Psoriasis is a chronic skin disease associated with the immune system. Worldwide, psoriasis affects about 125 million people. Males and females are equally affected, while adults are more affected compared with children (1, 2). There are different variants of psoriasis, including plaque psoriasis, guttate psoriasis, erythrodermic psoriasis, and pustular psoriasis. With over 80% of the cases, plaque psoriasis, or psoriasis vulgaris, is the most common subtype (1). The specific mechanism of psoriasis is not totally clear, given the complexity of multiple factors involved. Currently, widely recognized risk factors include genetic susceptibility, environmental influence, living habits, and psychological factors (3, 4). Several studies have confirmed that psoriasis is related to cardiovascular diseases (CVD) and a series of metabolic diseases, such as metabolic syndrome, non-alcoholic fatty liver, and type 2 diabetes (5, 6). In North America, the prevalence of CVD in psoriasis patients is 14.3%, while in the general population it is 11.3% (7). In patients with severe psoriasis, the risk of early myocardial infarction is higher than 50% (8). And according to Choudhary’s meta-analysis in 2020, the rate of metabolic disease in psoriasis patients was 30.29% and in general controls it is 21.7% (9). Considering all the current treatments targeting the possible pathogenic factors of psoriasis, few focus on mutually beneficial strategies. Therefore, we looked into these involving pathogenic factors for both psoriasis, CVD, and metabolic diseases.

In the pathogenesis of CVD and metabolic diseases, adipokines play a crucial role in regulation and mediation (10, 11). Retinol binding protein-4 (RBP-4) is one of these adipokines, which belongs to the lipocalin protein family. The main function of RBP-4 is to transport retinol from the liver to target cells or tissue and thus RBP-4 can regulate the metabolism of retinol (12). Additionally, RBP-4 is involved in numerous diseases, including cardiovascular disease, type 2 diabetes, metabolic dysfunctions, and obesity (12, 13). Studies have also found a change in RBP-4 levels in psoriasis patients, indicating that RBP-4 may be a meaningful factor in psoriasis. However, relying on the analysis of a single study can have drawbacks. For example, the sample sizes may be limited, which may lead to low statistical power. Additionally, divergent results may be shown among different studies. Therefore, we performed this meta-analysis, aiming to evaluate the association between RBP-4 and psoriasis vulgaris more comprehensively.

In this study, we investigated the relationship between retinol binding protein-4 and psoriasis vulgaris through meta-analysis. Our study included seven published studies, comprising 271 psoriasis patients and 235 control subjects. We found that levels of RBP-4 were significantly higher in patients with psoriasis vulgaris, and for patients with systematic treatment, a significant decrease of RBP-4 level was shown. Beyond skin lesions, psoriasis also affects multiple organs or systems such as cardiovascular diseases or metabolic diseases, in which RBP-4 plays vital roles (6, 25). The management of psoriasis has experienced rapid development in recent years, with numerous monoclonal antibodies being applied (26, 27), and better efficacy can be obtained. Furthermore, in the management of psoriasis, the management of comorbidities cannot be ignored. However, current therapy strategies mainly focus on the possible pathogenic factors of psoriasis, and few focus on mutually beneficial factors. Therefore, in this study, we wished to find a potential pathogenic factor both in psoriasis and CVD patients, looking to make a contribution to the understanding of the comorbidities of psoriasis.

The efficacy evaluation of psoriasis is relatively simple to conduct, and is assessed from the changes in plaques and the life quality of patients. However, biomarkers are still needed to assess the underlying inflammation and long-term efficacy, or to predict the efficacy in refractory or severe patients. Additionally, certain indicators can reflect the condition of the patients with comorbidities; for example, a recent study found that gingival crevicular fluid miRNAs from periodontitis patients were associated with cardiovascular disease risk (28). As a result, it is essential to find a biomarker targeting both goals. Generally, researchers have focused on the effects of inflammatory mediators, such as cytokines, chemokines, miRNA, or transglutaminase (28–31). Recently, increasing studies have found the importance of RBP-4 in multiple diseases, including psoriasis. However, due to the limitations of single studies, the results have not yet been good enough, so we used the method of meta-analysis to investigate further.

