Laser therapy for genital lichen sclerosus: A systematic review of the current evidence base

Abstract Background Lichen sclerosus (LS) is a chronic, inflammatory dermatosis. Initial treatment with superpotent topical corticosteroids is the accepted and evidence‐based first‐line therapy. For those who do not respond after exclusion of other potentiating factors, the best second‐line therapy is unclear. Laser therapy is an emerging treatment for genital LS and despite uncertain efficacy its use is gaining popularity in the private sector. Objectives We aimed to review the effectiveness of laser therapy for genital LS in men, women and children. Methods We conducted a systematic review of all primary studies reporting the use of laser in genital LS. Ovid MEDLINE, PubMed, Ovid Embase, Cochrane CENTRAL, Web of Science, CINAHL and PsycINFO were searched from inception to February 2021. The quality of the studies was assessed using the revised Cochrane risk‐of‐bias tool for randomized trials, ROBINS‐I tool for non‐randomized trials and Joanna Briggs Institute checklist for case studies. Results A total of 24 studies, involving 616 adults, met inclusion criteria. These were six randomized controlled trials (RCTs), one non‐randomized trial, nine single arm trials and eight case series. Where assessed, most studies suggest that laser therapy in patients with LS may improve symptoms, clinical signs, quality of life and sexual function. However, results were highly heterogeneous and methodological quality was very low, therefore meta‐analysis was not possible. Conclusions There is poor evidence to support the use of laser therapy for genital LS at present. Effectiveness of laser needs to be robustly investigated in well‐conducted RCTs.

It is unusual for female patients not to respond to topical steroids, and if there is ongoing active disease, it is important to investigate for another cause. Lack of compliance, secondary infection, contact dermatitis to treatment, development of vulval neuropathic pain and most importantly, progression to differentiated vulval intra-epithelial neoplasia all need to be excluded. In males who have severe phimosis or meatal involvement, surgical treatment would be required as topical steroids would not help this. The most effective secondline therapy is unclear.
'What surgical treatments should be offered for lichen sclerosus?' 9 was a research question prioritized during the Lichen Sclerosus Priority Setting Partnership in 2018. Surgical treatments were defined to include (but not limited to) laser, platelet-rich plasma and lipofilling.
Laser is an emerging treatment for genital LS. Despite uncertain efficacy, its use is gaining popularity. Statements have been issued by international bodies to warn that lasers used for vaginal rejuvenation can cause serious harm 10 and laser should not be used to treat LS outside the context of well-conducted clinical trials. 11 The aim of this systematic review (PROSPERO database registration-CRD42019143039) 12 was to establish the effectiveness of laser therapy for genital LS affecting men, women and children. All types of laser (any regimen, any time frame) were considered; the comparator was either active or placebo and the main outcomes assessed were (i) clinical signs, (ii) patient-reported symptoms, (iii) quality of life and (iv) sexual function.

| Patients and methods
Ovid MEDLINE, PubMed, Ovid Embase, Cochrane CENTRAL, Web of Science, CINAHL and PsycINFO were searched from inception to February 2021. PubMed search strategy used the following terms: ('LS' or 'lichen sclerosis' or 'lichen sclerosus et atrophicus' [MeSH Terms]

or 'vulvar lichen sclerosus' [MeSH Terms] or 'balanitis xerotica obliterans' [MeSH Terms] or 'balanitis xerotica' or BXO) AND (laser or lasers or 'lasers' [MeSH Terms] or 'laser therapy' [MeSH Terms])
Randomized controlled trials (RCTs), nonrandomized designs, cohort studies or case series with five or more participants were included. Studies including photodynamic therapy using laser as the source of light and articles in languages other than English were excluded.
An information specialist conducted the searches, screening took place independently by three authors, and data extraction/quality assessment were performed independently by two reviewers with a third reviewer to resolve any disagreements. Quality assessment was performed using published tools where available for the identified study types: the revised Cochrane risk-of-bias tool 13 (RCTs), ROBINS-I tool 14 (non-randomized trials) and The Joanna Briggs Institute checklist 15 (case studies). Data were extracted into an Excel spreadsheet (Table 1 summarizes the data and full details of what was extracted can be found on PROSPERO). 12 Reference lists of the included studies were also reviewed as well as the clinicaltrials.gov website.

| RESULTS
Of 360 studies, 24 studies met the inclusion criteria, with a total of 610 participants ( Figure 1) (women and/or men, but no children). The results of the studies are summarized in Table 1.

