Introduction

Psoriasis is characterised by chronic cutaneous inflammation in up to 3% of the population. A variable proportion (8%-35%) of such patients develop articular involvement that in turn exhibits a clinical spectrum including dactyilits, synovitis, enthesitis, spondylarthritis and arthritis mutilans. Topical and systemic immune modulatory agents used in various protocols form the current therapeutic state-of-the-art dependent upon disease severity and treatment resistance. The utility of therapeutic neutralisation of single cytokines in chronic inflammatory and autoimmune diseases has been unequivocally demonstrated in the success of biologic agents such as etanercept and infliximab. These agents target TNFa and have proven efficacy now across a range of diseases including rheumatoid arthritis, inflammatory bowel disease and uveitis (Taylor et al. 2001). Recent studies suggest that TNFa blockade is efficacious in psoriasis with remarkable responses detected via a number of clinical outcome measures in a substantial proportion of patients (Chaudhari et al. 2001; Leonardi et al. 2003). Similarly, improvements in articular disease in psoriatic arthritis is observed with etanercept and infliximab, and importantly the rate of articular destruction assessed by radiographic progression appears retarded, or arrested in some patients (Mease et al. 2000). Disease, however, recurs on discontinuation of therapy and partial or nonresponders remain problematic. In other inflammatory diseases, response rates may be improved with combination of methotrexate and/or treatment earlier in the disease course (Taylor et al. 2001; Klareskog et al. 2004). At present, it is uncertain whether combination therapies, revised dose schedules or indeed therapeutic strategies will be required to improve on existing response rates in psoriasis. It is clear, however, that there remains unmet clinical need. In particular, there is a critical requirement for agents that might not only suppress inflammation but also promote long-term recovery of peripheral tolerance and thereby disease remission, eventually achieved by 'drug-free' means.

Vital lessons have been learned in the therapeutic targeting of TNFa and of additional cytokines, particularly IL-1. Since single cytokine blockade can be successful despite the well-recognised functional overlap and pleiotropy of many described pro-inflammatory cytokines, this speaks to synergy whereby some cytokines may operate as 'keystones' or 'critical checkpoints' in the inflammatory cascade. Moreover, there appears to be an achievable therapeutic window in which critical immune suppression can be avoided whilst therapeutic response is achieved. A model has recently emerged that provides for rational choice of cytokines as targets. Cytokine expression should be examined in the tissue of interest in which functional bioactivities may be defined. Thereafter cytokines may be targeted in rodent models believed to reflect some component of human disease activity. Finally proof of concept trials may provide necessary data prior to continuing with appropriately powered placebo-controlled clinical trials. Pitfalls are evident in this approach, e.g. the relative disappointment of IL-1 blockade in humans relative to animal model studies. Nevertheless, this approach provides a useful basis upon which to discuss cytokine activities proposed as potential targets in chronic inflammatory diseases. This chapter will describe the basic biology of interleukin-15, an innate response cytokine that exhibits broad functional pleiotropy and that has been implicated in inflammatory dermatoses and malignancies. Thereafter it will describe current understanding of the role played by IL-15 in au-toimmunity. Finally, it will describe our current understanding of the biology of IL-15 in the context of psoriatic inflammation in skin and joints.

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