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. 2020 Aug 21;15(8):e0238005. doi: 10.1371/journal.pone.0238005

Risk of metabolic syndrome in patients with lichen planus: A systematic review and meta-analysis

Jieya Ying 1, Wenzhong Xiang 2,*, Yu Qiu 1, Xiaofang Zeng 1
Editor: Beatrice Nardone3
PMCID: PMC7444576  PMID: 32822406

Abstract

Background

Studies have investigated whether patients with lichen planus are at a high risk of metabolic syndrome; however, currently, no conclusive data are available in this regard.

Objective

This meta-analysis was performed to analyze the published literature investigating the association between metabolic syndrome and lichen planus.

Method

Two reviewers independently searched 4 databases (PubMed, Embase, the Cochrane Library and Web of Science) for observational studies assessing the prevalence of metabolic syndrome in patients with lichen planus. Review Manager 5.3 software was used to statistically analyze the data.

Results

200 relevant articles were searched. After a further reading, 12 studies with 1422 participants (715 with LP and 707 controls) fulfilled the eligibility criteria. Overall, the pooled odds ratio based on random effects analysis was 2.81 (95% confidence interval: 1.79–4.41, P<0.00001). This meta-analysis shows that compared with the general population, patients with lichen planus are more likely to develop metabolic syndrome. Subgroup analysis of prevalence of metabolic syndrome showed higher odds ratio in studies using International Diabetes Federation diagnostic criteria (odds ratio 4.65) and the Harmonized criteria (odds ratio 26.62) than studies using National Cholesterol Education Program Adult Treatment Panel III criteria (odds ratio 1.75), and thus might be more appropriate for diagnosing metabolic syndrome.

Conclusions

This meta-analysis shows that compared with the general population, patients with lichen planus are more likely to develop metabolic syndrome. Therefore, early diagnosis and prompt initiation of first-line therapy for metabolic disorders are important in patients with lichen planus.

Introduction

Lichen planus (LP) is an idiopathic inflammatory dermatosis of the skin and mucous membranes characterized by flat, pruritic, violaceous polygonal papules. The overall prevalence of LP is approximately 0.89% of the general population [1], and it commonly affects individuals aged >45 years [2]. Although the etiopathogenesis remains unclear, LP is attributed to a T cell-mediated autoimmune process that results in degeneration and destruction of keratinocytes [3]. Recent studies have reported that in addition to affecting the skin, LP may be associated with metabolic syndrome (MS).

MS is a complex group of metabolic disorders, which include central obesity, dyslipidemia, hypertension, and hyperglycemia with insulin resistance as the central pathophysiological feature. It was first described as syndrome X by GM Reaven in 1988 [4]. The other terms, such as Reaven syndrome and the insulin resistance syndrome, have also been largely used in the literature for several decades [5].

MS is implicated as an important risk factor for type 2 diabetes mellitus and cardiovascular disease and has therefore attracted increasing attention in recent years. Growing evidence has shown that some dermatological diseases such as psoriasis [6] alopecia areata [7], hidradenitis suppurativa [8], atopic dermatitis [9] and vitiligo [10] are associated with a high prevalence of MS compared with the general population. LP and psoriasis show a similar pathological background, including features of skin barrier dysfunction [11], T lymphocyte activation, and upregulation of cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and IL-4 [12] and may therefore be associated with a high risk of MS. It has been confirmed that LP is associated with dyslipidemia, indicated by increased serum triglyceride (TG), cholesterol, and low-density lipoprotein cholesterol (LDL-C) levels and decreased high-density lipoprotein (HDL-C) levels [13].

Studies have also investigated whether patients with LP are at a high risk of MS; however, currently, no conclusive data are available in this regard. Therefore, this meta-analysis was performed to analyze the published literature investigating the association between MS and LP and determine whether patients with LP are more likely to develop MS when compared with the general population.

