Introduction

Psoriasis is a common immune-mediated, genetic skin disorder, which most prominently manifests in the skin or joints or both1,2, and affects over 60 million adults and children worldwide, with overall prevalence ranging from 0.1% in east Asia to 1.5% in western Europe2. Psoriasis occurs at any age both in men and in women, leading to physical and psychological burden for individuals and the society. Visible disfiguration and disability can trigger a negative reaction in others and impair psychological quality of life. Symptoms reported by patients, such as itching, pain, burning sensations or bleeding, might relate to the high physical burden of the disease1,3.

Psoriatic inflammation appears to result in systemic inflammation4,5. Individuals with psoriasis are at an increased risk of developing comorbid disorders. Among the comorbidities, cardiovascular disease (CVD) is one of the most important comorbidities in patients with psoriatic diseases, which significantly contributes to the increased mortality and reduced life expectancy6,7. Recent evidence indicated that psoriasis skin manifestations and CVD in patients with psoriasis appear to share common pathogenic mechanisms evolving around IL-17A and its proinflammatory role8. The key inflammatory cells in psoriasis, especially neutrophils and monocytes, play a fundamental role in the interaction between the damaged endothelium and further leukocyte recruitment in atherosclerosis9.

It has been reported that psoriasis is linked with an elevated incidence of CVD10,11,12,13, such as myocardial infarction (MI), heart failure (HF), and coronary artery disease (CAD), although other studies have reported no association of psoriasis with coronary atherosclerosis14,15. Risk factors for CVD among the general population have been well established, such as smoking, hypertension, obesity, and diabetes. However, studies have rarely investigated risk or protective factors associated with comorbid CVD in patients with psoriasis. A study from the UK in 200616 showed that psoriasis severity may confer an independent risk of MI: the more severe the psoriasis, the higher the relative risk for MI.

Therefore, in this large-scale national register-based study, we sought to describe the prevalence and distribution of comorbid CVD in patients with psoriasis in China and further to explore a range of factors associated with comorbid CVD.

Methods

Study design

This national register-based cross-sectional study used data derived from the Register of China psoriasis center, part of the National Clinical Research Center for Skin and Immune Diseases, established in 2019 (http://www.psocenter.cn/). The register center was a collaborative project named the “Standardized Diagnosis and Treatment Center for Psoriasis”. It created a platform for a real-world clinical data collection involving over 1000 collaborating hospitals across China, primarily focusing on registry of outpatients with psoriasis. To guarantee the authenticity and validity of real-world big data, a quality control alliance was established within the center. Each participating hospital was required to record newly diagnosed cases of patients with psoriasis monthly with a high level of completeness in data entry. Researchers submitted applications to the center for use of registry data, and the center allocates a certain amount of data based on the contribution of the research hospital to the database.

The current study included a total of 12,313 patients clinically diagnosed with psoriasis between August 2020 and September 2021 in 215 hospitals across China. The clinical diagnosis of psoriasis was based on the ICD-10 code: L40 and the diagnosis was made primarily by dermatologists, relying on the clinical manifestations and characteristics of skin lesions according to the national guidelines for the diagnosis and treatment of psoriasis in China (2018 and 2023 edition)17,18. After excluding 753 patients under 18 years of age, the final analytical sample included 11,560 adult patients with psoriasis. Figure 1 shows flowchart of the study participants.

Fig. 1
figure 1

Flowchart of the study participants.

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Source databases

The register system included information of patients with psoriasis with regard to age, sex, onset age of psoriasis, education (middle school or below, high school, and university or above), height, weight, smoking status, history of drug allergy, and family history of psoriasis in first- and second-degree relatives.

Body mass index (BMI) was calculated as weight divided by height squared (kg/m2), and overweight was defined as BMI of 24–27.9 kg/m2 and obesity as BMI ≥ 28 kg/m22,19. Early-onset psoriasis (EOP) was defined as psoriasis with age of first onset ≤ 40 years and late-onset psoriasis (LOP) as age of first onset > 40 years20.

