Treatment Modalities for Genital Lichen Sclerosus: A Systematic Review
by
, , , and
Santina Conte
1
,
Sarah Daraj Mohamed
1,
Mahek Shergill
2,
Alexandra Yacovelli
1,
Leah Johnston
3,
Samantha Starkey
4,
Yossi Cohen
1,
Angela Law
5,6,
Ivan V. Litvinov
7
and
Ilya Mukovozov
8,* 1
Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H4A 3J1, Canada
2
Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON L8P 1H6, Canada
3
Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4Z5, Canada
4
Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
5
Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC V5Z 4E8, Canada
6
Providence Health Care Dermatology, Mount Saint Joseph Hospital, Vancouver, BC V5T 3N4, Canada
7
Division of Dermatology, Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada
8
Toronto Dermatology Centre, Toronto, ON M3H 5Y8, Canada
*
Author to whom correspondence should be addressed.
Dermato 2024, 4(4), 136-172; https://doi.org/10.3390/dermato4040014
Submission received: 4 August 2024
/
Revised: 12 October 2024
/
Accepted: 15 October 2024
/
Published: 19 October 2024
(This article belongs to the Special Issue Reviews in Dermatology: Current Advances and Future Directions)
Abstract
:Background: Lichen sclerosus (LS) is a chronic, inflammatory dermatosis that affects both genital and extragenital sites. It is often difficult to treat and may lead to a variety of complications if not adequately treated. The mainstay of therapy involves topical corticosteroids, topical calcineurin inhibitors, and systemic immunomodulators. Although a variety of topical, oral, and procedural therapies are available, a review comparing relative efficacy is lacking. To this end, this systematic review aimed to summarize the literature regarding treatment modalities and their respective response rates in patients with genital LS. Methods: A literature search was conducted in accordance with PRISMA guidelines. Results: This review qualitatively summarizes information from 31 randomized controlled trials, encapsulating a total of 1507 patients with LS, the majority of which were female (n = 1374, 91%). Topical corticosteroids, the mainstay of therapy for LS, were discussed throughout the literature, and proved to be more efficient than topical calcineurin inhibitors, topical hormonal therapy, topical vitamin E oil and cold cream. However, other treatment modalities proved to be more efficient than topical corticosteroids, including CO2 and Nd:YAG laser therapies, and the addition of polydeoxyribonucleotide intradermal injections, to steroid therapy. Finally, other modalities that proved to be efficient in the treatment of LS included silk undergarments, human fibroblast lysate cream, platelet-rich plasma, acitretin, and surgical intervention. The risk of bias was assessed using the Cochrane risk-of-bias tool for randomized trials. Limitations included the inclusion of only randomized controlled trials, moderate or high risk of bias, and heterogeneity in treatment regimens, among others. Conclusion: Although high-potency topical corticosteroids have validated efficacy in the management of LS, other treatment modalities, including steroid-sparing agents and/or procedural adjuncts, have been demonstrated to have a beneficial role in the treatment of LS.
1. Introduction
Lichen sclerosus (LS) is a chronic inflammatory dermatosis commonly affecting anogenital skin and is often difficult to treat, leading to a multitude of complications [1,2]. Most notably, LS has the capacity for malignant transformation, including anogenital squamous cell carcinoma and verrucous carcinoma [3,4]. Its exact prevalence is unknown, with the literature ranging from 1 in 1000 to 1 in 300 patients living with the disease [5]. Such variations are hypothesized to be secondary to frequent misdiagnosis and asymptomatic patients [5]. While both sexes can be affected, the prevalence is thought to be a lot higher in females with upwards of a 10:1 female to male ratio [5]. Moreover, all ages can be affected, with women typically presenting with a bimodal age distribution with one peak between the ages of 8 and 13, and the second being during the fifth and sixth decades [5]. It commonly presents with pruritus, pain/discomfort, atrophy and scarring, and has a significant impact on patients’ quality of life [6,7]. LS affects patients’ quality of life not only symptomatically, but also due to its associated loss of normal vaginal or penile architecture resulting in psychological distress [8]. Treatment is difficult, and, in cases where LS is not recognized early and treated aggressively, it can progress and cause debilitating symptoms and significant morbidity [9]. As with many inflammatory dermatoses, the gold standard treatment is high-potency topical corticosteroids, and in patients with penile involvement, circumcision is indicated if patients are refractory to corticosteroids [10]. However, recent studies have begun to explore a multitude of other treatment modalities for LS, including topical calcineurin inhibitors, topical and systemic retinoids, and phototherapy [11]. It is important to note that while a plethora of treatment modalities have been explored in the literature and may have been proven to be efficacious in managing the symptoms and architectural changes associated with LS, only corticosteroids have the capacity to reduce the risk for malignant potential [12]. Moreover, in addition to being useful in avoiding progression to differentiated vulvar intraepithelial neoplasia (dVIN), topical corticosteroids are useful in the follow-up of patients with previously surgically excised dVIN to reduce the risk of further invasive malignancy and should thus be recommended to this patient group [13]. Ultimately, a systematic review was conducted to summarize the efficiency of various treatment modalities for genital LS.
2. Methods
We conducted a systematic review of the literature adhering to PRISMA reporting guidelines [14].
2.1. Search Strategy, Study Eligibility Criteria, and Study Selection
A literature search of the PubMed, MEDLINE, and Embase databases was performed on 23 April 2024 using the following search strategy: “lichen sclerosus” and (“genital” or “vulvar” or “vaginal” or “penile”) and (“treatment” or “management”). All randomized controlled trials (RCTs) reporting treatment modalities and their associated outcomes for lichen sclerosus were included. In vitro, histological and animal studies were excluded. Non-English articles and non-RCT studies were also excluded. Finally, studies that did not distinguish treatment modalities used by sex were also excluded. Title and abstract screening was completed by three independent researchers (S.C., S.D.M., and M.S.) using Covidence online systematic review software (www.covidence.org). Full texts to identify relevant studies were assessed by six reviewers. Conflicts were resolved by the primary author (S.C.) and the senior author (I.M.).
2.2. Data Extraction and Synthesis
Three reviewers (S.C., S.D.M., and M.S.) independently extracted data from eligible studies using a standardized extraction form that included title, authors, year of publication, sample size, and key findings divided by sex, including mean age, age range, affected region(s), treatment modalities, treatment response, treatment-related adverse events, and follow-up duration. Three authors (S.C., S.D.M., and M.S.) evaluated the extracted data and synthesized the available evidence in an iterative manner. A pooled analysis was performed for studies with available outcome data. A risk of bias analysis was conducted by two different authors for all included studies using the Cochrane risk-of-bias tool for randomized trials. This systematic review was not registered in a database and a review protocol was not prepared.
3. Results
3.1. Study and Patient Characteristics
Following the title and abstract screening of 66 studies, and full text screening of 33 studies, 31 studies ultimately met inclusion criteria (Figure 1). This pooled analysis reports on 1507 cases of LS, 1374 (91%) of which occurred in females, with available data on treatment outcomes. The mean age of females included in this review was 56.4 years (range 12 to 86), whereas only one of the three male-only studies noted mean age (57.4 years) and one was focused on LS in male children. All 1374 cases of LS presenting in females were noted to affect the vulva, while 58 male LS cases affected the penis, and 51 cases localized to the male genitalia, not otherwise specified (Table 1 and Table 2).
3.2. Risk of Bias
A risk of bias analysis showed that 16 of the included studies had a low risk of bias, 14 had a moderate risk of bias, and 1 had a high risk of bias (Figure 2).
3.3. Topical Corticosteroids as a Single Modality
Unimodal topical corticosteroid therapy was the most commonly reported treatment modality for LS, with one male and four female studies uniquely discussing its usage. All studies noted the usage of high or very high potency topical corticosteroids, notably mometasone furoate 0.1% (MF) and clobetasol propionate 0.05% (CP). Each of the studies that evaluated the efficacy of topical corticosteroids for the treatment of LS interpreted response as clinical or symptomatic improvement of the affected areas. For instance, Cattaneo et al. described significant improvements in a cohort of 32 patients with vulvar LS, whereby 24 weeks of treatment with CP led to significant reductions in the cumulative symptom and gross aspect scores, evident reductions in hyperkeratosis and sclerosis, and the disappearance of erosions and purpura. Histological parameters were also significantly improved, with twelve biopsies showing complete regression of LS findings with improvement in the remaining patients, and overall improvements in inflammatory infiltrates, edema, and fibrosis [41]. Moreover, Lindhagen examined the efficacy of CP in male children with penile LS, and found that, at baseline, patients were more likely to respond to CP than placebo, and that patients initially in the placebo arm then treated with CP responded to CP therapy [15].