Materials and methods

Data sources and searches

In this systematic review and meta-analysis, two reviewers (JY and YQ) independently searched the literatures in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (see S1 Checklist for complete PRISMA checklist). We searched PubMed, Embase, the Cochrane Library and Web of Science for observational studies assessing the prevalence of MS in patients with LP published from their inception to July 16, 2020. To search relevant studies, the following terms were used: “(metabolic syndrome OR syndrome X OR insulin resistance syndrome OR Reaven syndrome) AND (lichen planus OR lesion planus)” (see S1 Table).

Inclusion criteria

The inclusion criteria for this study were as follows: (1) For studies: only studies reported in English, and observational study design (cross-sectional, cohort and case-control). (2) For experiment groups: LP affecting the skin or mucous membranes, no systemic treatment administered, and no topical therapy administered for >6 weeks. (3) The control groups included individuals without LP, who were randomly selected from the communities or hospitals. (4) Outcome measures: MS was diagnosed using the National Cholesterol Education Program Adult Treatment Panel III criteria (NCEP ATP III) (published in 2001) [14], the International Diabetes Federation (IDF) criteria (published in 2006) [15], the Harmonized criteria (proposed by IDF, National Heart, Lung and Blood Institute, American Heart Association, World Heart Federation, International Atherosclerosis Society and International Association for the Study of Obesity in 2009) [16] and other diagnostic criteria (Table 1). LP was diagnosed based on clinical manifestations and histopathological examination of biopsy specimens. Sex, race, and publication year were not considered in study selection.

Table 1. NCEP ATPⅢ, IDF and Harmonized criteria for MS.

NCEP ATPⅢ [14] IDF [15] Harmonized criteria [16]
Waist circumference expanding >102 cm in males and >88 cm in females ≥94 cm in males and ≥80 cm in females ≥94 cm in males and ≥80 cm in females
Hyper-triglyceridemia ≥150 mg/dL ≥150mg/dl or specific treatment for this lipid abnormality. ≥150mg/dl or specific treatment for this lipid abnormality.
Low HDL-C <40 mg/dL in males and <50 mg/dL in females <40 mg/dL in males and <50 mg/dL in females, or specific treatment for this lipid abnormality. <40 mg/dL in males and <50 mg/dL in females, or specific treatment for this lipid abnormality.
High blood pressure SBP≥130 mmHg and/or DBP≥85mmHg SBP≥130 and/or DBP≥85mmHg, or treatment of previously diagnosed hypertension. SBP≥130 mmHg and/or DBP≥85mmHg
Raised fasting blood glucose ≥110 mg/dL. ≥100mg/dl or previously diagnosed type 2 diabetes mellitus. ≥100mg/dl or previously diagnosed type 2 diabetes mellitus.
Criteria Meeting at least three out of five criteria Waist circumference expanding plus any two of the other criteria Meeting at least three out of five criteria
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Abbreviations: NCEP ATP Ⅲ, National Cholesterol Education Program’s Adult Treatment Panel Ⅲ diagnostic criteria for MS; IDF, New International Diabetes Federation diagnostic criteria for MS; Harmonized criteria, modified criteria proposed by IDF, National Heart, Lung and Blood Institute, American Heart Association, World Heart Federation, International Atherosclerosis Society and International Association for the Study of Obesity.

Exclusion criteria

The exclusion criteria for this study were as follows: (1) For studies: study types including reviews, comments, guidelines, case reports, letters, conference abstracts, or laboratory research. (2) For all participants: a known diagnosis of oral lichenoid reactions (a drug-induced LP-like reaction), hypertension, diabetes, dyslipidemia, chronic liver disease, chronic kidney disease, human immunodeficiency virus infection, and hereditary diseases; patients with psoriasis, atopic dermatitis, vitiligo or other diseases that are associated with MS. (3) incomplete or incorrect data.

Data collection

The retrieved literatures were screened for relevance in the titles and abstracts to determine whether they fulfilled the study selection criteria. Two authors (YJ and XZ) independently extracted data from the included studies and discussed with a third one of us (XW) when there was any disagreement. The gathered information included author and publication year, study type, country, diagnostic criteria of MS, sample size, prevalence of MS, sex and mean age of both groups.

