Abstract
Background/objective
Lichen sclerosus (LS) is a chronic inflammatory skin disease affecting both genital and extra-genital areas and is found predominantly in female patients. The relationship between LS and thyroid diseases remains unclear, with conflicting evidence reported in the literature. This systematic review and meta-analysis aimed to investigate the association between LS and thyroid diseases rigorously.
Materials and methods
We conducted a comprehensive search using two electronic databases, MEDLINE and Embase, from inception to May 2024, to identify observational studies investigating the relationship between LS and thyroid diseases. A random-effects model was used to meta-analyse the pooled odds ratio with a 95% confidence interval (CI) from the included articles.
Results
A total of 14 observational articles encompassing 22,112,979 participants were included. Nine of these studies included only female participants. The analysis revealed that LS was significantly associated with an increased risk of autoimmune thyroid diseases, with an odds ratio of 2.38 (95% CI, 1.46–3.86; I2 = 84%). Additionally, an association was found between hyperthyroidism and an odds ratio of 2.01 (95% CI, 1.40–2.88; I2 = 0%). Furthermore, patients with LS exhibited a non-significant increase in the odds ratio for Graves’ disease, Hashimoto’s thyroiditis, hypothyroidism and other unspecified thyroid disorders.
Conclusions
This meta-analysis provided insight into thyroid diseases in patients with LS, revealing a significant association with an increased risk of autoimmune thyroid disease and hyperthyroidism. Further research is needed to clarify this association and enhance the comprehensive care of patients with LS.
Keywords: Autoimmune thyroiditis, Graves’ disease, Hashimoto disease, hyperthyroidism, hypothyroidism, meta-analysis, thyroid diseases, vulvar Lichen sclerosus
Introduction
Lichen sclerosus (LS) is a chronic inflammatory skin disorder characterized by immunological involvement, primarily affecting the genital and perianal mucosa. It predominantly occurs in females, particularly within two age groups: prepubertal and postmenopausal [1,2]. The incidence of LS peaks during these periods, with typical presentations including ivory-coloured, waxy and hyperkeratotic lesions that may progress to scarring [2,3]. The symptoms of LS can vary depending on the affected area and may include severe itching, dyspareunia, erectile dysfunction, and dysuria. If left untreated, LS can result in complications such as increased fibrosis, scarring and a heightened risk of genital cancer, all of which can significantly impair quality of life [4,5].
The aetiology and pathophysiology of LS remain poorly understood. However, evidence suggests that genetic predisposition, oxidative damage and immune-mediated mechanisms may contribute to its development [2,6–9]. Specific associations have been identified between LS and certain alleles of human leukocyte antigen (HLA) genes, particularly DQ7, which may also relate to autoimmune thyroid diseases, such as Hashimoto’s thyroiditis [7,8].
A recent meta-analysis explored the association between LS and various comorbidities, revealing significantly higher odds of common dermatological conditions (such as lichen planus, vitiligo, alopecia areata, atopic dermatitis, and psoriasis), cardiovascular risk factors (including diabetes mellitus, dyslipidaemia, essential hypertension, and obesity), genital warts, and hypothyroidism [10]. Additionally, the meta-analysis by Untaaveesup et al. highlighted an increased risk of several cardiovascular risk factors, including diabetes mellitus, dyslipidaemia, obesity and metabolic syndrome, in patients with LS [11]. However, the generalizability of these findings is limited due to the reliance on low-quality case-control studies.
Several studies indicate an increased risk of thyroid diseases in LS patients [6,12,13], with one study reporting a statistically significant threefold increase in the risk of autoimmune thyroid disease among these patients [12]. Additionally, a 2.34-fold increase in the risk of Graves’ disease has also been noted [14]. Conversely, conflicting evidence exists, with some reports indicating a decreased risk of thyroid diseases in LS patients [15].
Given these inconsistencies, our study aimed to systematically review and meta-analyse the association between LS and thyroid diseases, and summarize the factors from all types of observational study and quality assessment that may influence this relationship to improve better therapeutic outcomes, generalizability and early management of these comorbidities.
Materials and methods
Search strategy
This meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [16]. (Supplementary Table S1) Four researchers (S.U., P.K., W.E. and P.C.) independently accomplished a comprehensive search across two databases, MEDLINE and Embase, from inception to May 2024 (Supplementary Table S2). Search terms related to LS and thyroid diseases were included, and the references of the identified studies were also screened. The protocol for this study was registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) prior to its execution [INPLASY202480040] [17].
