The significant findings of the randomized clinical trials are reviewed below. Table 1 provides additional details and expands on the significant results of each study.
Several studies have evaluated the cardiometabolic impact of TNF-α inhibitor agents in psoriasis patients. One study evaluated how treatment with TNF-α inhibitors in psoriatic patients with type II diabetes impacts insulin resistance and insulin sensitivity . Seventy psoriasis patients were randomized to receive treatment for 24 weeks with either TNF-α inhibitors (including etanercept, adalimumab, and infliximab) or a control (consisting of treatment with topicals, cyclosporine, or methotrexate). When compared to the control group, patients treated with TNF-α inhibitors showed a significant decrease from baseline in both fasting plasma glucose [− 2.74 vs. − 0.02 (p < 0.01)] and hemoglobin A1c [− 1.3% vs. 0.2% (p < 0.01)] values. Treatment with TNF-α inhibitors also led to a significantly greater change in mean insulin resistance, which was assessed using the homeostasis model assessment (HOMA), when compared to control patients treated with other agents [1.2 vs. − 0.3 (p < 0.01)].
Treatment with etanercept has demonstrated variable cardiovascular benefits in randomized clinical trials. An analysis of previously frozen patient blood from a randomized, double-blind, placebo-controlled study evaluated the effect of etanercept on C-reactive protein (CRP), which is a contributor to atherosclerosis and a predictor of coronary artery disease . For the first 12 weeks, patients with psoriasis and psoriatic arthritis were randomized to receive either varying dosages of etanercept (25 mg once weekly, 25 mg twice weekly, or 50 mg twice weekly) or placebo. From week 12 to week 24, patients initially on placebo received etanercept 25 mg twice weekly. Treatment with etanercept for 12 weeks resulted in significantly greater reductions in median CRP from baseline in psoriasis patients with and without psoriatic arthritis compared to placebo [2.7 mg vs. 0.1 mg and 1.0 mg vs. 0.1 mg, respectively (p < 0.001)]. Placebo patients were able to achieve comparable results in CRP reduction after 12 weeks of etanercept therapy at week 24.
The effect of etanercept treatment on metabolic parameters and risk factors has also been evaluated. A double-blind randomized pilot study treated 12 psoriasis patients with two or more risk factors for type 2 diabetes (in accordance with the American Diabetes Association) with either etanercept 25 mg twice weekly or placebo for 2 weeks . While the etanercept group did have a significant decrease in fasting serum insulin levels from baseline [baseline: 146 ± 117 vs. week 2: 111 ± 87 (p = 0.04)], there was no significant difference in insulin sensitivity or secretion. Furthermore, treatment with etanercept did not significantly impact any of the other metabolic characteristics, including fasting serum glucose, cholesterol, or uric acid.
A more recent study with a longer treatment duration assessed the impact of etanercept on cardiometabolic biomarkers, including cholesterol, plasma insulin, quantitative insulin sensitivity check index (QUICKI), apolipoprotein (APO), and high-sensitivity CRP (hs-CRP) . Plaque psoriasis patients were randomized double blind to etanercept 50 mg once or twice weekly for 12 weeks. Following 12 weeks of treatment with etanercept once and twice weekly, statistically significant mean percent changes from baseline were observed in several biomarkers, including QUICKI (− 2.2% and − 2.7%, respectively), Apo A1 (3.2% and 2.8%), Apo B:Apo A1 ratio (− 3.5% and − 4.6%), and hs-CRP (− 65.5% and − 74.4%) (p < 0.05). In addition, etanercept twice weekly resulted in significant mean percent changes in fasting plasma insulin (15.9%) and high-density lipoprotein cholesterol (HDL-C, 2.9%) from baseline at week 12 (p < 0.05).