Quality of the included studies

The quality assessment of the observational studies was performed based on the Newcastle-Ottawa Scale (NOS) [17]. The quality assessment tool was used to evaluate the validity of the included studies on three broad perspectives: the selection of the study groups; the comparability of the groups; and the ascertainment of either the exposure or outcome of interest. A study with a score ≥7 was considered high quality. Two authors (JY and WX) independently assessed the quality of each original study using the tool. Disagreements were resolved through discussion.

Statistical analysis

Review Manager 5.3 software (freeware available from The Cochrane Collaboration) was used to statistically analyze the data. We calculated the pooled odds ratios (ORs) and 95% confidence intervals (CIs) of the prevalence of MS in both groups using dichotomous data that were either provided by the studies or calculated data from the studies. The heterogeneity among the included studies was assessed by p and I2. When there was no heterogeneity (p>0.1, I2≤50%), a Mantel-Haenszel (M-H) fixed-effect model was used; whereas a random-effect model was used if heterogeneity among studies was significant (p≤0.1, I2>50%). A value of P<0.05 was considered statistically significant. Subgroup analysis of studies with different diagnostic criteria was also performed. Publication bias was assessed via visual inspection with a funnel plot when there were more than 8 articles.

Results

Literature search

We searched 4 databases (PubMed, Embase, the Cochrane Library and Web of Science) using the search term “(metabolic syndrome OR syndrome X OR insulin resistance syndrome OR Reaven syndrome) AND (lichen planus OR lesion planus)”, and it resulted 199 records. Duplicates, irrelevant articles, reviews, case reports were excluded after screening on titles and abstracts. After a further reading, 11 studies plus 1 additional record identified through articles and citations fulfilled the eligibility criteria, with a total of 1422 participants (715 with LP and 707 controls). Literature screening process and a corresponding flow chart are shown in Fig 1.

Fig 1. The literature screening process.

Fig 1

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Study characteristics

The literatures included were all clinic-based studies and presented 5 different countries (Table 2). 6 studied [18–23] were conducted in India, 3 [24–26] in Egypt, 1 [27] in Spain, 1 [28] in Turkey and 1 [29] in Nigeria. The population for the controls without LP were apparently healthy individuals or outpatients with skin diseases other than LP, psoriasis, atopic dermatitis, and vitiligo (mainly nevi, seborrheic keratosis, actinic keratosis, verruca vulgaris, or basal cell carcinoma). MS in 7 [19–21, 23, 27–29] of the included studies were diagnosed by NCEP ATP Ⅲ criteria [14], 3 [18, 24, 26] were diagnosed by IDF criteria [15] and 2 [22, 25] by Harmonized criteria [16].

Table 2. Characteristics of included studies in the meta-analysis and the participants enrolled.

Included studies study type country MS Diagnostic Criteria No. of No. of Mean age,y No. of M/F
participants MS
LP C LP C LP C LP C
Agarwala et al., 2016 [18] Abstract Indian IDF 39 78 23 25 NR NR NR NR
Al Refai et al., 2018 [24] Case-control study Egypt IDF 40 40 22 6 38.1±11.8 38±9 20/20 20/20
Arias-santiago et al., 2011 [27] Case-control study Spain NCEP-ATP Ⅲ 100 100 27 20 47.4±9 48.3±7 50/50 50/50
Baykal et al., 2015 [28] Case-control study Turkey NCEP-ATP Ⅲ 79 79 21 10 47.11±14.44 46.9±14.32 30/49 28/51
Krishnamoorthy et al., 2014 [19] Case-control study Indian NCEP-ATP Ⅲ 11 14 3 2 33.09 33.09 NR NR
Kumar et al., 2019 [20] Case-control study Indian NCEP-ATP Ⅲ 75 75 13 11 35.12±8.03 NR 32/43 NR
Kuntoji et al., 2016 [21] Case-control study Indian NCEP-ATP Ⅲ 50 50 3 1 41.24±16.17 39.48±11.36 28/22 29/21
Mushtaq et al., 2020 [22] Cross-sectional study Indian Harmonized criterion 61 61 18 6 42.48±13.47 42.46±13.02 36/25 36/25
Okpala et al., 2019 [29] Cross-sectional study Nigeria NCEP-ATP Ⅲ 90 90 17 12 37.44±13.88 37.47±12.24 48/42 42/58
Saleh et al., 2014 [25] Case-control, study Egypt Harmonized criterion 40 40 31 0 38.2±11.8 33.1±9.6 20/20 20/20
Sharaf et al., 2017 [26] Case-control study Egypt IDF 30 30 14 3 36 ± 11.52 36 ± 10.65 24/6 24/6
Singla et al., 2019 [23] Cross-sectional study Indian NCEP-ATP Ⅲ 100 50 43 13 42.02 ± 13.82 40.72 ± 10.83 60/40 NR
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Abbreviations: MS, metabolic syndrome; LP, lichen planus group; C, control group; NR, not reported; M/F, male/female.

