Serum vitamin E levels and chronic inflammatory skin diseases: A systematic review and meta-analysis.

BACKGROUND: Vitamin E has long been linked to skin health, including all of its possible functions in cosmetic products, to its roles in membrane integrity and even the aging process. However, reports on the relationship between serum vitamin E levels and the risk of chronic inflammatory skin diseases have been inconsistent. We performed a systematic review and meta-analysis to evaluate the association between serum vitamin E levels and chronic inflammatory skin diseases.
METHODS: We searched the PubMed, Web of Science and Scopus databases, with no time limit up to 30.06.2021. Studies examining serum vitamin E levels in patients with chronic inflammatory skin diseases were selected.
RESULTS: Twenty articles met the inclusion criteria. Compared with controls, a lower vitamin E level was found in patients with vitiligo (SMD: -0.70, 95% CI: -1.21 to -0.19), psoriasis (SMD: -2.73, 95% CI: -3.57 to -1.18), atopic dermatitis (SMD: -1.08, 95% CI: -1.80 to -0.36) and acne (SMD: -0.67, 95% CI: -1.05 to -0.30).
CONCLUSIONS: Our meta-analysis showed that serum vitamin E levels were lower in patients suffering from vitiligo, psoriasis, atopic dermatitis and acne. This study highlights the need to evaluate vitamin E status to improve its level in patients with skin diseases.

Introduction

Skin disease is a highly prevalent disease and is estimated to affect 30% -70% of individuals of all cultures and ages, causing a substantial burden worldwide. Skin disease has become a global public health problem [1-3]. Chronic inflammatory skin disease is an umbrella term grouping heterogeneous entities characterized by chronic immunologically driven skin inflammation, and encompasses many common disorders, including atopic dermatitis, psoriasis, lichenoid reactions, autoimmune bullous diseases and some granulomatous reactions [4,5]. These diseases are difficult to cure and often accompanied by long-term symptoms such as itching, pain and skin damage, which can diminish a patient’s quality and even length of life [6-8]. Chronic inflammatory skin disease also be associated and often coexisting with obesity, cardiovascular disease, diabetes mellitus and many other immune-related clinical conditions [9-11]. The pathophysiology of chronic inflammatory skin diseases is unclear, but it is presumed to be an ensemble of genetic and environmental aspects leading to an impaired immunological activation in patients of chronic inflammatory skin diseases.

Vitamin E is an essential and beneficial nutrient in various aspects of health that is attracting growing attention in skin care. Vitamin E can be divided into two groups, tocopherols and tocotrienols, with four isomers (alpha, beta, gamma and delta). Compared to the exogenous lipophilic vitamins that exist in the body, vitamin E was shown to be more evenly distributed in the whole body, especially in the plasma [12,13]. Aberrant changes in serum vitamins have been reported in chronic inflammatory skin diseases [14,15]. To date, studies on the level of serum vitamin E and skin diseases have mainly focused on chronic inflammatory skin diseases such as vitiligo, psoriasis, atopic dermatitis and acne [16-35]. Most of these studies generally support an inverse association between serum levels of vitamin E and the risk of skin diseases. However, the result is still controversial because other studies show that there is no relationship between serum levels of vitamin E and the risk of skin diseases. There is lack of meta-analysis on the relationship between serum levels of vitamin E and chronic inflammatory skin diseases.

Based on the results of previous studies, we speculated that the increased risk of chronic inflammatory skin diseases in some populations may partly be explained by their poor serum vitamin E status. As a first step in addressing this issue, we performed a systematic review and meta-analysis to determine the relationship between serum levels of vitamin E and chronic inflammatory skin diseases including vitiligo, psoriasis, atopic dermatitis and acne.

Materials and methods

Literature search

This meta-analysis was registered on Prospero (CRD42020207143). All literatures investigating the association of serum vitamin E levels and skin diseases were conducted in according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [36]. The studies were screened and selected independently by two authors (Q.L. and MX.L.). The quality assessment of articles was also performed by the two authors. Any disagreement was resolved through discussion with a third author (C.Z.).

The literature search on relationship between serum vitamin E levels and chronic inflammatory skin diseases was performed in PubMed, Scopus, and Web of Science databases and considered articles published until 30.06.2021. We included English-language studies of all designs. The literature search strategy was showed in S1 Table.

Eligibility criteria and study selection

Full-text articles were eligible if they met the following inclusion criteria: studies reporting relevant topics on comparing serum vitamin E levels in patients with chronic inflammatory skin diseases (vitiligo, atopic dermatitis, psoriasis or acne) and the control groups of healthy individuals without skin diseases. The review articles, case reports, animal studies and in vitro experiments were excluded from analysis.

