https://orcid.org/0000-0002-5284-2037
Abstract
Purpose
Few studies have investigated the impact of biologics on the risk of major adverse cardiovascular events (MACEs) among Korean patients with psoriatic diseases. We compared the risk of MACEs and all-cause mortality among patients with psoriatic disease treated with tumor necrosis factor (TNF)-α and interleukin (IL)-12/23 inhibitors in Korea.
Methods
Patients with psoriatic disease prescribed with TNF-α and IL-12/23 inhibitors since 2016 were selected from the Korean National Health Insurance Service (NHIS) Database. Follow-up data for MACEs and all-cause mortality between 2016 and 2020 were collected. A total of 2886 individuals were included, including 1987 IL-12/23 inhibitor users and 899 TNF-α inhibitor users.
Results
Compared with IL-12/23 inhibitor users, TNF-α inhibitor users had a higher prevalence of dyslipidemia and a significantly higher risk of all-cause mortality but not MACE. After controlling for age, female TNF-α inhibitor users had a significantly increased risk of all-cause mortality. Meanwhile, after controlling for sex, TNF-α inhibitor users aged 60 years or older demonstrated a significantly elevated risk of all-cause mortality. In conclusion, No statistically significant difference in MACE risk was observed between patients who used TNF-α and IL-12/23 inhibitors. Nevertheless, the use of IL-12/23 inhibitors, especially among older and female patients, resulted in a lower overall mortality.
Introduction
Psoriatic disease is a chronic inflammatory skin condition characterized by well-demarcated and scaly erythematous papules or plaques on the skin (Citation1). The disease is not only confined to the skin but is also involved in chronic systemic inflammation. ‘Psoriatic march’ is a concept that was introduced previously. It states that the chronic inflammation occurring in psoriatic disease drives systemic mechanisms that are shared with other chronic inflammatory diseases (Citation2). For example, patients with psoriatic disease can be accompanied psoriatic arthritis, cardiovascular diseases (CVDs), and metabolic syndromes (Citation3–6). Among them, CVDs are of particular interest because they can directly affect patient mortality. Although defined variably in studies (Citation7), major adverse cardiovascular events (MACEs) include acute myocardial infarction (AMI), stroke, and cardiovascular mortality. According to studies, patients with psoriatic disease have a higher risk of MACEs, especially when the disease is severe (Citation8–10). Psoriatic and cardiometabolic diseases share proinflammatory cytokine profiles and inflammatory pathways (Citation11–15). Thus, early biological therapies, which are expected to reduce systemic inflammation, are theoretically expected to alleviate the progression of cardiometabolic comorbidities (Citation5).
Biologics, such as anti-tumor necrosis factor (TNF)-α inhibitors, interleukin (IL)-12/23 inhibitors, IL-17 inhibitors, and IL-23 inhibitors have been widely used for treating psoriatic disease. Studies have investigated the impact of biologics on the risk of MACEs among patients with psoriatic disease, yielding conflicting reports (Citation16). While comparative studies on the impact of biologics on MACE risk or mortality are sparse, no large-scale study has been conducted among Korean patients.
In Korea, the National Health Insurance Service (NHIS) strictly restricts the prescription of biological agents to a limited group of patients with severe psoriasis who fail to respond to conventional treatments, and the prescriptions are monitored thoroughly. Although the NHIS covers both TNF-α and IL-23 inhibitors equally, alternating these agents is highly discouraged. The selection of a specific agent mainly depends on its cost, established efficacy, presence of comorbidities, and the physician’s preference.
In this nationwide population-based study, we aimed to compare the risk of MACEs and all-cause mortality among patients with psoriatic disease treated with TNF-α and IL-12/23 inhibitors in Korea.
Materials and methods
Database
The Republic of Korea’s National Health Insurance provides coverage to almost 98% of the population. Data on insurance classification based on income; sociodemographic characteristics; International Classification of Diseases, 10th Revision (ICD-10) diagnosis codes; services used; and prescription history are available from the NHIS.