There were no statistically significant differences with regard to age or sex between two groups in all literatures. Participants in the 12 studies were all older than 15 years of age. The studies included 1 abstract [18], 3 cross-sectional studies [22, 23, 29] and 8 case-control studies [19–21, 24–28], which characteristics are detailed in Table 2.

Quality of included studies

All the included studies were rated with a score according to the NOS guidelines. Eleven studies were rated “good quality” with 7 or more stars, indicating a low risk of bias. One study was rated “adequate quality” with 6 stars, indicating a high risk of bias. The rating details are provided in Table 3.

Table 3. Quality of included studies.

Included studies Selection Compatibility Exposure Total stars
Is the Case Definition Adequate? Representativeness of the Case Selection of Controls Definition of Controls Ascertainment of Exposure Same method of ascertainment for cases and controls Nonresponse Rate
Agarwala et al., 2016 [18] ✵ ✵ ✵✵ ✵ ✵ ✵ 7
Al Refai et al., 2018 [24] ✵ ✵ ✵ ✵✵ ✵ ✵ ✵ 8
Arias-santiago et al., 2011 [27] ✵ ✵ ✵ ✵✵ ✵ ✵ ✵ 8
Baykal et al., 2015 [28] ✵ ✵ ✵ ✵✵ ✵ ✵ ✵ 8
Krishnamoorthy et al., 2014 [19] ✵ ✵ ✵ ✵✵ ✵ ✵ ✵ 8
Kumar et al., 2019 [20] ✵ ✵ ✵ ✵✵ ✵ ✵ ✵ 8
Kuntoji et al., 2016 [21] ✵ ✵ ✵✵ ✵ ✵ ✵ 7
Mushtaq et al., 2020 [22] ✵ ✵ ✵ ✵✵ ✵ ✵ ✵ 8
Okpala et al., 2019 [29] ✵ ✵ ✵ ✵✵ ✵ ✵ ✵ 8
Saleh et al., 2014 [25] ✵ ✵ ✵ ✵✵ ✵ ✵ ✵ 8
Sharaf et al., 2017 [26] ✵ ✵ ✵✵ ✵ ✵ ✵ 7
Singla et al., 2019 [23] ✵ ✵✵ ✵ ✵ ✵ 6
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Meta-analysis results

We identified MS in the LP and control groups in 12 studies and observed marked heterogeneity across these studies (p = 0.009, I2 = 56%); therefore, the M-H random-effect model was used. Overall, the prevalence of MS was significantly higher in the LP group than in the control group (odds ratio [OR] 2.81, 95% confidence interval [CI] 1.79–4.41, p<0.00001, Fig 2).

Fig 2. Forest plot of the overall prevalence of MS in LP patients in the observational studies.

Fig 2

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Abbreviations: M-H, a Mantel-Haenszel model; CI, confidence interval.