Three studies performed comparisons of topical corticosteroid therapy in the treatment of females with LS. Corazza et al. compared CP and MF, two high potency topical steroids, as twice weekly maintenance therapy in patients who had already achieved disease stability with a course of topical corticosteroids, and found no significant differences in outcomes between the two groups over a 52-week period [16]. Virgili et al. also compared CP and MF, and similarly concluded that CP and MF were equally effective for treatment of LS, with the decrease in mean sign and symptom scores significant amongst both groups without significant differences between the groups [17]. Finally, Borghi et al. looked at MF alone, either in the form of a tapering (five days weekly for four weeks, alternate days for four weeks, twice weekly for four weeks) or continuous (five days per week) regimen, and found no statistically significant difference between the two treatment cohorts, concluding that both a tapering and continuous regimen were effective [19].
Overall, high potency topical corticosteroids recurrently proved to be effective in the symptomatic and physical management of LS in both males and females, and should remain the gold standard of therapy for genital LS therapy. There were no significant differences between corticosteroid subtypes, as well as no differences in patient outcomes with regards to varying treatment regimens, allowing physicians to prescribe the course of therapy that the patient feels most comfortable with.
3.4. Topical Corticosteroids and Adjunct Agents
An additional three studies (two female studies, one male study) discussed the use of topical corticosteroids, however these studies attempted to use steroid therapy in conjunction with adjunct agents. A study by D’Antuono et al. analyzed the potential for clothing therapy in the management of vulvar LS, comparing Dermasilk or cotton briefs in conjunction with CP and a vitamin E moisturizer [29]. While both groups had relief from soreness and pruritus, the Dermasilk group showed significant improvement in burning soreness and pruritus. The Dermasilk was also noted to have a greater, non-significant improvement in dyspareunia. Moreover, the severity of these symptoms was in favour of the Dermasilk group with regards to overall improvement and speed of reduction within four weeks. In terms of clinical signs, there was a significantly better improvement in erythema and a non-significant greater improvement in whitening in the Dermasilk group.
Another study analyzed the impact of CP, this time in conjunction with traditional Chinese medicine soaking and washing for 3–4 months, whereby the combination of Chinese and Western medicine has been shown to enhance curative effects, decrease adverse events, and improve the quality of life of vulvar LS patients [45]. More specifically, the traditional Chinese medicine soaking and washing regimen consisted of Fructus cnidii and sweet wormwood, however, elaboration pertaining to the specifics of the treatment plan was not provided [46]. Fructuss cnidii is commonly used in the treatment of chronic itch [46], while sweet wormwood has a therapeutic value in inflammatory diseases and autoimmune disorders [42]. Guo et al. found that there was a statistically significant reduction in pruritus when CP was combined with traditional Chinese medicine. Differences in skin elasticity, colour, and disease extent were not significant, with easy relapse after treatment completion [45]. Overall, patients were found to have better outcomes with multi-focused laser treatment (see “Energy-Based Devices” section).
Laino et al. evaluated the efficacy of polydeoxyribonucleotide (PDRN) administered intradermally in conjunction with topical CP, as compared to CP monotherapy [42]. The study found that PDRN + CP patients achieved better improvements than the CP monotherapy group, as well as better improvements in elasticity and decreased ecchymoses, infiltrating areas, erythematous areas, fissures, and lichenification. Moreover, PDRN + CP patients saw a significant reduction in Investigator Global Assessment (IGA) scores and Dermatology Life Quality Index (DLQI) scores, and maintained disease control at six months, while the CP patients demonstrated more signs of disease relapse at the 4–6 months follow up [20].
Altogether, while topical corticosteroids continuously prove to be efficacious in the management of LS, certain adjunct therapies have also proven to improve patient outcomes, and should be utilized in the clinical setting. Notably, silk briefs, traditional Chinese medicine soaks, and PDRN can be used in conjunction with high potency topical corticosteroids to provide patients with additional relief from their LS-associated symptoms.
3.5. Steroid-Sparing Topical Agents
Seven studies reported on the use of steroid-sparing topical therapies for the treatment of female patients with LS. Two reported on topical calcineurin inhibitors. Funaro et al. compared the efficacy of topical tacrolimus 0.1% to CP in patients with vulvar LS [21], and found significant decreases in papules, atrophic and erythematous patches, erosions, and ulcerations across in both groups. The CP group saw a more significant decrease in papules and atrophic patches than the tacrolimus group, and by the end of the study the number of patients with no clinical signs or reported symptoms was significantly higher in the CP group in comparison to the tacrolimus group, with Visual Analog Scale (VAS) scores reporting that CP was more effective than tacrolimus in reducing burning, pain, and pruritus [21]. Similar to tacrolimus, while pimecrolimus also appeared to be effective in the management of LS, CP showed a more robust clinical response [22]. While histopathological improvement in inflammation was significant for both CP and pimecrolimus groups, a comparison demonstrated a superior improvement in the CP group, and numerically more non-responders in the pimecrolimus group (n = 8) than the CP group (n = 1) [22]. However, VAS scores showed improvement in both groups, with a numerically greater improvement in the CP group, while IGA scores and subscales denoting disease severity, lichenification, and ulceration were equivalent between the two groups [22].
The efficacy of topical hormonal therapy was also investigated. Testosterone 2% ointment as maintenance therapy for vulvar LS, in patients who had already achieved disease control with CP, showed less-than-promising results [41]. Four (25%) patients experienced burning upon ointment application, while nine (56%) noted symptom recurrence, mainly pruritus. Overall, there was a statistically significant worsening of symptoms, whereby patients kept on CP reported further improvements in symptoms [41]. A study by Sideri et al. found that topical testosterone propionate was as effective as petroleum ointment in the management of vulvar LS, with no significant differences between the two groups [23]. Topical progesterone 8% ointment was also found to be inferior to CP treatment in managing LS clinical signs and symptoms [24]. Notably, there was less improvement in standardized LS clinical (p < 0.05), symptom (p = 0.095), and physical scores in progesterone patients as opposed to CP patients, and biopsies proved that more CP patients (81%) achieved disease remission in comparison to progesterone patients (60%) [24]. Interestingly, there were no randomized controlled trials investigating the efficacy of topical estrogen cream in the treatment of vulvar LS, despite being a widely recommended modality. Finally, a study conducted by Bracco et al. compared topical CP, testosterone, progesterone, and a cream-based preparation, and concluded that significant differences in gross and histologic changes before and after treatment were only observed with CP, and that CP-treated patients noted a much lower degree of patients with unchanged symptoms (CP 10%, testosterone 40%, progesterone 50%, cream-based preparation 69%), reinforcing CP as the mainstay of therapy for vulvar LS [25].
Human fibroblast lysate (HFL) cream, which contains multiple anti-inflammatory cytokines and wound-healing growth factors, did not show statistically significant differences in comparison to placebo [18]. Histopathological analysis revealed no significant changes after 12 weeks of therapy. Finally, Virgili et al. analyzed a cohort of patients who had achieved LS disease remission with the once-daily application of MF, who now sought disease maintenance with either MF twice weekly, topical vitamin E oil once daily, or cold cream once daily [26]. The study showed that MF applied twice weekly protected patients from relapsing in comparison to daily topical vitamin E or cold cream applications over three months [26]. Further studies by Virgili et al. showed that vulvar LS in remission from topical corticosteroid treatment may be managed with either vitamin E or emollient therapy, however, relapse rates are high at 52 weeks, with cumulative modified crude relapse rates between 50 and 55% [27].
In summary, while certain steroid-sparing topical agents may prove to be effective in the management of genital LS, they are suboptimal in comparison to topical corticosteroids, and should thus not be used as a first-line treatment. Other modalities, namely topical hormonal therapies, HFL cream, and vitamin E oils, are not effective tools in managing genital LS and should not be used.
3.6. Intradermal Injections
Intradermal injections were reported by three studies in the literature. Platelet-rich plasma (PRP) and nanofat infiltrations delivered twice at a three-month interval for patients with moderate-to-severe vulvar LS were noted to have no significant improvement in vulvar skin elasticity, however, patients noted a significant improvement in symptoms such as itching, pain, burning, and dyspareunia [28]. Objectively, there was noted improvement in clinical signs such as cervical erosions, fissures, stenosis, and leukoderma, and a significant decrease in all inflammatory cell types upon analysis of skin biopsies [28]. Importantly, when Gutierrez-Ontalvilla et al. compared the PRP group to the CP group, they found significant improvements in the PRP group with regards to fissures, stenosis, pallor, itching, burning, and dyspareunia, which were not achieved in the CP group, and treatment outcomes continued to be significantly more effective in the PRP group with regards to reduction in erosions, fissures, stenosis, and pallor at one-year follow-up, with no cases of relapse [28]. Moreover, histological evaluations and quality-of-life assessments (using the Skindex-29 questionnaire) also revealed statistically significant positive findings for the PRP group in comparison to the CP group [28]. However, Goldstein et al. also investigated the potential for PRP injections administered twice, six weeks apart, in the management of vulvar LS, but found more variable results, whereby 5 patients saw improvement in the histopathologic inflammation between pre- and post-treatment biopsies, 10 had no change, and 4 had more inflammation [44]. The mean difference in the Clinical Scoring System for Vulvar Lichen Sclerosus for the PRP and placebo groups was insignificant [44]. Finally, Tedesco et al. evaluated the efficacy of intradermally injected adipose tissue-derived stromal vascular fraction either as monotherapy or in conjunction with PRP, and found that both treatments were equally efficacious in all patients with the exception of those with late-stage disease (Table 3) [30].