Data extraction

Data were extracted from each study by two authors using a standardized data-collection protocol. In each study, the following information was extracted in tabular form: first author, publication year, country, number of cases and controls, skin diseases, patient gender and age, serum vitamin E determination method, and levels of serum vitamin E.

Data quality assessments

The Newcastle–Ottawa Scale was used to assess the quality of included case control studies [37]. Using this scale, every individual study is judged on eight items, categorized into three groups: selection of study groups; comparability of groups; and ascertainment of exposure/outcome. Stars are given for each quality item and the highest quality studies are given up to nine stars. A study is considered of high-quality if there are 3 or 4 stars in selection domain AND 1 or 2 stars in comparability domain AND 2 or 3 stars in exposure/outcome domain [37]. Studies with ≥ 6 stars, 4–6 stars were considered high and moderate quality, respectively. Studies with ≤ 4 stars were considered low quality and were excluded [38].

Statistical analysis

All analyses were performed using Stata software (Stata Statistical Software, Release 13; StataCorp LP, College Station, TX, USA). The standard mean differences (SMD) and corresponding 95% confidence intervals (CI) were pooled to evaluate the association between serum vitamin E levels and different chronic inflammatory skin diseases, as well as the association between serum vitamin E levels and disease severity. Heterogeneity test was performed by I2 statistic [39]. A random effects model was used because of the high heterogeneity (I2 > 50%). Publication bias was evaluated by using Egger’s test.

To explore heterogeneity, subgroup and meta-regression were performed to determine the effects of the study quality (< 6 vs. ≥6 stars), region (Europe vs. Asia), study size (n < 100 vs. n ≥ 100), age (children vs. other), gender (female > male vs. female < male vs. female = male) and whether gender or age-matched controls (yes vs. no) on the levels of serum vitamin E levels of patients with chronic inflammatory skin diseases and controls. Sensitivity analysis was performed to try to explain the influence of individual studies on the overall effect size.

Results

The search screened 892 studies: 192 from PubMed, 58 from Scopus, and 642 from Web of Science. After carefully selection and exclusion, 20 case-control studies involving a total of 1172 patients were included into this review (Fig 1) [16-35].

Fig 1

Flow diagram of systematic literature search.

Study characteristics

The main relevant information of the 20 case-control studies included in our review was summarized in Table 1. Studies were mainly focus on chronic inflammatory skin diseases, including vitiligo, psoriasis, atopic dermatitis and acne. Six studies were from India; four from Turkey, two each from Italy and Poland; and one each from South Korea, German, Portugal, Jordan, Nepal and Tunisia. Five studies included only children or teenagers, eight included only adults, six included children and adults and one without age description. Eleven studies adopted the measurement of high-performance liquid chromatography (HPLC), three with fluorescence spectrophotometry (FS), two with gas chromatography mass spectrometry (GC-MS), one with rapid determination of vitamin E assay, one with Baker and Frank’s protocol, and one with α-α dipyridyl antioxidant assay. Thirteen studies elaborated that alpha tocopherol was estimated in their investigations, seven studies did not describe the subunit of measured vitamin E. Serum vitamin E levels of different skin diseases were showed in S2 Table.

Table 1

Main characteristics of studies included in the review.