We also performed subgroup analysis of the prevalence of MS diagnosed by the NCEP ATP III criteria in 7 observational studies, the IDF criteria in 3 studies, and the Harmonized criteria in 2 studies separately. The pooled OR was much higher for studies that used the IDF diagnostic criteria (OR 4.65, 95% CI 2.52–8.58, p<0.00001, Fig 3) and the Harmonized criteria (OR 26.62, 95% CI 0.29–2471.37, p = 0.16, Fig 3) than for studies using the NCEP ATP III criteria (OR 1.75, 95% CI 1.25–2.44, p = 0.001, Fig 3), suggesting that studies using the IDF criteria and the Harmonized criteria reported a stronger association between MS and LP.

Fig 3. Forest plot of subgroup analysis of MS diagnosed by different diagnostic criteria in the observational studies.

Fig 3

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Risk of bias assessment

Considering potential publication bias, we generated a funnel plot of ORs on the x-axis against the standard error (logOR) of each study on the y-axis (Fig 4). Among the 12 studies included in this meta-analysis, the scatter funnel plot with estimable ORs appeared symmetrical, indicating the absence of publication bias.

Fig 4. Funnel plot of the overall prevalence of MS in LP patients in 12 observational studies.

Fig 4

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Abbreviations: OR, odds ratio; SE, standard error.

Discussion

To our knowledge, this is the first systematic review and meta-analysis of studies that investigated the prevalence of MS in patients with LP compared to the general population. This analysis shows that compared with the general population, patients with LP showed a statistically significant approximately 2-fold higher prevalence of MS, which was present in 32.87% of LP patients versus 15.42% of the controls.

The high risk of MS in patients with LP may be attributable to chronic inflammation observed in this patient population. T cell activation in LP triggers the release of pro-inflammatory cytokines such as IL-2, IL-4, IL-6, IL-10, interferon-gamma, and TNF-α, which promote the release of more cytokines. These cytokines also play an important role in the development of dyslipidemia [30]. Some researchers are of the view that chronic inflammatory markers are useful predictors of cardiovascular events [31]. Notably, oxidative stress injury is implicated as an important pathogenetic contributor to MS. Mitran et al. reported increased lipid peroxidation and impairment of the antioxidant defense mechanism in patients with LP [32].

Current studies reported an association between LP and cardiovascular disease. Sahin et al. reported increased P-wave dispersion in patients with LP [33]. A study performed by Baykal et al. reported higher systolic and diastolic blood pressures and arterial stiffness in patients with LP [34]. Notably, 10 [18, 20–27, 29] studies from the available literature, which were included in this meta-analysis, reported a high prevalence of dyslipidemia in patients with LP. Another meta-analysis by Lai et al. also reported the same findings; the authors observed that LP was significantly associated with a high risk of dyslipidemia (specifically, high TG levels) [35].

The risk of MS varies depending on the clinical types of LP observed in patients. Baykal et al. observed that patients with specifically mucosal LP showed a higher prevalence of MS [28]. Kumar et al. reported that compared with the overall prevalence of LP, oral LP was more common in patients with hypothyroidism [20]. Okpala et al. observed that patients with and without dyslipidemia showed a higher likelihood of developing hypertrophic and classic LP, respectively [29].

Subgroup analysis of the different diagnostic criteria of MS showed that the pooled OR was much higher for studies that used the IDF diagnostic criteria (OR 4.65, 95% CI 2.52–8.58, p<0.00001, Fig 3) and the Harmonized criteria (OR 26.62, 95% CI 0.29–2471.37, p = 0.16) than for studies using the NCEP ATP III criteria (OR 1.75, 95% CI 1.25–2.44, p = 0.001, Fig 3), suggesting that studies using the IDF diagnostic criteria and the Harmonized criteria reported a stronger association between MS and LP. This finding could be attributed to the lower obesity thresholds used to define central obesity, which consider a waist circumference of at least 94 cm in men and 80 cm in women. Therefore, based on this criterion, a greater number of patients would be diagnosed with MS. Some researchers are of the view that MS prevalence is higher using the IDF criteria; therefore, this definition could be more appropriate to diagnose MS [36]. Subramani et al. recorded maximum prevalence of MS when the Harmonized criteria was followed, and observed good agreement between Harmonized criteria and IDF criteria [37]. In this meta-analysis, we could not definitively conclude whether Harmonized criteria is better than IDF diagnostic criteria because only a few relevant articles were available for analysis.

