Supplementation with Folic Acid during Methotrexate Therapy for Rheumatoid Arthritis: A Double-Blind, Placebo-Controlled Trial

Morgan, Sarah; Baggott, Joseph E.; Vaughn, William H.; Austin, Janet; Veitch, Tonya A.; Lee, Jeannette; Koopman, William J.; Krumdieck, Carlos L.; Alarcón, Graciela S.

doi:10.7326/0003-4819-121-11-199412010-00002

Cited by 330 publications

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“…However, the effect of methotrexate treatment on lymphocyte proliferation and apoptosis in patients is transient (Յ48 hours) and is reversed by folic acid. In contrast, the antiinflammatory effects of methotrexate are lasting and are not reversed by either folic acid or folinic acid (17)(18)(19)(20)(21)(22). Previous research in animal models has demonstrated that low-dose methotrexate treatment promotes intracellular accumulation of AICAR, an intermediate in purine synthesis, and that accumulation of AICAR is associated with increased adenosine release into inflammatory exudates (1,23); adenosine mediates the antiinflammatory effects of methotrexate treatment in animal models of both acute inflammation and adjuvant arthritis (1,2,24).…”

Section: Discussionmentioning

confidence: 99%

Adenosine A_2A or A₃ receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68

Montesinos¹,

Desai²,

Delano³

et al. 2003

Arthritis & Rheumatism

189

116

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Objective. Low-dose weekly methotrexate therapy remains a mainstay in the treatment of inflammatory arthritis. Results of previous studies demonstrated that adenosine, acting at one or more of its receptors, mediates the antiinflammatory effects of methotrexate in animal models of both acute and chronic inflammation. We therefore sought to establish which receptor ( Results. Low-dose weekly methotrexate treatment increased the adenosine concentration in the exudates of all mice studied and reduced leukocyte and tumor necrosis factor ␣ accumulation in the exudates of wildtype mice, but not in those of A 2A or A 3 receptor knockout mice. Dexamethasone, an agent that suppresses inflammation by a different mechanism, was equally effective at suppressing leukocyte accumulation in A 2A knockout, A 3 knockout, and wild-type mice, indicating that the lack of response was specific for methotrexate and MX-68.Conclusion. These findings confirm that adenosine, acting at A 2A and A 3 receptors, is a potent regulator of inflammation. Moreover, these results provide strong evidence that adenosine, acting at either or both of these receptors, mediates the antiinflammatory effects of methotrexate and its analog MX-68.Low-dose weekly methotrexate is the "gold standard" of therapy in rheumatoid arthritis and other inflammatory diseases. Methotrexate's mechanism of action in the treatment of inflammatory diseases has been the subject of some controversy, although in previous studies, investigators in our group have demonstrated that adenosine mediates the antiinflammatory effects of methotrexate treatment in models of acute and chronic inflammation (1,2). Adenosine, whether released from injured cells or tissues or applied exogenously, regulates inflammation via interaction with one or more of the 4 known receptors for adenosine (A 1 , A 2A , A 2B , and A 3 ), as demonstrated by many in vitro and in vivo pharmacologic studies (for review, see ref.3). The demonstration that adenosine mediates the antiinflammatory effects of methotrexate in in vivo models of acute inflammation rests upon reversal of the antiinflammatory effects of methotrexate, either by enzymatic hydrolysis of adenosine by adenosine deaminase or by administration of adenosine receptor antagonists to reverse the antiinflammatory effects of methotrexate treatment (1,2). Although the antiinflammatory effects of methotrexate are mediated by multiple adenosine receptors in the adjuvant arthritis model of inflammation (2), the identity of the receptor(s) involved in the suppression of inflammation in models of acute inflammation has not been so well characterized.