Selection criteria
Studies were included according to the following criteria: (I) study designs were limited to cross-sectional, cohort or case-control studies; (II) the studies demonstrated the risk of thyroid diseases in LS patients, including autoimmune thyroid disease, hyperthyroidism, hypothyroidism or unspecified thyroid diseases. The relevant diagnosed parameters including thyroid-simulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), antithyroid antibodies, anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG) were assessed.; and (III) the studies were published in English. Unspecified thyroid diseases were defined as hyperthyroidism, hypothyroidism and other thyroid diseases.
Two researchers (S.U. and P.K.) used Covidence (Covidence.org, Australia) to independently screen the studies in two rounds. Initially, the titles and abstracts of each article were screened, followed by a full-text review of the retrieved articles. Any conflicts during the screening process were resolved by the third researchers (N.L. or C.S.).
Data extraction
Four investigators (S.U., P.K., P.C. and E.C.) independently extracted the following information into a standardized data extraction form: 1) baseline characteristics, including the name of the first author, country, year of publication, study design, duration of the study, number of participants, number of male participants, mean body mass index (BMI), mean age of participants, involved area of LS and diagnostic criteria of LS and thyroid diseases; 2) outcomes of interest, including the risk of autoimmune thyroid disease, Graves’ disease, Hashimoto’s thyroiditis, hyperthyroidism, hypothyroidism and unspecified thyroid diseases in LS patients compared to those without LS, reported as adjusted and unadjusted odds ratios (OR), relative risks (RR) or hazard ratios (HR), along with their 95% confidence intervals (CIs); and 3) adjusted factors for statistical analysis. Corresponding authors of articles with potential inclusion were contacted to retrieve any missing information.
Quality assessment
Two researchers (S.U. and P.K.) evaluated each included study using the Newcastle–Ottawa quality assessment tool for observational studies [18]. Any discrepancies were discussed and resolved with N.L.
Risk of bias assessment
Three researchers (S.U., P.K. and P.C.) applied the Quality In Prognosis Studies (QUIPS) tool to assess the risk of bias. The tool evaluated six domains of bias, including study participants, study attrition, prognostic factor measurements, outcome measurement, confounding, and statistical analysis and reporting. Any discrepancies were examined and resolved with N.L.
Certainty assessment
Three researchers (S.U. P.K. and P.C.) applied the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) tool to assess the certainty of evidence. Certainty was categorized into five domains: risk of bias, inconsistency, indirectness, imprecision and publication bias. The assessment was reported as high, moderate, low and very low certainty. Any discrepancies were finalized through discussion with N.L.
Statistical analysis
The odds ratio between LS and thyroid diseases was meta-analysed using Review Manager 5.3 software (clicktime.com, Inc., San Francisco, CA), provided by the Cochrane Collaboration. Due to variations in study methodologies and settings, a random-effect model was utilized. The Mantel–Haenszel method was applied to estimate the overall effect sizes. Heterogeneity among the included studies was assessed using the I2 statistic, where an I2 value ranging from 0 to 25% indicated insignificant heterogeneity, 51–75% represented moderate heterogeneity, and values of I2 above 75% suggested significantly high heterogeneity [19]. To explore the source of heterogeneity, meta-regression was performed based on the pooled odds ratio of autoimmune thyroid disease and potential factors, including study country, WHO region where the study was conducted, study design, percentage of male participants and mean participant age. Publication bias was evaluated through visual inspection of the funnel plot, without a statistical test for asymmetry. Significant asymmetry indicated potential publication bias or heterogeneity [20].
Results
Search results
We identified a total of 1123 relevant records from two databases: 791 from Embase and 332 from MEDLINE. After removing 247 duplicates through Covidence, 876 records were screened by their titles or abstracts. After reviewing the full texts of 81 articles, 14 articles were included in the final analysis. Figure 1 illustrates the screening and selection process.
Figure 1.
The PRISMA flowchart for the selection and screening process.