Limitations

Following are the limitations of our meta-analysis: (a) We observed a high degree of variability across studies owing to heterogeneity (I2 = 56%, Fig 2). Patients enrolled in this study included those with different types, severity levels, and courses of LP, as well as varying duration of follow-up. Moreover, the diagnostic criteria for MS varied widely across studies. (b) The studies included in this meta-analysis were mainly performed in Asia, Africa, and Europe; therefore, these study samples might not be representative of the entire population. (c) Only a small number of studies were included in this meta-analysis; therefore, the low statistical power of this study is a drawback of this research. Considering the limitations of the current study, further prospective studies and high-quality research are warranted to definitively establish the association between MS and LP.

Conclusions

This meta-analysis shows that compared with the general population, patients with LP are more likely to develop MS. Therefore, early diagnosis and prompt initiation of first-line therapy for metabolic disorders are important in patients with LP.

Supporting information

S1 Checklist. PRISMA checklist.

PRISMA statement for reporting systematic reviews and meta-analyses.

(DOC)

Click here for additional data file. (66KB, doc)
S1 Table. Search strategy.

(DOCX)

Click here for additional data file. (15.8KB, docx)

Acknowledgments

We would like to thank Ms. Yuan Zu and Ms. Yujia Cai for their assistance with the statistical aspects of this meta-analysis.

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

WX received a research grant (No. 2020364003) from Zhejiang Medical and Health Science and Technology Program, China (URL: http://www.msttp.com/). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Beatrice Nardone

25 Jun 2020

PONE-D-20-09664

Risk of metabolic syndrome in patients with lichen planus : A Systematic Review and Meta-analysis

PLOS ONE

Dear Dr. Xiang,

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.

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PLOS ONE

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[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: Partly

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: I Don't Know

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: Yes

Reviewer #2: No

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: Major comments:

Why did the authors did not differ between the various clinical forms of LP?

What is new about the findings compared to previously published data since link between LP and MS hat been previously reported?

Reviewer #2: Overall meta-analysis is interesting and well prepared according to PRISMA. Selection of articles and applied methods are performed correctly. The results are important and may have practical application on lichen planus patients management.

I have some comments and suggestions:

1. The sentence in the Introduction: “MS is a complex group of metabolic disorders, which include central obesity, dyslipidemia, hypertension, and hyperglycemia. MS is implicated as an important risk factor for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) and has therefore attracted increasing attention in recent years.” is repeted in the Disscussion: “MS comprises a combination of metabolic disorders including central obesity, dyslipidemia, hypertension, and hyperglycemia that predispose individuals to T2DM and CVD.”

2. In the first sentence in Introduction it is better use the word “flat” instead of “plan”. The sentence: “Studies have indicated that insulin resistance[4], 3 oxidative stress injury[5] and chronic inflammatory[6] play important roles in the pathogenesis of MS” need to be corrected. Others grammar mistakes should be also corrected.

“…a similar chronic inflammatory dermatological condition with an autoimmune etiology, such as psoriasis[7] alopecia areata[8], hidradenitis suppurativa[9] and vitiligo[10]….”

3. The sentence: “T cell activation in LP triggers the release of pro-inflammatory cytokines such as IL-2, IL-4, IL-6, IL10, interferon-gamma, and TNF-α, which promote the release of more cytokines that attack keratinocytes resulting in dyslipidemia[29]” is unclear and should be rewrite.

4. “To our knowledge, this is the first systematic review and meta-analysis of studies that investigated the prevalence of MS in both patients with LP and the general population.” – what was the aim of the study, why authors have stated that it is the first study investigated the prevalence of MS in the general population?

5. In the Discussion the sentence: “Lipid abnormalities are significant contributors to the onset and aggravation of CVD. 11 The accumulation of cholesterol in cells and formation of lipid-laden foam cells produces fatty streaks in arterial walls, which predispose an individual to atherosclerotic plaques and consequent CVD[29]”

- the information is obvious and well known to readers of the journal and should be removed.

