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Psoriasis is a frequent, inflammatory skin disease characterized by keratinocyte hyperproliferation and a disease- related infiltration of immune cells. Here, we identified a novel proinflammatory signaling pathway driven by cydin- dependent kinase 4 (CDK4) and CDK6 and the methyltransferase EZH2 as a valid target for psoriasis therapy. Delineation of the pathway revealed that CDK4/6 phosphorylated EZH2 in keratinocytes, thereby triggering a methylation-induced activation of STAT3. Subsequently, active STAT3 resulted in the induction of I[kappa]B[zeta], which is a key proinflammatory transcription factor required for cytokine synthesis in psoriasis. Pharmacological or genetic inhibition of CDK4/6 or EZH2 abrogated psoriasis- related proinflammatory gene expression by suppressing I[kappa]B[zeta] induction in keratinocytes. Importantly, topical application of CDK4/6 or EZH2 inhibitors on the skin was sufficient to fully prevent the development of psoriasis in various mouse models by suppressing STAT3-mediated I[kappa]B[zeta] expression. Moreover, we found a hyperactivation of the CDK4/6-EZH2 pathway in human and mouse psoriatic skin lesions. Thus, this study not only identifies a novel psoriasis-relevant proinflammatory pathway, but also proposes the repurposing of CDK4/6 or EZH2 inhibitors as a new therapeutic option for patients with psoriasis., Introduction Psoriasis is a mixed autoimmune and autoinflammatory skin disease, affecting 2% to 3% of the population worldwide. Psoriatic skin lesions are characterized by keratinocyte hyperproliferation and a massive infiltration [...]

Background: Evidence-based treatment algorithms, successfully established for asthma, are missing for atopic eczema (AE).Objectives: To investigate whether treatment according to an evidence-based algorithm is an effective and applicable concept for the management of AE.Methods: Based on a systematic literature review, we developed an evidence-based severity-score-oriented treatment algorithm for AE and compared its effectiveness to that of an individualised symptom-oriented treatment (individual therapy) in a randomised controlled trial. Sixty-three participants were randomised to algorithm (n = 32) or individual therapy (n = 31) and treated accordingly for 12 months. Study end points included difference between baseline SCORAD and mean SCORAD under treatment (primary end point), quality of life and treatment utilisation. Analysis was by intention to treat (registration: Clinical Trials.gov:NCT00148746).Results: No statistically significant differences in clinical or subjective response were observed between groups. Treatment following the algorithm and individual treatment both effectively controlled AE. Mean SCORAD reductions were 47% (95% confidence interval, CI = 38-55; algorithm) and 42% (95% CI = 29-54; individual). Clinical response was paralleled by improved quality of life in both groups. Physicians adhered to the algorithm option in 93% of their treatment decisions.Conclusion: Treatment following an evidence-based algorithm is an effective and applicable concept for the management of AE but does not show clear advantages compared to individualised treatment in a dermatological setting. [ABSTRACT FROM AUTHOR]

Systemic immunosuppressive agents are recommended for patients with atopic eczema in whom disease activity cannot be controlled adequately with topical treatments. Guidelines do not give clear advice which agents to prefer. We systematically reviewed clinical trials on systemic treatment for severe atopic eczema to provide evidence-based treatment recommendations. Standardized literature search, independent standardized assessment of eligibility and data abstraction was performed by 2 reviewers. Twenty-seven studies totalling 979 patients were included. Eleven studies consistently showed effectiveness of cyclosporine. Cyclosporine is recommended as first option for patients with atopic eczema refractory to conventional treatment. Evidence from randomized controlled trials also exists for interferon-7 and azathioprine. Although frequently used in clinical practice, systemic glucocorticosteroids have not been assessed adequately in studies. Mycophenolate mofetile showed effectiveness in 2 small uncontrolled studies. Intravenous immunoglobulins and infliximab are not recommended based on published data. [ABSTRACT FROM AUTHOR]