Overall, the efficacy of PRP in the management of LS would require further investigation given the variability of data currently available in the literature among only two randomized controlled trials, while adipose tissue-derived stromal vascular fractions as either monotherapy or in conjunction with PRP have the potential to provide early stage LS patients with symptomatic relief.
3.7. Energy-Based Devices
The use of energy-based devices was reported by 10 studies in females with LS. Guo et al. compared carbon dioxide (CO2) laser therapy and photodynamic therapy (PDT) using 5% 5-aminolevulinic acid (5-ALA) as a photosensitizer, and found that CO2 treatment led to statistically significant improvements in pruritus, skin elasticity and colour, lesion size, and total clinical scores, while 5-ALA PDT produced significant improvements in the degree of pruritus, skin colour, and total clinical scores [45]. Notably, significant differences were observed between the groups at three months post-treatment, with the study indicating that CO2 laser therapy has the most potential to improve clinical signs and symptoms and prevent relapse within two months [45]. CO2 lasers were used on two other occasions in the literature, and also demonstrated good efficacy in comparison to CP. Burkett et al. showed that patients treated with a CO2 laser had greater improvement in their Skindex-29 scores at six months in comparison to CP treatment [31]. The patients also viewed their treatment outcomes more positively, with more CO2-treated patients feeling a better improvement in their symptoms (89% vs. 62%) and feeling satisfied with their treatment (81% vs. 41%) [31]. Differently, Mitchell et al. placebo-controlled their CO2 laser therapy trial, and found insignificant improvements in LS upon histopathological examination when comparing the CO2 and placebo lasers [32]. Similarly, patient scores according to the Clinical Scoring System for Vulvar Lichen Sclerosus showed improvement, but the difference in comparison to the placebo group was insignificant, while physician scoring scales also did not demonstrate significant change in either treatment arm [32]. Additionally, Krause et al. investigated the impact of a CO2 laser’s dose on clinical improvement in LS scores, and found that higher dosages show no significant benefit with regards to LS scores, visual analog scores, sexual activity, or quality of life when compared to lower doses [33].
Other energy-based devices reported for LS include the non-ablative neodymium:yttrium aluminum garnet (Nd:YAG) laser and ultraviolet A (UVA) phototherapy. Bizjak Ogrinc et al. studied the efficacy of the Nd:YAG laser in comparison to topical corticosteroids, and found that while patients in both groups experienced a reduction in itching, burning, and pain intensity, the reduction was statistically significantly better for patients in the Nd:YAG laser group amongst all symptoms, and numerically more patients treated with the Nd:YAG laser remained disease-free at a three-month follow up (40% vs. 0%) [33]. Patients also experienced a greater degree of satisfaction when treated with laser therapy (100% very satisfied, compared to 12.5% in the topical steroid group). Zivanovic et al. assessed the efficacy of a combined Nd:YAG/Er:YAG laser in comparison to topical CP, concluding that total LS scores decreased significantly in both groups [35]. CO2 lasers were also compared to topical CP by Salgado et al., who noted similar findings: post-treatment vulvar characteristics and impact on quality of life did not differ significantly between the two groups, while laser-treated patients had a greater degree of satisfaction [36]. Light was also tried as a treatment modality for LS in two studies. Terras et al. investigated the efficacy of UVA phototherapy compared to CP in the management of LS, and found that both therapies resulted in significant decreases in total clinician’s scores, which took into account hypopigmentation, sclerosis, atrophy, hyperkeratosis, erosions, edema, and erythema, but the difference between the groups was not significant [37]. With regards to VAS scores, CP had more parameters that achieved statistically significant results, notably decreases in pruritus, burning and/or pain, and the Skindex-29 score, however, only the score for burning and/or pain significantly decreased for UVA-treated patients. Ultrasound and histopathological assessments also noted improvements in both groups, however, only the values in the CP group reached significance. Shi et al. investigated the use of PDT with 10% 5-ALA cream as compared to CP, and found that PDT resulted in twice the response elicited by CP in terms of hyperkeratosis, atrophy, sclerosis, and depigmentation [38]. Finally, Li et al. attempted to use focused ultrasound therapy for the treatment of vulvar dystrophy, including LS, with a transducer range between 5 and 8 MHz, and noted a dramatic improvement in the patients’ total response rates and the tissues’ return to normal appearance by 3–6 months, with continued response/clearance of disease at the two-year follow-up [39].
Generally, CO2 laser was often effective in comparison to other laser types and high potency topical corticosteroids, serving as an adjunct in the genital LS treatment armamentarium. Importantly, higher laser doses did not prove to be more effective than lower doses. Moreover, the Nd:YAG or Er:YAG lasers or UVA therapy also proved to be either equally effective or more effective than topical corticosteroids with regards to objective findings, while patients treated with laser modalities typically had greater treatment satisfaction. Finally, PDT-treated patients also had greater responses in their physical LS findings than patients treated with topical steroids. Of great importance, laser therapy is often costly and comes with a great out of pocket expense to patients, and thus might not be a feasible option for all.
3.8. Oral Therapies
Two studies analyzed the impact of oral therapy in the treatment of LS. Bousema et al. investigated acitretin, a second-generation retinoid dosed at 20 to 30 mg daily for 16 weeks [43]. While symptoms and signs improved in both the acitretin- and placebo-treated groups, sign and symptom intensity was statistically significantly lower for pruritus, atrophy, and hyperkeratosis in the acitretin group. The number of treatment-responsive patients was also noted to be significantly higher in the acitretin group (64%) as compared to the placebo (25%) (p < 0.05). Ioannides et al. also investigated the use of acitretin in the management of LS compared to the placebo, but instead in cases involving the male genitalia [40]. A larger number of acitretin-treated patients achieved complete or partial response compared to placebo-treated patients (36.4% and 36.4% vs. 6.3% and 12.5%). Finally, there was a significant improvement in the mean DLQI score for the acitretin group [40].
Overall, while acitretin proved to be effective in the management of genital LS, no direct comparisons with topical corticosteroids were noted in the literature. Such a comparison would be needed to further note the efficacy of acitretin as compared to the gold standard in LS management, while being cognizant of the fact that only topical corticosteroids prevent malignant progression of the disease.
3.9. Psychological Counselling
Vittrup et al. analyzed the impact of psychosexual counselling in addition to usual care with ultrapotent topical corticosteroids in combination with a fatty cream and oil massage of the vulva [47]. After six months of therapy, the patients who had underwent psychosexual counselling had a statistically significant improvement in their sexual functioning, as opposed to a non-significant improvement in the control group. The counselled group achieved better improvements in their sexual function indices, mean DLQI scores, and a higher degree of quality of life when compared to the controls, reinforcing the significant impact that psychosexual counselling has on outcomes in LS patients [47].
4. Discussion
In 2018 the British Association of Dermatologists published the first guidelines for the management of LS, in which a strong recommendation was made to start all female and male patients on topical CP [48]. In accordance with this guideline, topical corticosteroids remain the cornerstone of LS treatment, with high potency CP and MF demonstrating significant efficacy in improving cumulative symptoms and gross aspect scores in four RCTs [16,17,19,41]. Importantly, results from two RCTs, which compared CP and MF, showed no significant differences in effectiveness, suggesting that the two high-potency corticosteroids could be considered interchangeable for vulvar LS management, however, the above-mentioned guidelines do not mention the use of MF as an alternative to CP [16,17,48]. As for penile LS, despite the current guideline recommendation to initiate CP in males, only one RCT, which looked at the efficacy of unimodal therapy with CP compared to that of CP combined with subdermal injections of PDRN, was identified [20]. Finally, CP combined with other modalities, such as Dermasilk briefs and vitamin E moisturizers, showed promising results in symptom relief and clinical outcomes [26,29].
This review also identified several steroid-sparing topical agents and alternative therapies for LS management. Topical calcineurin inhibitors demonstrated some efficacy comparable to corticosteroids in improving symptoms and clinical signs, providing alternative treatment options, especially for patients who may be intolerant to corticosteroids or require long-term maintenance therapy. However, results from two RCTs suggest topical steroids remain superior [21,22]. Current guidelines conclude there is insufficient evidence to recommend the use of these therapies [48], and, thus, further research is warranted. An additional important consideration is the relatively high cost of these medications compared to that of topical corticosteroids.