Reviewer #3: This article gives an interesting perspective on a little studied topic. It is a meta-analysis to analyze the association between metabolic syndrome and lichen planus and shows that compared with the general population, patients with lichen planus are more likely to develop metabolic syndrome. The work is a valuable contribution to the Plos One readers. However, it needs corrections, as suggested to the authors.

Materials and methods

Page 4

Data sources and searches

As the terms syndrome x, insulin resistance syndrome and Reaven syndrome were used for the search, specify these synonyms in the introduction.

Inclusion criteria

Outcome measures: "MS was diagnosed using the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), the International Diabetes Federation (IDF) and other diagnostic criteria."

Cite the references for the criteria or define what they are.

Exclusion criteria

....(2) For all participants: a known diagnosis of oral lichenoid reactions (a drug-induced LP-like reaction), hypertension, diabetes, dyslipidemia, chronic liver disease, chronic kidney disease, human immunodeficiency virus infection, and hereditary diseases.

Why were participants with hypertension, diabetes and dyslipidemia excluded if these characteristics are criteria for the diagnosis of metabolic syndrome?

Page 6.

Literature search

"After a further reading, 11 studies with 1300 participants fulfilled the eligibility criteria".

Specify how many patients were in the lichen planus group and how many were controls.

Study characteristics

"The population for the controls without LP were apparently healthy individuals or outpatients with or without skin diseases other than LP".

There are diseases that are associated with metabolic syndrome. Were patients with these diseases excluded?

Results

Table 2, figures 2 and 3

In included studies complete with "et al." after the first author in studies that have more than one author.

Discussion

Page 10

First paragraph: "To our knowledge, this is the first systematic review and meta-analysis of studies that investigated the prevalence of MS in both patients with LP and the general population".

Change to: "To our knowledge, this is the first systematic review and meta-analysis of studies that investigated the prevalence of MS in patients with LP compared to the general population".

The authors should also include bibliographic references that mention the frequency of metabolic syndrome in the general population at the end of the paragraph.

Second paragraph: "...T cell activation in LP triggers the release of pro-inflammatory cytokines such as IL-2, IL-4, IL-6, IL- 10, interferon-gamma, and TNF-α, which promote the release of more cytokines that attack keratinocytes resulting in dyslipidemia".

It is not the attack on keratinocytes that results in dyslipidemia.

It would be more accurate to say: "These cytokines also play an important role in the development of dyslipidemia".

References

The references are not within the journal's formatting standards

The manuscript needs editing for language quality.

**********

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Reviewer #2: No

Reviewer #3: No

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PLoS One. 2020 Aug 21;15(8):e0238005. doi: 10.1371/journal.pone.0238005.r002

Author response to Decision Letter 0

21 Jul 2020

Dear Beatrice Nardone and reviewers:

Thank you for your letter and the reviewers’ comments on our manuscript entitled “Risk of metabolic syndrome in patients with lichen planus: A systematic review and meta-analysis” (ID: PONE-D-20-09664). Those comments are very helpful for revising and improving our paper, as well as the important guiding significance to other research. We have studied the comments carefully and made corrections which we hope meet with approval. The main corrections are in the manuscript and the responds to the reviewers’ comments are as follows.

Replies to the reviewers’ comments:

Reviewer #1:

1. Why did the authors did not differ between the various clinical forms of LP?

Response：That's an excellent question. Clinical forms of LP including linear LP, hypertrophic LP, oral LP, LP pigmentosus, generalized LP, lichen planopilaris, bullous LP and actinic LP. Emerging evidences suggest that risk of MS varies depending on the clinical types of LP. However, only 3 out of 12 included studies provided original data or assessed the association between MS and different clinical forms of LP. Moreover, the amount of data after classification is too small to draw any conclusions. It is a prospective direction for further research work with research value, and we are planning to take this as the next research direction.

2. What is new about the findings compared to previously published data since link between LP and MS hat been previously reported?