Baseline characteristics
The analysis included 22,112,979 participants from 14 observational studies [6,12–15,21–29], comprising four retrospective cohort studies [12,14,21,25], four cross-sectional study [24,27–29] and six case-control studies [6,13,15,22,23,26]. Nine of these articles included only female participants [6,12,13,15,21,23,25–27]. Only one paediatric study [21] was included, with a mean age of 10.8 years. The remaining ten studies [6,12–15,22–26] focused exclusively on adults, with median ages between 40.0 and 71.0 years. Four studies were conducted in the Americas [12,13,24,25], while ten were conducted in Europe [6,14,15,21,22,24,26–29]. We excluded Harrington and Dunsmore from our analysis, due to inconclusive results [29]. The baseline characteristics and quality assessment of the included studies are summarized in Table 1. The diagnostic criteria for LS patients, including history taking, physical examination, histopathology, clinical database, and International Classification of Diseases, are detailed in Supplementary Table S3. Supplementary Table S4 outlines the diagnostic criteria for thyroid diseases used in each included study.
Table 1.
The Baseline characteristics and quality assessment of eligible studies.
| References | Country | Study design | Study period/duration | Total participants, n (LS/non-LS) | Male sex, n (%) | Mean age, years (SD) | Mean BMI (SD) | Location of LS | Confounders | Newcastle-Ottawa scale |
|---|---|---|---|---|---|---|---|---|---|---|
| Bieber et al. | US | RC | 2015–2017 | 2168, 2020 (10,004/21,672,016) | 0 (0) | Total participants: 50.8a | NR | NR | NA | Selection: 3, Comparability: 1, Outcome: 3 |
| Cooper et al. | UK | CC | LS group: 2 years | 1238 (316/922) | 0 (0) | LS group: 63a non-LS group: 62a |
NR | Vulva | NA | Selection: 3, Comparability: 1, Outcome: 2 |
| Dulska et al. | Poland | RC | 2020–2021 | 55 (20/35) | 0 (0) | LS group: 10 years and 9 monthsa non-LS group: 10 years and 9 monthsa |
NR | Vulva, specifically involving the labia minora, clitoral hood and perianal region | NA | Selection: 3, Comparability: 2, Outcome: 3 |
| Fan et al. [13] |
US | CC | 2018–2022 | 3825 (765/3060) | 0 (0) | LS group: 66.2 (12.5)a Non-LS group: 66.2 (12.5)a |
NR | NR | Age, race and smoking status | Selection: 4, Comparability: 2, Outcome: 3 |
| Goolamali et al. [22] | UK | CC | NR | 469 (25/443) | 1 (0.21) | LS group: 55.2a | NR | NR | NA | Selection: 3, Comparability: 1, Outcome: 3 |
| Gulin et al. [14] | Sweden | RC | LS group: 2001–2021 | 368,248 (5680/362,568) | LS: 1802 (31.73) non-LS: 184,848 (50.98) |
LS group: 57b non-LS group: 40b |
NR | NR | age, sex | Selection: 3, Comparability: 0, Outcome: 3 |
| Halonen et al. [15] |
Finland | CC | 1998–2016 | 42,768 (10,692/32,076) | 0 (0) | LS group: 60.8a non-LS group: 60.8a |
NR | NR | NA | Selection: 4, Comparability: 1, Outcome: 3 |
| Harrington and Dunsmore [29] | UK | CS | 4 years | 100 (50/50) | NR | LS group: 54.9 (17.6)a non-LS group: NR |
NR | Vulva, perianal, anogenital and extragenital region | NA | Selection: 3, Comparability: 1, Outcome: 3 |
| Hieta et al. [27] | Finland | CS | 2004– 2012 | 5000 (455/4545) | 0 (0) | LS group: 64.4a non-LS group: NR |
NR | NR | NA | Selection: 4, Comparability: 1, Outcome: 3 |
| Hieta et al. [28] | Finland | CS | 2004–2012 | 6930 (630/6300) | 6930 (100) | LS group: 39.2a non-LS group: NR |
NR | NR | NA | Selection: 4, Comparability: 1, Outcome: 3 |
| Higgins and Cruickshank [26] |
UK | CC | NR | 158 (92/66) | 0 (0) | LS group: 65.0 (58.5, 71.5)b non-LS group: 46.0 (37.5, 53.0)b |
NR | Vulva | NA | Selection: 4, Comparability: 1, Outcome: 2 |
| Hu et al. [25] |
US | RC | 1996– 2019 | 1983 (865/1118) | 0 (0) | LS group: 54.4a (15.7) non-LS group: 42.9a (16.0) |
NR | Vulva | NA | Selection: 3, Comparability: 2, Outcome: 3 |
| Meyrick Thomas et al. [24] |
UK | CS | NR | 50 (25/25) | 50 (100) | LS group: 43a non-LS group: 44a |
NR | Penis, trunk and limbs | NA | Selection: 3, Comparability: 1, Outcome: 3 |
| Yen Luu et al. [23] |
US | CC | 2019–2021 | 135 (77/58) | 0 (0) | 71b | LS group: 29.8 (8.4) non-LS group: 24.9 (5.5) |
Vulva | NA | Selection: 4, Comparability: 1, Outcome: 3 |
BMI: body mass index; CC: case-control study; CI: confidence interval; CS: cross-sectional study; LS: lichen sclerosus; NA: not available; NR: not reported; PC: prospective cohort study; RC: retrospective cohort study; SD: standard deviation; UK: United Kingdom; US: United States
aThe data is presented in the form available from the study.
