Psoriatic flare after the concomitant administration of L-methylfolate and methotrexate.

Psoriasis is a chronic disease that causes erythematous patches with silver plaques and scales, often drastically affecting the quality of life of those afflicted by this disease. Psoriasis is a hyperproliferative disease, which is thought to be the result of a dysregulated immune system, specifically overactive T lymphocytes, which release excess proinflammatory cytokines and result in hyperproliferation of keratinocytes.1 Treatment for psoriasis ranges from topical corticosteroids to systemic agents such as biologic immune suppressants. One such systemic agent, methotrexate, has been used to treat moderate to severe psoriasis for more than 40 years.2 Methotrexate inhibits key steps in the metabolism of folic acid, a vitamin that contributes to numerous metabolic pathways necessary for cell survival. Folate or folinic acid is a B vitamin that is consumed in leafy greens or dietary supplements. These vitamins are necessary for crucial methylation reactions such as those seen in the synthesis of nitrogenous bases in DNA and RNA and to methylation reactions necessary for the production of amino acids and essential neurotransmitters. Metabolism of folic acid begins with its reduction into dihydrofolate and then tetrahydrofolate by dihydrofolate reductase (DHFR). Next, serine hydroxymethyltransferase converts tetrahydrofolate into 5,10 methylene tetrahydrofolate, which is converted to the metabolically active 5-methyl tetrahydrofolate (L-methylfolate) by methylenetetrahydrofolate reductase (MTHFR). Both the DHFR and the MTHFR genes are subject to numerous genetic differences that contribute to a variable rate of folate metabolism in the general population. Of note, methotrexate, which is used to treat cancers and autoimmune diseases including psoriasis, inhibits the DHRF enzyme, thereby preventing formation of active folate metabolites and inhibiting DNA replication and subsequent cell proliferation. In the case of psoriasis, methotrexate is thought to inhibit the growth of hyperproliferative T cells, preventing inflammatory damage to keratinocytes. Because of its nonspecific mechanism of action, methotrexate often induces numerous peripheral adverse effects such as gastrointestinal discomfort and hepatic dysfunction. Folic acid is therefore administered concomitantly with methotrexate. Some studies, however, indicate that this combination may be associated with decreased efficacy of methotrexate.3, 4, 5, 6, 7 L-methylfolate (Deplin Nestle Health Science; Pam Lab Inc, Covington, Louisiana) is a relatively new medical food used as an adjunctive therapy for treatment of depression. The mechanism of action is that L-methylfolate, the biologically active form of folate, is the only metabolite of folate that crosses the blood–brain barrier where it regulates the formation of the cofactor tetrahydrobiopterin (BH4), which is necessary for the synthesis of serotonin, dopamine, and norepinephrine. Because folate plays a crucial role in the central nervous system, it is proposed that individuals with decreased levels of it may experience higher rates of depression and experience a poor response to treatment with traditional antidepressants.8 Administration of L-methylfolate, therefore, is thought to improve symptoms of depression by promoting central nervous system health, especially in individuals prone to poor folate metabolism. Because of the high bioavailability of this active folate metabolite in the peripheral system, it is plausible that administration of L-methylfolate would adversely interact with the mechanism of a folate antagonist such as methotrexate, perhaps to a higher degree than folate supplementation, although this has not been studied to date. Here we present the case of a patient successfully treated with methotrexate for chronic plaque psoriasis who experienced a sudden psoriatic flare after the use of L-methylfolate for the treatment of depression.