A comprehensive literature search method was utilized to systemic examine all relevant literature from the inception of PubMed, Embase, and Cochrane Library databases up to October 2022, without any language restrictions. This study included randomized controlled trials (RCTs) involving secukinumab and ixekizumab in the treatment of psoriasis. The search employed specific terms such as “secukinumab,” “ixekizumab,” “psoriasis,” “randomized controlled trial,” and others, combining subject headings and free-text terms. A detailed overview of the retrieval strategy is presented in Figure 1.

The study specifically focused on adult patients aged 18 years or older who had been diagnosed with psoriasis for a duration of at least 6 months, regardless of gender. Psoriasis diagnoses were confirmed by dermatologists through examination and biopsy, while diagnoses of psoriatic arthritis (PsA) were made by rheumatologists following the CASPAR diagnostic criteria.

Exclusion criteria included patients below the age of 18, individuals unwilling to discontinue their current treatment regimen, participation in other clinical trials within the last 3 months, non-randomized controlled studies, reviews, animal studies, conference abstracts, and cases where the full text was inaccessible or data extraction was incomplete.

In the experimental group, subcutaneous administrations of secukinumab or ixekizumab were given. The dosage of secukinumab was set at 300 mg and 150 mg, respectively, while the dosage of ixekizumab varied in frequency, either once every 2 weeks or once every 4 weeks. The control group received subcutaneous placebos, encompassing both no treatment and treatment-as-usual.

This meta-analysis aimed to examine the impact of IL-17A inhibitors on MACEs in patients with psoriasis. The analysis focused on four key aspects:

Using the Endnote X9 literature management software, two researchers conducted a thorough screening of the literature, strictly adhering to pre-established inclusion and exclusion criteria. The initial step involved eliminating duplicate literature, followed by a detailed review of the article’s title and abstract for preliminary screening. Upon obtaining the full text, a secondary filtration process was carried out. Any discrepancies encountered during the screening process were resolved through negotiation or consultation with a third party. The extracted data were meticulously recorded in tabular form, capturing key details such as the first author, year of publication, country of publication, experimental design, basic characteristics of study subjects, sample size, intervention measures, outcome indicators, duration of disease, and the incidence of MACEs during the trial.

The methodological rigor of the incorporated studies was assessed utilizing the bias risk assessment tool designed for randomized controlled trials, as stipulated in the Cochrane Manual of Systematic Reviewers 5.1.0.

The comparison of MACEs between secukinumab and ixekizumab, as well as their comparison with a placebo was conducted using RevMan 5.4 software. Relative risk served as the effect statistic for dichotomous variables was expressed as the relative risk (RR), and a 95% confidence interval (CI) was employed for interval estimation. Statistical heterogeneity was assessed using the chi-square test, and the extent of heterogeneity was measured using I² test. If no significant heterogeneity was observed (p > 0.10, I² ≤ 50%), the fixed-effects model was applied. In case of where heterogeneity was present, a thorough analysis of its potential causes was conducted, and subsequently, the random-effects model was implemented.

Through a systematic search, a total of 1,129 articles were retrieved, distributed across PubMed (n = 181), Embase (n = 655), and the Cochrane Library (n = 293). After initial screening, 81 articles were selected for further evaluation. Following a rigorous secondary screening process, 20 articles were included for both qualitative and quantitative analysis. It worth noting that all of included articles were in English (Figure 1).

In conclusion, the analysis included a total of 20 studies, encompassing 23 randomized controlled trials, which involved 10,746 participants. The experimental group consisted of 7,738 participants, while the control group included 3,008 participants. The essential information from these studies is presented in Table 1.

All of the studies adhered to a randomized double-blind trial design. However, four studies (9–12) exhibited had unclear randomization methods, one study (11) lacked clarity in outcome index evaluation methods, and 12 studies (13–24) utilized distributive hiding. Apart from one study (20), the remaining 19 studies were conducted at multiple centers. It should be noted that all studies experienced participant due to adverse reactions, such as psoriatic erythroderma, alopecia, herpes and others. A detailed breakdown of the bias risk assessment results is illustrated in Figure 2.