Author (year)	Country of origin	Children*, adults or both	Gender	n, cases	n, total	Type of control	Method of vitamin E determination	Subsets of vitamin E	Skin disease	Method of Skin diseases determination	Matching or adjustment factors
Oh et al., 2010 [17]	Korea	Young children	Patients: 54.7% boys, 45.3% girls; Control: 50.8% boys, 49.2% girls	180	422	Non- atopic Dermatitis	HPLC	alpha tocopherol	Atopic Dermatitis	SCORAD	Gender, Age
Sivaranjani et al., 2013 [32]	India	An average age of 35 years (10–60 years)	NA	25	50	Healthy controls of same age group	Spectrophotometry	alpha tocopherol		NA	Age
Daniluk et al., 2019 [16]	Poland	Children aged from 1 to 15 years	Patients: 41.4% boys, 58.6% girls; Control: 63.6% boys, 36.4% girls	29	51	Healthy controls with negative history of allergy	HPLC	alpha tocopherol		SCORAD	Age
Hozyasz et al., 2004 [25]	Poland	Children with DA (age: 1–9 years).	NA	25	43	Healthy controls	HPLC	alpha tocopherol		Clinically diagnosed	Age
Ines et al.,2006 [18]	Tunisia	18–66 years old	Patients: 38.9% male, 61.1% female; Control: 37.5% male, 62.5% female	36	76	Healthy controls	HPLC	NA	Vitiligo	Clinically diagnosed	Age
Khan et al., 2009 [19]	India	22–41 years old aldult	Patients: 23.3% male, 76.7% female; Control: matched	30	60	Healthy controls	Fluorometery	alpha tocopherol		Clinically diagnosed	Gender, Age
Agrawal et al., 2014 [22]	Nepal	<15 years old	Patients: 48% male, 52% female; Control: 45% male, 55% female	80	160	Healthy controls	Spectrophotometric assay	alpha tocopherol		Clinically diagnosed	Age
Jain et al., 2008 [26]	India	11–20 years old	Patients: 50% male, 50% female; Control: 50% male, 50% female	40	80	Healthy controls	Rapid determination of vitamin E	NA		Clinically diagnosed	Gender, age
Dell’Anna et al., 2001 [23]	Italy	18–53 years old	Patients: 50% male, 50% female; Control: 50% male, 50% female	40	80	Healthy controls	Gas Chromatography Mass Spectrometry (GC-MS)	NA		Clinically diagnosed	Gender, age
Agrawal et al., 2004 [22]	India	5–45 years old	Patients: 37.5% male, 62.5% female; Control: 37.5% male, 62.5% female	63	123	Healthy controls	Spectrophotometry	NA		Clinically diagnosed	Age
Picardo et al., 1994 [29]	Italy	19–45 years old	Patients: 40.3% male, 59.7% female; Control: 40.3% male, 59.7% female	62	122	Healthy controls	GC-MS	alpha tocopherol		Clinically diagnosed	Age
Kökçam et al., 1999 [28]	Turkey	9 to 76 years old	Patients: 58.8% male, 41.2% female; Control: matched	34	68	Healthy controls	HPLC	alpha tocopherol	Psoriasis	Clinically diagnosed	Gender, age
Pereira et al., 2004 [21]	Portugal	Patients:47.4 ± 13.3 years old;Control:45.9 ± 12.2 years old	Patients: 57% male, 43% female; Control: 55% male, 45% female	70	110	Healthy controls	HPLC	alpha tocopherol		Clinically diagnosed	Gender, age, BMI
Jain, et al., 1988 [27]	India	Both sexes from various age groups	Both sexes	20	40	Healthy controls	By method of Baker and Frank	NA		Clinically diagnosed	Gender, age
Demir et al., 2013 [24]	Turkey	Patients:39.23 ± 15.32 years old; control: 38.46 ± 10.32 years old	Patients: 32.3% male, 67.7% female; Control: 35.1% male, 64.9% female	31	68	Healthy controls	HPLC	alpha tocopherol		Biopsy-proven diagnosed	Gender, age
Pujari et al., 2014 [30]	India	Aged 20–60 years	NA	90	180	Healthy controls	α-α dipyridyl antioxidant assay	NA		Clinical diagnosed	Gender, age
Severin et al., 1999 [31]	Germany	NA	NA	33	69	Healthy controls	HPLC	alpha tocopherol		Clinical diagnosed	NA
El-akawi et al., 2006 [35]	Jordan	Patients: 21.0 ± 5.4 years old; controls: 21.3 ± 5.3 years old	NA	100	200	Healthy controls	HPLC	NA	Acne	GAGS	Age
Ozuguz et al., 2013 [33]	Turkey	Patients: 28.54±8.30 years old	Patients: 35.1% male, 64.9% female; Control: 21.4% male, 78.6% female	94	150	Healthy controls	HPLC	alpha tocopherol		Clinical diagnosed	Gender, age
Tunçez Akyürek	Turkey	Patients:18.67 ± 3.36 years old; controls: 19.7 ± 2.49 years old	NA	90	120	Healthy controls	HPLC	alpha tocopherol		GAGS	NA

*Children defined as <18 years of age.

HPLC: High-performance liquid chromatography.

SCORAD: Scoring Atopic Dermatitis index.

GAGS: Global Acne Grading System.

In quality assessment, scores of all included case-control studies are showed in S3 Table. Most studies were high quality as assessed by the NOS. For selection of study groups, 11 of the 20 studies scored 3 or 4 stars. For comparability, all of the 20 studies scored 1 or 2 stars. For assessment of outcome, all of the 20 studies provided ascertainment of exposure, and had same method of ascertainment for cases and controls, but only one study provided non-response rates or described non-respondents.

Serum vitamin E levels and vitiligo

Levels of serum vitamin E in patients with vitiligo were reported in 7 studies, with 351 cases and 350 controls in total (p < 0.001, I2 = 90.4%). Compared with the control group, vitiligo patients had significant lower level of serum vitamin E (SMD: -0.70, 95% CI: -1.21 to -0.19) (Fig 2). No publication bias was detected by Egger’s test (p = 0.248).

