Background/Purpose: Psoriatic arthritis (PsA) is the rheumatic disease most associated with metabolic disorders, including obesity and metabolic syndrome, where inflammation is a determinant key factor, increasing the risk of cardiovascular disease. Thus, searching a therapeutic strategy that could target both inflammation and metabolic complications is of great interest to reduce cardiovascular risk in these patients. Objectives: 1) To analyze the effect of Apremilast in the adipocytokine pattern, metabolic syndrome components and endothelial dysfunction in patients with PsA and metabolic syndrome (MetSyn). 2) To explore the in vitro effects of PDE4 inhibition in the endothelial function and adipocyte biology in the PsA context.

Methods: Methods: human study: twelve PsA patients diagnosed with MetSyn were given apremilast 30 mg twice daily for 6 months. Microvascular endothelial function was measured through post occlusive hyperemia using Laser-Doppler. The levels of cytokines, inflammatory and oxidative stress markers, endothelial adhesion molecules and adipokines were analyzed on serum and peripheral mononuclear blood cells (PMBCs) by ELISA and RT-PCR. Treatment of adipocytes and endothelial cells with serum from PsA patients and apremilast: 3T3L1-differentiated adipocytes and HUVECs were treated with serum 10% of PsA patients and HDs alone or with apremilast (10 mM) for 24h. The expression of adipokines (leptin, adiponectin, visfatin and resistin), adhesion molecules (e-Selectin, VCAM, ICAM), genes involved in inflammation (TNF-a, IL-1b, IL-8 and IL-6), lipid metabolism (DGAT, PLIN, HSL, GLP-1 and PPAR-g), insulin signalling (IRS-1, IRS-2 and GLUT-4) and oxidative stress (SOD-1) was analysed by RT-PCR and western blot.

Results: Results: after 6 months of treatment, Apremilast significantly reduced BMI index, insulin resistance state and levels of complement C3, inflammation, and levels of ApoB. Microvascular endothelial dysfunction was significantly restored shown by an increase of the peak flow and hyperaemia area and decreased adhesion and inflammatory molecules in serum. Altered serum adipokines profile was minimized. mRNA expression levels of inflammatory, adhesion and migration molecules and adipokines were modulated in PMBCs from PsA patients after 6 months with apremilast.

In vitro treatment of endothelial cells with apremilast significantly reduced the expression of adhesion molecules, genes involved in proliferation, adipocytokines and oxidative molecules induced by the serum of PsA patients.

In vitro treatment of adipocytes with apremilast decreased the high levels of leptin, visfatin and resistin induced by PsA serum. In addition, levels of genes involved in lypolisis, adipogenesis and insulin signalling were modulated, favoring an improvement of the insulin resistance induced by PsA serum.  

Conclusion: Conclusions: Our in vivo and in vitro studies suggest that apremilast might reduce IR, inflammation and endothelial dysfunction, parameters strongly involved in cardiovascular disease, by directly targeting adipose tissue and endothelial cells.

Supported by the Minister of Health (ISCIII, PI17/01316, RIER RD16/0012/0015) cofinanced with FEDER funds.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pde4-inhibition-could-improve-endothelial-and-adipose-tissue-dysfunction-associated-with-psoriatic-arthritis-key-processes-in-cardiovascular-disease/