bMedian (IQR) is shown instead of mean (SD).
Risk of bias assessment
According to the QUIPs tool, the risk of bias was rated as moderate in eleven studies [12–15,23–29], while the remaining studies were rated as low [6,21,22]. The risk of bias evaluation is presented in Supplementary Table S5 and Supplementary Figure S1. The proportion through each domain of the QUIPs tool is encapsulated in Supplementary Figure S2.
Certainty of evidence assessment
Supplementary Table S6 presents an evaluation of the certainty of evidence using the GRADE tool. The evidence supporting the risk of autoimmune thyroid disease and hypothyroidism was classified as low certainty, while the evidence for other outcomes was classified as very low certainty.
Risk of thyroid diseases in LS patients
Autoimmune thyroid disease
A total of five studies with 21,676,602 patients with LS were included in this analysis [6,12,13,21,22]. The risk of autoimmune thyroid disease was significantly increased, with a pooled unadjusted odds ratio (OR) of 2.38 (95% CI: 1.46–3.86, p = 0.0005, I2 = 84%) (Figure 2(A)).
Figure 2.
The risk of thyroid diseases in patients with lichen sclerosus. (A) autoimmune thyroid disease; (B) hyperthyroidism; (C) Graves’ disease; (D) Hashimoto’s thyroiditis; (E) hypothyroidism; (F) unspecified thyroid diseases.
Hyperthyroidism
Two studies with a total of 857 LS patients were included [13,26]. The risk of hyperthyroidism was significantly increased, with a pooled unadjusted OR of 2.01 (95% CI: 1.40–2.88, p = 0.0002, I2 = 0%) (Figure 2(B)).
Graves’ disease
Three studies involving 26,376 patients with LS were included [12,14,15]. The risk of Graves’ disease was increased but did not reach statistical significance, with a pooled unadjusted OR of 1.61 (95% CI: 0.86–3.01, p = 0.14, I2 = 97%) (Figure 2(C)).
Hashimoto’s thyroiditis
Two studies with a total of 20,696 patients with LS were included [12,15]. The risk of Hashimoto’s thyroiditis was increased, with a pooled unadjusted OR of 2.29 (95% CI: 0.69–7.64, I2 = 85%, p = 0.18) (Figure 2(D)).
Hypothyroidism
Six studies were included in this analysis [13,15,24,26–28]. The risk of hypothyroidism was increased in patients with LS, with a pooled unadjusted OR of 1.50 (95% CI: 0.88–2.56, p = 0.13, I2 = 95%) (Figure 2(E))
Unspecified thyroid diseases
Two studies involving 942 LS patients were included [23,25]. Patients with LS had an increased risk of unspecified thyroid diseases, with a pooled unadjusted OR of 1.93 (95% CI: 0.97–3.88, p = 0.06, I2 = 69%) (Figure 2(F)).
Meta-regression
We found that country, WHO region, study design, the percentage of male participants, and mean age were not significantly associated with the pooled OR (p > 0.05 in all analyses), indicating that these factors did not contribute to the observed heterogeneity (Table 2).
Table 2.
Meta-regression for the association between lichen sclerosus and the risk of autoimmune thyroid disease.
| Possible source of heterogeneity |
Number of included studies |
Coefficient [95% CI] | p Value |
|---|---|---|---|
| % Male | 6 | 0.005 [−0.004, 0.014] | 0.273 |
| Age | 6 | −0.012 [−0.050, 0.025] | 0.519 |
| Study design | |||
| CC | 3 | Baseline | N/A |
| CS | 3 | 0.250 [−0.452, 0.951] | 0.486 |
| WHO region | |||
| AMR | 1 | Baseline | N/A |
| EUR | 5 | −0.500 [−1.087, 0.087] | 0.095 |
| Country | |||
| US | 1 | Baseline | N/A |
| Finland | 3 | −0.511 [−1.101, 0.079] | 0.089 |
| UK | 2 | −0.434 [−1.506, 0.638] | 0.427 |
AMR: region of the Americas; CC: case-control; CS: cross sectional; EUR: European Region; N/A: not applicable; RC: retrospective cohort; US: United States; WHO: World Health Organization
*The WHO regions’ classification was derived from World Health Organization. World Health Statistics 2023 [Internet]. Geneva: World Health Organization; 2023. Available from: https://www.who.int/publications/i/item/9789240074323.