Study population
This study was conducted in accordance with the guiding principles of the Declaration of Helsinki. The Asan Medical Center Institutional Review Board waived the requirement for ethical review and approval for this study because the NHIS database contains anonymized data that cannot allow patients’ identification. A previously confirmed diagnostic algorithm was used to identify patients with psoriatic disease in Korea. Patients with psoriatic disease were defined as those with at least one documented visit with psoriasis or psoriatic arthritis as a primary diagnostic code (L40, M071-073, and M090) and prescription of vitamin D derivatives. The algorithm demonstrated a sensitivity and specificity of 90.8% and 92.5%, respectively (Citation17). Patients with psoriatic disease were identified between January 2005 and December 2020. Patients with no link to the NHIS database and those less than 18 years of age were excluded.
Among them, patients with psoriatic disease prescribed with TNF-α inhibitor (adalimumab, etanercept, and infliximab) or IL-12/23 inhibitors (ustekinumab) since 1 January 2016 were included. Patients who were prescribed with biologics for indications other than psoriatic disease or who were not administered with the second dose within 90 d were excluded. Finally, the TNF-α and IL-12/23 inhibitor user cohorts were obtained after excluding patients with a prescription history of both biologics and those with a previous history of MACEs before starting the biologics.
Study design
Follow-up data for MACEs and death between January 2016 and December 2020 were included for the cohorts. MACEs (AMI, coronary revascularization, heart failure, ischemic stroke, hemorrhagic stroke, and cardiovascular death; codes specified in Supplementary Table 1) and all-cause mortality were the outcomes of interest. We used the 2007–2020 cause-of-death statistics data from the Microdata Integrated Service provided by Statistics Korea (Citation18). Statistics Korea generates data related to population changes. Healthcare professionals issue a death certificate upon the death of an individual. This certificate includes information including the resident registration number, age, sex, and cause of death. The cause-of-death data were anonymized and provided for research purposes under supervision.
Potential confounding factors, such as age at biologic initiation, sex, health insurance type, type of psoriatic disease, and health screening, were collected. Comorbidities were defined when at least two documented visits with the diagnosis occurred before 1 year of biologic initiation (Supplementary Table 1). Stratified analyses were performed according to sex and age (age < 60 years, age ≥ 60 years).
Statistical analysis
The chi-square test was employed for binary and categorical variables, whereas Student’s t-test was used to examine continuous variables. The incidence rates of MACEs and all-cause mortality were calculated per 1000 person-years. We estimated the 95% confidence intervals (CIs) of the incidence rates by adopting a Poisson distribution. The risks of MACEs and all-cause mortality were determined using multivariate Cox regression analysis. The results are presented as hazard ratios (HRs) with 95% CIs. All statistical tests were two-tailed. Statisticl significance was considered at p < 0.05. All statistical analyses were performed using SAS Enterprise Guide version 7.1 (SAS Institute, Inc., Cary, NC).
Results
Study population
A total of 2886 patients, comprising 899 TNF-α inhibitor users and 1987 IL-12/23 inhibitor users, were included in this study (). The total average follow-up time was 2.9 ± 1.2 years. The mean age of both groups was 46.03 and 46.66 (p = 0.210), respectively. The percentage of female patients was higher among TNF-α inhibitor users (36.60% [329/899] vs. 31.56% [627/1987], p = 0.008) than among IL-12/23 inhibitor users. Dyslipidemia was more common among TNF-α inhibitor users (51.06% [459/899] vs. 42.48% [844/1987], p < 0.001) than among IL-12/23 inhibitor users. The mean disease duration before biologic initiation was longer among IL-12/23 users (7.85 vs. 6.99 years, p < 0.001) than among TNF-α inhibitor users. No significant differences were observed in the composition of psoriatic disease type between groups. Moreover, no statistically significant difference was observed regarding comorbidities other than dyslipidemia between groups. In addition, the health insurance type, body mass index (BMI), smoking, and drinking showed no significant differences ().
