For dermatologists, it provides an in vivo demonstration of the effects of altered IFN-alpha signalling, potentially offering new therapeutic horizons. may upregulate interferon (IFN)-alpha activity (22). Observations in animal models and human disease increasingly implicate IFN-alpha as a key mediator in early psoriatic lesions (23), which are a recognized adverse effect of recombinant IFN-alpha therapy (24,25). Studies in anti-TNF-associated psoriasis show greater upregulation of IFN-alpha within skin plaques than in idiopathic disease (26). Immunologically, this is not unexpected because TNF-alpha is known to negatively regulate the maturation and function of plasmacytoid dendritic cells C the major source of type I IFNs, including IFN-alpha (22,23). Therapeutic inhibition of TNF-alpha FKBP4 signalling C resulting in derepression of this pathway C would increase IFN-alpha activity and could trigger psoriasis in susceptible individuals. Of note, established psoriatic lesions are characterized by enhanced sensitivity to IFN-alpha rather than persistently increased cytokine levels, which may explain why some cases of anti-TNF-induced disease persist despite the withdrawal of TNF inhibition (23). Why certain individuals are more susceptible to this than others is not clear, but differential levels of other regulating cytokines or a genetically decided sensitivity to specific cytokines may be relevant. The finding that patients developing palmoplantar pustulosis have reduced palmar sweat duct TNF activity supports this idea (27). While the mechanisms of anti-TNF-associated psoriasis are being clarified, how should a patient developing the condition be managed? A number of approaches have been reported including continuation of treatment (usually with conventional psoriasis Agomelatine therapy), switching to an alternative anti-TNF agent or complete withdrawal of the entire class of drugs. Due to the uncontrolled nature of data published in case reports, the optimal strategy is difficult to define; however, certain points should be considered (10,11): skin disease may improve or resolve in more than two-thirds of patients who simply continue anti-TNF therapy; in patients who stop treatment, persistent disease occurs in less than 5%; and up to 10% of patients whose skin condition is usually improved by stopping anti-TNF medication will develop recurrent disease if treated again with the same drug or an alternative anti-TNF agent. Ultimately, decisions need to be based on individual circumstances, including the extent and severity of skin disease, as well as the efficacy of the TNF agent in treating the condition for which it was initiated and the availability of realistic therapeutic alternatives. The majority of patients can be reassured that developing psoriasis while on anti-TNF therapy does not mandate withdrawal of treatment, nor is it necessarily associated with an adverse prognosis. Some patients improve without specific treatment of their skin disease; however, referral to a dermatologist for consideration of skin biopsy and specialist treatment is appropriate, particularly if anti-TNF treatment is to be continued. Recognition of this association has wider implications. For dermatologists, it provides an in vivo demonstration of the effects of altered IFN-alpha signalling, potentially offering new therapeutic horizons. However, it is the demonstration of another unpredicted and highly specific adverse effect associated with potent biological therapy that is surely the most important lesson here. Large Agomelatine numbers of such therapies are under development and are likely to become available shortly for conditions that include IBD. 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