Fig 2

Forest plot in the meta-analysis of vitamin E levels and vitiligo.

Serum vitamin E levels and psoriasis

Six studies investigated the change of serum vitamin E levels in psoriasis, with a total of 278 cases and 257 controls (p < 0.001, I2 = 97.6%). Compared with the control group, psoriasis patients had significant lower level of serum vitamin E (SMD: -2.37, 95% CI: -3.57 to -1.18) (Fig 3). No publication bias was detected by Egger’s test (p = 0.058).

Fig 3

Forest plot in the meta-analysis of vitamin E levels and psoriasis.

Serum vitamin E levels and atopic dermatitis

The serum vitamin E Levels in patients with atopic dermatitis were observed in 4 studies, with 259 cases and 307 controls in total (p < 0.001, I2 = 91.1%). Compared with the control group, atopic dermatitis patients had significant lower level of serum vitamin E (SMD: -1.08, 95% CI: -1.80 to -0.36) (Fig 4). No publication bias was detected by Egger’s test (p = 0.677).

Fig 4

Forest plot in the meta-analysis of vitamin E levels and atopic dermatitis.

Serum vitamin E levels and acne

Levels of serum vitamin E in acne patients were reported in 3 studies, with 284 cases and 186 controls in total (p = 0.240, I2 = 83.9%). Compared with the control group, acne patients had significant lower level of serum vitamin E (SMD: -0.67, 95% CI: -1.05 to -0.30) (Fig 5). No publication bias was detected by Egger’s test (p = 0.879).

Fig 5

Forest plot in the meta-analysis of vitamin E levels and acne.

Serum vitamin E levels and skin disease severity or stages

As showed in Fig 6, the level of serum vitamin E in active vitiligo group was similar to that observed in the stable vitiligo group, regardless of disease activity (SMD: -0.08, 95% CI: -0.45 to 0.30, n = 3), and no publication bias was detected by Egger’s test (p = 0.434). Compare with mild psoriasis patients, severe psoriasis patients had a lower serum vitamin E level without significant (SMD: -8.35, 95% CI: -17.46 to 0.76, n = 3), and no publication bias was detected by Egger’s test (p = 0.527). Severe atopic dermatitis patients had a significantly lower level of serum vitamin E compare with mild patients (SMD: -0.93, 95% CI: -1.76 to -0.10, n = 1). The level of serum vitamin E has no significant differences between severe and mild acne patients (SMD:-0.43, 95% CI: -1.32 to 0.45, n = 2).

Fig 6

Forest plot in the meta-analysis of vitamin E levels and skin disease severity.

Subgroup analysis and Sensitivity analysis

Because of high heterogeneity existed in the meta-analysis (>70%), we conducted subgroup and meta-regression analyses based on study quality, region, study size, age, gender, and whether gender or age-matched. Our result showed no modification by study quality, region, study size, age, gender, and whether sex or age-matched on the relationship between serum vitamin E levels and skin diseases (S4 Table).

In a sensitivity analysis, a meta-influence plot was used to analyze the influence of individual studies on the overall effect size. As shown in Fig 7, no single study has influence on the above-mentioned pooled effect of the association between serum vitamin E levels and skin diseases, further confirmed the robust of our findings.

Fig 7

Sensitivity analysis of studies included in meta-analysis.

A: Vitiligo; B: Psoriasis; C: Atopic dermatitis; D: Acne.

Discussion

As a dietary bioactive compound, vitamin E is very important for skin health. The level of vitamin E and its importance in the pathogenesis of skin disease has been evaluated in multiple investigations. Although most investigations showed a decrease in serum vitamin E levels in patients with skin diseases, some reports showed no significant change in the serum vitamin E status of patients with skin diseases. Previous studies have inspired the idea that the level of serum vitamin E is related to skin diseases. Therefore, we summed up the results of studies on serum levels of vitamin E in patients with skin diseases, and our study was indicating the lower vitamin E levels in patients with chronic inflammatory skin diseases such as vitiligo, psoriasis, atopic dermatitis and acne.