Information on clinical features of psoriasis recorded in the register included subtype of psoriasis, disease severity and distribution of skin lesions. The severity of psoriasis was assessed using the Psoriasis Area Severity Index (PASI). We graded skin lesions or psoriasis severity according to the lesion extension, erythema, infiltration, and desquamation using PASI. The severity of psoriasis was categorized into mild (PASI score < 3), moderate (PASI score 3–9), and severe (PASI score ≥ 10) psoriasis based on Finlay’s rule of tens21. In the present study, the types of psoriasis were divided into plaque psoriasis, guttate psoriasis, erythrodermic psoriasis, pustular psoriasis, and arthritic psoriasis. The season of exacerbation was recorded according to self-reported information and was categorized into spring, summer, autumn, winter, irregular, and seasonal.

Definition of psoriasis comorbidities

Hypertension, diabetes, and CVD in patients with psoriasis were identified via integrating self-report history of the disease, use of medications (e.g., antihypertensive and blood glucose-lowering drugs), and other treatments (e.g., stent or other surgical procedure). In the present study, CVD was referred to as the presence of arterial obstructive disease, cerebrovascular disease, heart failure, coronary heart disease, atrial fibrillation, and arrhythmia. In addition, diabetes was diagnosed using blood glucose test, whenever available (n = 740), according to the guideline for the prevention and treatment of type 2 diabetes mellitus in China22.

Ethics consideration

This multicenter cross-sectional study was conducted in accordance with the Declaration of Helsinki. This study was approved by the Ethical Committee of the Register of China National Clinical Center for Skin and Immune Diseases (2020keyan255, dated August 21, 2020). The electronic informed consent was obtained from all the patients in the study.

Statistical analysis

All statistical analyses were performed with IBM SPSS Statistics for Windows, version 26.0 (IBM Incorp., Armonk, NY, USA). Characteristics of study participants are presented as frequencies (%) for categorical variables and means (standard deviation, SD) for continuous variables. The chi-square test was used to compare the patients’ characteristics of by sex and CVD status. Univariate and multivariate logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (CIs) of CVD in association with various factors among psoriasis patients. Two-tailed P < 0.05 was considered to be statistically significant.

Mediation and comprehensive bioinformatic analyses were designed to explore the potential mechanism underlying the association of psoriasis and CVD, R package “clusterProfiler” was used for Gene Ontology (GO) pathway enrichment analyses. We utilized the protein–protein interaction (PPI) network to elucidate protein–protein physical and functional interactions via the STRING (https://cn.string-db.org) database and Cytoscape software (Version: 3.9.1).

Results

Characteristics of study participants

A total of 11,560 patients with psoriasis were included in this study. Of these, 64.88% were male, and the male-to-female ratio was 1.85. The mean age of all the patients was 41.87 years (SD, 14.80), and the mean age at first onset of psoriasis was 33.02 years (SD, 15.08) (Table 1).

Table 1 Characteristics of patients with psoriasis.
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Compare with females, male patients were older and more likely to be overweight or obese, to smoke, and to have higher levels of educational attainment (P < 0.05). In addition, male patients were more likely to have hypertension and diabetes, but less likely to have a history of drug allergy, and family history of psoriasis than female patients (P < 0.05).

Male patients tended to be exacerbating in winter, whereas females tended to be exacerbating in irregular. The skin lesions of male patients with psoriasis were more likely to distribute in scalp, face, chest, back, upper limb, lower limb, hands, foots, and genitals than female patients.

The most common type of psoriasis was plaque psoriasis (78.74%), followed by guttate psoriasis (13.47%), erythrodermic psoriasis (3.30%), pustular psoriasis (3.19%), and arthritic psoriasis (2.79%). There was no significant sex difference in arthritic psoriasis but there was statistically different in other types of psoriasis between males and females (P < 0.001). The proportion of moderate and severe psoriasis assessed using PASI was higher in male patients than female patients (P < 0.001) (Table 1).

Distributions of comorbid cardiovascular disease in patients with psoriasis

Of the 11,560 psoriasis patients, 2541 were excluded due to missing information on history of CVD or medical treatment. The overall prevalence of comorbid CVD among psoriasis patients was 2.62% (236/9019) in the total sample, 3.01% (174/5789) in males, and 1.92% (62/3230) in females; the corresponding figures among psoriasis patients who were aged ≥ 65 years were 10.69%, 11.85%, and 8.59%, respectively. Figure 2 shows the age- and sex-specific prevalence rate (per 100 patient population) of comorbid CVD among psoriasis patients. The prevalence of comorbid CVD was increased with age and was higher in male patients than in female patients across all age groups (Fig. 2).

