Next Article in Journal
Nutritional Genomics in Nonalcoholic Fatty Liver Disease
Next Article in Special Issue
Facial Skin Microbiome: Aging-Related Changes and Exploratory Functional Associations with Host Genetic Factors, a Pilot Study
Previous Article in Journal
Cancer Is Associated with the Emergence of Placenta-Reactive Autoantibodies
Previous Article in Special Issue
New Indications of Biological Drugs in Allergic and Immunological Disorders: Beyond Asthma, Urticaria, and Atopic Dermatitis
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomedicines
Volume 11
Issue 2
10.3390/biomedicines11020318
biomedicines-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Systematic Review

The Impact of Treatment with IL-17/IL-23 Inhibitors on Subclinical Atherosclerosis in Patients with Plaque Psoriasis and/or Psoriatic Arthritis: A Systematic Review

by
Aikaterini Tsiogka
1,*,
Stamatios Gregoriou
1,
Alexander Stratigos
1,
Stergios Soulaidopoulos
2,
Natalia Rompoti
1,
Pantelis Panagakis
1,
Marina Papoutsaki
1,
Panagiotis Kostakis
1,
George Kontochristopoulos
1,
Konstantinos Tsioufis
2,
Anna Campanati
3,
Annamaria Offidani
3,
Charalambos Vlachopoulos
2 and
Dimitrios Rigopoulos
1
1
First Department of Dermatology-Venereology, Faculty of Medicine, “A. Sygros” Hospital for Skin and Venereal Diseases, National and Kapodistrian University of Athens, 16121 Athens, Greece
2
First Cardiology Department, Hippokration General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
3
Department of Clinical and Molecular Sciences, Dermatology Clinic, Polytechnic Marche University, 60121 Ancona, Italy
*
Author to whom correspondence should be addressed.
Biomedicines 2023, 11(2), 318; https://doi.org/10.3390/biomedicines11020318
Submission received: 28 December 2022 / Revised: 16 January 2023 / Accepted: 22 January 2023 / Published: 23 January 2023
(This article belongs to the Special Issue Immune-Mediated Skin Diseases: From Pathophysiology to Novel Therapeutic Approaches 2.0)
Browse Figures
Versions Notes

Abstract

:
Accumulating evidence considers psoriasis a systemic inflammatory disorder that is associated with comorbidities such as psoriatic arthritis, cardiovascular disease, and metabolic syndrome. Although the precise pathogenetic links between psoriasis and atherosclerosis warrants further investigation, it is believed that chronic systemic inflammation along with the T helper (Th)-1 and Th17 polarization are associated with endothelial dysfunction and subsequent acceleration of atherosclerosis. Considering the above, several studies have evaluated if optimal control of the inflammation in psoriasis by inhibiting interleukins targeting the Interleukin (IL)-23/Th17 axis could subsequently reduce the atherosclerotic process during anti-psoriatic treatment by using a variety of surrogate markers of subclinical atherosclerosis. This systematic review summarizes current knowledge on the pathogenetic mechanisms and diagnostic evaluation of atherosclerosis in the context of psoriasis and provides a systematic review of the literature on the impact of treatment with biologics targeting the IL-23/Th17 axis on subclinical atherosclerosis in patients with plaque psoriasis and/or psoriatic arthritis.

1. Introduction

Psoriasis is a chronic, immune-mediated disease affecting 2–3% of the general population. It is recognized as a systemic inflammatory disease that is associated with comorbidities such as psoriatic arthritis (PsA), cardiovascular disease (CVD), metabolic syndrome, and depression [1]. Except for the increased prevalence of the classical cardiovascular risk factors in patients with psoriasis, including obesity, dyslipidemia, hypertension, and diabetes mellitus, current knowledge considers psoriasis also as an independent risk factor for CVD, as it is thought to increase by 25% the risk for CVD especially in patients with severe skin disease [2,3,4]. This is largely attributed to the chronic systemic inflammation, which leads to endothelial dysfunction and subsequent acceleration of atherosclerosis, as it occurs in other systemic inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus [5,6,7].
Over the recent decades, there have been major advances in the systemic treatment of psoriasis. The introduction of biological agents targeting core inflammatory components of the disease, including tumor necrosis factor-alpha (TNFa) inhibitors, and the interleukin (IL)-12/IL-23 inhibitor ustekinumab, IL-17 and IL-23 inhibitors, has greatly improved the management of psoriasis and, therefore, patients’ quality of life (QoL) [8]. The promising outcomes regarding the efficacy and safety of these agents that has been demonstrated in clinical trials has been confirmed in real-life studies, which have also evaluated their efficacy in sequential use and directly compared different agents of the same category [9,10,11,12]. Literature data suggest that psoriasis and atherosclerosis share common pathogenetic mechanisms and, in this sense, many studies have investigated whether inhibition of the aforementioned inflammatory cytokines to treat psoriasis, could additionally modify the progression of the atherosclerotic process, by evaluating diverse surrogate markers of subclinical atherosclerosis [13,14,15,16,17]. In this regard, the greater amount of evidence exists for TNFa inhibitors, given their longer availability in the market, while data regarding newer biological agents are negligible. As such, many observational and non-controlled studies on TNF-a inhibitors have reported positive findings and suggest that these agents could lead to a reduction of cardiovascular events in patients with psoriasis [18,19,20,21,22,23,24,25,26,27,28]. However, a systematic review of six randomized controlled trials did not provide strong evidence for a positive impact of anti-TNFa agents on subclinical atherosclerosis [29].
The IL-23/T helper-17 (Th17) pathway is recognized to play a fundamental role in psoriasis pathogenesis and is believed to be further implicated in the development of cardiometabolic comorbidities [30,31,32]. The purpose of this article is to summarize current knowledge on the pathogenetic mechanisms and diagnostic evaluation of atherosclerosis in the context of psoriasis and provide a systematic review of the literature on the impact of treatment with biologics targeting the IL-23/Th17 axis on subclinical atherosclerosis in patients with plaque psoriasis and/or PsA.

2. Materials & Methods

This systematic review was performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA). All research was conducted according to a protocol that was registered in INPLASY (ID number: INPLASY2022120102, DOI: 10.37766/inplasy2022.12.0102). Apart from the systematic review, a narrative review of the literature regarding the diagnostic evaluation of atherosclerosis in the context of psoriasis as well as the common pathogenetic mechanisms between psoriasis and atherosclerosis was performed and is addressed below.

2.1. Search Strategy and Eligibility Criteria

The MEDLINE electronic database was searched systematically via PubMed for randomized controlled trials (RCTs) and prospective cohort studies assessing the effect of IL-17 and IL-23 inhibitors on subclinical atherosclerosis in patients with psoriasis from inception to August 2022. Subclinical atherosclerosis could be assessed by any markers or diagnostic examinations, addressed so far in the literature. Non-human studies and articles reporting the effect of IL-17/IL-23 inhibitors on cardiovascular risk factors (e.g., lipid metabolism, adipocytes, etc.) were excluded. Studies reporting the effect of the IL-12/23 inhibitor, ustekinumab, on subclinical atherosclerosis were excluded, as this agent blocks the common p40 subunit of IL-12 and IL-23 and, thus, inhibits not only the IL-23-dependent Th17 but also the IL-12-dependent Th1 immune response. The search strategy is summarized in Table 1.

2.2. Selection Process and Data Extraction

The title and abstract review was conducted by two independent reviewers (A.T., S.G.) in order to identify eligible articles. Discrepancies between the two authors that performed the full text review and the quality assessment of the included studies, were performed by the contribution of a third author (D.R.). Reference lists of the included articles were also screened in order to detect any relevant studies that were not identified during the initial search. The following data were extracted by the two independent reviewers (A.T., S.G.): first author, year of publication, type of study, number of participants, type of treatment and follow-up period, assessed marker of subclinical atherosclerosis, and study results.

2.3. Study Selection

The initial search yielded 1386 articles (no filters used). The title and abstract identified 25 articles, which were selected for full text review. Finally, 8 studies were included in the systematic review after the exclusion of irrelevant studies (Figure 1).