Response: Previous studies investigating the relationship between LP and MS were observational studies, and no meta-analysis in this area has yet been published. In this meta-analysis, we examined data on the relationship between LP and odds of MS by searching for studies published before July 16, 2020. In addition, we also conducted a comparison of three different diagnostic criteria of MS.

Reviewer #2: 

1. what was the aim of the study, why authors have stated that it is the first study investigated the prevalence of MS in the general population?

Response：The aim of the study is to systematically evaluate the published literatures and determine a clinical relationship between MS and LP. Currently, no systematic review and meta-analysis in this area has yet been published; therefore, we stated that “this is the first systematic review and meta-analysis of studies that investigated the prevalence of MS in patients with LP compared to the general population.”

Reviewer #3:

1. Why were participants with hypertension, diabetes and dyslipidemia excluded if these characteristics are criteria for the diagnosis of metabolic syndrome?

Response：Firstly, we aim to determine whether patients with LP are more likely to develop MS when compared with the general population; therefore, we need untested LP patients and controls, who are not sure if they have had MS before. Besides, participants with known hypertension, diabetes and dyslipidemia often have a long history of medication, and we cannot rule out the possibility of drug-induced MS.

2. There are diseases that are associated with metabolic syndrome. Were patients with these diseases excluded?

Response：Yes, skin disease such as psoriasis, atopic dermatitis, and vitiligo that are associated with MS were excluded. The outpatients with skin diseases were mainly nevi, seborrheic keratosis, actinic keratosis, verruca vulgaris, or basal cell carcinoma. We have added these to the “Materials and methods--Exclusion criteria” and “Results--Study characteristics” section.

3. We’ve also made the relevant changes to the Inclusion criteria, Literature search, Results and Discussion accordingly.

In addition, we have made the following changes to the article:

1. All three reviewers made reference to awkward sentences and lack of clarity in the flow of the text. We’ve addressed this issue across and within each section, paragraph, and sentence.

2. We re-searched the literature prior to July 16, 2020 according to the search strategy, and added 1 recently published eligible literature (Mushtaq S, Dogra D, Dogra N, Shapiro J, Fatema K, Faizi N, et al. Cardiovascular and Metabolic Risk Assessment in Patients with Lichen Planus: A Tertiary Care Hospital-based Study from Northern India. Indian Dermatol Online J. 2020;11(2):158-66.).

3. We removed Medline from the databases because PubMed comprises citations for biomedical literature from MEDLINE. The number of results is different because the new PubMed, launched after 18 May 2020, has some changes in search syntax and search translations.

4. We reedited the article to ensure that it meets PLOS ONE's style requirements and assessed study quality based on the Newcastle-Ottawa Scale. Complete search strategy is shown in S2 Table.

Once again, thank you very much for your constructive comments and suggestions which would help us both in English and in depth to improve the quality of the paper.

We look forward to hearing from you soon.

Best wishes,

Wenzhong Xiang

E-mail: xiangwenzhong@126.com

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (21KB, docx)

Decision Letter 1

Beatrice Nardone

7 Aug 2020

Risk of metabolic syndrome in patients with lichen planus : A Systematic Review and Meta-analysis

PONE-D-20-09664R1

Dear Dr. Xiang,

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.

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Kind regards,

Beatrice Nardone

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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 #2: (No Response)

Reviewer #3: 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 #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #2: Yes

Reviewer #3: 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 #2: Yes

Reviewer #3: 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 #2: Yes

Reviewer #3: 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 #2: The results presented in the manuscript are interesting and may have some significant influence on the management of lichen planus patients in clinical practice. The manuscript has been corrected and improved. The article may be published in this form.

Reviewer #3: The authors have adequately addressed my comments raised in a previous round of review and I feel that this manuscript is now acceptable for publication.

**********

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 #2: No

Reviewer #3: Yes: Marilda Aparecida Milanez Morgado de Abreu

Acceptance letter

Beatrice Nardone

11 Aug 2020

PONE-D-20-09664R1

Risk of metabolic syndrome in patients with lichen planus: A Systematic Review and Meta-analysis

Dear Dr. Xiang:

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.

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on behalf of

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Academic Editor

PLOS ONE

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