Psoriasis is linked to systemic inflammation and cardiovascular comorbidities, but studies of the underlying cellular mechanisms are lacking. The NLRP3 inflammasome is genetically associated with psoriasis, and its activation is increasingly linked with cardiovascular disease. In this study, we show that patients with psoriasis exhibited higher plasma levels of inflammasome-generated IL-1b and IL-18, without any correlation to skin lesion severity. Increased constitutive expression of the inflammasome sensors NLRP3, NLRP1, and AIM2 was found in peripheral blood cells of the patients and also of those with mild disease, and this was accompanied by an increased caspase-1 reactivity in the myeloid blood subsets. TNF-a was found to activate selectively the NLRP3 inflammasome without the requirement for a priming signal. TNF-a was found to signal through the TNFR-caspase-8-caspase-1 alternative inflammasome pathway, which proceeds independently of pyroptosis. Patients who received anti-TNF therapy had normalized plasma IL-1b and IL-18 levels as well as normalized caspase-1 reactivity. This was in contrast to the patients treated with methotrexate who exhibited persistent, increased caspase-1 reactivity. Thus, we show that the TNF-aemediated activation of NLRP3 inflammasomes in patients with psoriasis may contribute to systemic inflammation. Anti-TNF therapy normalized inflammasome function, suggesting a mechanism for the cardiovascular risk-reducing effect.

Chemokines may contribute to the systemic inflammation that is linked to the increased risk of co-morbidities in patients with psoriasis. The aim of this study was to investigate circulating chemokines in patients with psoriasis and their relationship to disease severity. Analysis of plasma levels of chemokines in patients with psoriasis before narrowband ultraviolet B (UVB) therapy revealed increased expression of Th1-associated CXCL9 and -10, Th2-associated CCL17 and CCL22, and Th17-associated CCL20. CCL20 correlated with disease severity. UVB therapy reduced skin symptoms, but did not affect the chemokine levels in plasma. Anti-CD3 and anti-CD28-mediated activation of peripheral blood mononuclear cells (PBMCs) caused a higher secretion of Th2 cytokine interleukin (IL)-13 by PBMCs from patients with psoriasis than from healthy controls. The sustained high expression of inflammatory chemokines is a potential link to systemic inflammation in psoriasis. UVB therapy may be a more effective treatment of local rather than systemic inflammation.

Background: Psoriasis is associated with a systemic inflammation and an increased frequency of

Background: In psoriasis, a common immune-mediated disease affecting 2–3% of the population worldwide, there is an increased prevalence of extracutaneous diseases including obesity, the metabolic syndrome, and cardiovascular disease. This is believed to be linked to systemic inflammation. In previous studies, we have explored various markers in plasma and serum to characterize the ongoing systemic inflammation in psoriasis patients compared to controls. We have identified several markers that were altered in psoriasis patients, but which all were unresponsive to narrowband UVB (NB-UVB) treatment. Objective: The objective of the study was to evaluate the effect of NB-UVB treatment on markers of cardiovascular risk and systemic inflammation in psoriasis. Methods: The levels of 17 potential biomarkers with an association with cardiovascular risk were quantitated in plasma from 37 age- and gender-matched psoriasis patients and controls at baseline and in 21 psoriasis patients after 12 weeks of NB-UVB treatment to identify a systemic treatment response. Results: We identified the mediators endocan-1, CXCL16, and sVEGFR1, which were systemically decreased in psoriasis at baseline, as well as FABP3, FABP4, and sIL-1R1, which showed normal baseline levels. After 10–12 weeks of NB-UVB treatment, endocan-1 and CXCL16 were restored to normal levels, while sVEGFR1, FABP3, FABP4, and sIL-1R1 showed a significant reduction. Conclusion: The current study expands the number of potential biomarkers in psoriasis by including a greater number and variety of mediators, approaching the systemic inflammation from additional vantage points, including soluble immune receptors and adipocyte contribution, to provide a more complete picture of the systemic inflammatory state in psoriasis.

Domperidone increases blood pressure and heart rate without inducing nocturnal hypertension in apomorphine treated patients with idiopathic Parkinson's disease. Increased heart rate by domperidone is a new finding but the clinical significance is unclear and requires further investigation.