1 INTRODUCTION

Despite the successful eradication of several old infectious diseases in the world, noncommunicable diseases (NCDs) have become the predominant cause of morbidity and mortality not only for people in the developed world but also for the population of underdeveloped countries.¹ Metabolic syndrome (MetS) is considered one of the major scourges among all of these NCDs, with a prevalence of 12.5%−31.4% of all individuals suffering from this condition globally.² MetS, also known as “insulin resistance syndrome” or “syndrome X” is a cluster of conditions, including dyslipidemia, hypertension, abdominal obesity, and high blood glucose, that together raise the risk of several serious health problems such as cardiovascular diseases, type 2 diabetes, and even death.^{1, 3, 4} Diagnosis of MetS is based on different criteria, such as those used by the World Health Organization, National Cholesterol Education Program's Adult Treatment Panel III (NCEP ATP III), and the International Diabetes Federation (IDF), which differ slightly from one another.^{1, 5} In the pathophysiology of MetS, insulin resistance is generally claimed to be the most common factor.^{5, 6} In detail, the poor insulin response in the target cells, including the muscle, liver, and fat tissue, to uptake the blood glucose leads to borderline glucose levels. In the beginning, the pancreas secrets more insulin to achieve euglycemia. Over time, however, an excessive amount of glucose remains in the blood as the cycle progresses.

Due to the increasing prevalence of MetS as a global health concern, the correlation of MetS with other diseases related to the immune system or inflammation is under investigation.⁷ In the case of any pathophysiological disorder that results in a loss of metabolic control, skin manifestations can occur.⁶ To cite an example, psoriasis, hidradenitis suppurativa (HS), acanthosis nigricans, lichen planus (LP), vitiligo, and atopic dermatitis are known to be associated with MetS.³ The accumulation of fat in MetS, along with a gradual increase in insulin resistance, causes a cascade of hormonal changes, such as effects on the growth hormone.⁸ Hormones follow the principle of synergistic self-regulation. Consequently, skin diseases that are influenced by androgenic hormones, such as acne or androgenic alopecia (AGA), may deteriorate.^{7, 8} In addition, there is evidence that inflammatory factors such as IL-17, IL23, TNF, and oxidative stress play a significant role in many autoimmune and inflammatory skin conditions.⁷ Likewise, these factors are present in the body in greater amounts in patients with MetS; therefore, the pathophysiology of both conditions can be described by the same pathways. In this study, we sought to systematically assess the most prevalent skin diseases with the highest association with MetS.

2 MATERIALS AND METHODS

The current systematic review was carried out based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklists. The checklists are attached as supplementary documents (Supporting Information: Tables S1 and S2).

3 RESULTS

3.1 Search results

A total of 6055 records were detected in the search up to November 15, 2022. The number of 200 duplicates were detected and removed. In the first and second phases of the screening, 5855 studies were reviewed by two independent reviewers who read the titles and abstracts to ensure their quality to be selected. Disagreements between the reviewers were resolved with discussion or the consensus of the corresponding authors. Among these articles, 5408 articles were excluded. In the last screening phase, full texts of 417 articles were reviewed based on the inclusion criteria, and a total of 37 publications were included for data extraction. Figure 1 illustrates the PRISMA flowchart of the current study.

3.4 Meta-analysis results: Association of seven skin diseases with MetS and subgroup analyses

3.4.1 Prevalence of MetS in seven skin diseases

Thirty-seven studies had adequate data for this meta-analysis. We used the random effects model due to a high heterogeneity (I² = 82.6%) among the included studies. The pooled OR for the prevalence of MetS between the skin diseases and control group was 3.28 (95% CI: 2.62−4.10). Based on the overall pooled OR, these results suggest that MetS is significantly associated with skin diseases (Figure 2).

3.4.2 Associations of seven skin diseases with MetS: Disease type subgroup analysis

In consideration of heterogeneity, further subgroup analyses based on skin disease type and country were conducted (Figure 3 and Figure 4, respectively). Regarding the disease type subgroup, AGA (OR: 11.86, 95% CI: 7.74−18.16), HS (OR: 4.46, 95% CI: 2.14−9.30), and psoriasis (OR: 2.89, 95% CI: 2.20−3.80) demonstrated a significant association with MetS. A moderate association was also found between MetS and LP (OR: 3.79, 95% CI: 2.32−6.20), SED (OR: 2.45, 95% CI: 1.05−5.75), and vitiligo (OR: 2.28, 95% CI: 1.32−3.93). Conversely, rosacea showed a weak association with MetS (OR: 1.56, 95% CI: 0.96−2.52). The MetS appears to be significantly associated with AGA, HS, LP, and SED. Although the studies were highly heterogeneous, psoriasis and MetS were also strongly correlated. In contrast, vitiligo and rosacea appeared to be associated with MetS in a weaker way.

