-two evaluable patients were analyzed (44 took leucovorin and 48 placebo). Twenty-two patients withdrew early because of side effects unresponsive to our protocol, and 1 because of inefficacy; 17 had been taking placebo and 6 had been taking leucovorin (35% versus 14%,P < 0.02). The number of visits during which side effects were reported was reduced by almost 50% in the leucovorin treatment group (P < 0.001). There were significant reductions in the frequencies of all common side effects. At 52 weeks, disease activity was similar in both patient groups.

Conclusion. The methotrexate–leucovorin protocol used significantly reduces common side effects of methotrexate therapy without significantly altering efficacy.

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