3. Results of Narrative Review

3.1. Diagnostic Evaluation of Subclinical Atherosclerosis in the Context of Psoriasis

To date, many studies have utilized a variety of surrogate markers to evaluate the presence of subclinical atherosclerosis in patients with psoriasis and its evolution during anti-psoriatic treatment, given the broadening understanding of the shared pathophysiology between psoriasis and atherosclerosis. These comprise a wide spectrum of markers, assessed through static or dynamic imaging techniques or blood-based, soluble biomarkers, that either indicate or are indirectly related with early structural or functional alterations of the vasculature, such as endothelial dysfunction (Table 2).
The gold standard method to assess arterial stiffness is carotid-femoral pulse wave velocity (PVW). It is measured by dividing the distance between these two sites with the time taken for a pulse wave to travel between them. PWV is a validated predictor of cardiovascular events and was one of the first markers that was utilized to assess vascular abnormalities in patients with psoriasis compared to healthy controls, supporting that psoriasis is independently associated with increased arterial stiffness [33,34]. The flow-mediated vasodilatation (FMD), which refers to the stimulus-activated (mainly nitric oxide-dependent) vasodilation has been found to be lower in patients with PsA compared to controls [35]. Normally it is performed in the branchial artery, although the radial and the femoral arteries may also be used [36]. Studies have demonstrated that even a 1% increase in FMD is associated with a 13% decrease in the relative cardiovascular risk [37].
The measurement of the intima media thickness (IMT) has also been used to predict coronary artery disease in patients with psoriasis, since thickening of the intima is known to precede the development of plaque and stenosis [38]. High resolution B-mode ultrasonography can be used to measure IMT of the carotid, brachial, or femoral artery, with the latter being more informative [39]. Further static imaging techniques, such as coronary computed tomography angiography (CTA) and fluorodeoxyglucose-positron emission tomography (FDG PET-CT) may be implemented to provide information regarding the coronary plaque characteristics, the epicardial fat thickness, the aortic vascular inflammation, and the coronary calcium score [4,40,41,42,43]. All of the above aid in the prognostication in patients that are at risk of coronary disease and the prediction of cardiovascular outcomes in asymptomatic individuals [44]. Finally, a great variety of soluble biomarkers, including markers of chronic inflammation, markers with pro-atherogenic properties, or endothelial dysfunction markers, have been studied thoroughly, to assess their ability to predict CVD in patients with psoriasis (Table 2) [45,46,47,48,49,50,51,52,53,54,55,56,57,58].

3.2. Shared Pathogenetic Mechanisms between Psoriasis and Atherosclerosis

3.2.1. The “Psoriatic March” Concept

In 2011, Boehncke et al. proposed a concept of how severe psoriasis may be related to cardiovascular comorbidity. The main principle of the so-called “psoriatic march” is that the increased inflammatory burden of severe psoriasis results in insulin resistance, which, in turn, causes endothelial dysfunction and subsequently atherosclerosis and major adverse cardiovascular events (MACEs) [59]. In particular, it has been observed, that several biomarkers of inflammation, such as C-reactive protein (CRP) and vascular endothelial growth factor (VEGF), as well as adipokines, such as the insulin antagonists resistin and leptin, and indicators of platelet activation, such as P-selectin, are elevated in the blood of psoriatic patients, indicating an increased inflammatory state [46,60,61]. In addition, visceral adipocytes represent a source of proinflammatory mediators, underlining the role of obesity as an aggravating factor for systemic inflammation. The pro-inflammatory cytokines and adipokines could, subsequently, drive insulin resistance, which has been proven to induce endothelial dysfunction, for example by activating the pro-atherogenic mitogen-activated protein kinase (MAPK) pathway in endothelial cells or by inducing nitric oxide (NO)-dependent vasodilatation [62]. As a result, the imbalance between vasodilating and vasoconstricting substances could lead to an abnormal response to physical and chemical stimuli, which characterizes endothelial dysfunction and constitutes an early feature of the atherosclerotic process [63] (Figure 2).

3.2.2. Angiogenesis and Platelet Activation

Angiogenesis constitutes an important inflammatory response in psoriasis, while pro-angiogenic cytokines, including TNFa, IL-8, and IL-17, seem to be involved in the pathogenesis of both psoriasis and atherosclerosis [6]. VEGF, a major angiogenic growth factor, is overexpressed in psoriatic lesions, while this cytokine as well as its receptors have also been found to be expressed in atherosclerotic lesions in coronary arteries [60]. Moreover, diversity in genes which regulate angiogenesis has been linked to increased susceptibility to atherosclerosis [64].
Moreover, the pathophysiology of psoriasis involves platelet activation, a term, which refers to changes in platelet shape, aggregation, and release of platelet components. The assessment of platelet activation may be accomplished with the evaluation of markers, such as the mean platelet volume and expression of the surface antigen, p-selectin (CD62) [65]. The latter serves multiple proinflammatory roles and it has been found to be overexpressed in patients with psoriasis, exhibiting a significant correlation with the Psoriasis Area and Severity Index (PASI) score, and to be further implicated in the development of atherosclerosis [66]. A case-control study of 25 patients with psoriasis and 25 matched healthy individuals identified an increased risk of atherosclerosis, as assessed by increased expression of p-selectin, especially in patients with moderate to severe psoriasis, compared with healthy controls [61].

3.2.3. The Involvement of Th1 and Th17 Immune Responses

Psoriasis is characterized by the Th1 and Th17 polarization of the adaptive immune response, with keratinocytes being activated mainly by the mediators such as interferon gamma (IFN-γ), TNFa, IL-2, and IL-17 [67]. In psoriatic lesions, Th1 cells produce IFN-γ and TNFa, which induce activation and proliferation of keratinocytes as well as the expression of adhesion molecules, whereas Th17 cells secrete IL-17 and IL-22, promoting keratinocyte proliferation and angiogenesis [30]. A recent study of Wang et al. proposed the utilization of IL-17C, the most abundant IL-17 isoform, along with peptidase inhibitor 3 (PI3) as potential biomarkers of effective systemic antipsoriatic treatment end evaluated their relationship to co-existent CVD [68]. Plasma proteins from 36 patients with moderate–severe psoriasis that was effectively treated with either methotrexate or adalimumab or secukinumab or ustekinumab were compared to those from 23 systematically untreated patients. The treated patients exhibited lower levels of IL-17 pathway proteins, while specifically IL-17C and PI3 levels were highly correlated with each other and PASI score. Interestingly, this correlation was modulated in patients with concurrent CVD, who exhibited lower levels of IL-17A compared to those without CVD [68].
The findings of the aforementioned study highlight the complex effects of the IL-17 pathway on psoriasis-related CVD, as IL-17 has been implicated to have both proatherogenic and atheroprotective effects [69]. For instance, low serum IL-17A has been associated with recurrent major cardiovascular events and increased mortality in patients with acute myocardial infarction, suggesting a protective role of IL-17A [70]. On the other hand, a variety of studies demonstrated a reduction of cardiovascular risk in patients with psoriasis that were treated with IL-17 inhibitors (see below). In addition to that, histopathological studies have shown that atherosclerotic plaques contain increased levels of cells IFN-γ, IL-17, and IL-23, with the latter being correlated with disease duration and mortality, implying that both psoriasis and atherosclerosis share common inflammatory cytokine profiles locally and systemically [30]. Differentiated Th1 cells promote plaque growth, while increased levels of intraplaque IL-17 may lead to neoangiogenesis, intensification of inflammation, degradation of the collagen of the fibrous cap, destabilization, and rupture of the atherosclerotic plaque [71,72]. Except for their implication in endothelial dysfunction, the aforementioned cytokines are also considered to be implicated in the pathogenesis of cardiometabolic comorbidities, such as insulin resistance, obesity, and non-alcoholic fatty liver disease [31].
In a study by Gao et al., the production and function of Th17 and Th1 cells was evaluated in atherosclerotic-susceptible mice, where higher expression of IL-17 and retinoic acid-related orphan receptor γt (RORγt) was observed in the arterial wall with plaque than without plaque, and exposure to anti-IL-17 antibodies significantly inhibited the plaque formation [73]. It has to be highlighted that RORC2 is a crucial transcription factor for Th17 cell differentiation. RORγt is expressed in human epidermal keratinocytes and studies have shown disturbed expression in inflammatory skin lesions, including psoriasis, supporting that targeted inhibition of its signaling may represent a promising strategy for the treatment of psoriasis [74,75,76].

4. Results of Systematic Search

Characteristics of Studies Assessing the Impact of Treatment with IL-17 and IL-23 Inhibitors on Subclinical Atherosclerosis in Patients with Psoriasis