The efficacy of hormonal therapies, such as testosterone and progesterone ointments, was also investigated in four RCTs. However, the results appeared less promising compared to corticosteroids [24,25,41]. Importantly, one study showed significant worsening of symptoms with topical testosterone, suggesting limited utility in LS management [41]. Similarly, current guidelines do not recommend the use of topical hormonal therapy [48]. However, topical estrogen has been successfully used in conjunction with CP for treatment of LS [49,50,51], and this is commonly recommended by clinicians for well-controlled LS.
Importantly, various studies demonstrated therapies with outcomes superior to those of CP. Energy-based devices, namely CO2 and Nd:YAG lasers, showed promising results in improving symptoms and clinical outcomes, with the CO2 laser improving symptoms and quality of life more than CP, and Nd:YAG leading to a greater improvement in remission rates at three months compared to CP [31,34]. Importantly, these RCTs were all published following the release of the 2018 guidelines. PRP injections also demonstrated superior efficacy compared to corticosteroids, with sustained benefits and minimal adverse effects observed over long-term follow-up in one study [28], however, results were variable in another [44]. Given the variability in the reproducibility of the results, the generalization of the results is limited, and further research is warranted.
In one RCT, oral acitretin demonstrated significant efficacy in improving symptoms and clinical signs, suggesting its potential role as an alternative or adjunctive therapy [43]. Current guidelines report insufficient evidence to recommend this intervention [48]. Finally, given that multiple studies have proven that LS is associated with increased psychological distress, decreased quality of life and overall negative health outcomes, more studies evaluating the efficacy and importance of psychological intervention are paramount to improving patients’ quality of life, in addition to pharmacologic therapies [8,52].
Despite the comprehensive nature of this systematic review, there are several limitations. Firstly, the inclusion criteria focused exclusively on RCTs, potentially excluding relevant studies published in other study designs. This may have resulted in the omission of valuable data on different treatment modalities for LS. Moreover, although only RCTs were included to provide a summary of the highest level of evidence, when analyzed using the revised Cochrane tool for risk of bias, eleven studies out of nineteen were associated with “moderate risk” and one study with “high risk” of bias, which underscores the need for cautious interpretation of the findings and highlights potential systematic errors that can influence the validity and reliability of the results [53]. Moreover, the heterogeneity in treatment regimens and outcome measures across studies hindered direct comparisons between different modalities via a meta-analysis. Importantly, the predominance of female-focused studies in the RCT literature suggests a gap in the current understanding of LS management in males, in addition to limiting conclusions that can be made from this review for this population. Finally, comparisons of the efficacies associated with various treatment modalities proved to be a challenge across different studies, given that a plethora of investigator scores were used to objectify LS findings.
Despite these limitations, this systematic review provides a comprehensive synthesis of the current evidence on treatment modalities for LS, serving as a valuable resource for clinicians and researchers in guiding clinical decision-making and future research endeavors, and reinforcing high potency topical corticosteroids as the mainstay of treatment for LS with regards to the prevention of malignant progression, symptomatic management, and improvement in architectural changes. While we strongly reinforce the importance of topical corticosteroids as the cornerstone of treatment for genital LS, more extensive research is needed to better formulate therapeutic algorithms based on a multitude of factors.
5. Conclusions
In conclusion, while LS is reportedly difficult to treat and is known to have a significant impact on patients’ quality of life, the literature contains a plethora of potential treatment modalities with varying outcomes. Physicians should be aware that while topical corticosteroids are the mainstay of treatment, they are not the sole modality available to manage this condition, and that multimodal therapies that combine topical steroids, clothing therapy, and procedural interventions for long-term management also prove to be effective and tolerable.
Author Contributions
Conceptualization, S.C. and I.M.; methodology, S.C. and I.M.; software, S.C., S.D.M. and M.S.; validation and formal analysis, S.C., S.D.M., M.S., A.Y., L.J., S.S. and Y.C.; investigation, S.C., S.D.M., M.S., A.Y., L.J., S.S. and Y.C.; resources, S.C., S.D.M., M.S., A.Y., L.J., S.S. and Y.C.; data curation, S.C., S.D.M., M.S., A.Y., L.J., S.S. and Y.C.; writing—original draft preparation, S.C., S.D.M. and M.S.; writing—review and editing, S.C., S.D.M., M.S., A.Y., L.J., S.S., Y.C., A.L., I.V.L. and I.M.; visualization, S.C. and I.M.; supervision, I.M., I.V.L. and A.L.; project administration, S.C. and I.M.; funding acquisition, none. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Template data collection forms are available within our manuscript; data extracted from included studies are originally available in included studies; data used for all analyses are originally available in included studies; analytic code is not applicable and no formal analysis occurred.
Conflicts of Interest
The authors declare no conflicts of interest.
References
- Radenska-Lopovok, S.G.; Potapov, A.L.; Loginova, M.M.; Elagin, V.V.; Bychkova, A.E.; Karabut, M.M.; Kuznetsov, S.S.; Asaturova, A.V.; Kuznetsova, I.A.; Apolikhina, I.A.; et al. Possibilities of multiphoton microscopy for the diagnosis of the vulvar lichen sclerosus. Arkh Patol. 2023, 85, 29–39. [Google Scholar] [CrossRef] [PubMed]
- Marzec, A.; Olejek, A.; Stopinska, K.; Cnota, W.; Gabriel, I. The use of CO2 laser in vulvar lichen sclerosus treatment—Molecular evidence. Ginekol. Pol. 2023, 94, 903–906. [Google Scholar] [CrossRef] [PubMed]
- Preti, M.; Borella, F.; Ferretti, S.; Caldarella, A.; Corazza, M.; Micheletti, L.; De Magnis, A.; Borghi, A.; Salvini, C.; Gallio, N.; et al. Genital and extragenital oncological risk in women with vulvar lichen sclerosus: A multi-center Italian study. Maturitas 2023, 175, 107767. [Google Scholar] [CrossRef]
- Gutiérrez-Pascual, M.; Vicente-Martín, F.J.; López-Estebaranz, J.L. Lichen Sclerosus and Squamous Cell Carcinoma. Actas Dermo-Sifiliográficas 2012, 103, 21–28. [Google Scholar] [CrossRef]
- Chamli, A.; Souissi, A. Lichen Sclerosus. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA.
- Copyright © 2024; StatPearls Publishing LLC.: Treasure Island, FL, USA, 2024.