| Randomized controlled trials
Of six identified RCTs, [16][17][18][19][20][21] three were conference abstracts 16,17,20 and all included female participants. Laser was compared with either topical corticosteroid 16,17,18,20 sham laser 19 or ultrasound. 21 Four studies used different types of laser (diode laser, non-ablative neodymium: yttrium aluminium garnet (Nd:YAG) laser and fractional CO 2 laser) with differing regimens in women with biopsy proven LS (except one study which did not state how LS was confirmed), 16 were compared against short courses (4-8 weeks) of superpotent topical corticosteroids. 16,17,18,20 A variety of outcomes were used in What's already known about this topic?
� A super-potent topical steroid is the evidence-based first line therapy for genital lichen sclerosus (LS). � For those who do not respond to treatment, after exclusion of other potentiating factors, the best second-line therapy is unclear. � Laser therapy is an emerging treatment for genital LS and despite uncertain efficacy, its use is gaining popularity in the private sector.

What does this study add?
� There is not enough evidence to recommend laser for the treatment of genital LS. � There is a lack of long-term data on the procedure.

Study design Study (Stated if Abstract
Only) n Sex

Conflicts of Interests (CoI)/Funding Duration of Study and Follow up
Overall

Study design Study (Stated if Abstract
Only) n Sex

Conflicts of Interests (CoI)/Funding Duration of Study and Follow up
Overall

Study design Study (Stated if Abstract
Only) n Sex

Conflicts of Interests (CoI)/Funding Duration of Study and Follow up
Overall these RCTs; clinical signs such as skin thickness and histology, patient reported symptoms, quality of life scores and sexual function. Results suggest that patients allocated to receive laser had significant improvement in skin thickness (increased by 49.07% vs. −27.51% in the corticosteroid group, p = 0.006). 16 There was no significant difference in improvement of clinical photographs from baseline and 3 months after treatment (0.58 +/− 1.25 in the laser group and −0.27 +/− 1.27 in the control group). 18 Symptoms including itch, burning and pain rated on a visual analogue scale were reduced in both groups compared with baseline but they were statistically significantly better in the laser group at one and 3 month follow up and the effect was still significant at 6 months, although these symptoms started to increase again. 18  After crossing over at 6 months, the steroid to laser group had a greater decrease in score than the laser to steroid group and in terms of satisfaction measured by PGI-S, the steroid to laser group were significantly more satisfied than the laser to steroid group, however there was no statistical comparison between the groups at any point. 20 The impact of LS on the quality of patients' sex life was reduced significantly only in the laser group but the problems recurred at 6-month follow-up. 18 Mitchell et al. was the only RCT to compare CO 2 laser with sham laser treatment. Forty women with LS were randomized in a 1:1 ratio to receive either five fractional CO 2 treatments or five sham treatments in a 24-week period. Histology was the primary outcome and although there was improvement in Histopathologic Scale (HS) in the active treatment group, the change in HS between the active and sham arm was not statistically significant (−0.17; 95% CI = −1.14, 1.06, p = 0.78). There was an improvement in the patientreported Clinical Scoring System for Vulvar Lichen Sclerosus (6.82-point reduction from baseline in the active (95% CI = −11.28, −2.37, p = 0.004) and a 4.83point reduction in the sham treatment group (95% CI = −9.16, −0.51, p = 0.03). However, when the clinicians completed this scoring system, a 0.82 increase (worsening) was found in the active treatment group (95% CI = −0.46, 2.11, p = 0.20) and a 0.28 reduction in the sham treatment group (95% CI = −1.53, 0.97, p = 0.65), although the results were not significant. The authors conclude that CO 2 laser is not an effective monotherapy treatment for vulvar LS but suggest it may be a useful adjunct to topical steroids. 19 One RCT included 60 females with 'white lesions of the vulva' (12/60 had biopsy-proven LS). Participants were randomized to either fractional ultra-pulsed CO 2 laser or high-intensity focused ultrasound (US). Compared to focused US, clinical signs of colour, elasticity and symptoms of pruritis were 'cured' in 1 participant in the laser group and 0 in the US group; 'basically disappeared' in three in the laser group and two in the US group; 'improved' in one in the laser group and two in the US group; and was 'ineffective' in one in the laser group and two in the US group. Statistically improved outcomes across all patients with 'white lesions of the vulva' were stated for total cured (p = 0.01) and total effective rate (p = 0.02). The results for LS patients were not reported separately. Overall risk of bias using the Cochrane risk-ofbias tool was high for all of these RCTs. 21

| Non-randomized trials
There was one non-randomized trial comparing fractional CO 2 versus topical triamcinolone acetonide for six weeks to treat vulval LS. 22 The authors state the skin elasticity score in the laser group was statistically lower than that of the topical steroid group at 6 months after treatment (p < 0.05). Itch and dyspareunia were reported as being statistically significantly better after treatment in both groups but no further details were given in this abstract. Overall risk of bias using ROBINS-I tool was high.

| Single arm trials
Of nine single arm trials, [23][24][25][26][27][28][29][30][31] seven were studies of women with vulval LS and two included men with genital LS. 26,31 The intervention was ablative Er:YAG laser in 1 study, non-ablative Er:YAG in 1 study, 24,27 and fractional CO 2 laser 6, with ablative CO 2 in one. One study using fractional (sub-ablative) CO 2 had additional treatment with autologous plasma and immunity modulation with nutrition factors. 25 The latter study states 50% of participants (9/18) were asymptomatic and 4 had reduced itching and dyspareunia although one continued with severe dyspareunia but her itching improved.

| Case series
Of eight case series, 32-39 six included women with vulval LS and two included both men and women with genital LS. 13,39 All studies used CO 2 laser except one which used blue diode laser. 36 Improved clinical signs include decreased white epithelium by 20%, 32 improved erythema, oedema and erosions 36 no visible recurrence of disease (5/7) 38 and improvement in the appearance of the introitus, 39 however one study mentioned urethral lesions of one patient recurred despite three separate treatments (n = 5 males) and LS recurred in one female patient with perineum LS (n = 2). 35 Studies report 65% improvement of symptoms (range 10%-100%), 33 18/21 questions assessing symptoms significantly improved, 34 symptom score decreased from 5.25 to 2.75, 36 there was a statistically significant reduction in vaginal pain, itch and dysuria, 32 resolution of itch in 5/7 patients, 38 pruritus disappeared in 50% and reduced in the other 50% as well as resolution of burning in 60%, however there was little improvement in urinary problems. 39 One study reports DLQI score decreased from 5.75 to 3.75. 36 Other studies report a statistically significant reduction in dyspareunia 32 and 2/9 with dyspareunia had complete resolution. 39 Meta-analysis was not possible due to high heterogeneity of studies and low methodological quality. TASKER ET AL.
-15 of 18 We note a recently published systematic review 40 which performed meta-analysis on two of the RCTs which were also identified in our study (Bizjak 2019 and Burkett 2020). 8,41 The latter is a conference abstract, later published by Siddique et al in 2020. 20 We assessed these studies as having high risk of bias. Outcome measures used to assess symptom score were very different (total symptom score vs. Skindex 29). The reports lacked the necessary detail required to independently calculate odds ratios and therefore, meta-analysis was not possible. In addition, the systematic review by Li only looked at 13 studies; they did not include an additional 13 studies that we identified, 16,17,19,21,22,25,26,28,31,[33][34][35][36] four of which were RCTs. 16,17,19,21 There are many limitations of the studies identified in our systematic review. Conference abstracts (not peer reviewed) comprise 9 of the 24 included studies. Of the six RCTs, three were published in peer reviewed journals and only two 18,19 had a prospectively published protocol, despite all having been commenced after the introduction of mandatory trial registration guidelines. 42 All RCTs identified were assessed to have a high risk of bias. In studies where the control group received topical steroids, the topical regimen was often shorter than 12 weeks, which is the recommended duration of treatment. 8 The one non-randomized trial (serious risk of bias) did not use super-potent topical corticosteroids in the control group. 22 The single arm trials are subject to considerable bias due to study type. Many studies are also underpowered. Published case series lacked methodological detail and confounding factors, including concomitant use of topical treatments such as oestrogen during laser treatment were noted. 32,37 7/24 of the studies were either commercially funded or declared conflicts of interest and 11/24 did not include conflicts of interest/funding statement.
Three studies included patients without biopsyproven LS and a further three did not state how LS diagnosis was confirmed, therefore there may be conditions which can mimic LS clinically included in these studies. The period of follow up after the last laser treatment was short in the majority of studies; between 1 month and 12 months in 16/24 studies; 11 of these followed up patients for 6 months or less. Three studies followed up the participants between 6 and 48 months 29,37,38 and another study between 3 months and 6 years 35 Three studies did not report the duration of follow-up. Only one retrospective study had a long follow up period of 14 years; however not all patients were alive at follow up and those who were, were contacted by email or telephone and only symptomatic patients were invited to clinic for clinical examination to confirm the presence of no lesions. 31 The limitations of this systematic review includes a lack of detailed data from some of the abstracts which published limited information and possibly the exclusion of negative studies due to publication bias. There are seven ongoing registered trials of which the results are awaited [43][44][45][46][47][48][49] ; five of which are RCTs. 44,46,47,48,49 In summary, there is no high-quality evidence to support the use of laser for the treatment of genital LS in males and females. Long-term data of laser are lacking including its adverse side effects. High quality RCTs are needed.