According to the results of this systematic review, to date, eight studies have evaluated patients with psoriasis that were treated with biologics targeting the IL-23/Th17 axis, aiming to evaluate their effect on diverse surrogate markers of subclinical atherosclerosis (Table 3).
A prospective, observational study that was conducted by Elnabawi et al. in 2019, assessed the phenotypes of coronary plaques using coronary CTA, in biologic naïve patients that were treated with TNFa-, IL-12/23-, or IL-17- inhibitors compared to those that were treated with topical and/or light therapies, at baseline and after one year [78]. All the participants had low cardiovascular risk by Framingham score (median score, 3) and moderate-to-severe plaque psoriasis (median PASI, 8.6) at baseline. The assessed coronary artery parameters included the total, dense-calcified, and non-calcified plaque burden as well as the plaque morphology index (fibrous, fibro-fatty, and necrotic burden). In one year of treatment, there was a 12% reduction (p < 0.001) in non-calcified plaque burden in patients that were receiving anti-IL-17 treatment. Moreover, this group exhibited a significantly greater reduction in coronary plaque burden than that which was observed in the anti-IL-12/23 and non-biologic groups [78].
Changes in the lipid-rich necrotic core (LRNC) during 1-year biologic treatment were assessed in another prospective, observational study of 209 biologic-naïve patients with moderate-to-severe psoriasis [77]. Overall, a statistically significant LRNC reduction [mm2; 3.12 (1.99–4.66) versus 2.97 (1.84–4.35) after one year; p = 0.028] was observed only in biologic group (TNFa-, IL-12/23-, and IL-17- inhibitors; n = 124) and not in those on non-biologic therapy (topical, light, or conventional systemic therapies; n = 85). In particular, anti-IL-17 therapy (n = 29) reduced the LRNC by 0.39 mm2, while no statistically significant LRNC reduction was observed between the different biologic therapy groups [77].
Elnabawi et al. conducted another study to investigate the association of biologic therapy for psoriasis with coronary inflammation using the perivascular fat attenuation index (FAI) via coronary CTA [24]. Overall, 82 patients received biologic therapy with either anti-TNFa, anti-IL-12/23, or anti-IL-17 agents and 52 patients received only topical or light therapy (control group), while most of them had low cardiovascular risk by traditional risk scores and moderate–severe psoriasis. After one year of treatment, there was a significant decrease in FAI compared to baseline only in those that were treated with biologics, with the greater improvement being observed in the anti-IL-17 group [median FAI change (range), −76.92 (−81.16 to −71.67), p < 0.001] [24].
In the same year, von Stebut et al. conducted the CARIMA study, a 52-week RCT assessing the endothelial function measured by FMD in patients with moderate–severe psoriasis without evident CVD receiving secukinumab 300 mg vs. 150 mg for 52 weeks or placebo until week 12, followed by secukinumab 300 mg vs. 150 mg until week 52 [83]. Although no statistically significant change was observed at week 12, the mean FMD increased across the groups until week 52 and it was significantly higher compared to baseline in patients receiving secukinumab 300 mg continuously for 52 weeks [+2.1%, 95% confidence interval (CI) 0.8–3.3; p = 0.0022]. Secondary endpoints, including PWV, augmentation index, blood-based biomarkers, and plaque burden by MRI, did not exhibit relevant changes during the study [83].
In a following cohort study by Makavos et al., anti-IL-17 treatment was compared to conventional treatment with cyclosporine or methotrexate regarding their ability to improve myocardial deformation and vascular function in moderate–severe psoriasis [80]. A total of 150 patients received either secukinumab (n = 50), cyclosporine (n = 50), or methotrexate (n = 50) for 12 months. At the end of treatment, anti-IL-17 treatment led to greater improvement of myocardial and vascular function, as assessed by global longitudinal strain, left ventricular twisting/untwisting indices, coronary flow reserve (CFR) (CFR change at 12 months: 19%, p = 0.02), and PWV (PWV reduction at 12 months: −11%, p = 0.04). Interestingly, higher PWV values were observed in the cyclosporine group (PWV increase at 12 months: 14%). Soluble markers of oxidative stress (malondialdehyde, protein carbonyl) were reduced only in the anti-IL-17 group (p < 0.05) [80].
Piros et al. conducted another observational study on 31 severe psoriatic patients who received secukinumab (n = 20) or ixekizumab (n = 11), in order to evaluate the impact of biologic therapy on vascular wall inflammation, as assessed by arterial IMT after 6 months of treatment [82]. All of the indices, including right and left carotid, right and left branchial as well, as right and left femoral IMT, exhibited a statistically significant reduction compared to baseline [82].
In contrast to the aforementioned positive findings, the two following studies failed to demonstrate a significant improvement of the selected parameters of subclinical atherosclerosis in patients with psoriasis. Marovt et al. evaluated 15 biologic-naïve patients, who received either ustekinumab (n = 4), secukinumab (n = 10), or ixekizumab (n = 1) for 6 months [81]. At the end of treatment, no significant changes in the mean (left and right carotid) IMT (p = 0.737) and carotid-femoral PWV (p = 0.031) were observed, although it has to be highlighted that a short observational time of six months was determined [81]. A placebo-controlled RCT (VIP-S) that was conducted by Gelfand et al. sought to assess the effect of secukinumab therapy on aortic vascular inflammation using FDG-PET/CT and other soluble biomarkers during 52 weeks of treatment in patients with moderate–severe psoriasis [84]. Initially, 46 patients were randomized to secukinumab and 45 to the placebo group during the first 12 week placebo-controlled period, from whom 86 entered the following 40 week treatment period with secukinumab. At week 12, there was no statistically significant difference in aortic inflammation between the secukinumab and placebo groups. A neutral effect of secukinumab on vascular inflammation and cardiometabolic biomarkers (e.g., lipoprotein, adiposity, insulin resistance) was also observed at the end of treatment [79].

5. Discussion and Future Perspectives

Although the precise pathogenetic links between psoriasis and atherosclerosis warrants further investigation, it is increasingly recognized that inflammatory processes involving the Th1 and Th17 immune responses have a prominent role in their shared pathogenesis as well as in the pathogenesis of the most cardiometabolic psoriasis-associated conditions. To date, some studies have evaluated if optimal control of the inflammation in psoriasis by inhibiting interleukins targeting the IL-23/Th17 axis could subsequently reduce the accompanied atherosclerotic process, providing conflicting results. In particular, this systematic review has identified six observational studies and two RCTs that evaluated the effect of anti-IL-17 therapy on diverse surrogate markers of subclinical atherosclerosis. A total of five of them utilized different static imaging techniques to evaluate structural changes of the vasculature, and two utilized dynamic imaging techniques to assess arterial stiffness. Although six studies demonstrated positive effects of biologic therapy, two showed no statistically significant benefit on subclinical atherosclerosis. Interestingly, during the literature search, no studies assessing the effect of IL-23 inhibitors were identified.
Some further studies assessed the effect of biological agents on psoriasis-associated CVD and cardiometabolic comorbidities, including diabetes, lipoprotein function, obesity/adipokines, and other metabolic parameters [84,85,86,87,88]. A systematic review and meta-analysis, that was conducted by Gonzáles-Cantero et al., included five RCTs, that examined the impact of adalimumab, ustekinumab, or secukinumab on imaging (aortic vascular inflammation on PET-CT, FMD) and biomarkers of CVD (lipoproteins, inflammation, obesity, insulin resistance) [14]. It has been shown that ustekinumab reduced aortic vascular inflammation and TNF-a inhibitors reduced CRP and IL-6. Otherwise, there was no beneficial effect on the assessed biomarkers in patients that were receiving biologics compared to those that were exposed to the placebo [14]. Interestingly, a meta-analysis of RCTs that was published in 2011, reported a potential risk of severe cardiovascular events during the initiation period of ustekinumab [89]. This observation was supported by a recent case-control study (n = 9290), which suggested that the initiation of ustekinumab may trigger severe cardiovascular events in patients presenting with high cardiovascular risk [90]. Finally, a recent systematic review and meta-analysis on vascular inflammation (PET-CT) and its evolution during treatment with biologics underlined the association between psoriasis and aortic vascular inflammation but it could not support a beneficial effect of biologic treatment [91].
Considering the growing amount of evidence supporting the systemic inflammatory nature of psoriasis and its association with an increased prevalence of cardiometabolic comorbidities, the last EuroGuiderm guideline on the treatment of psoriasis vulgaris, published in 2020, provided detailed recommendations regarding the management of patients with comorbid situations, including ischemic heart disease/atherosclerosis. In particular, appropriate investigations and treatment should be initiated in accordance with current European Society of Cardiology guidance in patients with established CVD, while regarding antipsoriatic treatment, the authors suggested the use of methotrexate, TNF-a inhibitors, ustekinumab, and IL-17 inhibitors and avoidance of cyclosporine or acitretin in patients with psoriasis and ischemic heart disease [92,93].
The main limitation of the present review is the heterogeneity of the included studies, especially regarding the diagnostic methods that were utilized to assess the impact of biologics on subclinical atherosclerosis in psoriasis patients, prohibiting a meta-analysis of outcomes and subgroup analysis, to draw stronger conclusions on this topic. Another limitation is that only the PubMed search engine was used for study selection, which provides access in most studies with high level of evidence, such as RCTs and prospective cohort studies, which were included in the present study.
Considering the above, it is yet to be elucidated if the aforementioned discrepancies on the anti-atherogenic effect are associated with differences in patient-related characteristics, principally with regards to their CVD-risk profile at the onset of biologic therapy, drug-related characteristics such as pharmacologic properties of each IL-17 inhibitor, or difference in sensitivity between the utilized diagnostic techniques. In the era of the increasing understanding of the involvement of systemic inflammation in the pathogenesis of atherosclerosis and consideration of psoriasis as an independent cardiovascular risk factor, future research could include the identification of clinical markers in patients with psoriasis and/or PsA that could predict an optimal anti-atherogenic effect of systemic treatment of psoriasis with biologics. In that respect, an important aspect could be the establishment of sensitive but also accessible and cost-effective diagnostic methods to be included in the evaluation of the cardiovascular status in patients with moderate–severe psoriasis, especially in those presenting with additional classical cardiovascular risk factors. Finally, future, well-controlled studies could elucidate if different biologic agents may exhibit a more pronounced anti-atherogenic effect and target CVD inflammation more effectively, an association which is yet particularly to be studied in patients receiving IL-23 inhibitors, considering the sparsity of such data in the medical literature.