Publication bias
The potential for publication bias in this systematic review was evaluated using a funnel plot. Studies examining the risks of autoimmune thyroid disease in LS patients were utilized to construct the funnel plot, as this was the only outcome with sufficient publications (Supplementary Figure S3). The observed asymmetry in the funnel plot suggests that the possibility of publication bias cannot be excluded.
Discussion
This meta-analysis demonstrated that patients with LS have significantly increased odds of risk of autoimmune thyroid disease and hyperthyroidism, with OR of 2.38 and 2.01, respectively, compared to non-LS patients. Additionally, LS patients exhibited a non-significantly increased risk of Graves’ disease, Hashimoto’s thyroiditis, hypothyroidism and unspecified thyroid diseases.
A previous meta-analysis, consistent with our results, thoroughly assessed the association between thyroid disease and LS patients across both sexes. It revealed a 1.86-fold (95% CI: 1.35–2.57) increased risk of hypothyroidism in females and a 2.63-fold (95% CI: 1.45–4.76) increased risk in males. The suggested mechanism was the deregulation of regulatory T-cell function, resulting in the activation of immune processes [10].
The significantly increased risk of autoimmune thyroid disease in LS patients may be attributed to genetic factors, molecular mimicry and environmental influences involved in the pathogenesis of this association [30]. Genetic factors, particularly the roles of HLA-DR and DQ have been identified in at least two studies [31,32]. Consequently, HLA markers have a pivotal role in the regulation of adaptive immune systems, such as CD4+ Th cells and CD8+ Th cells, which are involved in this correlation [33]. Evidence suggests that Borrelia infection may trigger autoimmune thyroid disease in LS patients through molecular mimicry [30,34,35].
Our findings indicate a notable association between LS and hyperthyroidism, which may be explained by the presence of autoimmune thyroid antibodies, such as anti-thyroid peroxidase autoantibodies (anti-TPO) [7]. This association could be mediated by Th 22, Th 17, T follicular helper (Tfh) cells and related cytokines, which contribute to a systemic inflammatory process that induces hyperthyroidism [36]. Certain studies have highlighted the role of HLA, including HLA-DR3, in inducing hyperthyroidism [30,37].
Our results emphasize the increased prevalence of autoimmune thyroid disease and hyperthyroidism in LS patients. Furthermore, the presence of thyroid symptoms in LS patients warrants further investigation. These findings align with recent European dermatology guidelines recommending that healthcare providers implement educational initiatives to enhance awareness of autoimmune disease symptoms, particularly thyroid diseases, based on expert consensus [38]. A previous evidence-based dermatology guideline suggested that ‘some recommend screening for associated autoimmune diseases with an autoantibody screen and thyroid status’ [39]. According to American Thyroid Association (ATA)/American Association of Clinical Endocrinology (AACE) recommendations, TSH screening is advised for asymptomatic patients at high risk of thyroid dysfunction, including those with autoimmune disorders. While there is currently no specific consensus for LS, our findings highlight the potential need for thyroid dysfunction screening in this population [40]. Furthermore, raising thyroid awareness in patients with LS is essential. If hyperthyroidism or hypothyroidism is suspected, FT4 and TSH levels should be assessed.
The comprehensive nature of this meta-analysis and the robustness of its findings are significant strengths. This study comprehensively summarized the association between thyroid diseases and LS. The study also rigorously adhered to PRISMA guidelines, enhancing clarity and reliability. Nonetheless, our study has certain limitations. First, the included studies for the meta-analysis of autoimmune thyroid disease and hyperthyroidism varied in characteristics, such as being conducted at vulval clinics, focusing exclusively on female participants and differing study designs and diagnostic criteria, which may influence the heterogeneity of the results. Second, sensitivity analysis was not feasible due to insufficient included studies. Lastly, various populations, particularly paediatric, African and Asian groups, were not adequately represented in our study, limiting the generalizability of our findings. Therefore, prospective studies are required to further validate these associations and assess their impact on therapeutic results for LS patients with thyroid diseases.
