Effectiveness of biological therapy in reducing psoriasis-related cardiovascular risk

KEYWORDS:

• Psoriasis
• biological therapy
• cardiovascular disease
• prevention

1. Introduction

Psoriasis is a chronic inflammatory disease of the skin, associated with systemic inflammation leading to the concept of ‘psoriatic march’ or ‘inflammatory skin march.’ In particular, psoriasis is associated with an increased risk of developing severe vascular events such as myocardial infarction and stroke; the prevalence of cardiovascular (CV) risk factors such as hypertension, diabetes mellitus, dyslipidemia, obesity, subclinical atherosclerosis and smoking is increased. Consequently, mortality rates have been found to be increased in patients with psoriasis, mainly due to CV comorbidities, with a life expectancy decreased by approximately 5 years in moderate to severe cases [1]. CV disease (CVD) constitutes the first cause of mortality among psoriasis patients, with a higher risk among severe patients (psoriatic patients have a risk for myocardial infarction 2.4 times higher than general population, and a 48% and 38% higher risk for stroke and CV mortality, respectively). Duration of psoriasis has also been associated with CVD risk [2,3].

This expert opinion endpoint is to review the clinical and pathogenetic correlation between psoriasis and CVD and to assess the effectiveness of biological therapies in reducing CV risk.

2. Psoriasis and CVD

Atherosclerosis is the major pathological change preceding myocardial infarction and stroke. Psoriatic patients have shown an increased arterial stiffness compared to healthy controls, with a positive correlation between arterial stiffness and psoriasis disease duration [1]. Cumulative exposure to systemic inflammation in psoriatic patients may promote impaired insulin sensitivity, endothelial dysfunction, increased aortic stiffness and vascular inflammation contributing to CVD. Coronary computed tomography has been used to quantify coronary artery calcification (CAC) as a biomarker of coronary atherosclerosis and a predictor of future CV events in psoriatic patients: an increase in CAC prevalence (59.4% vs 28.1%, p = 0.015) and severity (3.7 vs 0.0, p = 0.019), assessed with Agatston score, has been demonstrated in individuals with a negative history of current or previous heart diseases [4].

Psoriasis skin disease severity was associated with aortic vascular inflammation (AVI) using 18 fluorodeoxyglucose positron emission tomography or computed tomography; an improvement in AVI has been observed in those who had higher than 75% reduction in skin disease severity [5].

Epicardial fat tissue has been shown to be a CV risk factor associated with the development of atherosclerosis: epicardial fat thickness (measured by transthoracic echocardiography or computed tomography) is greater in patients with psoriasis compared to healthy controls, which may contribute to the greater CV risk in patients with psoriasis [1].

3. CVD and psoriasis: a common pathogenesis

Psoriasis and atherosclerosis share interleukin (IL)12/Th1 and IL23/Th17 pathways, leading either to atherosclerotic plaque growth promoted by tumor necrosis factor-α (TNFα) and interferon-γ or to plaque vulnerability caused by intraplaque hemorrhages and angio-neogenesis promoted by Th17 effector cytokines. Th1 and Th17 proliferation would be favored by an increase in Treg function leading to TGFβ and IL10 higher levels; this is associated with anti‐inflammatory and CV protective effects [2,6]. Increased IL23 levels induced by the granulocyte‐macrophage colony‐stimulating factor are able to promote plaque instability by increasing macrophages and dendritic cells susceptibility to apoptosis and by downregulating Bcl2, which triggers Th1 and Th17 responses and releases reactive oxygen species (ROS) [2].

Adipokines such as leptin, resistin, and adiponectin can contribute to immune and inflammatory pattern: leptin and resistin increase proinflammatory cytokines such as TNFα and CXCL8, whereas adiponectin is an anti-inflammatory adipokine that increases the secretion of anti-inflammatory cytokines such as IL10 and plays an anti-inflammatory role in keratinocytes. In the general population, leptin and resistin levels are lower than in psoriatic patients, while adiponectin concentrations are higher [7,8]. Moreover, also platelets have been linked to the development of atherosclerosis. Regarding this, markers of platelet activation, including mean platelet volume, platelet-neutrophil, and lymphocyte aggregates, are elevated in psoriasis and correlate with psoriasis severity, stressing another interplay [9].