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Section: Discussionmentioning

confidence: 99%

Adenosine A_2A or A₃ receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68

Montesinos¹,

Desai²,

Delano³

et al. 2003

Arthritis & Rheumatism

189

116

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“…A study in Psoriasis patients showed, that a dose of 20mg folic acid per week tended to decrease the efficacy of MTX (Chládek 2008). However, a study in rheumatoid arthritis showed that, administration of 5mg folic acid per week successfully reduced the hepatotoxicity without loss of efficacy (Morgan 1994). Thus, administration of 5 mg folic acid 24 hours after application of MTX is recommended (Pathirana 2009).…”

Section: Introductionmentioning

confidence: 99%

An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Warren

Mrowietz

Kiedrowski³

et al. 2017

The Lancet

102

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Background: We report the study of an intensified dosing schedule of subcutaneous methotrexate (MTX) in patients with moderate-tosevere psoriasis. Methods: In this prospective, double-blind, multicentre phase 3 study (METOP) eligible patients were 18 years or older with a diagnosis of chronic plaque psoriasis at least 6 months before baseline, had a psoriasis area and severity index (PASI) of 10 or more or 10% or greater body-surface area involvement or a dermatology life quality index (DLQI) of 10 or more and were naïve to treatment with MTX. Participants were randomly assigned 3:1 by computer-generated random sequence integrated in the electronic data capture system to receive either MTX at a starting dose of 17.5 mg/week or placebo for the first 16 weeks, followed by openlabel MTX treatment of all patients up to 52 weeks (MTX/MTX and PLC/MTX groups, respectively). Dose escalation to 22.5 mg/week was allowed after 8 weeks of MTX therapy if patients failed to achieve an at least 50% improvement of their baseline PASI (PASI50); blinding was maintained by a corresponding volume increase of placebo injections. Treatment was combined with folic acid 5 mg/week. The primary efficacy endpoint was the proportion of patients achieving a PASI75 response at week 16 analysed by intention to treat with non-responder imputation. This study is registered with the European Medicines Agency, EudraCT number 2012-002716-10. Findings: Between February 2013 and May 2015 120 patients were randomly assigned to receive subcutaneous MTX (n=91) or placebo (n=29). The primary endpoint was met; the PASI75 response rate at week 16 was 41% (n=37) in the MTX group compared to 10% (n=3) in the placebo group [p=0.0026; effect size 30.3% (95% CI 15.3-45.3) MTX vs placebo]. Subcutaneous MTX was generally well tolerated; no cases of serious infections, malignancies, major adverse cardiovascular events or deaths were noted. Serious adverse events were observed in 3 patients started on MTX during the 52-week study period. Interpretation: The study documents a favourable 52-week benefit-risk profile of subcutaneous MTX in psoriasis. The route of administration and the intensified dosing schedule should be considered when using MTX in patients with psoriasis. Role of the funding source (see also below)The study was an investigator-initiated trial supported by a grant from Medac to K.R. Manuscript 2 SummaryBackground: We report the study of an intensified dosing schedule of subcutaneous methotrexate (MTX) in patients with moderate-to-severe psoriasis.

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“…RA patients taking MTX are more likely to discontinue treatment because of adverse reactions than because of lack of efficacy (71). Stomatitis, nausea, diarrhea, and perhaps, alopecia caused by MTX may decrease with concomitant folic acid (81,82) or folinic acid (83) treatment without significant loss of efficacy. Relative contraindications for MTX therapy are preexisting liver disease, renal impairment, significant lung disease, or alcohol abuse.…”

Section: Pharmacologic Treatment Of Ramentioning

confidence: 99%

Guidelines for the management of rheumatoid arthritis: 2002 Update

2002

Arthritis & Rheumatism

1,171

176

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Supplementation with Folic Acid during Methotrexate Therapy for Rheumatoid Arthritis: A Double-Blind, Placebo-Controlled Trial

Abstract: Folic acid, an inexpensive vitamin, is safe in a broad range of doses and protects patients with rheumatoid arthritis who are taking methotrexate from toxicity while preserving the efficacy of methotrexate.

Cited by 330 publications

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Adenosine A_2A or A₃ receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68

Adenosine A_2A or A₃ receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68

An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Guidelines for the management of rheumatoid arthritis: 2002 Update

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Supplementation with Folic Acid during Methotrexate Therapy for Rheumatoid Arthritis: A Double-Blind, Placebo-Controlled Trial

Abstract: Folic acid, an inexpensive vitamin, is safe in a broad range of doses and protects patients with rheumatoid arthritis who are taking methotrexate from toxicity while preserving the efficacy of methotrexate.

Cited by 330 publications

References 0 publications

Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68

Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68

An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Guidelines for the management of rheumatoid arthritis: 2002 Update

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Adenosine A_2A or A₃ receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68

Adenosine A_2A or A₃ receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68