Methotrexate is extremely effective for control of severe psoriasis; however, its mode of action is not yet fully understood. Deoxyribonucleic acid synthesis and its inhibition by methotrexate in normal and psoriatic epidermis was studied autoradiographically. Intradermally given methotrexate inhibits DNA synthesis for 12 to 16 hours in normal and psoriatic skin. Intramuscularly it causes complete inhibition in psoriasis but only partial inhibition in normal epidermis. Psoriatic epidermis is more sensitive to the action of methotrexate than normal epidermis. This may be due to increased drug sensitivity of the individual abnormal cell, as well as to increased percentage of psoriatic cells in the methotrexate-susceptible part of the cell cycle (S period). The local (cutaneous) effect of methotrexate to inhibit DNA synthesis suggests the further investigation of a topically administered form of methotrexate or its analogues for the treatment of psoriasis.
Weinstein GD, Goldfaden G, Frost P. MethotrexateMechanism of Action on DNA Synthesis in Psoriasis. Arch Dermatol. 1971;104(3):236-243. doi:10.1001/archderm.1971.04000210010003