4. Biological therapies in reducing CV risk

Biological therapies are the first-line treatment in patients with moderate to severe psoriasis. Currently approved biologics to treat psoriasis are TNFα (adalimumab, certolizumab pegol, etanercept, and infliximab), IL17 (bimekizumab, brodalumab, ixekizumab, and secukinumab), IL12/IL23 (ustekinumab), IL23 (guselkumab, risankizumab, and tildrakizumab) inhibitors, as shown in Table 1.

Table 1. Biologics for psoriasis treatment.

Mechanism of action	Drug names
TNFα inhibitors	Adalimumab
	Certolizumab pegol
	Etanercept
	Infliximab
IL17 inhibitors	Bimekizumab
	Brodalumab
	Ixekizumab
	Secukinumab
IL12/IL23 inhibitors	Ustekinumab
IL23 inhibitors	Guselkumab
	Risankizumab
	Tildrakizumab

In recent years, biological drugs have shown to target key inflammatory molecules involved in the pathogenesis of both psoriasis and CVD:

TNFα inhibitors demonstrated a reduction in endothelial dysfunction inflammatory-related markers such as C-reactive protein and vascular endothelial growth factor and also with CV inflammatory markers such as glycoprotein acetylation (GlycA), IL6, and TNFα. TNFα inhibitor’s role in modulating psoriasis CV risk was further demonstrated by their ability to reverse the microvascular dysfunction measured by coronary flow reserve. The same drugs have shown controversial role, since the efficacy of infliximab was assessed in the Antihypertensive Treatment of Acute Cerebral Hemorrhage trial, where patients receiving high doses of infliximab (10 mg/kg) demonstrated worsening of heart failure. Contrarily, another study with etanercept has reported a dose-dependent improvement of ventricular function [10].

IL17 inhibitors treatment showed a reduction in peripheral oxidative stress levels, vascular inflammation in psoriasis, and proinflammatory cytokines, along with a greater reduction in coronary plaque markers compared to patients treated with TNFα and IL12/IL23 inhibitors [4]. IL17A inhibitors (ixekizumab, secukinumab) decrease the development, apoptosis, and vulnerability of cardiac plaques, as well as reduce inflammatory cellular infiltration, cytokine/chemokine expression, and tissue activation in the heart. No data are reported on brodalumab and bimekizumab [11].

IL12/IL23 inhibitors demonstrated a reduction of more than 40 inflammatory and CV-related proteins after 12 weeks of psoriasis treatment, 25 of which were initially up-regulated at baseline. Treatment lowered below their risk thresholds eight proteins (myeloperoxidase, CXC motif chemokine 10, E-selectin, IL6, cystatin B, von Willebrand factor, tumor necrosis factor receptor 1, and N-terminal prohormone brain natriuretic peptide), associated with enhanced CV risk that were initially elevated above thresholds: IL6 was lowered but remained at its risk threshold despite successful psoriasis skin treatment. Imaging techniques have shown a reduction of coronary artery disease progression with biologics in a study that included ustekinumab, an antibody to p40, blocks cytokines IL-12 and IL-23, but did not differentiate its effects from tofacitinib and etanercept [12]. In a recent study that included ustekinumab, coronary CT angiography showed a modification in high-risk coronary plaque features with a year of biologic therapy. After 52 weeks of treatment, a persistent reduction of inflammatory blood biomarkers associated with atherosclerotic CV disease, specifically TNFα, IL1B, IL17A, and IL6, was confirmed as a secondary endpoint [12,13]. Ustekinumab has also shown a better effectiveness than TNFα inhibitors regarding an increase of adiponectin, leptin and omentin levels. These results show that blockade of IL-12 and/or IL-23 may transiently reduce AVI, with more durable reduction in inflammatory cytokines associated with CV disease [13].

In the previously quoted study where cardiac plaques were evaluated with CCT, after one year of treatment with both anti-TNFα agents or Anti-IL 12/23 agents, the total plaque burden was reduced in patients with decrease of skin inflammation; however, in those with increase of index of skin inflammation, high-risk plaques became more frequent [14].

No studies assessing IL23 inhibitors’ effectiveness in reducing CV risk were identified.

5. Expert opinion

The association of psoriasis with CVD and the prevalence of CV risk factors in psoriatic patients makes it necessary to implement specific recommendations for the clinical management of these patients. Multidisciplinary management is mandatory for these patients with dermatologist, cardiologist, endocrinologist, psychologists or psychiatrists, nutritionist, and others. Based on this evidence, the following recommendations can be highlighted.

Firstly, in clinical practice, it is important to assess CV risk in psoriatic patients, probably independently from the age of the patients when older than 40 years old. High CV risk is often assessed using risk calculators or scoring systems, such as the Framingham Risk Score or the Atherosclerotic Cardiovascular Disease Risk Calculator or the European Society of Cardiology Score [15]. These scores consider a combination of risk factors such as: age, gender, smoking, high blood pressure, high cholesterol, diabetes, obesity, family history, physical inactivity, previous heart disease, and metabolic syndrome. The specific threshold for defining high risk may vary depending on the guideline used, but generally, a 10-year risk of a CV event greater than 10% is considered high.

Dermatologists or healthcare providers who look after psoriatic patients should therefore assess individual risk through the evaluation of CV risk factors.

Among CVD markers that in psoriatic patients we can list triglyceride glucose index, which might indicate atherosclerosis in patients with psoriasis and psoriatic arthritis; also higher noncalcified coronary burden had higher prevalence of fractional flow reserve by computed tomography ≤0.80 and a > 2fold higher odds of positive serum high‐sensitivity troponin‐T; furthermore resistin serum levels were higher in psoriatic patients than controls, especially in those with metabolic syndrome and diabetes mellitus [16,17].

Patients with CVD or significant CV risk should be referred to a specialized cardiologist for an assessment of their CV risk using scoring systems. This will enable the administration of appropriate treatments tailored to their needs through the development of a personalized prevention and management plan.

Indeed, the use of biological drugs has emerged as a groundbreaking approach in the management of psoriasis, offering significant potential in reducing CV risk by both decreasing systemic inflammation, potentially lowering the risk of endothelial damage and plaque formation, and reducing traditional CV risk factors. A great outcome in the upcoming years will be to treat present comorbidities or to prevent them when treating psoriatic patients with biologics.

Patients with high CV risk may need specialized investigations, while low-to-moderate risk may benefit from a risk-reducing therapy. If biological therapy is required, IL17 inhibitors and IL12/IL23 inhibitors are first choice in individuals with moderate-to-severe skin involvement, while TNFα inhibitors are better choices in individuals with significant joint involvement and low-to-moderate skin involvement. There is currently no evidence of IL23 inhibitors’ efficacy in reducing CV risk, while they do not appear to increase it.

In conclusion, assessing CV risk should become a widespread clinical practice; nonetheless, treatment decisions should be individualized, and patients should work closely with their healthcare providers to assess the potential benefits and risks of biologic therapy in their specific case.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have been an investigator on several clinical trials for biologics in this indication in the U.S.A. and are a member of the advisory boards for Abbvie, Eli Lilly, Amgen, Janssen, Pfizer, UCB and BMS. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Author contributions

S Boskovic and S Borriello have given substantial contributions to the conception or the design of the manuscript. All authors have participated in drafting the manuscript. All authors read and approved the final version of the manuscript.

Additional information

Funding

This manuscript was funded through a donation by AbbVie S.p.a.