Author Contributions

Conceptualization, A.T, C.V., S.G., A.S., N.R. and D.R.; methodology, A.T., S.G. and S.S.; software, A.T. and S.S.; validation, A.T., C.V., S.G., A.S. and D.R.; formal analysis, A.T., C.V., S.G., A.S. and D.R.; investigation, A.T., C.V., S.G., A.S. and D.R.; resources, A.T., S.S., N.R., P.P., M.P., P.K. and G.K.; data curation, A.T. and S.G.; writing—original draft preparation, A.T., C.V., S.G. and S.S.; writing—review and editing, all authors; visualization, A.T., C.V., S.G., A.S. and D.R.; supervision, C.V., S.G., A.S., K.T. and D.R.; project administration, A.T. and S.S.; funding acquisition, N/A. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of “A. Sygros” Hospital for Skin and Venereal Diseases, Athens, Greece (3613/20-05-21).

Informed Consent Statement

Not applicable.

Data Availability Statement

The authors confirm that the data supporting the findings of this study are available within the article.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Reich, K. The concept of psoriasis as a systemic inflammation: Implications for disease management. J. Eur. Acad. Dermatol. Venereol. 2012, 26 (Suppl. S2), 3–11. [Google Scholar] [CrossRef] [PubMed]
  2. Lockshin, B.; Balagula, Y.; Merola, J.F. Interleukin 17, inflammation, and cardiovascular risk in patients with psoriasis. J. Am. Acad. Dermatol. 2018, 79, 345–352. [Google Scholar] [CrossRef] [Green Version]
  3. Gisondi, P.; Bellinato, F.; Girolomoni, G.; Albanesi, C. Pathogenesis of Chronic Plaque Psoriasis and Its Intersection with Cardio-Metabolic Comorbidities. Front. Pharmacol. 2020, 11, 117. [Google Scholar] [CrossRef] [PubMed]
  4. Kaiser, H.; Abdulla, J.; Henningsen, K.M.; Skov, L.; Hansen, P.R. Coronary Artery Disease Assessed by Computed Tomography in Patients with Psoriasis: A Systematic Review and Meta-Analysis. Dermatology 2019, 235, 478–487. [Google Scholar] [CrossRef] [PubMed]
  5. Fang, N.; Jiang, M.; Fan, Y. Association Between Psoriasis and Subclinical Atherosclerosis: A Meta-Analysis. Medicine 2016, 95, e3576. [Google Scholar] [CrossRef]
  6. Ghazizadeh, R.; Shimizu, H.; Tosa, M.; Ghazizadeh, M. Pathogenic Mechanisms Shared between Psoriasis and Cardiovascular Disease. Int. J. Med. Sci. 2010, 7, 284–289. [Google Scholar] [CrossRef] [Green Version]
  7. Martinez-Moreno, A.; Ocampo-Candiani, J.; Garza-Rodriguez, V. Psoriasis and Cardiovascular Disease: A Narrative Review. Korean J. Fam. Med. 2021, 42, 345–355. [Google Scholar] [CrossRef]
  8. Lin, C.P.; Merola, J.F.; Wallace, E.B. Current and emerging biologic and small molecule systemic treatment options for psoriasis and psoriatic arthritis. Curr. Opin. Pharmacol. 2022, 67, 102292. [Google Scholar] [CrossRef]
  9. Megna, M.; Potestio, L.; Ruggiero, A.; Camela, E.; Fabbrocini, G. Guselkumab is efficacious and safe in psoriasis patients who failed anti-IL17: A 52-week real-life study. J. Dermatol. Treat. 2022, 33, 2560–2564. [Google Scholar] [CrossRef]
  10. Ruggiero, A.; Fabbrocini, G.; Cinelli, E.; Megna, M. Real world practice indirect comparison between guselkumab and risankizumab: Results from an Italian retrospective study. Dermatol. Ther. 2022, 35, e15214. [Google Scholar] [CrossRef]
  11. Megna, M.; Tommasino, N.; Potestio, L.; Battista, T.; Ruggiero, A.; Noto, M.; Fabbrocini, G.; Genco, L. Real-world practice indirect comparison between guselkumab, risankizumab, and tildrakizumab: Results from an Italian 28-week retrospective study. J. Dermatol. Treat. 2022, 33, 2813–2820. [Google Scholar] [CrossRef] [PubMed]
  12. Megna, M.; Potestio, L.; Ruggiero, A.; Camela, E.; Fabbrocini, G. Risankizumab treatment in psoriasis patients who failed anti-IL17: A 52-week real-life study. Dermatol. Ther. 2022, 35, e15524. [Google Scholar] [CrossRef] [PubMed]
  13. Dufour, J.; Hassan, M.; Netchiporouk, E.; Litvinov, I.V. Recent Advances in Evaluating Impact of Biologic Therapy for Moderate-Severe Psoriasis on Cardiovascular Events and Atherosclerotic Plaque Formation. J. Cutan. Med. Surg. 2020, 24, 209–210. [Google Scholar] [CrossRef] [PubMed]
  14. González-Cantero, A.; Ortega-Quijano, D.; Álvarez-Díaz, N.; Ballester, M.A.; Jimenez-Gomez, N.; Jaen, P.; González-Cantero, J.; González-Calvin, J.L.; Barderas, M.G.; Shin, D.B.; et al. Impact of Biological Agents on Imaging and Biomarkers of Cardiovascular Disease in Patients with Psoriasis: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials. J. Investig. Dermatol. 2021, 141, 2402–2411. [Google Scholar] [CrossRef] [PubMed]
  15. Hjuler, K.F.; Bøttcher, M.; Vestergaard, C.; Bøtker, H.E.; Iversen, L.; Kragballe, K. Association Between Changes in Coronary Artery Disease Progression and Treatment with Biologic Agents for Severe Psoriasis. JAMA Dermatol. 2016, 152, 1114–1121. [Google Scholar] [CrossRef]
  16. Montaudié, H.; Albert-Sabonnadiere, C.; Acquacalda, E.; Fontas, E.; Danré, A.; Roux, C.; Ortonne, J.; Lacour, J.-P.; Euller-Ziegler, L.; Passeron, T. Impact of systemic treatment of psoriasis on inflammatory parameters and markers of comorbidities and cardiovascular risk: Results of a prospective longitudinal observational study. J. Eur. Acad. Dermatol. Venereol. 2013, 28, 1186–1191. [Google Scholar] [CrossRef]
  17. Mosca, M.; Hong, J.; Hadeler, E.; Hakimi, M.; Brownstone, N.; Liao, W.; Bhutani, T. Psoriasis and Cardiometabolic Comorbidities: An Evaluation of the Impact of Systemic Treatments in Randomized Clinical Trials. Dermatol. Ther. 2021, 11, 1497–1520. [Google Scholar] [CrossRef]
  18. Piaserico, S.; Osto, E.; Famoso, G.; Zanetti, I.; Gregori, D.; Poretto, A.; Iliceto, S.; Peserico, A.; Tona, F. Treatment with tumor necrosis factor inhibitors restores coronary microvascular function in young patients with severe psoriasis. Atherosclerosis 2016, 251, 25–30. [Google Scholar] [CrossRef]
  19. Pina, T.; Corrales, A.; Lopez-Mejias, R.; Armesto, S.; Gonzalez-Lopez, M.A.; Gómez-Acebo, I.; Ubilla, B.; Remuzgo-Martínez, S.; Gonzalez-Vela, M.C.; Blanco, R.; et al. Anti-tumor necrosis factor-alpha therapy improves endothelial function and arterial stiffness in patients with moderate to severe psoriasis: A 6-month prospective study. J. Dermatol. 2016, 43, 1267–1272. [Google Scholar] [CrossRef]
  20. Jókai, H.; Szakonyi, J.; Kontár, O.; Marschalkó, M.; Szalai, K.; Kárpáti, S.; Holló, P. Impact of effective tumor necrosis factor-alfa inhibitor treatment on arterial intima-media thickness in psoriasis: Results of a pilot study. J. Am. Acad. Dermatol. 2013, 69, 523–529. [Google Scholar] [CrossRef]
  21. Eder, L. TNFa inibitors are associated with reduced indices of subclinical atherosclerosis in patients with psoriatic disease. Arthritis Rheumatol. 2018, 38, 42–49. [Google Scholar]
  22. Herédi, E.; Végh, J.; Pogácsás, L.; Gáspár, K.; Varga, J.; Kincse, G.; Zeher, M.; Szegedi, A.; Gaál, J. Subclinical cardiovascular disease and it’s improvement after long-term TNF-α inhibitor therapy in severe psoriatic patients. J. Eur. Acad. Dermatol. Venereol. 2016, 30, 1531–1536. [Google Scholar] [CrossRef] [PubMed]
  23. Bissonnette, R.; Harel, F.; Krueger, J.G.; Guertin, M.-C.; Chabot-Blanchet, M.; Gonzalez, J.; Maari, C.; Delorme, I.; Lynde, C.W.; Tardif, J.-C. TNF-α Antagonist and Vascular Inflammation in Patients with Psoriasis Vulgaris: A Randomized Placebo-Controlled Study. J. Investig. Dermatol. 2017, 137, 1638–1645. [Google Scholar] [CrossRef] [PubMed]
