Folate supplementations for methotrexate therapies in cancer and arthritis: rationales revisited

For many decades, the folate antagonist methotrexate (MTX) has served as anchor drug in the treatment of selected cancer types, e.g., (pediatric) leukemia, and chronic inflammatory and joint destructive diseases like rheumatoid arthritis (RA). MTX treatment of leukemia commonly includes high dose MTX therapy (1–10 g/m) [1], whereas RA treatment is based on low-dose MTX therapy (7.5–30 mg/wk) [2]. In both treatment modalities, therapy-induced toxicities, e.g., mucositis with high dose MTX and liver toxicities with long-term low dose MTX, are antagonized by post-supplementation of folates; leucovorin (LV) after HD-MTX and folic acid with low-doseMTX. Despite longstanding experience with various MTX/folate supplementation schedules in clinical practice, it is still an unresolved issue what is the most optimal schedule of MTX and folate supplementation is in terms of dosing and timing of folate supplementation. Furthermore, given the large variation in folic acid supplementation dosages prescribed with MTX treatment of RA patients worldwide, awareness for folate over-supplementation and concomitant long term adverse effects is called for. This commentary will address this issue in light of recent insights from laboratory, nutritional and clinical studies.