Chronic skin diseases are related to immune disorders that involve the interplay between oxidative stress and the immune system. Recently, oxidative stress and the accumulation of free radicals in the epidermal layer of affected skin have been shown to be involved in the pathophysiology of vitiligo [40]. In patients with atopic dermatitis, urine 8-hydroxydeoxyguanosine which is a product of DNA oxidation by free radicals, levels were higher than those in healthy people [41]. Accordingly, the imbalance of Th2 to Th1 cytokines can create alterations in cell-mediated immune responses and can promote IgE-mediated hypersensitivity [42]. As another clinically inflammatory skin disease, psoriasis can occur due to abnormalities in essential fatty acid metabolism, lymphokine secretion, lipid peroxidation and free radical generation [43]. Propionibacterium acnes (P. acnes) produces a variety of chemical factors that induce neutrophil chemotaxis, while neutrophils attempt to attack P. acnes by ROS secretion, which can initiate inflammation in normal tissues, leading to acne skin symptoms [44]. Vitamin E has gained researchers’ attention as a potential adjuvant therapy for various skin disorders due to its excellent antioxidant and anti-inflammatory properties. Vitamin E supplementation resulted in the significant improvement of clinical conditions and normalization of oxidative stress markers in patients with psoriasis and vitiligo [45,46]. In our study, there were lower serum vitamin E levels in patients with vitiligo, psoriasis, atopic dermatitis and acne than in controls. We believe this might depend on the antioxidant function as well as the many other important functions by vitamin E, such as its essential role in the function of neutrophils and it also influence lipid metabolism or directly affect T cells in immune response [47]. The exact mechanisms of serum vitamin E levels and chronic inflammatory skin diseases need further investigation.

Apart from immune disorders/autoimmunity, oxidative stress and genetic predisposition, environmental risk factors including lifestyle behaviors are the main determinants of skin diseases, especially dietary patterns. An increasing body of research indicates that dietary changes may play an important role in chronic skin diseases, especially nutrients that have bioactive functions such as antioxidant or anti-inflammatory activities [48]. It has also been found that dietary habits play an important role in pathogenesis and treatment of chronic skin diseases including psoriasis, vitiligo, acne and atopic dermatitis [49-52]. Deficiency of vitamin E has been shown to cause skin anomalies [53]. Natural sources of vitamin E include nuts, plant-based oils and vegetables. It was found that >60% of adults have vitamin E intakes below the EAR (<12 mg/d) in the United States [54,55]. Vitamin E deficiencies are more frequently found in children, likely because they have limited stores and are growing rapidly [56]. Many studies of dietary interventions on skin diseases have proven that nutrient supplementation is an auxiliary means for the treatment of skin diseases. Elgoweini et al. founded that vitamin E supplementation prevented lipid peroxidation in the cellular membrane of melanocytes and increased the effectiveness of NB-UVB in patients with stable vitiligo [57]. Goforoushan et al. reported that vitamin E prevents dermal complications of isotretinoin [58]. Oh et al. observed a lower likelihood of atopic dermatitis in children who consumed more dietary vitamin E, which led to higher serum vitamin E levels [52]. Therefore, the importance of maintaining serum vitamin E levels might be suggested for patients diagnosed with skin diseases.

Some clinical studies have been investigated as a mainstay treatment of vitamin E in skin diseases. Two randomized, double-blind, placebo-controlled clinical trials (RCTs) using the same model performed by Javanbakht et al. and Jaffary et al. concluded that alpha tocopherol increased erythrocyte superoxide dismutase activity and reducted the Scoring Atopic Dermatitis index in patients with atopic dermatitis [59,60]. A clinical trial conducted by Tsoureli-Nikita et al. showed that in patients with atopic dermatitis, treatment with oral vitamin E (400 IU/day) for 8 months had observable reductions in skin lesions and pruritus, comparable to treatment with topical corticosteroid and oral antihistamines [61]. One RCT performed by Kharaeva et al. found that supplementation with antioxidants containing vitamin E resulted in the significant improvement of clinical conditions and normalization of oxidative stress markers in patients with severe erythrodermic and arthropathic forms of psoriasis [46]. Improving vitamin E levels in patients with skin diseases might have a positive effect. However, much more research is needed on this subject due to the small amount of currently published studies.

Between-study heterogeneity is common in meta-analyses and it is essential to explore its potential sources. We conducted subgroup and meta-regression analyses on variables including study quality, region, study size, age (children vs. other), gender, and whether gender or age-matched controls to explore the potential sources of heterogeneity. However, these factors were not found to be sources of heterogeneity in our meta-analysis, but other possibilities related to skin diseases, such as variations in lifestyle and dietary practices, cannot be ruled out. Furthermore, a sensitivity analysis was performed to assess the influence of individual studies on the overall effect size. Our findings did not change significantly with the removal of any of the studies, suggesting that the association of interest is minimally impacted by the inclusion of these studies.

Several limitations should be considered for interpretation of the results. First, the number of studies for each skin disease was relatively small. Second, dietary vitamin E can vary significantly by country, religion, geographic location and food culture. Third, the studies was heterogeneous in several aspects, such as method of vitamin E determination and diagnostic criteria for skin diseases. Fourth, it is worth noting that an individual’s response to vitamin E varies depending on several factors including health condition, nutritional status, medication effect, life stage, and genetic heterogeneity. The reported associations may be confounded by other nutrients due to the synergistic or antagonistic effects of nutrients, and/or lifestyle factors known to influence the risk of skin diseases. Future large-scale studies are warranted to explore such combined effects.

