Clinical clearing of psoriasis by 6-thioguanine correlates with cutaneous T-cell depletion via apoptosis: evidence for selective effects on activated T lymphocytes.

Overview

abstract

BACKGROUND: Psoriasis is a common and persistent disease characterized chiefly by marked epidermal and endothelial cell proliferation and inflammation. These changes are likely a result of activated T lymphocytes infiltrating skin tissue or, in the case of psoriatic arthritis, the joints. OBJECTIVE: To test the hypothesis that the antimetabolite 6-thioguanine (Sigma-Aldrich, St Louis, Mo) might be an effective treatment for psoriasis vulgaris because of its antilymphocytic effects. METHODS: Twenty patients with moderate to severe plaque-type psoriasis were treated with 6-thioguanine for 6 months. The clinical disease was assessed by the psoriasis severity index. Biopsy specimens obtained from lesional skin before treatment and after 1 and 2 months of treatment were examined for disease-related abnormalities using histochemical and computer-assisted image analysis. Antiproliferative effects of 6-thioguanine were compared in human keratinocytes and mitogen-activated lymphocytes over a range of drug concentrations, while viability, cell-cycle, and DNA fragmentation analysis were done using flow cytometry-based assays. RESULTS: After 6 months of treatment, disease severity in 18 of 20 patients showed a significant response to 6-thioguanine: 12 patients were completely cleared of trace disease; 6 showed marked clinical improvement; and 2 did not respond. Patients showed reductions in peripheral blood lymphocytes and total leukocytes, but therapeutic response correlated best with cutaneous T-cell depletion. In vitro assays established that 6-thioguanine has major cytotoxic effects (apparently S-phase specific) on activated T lymphocytes via the induction of apoptosis. Keratinocytes and unactivated T cells, on the other hand, were largely unaffected by incubation with 6-thioguanine. CONCLUSIONS: 6-Thioguanine is effective for the treatment of moderate to severe plaque-type psoriasis, and may be safe when given for defined periods and with careful hematologic monitoring. The mechanism of action of this drug seems to be the induction of apoptosis in activated T lymphocytes.