  24. Elnabawi, Y.A.; Oikonomou, E.; Dey, A.K.; Mancio, J.; Rodante, J.A.; Aksentijevich, M.; Choi, H.; Keel, A.; Erb-Alvarez, J.; Teague, H.L.; et al. Association of Biologic Therapy with Coronary Inflammation in Patients with Psoriasis as Assessed by Perivascular Fat Attenuation Index. JAMA Cardiol. 2019, 4, 885–891. [Google Scholar] [CrossRef] [PubMed]
  25. Mehta, N.N.; Shin, D.B.; Joshi, A.A.; Dey, A.K.; Armstrong, A.W.; Duffin, K.C.; Fuxench, Z.C.; Harrington, C.L.; Hubbard, R.A.; Kalb, R.E.; et al. Effect of 2 Psoriasis Treatments on Vascular Inflammation and Novel Inflammatory Cardiovascular Biomarkers: A Randomized Placebo-Controlled Trial. Circ. Cardiovasc. Imaging 2018, 11, e007394. [Google Scholar] [CrossRef] [Green Version]
  26. Wegner, J.; Karbach, S.; Drosos, I.; Schnorbus, B.; Muxel, S.; Schmidt, F.; Wenzel, P.; Waisman, A.; Münzel, T.; Gori, T.; et al. TNF-α blockade may lead to improvement of vascular function in psoriasis patients. Exp. Dermatol. 2022, 31, 237–241. [Google Scholar] [CrossRef]
  27. Avgerinou, G.; Tousoulis, D.; Siasos, G.; Oikonomou, E.; Maniatis, K.; Papageorgiou, N.; Praskevopoulos, T.; Miliou, A.; Koumaki, D.; Latsios, G. Anti-tumor necrosis factor α treatment with adalimumab improves significantly endothelial function and decreases inflammatory process in patients with chronic psoriasis. Int. J. Cardiol. 2011, 151, 382–383. [Google Scholar] [CrossRef]
  28. Onsun, N.; Akaslan, T.Ç.; Sallahoglu, K.; Gülcan, A.S.; Bulut, H.; Yabacı, A. Effects of TNF inhibitors and an IL12/23 inhibitor on changes in body weight and adipokine levels in psoriasis patients: A 48-week comparative study. J. Dermatolog. Treat. 2022, 33, 1727–1732. [Google Scholar] [CrossRef]
  29. Knowles, L.; Nadeem, N.; Chowienczyk, P.J. Do anti-tumour necrosis factor-α biologics affect subclinical measures of atherosclerosis and arteriosclerosis? A systematic review. Br. J. Clin. Pharmacol. 2020, 86, 837–851. [Google Scholar] [CrossRef]
  30. Egeberg, A.; Gisondi, P.; Carrascosa, J.M.; Warren, R.B.; Mrowietz, U. The role of the interleukin-23/Th17 pathway in cardiometabolic comorbidity associated with psoriasis. J. Eur. Acad. Dermatol. Venereol. 2020, 34, 1695–1706. [Google Scholar] [CrossRef] [Green Version]
  31. Owczarczyk-Saczonek, A.; Placek, W. Interleukin-17 as a factor linking the pathogenesis of psoriasis with metabolic disorders. Int. J. Dermatol. 2017, 56, 260–268. [Google Scholar] [CrossRef] [PubMed]
  32. Wang, Y.; Zang, J.; Liu, C.; Yan, Z.; Shi, D. Interleukin-17 Links Inflammatory Cross-Talks Between Comorbid Psoriasis and Atherosclerosis. Front. Immunol. 2022, 13, 835671. [Google Scholar] [CrossRef] [PubMed]
  33. Vlachopoulos, C.; Aznaouridis, K.; Stefanadis, C. Prediction of Cardiovascular Events and All-Cause Mortality with Arterial Stiffness: A Systematic Review and Meta-Analysis. J. Am. Coll. Cardiol. 2010, 55, 1318–1327. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Gisondi, P.; Fantin, F.; Del Giglio, M.; Valbusa, F.; Marino, F.; Zamboni, M.; Girolomoni, G. Chronic Plaque Psoriasis Is Associated with Increased Arterial Stiffness. Dermatology 2009, 218, 110–113. [Google Scholar] [CrossRef]
  35. Gonzalez-Juanatey, C.; Llorca, J.; Miranda-Filloy, J.A.; Amigo-Diaz, E.; Testa, A.; Garcia-Porrua, C.; Martin, J.; Gonzalez-Gay, M.A. Endothelial dysfunction in psoriatic arthritis patients without clinically evident cardiovascular disease or classic atherosclerosis risk factors. Arthritis Rheum. 2007, 57, 287–293. [Google Scholar] [CrossRef] [PubMed]
  36. Moroni, L.; Selmi, C.; Angelini, C.; Meroni, P.L. Evaluation of Endothelial Function by Flow-Mediated Dilation: A Comprehensive Review in Rheumatic Disease. Arch. Immunol. Ther. Exp. 2017, 65, 463–475. [Google Scholar] [CrossRef]
  37. Inaba, Y.; Chen, J.A.; Bergmann, S.R. Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: A meta-analysis. Int. J. Cardiovasc. Imaging 2010, 26, 631–640. [Google Scholar] [CrossRef]
  38. Martinez-Lopez, A.; Blasco-Morente, G.; Perez-Lopez, I.; Tercedor-Sanchez, J.; Arias-Santiago, S. Studying the effect of systemic and biological drugs on intima-media thickness in patients suffering from moderate and severe psoriasis. J. Eur. Acad. Dermatol. Venereol. 2018, 32, 1492–1498. [Google Scholar] [CrossRef]
  39. Balci, D.; Balci, A.; Karazincir, S.; Ucar, E.; Iyigun, U.; Yalcin, F.; Seyfeli, E.; Inandi, T.; Egilmez, E. Increased carotid artery intima-media thickness and impaired endothelial function in psoriasis. J. Eur. Acad. Dermatol. Venereol. 2009, 23, 1–6. [Google Scholar] [CrossRef]
  40. Bulbul Sen, B.; Atci, N.; Rifaioglu, E.N.; Ekiz, O.; Kartal, I.; Buyukkaya, E.; Kurt, M.; Karakas, M.F.; Buyukkaya, S.; Akcay, A.B.; et al. Increased epicardial fat tissue is a marker of subclinical atherosclerosis in patients with psoriasis. Br. J. Dermatol. 2013, 169, 1081–1086. [Google Scholar] [CrossRef]
  41. Dey, A.K.; Joshi, A.A.; Chaturvedi, A.; Lerman, J.B.; Aberra, T.M.; Rodante, J.A.; Teague, H.L.; Harrington, C.L.; Rivers, J.P.; Chung, J.H.; et al. Association Between Skin and Aortic Vascular Inflammation in Patients with Psoriasis: A Case-Cohort Study Using Positron Emission Tomography/Computed Tomography. JAMA Cardiol. 2017, 2, 1013–1018. [Google Scholar] [CrossRef] [PubMed]
  42. Bissonnette, R.; Tardif, J.C.; Harel, F.; Pressacco, J.; Bolduc, C.; Guertin, M.C. Effects of the tumor necrosis factor-α antagonist adalimumab on arterial inflammation assessed by positron emission tomography in patients with psoriasis: Results of a randomized controlled trial. Circ. Cardiovasc. Imaging 2013, 6, 83–90. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Groenendyk, J.W.; Shukla, P.; Dey, A.K.; Elnabawi, Y.A.; Aksentijevich, M.; Choi, H.; Genovese, L.D.; Harrington, C.L.; Natarajan, B.; Goyal, A.; et al. Association of aortic vascular uptake of 18FDG by PET/CT and aortic wall thickness by MRI in psoriasis: A prospective observational study. Eur. J. Nucl. Med. 2019, 46, 2488–2495. [Google Scholar] [CrossRef] [PubMed]
  44. Rumberger, J. Using noncontrast cardiac CT and coronary artery calcification measurements for cardiovascular risk assessment and management in asymptomatic adults. Vasc. Health Risk Manag. 2010, 6, 579–591. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Borsky, P.; Fiala, Z.; Andrys, C.; Beranek, M.; Hamakova, K.; Kremlacek, J.; Malkova, A.; Svadlakova, T.; Krejsek, J.; Palicka, V.; et al. C-reactive protein, chemerin, fetuin-A and osteopontin as predictors of cardiovascular risks in persons with Psoriasis Vulgaris. Physiol. Res. 2021, 70, 383–391. [Google Scholar] [CrossRef] [PubMed]
  46. Campanati, A.; Ganzetti, G.; Giuliodori, K.; Marra, M.; Bonfigli, A.; Testa, R.; Offidani, A. Serum levels of adipocytokines in psoriasis patients receiving tumor necrosis factor-α inhibitors: Results of a retrospective analysis. Int. J. Dermatol. 2015, 54, 839–845. [Google Scholar] [CrossRef] [PubMed]