Fig. 2
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The age- and sex-specific prevalence (per 100 patient population) of cardiovascular disease in patients with psoriasis.

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Factors associated with comorbid cardiovascular disease in patients with psoriasis

Multivariate logistic regression analysis suggested that CVD in psoriasis patients was significantly associated with older age, male sex, obesity, and smoking. Patients who had hypertension, diabetes, history of drug allergy, or family history of psoriasis were more likely to have comorbid CVD (P < 0.05) (Table 2).

Table 2 Associations of comorbid cardiovascular disease with demographic, lifestyle, and clinical factors in patients with psoriasis.
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Patients with moderate and severe psoriasis were more likely to have CVD than those with mild psoriasis. We found a dose–response relationship between the severity of psoriasis and the likelihood of comorbid CVD in patients with psoriasis (Ptrend < 0.001).

No statistically significant associations were observed between skin lesions and the likelihood of comorbid CVD (Table 2).

Mediation and bioinformatic analyses

DisGeNET (v7.0) platform (https://www.disgenet.org/) was used to investigate the molecular underpinnings of psoriasis and the comorbid CVD. Venn diagram was utilized and found 470 genes associated with both psoriasis and CVD. Gene Ontology (GO) pathway enrichment analyses revealed that the top three biological processes of the co-interactive genes were positive regulation of cytokine production, leukocyte migration, and regulation of inflammatory response, and the top three molecular functions of the genes were cytokine receptor binding, cytokine activity, and G protein-coupled receptor binding (Fig. 3A). The PPI network (Fig. 3B–E) included 448 nodes and 1322 edges, most of the genes showed strong interactions with other genes, the clustering coefficient was 0.557, and the level of interactions with the network was significantly higher than expected (PPI enrichment P-value < 1.0e−16).

Fig. 3
figure 3

The GO enrichment analysis (A) and PPI network (B–E) of the co-interactive genes involved in psoriasis and CVD. (C–E) show the top 3 cluster networks according to the score (9.25, 7.56, and 5.63, respectively). GO gene ontology, PPI protein–protein interaction, CVD cardiovascular disease.

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Discussion

In this large-scale national register-based study, we described the demographic and clinical characteristics of patients with psoriasis in China and further analyzed the lifestyle factors, cardiometabolic risk factors, and clinical features of psoriasis associated with comorbid CVD. The data showed that the prevalence of CVD in patients with psoriasis increased with age. Comorbid CVD in patients with psoriasis was associated with the severity of psoriasis, smoking, obesity, hypertension, diabetes, history of drug allergy, and family history of psoriasis. Our study contributes to the real-world clinical data regarding epidemiological features of comorbid CVD in patients with psoriasis in China in the clinical setting.

In the present study, the prevalence of comorbid CVD was lower in female patients than in male patients. A previous study has suggested a correlation of high oestrogen levels with improvement of psoriasis23. Recent studies have demonstrated that oestrogen improves cardiovascular function, through vasodilation, atheroprotection, and acceleration of endothelial healing in response to injury24,25,26. It still needs to further clarify the mechanisms underlying the association between oestrogen and CVD in patients with psoriasis. Psoriasis patients have a higher prevalence of traditional modifiable cardiovascular risk factors such as arterial hypertension, diabetes, obesity, and smoking27,28. A population-based study in the UK found a correlation between obesity and CVD in patients with psoriasis29. In consistence with these studies, our data showed that psoriasis patients with obesity, smoking, hypertension, or diabetes tended to be more likely to have CVD. It is suggested that oxidative stress and inflammatory pathway may play a vital role in the pathogenesis of CVD in patients with psoriasis. Some population-based cohort studies16,30,31 have suggested that psoriasis is being increasingly recognized as a new risk factor for CVD. A key study from the UK in 2006 showed that CVD was correlated with psoriasis severity—the more severe the psoriasis, the higher the relative risk16. In a meta-analysis, an increased risk for MI and stroke was seen in patients with severe psoriasis, with around threefold increased risk for MI and 1.6-fold increased risk for stroke relative to the general population32. In our study, we found that patients with moderate and severe psoriasis were more likely to have CVD than those with mild psoriasis. However, whether cutaneous measures such as psoriasis area, severity index (PASI), and body surface area (BSA) could predict cardiovascular risk at an individual level should be further studied in the future.