Conclusions
We have provided new insights into the natural course and the association of thyroid diseases in patients with LS. Despite the limited number of LS patients in our study, recognizing these conditions is essential for optimizing patient care. To validate our findings, particularly in male, paediatric, African and Asian populations, further prospective studies are needed. This will contribute to improving therapeutic outcomes and enable earlier management of these comorbidities.
Supplementary Material
Acknowledgments
Not applicable. SU - conceptualization, data curation, investigation, methodology, project administration, resources, validation, visualization and writing-original draft. PK- conceptualization, data curation, investigation, methodology, resources, validation, visualization and writing-original draft. NL - conceptualization, formal analysis, investigation, methodology, validation, visualization, writing- review and editing. WE - conceptualization, data curation, investigation, methodology and validation. PC - conceptualization, data curation, investigation, methodology, validation and writing-original draft. WP - conceptualization, data curation, investigation, methodology, project administration, validation, writing- review and editing. CS - conceptualization, data curation, investigation, methodology, project administration, supervision, validation, writing- review and editing. All the authors approved the final version and agreed to be accountable for all aspects of the work.
Funding Statement
No funding was received for this study.
Key messages
Based on the current evidence, the relationship between thyroid diseases and patients with LS patients remains inconclusive. In this study, we established an association between autoimmune thyroid disease, hyperthyroidism and LS. Therefore, there should be increased awareness regarding the screening of thyroid diseases in patients with LS.
Disclosure statement
The authors report no conflict of interest
Author contributions statement
CRediT: Suvijak Untaaveesup: Conceptualization, Data curation, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing – original draft; Piyawat Kantagowit: Conceptualization, Data curation, Investigation, Methodology, Resources, Validation, Visualization, Writing – original draft; Nattawut Leelakanok: Conceptualization, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – review & editing; Wongsathorn Eiumtrakul: Conceptualization, Data curation, Investigation, Methodology, Validation; Petcharpa Chansate: Conceptualization, Data curation, Investigation, Methodology, Validation, Writing – original draft; Walaiorn Pratchyapruit: Conceptualization, Data curation, Investigation, Methodology, Project administration, Validation, Writing – review & editing; Chutintorn Sriphrapradang: Conceptualization, Data curation, Investigation, Methodology, Project administration, Supervision, Validation, Writing – review & editing.
Data availability statement
The authors confirm that the data supporting the findings of this study are available within the article [and/or] its Supplementary materials.
References
- 1.Singh N, Ghatage P.. Etiology, clinical features, and diagnosis of vulvar Lichen Sclerosus: a scoping review. Obstet Gynecol Int. 2020;2020:7480754–7480758. doi: 10.1155/2020/7480754. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.De Luca DA, Papara C, Vorobyev A, et al. Lichen sclerosus: the 2023 update. Front Med (Lausanne). 2023;10:1106318. doi: 10.3389/fmed.2023.1106318. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.O’Grady C, O’Connor C, Al Moosa A, et al. Burden of treatment in vulval lichen sclerosus. Skin Health Dis. 2022;2(3):e125. doi: 10.1002/ski2.125. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Kirtschig G. Lichen sclerosus-presentation, diagnosis and management. Dtsch Arztebl Int. 2016;113(19):337–343. doi: 10.3238/arztebl.2016.0337. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Kirtschig G, Kinberger M, Kreuter A, et al. EuroGuiderm guideline on lichen sclerosus-introduction into lichen sclerosus. J Eur Acad Dermatol Venereol. 2024;38(10):1850–1873. doi: 10.1111/jdv.20082. [DOI] [PubMed] [Google Scholar]
