The mechanisms of action of marketed TNF-blocking drugs in lesional tissues are still incompletely understood. Because psoriasis plaques are accessible to repeat biopsy, the effect of TNF/lymphotoxin blockade with etanercept (soluble TNFR) was studied in ten psoriasis patients treated for 6 months. Histological response, inflammatory gene expression, and cellular infiltration in psoriasis plaques were evaluated. There was a rapid and complete reduction of IL-1 and IL-8 (immediate/early genes), followed by progressive reductions in many other inflammation-related genes, and finally somewhat slower reductions in infiltrating myeloid cells (CD11c+ cells) and T lymphocytes. The observed decreases in IL-8, IFN-γ-inducible protein-10 (CXCL10), and MIP-3α (CCL20) mRNA expression may account for decreased infiltration of neutrophils, T cells, and dendritic cells (DCs), respectively. DCs may be less activated with therapy, as suggested by decreased IL-23 mRNA and inducible NO synthase mRNA and protein. Decreases in T cell-inflammatory gene expression (IFN-γ, STAT-1, granzyme B) and T cell numbers may be due to a reduction in DC-mediated T cell activation. Thus, etanercept-induced TNF/lymphotoxin blockade may break the potentially self-sustaining cycle of DC activation and maturation, subsequent T cell activation, and cytokine, growth factor, and chemokine production by multiple cell types including lymphocytes, neutrophils, DCs, and keratinocytes. This results in reversal of the epidermal hyperplasia and cutaneous inflammation characteristic of psoriatic plaques.
Psoriasis is a chronic, incurable, disabling skin disease characterised by red, scaly plaques. Approximately 23% of psoriasis patients also have an accompanying arthritis that can become debilitating. Psoriasis has a stigmatising effect on its victims, who often feel socially isolated. Although the exact aetiology of psoriasis is still unknown, it is clearly an immune-mediated disease. Traditional therapies for psoriasis include topical drugs, such as corticosteroids, retinoids and vitamin D3 analogues; systemic drugs, such as methotrexate, ciclosporin and retinoids; and phototherapy. These mainstays of treatment are efficacious for the treatment of severe disease; however, most are associated with toxicities or are inconvenient. Recent advances in biotechnology have produced new pharmaceuticals that interfere with immune responses thought to be involved in the pathogenesis of psoriasis and other inflammatory diseases. The immunobiologicals, one new family of drugs, consist of monoclonal antibodies and fusion proteins. Many have demonstrated efficacy in treating psoriasis. Some appear to offer safety benefits over traditional therapies; further monitoring and surveillance of these agents is required to adequately establish safety profiles. This article discusses existing and emerging treatments for moderate-to-severe psoriasis.
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