3.4.3 Associations of seven skin diseases with MetS: Country subgroup analysis

In the case of the country subgroup, a meaningful association was found between MetS and skin diseases in Spain (OR: 5.25, 95% CI: 1.66−16.58). In addition, Skin diseases and MetS are strongly associated in Thailand (OR: 11.86, 95% CI: 4.15−33.89). There were no statistical significances found for the OR of Turkey, Pakistan, Iran, India, Germany, Kuwait, Korea, Japan, Tunisia, the Republic of Macedonia, Mexico, Brazil, Lebanon, Morocco, Montenegro, Morocco/Tunis/Algeria, Afghanistan, or China in the analysis.

3.4.4 Meta-regression analysis results

Lastly, meta-regression was also performed to explore the potential heterogeneity sources. A meta-regression was conducted to determine how covariates affected the pooled meta-analysis result. We included age, year of publication, and sample size as covariates. Furthermore, AG was found to have the greatest impact on the outcome, with a significantly larger effect size than the overall pooled result; a covariate was included in the metaregression to account for this disease.

Within utilizing a backward approach, only covariates with p-values <0.1 were retained in the final metaregression model. Among the four variables (age, year of publication, sample size, and AGA), only age and AGA remained in the final model. In summary, each year's increase on average age was associated with a reduction in the effect size (OR: 0.965, Figure 5). In contrast, AGA was associated with increased effect size (OR: 3.064, Figure 6). The crude (unadjusted) results are also presented in Table 2.

Table 2. The adjusted and unadjusted (crude model) for final covariates in the metaregression model.

Covariates	Adjusted model			Crude model
	OR	95% CI	p Value*	OR	95% CI	p Value
Age	0.965	0.944−0.987	0.003	0.960	0.936−0.983	0.002
Androgenic alopecia	3.064	1.410−6.657	0.006	3.874	1.850−8.107	0.001
Constant	13.572	4.895−37.630	<0.001

• Abbreviations: CI, confidence interval; OR, odds ratio.
• * p < 0.001 was considered significant.

3.6 Publication bias

This funnel diagram indicates a low probability of publication bias due to the symmetric distribution of studies (Figure 7).

4 DISCUSSION

Taking into account the growing prevalence of MetS as a significant health issue worldwide, there has been an increase in the number of studies assessing the relationship between MetS and skin disease in recent years.⁷ MetS is a well-known NCD identified by its side effects, such as end-organ damage, elevated levels of glucose and blood lipids, as well as high BP.⁵⁰ This makes patients susceptible to type 2 diabetes and cardiovascular diseases, such as atherosclerosis and hypertension. Insulin resistance is known to be the underlying pathophysiology of MetS.⁶ Evidence of primary and secondary associations between several skin disorders and MetS exists. According to the available findings, we conducted a thorough systematic review of case-control studies to confirm the validity of this hypothesis. A total of 37 case-control studies were included; 21 on psoriasis, five articles on AGA, four on LP, one on HS, two on rosacea, two on vitiligo, and two on SED. Regarding conditions such as discoid lupus, types of acne, atopic dermatitis, alopecia areata, and blistering diseases such as pemphigus vulgaris, no case-control studies have been published to investigate their relationship with MetS. Nonetheless, in a number of publications, the association of the very diseases with the components of MetS, such as insulin resistance, has been discussed.

In our study, the prevalence of MetS was found to be significantly higher in people with AGA. These results are in accordance with a recent systematic review and meta-analysis conducted by Qiu et al. in which the risk of MetS in patients with AGA was evaluated among 19 studies (pooled OR: 3.46, 95% CI: 2.38−5.05, p < 0.01).⁵¹ Regarding subgroup results, female gender, early onset, and African ethnicity were associated with higher odds of MetS. In addition, individuals with AGA had significantly poorer metabolic profiles, such as BMI, waist circumference, fasting glucose, blood lipids, and BP. In addition, the correlation between LP and MetS has been assessed in our study. According to the results, two studies expounded that the rate of MetS in people with LP was higher than in the normal population^{18, 19}; however, the same result was not obtained in the other two studies.^{20, 21} Based on a recent case-control study conducted in India, a statistically significant correlation was found between LP and diabetes mellitus, as well as elevated triglyceride levels (TG), increased low-density lipoprotein (LDL) levels, and low high-density lipoprotein levels (HDL).²¹ Another case-control study illustrated an association between dyslipidemia and LP.²⁰ Notably, a systematic review and meta-analysis carried out in 2020 indicated a meaningful correlation between LP and MetS (pooled OR: 2.81, 95% CI: 1.79−4.41, p < 0.01).⁵²