Adalimumab has demonstrated mixed efficacy in reducing cardiovascular and metabolic risk factors. Two studies demonstrated that treatment with adalimumab resulted in no significant improvement in vascular inflammation of the aorta or carotid arteries [15, 16]. One randomized, double-blind, placebo-controlled study evaluated 107 psoriasis patients randomized to treatment with either adalimumab for 52 weeks or placebo for 16 weeks followed by adalimumab for 52 weeks . Vascular inflammation was measured using positron emission tomography–computed tomography (PET/CT) with an injection of radiolabeled 18F-fluoro-2-deoxy-D-glucose (18F-FDG), which accumulates in the macrophage-dense atherosclerotic plaques in inflamed vessel walls. FDG uptake was then quantified via the vessel wall target-to-background ratio (TBR), providing a noninvasive measure of arterial plaque inflammation . No significant differences in aortic or carotid artery TBR were demonstrated after 16 weeks of treatment with adalimumab. In fact, TBR in the carotid arteries increased from baseline after 52 weeks of adalimumab (p = 0.046). However, 16 weeks of treatment with adalimumab resulted in a statistically significant decrease from baseline in hs-CRP when compared to placebo [− 28.67% vs. 1.09%, respectively (p = 0.012)].
The second study, which confirmed those findings, was a randomized, double-blind, placebo-controlled trial comparing the effects of adalimumab, narrowband ultraviolet B (NB-UVB) phototherapy, and placebo on vascular inflammation of the ascending aorta and metabolic biomarkers . Following the randomization phase (12 weeks), all patients either continued or started on adalimumab for a total of 52 weeks of treatment. After 12 weeks of treatment with adalimumab and NB-UVB, there was no significant change in maximum TBR compared to placebo [change compared to placebo: 0.64% (p = 0.795) and − 1.60% (p = 0.540), respectively]. NB-UVB did result in a significantly decreased TBR compared to baseline [change compared to baseline: − 4.09% (p = 0.031)]. Treatment with 52 weeks of adalimumab resulted in a significant decrease in TBR when compared to the absolute study baseline, but not to the adalimumab treatment baseline [− 3.80% (p = 0.005) and 0.02% (p = 0.987), respectively]. Following 12 weeks of treatment, both adalimumab and phototherapy resulted in significant decreases in serum CRP and IL-6 when compared to placebo (p < 0.05). Furthermore, treatment with adalimumab for 12 weeks also resulted in significant reductions in TNF-α, a key proinflammatory cytokine, and glycoprotein acetylation (GlycA), which is positively associated with risk of death and major cardiovascular events [vs. placebo (p < 0.01)] . Following 52 weeks of treatment with adalimumab, significant improvements were noted in the biomarker levels of TNF-α, GlycA, and CRP, but significantly negative impacts were seen in both IL-6 and high-density lipoprotein particle (HDL-P) levels (p < 0.05). Neither treatment had a significant impact on serum glucose metabolism markers.
Several studies have evaluated the impact of secukinumab on cardiovascular disease parameters such as endothelial dysfunction, vascular inflammation, and myocardial deformation. A randomized, double-blind, placebo-controlled study evaluated the impact of secukinumab versus placebo on flow-mediated dilation (FMD), which is a measure of vascular endothelial function and an early predictor of future cardiovascular events [19, 20]. In total, 151 patients were randomized to either secukinumab 150 mg or 300 mg for 52 weeks or placebo for 12 weeks followed by one of the two secukinumab doses until week 52. Although no differences in FMD were noted at week 12 between secukinumab groups and placebo, significant improvements in FMD from baseline were present in both the secukinumab 150 mg and secukinumab 300 mg groups after 52 weeks of treatment [+ 2.1% (p = 0.0034) and + 2.1% (p = 0.0022), respectively]. Additionally, when compared to placebo at week 12 and baseline at week 52, secukinumab treatment was associated with a decrease in adiponectin, a biomarker that is suggested to be protective against the development of hypertension, insulin resistance, and cardiovascular disease (p < 0.05) . No other clinically relevant changes were demonstrated in arterial stiffness, total plaque burden of the carotid artery or aorta, or serum biomarkers of systemic inflammation, lipids, or glucose metabolism.
The impact of secukinumab on vascular inflammation via 18F-FDG PET/CT scans and serum cardiometabolic biomarkers was evaluated in a randomized, double-blind, placebo-controlled study of psoriasis patients . Patients were randomized to either secukinumab 300 mg or placebo for the first 12 weeks. Following this, placebo patients were switched to secukinumab for the remainder of the 52-week study. Evaluation with 18F-FDG PET/CT scans revealed no significant changes in TBR of the aorta following secukinumab treatment. Furthermore, no significant differences at week 12 in any markers of inflammation, insulin resistance, diabetic predictors, or adiposity were noted. At week 52, treatment with secukinumab was associated with a significant reduction from baseline in TNF-α (p = 0.0063) and ferritin (p = 0.035), a biomarker positively associated with cardiovascular risk factors and occurrence of insulin resistance .