It is noteworthy that psoriasis may manifest as a multisystem disease not restricted to the skin and its appendages. The association of psoriasis with several comorbidities may occur due to various factors, such as the chronic inflammatory nature of the disease, genetic susceptibility, environmental factors and/or related to the patient’s quality of life and even adverse effects of drugs used for systemic therapy. The chronic skin-specific inflammation in psoriasis has systemic, specifically vascular, inflammation effects as demonstrated by mouse models.

The pathogenesis of psoriasis involves three key interconnected inflammatory pathways33,34,35,36,37: Th17 and Tc (cytotoxic T cell) 17 responses driven by IL-17, IL-23, and CCL20 feedback circuit; IFN-γ secreting T-cells (Th1 and Tc1) through a CXCL9 and CXCL10 feedback circuit; and an IL-36 and neutrophil axis driven by the neutrophil chemokines CXCL1, CXCL2, and CXCL82. Multiple proinflammatory cytokines such as TNF-α, IFN-γ, IL-6, IL-17, and IL-8 are found in both psoriatic and atherosclerotic plaques27.

Through the analysis of a protein–protein interaction (PPI) network and gene ontology (GO), core proteins such as IL6, TNF-α, MAPK3, AKT1, and TLR4 have been identified. The development of comorbid CVD associated with psoriasis may be elucidated by common inflammatory pathway involving chronic Th1- and Th17-mediated inflammation, modulation of monocytes and neutrophils cytokine production regulation, and the involvement of PI3K/AKT, MAPK, and TLR4/NF-kappa B signalling pathways. A retrospective study found that TNF-α inhibitors could ameliorate dyslipidaemia in patients with psoriasis38, highlighting a potential benefit for cardiovascular health. Additionally, in a prospective observational study, biologic therapy administered to individuals with severe psoriasis led to favourable changes in coronary plaque indices as evaluated by coronary computed tomography angiography (CCTA)39. This evidence suggests that biologic therapy may not only improve psoriasis symptoms but also have a positive impact on comorbid CVD.

Our study had several limitations. In our study, psoriasis was clinically diagnosed primarily based on clinical manifestations and characteristics of skin lesions by dermatologists following the national guidelines for the diagnosis and treatment of psoriasis in China (2018 and 2023 edition). It is worth noting that the clinical diagnosis was not verified through histopathological examination (e.g., skin biopsy), although, additional information regarding the current and past treatment for psoriasis was considered in the diagnosis of psoriasis. The present study was a retrospective study based on clinical examination and self-report information without detailed histopathologic diagnostic or imaging modalities (e.g., coronary angiography, CT angiography, and MR angiography) to identify CVD. Previous studies suggest that patients hospitalized for psoriasis have an increased frequency of a variety of CVD. Our study sample was mainly composed of outpatients at dermatology clinics, which may be biased toward younger and less severe patients. In the present study, the mean age of the psoriasis patients was 41.87 years. The proportion of patients who were younger than 50 years was 68.33%. This could partially contribute to the relatively low prevalence of CVD in our patients with psoriasis. However, the age-specific prevalence rate of CVD was increased with age, the prevalence of comorbid CVD among psoriasis patients who were aged 55–64 years and those aged ≥ 65 years was 6.50% (6.86% in males and 5.84% in females) and 10.69% (11.85% in males and 8.59% in females), respectively. In this study, we did not have sufficient data on key indicators such as total cholesterol, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) or triglyceride (TG). Moreover, crucial indicators such as interleukin (IL)-23, IL-17, and tumor necrosis factor (TNF)-α were unavailable for the analysis. Despite conducting DisGeNET analyses and pinpointing the top three biological processes of the co-interactive genes, further research is needed to investigate the mechanisms underlying the association between psoriasis and comorbid CVD.

Conclusions

This is a nationwide multicenter register-based study using data from a real-world clinical database comprising patients with psoriasis in China. The insights gleaned from this study shed light on the epidemiology of comorbid CVD in patients with psoriasis in the real-world clinical setting. Future research efforts should focus on the mechanisms underlying the comorbid CVD in patients with psoriasis, which may pave the way for effective preventive and therapeutic interventions.