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Biological and biochemical actions of methotrexate in psoriasis.

The purpose of this study was to determine whether the biological effects of methotrexate (MTX) in psoriasis occur by direct drug action on the psoriatic plaque or are mediated by systemic action at a site distant from skin. Injection of intralesional MTX into plaques showed a dose-related decrease in mitotic activity accompanied by a production of MTX "damaged cells" beginning 2hr after injection. These effects were similar to those found in psoriatic epidermis with systemically administered MTX. The data suggest that MTX acts directly on the psoriatic plaque rather than systemically at a distant site. In the EFA rat with a hyperproliferative epidermis intradermal MTX decreased epidermal mitoses and thymidine reversed this effect. Additionally, psoriatic patients were injected intralesionally with MTX simultaneously with either leucovorin, thymidine, uridine, or saline. Thymidine protected against the biologic effects of MTX described above in all patients. Leucovorin with MTX provided only partial protection while uridine and saline had no influence on the MTX effects. These data suggest that the biologic effects of MTX in psoriasis are mediated by the local depletion of the thymidine pool rather than by other biochemical actions. Continued efforts in the investigation of topical MTX analogs seems warranted for the treatment of psoriasis.