From the comparison of levels in patients at baseline and in controls in the seven studies, we found that the levels of RBP-4 increased significantly in patients with psoriasis vulgaris compared with control subjects. In previous studies, different results have been shown. For example, Gul et al. (20) and Romani et al. (19) found that RBP-4 concentrations were significantly higher in patients, while Baran et al. (22) and Karadag et al. (18) did not observe significant changes in patients and control subjects. Through meta-analysis, the results from different studies were merged, so a more solid conclusion can be made that levels of RBP-4 were significantly higher in patients with psoriasis vulgaris. RBP-4 may be a participant in the mechanism of psoriasis, for the correlation with PASI (psoriasis area and severity index) scores in some research (19, 32, 33). Additionally, the common comorbidities of psoriasis include insulin resistance, obesity, and metabolic syndrome, in which RBP-4 has been found to be involved; hence, it is rather complicated to expound the specific actions of RBP-4 in psoriasis with current data.

There were five studies included that contained the data of RBP-4 level before and after treatment. Therefore, we compared the RBP-4 levels before and after treatment, and no significance was found. Then, when we compared the levels in patients after treatment to the levels in control subjects in these five studies, no significance was found either. Since the level of RBP-4 was higher than that in controls according to our previous analysis with seven studies, we further conducted subgroup analysis by topical or systematic therapy and found that the levels decreased significantly in patients undergoing systematic treatment compared with before the treatment. Additionally, we excluded the study with mixed methods (23), and significant decreases were shown both in the total effect and in the subgroup with systematic treatment in the new comparison. Therefore, we assumed systematic treatment can lower levels of RBP-4 in patients with psoriasis vulgaris. RBP-4 may be a participant in the genesis of psoriasis, and with the application of systemic treatment, the pathway with RBP-4 involved may be blocked.

Biologic therapy of psoriasis has experienced rapid development in recent years (34). In our study, there was one publication investigating the changes in RBP-4 level after anti-TNF-α biologic therapy (24), but no significant change was shown. The reason for this could be that biologic therapy blocks the targets on the pathways more accurately, and certain markers may not possess interactions with RBP-4. Meanwhile, considering the higher RBP-4 levels in patients, future studies should pay more attention to the functions of RBP-4 in psoriasis. Although there has been some rapid development in the systematic treatment for psoriasis, especially in biologic therapies, topical treatment is still important to psoriasis (35). Through our analysis, no significant change in RBP-4 levels was shown for patients undergoing topical treatment, but there was only one included study with topical treatment applied, so it is hard to draw a conclusion to deny the effect of topical treatment on RBP-4 levels.

In this study, three comparisons were conducted: the levels of RBP-4 in patients at baseline and in controls in seven studies; the levels of RBP-4 in patients after and before treatment in five studies; and the levels of RBP-4 in patients after treatment and in controls in five studies. The heterogeneities were all significant, so subgroup analysis was needed. When we performed subgroup analysis by different region, we found that the levels of RBP-4 were not elevated significantly in patients in Asia and Europe. Region could be a source of the heterogeneity. Among different regions, there might be differences in genetic backgrounds (36, 37), which could have also caused the heterogeneity. Additionally, most of the included studies in Europe investigated the changes after treatment, in which the patients were mainly recruited from clinical trials which were strict with the included patients, some psoriasis patients with severe CVD might be excluded from the clinical trial, thus causing data bias. Different treatment methods may attract and target patients with different manifestations, so differences were shown in the patients among the studies, which caused the heterogeneity. Therefore, further studies with well-designed protocols and enlarged populations are still needed.

Some limitations existed in this study. First, the sensitivity analysis showed that the results were not perfectly robust, and further studies with more cases including the levels before and after topical/systematic treatments are needed. Secondly, the relationship between severity and RBP-4 levels was not analyzed, because the original datasets were not attainable. For the same reason, the relationship between the efficacy and changes was not investigated. Additionally, it would be more beneficial to analyze RBP-4 in psoriasis patients with different comorbidities, especially cardiovascular disease and metabolic diseases. Additionally, in the subgroup analysis based on treatment, further classification of specific treatment methods was not possible to conduct due to the limited studies. In conclusion, larger sample sizes with different treatment strategies with different comorbidities and documenting detailed before/after levels of RBP-4 would help generate more thorough and robust results.

For patients with psoriasis vulgaris, the levels of retinol binding protein-4 are elevated, and systematic treatment can lower RBP-4 levels. As RBP-4 plays an important role in psoriasis, CVD, and metabolic disease, it might act as a key indicator for the diagnosis and efficacy assessment of psoriasis and especially for the mutual pathogenic factors of the comorbidities in psoriasis patients, which might help contribute to future mutually beneficial treatment strategies. Therefore, further studies with well-designed protocols and enlarged populations are still needed.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

GG and YC conducted the literature research and data extraction. GG wrote this manuscript. HC designed the study, edited the manuscript, evaluated methodological quality, analyzed the data, and created all the figures and tables. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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