- 6.Cooper SM, Ali I, Baldo M, et al. The association of lichen sclerosus and erosive lichen planus of the vulva with autoimmune disease: a case-control study. Arch Dermatol. 2008;144(11):1432–1435. doi: 10.1001/archderm.144.11.1432. [DOI] [PubMed] [Google Scholar]
- 7.Aslanian FMNP, Marques MTQ, Matos HJ, et al. HLA markers in familial Lichen sclerosus. J Dtsch Dermatol Ges. 2006;4(10):842–847. doi: 10.1111/j.1610-0387.2006.06087.x. [DOI] [PubMed] [Google Scholar]
- 8.Azurdia RM, Luzzi GA, Byren I, et al. Lichen sclerosus in adult men: a study of HLA associations and susceptibility to autoimmune disease. Br J Dermatol. 1999;140(1):79–83. doi: 10.1046/j.1365-2133.1999.02611.x. [DOI] [PubMed] [Google Scholar]
- 9.Tran DA, Tan X, Macri CJ, et al. Lichen Sclerosus: an autoimmunopathogenic and genomic enigma with emerging genetic and immune targets. Int J Biol Sci. 2019;15(7):1429–1439. doi: 10.7150/ijbs.34613. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Šuler Baglama Š, Jemec GBE, Zmazek J, et al. Sex-related variations in comorbidities in Lichen Sclerosus: a systematic review and meta-analysis. Acta Derm Venereol. 2024;104:adv39982. doi: 10.2340/actadv.v104.39982. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Untaaveesup S, Kantagowit P, Leelakanok N, et al. The association between cardiovascular risk factors and Lichen Sclerosus: a systematic review and meta-analysis. J Clin Med. 2024;13(16):4668. doi: 10.3390/jcm13164668. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Bieber AK, Steuer AB, Melnick LE, et al. Autoimmune and dermatologic conditions associated with lichen sclerosus. J Am Acad Dermatol. 2021;85(1):228–229. doi: 10.1016/j.jaad.2020.08.011. [DOI] [PubMed] [Google Scholar]
- 13.Fan R, Leasure AC, Maisha FI, et al. Thyroid disorders associated with lichen sclerosus: a case-control study in the all of us research program. Br J Dermatol. 2022;187(5):797–799. doi: 10.1111/bjd.21702. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Gulin SJ, Lundin F, Seifert O.. Comorbidity in patients with Lichen sclerosus: a retrospective cohort study. Eur J Med Res. 2023;28(1):338. doi: 10.1186/s40001-023-01335-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Halonen P, Heikinheimo O, Hadkhale K, et al. Risk factors for Lichen Sclerosus: a case-control study of 43,000 finnish women. J Low Genit Tract Dis. 2024;28(2):164–168. doi: 10.1097/LGT.0000000000000796. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi: 10.1136/bmj.n71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Untaaveesup S, Kantagowit P, Leelakanok N, et al. The risk of thyroid diseases in lichen sclerosus patients: a systematic review and meta-analysis. INPLASY. 2024. doi: 10.37766/inplasy2024.8.0040. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Herzog R, Álvarez-Pasquin MJ, Díaz C, et al. Are healthcare workers’ intentions to vaccinate related to their knowledge, beliefs and attitudes? a systematic review. BMC Public Health. 2013;13(1):154. doi: 10.1186/1471-2458-13-154. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–560. doi: 10.1136/bmj.327.7414.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–634. doi: 10.1136/bmj.315.7109.629. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Dulska A, Bodziony J, Janik M, et al. The potential coexistence of autoimmune thyroid diseases and pediatric vulvar Lichen sclerosus. Children (Basel). 2024;11(2)255. doi: 10.3390/children11020255. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Goolamali SK, Barnes EW, Irvine WJ, et al. Organ-specific antibodies in patients with lichen sclerosus. Br Med J. 1974;4(5936):78–79. doi: 10.1136/bmj.4.5936.78. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Luu Y, Cheng AL, Reisz C.. Elevated body mass index, statin use, and cholecystectomy are associated with vulvar lichen sclerosus: a retrospective, case-control study. J Am Acad Dermatol. 2023;88(6):1376–1378. doi: 10.1016/j.jaad.2023.01.023. [DOI] [PubMed] [Google Scholar]
- 24.Meyrick Thomas RH, Ridley CM, Black MM.. The association of lichen sclerosus et atrophicus and autoimmune-related disease in males. Br J Dermatol. 1983;109(6):661–664. doi: 10.1111/j.1365-2133.1983.tb00546.x. [DOI] [PubMed] [Google Scholar]