Funnel plots were used to analyze publication bias in the literatures reporting the incidence of MACEs in each group (Figure 7). The results showed that all funnel plots had good symmetry, suggesting that the study results were less affected by publication bias.

The search strategy employed is robust and designed to minimize the likelihood of overlooking eligible studies. Most of the included studies exhibit a clear and high risk of bias (ROB), with explicit references to randomization and blinding strategies. For example, Nash et al. (21) implemented treatment allocation concealment and generated a random sequence using a computer. The study ensured that investigators, study site staff, and patients remained unaware of treatment allocations until the initial data analysis. However, a few studies lack clarity in their descriptions of randomization and blinding methods. In the study conducted by Nguyen et al. (10), for instance, the randomization method was unclear, and no specific treatment allocation scheme was specified.

Psoriasis, a chronic inflammatory skin disease, has a significant impact on both the physical and mental well-being of individuals affected by it. Emerging evidence suggests that severe psoriasis is not only linked to metabolic disorders, obesity, and heightened mortality but also serve as an independent risk factor for atherosclerosis, myocardial infarction, and stroke (29). The condition is associated with various comorbidities, including cardiovascular disease, metabolic syndrome, cancer, gastrointestinal disorders, and chronic obstructive pulmonary disease (COPD) (30). A recent study conducted in UK revealed that individuals with moderate to severe psoriasis had a lifespan that was approximately 6 years shorter than their healthy counterparts, possibly attributed to inflammation-induced cardiovascular diseases (CVD), such as myocardial infarction and cerebral infarction (31).

Furthermore, research indicates a 57% increased risk of cardiovascular (CV) death among patients with severe psoriasis compared to those with traditional CV risk factors. Notably, while the majority of CV death risks are typically attributed to explained by major cardiac risk factors, this association is not consistently observed in severe psoriasis cases, implying an independent association between severe psoriasis and CV death (32). Additionally, Psoriatic Arthritis (PsA) is linked to a higher incidence of CVD complications in Western countries and Japan. Recent analyses of cytokines from psoriasis patients suggest that certain cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-17, and IL-23, have cardiovascular effects (31).

The IL-17A inhibitors such as secukinumab and ixekizumab have been approve for the treatment of psoriasis in China. Many studies have shown that the efficacy and safety of these two drugs in treating psoriasis, but their impact on psoriasis comorbidities, particularly cardiovascular disease has received less attention. Therefore, studies have been conducted to investigated the effect of IL-17A inhibitors on cardiovascular events in patients with psoriasis.

This study included 20 studies to investigate the association between IL-17A inhibitors and psoriasis comorbidities (specifically cardiovascular disease) based on the occurrence of MACEs in patients with psoriasis treating with secukinumab and ixekizumab. With the exception of one study, the other included studies were multi-center randomized double-blind controlled trials with well-defined inclusion and exclusion criteria. Among the 20 studies, only 4 studies had a large bias due to unclear randomization methods, while most of the studies had a low risk of bias. The meta-analysis results of this study showed no significant difference in the incidence of MACEs between secukinumab and ixekizumab compared to placebo, and the difference between the two groups was not statistically significant. The findings were consistent with the study by Rungapiromnan et al. (33) which demonstrated that secukinumab and ixekizumab did not significantly affect the risk of MACEs in adult patients with psoriasis in the short term, and there was no dose-dependent increase in the incidence of adverse events.

The baseline characteristics of the included literature in this study were comparable, ensuring reliable results, high literature quality, and a large sample size. However, certain limitations should be acknowledged:

Future research directions should encompass RCTs involve a broader spectrum of age groups among patients. This would help provide more comprehensive insights into the impact of IL-17A inhibitors on cardiovascular events across different age range. Furthermore, there is a need for more direct comparisons between different drugs to enhance the understanding of their relative efficacy in treating psoriasis and their effect on CV outcomes. Additionally, it would be valuable to conduct additional trials with consistent follow-up regimens, allowing for a more in-depth exploration of associated long-term and post-discontinuation safety concerns with IL-17A inhibitors. It is imperative that these studies are substantiated by an increased number of high-quality clinical trials to ensure the reliability and robustness of the findings.