Figure 1. Study flowchart. MACEs: major adverse cardiovascular events; NHIS: national health insurance service; TNF: tumor necrosis factor.
Table 1. Patient demographics.
Risk of MACEs and all-cause mortality among patients using biologics for psoriatic disease
The incidence rates per 1000 person-years and adjusted HRs (aHRs) of MACEs and all-cause mortality are shown in . After adjusting for age, sex, and dyslipidemia, TNF-α inhibitor users showed a significantly higher risk of all-cause mortality (aHR, 2.36; 95% CI, 1.02–5.49) than IL-12/23 inhibitor users. Other factors were not included in adjustment as they did not show any significant difference between the two groups. The risk of MACEs and the individual components of MACEs did not significantly differ between the two groups. However, the risk of MACEs, AMI, and cardiovascular death showed an increasing trend with the use of TNF-α inhibitors.
Figure 2. Risk of MACEs and all-cause mortality among TNF-α inhibitor users compared with IL-12/23 inhibitor users. CI: confidence interval; IL: interleukin; MACEs: major adverse cardiovascular events; NE: not estimated; TNF: tumor necrosis factor. †Adjusted for age, sex, and dyslipidemia.
Risk of MACEs and all-cause mortality according to sex and age
Stratified analysis according to sex was performed accordingly (). Among male patients, the use of TNF-α and IL-12/23 inhibitors showed no difference in the risk of MACEs and all-cause mortality. However, among female patients, the use of TNF-α inhibitors showed a significantly higher risk of all-cause mortality (aHR, 5.29; 95% CI, 1.32–21.28) than that of IL-12/23 inhibitors after adjusting for age. We also divided the groups based on age (). Among patients below the age of 60 years, the use of TNF-α and IL-12/23 inhibitors exhibited similar risk levels for MACEs and all-cause mortality. However, among patients aged 60 years or older, the use of TNF-α inhibitors demonstrated a significantly elevated risk of all-cause mortality (aHR, 5.81; 95% CI, 1.74–19.23) than that of IL-12/23 inhibitors after adjusting for sex.
Figure 3. Risk of MACEs and all-cause mortality among TNF-α inhibitor users compared with IL-12/23 inhibitor users according to sex. CI: confidence interval; IL: interleukin; MACEs: major adverse cardiovascular events; NE: not estimated; TNF: tumor necrosis factor. †Adjusted for age.
Figure 4. Risk of MACEs and all-cause mortality among TNF-α inhibitor users compared with IL-12/23 inhibitor users according to age. CI: confidence interval; IL: interleukin; MACEs: major adverse cardiovascular events; NE: not estimated; TNF: tumor necrosis factor. †Adjusted for sex.
Discussion
The mechanism by which psoriatic disease affects the cardiovascular system remains unknown. Smoking, excess alcohol intake, obesity, hypertension, dyslipidemia, and insulin resistance are traditional risk factors for CVDs. These risk factors are reported to be prevalent in patients with psoriatic disease (Citation19–21). Although some studies have failed to find a significant association between psoriatic disease and CVD (Citation6,Citation22,Citation23), the argument revolves around whether the link between psoriatic disease and CVD signifies a cause-and-effect relationship or is a tendency stemming from the inherent risk factors observed in severe psoriatic disease.
