Rufus R. Noble The dermatosis Lichen sclerosis is a chronic inflammatory dermatosis that affects the skin. The plaques can be thin and porcelain-white, with purpura or hyperkeratosis. They may also have fissures, ulcerations, erosions, or erosions. [1] Widespread lesions are often seen in the anogenital region, but extragenital lesions are also possible. The risk and development of precursor lesions are higher in advanced LS. These include intraepithelial neoplasia and squamous-cell vulvar cancer. 2, 3 ]. Approximately four to seven percent (47%) of women with LS can develop vulvar cancer. Fig. 1 ).
Fig. 1CONSORT diagram.
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A clinical diagnosis of LS can be made using the CSS (clinical score system). [4] [ of vulvar LS. Biopsy is not required, except in cases of doubtful clinical presentation and dysplasia, which must be excluded. Fig. 2 ).
Fig. 2 VAS Score before and after treatment; NDG: normal dose group, LDG = low dose group.
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Fig. 3
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Early LS presents a difficult histopathological diagnostic challenge 5, 6 This may lead to a discrepancy in the histopathological and clinical results [5] ]. The gold standard for LS therapy is to use potent or extremely potent topical steroids such as Clobetasol. However, in many cases, the clinical symptoms of LS do not improve despite the corticosteroids being applied. This requires the patient’s long-term commitment and can be refractory in terms of therapeutic effects. Clobetasol can also be harmful to the skin if used excessively. In a recent cross-sectional study of patients with dermatophytosis, 92% reported steroid abuse, with the resultant hypopigmentation and striae. [7] The need for second-line therapy, such as topical inhibitors of calcineurin, oral or topically applied retinoids, and immunosuppressors, is evident. [8] The use of fractionated carbon dioxide (CO) is also a promising alternative. 2 Laser application is a new alternative in the treatment of LS. The treatment tissue can be superficially ablated by the application of laser spots with a spacing of 1000 um. The micro ablation causes a remodeling of the tissue connected to the treated area and an ultrastructural change in the dermis. [9] ]. A number of publications confirm the effects described in several publications. 9, 10, 11, 12 Recent systematic reviews [13] Only two studies had a prospectively published protocol, and the follow-up was shorter than 12 weeks, which is the recommended duration of treatment. Studies were underpowered; seven out of 24 were commercially funded, implying bias. Eleven did not include a conflict of interest. The study compared the effects of a high-dose CO2 laser treatment on a variety of symptoms for women with LS to a low-dose laser treatment that could be considered a sham or placebo. It could lead to the unblinding of patients. We chose a low-dose laser therapy because we thought it was too low to have any effect.
Materials and Methods
We performed the current study in our tertiary referral dysplasia unit, which specialized in vulvar dysplasia in the University Women’s Hospital Bern, Inselspital, Switzerland, between 1/ 2020 and 1/2022.The study was prospectively registered at the Swiss National Clinical Trial Portal (SNCTP via BASEC; SNCTP 000003817, BASEC 2019-01524, changed 29.04.2022).Ethical consent from the local ethics committee was obtained (Kantonale Ethikkommission Bern, 11/2020), and Swiss medic (Medical Devices Clinical Investigations) approved the study (Ref.10000575; 10/2020).Randomization was computer generated, using “Research Randomizer,” version 1997-2019, by Geoffrey C. Urbaniak and Scott Plus, in order to randomize the order of patients to the two groups in a ratio of 1:1. Participants were randomly assigned to either the normal dosed or low dosed groups. The randomization process consisted of three stages: the generation of the allocation sequence, the concealment of allocation, and the implementation of the allocation sequence. This was done using a computer-based fixed allocation system, which was hidden from the patients in order to ensure blinding. The investigator could not be blinded due to the need to define the laser settings. The same clinician treated all patients with lasers (EK).The primary objective was to measure the change in symptom discomfort as a continuous measure using a VAS (visual analog scale) from 0 to 10. The primary objective was the change in symptom bother as a continuous measure, determined by VAS (visual analog scale) from 0 = no bother to 10 = the worst possible pain. I can imagine asking the patient the question, “How is your current discomfort in the vulva region? [4] All participants had genital LS, which was confirmed either by biopsy or the validated clinical score system for vulvar Ls. [4] ].Exclusion criteria included pregnancy, local bacterial or fungal infection, as determined by native microscopic, other severe dermatoses, except for LS, vulvar carcinoma, dysplasia in the vulvar area as determined by colposcopy, and a Lichen score of 5. For anesthesia, we used a topical lidocaine 30% cream that was applied to the skin 20 minutes before laser therapy. The cream was provided to the patient to apply herself. Medical gauze was also given to the patient to place on top to help the cream settle. The cream was removed completely before laser therapy to ensure the laser treatment would be effective. We used a fractional micro ablative CO 2 Laser system (SmartXide Touch, MonaLisa Touch by DEKA, Florence, Italy). Hi-Scan V is used for the vulvar. 2 LR scanning system was connected.Immediately before laser application, all patients received lidocaine cream 30% locally that was applied on the vulva region and was removed after 10 min.Laser application was performed in the semi-upright position on a gynecological examination chair.Radiation of the normal dosed group was adjusted with power 24 W, exposure time 400 microsec, and DOT spacing 1000. The low-dose group received the same dose but with a power of 0,5 W. Exposure time and DOT were the same. In the first consultation, we explained the study to the participants and screened for exclusions. We also gave them all the information they needed. In all premenopausal females, we performed a vulvar exam, a photo documentation of the vulva, and an additional urine pregnancy test. At the second consultation (T1), after randomization, the lichen scores were determined, and the first laser treatment was started based on the randomization. A score >4 indicates that lichen sclerosis is likely in >90% of women. [4] The participants completed two validated questions: the visual analog score (VAS) for current symptoms and FSFI (female sexual functions index). We used the Female Sexual Function Index (FSFI), a questionnaire, to assess sexual function. The FSFI questionnaire consists of 19 questions that cover the domains of desire, arousal, and lubrication, as well as satisfaction. The FSFI scoring guide describes the range of scores for each question. These are 0-5, 1-5, and 0-5. [14] The VAS asked patients about the most significant disturbance caused by lichen, including itching and burning. It was phrased as “How much do you feel disturbed by the symptoms of lichen?” Please rate the severity of your symptoms between 0 and 10 (no disturbance) or 0 to no disturbance. At all subsequent meetings (T2-4), we conducted a vulvar exam with photo documentation. The women were asked to complete a VAS and answer the FSFI at each meeting. Three laser treatments followed, with intervals of 3 weeks. The lichen score was calculated at the fourth and fifth meetings (T3 and T4). The overall quality of living was assessed when asking patients, “How has your overall quality of lifestyle regarding lichen changed since last time?” Better; 2. Better; 2. The primary outcome determines the sample size: the change from baseline to six weeks after treatment (i.e., Three months after baseline, we rated symptoms using a VAS scale ranging from 0-10. We considered a change in VAS score of 2 to be clinically significant. The standard deviation was derived from Bizjak et al.’s publication. 15, 16 ]. The change in a summary VAS range of 0-30 was reported as 17.5 (95% Confidence Interval 14.4-20.5) after three months for 20 patients who received non-ablative Laser Therapy. In the 16-patient control group, the change was reported as 9.1 (95% confidence interval 5.0-13.2). We calculated the standard deviation based on these confidence intervals. The standard deviations for the laser group and the control groups were 2.8 and 2.3, respectively. A two-sample means test based on these assumptions yields a sample size of approximately 58 patients. We increased the sample size from 32 patients in each group to 64 to account for dropouts up to 10%.
Results
The Consort Diagram describes the progression through the phases of the trial in the following manner. : Table 1: Patients’ characteristics. Table 1Summarizes patients’ baseline characteristics. Laser group mean Age (years and range)Mean weight (kg, range)Menopause status.
(1 = premenopausal, 2 = postmenopausal)
Normal dose laser (n = 34) 52 (20-79) 67.5 (55-81.5) 1: n = 12.
2: n = 22,
Low dose laser (n = 29) 53 (21-80) 66.2 (54-80.5) 1: n = 13.
2: n = 16.
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Primary endpoint
The VAS score in the group treated with normal dose laser was 4.26 (+-2.39 sd) ). The VAS score was a. 5.14 (+-2.56 SD). After the first treatment, the mean VAS-Sore for the group treated with normal dose laser was 3.44. +- 1.91 SD). The VAS score was the same in the group of low-dose lasers. 3.65 (+-1.89 %) After 18 weeks, the difference in mean VAS scores between the low-dose laser and normal-dose laser groups was not significant.
Secondary endpoints
Before the laser application, the mean LS score was calculated. 7.4 (+-1.7) After the treatment, 4.1 (+-2.2). The first LSc in the group of normal dose lasers was 7.2 (+-1.6), And in the end, 3.9 (+-2.1); the difference is significant (p = 0.0001). The LS was higher at the start of the group with low-dose lasers. 7.5 (+-1.7) After treatment 4.3 (+-2.4) The mean reduction for the LS group in the normal-dose laser group was 3.4 Low dose laser group 3.3. The difference between the two groups is not statistically significant (p = 0.88)
Sexual Activity
After the treatment, 16 (55%) patients reported being sexually active, only 7 (24%) were not sexually able because of lichen sclerosis, and 6 (21%) for other reasons. After the treatment, 16 (55%) of the patients were still sexually engaged, while only 7 (24%) of them were no longer sexually engaged due to lichen sclerosis. Six (21%) of the patients were no longer sexually involved for other reasons. In the normal dose group, 18 (53%) of the patients were active sexually before the treatment. Ten (29%) of the patients were not actively sexual due to the condition.
Quality of Life
In the low-dose laser group, 15 patients (52%) reported severe limitations and 13 (45%) intermittent restrictions before the laser treatment began. One patient (3%) had no restrictions after the laser treatment, seven (20%) reported severe conditions and twenty (77%) intermittent ones. In eight patients (53%), we were able to detect a significant improvement. Seven (23%) of the patients experienced severe limitations, and 24 (77%) reported intermittent restrictions after treatment. Ten participants (58%) showed an improvement. In the normal laser dose group, 14 (41% of patients) had an improved QoL. In the low laser dose group, eleven (38%) patients experienced an improvement. This difference was not statistically significant (p = 0.80).
Side effects
Thirty-one patients experienced some burning during the application of lasers without requiring any intervention. The burning sensation lasted for up to 12 hours and then disappeared.
Discussion
This prospective randomized trial shows that patients with lichen sclerosis can improve their symptoms and score without experiencing any serious side effects, either short-term or long-term. These improvements were seen in both the normal dose and low dose laser groups, which were originally intended to be a placebo. It is important to note that no activation (Koebner phenomena) of lichen has been detected, which is encouraging for future patients with lichen who wish to undergo laser treatments. When the repeated applications were being performed, we noticed a high level of satisfaction among the participants. Perhaps the frequent medical contact with patients and the intense discussion of their subjective feelings about their symptoms cause a kind of placebo effect. This study’s weakness was the incomplete FSFI questionnaire, which was not sufficient to draw any conclusions. This could be due to the patient’s embarrassment when it comes to sexual function. This will be taken into account for future research.