  47. Awad, S.M.; Attallah, D.A.; Salama, R.H.; Mahran, A.M.; Abu El-Hamed, E. Serum levels of psoriasin (S100A7) and koebnerisin (S100A15) as potential markers of atherosclerosis in patients with psoriasis. Clin. Exp. Dermatol. 2018, 43, 262–267. [Google Scholar] [CrossRef]
  48. Dey, A.K.; Gaddipati, R.; Elnabawi, Y.A.; Ongstad, E.; Goyal, A.; Chung, J.H.; Teague, H.L.; Rodante, J.A.; Sajja, A.A.; Sorokin, A.V.; et al. Association Between Soluble Lectinlike Oxidized Low-Density Lipoprotein Receptor-1 and Coronary Artery Disease in Psoriasis. JAMA Dermatol. 2020, 156, 151–157. [Google Scholar] [CrossRef]
  49. Niknezhad, N.; Haghighatkhah, H.R.; Zargari, O.; Ghalamkarpour, F.; Younespour, S.; Niknejad, N.; Alikhan, A.; Abdollahimajd, F. High-sensitivity C-reactive protein as a biomarker in detecting subclinical atherosclerosis in psoriasis. Dermatol. Ther. 2020, 33, e13628. [Google Scholar] [CrossRef]
  50. Pietrzak, A.; Bartosinska, J.; Blaszczyk, R.; Chodorowska, G.; Brzozowski, W.; Hercogova, J.; Donica, H.; Lotti, T. Increased serum level of N-terminal Pro-B-type natriuretic peptide as a possible biomarker of cardiovascular risk in psoriatic patients. J. Eur. Acad. Dermatol. Venereol. 2014, 29, 1010–1014. [Google Scholar] [CrossRef]
  51. Demirbaş, A.; Kurtipek, G.S.; Tunçez, A.; Akyürek, F.; Demirbaş, G.U. The role of cystatin-C and fetuin-A in the determination of early atherosclerotic risk in psoriasis patients. Dermatol. Ther. 2020, 33, e13898. [Google Scholar] [CrossRef] [PubMed]
  52. Balta, I.; Balta, S.; Demirkol, S.; Mikhailidis, D.; Celik, T.; Akhan, M.; Kurt, O.; Kurt, Y.; Aydin, I.; Kilic, S. Elevated serum levels of endocan in patients with psoriasis vulgaris: Correlations with cardiovascular risk and activity of disease. Br. J. Dermatol. 2013, 169, 1066–1070. [Google Scholar] [CrossRef] [PubMed]
  53. Balta, S.; Balta, I.; Mikhailidis, D.P.; Ozturk, C.; Demirkol, S.; Celik, T.; Kilic, S.; Demir, M.; Iyisoy, A. Bilirubin Levels and Their Association with Carotid Intima Media Thickness and High-Sensitivity C-reactive Protein in Patients with Psoriasis Vulgaris. Am. J. Clin. Dermatol. 2014, 15, 137–142. [Google Scholar] [CrossRef]
  54. Erfan, G.; Guzel, S.; Alpsoy, S.; Rifaioglu, E.N.; Kaya, S.; Kucukyalcın, V.; Topcu, B.; Kulac, M. Serum YKL-40: A potential biomarker for psoriasis or endothelial dysfunction in psoriasis? Mol. Cell Biochem. 2015, 400, 207–212. [Google Scholar] [CrossRef]
  55. Erturan, I.; Köroğlu, B.K.; Adiloğlu, A.; Ceyhan, A.M.; Akkaya, V.B.; Tamer, N.; Başak, P.Y.; Korkmaz, S.; Ersoy, I.H.; Kılınç, O. Evaluation of serum sCD40L and homocysteine levels with subclinical atherosclerosis indicators in patients with psoriasis: A pilot study. Int. J. Dermatol. 2014, 53, 503–509. [Google Scholar] [CrossRef] [PubMed]
  56. Joshi, A.A.; Lerman, J.B.; Aberra, T.M.; Afshar, M.; Teague, H.L.; Rodante, J.A.; Krishnamoorthy, P.; Ng, Q.; Aridi, T.Z.; Salahuddin, T.; et al. GlycA Is a Novel Biomarker of Inflammation and Subclinical Cardiovascular Disease in Psoriasis. Circ. Res. 2016, 119, 1242–1253. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Kaiser, H.; Wang, X.; Kvist-Hansen, A.; Krakauer, M.; Gørtz, P.M.; McCauley, B.D.; Skov, L.; Becker, C.; Hansen, P.R. Biomarkers of subclinical atherosclerosis in patients with psoriasis. Sci. Rep. 2021, 11, 21438. [Google Scholar] [CrossRef]
  58. Kyriakou, A.; Patsatsi, A.; Sotiriadis, D.; Goulis, D. Effects of treatment for psoriasis on circulating levels of leptin, adiponectin and resistin: A systematic review and meta-analysis. Br. J. Dermatol. 2018, 179, 273–281. [Google Scholar] [CrossRef]
  59. Boehncke, W.-H.; Boehncke, S.; Tobin, A.-M.; Kirby, B. The “psoriatic march”: A concept of how severe psoriasis may drive cardiovascular comorbidity. Exp. Dermatol. 2011, 20, 303–307. [Google Scholar] [CrossRef]
  60. Shahidi-Dadras, M.; Haghighatkhah, H.R.; Abdollahimajd, F.; Younespour, S.; Kia, M.P.; Zargari, O. Correlation between vascular endothelial growth factor and subclinical atherosclerosis in patients with psoriasis. Int. J. Dermatol. 2016, 55, 52–59. [Google Scholar] [CrossRef]
  61. Saleh, H.M.A.; Attia, E.A.S.; Onsy, A.M.; Saad, A.A.; Abd Ellah, M.M.M. Platelet activation: A link between psoriasis per se and subclinical atherosclerosis—A case-control study. Br. J. Dermatol. 2013, 169, 68–75. [Google Scholar] [CrossRef] [PubMed]
  62. Kim, J.A.; Montagnani, M.; Kwang, K.K.; Quon, M.J. Reciprocal relationships between insulin resistance and endothelial dysfunction: Molecular and pathophysiological mechanisms. Circulation 2006, 113, 1888–1904. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Hansson, G.K. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 2005, 352, 1685–1695. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Purzycka-Bohdan, D.; Kisielnicka, A.; Bohdan, M.; Szczerkowska-Dobosz, A.; Sobalska-Kwapis, M.; Nedoszytko, B.; Nowicki, R.J. Analysis of the Potential Genetic Links between Psoriasis and Cardiovascular Risk Factors. Int. J. Mol. Sci. 2021, 22, 9063. [Google Scholar] [CrossRef] [PubMed]
  65. Fisher, M.; Levine, P.H.; Fullerton, A.L.; Forsberg, A.; Duffy, C.P.; Hoogasian, J.J.; Drachman, D.A. Marker Proteins of Platelet Activation in Patients with Cerebrovascular Disease. Arch. Neurol. 1982, 39, 692–695. [Google Scholar] [CrossRef] [PubMed]
  66. Garbaraviciene, J.; Diehl, S.; Varwig, D.; Bylaite, M.; Ackermann, H.; Ludwig, R.J.; Boehncke, W.-H. Platelet P-selectin reflects a state of cutaneous inflammation: Possible application to monitor treatment efficacy in psoriasis. Exp. Dermatol. 2010, 19, 736–741. [Google Scholar] [CrossRef]
  67. Von Stebut, E.; Boehncke, W.-H.; Ghoreschi, K.; Gori, T.; Kaya, Z.; Thaci, D.; Schäffler, A. IL-17A in Psoriasis and Beyond: Cardiovascular and Metabolic Implications. Front. Immunol. 2019, 10, 3096. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Wang, X.; Kaiser, H.; Kvist-Hansen, A.; McCauley, B.D.; Skov, L.; Hansen, P.R.; Becker, C. IL-17 Pathway Members as Potential Biomarkers of Effective Systemic Treatment and Cardiovascular Disease in Patients with Moderate-to-Severe Psoriasis. Int. J. Mol. Sci. 2022, 23, 555. [Google Scholar] [CrossRef]
  69. Robert, M.; Miossec, P.; Hot, A. The Th17 Pathway in Vascular Inflammation: Culprit or Consort? Front. Immunol. 2022, 13, 888763. [Google Scholar] [CrossRef]
  70. Simon, T.; Taleb, S.; Danchin, N.; Laurans, L.; Rousseau, B.; Cattan, S.; Montely, J.-M.; Dubourg, O.; Tedgui, A.; Kotti, S.; et al. Circulating levels of interleukin-17 and cardiovascular outcomes in patients with acute myocardial infarction. Eur. Heart J. 2013, 34, 570–577. [Google Scholar] [CrossRef] [Green Version]
  71. Valaiyaduppu Subas, S.; Mishra, V.; Busa, V.; Antony, I.; Marudhai, S.; Patel, M.; Cancarevic, I. Cardiovascular Involvement in Psoriasis, Diagnosing Subclinical Atherosclerosis, Effects of Biological and Non-Biological Therapy: A Literature Review. Cureus 2020, 12, e11173. [Google Scholar] [CrossRef]
  72. Gisterå, A.; Robertson, A.-K.L.; Andersson, J.; Ketelhuth, D.F.J.; Ovchinnikova, O.; Nilsson, S.K.; Lundberg, A.M.; Li, M.O.; Flavell, R.A.; Hansson, G.K. Transforming Growth Factor–β Signaling in T Cells Promotes Stabilization of Atherosclerotic Plaques Through an Interleukin-17–Dependent Pathway. Sci. Transl. Med. 2013, 5, 196ra100. [Google Scholar] [CrossRef]
