Clinical clearing of psoriasis by B-thioguanine correlates with cutaneous T-cell depletion via apoptosis - Evidence for selective effects on activated T lymphocytes

Background: Psoriasis is a common and persistent disease characterized chie fly 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 (Si gma-Aldrich, St Louis, Mo) might be an effective treatment for psoriasis vu lgaris 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 s kin before treatment and after 1 and 2 months of treatment were examined fo r disease-related abnormalities using histochemical and computer-assisted i mage-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 completel y cleared of trace disease; 6 showed marked clinical improvement; and 2 did not respond. Patients showed reductions in peripheral blood lymphocytes an d 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 se vere plaque-type psoriasis, and may be safe when given for defined periods and with careful hematologic monitoring. The mechanism of action of this dr ug seems to be the induction of apoptosis in activated T lymphocytes.