- Qing, C.; Mao, X.; Liu, G.; Deng, Y.; Yang, X. The Efficacy and Safety of 5-Aminolevulinic Acid Photodynamic Therapy for Lichen Sclerosus: A Meta Analysis. Indian J. Dermatol. 2023, 68, 1–7. [Google Scholar] [CrossRef] [PubMed]
- Geisler, A.N.; Koptyev, J.; Strunk, A.; Shah, P.R.; Garg, A. Quality of Life and Treatment Adherence in Patients with Vulvar Lichen Sclerosus. Dermatology 2023, 239, 494–498. [Google Scholar] [CrossRef]
- Fan, R.; Leasure, A.C.; Maisha, F.I.; Little, A.J.; Cohen, J.M. Depression and Anxiety in Patients with Lichen Sclerosus. JAMA Dermatol. 2022, 158, 953–954. [Google Scholar] [CrossRef]
- Tausch, T.J.; Peterson, A.C. Early aggressive treatment of lichen sclerosus may prevent disease progression. J. Urol. 2012, 187, 2101–2105. [Google Scholar] [CrossRef]
- Kirtschig, G. Lichen Sclerosus-Presentation, Diagnosis and Management. Dtsch. Arztebl. Int. 2016, 113, 337–343. [Google Scholar] [CrossRef]
- Fistarol, S.K.; Itin, P.H. Diagnosis and treatment of lichen sclerosus: An update. Am. J. Clin. Dermatol. 2013, 14, 27–47. [Google Scholar] [CrossRef]
- Luque-Luna, M.; Bosch-Amate, X.; Morgado-Carrasco, D. RF—Importance of Topical Corticosteroid Treatment for Vulvar Lichen Sclerosus to Prevent Recurrences of Vulvar Carcinoma. Actas Dermo-Sifiliográficas 2022, 113, T722–T723. [Google Scholar] [CrossRef]
- Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021, 372, n71. [Google Scholar] [CrossRef] [PubMed]
- Lindhagen, T. Topical clobetasol propionate compared with placebo in the treatment of unretractable foreskin. Eur. J. Surg. 1996, 162, 969–972. [Google Scholar]
- Corazza, M.; Borghi, A.; Minghetti, S.; Toni, G.; Virgili, A. Clobetasol propionate vs. mometasone furoate in 1-year proactive maintenance therapy of vulvar lichen sclerosus: Results from a comparative trial. J. Eur. Acad. Dermatol. Venereol. 2016, 30, 956–961. [Google Scholar] [CrossRef]
- Virgili, A.; Borghi, A.; Toni, G.; Minghetti, S.; Corazza, M. First randomized trial on clobetasol propionate and mometasone furoate in the treatment of vulvar lichen sclerosus: Results of efficacy and tolerability. Br. J. Dermatol. 2014, 171, 388–396. [Google Scholar] [CrossRef]
- Goldstein, A.T.; Burrows, L.J.; Belkin, Z.R.; Pfau, R.; Bremmer, M.; Goldfinger, C.; Dreher, F. Safety and efficacy of human fibroblast lysate cream for vulvar lichen sclerosus: A randomized placebo-controlled trial. Acta Derm. Venereol. 2015, 95, 847–849. [Google Scholar] [CrossRef] [PubMed]
- Borghi, A.; Corazza, M.; Minghetti, S.; Toni, G.; Virgili, A. Continuous vs. tapering application of the potent topical corticosteroid mometasone furoate in the treatment of vulvar lichen sclerosus: Results of a randomized trial. Br. J. Dermatol. 2015, 173, 1381–1386. [Google Scholar] [CrossRef]
- Laino, L.; Suetti, S.; Sperduti, I. Polydeoxyribonucleotide Dermal Infiltration in Male Genital Lichen Sclerosus: Adjuvant Effects during Topical Therapy. Dermatol. Res. Pract. 2013, 2013, 654079. [Google Scholar] [CrossRef]
- Funaro, D.; Lovett, A.; Leroux, N.; Powell, J. A double-blind, randomized prospective study evaluating topical clobetasol propionate 0.05% versus topical tacrolimus 0.1% in patients with vulvar lichen sclerosus. J. Am. Acad. Dermatol. 2014, 71, 84–91. [Google Scholar] [CrossRef]
- Goldstein, A.T.; Creasey, A.; Pfau, R.; Phillips, D.; Burrows, L.J. A double-blind, randomized controlled trial of clobetasol versus pimecrolimus in patients with vulvar lichen sclerosus. J. Am. Acad. Dermatol. 2011, 64, e99–e104. [Google Scholar] [CrossRef]
- Sideri, M.; Origoni, M.; Spinaci, L.; Ferrari, A. Topical testosterone in the treatment of vulvar lichen sclerosus. Int. J. Gynaecol. Obstet. 1994, 46, 53–56. [Google Scholar] [CrossRef] [PubMed]
- Günthert, A.R.; Limacher, A.; Beltraminelli, H.; Krause, E.; Mueller, M.D.; Trelle, S.; Bobos, P.; Jüni, P. Efficacy of topical progesterone versus topical clobetasol propionate in patients with vulvar Lichen sclerosus—A double-blind randomized phase II pilot study. Eur. J. Obstet. Gynecol. Reprod. Biol. 2022, 272, 88–95. [Google Scholar] [CrossRef] [PubMed]
- Bracco, G.L.; Carli, P.; Sonni, L.; Maestrini, G.; De Marco, A.; Taddei, G.L.; Cattaneo, A. Clinical and histologic effects of topical treatments of vulval lichen sclerosus. A critical evaluation. J. Reprod. Med. 1993, 38, 37–40. [Google Scholar]
- Virgili, A.; Minghetti, S.; Borghi, A.; Corazza, M. Proactive maintenance therapy with a topical corticosteroid for vulvar lichen sclerosus: Preliminary results of a randomized study. Br. J. Dermatol. 2013, 168, 1316–1324. [Google Scholar] [CrossRef] [PubMed]
- Virgili, A.; Minghetti, S.; Borghi, A.; Corazza, M. Long-term maintenance therapy for vulvar lichen sclerosus: The results of a randomized study comparing topical vitamin E with an emollient. Eur. J. Dermatol. 2013, 23, 189–194. [Google Scholar] [CrossRef]
- Gutierrez-Ontalvilla, P.; Giner, F.; Vidal, L.; Iborra, M. The Effect of Lipofilling and Platelet-Rich Plasma on Patients with Moderate-Severe Vulvar Lichen Sclerosus who were Non-Responders to Topical Clobetasol Propionate: A Randomized Pilot Study. Aesthetic Plast. Surg. 2022, 46, 2469–2479. [Google Scholar] [CrossRef]
- D’Antuono, A.; Bellavista, S.; Negosanti, F.; Zauli, S.; Baldi, E.; Patrizi, A. Dermasilk briefs in vulvar lichen sclerosus: An adjuvant tool. J. Low. Genit. Tract. Dis. 2011, 15, 287–291. [Google Scholar] [CrossRef]
- Tedesco, M.; Bellei, B.; Garelli, V.; Caputo, S.; Latini, A.; Giuliani, M.; Cota, C.; Chichierchia, G.; Romani, C.; Foddai, M.L.; et al. Adipose tissue stromal vascular fraction and adipose tissue stromal vascular fraction plus platelet-rich plasma grafting: New regenerative perspectives in genital lichen sclerosus. Dermatol. Ther. 2020, 33, e14277. [Google Scholar] [CrossRef] [PubMed]
- Burkett, L.S.; Siddique, M.; Zeymo, A.; Brunn, E.A.; Gutman, R.E.; Park, A.J.; Iglesia, C.B. Clobetasol Compared with Fractionated Carbon Dioxide Laser for Lichen Sclerosus: A Randomized Controlled Trial. Obstet. Gynecol. 2021, 137, 968–978. [Google Scholar] [CrossRef]
- Mitchell, L.; Goldstein, A.T.; Heller, D.; Mautz, T.; Thorne, C.; Joyce Kong, S.Y.; Sophocles, M.E.; Tolson, H.; Krapf, J.M. Fractionated Carbon Dioxide Laser for the Treatment of Vulvar Lichen Sclerosus: A Randomized Controlled Trial. Obstet. Gynecol. 2021, 137, 979–987. [Google Scholar] [CrossRef]
- Krause, E.; Neumann, S.; Maier, M.; Imboden, S.; Knabben, L.; Mueller, M.D.; Kuhn, A. LASER treatment in gynaecology -A randomized controlled trial in women with symptomatic lichen sclerosus. Eur. J. Obstet. Gynecol. Reprod. Biol. 2023, 287, 171–175. [Google Scholar] [CrossRef] [PubMed]
- Bizjak Ogrinc, U.; Senčar, S.; Luzar, B.; Lukanović, A. Efficacy of Non-ablative Laser Therapy for Lichen Sclerosus: A Randomized Controlled Trial. J. Obstet. Gynaecol. Can. 2019, 41, 1717–1725. [Google Scholar] [CrossRef] [PubMed]
- Zivanovic, I.; Gamper, M.; Fesslmeier, D.; Walser, C.; Regauer, S.; Viereck, V. Nd:YAG/Er:YAG dual laser compared with topical steroid to treat vulvar lichen sclerosus: A randomised controlled trial. BJOG 2024, 131, 740–749. [Google Scholar] [CrossRef]
- Salgado, H.C.; Drumond, D.G.; Pannain, G.D.; de Melo, E.C.L.G.; Sampaio, F.S.; Leite, I.C.G. Randomized clinical trial with fractional CO(2) laser and Clobetasol in the treatment of Vulvar Lichen Sclerosus: A clinic study of feasibility. BMC Res. Notes 2023, 16, 33. [Google Scholar] [CrossRef]
- Terras, S.; Gambichler, T.; Moritz, R.K.; Stücker, M.; Kreuter, A. UV-A1 phototherapy vs clobetasol propionate, 0.05%, in the treatment of vulvar lichen sclerosus: A randomized clinical trial. JAMA Dermatol. 2014, 150, 621–627. [Google Scholar] [CrossRef]
- Shi, L.; Miao, F.; Zhang, L.L.; Zhang, G.L.; Wang, P.R.; Ji, J.; Wang, X.J.; Huang, Z.; Wang, H.W.; Wang, X.L. Comparison of 5-Aminolevulinic Acid Photodynamic Therapy and Clobetasol Propionate in Treatment of Vulvar Lichen Sclerosus. Acta Derm. Venereol. 2016, 96, 684–688. [Google Scholar] [CrossRef] [PubMed]