Considering rosacea, no correlation was found with MetS. Howbeit, the prevalence of insulin resistance, hypertension, and dyslipidemia was remarkably higher in peers suffering from rosacea. Our findings corroborate the results of a systematic review and meta-analysis with a sample size of 40,752 subjects.⁵³ Following this evidence, a meaningful association between high BP (OR: 1.204, 95% CI: 1.09−1.33) as well as insulin resistance (OR: 2.33, 95% CI: 1.18−4.60) and rosacea was depicted, leading to an increased risk of cardiovascular diseases and other related comorbidities. Another investigation illustrated that the level of total cholesterol, LDL, and C-reactive protein, was higher in patients with rosacea.⁵⁴ These findings support the escalation in the level of inflammation in these patients, which is common in MetS as well. Likewise, the association of rosacea with hypertension and dyslipidemia was evident in the results of the study. Nevertheless, no strong link was found between rosacea and ischemic heart disease. Besides, some evidence indicates a higher level of insulin resistance and obesity in subjects suffering from rosacea.

Moreover, our results suggested that these studies reported no significant association between SED and MetS. Even so, the correlation between this disease and elevated levels of blood lipids, insulin resistance, high BP, and increased waist circumference was found to be meaningful. Previous evidence showed a lower level of HDL in people with SED compared to those without this condition.⁵⁵ Further, a recent cross-sectional study illustrated that the prevalence of MetS was substantially higher in patients with SED than in the control group (p = 0.004).⁵⁶ Furthermore, the number of people with elevated TG levels in the SED group was significantly greater than in the control group (p = 0.015). In the patient group, HDL levels were significantly lower in comparison with those in the control group (p = 0.050). Both systolic and diastolic BP were also escalated in these patients (p = 0.016 and p = 0.029, respectively). This study expounded that the presence of SED should be considered a marker for MetS. Thus, further examination is mandatory in this group of patients to confirm the presence of MetS.

Our results also supported the higher prevalence of MetS in HS patients compared to the general population. Based on a subgroup analysis related to the type of HS patient (general patients vs. patients) and age group (adults vs. children), MetS was present in 9.64% of HS patients (OR: 1.82, 95% CI: 1.39−2.25).⁵⁷ An increased risk for MetS was reported in patients of tertiary hospitals and dermatology clinics (OR: 2.82, 95% CI: 0.58−5.06) compared to those treated outside the hospitals (OR: 1.78, 95% CI: 1.34−2.22). A significant correlation was also evident in the included studies considering the pediatric populations (OR: 2.10, 95% CI: 1.58−2.62). In addition, the association between HS and MetS was assessed in an adjusted systematic review and meta-analysis in 2019.⁵⁸ According to the unadjusted analysis, a significant correlation was found between HS and MetS in adult cases (OR: 1.95, 95% CI: 1.31−2.89, p = 0.001). Following adjustment for age, sex, other cardiovascular risk factors, and comorbidities, an adjusted meta-analysis indicated a significant association (OR: 2.19, 95% CI: 1.70−2.81, I² = 32%, p < 0.001). These findings highlight the need to screen patients suffering from HS for MetS.

Furthermore, we found a significant relationship between vitiligo and MetS. In accordance with our results, a recent meta-analysis study elaborated that vitiligo is associated with diabetes (pooled OR: 3.30, 95% CI: 2.10−5.17) and obesity (pooled OR: 2.08, 95% CI: 1.40−3.11).⁵⁹ As well, the prevalence of hypertension was reported to be 19.0% in vitiligo cases (95% CI: 2.0%−36.0%). However, another recent meta-analysis proposed that patients suffering from vitiligo did not have a greater risk of developing MetS than control patients (OR: 1.66, 95% CI: 0.83−3.33, p = 0.01).⁶⁰ Despite that, there were significant elevations in fasting glycemic index (mean difference 5.35, 95% CI: 2.77−7.93, p < 0.001) and diastolic BP (mean difference 1.97, 95% CI: 0.02−3.92, p = 0.05) in patients with vitiligo in comparison with control patients. It is important to note that vitiligo patients shall be monitored in terms of the indicators, including BMI, blood sugar, and BP levels.