Additionally, there were no differences in serum vitamin E levels between patients with active vitiligo and patients with stable vitiligo, patients with severe acne and patients with mild acne, or patients with severe psoriasis and patients with mild psoriasis, although there was a significantly decreased serum vitamin E level in patients with severe atopic dermatitis compare with patients with mild atopic dermatitis. This might be because the number of studies on serum vitamin E levels and skin disease severity is different between atopic dermatitis (n = 1) and the others (n>1). The inadequate number of studies indicates the need for the consensus on definitions for low levels of vitamin E and skin disease severity in future studies.

Finally, except for 7 studies that did not report vitamin E subtypes in their measurements, 13 of 20 studies elaborated that alpha tocopherol (α-tocopherol) was estimated in their investigations. Are other tocopherols associate with human chronic inflammatory skin diseases? The α-tocopherol structure is unique and not substitutable with other tocopherols or tocotrienols, because functions attributed to vitamin E were not only antioxidant and anti-inflammation. There are many possible mechanisms like gene expression regelation, microRNA modifications, tocopherol associated proteins, albumin binding and stem cell differentiation, as well as active forms of vitamin E including tocopheryl phosphate and vitamin E metabolites could be involved in vitamin E’s benefit [62], which we should pay attention now and explore in future.

Conclusion

Our review and meta-analysis indicated that lower serum vitamin E levels were associated with several chronic inflammatory skin diseases, such as vitiligo, psoriasis, atopic dermatitis, and acne. This is an important finding in terms of future randomized controlled trials that might reveal a direct cause and effect relationship between vitamin E intake, as well as serum vitamin E levels, and the risk of skin diseases. Furthermore, the potential mechanism associated with the preventive effects of vitamin E should be further elucidated in future studies.

PRISMA 2020 checklist.

(DOCX)

Click here for additional data file.

Systematic search strategy.

(DOCX)

Click here for additional data file.

Serum vitamin E levels of different skin diseases.

(DOCX)

Click here for additional data file.

Quality of case control studies.

(DOCX)

Click here for additional data file.

Subgroup analysis of the association between serum vitamin E levels and skin diseases.

(DOCX)

Click here for additional data file.

31 Aug 2021

PONE-D-21-21726

Available information of serum vitamin E levels and chronic inflammatory dermatosis: systematic review and meta-analysis

PLOS ONE

Dear Dr. Zhang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Having intensively reviewed your revised draft, our external reviewers differed with their final recommendations, at least to some extent. Thus, I have double checked your revised version, to come to a more balanced decision (see R #1). All in all, our  identified shortcomings are considered reasonable with regard to both PLOS ONE’s quality standards and our readership's expectations. Therefore, we invite you to submit a carefully revised version of the manuscript that addresses EACH AND EVERY point raised during the current review process. Please note that a non-convincing revision (not considered acceptable with regard to language, content, reviewers' constructive criticisms, generalizable conclusions, and/or Authors' Guidelines) must lead to outright reject.

Please submit your revised manuscript by Oct 15 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Andrej M Kielbassa

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please consider modifying your title to ensure that it is specific, descriptive, concise, and comprehensible to readers outside the field (for example by clarifying the research question that this study aims to answer).

3. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match.

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

4. Thank you for stating the following in the Acknowledgments Section of your manuscript:

“The study was funded by Higher education reform project of 2018 (Liaoning, China)”

We note that you have provided additional information within the Acknowledgements Section that is not currently declared in your Funding Statement. Please note that funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

“The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

5. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

6. Please ensure that you refer to Figure 2, 3, 4 and 5 in your text as, if accepted, production will need this reference to link the reader to the figure.

7. We note you have included a table to which you do not refer in the text of your manuscript. Please ensure that you refer to Table 5 in your text; if accepted, production will need this reference to link the reader to the Table.

8. Please include your tables as part of your main manuscript and remove the individual files. Please note that supplementary tables (should remain/ be uploaded) as separate "supporting information" files.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Partly

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: General remark

- English remains a concern, and several minor shortcomings regarding grammar and punctuation must be polished with a revised version. Remember that a flawless manuscript is the task of all co-authors, having read and approved the submission.

Abstract

- Please note the word maximum which is allowed with PLOS ONE (see Guidelines for Authors), to increase your information regarding your results, and to allow future readers to switch to your full text.