- Li, C.; Bian, D.; Chen, W.; Zhao, C.; Yin, N.; Wang, Z. Focused ultrasound therapy of vulvar dystrophies: A feasibility study. Obstet. Gynecol. 2004, 104, 915–921. [Google Scholar] [CrossRef]
- Ioannides, D.; Lazaridou, E.; Apalla, Z.; Sotiriou, E.; Gregoriou, S.; Rigopoulos, D. Acitretin for severe lichen sclerosus of male genitalia: A randomized, placebo controlled study. J. Urol. 2010, 183, 1395–1399. [Google Scholar] [CrossRef]
- Cattaneo, A.; Carli, P.; De Marco, A.; Sonni, L.; Bracco, G.; De Magnis, A.; Taddei, G.L. Testosterone maintenance therapy. Effects on vulvar lichen sclerosus treated with clobetasol propionate. J. Reprod. Med. 1996, 41, 99–102. [Google Scholar]
- Lu, B.W.; Baum, L.; So, K.F.; Chiu, K.; Xie, L.K. More than anti-malarial agents: Therapeutic potential of artemisinins in neurodegeneration. Neural Regen. Res. 2019, 14, 1494–1498. [Google Scholar] [CrossRef]
- Bousema, M.T.; Romppanen, U.; Geiger, J.M.; Baudin, M.; Vähä-Eskeli, K.; Vartiainen, J.; Vuopala, S. Acitretin in the treatment of severe lichen sclerosus et atrophicus of the vulva: A double-blind, placebo-controlled study. J. Am. Acad. Dermatol. 1994, 30, 225–231. [Google Scholar] [CrossRef] [PubMed]
- Goldstein, A.T.; Mitchell, L.; Govind, V.; Heller, D. A randomized double-blind placebo-controlled trial of autologous platelet-rich plasma intradermal injections for the treatment of vulvar lichen sclerosus. J. Am. Acad. Dermatol. 2019, 80, 1788–1789. [Google Scholar] [CrossRef] [PubMed]
- Guo, J.Q.; Chen, S.Y.; Chen, X.M.; Lu, J.Q.; Song, Y.; Liu, H.Y.; Hu, L.N.; Zhu, Z.Y. Clinical study on multi-focused laser in the treatment of vulvar lichen sclerosus. Front. Surg. 2022, 9, 919135. [Google Scholar] [CrossRef] [PubMed]
- Chen, X.; Zhu, C.; Zhang, Y.; Yang, N.; Shi, H.; Yang, W.; Yang, Y.; Liang, J.; Chen, L.; Zeng, X.; et al. Antipruritic Effect of Ethyl Acetate Extract from Fructus cnidii in Mice with 2,4-Dinitrofluorobenzene-Induced Atopic Dermatitis. Evid. Based Complement. Alternat Med. 2020, 2020, 6981386. [Google Scholar] [CrossRef]
- Vittrup, G.; Westmark, S.; Riis, J.; Mørup, L.; Heilesen, T.; Jensen, D.; Melgaard, D. The Impact of Psychosexual Counseling in Women with Lichen Sclerosus: A Randomized Controlled Trial. J. Low. Genit. Tract. Dis. 2022, 26, 258–264. [Google Scholar] [CrossRef]
- Lewis, F.M.; Tatnall, F.M.; Velangi, S.S.; Bunker, C.B.; Kumar, A.; Brackenbury, F.; Mohd Mustapa, M.F.; Exton, L.S. British Association of Dermatologists guidelines for the management of lichen sclerosus, 2018. Br. J. Dermatol. 2018, 178, 839–853. [Google Scholar] [CrossRef]
- Desai, S.; Corley, S.B. Treating co-existent genitourinary syndrome of menopause in patients with lichen sclerosus improves symptoms. Int. J. Womens Dermatol. 2023, 9, e071. [Google Scholar] [CrossRef]
- Brandon, A.; Joshi, T.; Ahmed, Z.; Tahir, M.; Phung, T.; Pierce, J.Y.; Knowles, K. A Rare Presentation of Lichen Sclerosus Involving the Vaginal Canal After Radiation Therapy: A Case Report and Review of the Literature. Cureus 2023, 15, e47077. [Google Scholar] [CrossRef]
- Sevcan Arzu Arınkan, F.V.; Güneş, P.G.; Aka, N. Vaginal Atrophy and Lichen Sclerosus: A Case Report. Haydarpaşa Numune Med. J. 2018, 58, 112–115. [Google Scholar]
- Jabłonowska, O.; Woźniacka, A.; Szkarłat, S.; Żebrowska, A. Female genital lichen sclerosus is connected with a higher depression rate, decreased sexual quality of life and diminished work productivity. PLoS ONE 2023, 18, e0284948. [Google Scholar] [CrossRef]
- Sterne, J.A.C.; Savović, J.; Page, M.J.; Elbers, R.G.; Blencowe, N.S.; Boutron, I.; Cates, C.J.; Cheng, H.Y.; Corbett, M.S.; Eldridge, S.M.; et al. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ 2019, 366, l4898. [Google Scholar] [CrossRef] [PubMed]
Figure 1.
PRISMA flow diagram of included studies.
Figure 2.
Risk-of-bias assessment of included studies. Low risk of bias is represented by a green circle, moderate risk of bias by a yellow circle, and high risk of bias by a red circle [14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44].
Table 1.
Management of LS in female patients.
| # Patients | Mean Age (Age Range) | Affected Region | Treatment Modality | Response | Adverse Events | Follow Up Duration | Remission or Relapse | Risk of Bias | |
|---|---|---|---|---|---|---|---|---|---|
| Topical Steroids as a Single Modality | |||||||||
| Corazza 2016 [15] | 48 | 64.14 (NR) | Vulva | Group 1 (24): Clobetasol propionate 0.05% ointment twice weekly for 52 weeks (CP) Group 2 (24): Mometasone furoate 0.1% ointment twice weekly for 52 weeks (MF) | Mean change in features:
| None | 52 weeks | 3 cases of relapse: 2 in CP, 1 in MF Mean time to relapse: 30 weeks (range 20–38) | Some concern |
| Virgili 2014 [16] | 54 | 64.2 (NR) | Vulva | Group 1 (27): Clobetasol propionate 0.05% ointment five days per week for 4 weeks, then on alternate days for 4 weeks, then twice weekly for 4 weeks (CP) Group 2 (27): Mometasone furoate 0.1% ointment five days per week for 4 weeks, then on alternate days for 4 weeks, then twice weekly for 4 weeks (MF) | CP:
MF:
| None | 12 weeks | 24 patients responded, while 1 did not for CP 24 patients responded, while 2 did not for MF | Some concern |
| Borghi 2015 [17] | 64 | 60.95 (NR) | Vulva | Group A (32): Mometasone furoate 0.1% ointment daily for 5 days per week for 4 weeks, then on alternate days for 4 weeks, then twice weekly for 4 weeks Group B (32): Mometasone furoate 0.1% ointment 5 days weekly |
| None | 12 weeks | 27 responders and 4 non-responders in MF1 25 responders and 4 non-responders in MF2 | Some concern |
| Virgili 2013 [18] | 27 | 60.53 (NR) | Vulva | Treatment Phase (12 weeks):
Maintenance Phase (52 weeks), whereby all patients were assigned to one modality:
| Treatment Phase (27 patients):
Maintenance Phase (25 patients):
| None | 64 weeks | MF: 7 remission, 0 relapse VitE: 4 remission, 5 relapse CC: 3 remission, 5 relapse Median time to relapse for VitE and CC: 21.6 weeks | Some concern |
| Topical Corticosteroids and Adjunct Therapies | |||||||||
| D’Antuono 2011 [19] | 42 | 51.5 (22–79) | Vulva | Treatment Phase (6 months):
| CT Group:
DS Group:
| 3 cases of Candida vulvovaginitis in CT group | 6 months | CT: Remission in 0 patients, relapse not noted DS: Remission in 2 patients, relapse not noted | Some concern |
| Non-Steroid Topicals | |||||||||
| Cattaneo 1996 [14] | 32 | 60 (28–85) | Vulva | First part of treatment (32):
Second part of treatment:
| First part of treatment:
Second part of treatment:
| Burning (4) and itching (9) on application of testosterone ointment | 48 weeks | Symptomatic relief in all patients in first phase Worsening of symptoms in patients in TP arm of study 3 patients maintained on placebo improved | Low concern |
| Funaro 2014 [20] | 55 | 46.6 (NR) | Vulva | Group 1 (28): Tacrolimus 0.1% ointment daily for 3 months (CL) Control group (27): Clobetasol propionate 0.05% ointment daily for 3 months (CP) |
| None | 3 months | Remission in 9/28 (32%) of CP patients, only 19/27 (70%) of TL patients | Low concern |
| Goldstein 2011 [21] | 38 | NR (NR) | Vulva | Group 1 (17): Pimecrolimus 1% cream twice daily for 12 weeks (PIM) Group 2 (19): Clobetasol propionate 0.05% cream twice daily for 12 weeks (CP) |
| None | 12 weeks | 26 patients completed the follow-up period, where 24 showed improvement and 11 (42%) experienced remission (not broken down by treatment arm) | Low concern |
| Sideri 1994 [22] | 58 | 56.5 (35–83) | Vulva | Group 1 (30): 2% Testosterone propionate in Vaseline Group 2 (28): Petroleum ointment | Symptom improvement (pruritus vulvae, burning): Testosterone propionate group:
Placebo:
No significant difference found between groups. | n = 4, adverse events not specified | 12 months | Improvement in dystrophy in 17 patients (group not specified), but no histological demonstration of regression in any of the cases. | Low concern |
| Gunthert 2022 [23] | 37 | 34.52 (NR) | Vulva | Group 1 (17): Progesterone 8% ointment, 2 g daily for 12 weeks (PRO) Group 2 (20): Clobetasol propionate 0.05% ointment, 2 g daily for 12 weeks (CP) | Change in:
| CP: Genital herpes (2), mycotic genital infection (1), urinary tract infection (2) PRO: Mycotic genital infection (1), vulvitis (2), urinary tract infection (1), peritonitis (1) | 24 weeks | Remission in 6/10 PRO patients, 13/16 CP patients | Low concern |
| Bracco 1993 [24] | 79 | 57 (27–83) | Vulva | Group 1 (20): Clobetasol propionate 0.05% topical Group 2 (20): Testosterone 2% topical Group 3 (20): Progesterone 2% topical Group 4 (19): Cream-based preparation topical | Symptoms (itching, burning, pain and dyspareunia) were classified from 0–3, with 3 most severe. Symptom improvement:
Symptom unchanged:
Gross changes: Significant difference in clobetasol group only (p < 0.001, CI 2.93–4.97) Gross appearance mean score, clobetasol: 5.8 to 1.9 Histological evaluation: Significant difference in clobetasol group only (p < 0.001, CI 2.29–4.65), mean score 7.1 to 3.7 | None | 3 months | Symptom remission (no symptoms and/or lesions remaining): Clobetasol propionate: 75% Testosterone: 20% Progesterone: 10% Cream-based preparation: 10.5%. Follow up encouraged for an additional 3 months for clobetasol group, in which patients encouraged to use it twice weekly for 3 more months. Of remaining 13 patients, 11 continued good response to therapy, 2 who discontinued had recurrence. | Low concern |
| Goldstein 2015 [25] | 30 | 58 (NR) | Vulva | Treatment Group (TG) (15): Human fibroblast lysate cream twice daily for 12 weeks Control Group (CG) (15): Placebo cream with the same emollient base as the treatment cream twice daily for 12 weeks |
| None | 12 weeks | No relapse noted | Some concern |
| Virgili 2013 [26] | 80 | 61.85 (12.17–84.92) | Vulva | Maintenance therapy (following a 12-week active treatment phase on topical 0.1% mometasone furoate ointment daily; patients who achieved a symptomatologic VAS global score ≤ 5/30 and an IGA score ≤ 2 (total or almost total healing) were judged as “treatment responsive” and were eligible for the MP) with:
| Primary efficacy point: relapse rate at both week 26 and 52 Second efficacy variable: mean time to relapse, defined as number of weeks from start of maintenance phase (MP) until LS relapse Total cumulative crude relapse rate (intention to treat): 25% (20/80) Total cumulative modified crude relapse rate: 52.36% (20/38) Crude relapse rates after 52 weeks of maintenance treatment:
Median time to relapse:
| No observed adverse events | 52 weeks | Relapses
Dropouts (total n = 42):
| Low concern |
| Intradermal Injections | |||||||||
| Gutierrez-Ontalvilla 2022 [27] | 19 | 55.17 (NR) | Vulva | Treatment Group (TG) (9): 24 mL of nanofat mixed with PRP, 2 infiltrations 3 months apart Control Group (CG) (10): Topical clobetasol propionate 0.05% cream once or twice weekly | Mean change in feature, standard deviation within brackets:
| None | 12 months | 3 cases of relapse, all patients in control group | Some concern |
| Goldstein 2019 [28] | 30 | 52.6 (NR) | Vulva | Group 1 (20): Platelet-rich plasma intradermal injections, separated by 6 weeks (PRP) Group 2 (10): Placebo saline injections (PLA) | Change in histopathologic inflammation:
Change in Clinical Scoring System for Vulvar LS: −7.74 in PRP, −9.44 in PLA, p = 0.654 | Bruising | 12 weeks | Not specified | Low concern |
| Energy-Based Devices | |||||||||
| Guo 2022 [29] | 50 | NR (NR) | Vulva | Experimental group: CO2 laser once monthly for 3 months (CO2) Control group 1: Radiofrequency treatment with 5-aminolevulinic acid as a photosensitizer once weekly for 10 weeks (RF) Control group 2: Clobetasol propionate 0.05% ointment with traditional Chinese medicine soaking and washing for 3–4 months, then once every other day for 4 weeks, then twice weekly for 4 weeks (CP) | Change in scores at 1 month after treatment:
Change in scores at 3 months after treatment:
| None reported | 3 months | Not specified | Some concern |
| Burkett 2021 [30] | 52 | 64.5 (NR) | Vulva | Group 1 (19): Fractionated CO2 laser therapy, 5 courses 4–6 weeks apart (CO2) Group 2 (18): Clobetasol propionate 0.05% ointment nightly for 1 month, then three times weekly for 2 months, then as needed (CP) | Change in…
| Minor burning and blistering with CO2 (1); reactivation of genital herpes 1 week after starting CP (1) | 6 months | Not specified | Some concern |
| Mitchell 2021 [31] | 37 | 59 (51–64) | Vulva | Group 1 (19): Fractionated CO2 laser therapy, 5 courses in 24 weeks (CO2) Group 2 (18): Placebo laser (PLA) | Change in…
| Transient, mild discomfort (n not specified) | 24 weeks | No remission achieved | Low concern |
| Krause 2023 [32] | 67 | Low dose group: 53 (21–80) Normal dose group: 52 (20–79) | Vulva | Microablative CO2 laser low dose group (LDG) (29): three laser applications in three subsequent sessions of three weeks. Microablative CO2 laser normal dose group (NDG) (34): three laser applications in three subsequent sessions of three weeks. | Mean change in total VAS score at 18 weeks
Mean change in total LS score at 18 weeks:
Regarding sexual activity:
Regarding quality of life (QoL):
| Burning sensation during laser application, not requiring intervention: 31 No other adverse events or side effects reported. | 18 weeks | No reported relapses or remissions. | Low concern |
| Bizjak Ogrinc 2019 [33] | 40 | 58 (NR) | Vulva | Experimental group (20): 3 neodymium-doped yttrium aluminium garnet (Nd:YAG) laser treatments every 14 days (Nd:YAG) Control group (20): Topical betamethasone twice daily for 2 weeks, then once daily for one week, then every second day for one week (BM) | Change in scores at 3 months after treatment:
Change in scores at 6 months after treatment:
| None | 6 months | 8/20 Nd:YAG-treated patients were free of symptoms at 3-month follow up, compared with none of the 16 patients in the control group; 4/16 Nd:YAG-treated patients were free of symptoms at 6-month follow up. | High concern |
| Zivanovic 2024 [34] | 66 | 59.3 (22–86) | Vulva | Group 1 (44): l dual neodymium:yttrium–alumin-ium–garnet (Nd:YAG)/erbium:yttrium–aluminium–gar-net (Er:YAG) laser at baseline, months 1, 2 and 4 Group 2 (22): topical clobetasol propionate (17 patients used 0.05% oitment and 5 preferred 0.05% cream) first 4 days/week for 8 weeks (phase I) then 4 days/week every 2nd week for 8 weeks (phase II) and finally 4 days/week every 4th week for 8 weeks (phase III) |
Mean change in total LS score and subcategories at 6 months:
Mean change in total VAS score (itching, burning and pain) and subcategories at 6 months:
Mean change in total VSQ score and subcategories at 6 months:
Regarding reported patient satisfaction (PGI-I) for laser vs. steroid groups respectively:
* p < 0.05 considered statistically significant | Pain/discomfort during laser sessions:
Within the first week of laser:
| 6 months total with 2 months follow up | No reported relapses or remissions | Low concern |
| Salgado 2023 [35] | 20 | Not reported | Vulva | Fractional CO2 laser (11): three sessions, with the following settings: 25 watts/ Stack 1/ime 700 microseconds/Spacing 700 micromillimeters. Clobetasol propionate ointment 0.05% (9): nightly in the first month, followed by nightly on alternate days in the second month, then nightly on two consecutive days of the same week (Saturdays and Sundays) in the third month, as needed afterwards without exceeding twice weekly | Mean change in WHOQOL-BREF domains after 3 months of treatment:
Regarding self-perceived itch, dysuria, pain/sting, sexual activity, appearance, difficulty and patient satisfaction at 3 months:
At 12 months:
| No reported adverse events | 12 months | No reported relapses or remissions at 12 months, however higher occurrence of mild hyperkeratosis and lichenification and excoriations in laser groups | Low concern |
| Terras 2014 [36] | 26 | 60.83 (20–81) | Vulva | Group 1 (13): Clobetasol propionate 0.05% ointment once daily for 3 months (CP) Group 2 (13): Medium-dose ultraviolet A1 (50 J/cm2) home-based phototherapy, performed 4 times weekly for 3 months (UVA) | Change in mean…
