Lowering Interleukin-12 Activity Improves Myocardial and Vascular Function Compared With Tumor Necrosis Factor-a Antagonism or Cyclosporine in Psoriasis.

BACKGROUND: Interleukin (IL)-12 activity is involved in the pathogenesis of psoriasis and acute coronary syndromes. We investigated the effects of IL-12 inhibition on vascular and left ventricular (LV) function in psoriasis. METHODS AND RESULTS: One hundred fifty psoriasis patients were randomized to receive an anti-IL-12/23 (ustekinumab, n=50), anti-tumor necrosis factor-a (TNF-α; etanercept, n=50), or cyclosporine treatment (n=50). At baseline and 4 months post-treatment, we measured (1) LV global longitudinal strain, twisting, and percent difference between peak twisting and untwisting at mitral valve opening (%untwMVO) using speckle-tracking echocardiography, (2) coronary flow reserve, (3) pulse wave velocity and augmentation index, (4) circulating NT-proBNP (N-terminal pro-B-type natriuretic peptide), TNF-α, IL-6, IL-12, IL-17, malondialdehyde, and fetuin-a. Compared with baseline, all patients had improved global longitudinal strain (median values: -17.7% versus -19.5%), LV twisting (12.4° versus 14°), %untwMVO (27.8% versus 35%), and coronary flow reserve (2.8 versus 3.1) and reduced circulating NT-proBNP, IL-17, TNF-α, and IL-6 post-treatment (P<0.05). Compared with anti-TNF-α and cyclosporine, anti-IL-12/23 treatment resulted in a greater improvement of global longitudinal strain (25% versus 17% versus 6%,), LV twist (27% versus 17% versus 1%), %untwMVO (31% versus 27% versus 17%), and coronary flow reserve (14% versus 11% versus 4%), as well as a greater reduction of IL-12 (-25% versus -4% versus -2%), malondialdehyde (-27% versus +5% versus +26%), and NT-proBNP(-26% versus -13.6% versus 9.1%) and increase of fetuin-a (P<0.01). Pulse wave velocity and augmentation index were improved only after anti-IL-12/23 treatment and correlated with changes in global longitudinal strain, LV twisting-untwisting (P<0.05). CONCLUSIONS: In psoriasis, IL-12/23 inhibition results in a greater improvement of coronary, arterial, and myocardial function than TNF-α inhibition or cyclosporine treatment. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02144857.

Increased levels of circulating platelet-derived microparticles in psoriasis: Possible implications for the associated cardiovascular risk.

AIM: To evaluate platelet activation markers in psoriasis patients, compared to controls, and investigate their association with the inflammatory burden of psoriasis. METHODS: Forty psoriatic patients without cardiovascular disease, and 12 healthy controls were subjected to measurement of baseline platelet CD62P, CD63 and CD42b expression, platelet-leukocyte complexes, i.e., platelet-monocyte complexes (PMC), platelet-neutrophil complexes (PNC) and platelet-lymphocyte complexes, and concentrations of platelet-derived microparticles (PMPs) using flow cytometry. Both larger-size (0.5-0.9 µm) and smaller-size (< 0.5 µm) PMPs were determined. Serum interleukin (IL)-12 and IL-17 levels were also measured by enzyme-linked immunosorbent assay. The severity of psoriasis was evaluated by the Psoriasis Area Severity Index (PASI). RESULTS: PMP concentrations were significantly higher in psoriasis patients than controls [mean ± standard error of mean (SEM): 22 ± 5/µL vs 11 ± 6/µL; P = 0.018), for both smaller-size (10 ± 2/µL vs 4 ± 2/µL; P = 0.033) and larger-size (12 ± 3/µL vs 6 ± 4/µL; P = 0.014) PMPs. Platelet CD62P, CD63 and CD42b expression and circulating PMC and PNC were similar between the two groups. Lower circulating PLC were observed in psoriasis patients compared to controls (mean ± SEM: 16% ± 3% vs 23% ± 6%; P = 0.047). Larger-size PMPs were related with IL-12 levels (P < 0.001) and smaller-size PMPs with both IL-12 and IL-17 levels (P < 0.001). Total PMPs also correlated with IL-12 (P < 0.001). CD63 expression was positively correlated with both IL-12 and IL-17 (P < 0.05). Increased PASI score was associated with increased levels of larger-size PMPs (r = 0.45; P = 0.011) and increased CD63 expression (r = 0.47; P < 0.01). CONCLUSION: PMPs, known to be predictive of cardiovascular outcomes, are increased in psoriasis patients, and associated with high inflammatory disease burden. Enhanced platelet activation may be the missing link leading to cardiovascular events in psoriatic patients.

Similarities in coronary function and myocardial deformation between psoriasis and coronary artery disease: the role of oxidative stress and inflammation.

BACKGROUND: Psoriasis has been associated with increased risk for coronary artery disease (CAD). We investigated the presence of vascular and subclinical left ventricular (LV) dysfunction in patients with psoriasis compared with patients with CAD. METHODS: We compared 59 patients with psoriasis without evidence of CAD (psoriasis area and severity index [PASI], 11.5 ± 8) with 59 patients with angiographically documented CAD and 40 controls. We measured (1) the carotid-femoral pulse wave velocity (PWVc) and central augmentation index (CAI), (2) coronary flow reserve (CFR) by Doppler echocardiography, (3) flow-mediated dilation (FMD) of the brachial artery and carotid intima media thickness (IMT), (4) LV global longitudinal strain (GLS) and GLS rate (GLSR) using speckle tracking echocardiography, and (5) malondialdehyde (MDA) and interleukin-6 (IL-6) levels. RESULTS: Patients with psoriasis had higher PWVc, CAI, IMT, MDA, and IL-6 levels and lower FMD, CFR, GLS, and GLSR than did controls (P < 0.05), but they had values of these markers that were similar to those of patients with CAD (P > 0.05) after adjustment for atherosclerotic risk factors: (PWVc [m/s], 10.4 ± 1.8 vs 8.6 ± 1.5 vs 10.3 ± 2, respectively; CFR, 2.4 ± 0.1 vs 3.4 ± 0.6 vs 2.6 ± 0.6, respectively; GLS [%], -16.2 ± 4 vs -21.9 ± 1.6 vs -16.6 ± 4.5, respectively; GLSR [L/sec], -0.85 ± 0.2 vs -1.2 ± 0.12 vs -0.9 ± 0.4, respectively; MDA [nM/L], 1.68 vs 1.76 vs 1.01, respectively; IL-6 [pg/mL], 2.26 vs 2.2 vs 1.7, respectively; P < 0.05 for all comparisons). PASI was related to IMT (r = 0.67; P < 0.01). Decreased GLS was associated with increased MDA, IL-6, PWVc, CAI, and reduced CFR (P < 0.05). CONCLUSIONS: Psoriasis and CAD present similar vascular and LV myocardial dysfunction, possibly because of similar underlying inflammatory and oxidative stress processes. Vascular dysfunction in psoriasis is linked to abnormal LV myocardial deformation.