- Your aim was "To clarify the serum level of vitamin E in chronic inflammatory dermatosis, (...)." And you have concluded that "low serum Vitamin E levels increased the susceptibility risk of certain chronic inflammatory skin diseases." This would not seem convincing. Indeed, this would even seem meaningless. With your Conclusions, please stick exclusively to your aims. Do not simply repeat your results here. Do not provide banalities (known from each and every other paper). Instead, provide a reasonable and generalizable extension of your outcome.

Intro

- "Skin disease is one of the most common human illnesses." How can you say this? Please have a close look on caries, and on periodontitis. Again, please avoid common phrases seen with almost every paper.

- Please revise for referencing according to Journal style. "(...) pruritus, and so on[1, 2]." must read "(...) pruritus, and so on[1, 2]." First, make use of your spacebar, and revise thoroughly. Second, what do you mean when referring to "and so on"?

- Do not repeat statements. "(...) the relationship between serum vitamin E level and skin diseases is still unclear." and "However, the existing studies produced conflicting results." would provide comparable (or even the same) information. Please revise carefully, to facilitate reading.

- "So far, researches on level of serum vitamin E and skin diseases mainly focus on chronic inflammation skin diseases like vitiligo, psoriasis, atopic dermatitis and acne." References missing.

- Please clarify whether there already been any "systematic reviews of literature and meta-analyses" referring to vitamin E and dermal diseases. Make clear what you will add to the literature.

- Moreover, you surely had some idea prior to starting your study. What was your null hypothesis. Remember that H0 must be deducible from the foregoing thoughts. Revise carefully.

Meths

- Heading must read "Materials and methods". Again, you are strongly encouraged to consult the Journal's guidelines. Additionally, double checking some recently published PLOS ONE papers will help.

- "(...) by two authors (Qi Lan and Mengxin Luo)." must read "(...) by two authors (Q.L. and M.L.). Same with "C.Z.".

- "The literature search strategy was showed in Table. 1." must read "The literature search strategy is given with Table 1.". Revise carefully, to avoid any typos/delete full stops not considered necessary.

- "(version 13, StataCorp LP, College Station, TX)." must read "(Stata Statistical Software, Release 13; StataCorp LP, College Station, TX, USA)."

Results

- "In quality assessment, scores of all included case-control studies are showed in Table 3" Please clarify the quality grades with your text. Remember that only high-quality papers should be included, to avoid repetition of any "conflicting results" (which have been deemed by the Authors). Please clarify, and discuss.

- "(P < 0.00)" would seem unclear. As a general rule, please always provide p values on a 3-digit basis. Format must be "(p = 0.838)", or "(p < 0.001)". Note that lower case "p" would fit to the Journal style.

- High heterogeneity would seem a problem, and there must be a convincing rationale to proceed with your paper. Please discuss.

- "As a sensitivity analysis, a meta-influence plot was used to analyze the influence of individual studies on the overall effect size (Figure. 7)." This would not seem acceptable. Please remember that it is considered the task of the Authors to guide the reader. Simply referring to a Table, or to a Figure (without providing any explanations) is not deemed professional.

Disc

- Refer to H0 with the first paragraph of this section.

- "It was found that >60% of adults have vitamin E intakes below the EAR (<12 mg/d) in the United States." Again, each and every statement calls for reference(s). Revise thoroughly throughout your text.

- "In our study, the lower serum vitamin E levels in patients of vitiligo, psoriasis, atopic dermatitis and acne compared with controls." Please double check and revise sentence.

- This section has not been thoroughly elaborated, and there would seem room for more profound discursive aspects.

Concl

- Please see comments given above. Again, do not simply repeat your results here - these already have been presented (and should be thoroughly discussed, see comments given above). Instead, provide a reasonable and generalizable extension of your outcome.

- Same with "It might be due to the number of researches on (...)." Explanations (and even speculations) are welcome, but must be provided with the Disc section.

- Same with "The low quality and high heterogeneity of some included studies means that our results must be interpreted with caution (...)." Again, this is not considered a Conclusion. You should discuss these aspects at the right place. Why did you include those poor papers? Why did you finish such a study involving several poor papers? Please provide a sound and reasonable rationale. Moreover (and again), this is a clear limitation, and the Authors must thoroughly clarify, why PLOS ONE should proceed with this draft. At the end of the day, this only will be another paper considered "unclear", "controversial", or "conflicting". Please see comments given above.

- "More studies of high-quality observational are required to confirm the association between low serum vitamin E levels and skin diseases." Again, this is a meaningless platitude. And, moreover, this would clarify that your study did not reveal any associations, right?

Refs

- Please revise for uniform formatting. Consult some previously published PLOS ONE papers.

