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

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 unrespon-

A deadly prescription: combination of methotrexate and trimethoprim-sulfamethoxazole

“…However, a systematic review found that concurrent use of most NSAIDs with MTX is safe, yet, anti-inflammatory doses of ASA should not be used with MTX [9]. Folate has been shown to reduce the toxicity of MTX especially GI and liver toxicity without affecting the efficacy of MTX through unknown mechanisms [10,11]. …”

Antifolate effect of methotrexate: Comment on the article by cronstein

“…I know the editorialist is trying to be fair and write a balanced review, but he has the disadvantage of not seeing these patients. Dr. Rose (1) writes that the Hennekens study (2) should be considered a "worst-case scenario" (231 cases from 110,997 patient years). Yet a random sample of claims data for the global settlement showed that 72,000 of t h e first 200,000 applicants were symptomatic (Swan SH, University of California-Berkeley: personal communication).…”

“…He states that neither "a valid statistical association" between implants and systemic disease nor "a feasible biologic mechanism" exists. I would have thought that the Hennekens study (2) proves that breast implants can make one sick. I would have thought that the angry local macrophage and lymphocytic infiltrate described by Hill, Lendavere, and Rose (8), coupled with evidence of widespread silicone/silica debris throughout the patient's body (breast capsule, lymph nodes, blood, skin, synovium) would provide sufficient biologic plausibility.…”

“…In his review of the mechanism of action of methotrexate (MTX) (l), Cronstein cites the failure of supplementation by folk or folinic acid to abrogate the efficacy of MTX in rheumatoid arthritis (RA) as evidence that folate dependency is not critical to its therapeutic effect. The reference that he uses to support this statement with respect to folinic acid, the more potent metabolite, merits close scrutiny (2). In the study cited, patients were started at the outset on a regimen of MTX with folinic acid supplementation simultaneously, so that there was no possibility of any previous antifolate effect by prior MTX therapy.…”

“…We are all guilty of selectivly citing the literature. Indeed, Dr. Jaffe might have found 4 other double-blind, controlled studies of the use of leucovorin in patients taking MTX (2)(3)(4)(5). The dose and timing of leucovorin administration varied greatly in these studies; however, reversal by leucovorin of MTXs therapeutic effects was observed in only 1 of these studies (4).…”