Nevertheless, to elaborate on the possible cause-and-effect relationship, psoriatic, and atherosclerosis lesions have similar molecular mechanisms and proinflammatory cytokine profile, with a comparable inflammatory infiltrate of T cells, macrophages, and monocytes. Interferon-γ, TNF-α, and IL-17, which are proinflammatory cytokines associated with psoriatic disease, are increased in atherosclerotic plaques and sera of patients with unstable CVD (Citation12,Citation15,Citation24). In addition, psoriatic disease and atherosclerosis display a common pattern of T-cell activation, with T helper (Th)1 and Th17 cytokine upregulation and increased local and systemic expression of adhesion molecules and endothelins (Citation13,Citation14). Th17 cells appear to play a key role in stabilizing atherosclerotic plaques (Citation25). Th17 cells maintain the balance between proatherogenic and atheroprotective effects, based on the cytokine environment (Citation26). A low level of IL-17 in sera is also associated with an increased risk of cardiovascular recurrence in patients with coronary artery disease (Citation27).
These findings led researchers to study how the use of biologics in patients with psoriatic disease affects the cardiovascular system. Previous studies have reported that systemic therapies can decrease cardiovascular risk in patients (Citation28–31). However, not all studies reached the same conclusion (Citation32).
TNF-α inhibitors, which are primarily approved for rheumatic diseases, were the first to be approved. In patients with rheumatic arthritis (RA), TNF-α inhibitors had beneficial effects on cardiovascular risks (Citation33,Citation34). By observing 101 patients with RA for 6.9 years on average, Karpouzas et al. revealed that TNF-α inhibitors not only inhibit coronary plaque formation but also stabilize high-risk lesions. Additionally, they were associated with lower long-term CVD risk (OR, 0.15; 95% CI, 0.04–0.60) (Citation33). Similarly, compared with conventional systemic disease-modifying antirheumatic drugs (DMARDs), Ozen et al. demonstrated a reduction in CVD risk with the administration of TNF-α inhibitors (HR, 0.81; 95% CI, 0.71–0.93) in a cohort of 18,754 patients with RA during a median follow-up of 4.0 years (Citation34). Some studies have explored the subclinical indices of atherosclerosis. The use of TNF-α inhibitors was associated with reduced atherosclerosis progression, measured using the carotid total plaque area, and vascular inflammation, measured by F-18 fluorodeoxyglucose positron emission tomography–computed tomography, in men (Citation35). A literature search on prothrombotic parameters, such as platelet mass, low-level platelet activation, proinflammatory mediators, endothelial activation, vascular adaptation, coagulation, and fibrinolysis, has shown that some of these parameters normalize in rheumatoid patients treated with methotrexate or TNF-α inhibitors (Citation36). However, extra care is warranted for congestive heart failure (CHF) because the initial studies of TNF inhibitors on patients with RA have reported worsening CHF in New York Heart Association Class III or IV individuals. In this study, patients in the high-dose infliximab (10 mg/kg) group (n = 51) were more likely to experience death or hospitalization for heart failure than those in the placebo group (n = 49) during 28-week follow-up period (HR, 2.84; 95% CI, 1.01–7.97) (Citation37). Subsequently, in patients with psoriatic disease, several studies found that TNF inhibitors can positively affect cardiovascular risk (Citation12,Citation31,Citation38). In a meta-analysis of clinical trials, including five studies involving 49,795 patients, TNF-α inhibitors were associated with a significantly lower risk of cardiovascular events than topical or photo treatments (Citation31). In another study on patients with psoriatic arthritis, the carotid intima–media thickness was lower in patients using TNF-α inhibitors than in those using traditional DMARDs (Citation39).
IL-12/23 inhibitors, which are relatively newer drugs, have shown more conflicting results. Safety concerns have been raised regarding the possibility of an increased risk of MACEs. Similar to ustekinumab, briakinumab binds to the p40 subunit of IL-12/23. However, briakinumab is a recombinant, solely human-sequence IgG1, L monoclonal antibody extracted from the human phage display library, whereas ustekinumab is a fully human IgG1, K monoclonal antibody produced in human immunoglobulin transgenic mice (Citation40). Briakinumab was withdrawn because one of its clinical trials recorded 18 MACEs with 4 CV deaths, compared with no events in the placebo group (Citation41). For ustekinumab, several reports have shown an insignificantly higher rate of MACEs among its users (Citation42–44). In previous studies, MACEs tended to occur within the first year of ustekinumab initiation (Citation45,Citation46), especially in patients with high baseline cardiovascular risk (Citation42,Citation46,Citation47). However, studies with observation periods ranging from 10 to 24 weeks and up to 5 years have reported no significant risk of MACEs with the use of ustekinumab (Citation32,Citation42,Citation43,Citation48).