- 25.Hu J, Hesson A, Haefner HK, et al. The prevalence of self-reported medical comorbidities in patients with vulvar lichen sclerosus: a single-center retrospective study. Int J Gynaecol Obstet. 2021;153(2):340–343. doi: 10.1002/ijgo.13480. [DOI] [PubMed] [Google Scholar]
- 26.Higgins CA, Cruickshank ME.. A population-based case-control study of aetiological factors associated with vulval lichen sclerosus. J Obstet Gynaecol. 2012;32(3):271–275. doi: 10.3109/01443615.2011.649320. [DOI] [PubMed] [Google Scholar]
- 27.Hieta N, Rintala M, Söderlund JM, et al. Comorbidity of dermal and cardiovascular disorders with Lichen Sclerosus: a case-control study. Acta Derm Venereol. 2021;101(11):adv00594 doi: 10.2340/actadv.v101.433. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Hieta NK, Haataja MAM, Tapana L.. Comorbidities in male patients with Lichen Sclerosus: a case-control study. J Low Genit Tract Dis. 2023;27(4):378–383. doi: 10.1097/LGT.0000000000000769. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Harrington CI, Dunsmore IR.. An investigation into the incidence of auto-immune disorders in patients with lichen sclerosus and atrophicus. Br J Dermatol. 1981;104(5):563–566. doi: 10.1111/j.1365-2133.1981.tb08172.x. [DOI] [PubMed] [Google Scholar]
- 30.Guarneri F, Giuffrida R, Di Bari F, et al. Thyroid autoimmunity and Lichen. Front Endocrinol (Lausanne). 2017;8:146. doi: 10.3389/fendo.2017.00146. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Gao X-H, Barnardo MCMN, Winsey S, et al. The association between HLA DR, DQ antigens, and vulval lichen sclerosus in the UK: HLA DRB112 and its associated DRB112/DQB10301/04/09/010 haplotype confers susceptibility to vulval lichen sclerosus, and HLA DRB10301/04 and its associated DRB10301/04/DQB10201/02/03 haplotype protects from vulval lichen sclerosus. J Invest Dermatol. 2005;125(5):895–899. doi: 10.1111/j.0022-202X.2005.23905.x. [DOI] [PubMed] [Google Scholar]
- 32.Tasker GL, Wojnarowska F.. Lichen sclerosus. Clin Exp Dermatol. 2003;28(2):128–133. doi: 10.1046/j.1365-2230.2003.01211.x. [DOI] [PubMed] [Google Scholar]
- 33.Antonelli A, Ferrari SM, Corrado A, et al. Autoimmune thyroid disorders. Autoimmun Rev. 2015;14(2):174–180. doi: 10.1016/j.autrev.2014.10.016. [DOI] [PubMed] [Google Scholar]
- 34.Benvenga S, Alesci S, Trimarchi F, et al. Homologies of the thyroid sodium-iodide symporter with bacterial and viral proteins. J Endocrinol Invest. 1999;22(7):535–540. doi: 10.1007/BF03343605. [DOI] [PubMed] [Google Scholar]
- 35.Vaccaro M, Guarneri F, Borgia F, et al. Association of lichen sclerosus and autoimmune thyroiditis: possible role of Borrelia burgdorferi? Thyroid. 2002;12(12):1147–1148. doi: 10.1089/105072502321085261. [DOI] [PubMed] [Google Scholar]
- 36.Li Q, Wang B, Mu K, et al. The pathogenesis of thyroid autoimmune diseases: new T lymphocytes - Cytokines circuits beyond the Th1-Th2 paradigm. J Cell Physiol. 2019;234(3):2204–2216. doi: 10.1002/jcp.27180. [DOI] [PubMed] [Google Scholar]
- 37.Guarneri F, Benvenga S.. Environmental factors and genetic background that interact to cause autoimmune thyroid disease. Curr Opin Endocrinol Diabetes Obes. 2007;14(5):398–409. doi: 10.1097/MED.0b013e3282ef1c48. [DOI] [PubMed] [Google Scholar]
- 38.Kirtschig G, Kinberger M, Kreuter A, et al. EuroGuiderm guideline on lichen sclerosus-Treatment of lichen sclerosus. J Eur Acad Dermatol Venereol. 2024;. ;38(10):1874–1909. doi: 10.1111/jdv.20083. [DOI] [PubMed] [Google Scholar]
- 39.Kirtschig G, Becker K, Günthert A, et al. Evidence-based (S3) guideline on (anogenital) Lichen sclerosus. J Eur Acad Dermatol Venereol. 2015;29(10):e1-43–43. doi: 10.1111/jdv.13136. [DOI] [PubMed] [Google Scholar]
- 40.Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 2012;22(12):1200–1235. 22954017. doi: 10.1089/thy.2012.0205. [DOI] [PubMed] [Google Scholar]
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Data Availability Statement
The authors confirm that the data supporting the findings of this study are available within the article [and/or] its Supplementary materials.