| Initial increase in pruritus for UVA-treated patients, treated with petroleum jelly applied within 30 min of radiation to prevent dehydration, which led to marked improvement | 6 months | Three months after end of therapy, all primary and secondary outcomes points returned to baseline levels in all patients, suggesting only transient benefit from these therapies | Some concern |
| Shi 2016 [37] | 40 | 51.4 ± 15.6 (range not reported) | Vulva | ALA-PDT (20): 10% 5-aminolevulinic acid photodynamic therapy (ALA-PDT) cream applied to the lesions with a 1-cm margin and incubated for 3 h. The lesions were irradiated with 100 J/cm2 633 nm red light at 100 mW/cm2. The same PDT procedure was repeated 3 times at 2-week intervals. CP (20): Topical 0.05% clobetasol propionate ointment applied by the patient nightly for 8 weeks. | Changes in clinical scores (hyperkeratosis, sclerosis, atrophy, depigmentation) Scores: 0 = absent, 1 = mild, 2 = moderate, 3 = severe Mean changes not reported. Hyperkeratosis:
Atrophy:
Sclerosis:
Depigmentation:
Changes in symptom scores (pruritus, burning and pain feeling)
Mean reduction in lesion size:
Change in ratios of the vulvar surface affected by VLS: Scored as 0 = none, 1 = less than 25%, 2 = 25–50%, 3 = more than 75% of the vulvar surface affected
| ALA-PDT:
CP:
| 6 months | ALA-PDT: 14/20 (70%) complete response 4 (20%) partial response 2 (10%) minimal response Clobetasol propionate: 7/20 (35%) complete response 6 (30%) partial response 7 (35%) minimal response. Rate of complete response in the ALA-PDT group was much higher than that in the CP group (p < 0.05, χ2 = 4.912) Rate of relapse: All patients finished the 6-month follow-up. In ALA-PDT group: 1 out of 14 (7.1%) patients relapsed one month after completion of treatment. The remaining 13 patients showed no signs of recurrence during follow-up. In CP group, 7 out of 7 (100%) patients relapsed one month after treatment. | Some concerns |
| Li 2004 [38] | 31 | 38.5 | Vulva | Focused ultrasound therapy
| Response measured based on the reduction of pruritus, changes of the skin elasticity and color, decreased percentage of the involved area, and changes in histological findings Cured: (17/31, 54.84%) Improvement: (12/31, 38.71%) Persistent disease: (2/31, 6.45%) Overall response rate: (29/31, 93.55%) | None | 2 years | 17 patients in remission | Some concerns |
| Oral Therapies | |||||||||
| Bousema 1994 [39] | 78 | NR (18-83) | Vulva | Experimental group (22): Acitretin 30 mg once daily for 16 weeks, could be reduced to 20 mg once daily in case of adverse reactions after 4 weeks (AC) Control group (24): Placebo (PLA) | Improvement in…
| Cheilitis and xerosis in all AC patients, 1/3 of PLA patients Severe peeling of palms and soles in AC group (11) Increased hair loss higher in AC (23) than PLA (2) | 16 weeks | None | Low concern |
| Psychological Counselling | |||||||||
| Vittrup 2022 [40] | 158 | Median, IQR Intervention group: 53 (33.2–60.5) Median, IQR Treatment Group: 50.5 (30.8–57.0) | Vulva | Control group: usual management where woman would receive oral instruction at diagnosis, treatment, and consultation with nurse specialized in vulvar diseases to follow-up regarding compliance, adherence and support (80) Usual treatment + psychosexual counselling group offered 8 individual sessions of 45 min of counselling based on individual needs (78) | Female Sexual Function Index-FSFI Scores:
Dermatology Life Quality Index-DLQI Scores:
WHO-5 Wellbeing Index Scores:
Effect size of sexual counselling on sexual activity:
| None | 6 months | Not applicable to this study | Low concern |
* Signifies statistical significance.
Table 2.
Management of LS in Male Patients.
| # Patients | Mean Age (Age Range) | Affected Region | Treatment Modality | Response | Adverse Events | Follow Up Duration | Remission or Recurrence | Risk of Bias | |
|---|---|---|---|---|---|---|---|---|---|
| Lindhagen 1996 [41] | 30 | NR | Penis | Group 1 (15): Clobetasol propionate Group 2 (15): Placebo | Clobetasol Propionate: Improvement: n = 10 (+7 from placebo group who were switched) No effect: n = 3 Withdrawal: n = 2 Placebo: Improvement: n = 7 No effect: n = 7 (subsequently given clobetasol propionate and improved) Withdrawal: n = 1 | NR | 6 months | No information about relapse or complete remission provided. | Low concern |
| Laino 2013 [42] | 28 | NR (25–65) | Penis | Group 1 (14): Subdermal polydeoxyribonucleotide infiltration, 8 sessions total, in association with nightly clobetasol propionate 0.05% (PDRN) for 4 months Group 2 (14): Clobetasol propionate 0.05% nightly (CP) for 4 months | Change in median value of…
| None | 6 months | PDRN: 14 remission, 0 relapse CP: 8 remission, 6 relapse | Some concerns |
| Ioannides 2010 [43] | 51 | For control group: 57.79 (38–75) For treatment group: 56.56 (38–74) | Male genitalia | Treatment (34): systemic acitretin 35 mg daily for 20 weeks Control (17): placebo capsules (identical in size and color to acitretin) for 20 weeks | Two patients, 1 on acitretin and 1 on placebo, withdrew from the study due to disease associated complications (phimosis) which demanded surgical management Mean change in total clinician score (TCS)
Mean change in total quality of life
| Acitretin group:
Control group:
| 36 weeks | Complete response: 36.4% (12 of 33) of the subjects on acitretin and 6.3% (12 of 16) of controls Partial response: 36.4% (12 of 33) of the treatment group and in 12.5% (2 of 16) of the control group. Disease remained stable in: 21.2% (7 of 33) of the acitretin group and 31.3% (5 of 16) of the control groups Disease progression: 6.1% (2 of 33) of individuals on acitretin and 50.0% (8 of 16) on placebo | Low concern |
Table 3.
Management of LS in both female and male patients.
| # Patients | Mean Age (Age Range) | Affected Region | Treatment Modality | Response | Adverse Events | Follow Up Duration | Remission or Relapse | Risk of Bias | |
|---|---|---|---|---|---|---|---|---|---|
| Tedesco 2020 [44] | 40 (24 M, 16 F) | Entire sample: 43 (18–78) Female patients: 59 (29–78) Male patients:49 (18–76) | Female and male genitalia, not otherwise specified | Group 1 (20 total, 5F and 15M): Intradermal injection of adipose tissue derived-stromal vascular fraction; 2 surgical procedures 4 months apart Group 2 (20 total, 11F and 9M): Intradermal injection of combined purified AD-SVF and platelet rich plasma (PRP); 2 surgical procedures 4 months apart | Mean clinical score at 6 months post-second injection (score ranging from 0 (disease stability) to 3 (great functional improvement with reduction of symptoms until their disappearance) based on subjective itch, pain, burning sensation and dyspareunia on 10 level VAS)
Mean change in QoL (based on DLQI questionnaire)
| None | 6 months | 13 patients had complete resolution of symptoms 23 showed significant improvement in symptoms 4 showed no changes 2 reported a reduction of white lesions | Some concerns |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Conte, S.; Daraj Mohamed, S.; Shergill, M.; Yacovelli, A.; Johnston, L.; Starkey, S.; Cohen, Y.; Law, A.; Litvinov, I.V.; Mukovozov, I. Treatment Modalities for Genital Lichen Sclerosus: A Systematic Review. Dermato 2024, 4, 136-172. https://doi.org/10.3390/dermato4040014
AMA Style
Conte S, Daraj Mohamed S, Shergill M, Yacovelli A, Johnston L, Starkey S, Cohen Y, Law A, Litvinov IV, Mukovozov I. Treatment Modalities for Genital Lichen Sclerosus: A Systematic Review. Dermato. 2024; 4(4):136-172. https://doi.org/10.3390/dermato4040014
Chicago/Turabian StyleConte, Santina, Sarah Daraj Mohamed, Mahek Shergill, Alexandra Yacovelli, Leah Johnston, Samantha Starkey, Yossi Cohen, Angela Law, Ivan V. Litvinov, and Ilya Mukovozov. 2024. "Treatment Modalities for Genital Lichen Sclerosus: A Systematic Review" Dermato 4, no. 4: 136-172. https://doi.org/10.3390/dermato4040014
APA StyleConte, S., Daraj Mohamed, S., Shergill, M., Yacovelli, A., Johnston, L., Starkey, S., Cohen, Y., Law, A., Litvinov, I. V., & Mukovozov, I. (2024). Treatment Modalities for Genital Lichen Sclerosus: A Systematic Review. Dermato, 4(4), 136-172. https://doi.org/10.3390/dermato4040014