Literature has shown inconclusive results regarding the comparison of TNF-α inhibitors and ustekinumab. A meta-analysis comprising 22 RCTs involving 10,183 patients with chronic plaque psoriasis showed no significant difference in the rate of MACEs observed in patients receiving ustekinumab or TNF-α inhibitors (Citation44). Some trials reported a comparable risk of MACEs among ustekinumab, TNF-α inhibitors, and IL-17 inhibitors (Citation48–50). In patients with psoriatic arthritis, new users of IL-12/23 inhibitors had a greater risk for MACEs than those of TNF inhibitors during a median follow-up of 12 months, with a total of 9510 new biologics users analyzed (HR, 2.0; 95% CI, 1.3–3.0) (Citation51). Another study reported a small, nonsignificant increase in the risk of MACEs among ustekinumab users (Citation52). Adding to the literature, our study results showed no significant difference in the risk of AMI, stroke, coronary revascularization, and cardiovascular death associated with the use of ustekinumab vs. TNF-α inhibitors. Furthermore, these risks appeared to be consistent among the subgroups included in our study. However, MACEs tended to occur more frequently among TNF-α inhibitor users, although the difference was not statistically significant. This may be explained by the fact that in some studies ustekinumab had potential anti-inflammatory properties (Citation53) and even showed improvement in vascular, coronary, and myocardial function (Citation50,Citation54). Because IL-23 is an upstream signaling molecule of Th17 cells, a positive influence on cardiovascular risk can be expected. The higher HR of all-cause mortality in TNF-α inhibitors may stem from such associations. In our stratified analysis, the difference remained significant in the female and older (age ≥ 60 years) groups. The root causes are unclear, necessitating further investigations.
The strengths of this study stem from the nationwide coverage of the database. The NHIS database reflects a real-world setting with a diverse patient population. In addition, we could include deaths we might have missed by implementing the cause-of-death statistics. Finally, because our insurance restricts the prescription of biologics for patients with severe psoriatic disease showing insufficient clinical response to conventional treatments, the study population was relatively homogenous. However, our study had a few limitations. First, the observation period was limited to approximately 5 years. Although it was a nationwide study, the sample size of patients using biologics was extremely small for observing rare events such as stroke and heart failure, largely due to the restriction in practices. Second, because the database was not created for the study, there may be inherent inaccuracies in the diagnosis. Third, although we considered many factors, including age, gender, insurance type, comorbidity, BMI, smoking, and drinking, we cannot rule out the possibility that unknown confounders may have affected the results. Finally, the results may not be generalizable to other ethnicities.
In conclusion, there was no significant difference in the MACE risk between TNF-α and IL-12/23 inhibitors. Therefore, the previously reported cardiovascular risk with regard to the use of IL-12/23 inhibitors may be less concerning in the Korean population. Overall mortality was higher among TNF-α than IL-12/23 inhibitor users, with some trend toward older and female patients. Thus, caution should be taken when prescribing TNF-α inhibitors among these patients. Unknown confounders may influence the above results. Hence, studies with longer follow-ups are needed for more definitive conclusions.
Role of the funder/sponsor
The funding sources had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication.
Supplemental Material
Download MS Word (18.1 KB)Disclosure statement
The authors have no conflicts of interest to declare.
Data sharing statement
Raw data were generated and stored at the National Health Insurance Service and Statistics Korea. Derived data supporting the findings of this study are available from the corresponding authors SE Chang and JM Jung on request.
Additional information
Funding
References
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