Accumulating evidence suggests that
psoriasis may be a genetically determined immunogenic, inflammatory disorder based on an ongoing autoreactive Th-1 response. Systemic immunosuppressive therapy is highly effective but fraught with longterm side effects. Our research therefore focuses on therapeutic strategies that induce local immunosuppression in the skin by topical, transepidermal delivery of immunosuppressive drugs.
SDZ 281-240 is a newly developed
macrolide of the
ascomycin type. It is immunosuppressive by mechanism of action similar to that of
FK506 but has no antiproliferative activity against keratinocytes in vitro. To evaluate whether
SDZ 281-240 exhibits antipsoriatic activity when applied topically, we tested 15 patients with severe, recalcitrant
psoriasis, using a microplaque assay in randomized, double-blind, placebo-controlled study, comparing the therapeutic efficacy of the
macrolide with a potent halogenated
corticosteroid and vehicle. All patients showed a significant improvement of psoriatic lesions treated with two concentrations of the
macrolide and, as expected, with the
corticosteroid but not with placebo. Both concentrations of the
macrolide led to clearing of
psoriasis after 10 days of treatment and biopsies confirmed a reversal of the histopathological and immunopathological phenotype of
psoriasis to that of normal skin. Thus, an
immunosuppressive agent that interferes with early T cell activation can be designed to penetrate into psoriatic lesions when applied topically and to be functionally active within the skin to suppress the ongoing psoriatic process.