Reviewer #2: This systematic review focuses on the relation between vitamin E levels and chronic inflammatory dermatoses.

It is widely recognised that it would be better to study dietary patterns rather than single nutrients since nutrients and foods may interact in their biological effects.

Reverse causation is a major issue and should be clearly discussed in the study. Reverse causation can occur when people change their diet or other lifestyle habit after developing a disease or perhaps after having a close family member suffer an event like vitiligo or other immune-related conditions

Reviewer #3: This is a commendable review by the authors to understand how vitamin E can relate to various skin issues. There are a couple revisions that are needed before this article can be considered for acceptance:

1) The English is poor. I can't detail every single grammatical error as they are numerous. Please have a native English speaker review this for grammatical accuracy.

2) The authors should not refer to vitamin E as if it is just one molecule. Please detail the subsets of vitamin E to detail what was actually measured. Was is alpha tocopherol, gamma tocopherol, tocotrienol subvariants, etc?

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

24 Oct 2021

We uploaded our respond to reviewers as an attachment.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

10 Nov 2021

PONE-D-21-21726R1Serum vitamin E levels and chronic inflammatory skin diseases: A systematic review and meta-analysis

PLOS ONE

Dear Dr. Zhang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Having intensively reviewed your revised draft, our external reviewers basically have agreed with their final recommendations. Additionally, I have double checked your revised version, to come to a final decision (see R #1). All in all, I am still convinced that your revised paper will be worth following, even if your revised version still would benefit from minor re-edits and some polishing.

Please submit your revised manuscript by Dec 25 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Andrej M Kielbassa

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: With the help of the reviewers, this revised and re-sublmitted draft has been considerably improved, and would seem ready to be forwarded to the external referees.

Reviewer #3: Thank you for the edits and this is suitable for publication. The authors now delineate the different subsets of vitamin E more clearly and the English is improved.

Reviewer #4: In this study, a comprehensive systematic review and metaanalysis was conducted to evaluate the effects of vitamin e levels on chronic inflammatory skin diseases in human subjects. This review is well written. Also, in the first revise, the reviewer's comments were responded appropriately. To the reviewer's knowledge, there has been no systematic review on this topic in the past, and it will provide important knowledge and useful information for this research area. However, there are some comments that could elevate the quality of this paper. Reviewer added recommendations and suggestions regarding this.

Comment 1

This review focuses primarily on chronic inflammatory skin diseases. Are there any reported synergies between chronic inflammatory skin diseases and other physiological effects (such as lifestyle disease and immunologic disease)? It would be more interesting for the reader to add these explanations in the first half of the article.

Comment 2

Reviewer concern about the subjects’ characteristics used for this analysis. Authors mentioned about their age but less information about their sex even though some investigations the number of male/ female is considerably biased. Was the sex a considerable factor?

Comment 3

Reviewer felt the resolution of each figure was low. Reviewer recommends that the author replace it with a higher resolution figure.

Comment 4

The authors state that the effects of vitamin E on chronic inflammatory skin diseases are predominantly antioxidant and anti-inflammatory.

On the other hand, for example, in the following review reported this year,

Reflections on a century of vitamin E research: Looking at the past with an eye on the future,

Free Radical Biology and Medicine,

Volume 175, 2021, Pages 155-160, ISSN 0891-5849,

doi.org/10.1016/j.freeradbiomed.2021.07.042.

https://www.sciencedirect.com/science/article/pii/S0891584921007048?via%3Dihub

These review mention that vitamin E's antioxidant and anti-inflammatory effects do not work in the body. What do the authors think of such a debate?

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #3: No

Reviewer #4: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

24 Nov 2021

The respond to reviewers has been uploaded.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

26 Nov 2021

Serum vitamin E levels and chronic inflammatory skin diseases: A systematic review and meta-analysis

PONE-D-21-21726R2

Dear Dr. Zhang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards, congratulations, and stay healthy

Prof. Dr. med. dent. Dr. h. c. Andrej M. Kielbassa

Academic Editor

PLOS ONE

----------------------------------------------------

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The Authors have re-submitted a revised draft which has been considerably improved, not only with the help of the reviewers. This manuscript is ready to proceed.

Reviewer #4: Reviewer confirmed the authors' reply and the revised manuscript in detail. The authors have responded and revised appropriately to the reviewers' comments. Thank you for the revision.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #4: No

2 Dec 2021

PONE-D-21-21726R2

Serum vitamin E levels and chronic inflammatory skin diseases: A systematic review and meta-analysis

Dear Dr. Zhang:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Prof. Dr. med. dent. Dr. h. c. Andrej M Kielbassa

Academic Editor

PLOS ONE