Despite the heterogenicity of the studies in the case of psoriasis, our results indicated a strong correlation with MetS. In line with our study, a systematic review with a total of 137,053 participants illustrated that psoriasis was correlated with MetS (combined OR: 2.02, 95% CI: 1.67−2.43).⁶¹ Moreover, another systematic meta-analysis with the Latin American population claimed that psoriasis and MetS are significantly correlated (pooled OR: 1.66, 95% CI: 1.27−21.42).⁶² Further, a higher risk of MetS was detected in patients with chronic and severe forms of psoriasis (pooled OR: 6.65, 95% CI: 3.32−13.31). On the other hand, based on another systematic review study with evaluations totaling 25,042 patients, the correlation was weak (OR: 1.42, 95% CI: 1.28−1.65).⁶³ Also, the risk of MetS was found to be greater in Middle Eastern studies (OR: 1.76, 95% CI: 0.86−2.67) than in European studies (OR: 1.40, 95% CI: 1.25−1.55).⁶³ Lastly, monitoring the components of MetS can be advantageous in subjects with psoriasis. MetS, along with the risk of developing its components, will be more likely to affect patients with severe and active forms of psoriasis.

Our results suggest an increased risk of MetS in patients with skin diseases such as psoriasis, vitiligo, HS, LP, SED, and rosacea. Since all the studies included were case-control studies, causality and generalizability may be limited. Further cohort studies and randomized trials are warranted to better understand the relationship between MetS and these skin diseases. Besides, MetS and associated complications, including type 2 diabetes, hypertension, and cardiovascular diseases, should not be neglected. These conditions negatively impact affected individuals' quality of life and life expectancy. Patients with these metabolic risk factors must be assessed and managed appropriately to prevent or mitigate complications. Additionally, clinicians can improve long-term outcomes and overall well-being by addressing modifiable risk factors and implementing preventive measures for individuals who suffer from these skin diseases.

5 CONCLUSION

This systematic review consolidates that patients with psoriasis, vitiligo, HS, and LP are more likely to suffer from MetS compared to the general population. Moreover, the prevalence of increased BP, impaired lipid profile, and evidence of insulin resistance is found to be higher in peers with SED and rosacea than in the general population. Howbeit, there is still no robust evidence regarding an increased risk of MetS in these patients. MetS, along with its irreparable consequences, such as type 2 diabetes, high BP, and cardiovascular diseases, have a huge impact on not only the life expectancy of individuals but also the quality of their lives. Hence, early diagnosis and rapid treatment initiation for metabolic disorders in these patients are of great significance. It is imperative to note that maintaining a healthy lifestyle by following a balanced diet and engaging in regular exercise can notably slow or halt the development and progression of such comorbidities.

6 LIMITATION AND RECOMMENDATION

The main limitation of this study is the fact that it cannot be determined whether skin diseases are a risk factor for MetS or vice versa. Moreover, the diagnostic criteria of MetS vary among different studies. The presentation of the statistical reports was not homogeneous in the articles as well. Also, the limited number of case-control studies in some diseases, such as SED, rosacea, and HS, affects the reliability of the results. Further, no case-control studies were found regarding a number of skin diseases, such as atopic dermatitis, alopecia areata, lupus, and discoid lupus. There has been no case-control study investigating the relationship between acne and MetS despite numerous studies related to insulin resistance.

AUTHOR CONTRIBUTIONS

Sogand Sodagar: Conceptualization; data curation; writing—original draft; writing—review and editing. Yekta Ghane: Data curation; validation; writing—original draft; writing—review and editing. Amirhossein Heidari: Data curation; validation; writing—original draft; writing—review and editing. Nazila Heidari: Data curation; validation; writing—review and editing. Elaheh Khodadust: Validation; writing—review and editing. Seyyed Amir Yasin Ahmadi: Formal analysis. Farnoosh Seirafianpour: Data curation; validation. Hamid Baradaran: Methodology; project administration. Azadeh Goodarzi: Conceptualization; methodology; project administration.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

ETHICS STATEMENT

Patients or the public were not involved in our research's design, conduct, reporting, or dissemination plans.

TRANSPARENCY STATEMENT

The corresponding author Azadeh Goodarzi affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.