Further investigation demonstrated the effects of secukinumab on vascular and left ventricular (LV) function in patients with plaque psoriasis and psoriatic arthritis . In the 1-year study, 100 psoriatic patients were randomized to receive secukinumab or cyclosporine, and 50 psoriatic patients who were beginning treatment with methotrexate served as control. Secukinumab resulted in greater improvements in LV myocardial function (LV global longitudinal strain, global longitudinal strain rate, global longitudinal strain rate at early diastole, and LV twisting), arterial elasticity (pulse wave velocity), and coronary flow reserve when compared to both cyclosporine and methotrexate. Oxidative stress, as measured by malondialdehyde and protein carbonyl levels, was also significantly improved after 1 year of secukinumab treatment (p = 0.03 and p = 0.02, respectively). However, cyclosporine was associated with a negative effect on oxidative stress markers (p < 0.05) and on arterial elasticity, as measured by pulse wave velocity [month 4: + 11%, month 12: + 14% (p = 0.02)].
The effect of ustekinumab on aortic vascular inflammation was evaluated via TBR with 18F-FDG PET/CT scans and biomarkers of systemic inflammation, lipids, and glucose metabolism in a phase IV, randomized, double-blind, placebo-controlled trial . In total, 43 patients were randomized to either ustekinumab for 52 weeks or placebo for 12 weeks followed by ustekinumab for an additional 52 weeks. At week 12, psoriasis patients treated with ustekinumab were found to have a statistically significant (18.65%) reduction in aortic vascular inflammation compared to placebo (p = 0.001), although the improvement was transient. At week 52 of treatment, ustekinumab demonstrated a neutral effect on vascular inflammation in both groups when compared to baseline. Ustekinumab treatment was also associated with several statistically significant changes to serum biomarkers at week 12 when compared to placebo. Decreases in vascular cell adhesion molecule 1, a mediator in the development of atherosclerosis, and IL-2 receptor α, which is positively associated with cardiovascular mortality and incident stroke and heart failure, were noted at week 12 [vs. placebo (p < 0.05)] . However, ustekinumab treatment for 12 weeks also resulted in increases in LDL and several other apolipoprotein-B lipoproteins [vs. placebo (p < 0.05)]. Following 52 weeks of treatment, both ustekinumab treatment groups had significant decreases in IL-1β, IL-17a, and IL-18 and significant increases in IL-12/23, high-density lipoprotein particle size (hdl-z), large very-low-density lipoprotein particle number (vldl-p), and leptin compared to baseline (p < 0.05).
Other systemic agents
The impact of tofacitinib versus etanercept on inflammatory and cardiovascular proteins was investigated with archived blood samples from 266 psoriasis patients in a randomized, double-blind, phase III psoriasis trial . Following 4 weeks of treatment with tofacitinib and etanercept, IL-6, CCL20, and CXCL10, which are reported to be common inflammatory molecules in both psoriasis and atherosclerosis, were reduced [fold change (FCH) > 1.2 and false discovery rate (FDR) < 0.05]. Furthermore, only tofacitinib responders who achieved PASI 75 demonstrated a significant reduction in some psoriasis-associated cardiovascular proteins, including CHI3L1, E-selectin, hK11, IL-16, TNF receptor 1, TNF-related activation-induced cytokine, and matrix metalloproteinase-12 (FCH > 1.2 and FDR < 0.05).
While methotrexate served as a control for two of the abovementioned studies [11, 24], it was also studied in a randomized, double-blind, placebo-controlled trial evaluating vascular inflammation as measured by 18F-FDG PET/CT . A total of 15 psoriasis patients were randomized to four different treatments: methotrexate, methotrexate and pioglitazone, pioglitazone, or placebo. Vascular inflammation of the ascending aorta was higher in psoriasis patients at baseline compared to historical controls. However, no significant difference in aortic vascular inflammation, which was calculated through the maximum standardized uptake value of FDG in the arterial wall, was observed in any of the treatment groups following 12 weeks of treatment.