  73. Gao, Q.; Jiang, Y.; Ma, T.; Zhu, F.; Gao, F.; Zhang, P.; Guo, C.; Wang, Q.; Wang, X.; Ma, C.; et al. A Critical Function of Th17 Proinflammatory Cells in the Development of Atherosclerotic Plaque in Mice. J. Immunol. 2010, 185, 5820–5827. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Slominski, A.T.; Kim, T.K.; Takeda, Y.; Janjetovic, Z.; Brozyna, A.A.; Skobowiat, C.; Wang, J.; Postlethwaite, A.; Li, W.; Tuckey, R.C.; et al. RORα and RORγ are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23-dihydroxyvitamin D. FASEB J. 2014, 28, 2775–2789. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Campione, E.; Cosio, T.; Di Prete, M.; Lanna, C.; Dattola, A.; Bianchi, L. Experimental Pharmacological Management of Psoriasis. J. Exp. Pharmacol. 2021, 13, 725–737. [Google Scholar] [CrossRef] [PubMed]
  76. Brożyna, A.A.; Żmijewski, M.A.; Linowiecka, K.; Kim, T.; Slominski, R.M.; Slominski, A.T. Disturbed expression of vitamin D and retinoic acid-related orphan receptors α and γ and of megalin in inflammatory skin diseases. Exp. Dermatol. 2022, 31, 781–788. [Google Scholar] [CrossRef] [PubMed]
  77. Choi, H.; Uceda, D.E.; Dey, A.K.; Abdelrahman, K.M.; Aksentijevich, M.; Rodante, J.A.; Elnabawyi, Y.A.; Reddy, A.; Keel, A.; Erb-Alvarez, J.; et al. Treatment of Psoriasis with Biologic Therapy Is Associated with Improvement of Coronary Artery Plaque Lipid-Rich Necrotic Core: Results from a Prospective, Observational Study. Circ. Cardiovasc. Imaging 2020, 13, e011199. [Google Scholar] [CrossRef]
  78. Elnabawi, A.Y.; Dey, A.K.; Goyal, A.; Groenendyk, J.W.; Chung, J.H.; Belur, A.D.; Rodante, J.; Harrington, C.L.; Teague, H.L.; Baumer, Y.; et al. Coronary artery plaque characteristics and treatment with biologic therapy in severe psoriasis: Results from a prospective observational study. Cardiovasc. Res. 2019, 115, 721–728. [Google Scholar] [CrossRef]
  79. Gelfand, J.M.; Shin, D.B.; Duffin, K.C.; Armstrong, A.W.; Blauvelt, A.; Tyring, S.K.; Menter, A.; Gottlieb, S.; Lockshin, B.N.; Simpson, E.L.; et al. A Randomized Placebo-Controlled Trial of Secukinumab on Aortic Vascular Inflammation in Moderate-to-Severe Plaque Psoriasis (VIP-S). J. Investig. Dermatol. 2020, 140, 1784–1793. [Google Scholar] [CrossRef]
  80. Makavos, G.; Ikonomidis, I.; Andreadou, I.; Varoudi, M.; Kapniari, I.; Loukeri, E.; Theodoropoulos, K.; Pavlidis, G.; Triantafyllidi, H.; Thymis, J.; et al. Effects of Interleukin 17A Inhibition on Myocardial Deformation and Vascular Function in Psoriasis. Can. J. Cardiol. 2020, 36, 100–111. [Google Scholar] [CrossRef]
  81. Marovt, M.; Marko, P.B.; Pirnat, M.; Ekart, R. Effect of biologics targeting interleukin-23/-17 axis on subclinical atherosclerosis: Results of a pilot study. Clin. Exp. Dermatol. 2020, 45, 560–564. [Google Scholar] [CrossRef] [PubMed]
  82. Piros, É.A.; Szabó, Á.; Rencz, F.; Brodszky, V.; Szalai, K.; Galajda, N.; Szilveszter, B.; Dósa, E.; Merkely, B.; Holló, P. Impact of Interleukin-17 Inhibitor Therapy on Arterial Intima-media Thickness among Severe Psoriatic Patients. Life 2021, 11, 919. [Google Scholar] [CrossRef] [PubMed]
  83. Von Stebut, E.; Reich, K.; Thaçi, D.; Koenig, W.; Pinter, A.; Körber, A.; Rassaf, T.; Waisman, A.; Mani, V.; Yates, D.; et al. Impact of Secukinumab on Endothelial Dysfunction and Other Cardiovascular Disease Parameters in Psoriasis Patients over 52 Weeks. J. Investig. Dermatol. 2019, 139, 1054–1062. [Google Scholar] [CrossRef] [Green Version]
  84. Kamata, M.; Tada, Y. Efficacy and Safety of Biologics for Psoriasis and Psoriatic Arthritis and Their Impact on Comorbidities: A Literature Review. Int. J. Mol. Sci. 2020, 21, 1690. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Gerdes, S.; Pinter, A.; Papavassilis, C.; Reinhardt, M. Effects of secukinumab on metabolic and liver parameters in plaque psoriasis patients. J. Eur. Acad. Dermatol. Venereol. 2020, 34, 533–541. [Google Scholar] [CrossRef] [Green Version]
  86. Lebwohl, M. Does Treatment of Psoriasis Reduce Cardiovascular Comorbidities? J. Investig. Dermatol. 2017, 137, 1612–1613. [Google Scholar] [CrossRef]
  87. Marsche, G.; Holzer, M.; Wolf, P. Antipsoriatic treatment extends beyond the skin: Recovering of high-density lipoprotein function. Exp. Dermatol. 2014, 23, 701–704. [Google Scholar] [CrossRef] [Green Version]
  88. Wang, H.N.; Huang, Y.H. Changes in metabolic parameters in psoriatic patients treated with secukinumab. Ther. Adv. Chronic Dis. 2020, 11, 2040622320944777. [Google Scholar] [CrossRef] [PubMed]
  89. Ryan, C.; Leonardi, C.L.; Krueger, J.G.; Kimball, A.B.; Strober, B.E.; Gordon, K.B.; Langley, R.G.; de Lemos, J.A.; Daoud, Y.; Blankenship, D.; et al. Association between biologic therapies for chronic plaque psoriasis and cardiovascular events: A meta-analysis of randomized controlled trials. JAMA 2011, 306, 864–871. [Google Scholar] [CrossRef]
  90. Poizeau, F.; Nowak, E.; Kerbrat, S.; Le Nautout, B.; Droitcourt, C.; Drici, M.D.; Sbidian, E.; Guillot, B.; Bachelez, H.; Ait-Oufella, H.; et al. Association Between Early Severe Cardiovascular Events and the Initiation of Treatment with the Anti-Interleukin 12/23p40 Antibody Ustekinumab. JAMA Dermatol. 2020, 156, 1208–1215. [Google Scholar] [CrossRef]
  91. Kleinrensink, N.J.; Pouw, J.N.; Leijten, E.F.A.; Takx, R.A.P.; Welsing, P.M.J.; de Keizer, B.; Jong, P.A.; Foppen, B. Increased vascular inflammation on PET/CT in psoriasis and the effect of biologic treatment: Systematic review and meta-analysis. Clin. Transl. Imaging 2022, 10, 225–235. [Google Scholar] [CrossRef]
  92. Nast, A.; Smith, C.; Spuls, P.I.; Valle, G.A.; Bata-Csörgö, Z.; Boonen, H.; De Jong, E.; Garcia-Doval, I.; Gisondi, P.; Kaur-Knudsen, D.; et al. EuroGuiDerm Guideline on the systemic treatment of Psoriasis Vulgaris—Part 1: Treatment and monitoring recommendations. J. Eur. Acad. Dermatol. Venereol. 2020, 34, 2461–2498. [Google Scholar] [CrossRef] [PubMed]
  93. Nast, A.; Smith, C.; Spuls, P.I.; Valle, G.A.; Bata-Csörgö, Z.; Boonen, H.; De Jong, E.; Garcia-Doval, I.; Gisondi, P.; Kaur-Knudsen, D.; et al. EuroGuiDerm Guideline on the systemic treatment of Psoriasis Vulgaris—Part 2: Specific clinical and comorbid situations. J. Eur. Acad. Dermatol. Venereol. 2021, 35, 281–317. [Google Scholar] [CrossRef] [PubMed]
Biomedicines 11 00318 g001 550
Figure 1. Flow diagram.
Figure 1. Flow diagram.
Biomedicines 11 00318 g001
Biomedicines 11 00318 g002 550
Figure 2. Shared immunologic mechanisms between psoriasis and atherosclerosis.
Figure 2. Shared immunologic mechanisms between psoriasis and atherosclerosis.
Biomedicines 11 00318 g002
Table
Table 1. MEDLINE search strategy *.
Table 1. MEDLINE search strategy *.
Search TermsResults
Cardiovascular 2,051,829
Coronary disease 355,309
Atherosclerosis 165,432
Cardiovascular OR coronary disease OR atherosclerosis 2,286,796
Psoriasis 59,808
Psoriatic arthritis 12,928
psoriasis OR psoriatic arthritis 62,289
Biologics 7,336,51
Interleukin 17 inhibitor 2846
Interleukin 23 inhibitor 1077
Secukinumab 1734
Brodalumab 473
Ixekizumab 875
Guselkumab 473
Rizankizumab 296
Biologics OR interleukin 17 inhibitor OR interleukin 23 inhibitor OR secukinumab OR brodalumab OR ixekizumab OR guselkumab OR rizankizumab 7,337,887
