fumaric acid esters + methotrexate

This is a combination therapy consisting of fumaric acid esters (FAEs) and methotrexate, both of which are small molecule immunomodulatory drugs primarily used in the treatment of moderate-to-severe psoriasis. FAEs, most notably dimethyl fumarate and monoethyl fumarate salts, exert their effects through immunomodulation, anti-inflammatory activity, and antioxidative mechanisms. They modulate pro-inflammatory signal transduction pathways—particularly by depleting intracellular glutathione and inducing the anti-inflammatory stress protein heme oxygenase 1 (HO-1)—and affect various immune cells including T-lymphocytes and keratinocytes. Methotrexate is an antimetabolite that inhibits dihydrofolate reductase, leading to suppression of DNA synthesis in rapidly dividing cells such as activated lymphocytes. The combination is used off-label for patients with severe or refractory psoriasis who may not respond adequately to monotherapy. Clinical studies suggest that this combination can be safe and beneficial for long-term use; however, it requires careful monitoring due to potential additive toxicity risks (especially renal or hepatic). The main adverse effects include gastrointestinal complaints from FAEs and possible hepatotoxicity or myelosuppression from methotrexate[2][4][5].