Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis

Modulation of Orphan Nuclear Receptor NURR1 Expression by Methotrexate in Human Inflammatory Joint Disease Involves Adenosine A2A Receptor-Mediated Responses

“…The effect of MTX treatment on lymphocyte and monocyte proliferation and apoptosis in patients is transient and is reversed by administration of folic acid (8,66,71). Significantly, folic acid or folinic acid supplementation (1-5 mg/ day) during MTX treatment of patients with inflammatory joint disease moderates MTX toxicity with no consequences on the antiinflammatory efficacy of the drug (54,72). MTX reduces ST inflammation by decreasing infiltration of lymphocytes and monocytes, possibly through down-regulation of cytokine levels including IL-1␤ and TNF-␣ and consequently a reduction in cytokine-induced expression of adhesion molecules (18,63,66).…”

Low-Dose Methotrexate: A Mainstay in the Treatment of Rheumatoid Arthritis

“…Indeed, an early study (Tishler et al, 1988) suggested that folinic acid, when administered concomitantly with methotrexate at 3-fold higher doses than the methotrexate, reversed the anti-inflammatory effects of the drug. However, blinded and controlled trials of the concomitant administration of either folinic acid or folic acid to patients with rheumatoid arthritis taking methotrexate demonstrated no difference in therapeutic efficacy of the methotrexate and prevention of methotrexate-mediated toxicity (Morgan et al, 1990(Morgan et al, , 1994(Morgan et al, , 1998Morgan et al, 1993;Dijkmans, 1995;Cooper, 1996;Kavanaugh and Kavanaugh, 1996;Shiroky, 1996Shiroky, , 1997Hunt et al, 1997;Ortiz et al, 1998Ortiz et al, , 2000Pincus, 1998;Ravelli et al, 1999;Endresen and Husby, 2001;van Ede et al, 2001b). Indeed, although regular use of folic acid or folinic acid supplements during methotrexate therapy are not explicitly recommended, the most recent guidelines issued by the American College of Rheumatology for the therapy of rheumatoid arthritis include the suggestion that folic acid or folinic acid may be useful in the prevention of complications of methotrexate therapy (American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines, 2002).…”

“…Indeed, T cells taken from patients taking methotrexate exhibit diminished antigen-dependent proliferation of T cells that is folate-reversible (Genestier et al, 1998), although this effect is only detectable for 24 h after a dose of methotrexate. Despite the in vitro and clinical data, the observation that neither folic acid nor folinic acid reverses the anti-inflammatory effects of methotrexate in patients with rheumatoid arthritis (see above) is strong evidence that other mechanisms must account for the anti-inflammatory effects of the drug (Morgan et al, 1990(Morgan et al, , 1993(Morgan et al, , 1994(Morgan et al, , 1998Dijkmans, 1995;Cooper, 1996;Kavanaugh and Kavanaugh, 1996;Shiroky, 1996Shiroky, , 1997Hunt et al, 1997;Ortiz et al, 1998Ortiz et al, , 2000Pincus, 1998;Ravelli et al, 1999;Endresen and Husby, 2001;van Ede et al, 2001b).…”

Folic acid supplementation during methotrexate immunosuppression is not associated with early toxicity, risk of acute graft-versus-host disease or relapse following hematopoietic transplantation

“…20,21 In a meta-analysis, Ortiz et al 22 found a statistically significant reduction in mucosal and gastrointestinal side effects for RA patients receiving MTX with folic acid supplementation (odds ratio ¼ 0.21, 95% confidence interval: 0.1-0.4) compared with individuals who did not receive supplementation. Patients receiving folinic acid supplementation reported less toxicity, but also reported a more modest improvement in joint tenderness.…”