(cardiovascular OR atherosclerosis OR coronary disease) AND (psoriasis OR psoriatic arthritis) AND (biologics OR interleukin 17 inhibitor OR interleukin 23 inhibitor OR secukinumab OR brodalumab OR ixekizumab OR guselkumab OR rizankizumab) 1386
* via PubMed, performed on 31 August 2022, no filters used.
Table
Table 2. Surrogate markers of subclinical atherosclerosis in patients with psoriasis.
Table 2. Surrogate markers of subclinical atherosclerosis in patients with psoriasis.
MarkerDiagnostic MethodComments
Assessment of functional alterations
Pulse wave velocityHigh resolution B-mode ultrasoundGold standard measurement of arterial stiffness
Flow-mediated dilatationHigh resolution B-mode ultrasoundassesses stimulus-activated (mainly nitric oxide-dependent) vasodilation, normally performed in the brachial artery, some studies have also used the radial and femoral arteries
Assessment of structural alterations
Intima media thicknessHigh resolution B-mode ultrasound-carotid, branchial, femoral (more informative), thickening of the intima precedes the development of plaque and stenosis
Coronary artery calcium (CAC score)Non-contrast coronary artery calcium CTMeasures the amount of calcium in coronary arteries, indicates cardiovascular disease, assists in cardiovascular risk assessment
Coronary plaque characterizationCoronary CTAe.g., total coronary plaque burden, non-calcified coronary plaque burden, high risk plaque prevalence
Lipid-rich necrotic coreCoronary CTAHigh risk coronary plaque feature, histopathologic correlate of low-attenuation plaque
Perivascular fat attenuation indexCoronary CTAQuantification of coronary inflammation, may predict the risk of developing atherosclerosis
Aortic vascular inflammationFDG PET scanMarker of subclinical vascular disease, predictive of future major cardiovascular events
Epicardial fat thicknessNative CT, MRI, TTEEpicardial adipose tissue functions as a lipid store that secrets hormones/cytokines etc., may be related with disease duration
Soluble biomarkers
N-terminal pro B-type natriuretic peptide (NT-proBNP), homocysteine, sCD40L, soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1), leptin, high sensitivity C-reactive protein (hs-CRP), fetuin-A, cystatin-C, osteopontin, chemerin, GlycA, endocan, vascular endothelial growth factor (VEGF), YKL-40, leptin, fetuin-A, cystatin-C, psoriasin, koebnerisin
CT, computed tomography; CTA, computed tomography angiography; FDG PET-CT, fluorodeoxyglucose-positron emission tomography; MRI, magnetic resonance imaging; NMR, nuclear magnetic resonance; TTE, transthoracic echocardiography.
Table
Table 3. Included studies, listed alphabetically based on first author’s name.
Table 3. Included studies, listed alphabetically based on first author’s name.
First Author, YearStudy TypenInterventionFollow UpAssessed Marker of Subclinical AtherosclerosisResults
Choi et al., 2020 [77]Prospective, cohort209Group A (n = 124): biologic therapy (anti-TNFa, anti-IL12/23, anti-IL-17)
Group B (n = 85): non biologic therapy (topical, light, systemic therapy)		1 yearLipid-rich necrotic core assessed by CTA-Favorable modification of lipid-rich necrotic core in patients under biologics
-No significant difference between different biologic groups
Elnabawi et al., 2019 [24]Prospective, cohort134Group A (n = 82): anti-TNFα, anti-IL-12/23, anti-IL17)
Group B (n = 52): non biologic therapy (topical, light therapy)		1 yearPerivascular fat attenuation index assessed by coronary CTA-Significant decrease in median fat attenuation index only in biologic group
-Similar changes between different biologic groups
Elnabawi et al., 2019 [78]Prospective, cohort121Group A (n = 89): biologic therapy (anti-TNFa, anti-IL-12/23, anti-IL-17)
Group B (n = 32): non biologic therapy (topical/light therapy)		1 yearCoronary plaque burden and plaque subcomponents (calcified vs. non-calcified) assessed by coronary CTAFavorable modulation of coronary plaque indices
Gelfand et al., 2020 (VIP-S) [79]RCT9112-week period [Secukinumab (n = 46)
vs. placebo (n = 45)]
followed by a 40-week period [secukinumab (n = 86)]		1 yearAortic vascular inflammation assessed by FDG-PET/CTNon-statistically significant −0.75% reduction in target-to-blood at week 12 and at week 52
Makavos et al., 2020 [80]Prospective, cohort150Secukinumab (n = 50) vs. cyclosporine (n = 50) vs. methotrexate (n = 50)1 yearGLS, GLSR, GLSRE, LVtwist and untwisting, CFR, PWV, MDA, PCGreater improvement of all markers in secukinumab group
Marovt et al., 2020 [81]Prospective, cohort15Ustekinumab (n = 4) vs. secukinumab (n = 10) vs. ixekizumab (n = 1)
6 monthsPWV, IMTNo significant changes in all groups
Piros et al., 2021 [82]Prospective, cohort31Secukinumab (n = 20) vs. ixekizumab (n = 11)6 monthsIMTSignificant reduction of IMT
von Stebut et al., 2019 (CARIMA) [83]RCT151Secukinumab 300 mg for 52 weeks (n = 48) vs. secukinumab 150 mg for 52 weeks (n = 54) vs. placebo for 12 weeks followed by secukinumab 300 mg for 40 weeks (n = 26) vs. placebo for 12 weeks followed by secukinumab 150 mg for 40 weeks (n = 23)1 yearFMDNon-significant difference in FMD until week 12; significantly improved FMD in patients receiving secukinumab 300 mg for 52 weeks
CFR, coronary flow reserve; CTA, computed tomography angiography; FDG-PET/CT, fluorodeoxyglucose-positron emission tomography/computed tomography; FMD, flow-mediated dilatation; GLS, global longitudinal strain; GLSR, global longitudinal strain rate; GLSRE, global longitudinal strain rate at early diastole; IL, interleukin; IMT, intima media thickness; LV, left ventricular; MDA, malondialdehyde; PC, protein carbonyl; PWV, pulse wave velocity; RCT, randomized controlled trial; TNFa, tumor necrosis factor alpha.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Tsiogka, A.; Gregoriou, S.; Stratigos, A.; Soulaidopoulos, S.; Rompoti, N.; Panagakis, P.; Papoutsaki, M.; Kostakis, P.; Kontochristopoulos, G.; Tsioufis, K.; et al. The Impact of Treatment with IL-17/IL-23 Inhibitors on Subclinical Atherosclerosis in Patients with Plaque Psoriasis and/or Psoriatic Arthritis: A Systematic Review. Biomedicines 2023, 11, 318. https://doi.org/10.3390/biomedicines11020318

AMA Style

Tsiogka A, Gregoriou S, Stratigos A, Soulaidopoulos S, Rompoti N, Panagakis P, Papoutsaki M, Kostakis P, Kontochristopoulos G, Tsioufis K, et al. The Impact of Treatment with IL-17/IL-23 Inhibitors on Subclinical Atherosclerosis in Patients with Plaque Psoriasis and/or Psoriatic Arthritis: A Systematic Review. Biomedicines. 2023; 11(2):318. https://doi.org/10.3390/biomedicines11020318

Chicago/Turabian Style

Tsiogka, Aikaterini, Stamatios Gregoriou, Alexander Stratigos, Stergios Soulaidopoulos, Natalia Rompoti, Pantelis Panagakis, Marina Papoutsaki, Panagiotis Kostakis, George Kontochristopoulos, Konstantinos Tsioufis, and et al. 2023. "The Impact of Treatment with IL-17/IL-23 Inhibitors on Subclinical Atherosclerosis in Patients with Plaque Psoriasis and/or Psoriatic Arthritis: A Systematic Review" Biomedicines 11, no. 2: 318. https://doi.org/10.3390/biomedicines11020318

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop