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Efficacy of Non-ablative Laser Therapy for Lichen Sclerosus: A Randomized Controlled Trial

Open AccessPublished:April 11, 2019DOI:https://doi.org/10.1016/j.jogc.2019.01.023

      ABSTRACT

      Objective

      The aim of this randomized controlled trial was to evaluate the safety and efficacy of neodymium: yttrium aluminum garnet laser treatment of lichen sclerosus (LS) by comparing it with topical corticosteroid treatment.

      Methods

      A total of 40 female patients with vulvar LS were randomized 1:1 into a study (laser) group and a control (topical corticosteroids) group. The laser group received three laser treatments. Blinded evaluators evaluated biopsies and graded improvement on clinical photographs at baseline and at 3 months. Patients graded the intensity of symptoms on a 0 to 10 visual analogue scale at baseline and 1-, 3-, and 6-month follow-up. Patients also rated the tolerability of laser treatments, and side effects were monitored. (Canadian Task Force classification I)

      Results

      Laser treatment discomfort was on average 1.5 of 10 on the visual analogue scale. At 1- and 3-month follow-up, patients in the laser group had significantly greater improvement in LS symptoms (burning, itching, pain, and dyspareunia), better patient satisfaction, and greater reduction of sclerosis than patients in the topical corticosteroid group. At 6-month follow-up, the improvement of symptoms in the laser group was still significant. The correct order of photographs (before and after treatment) was assigned significantly more often in the laser-treated patients compared with the control group.

      Conclusion

      Laser therapy for LS caused minimal patient discomfort during the treatment, with no adverse effects, and demonstrated better efficacy than in the control group, with significant improvement lasting up to 6 months. Laser therapy is a promising option for patients not responding to topical corticosteroid therapy or patients wishing to reduce long-term corticosteroid maintenance use.

      Résumé

      Objectif

      Cet essai clinique randomisé visait à comparer l'innocuité et l'efficacité du laser néodymium : YAG (grenat d'yttrium et d'aluminium) à celles des corticostéroïdes topiques pour le traitement du lichen scléreux (LS).

      Méthodologie

      Quarante femmes atteintes de LS vulvaire ont été réparties également dans un groupe expérimental (laser) et un groupe témoin (corticostéroïdes topiques). Le groupe expérimental a reçu trois traitements au laser. Des évaluateurs ignorant le traitement reçu ont examiné des tissus prélevés par biopsie et ont évalué l'amélioration selon des photographies cliniques prises au début de l'étude et après trois mois. Les patientes ont noté l'intensité de leurs symptômes sur une échelle visuelle analogue de 0 à 10 au début de l'étude, puis après un, trois et six mois. Elles ont également noté la tolérabilité des traitements au laser, et les effets secondaires ont été suivis (classification I du Groupe d'étude canadien).

      Résultats

      La douleur liée au traitement laser était en moyenne de 1,5 sur 10 à l'échelle visuelle analogue. Après un et trois mois, les patientes du groupe expérimental présentaient des résultats significativement supérieurs à celles du groupe témoin pour ce qui est de l'amélioration des symptômes de LS (sensation de brûlure, démangeaison, douleur, dyspareunie), du degré de satisfaction et de la réduction de la sclérose. Au suivi de six mois, l'amélioration des symptômes chez les femmes du groupe laser était toujours significative. L'identification correcte des photos (avant et après) était significativement plus fréquente pour les patientes du groupe expérimental que pour celles du groupe témoin.

      Conclusion

      Le traitement au laser du LS entraîne une douleur minime, n'est associé à aucun effet indésirable et a une meilleure efficacité que le traitement témoin; il est associé à une amélioration demeurant significative six mois plus tard. Il s'agit donc d'une option prometteuse pour les patientes ne répondant pas à la corticothérapie topique ou souhaitant éviter l'utilisation à long terme de corticostéroïdes.

      Key Words

      INTRODUCTION

      Lichen sclerosus (LS) is a chronic inflammatory skin disease mainly found in the anogenital area, predominantly in older (postmenopausal) women.
      • Kirtschig G
      Lichen sclerosus-presentation, diagnosis and management.
      Risk factors include hormonal changes, trauma, and infections.
      • Kirtschig G
      Lichen sclerosus-presentation, diagnosis and management.
      Twenty to thirty percent of women with LS have autoimmune diseases.
      • Kirtschig G
      Lichen sclerosus-presentation, diagnosis and management.
      Initial whitish patches and nodules usually develop into large, white patches of atrophic skin.
      • Kirtschig G
      Lichen sclerosus-presentation, diagnosis and management.
      Lacerations, ecchymosis, and scarring may develop, which may lead to fusion of labia minora, narrowing of the introitus, and burying of the clitoris.
      • Kirtschig G
      Lichen sclerosus-presentation, diagnosis and management.
      The most common symptoms are itching, pain, and dyspareunia, interfering with sexual function and quality of life.
      • Kirtschig G
      Lichen sclerosus-presentation, diagnosis and management.
      • Kirtschig G
      • Becker K
      • Günthert A
      • et al.
      Evidence-based (S3) guideline on (anogenital) lichen sclerosus.
      Untreated LS is associated with an elevated risk of cancer.
      • Kirtschig G
      Lichen sclerosus-presentation, diagnosis and management.
      • Kirtschig G
      • Becker K
      • Günthert A
      • et al.
      Evidence-based (S3) guideline on (anogenital) lichen sclerosus.
      The recommended initial treatment of LS is a 3-month application of potent to ultrapotent topical corticosteroids.
      • Kirtschig G
      Lichen sclerosus-presentation, diagnosis and management.
      However, because the treatment is not curative, long-term maintenance treatment is required.
      • Kirtschig G
      Lichen sclerosus-presentation, diagnosis and management.
      Patient noncompliance can considerably reduce treatment effectiveness.
      • Kirtschig G
      Lichen sclerosus-presentation, diagnosis and management.
      Long-term steroid use can cause skin thinning, especially in children.
      • Kirtschig G
      Lichen sclerosus-presentation, diagnosis and management.
      Effective treatment alternatives and/or adjuncts are therefore sought to reduce the need for long-term maintenance and to help in cases that do not respond to corticosteroids.
      Non-ablative lasers with wavelengths of 810 to 1210 nm improved skin healing and scar prevention after surgery in randomized clinical trials.
      • Casanova D
      • Alliez A
      • Baptista C
      • et al.
      A 1-year follow-up of post-operative scars after the use of a 1210-nm laser-assisted skin healing (LASH) technology: a randomized controlled trial.
      • Capon A
      • Iarmarcovai G
      Scar prevention using laser-assisted skin healing (LASH) in plastic surgery.
      The controlled elevation of skin temperature induced by laser activates overexpression of heat shock protein 70.
      • Casanova D
      • Alliez A
      • Baptista C
      • et al.
      A 1-year follow-up of post-operative scars after the use of a 1210-nm laser-assisted skin healing (LASH) technology: a randomized controlled trial.
      These chaperone proteins shorten the inflammatory phase of the wound healing process and hasten scar maturation and tissue regeneration.
      • Casanova D
      • Alliez A
      • Baptista C
      • et al.
      A 1-year follow-up of post-operative scars after the use of a 1210-nm laser-assisted skin healing (LASH) technology: a randomized controlled trial.
      Furthermore, in recent years, non-ablative lasers have been applied in gynaecology for improvement of symptoms of genitourinary syndrome of menopause and stress urinary incontinence, with the mechanism relying on thermally induced collagen remodelling.
      • Gambacciani M
      • Palacios S
      Laser therapy for the restoration of vaginal function.
      The safety and efficacy of such application have been demonstrated in a randomized controlled trial.
      • Blaganje M
      • Scepanovic D
      • Zgur L
      • et al.
      Non-ablative Er:YAG laser therapy effect on stress urinary incontinence related to quality of life and sexual function: a randomized controlled trial.
      Histological examination before and after laser stress urinary incontinence treatment showed signs of neocollagenesis, neoangiogenesis, elastogenesis, reduction of epithelial degeneration and atrophy, and an increase in the fibroblast population in the vaginal wall.
      • Lapii GA
      • Yakovleva AY
      • Neimark AI
      Structural reorganization of the vaginal mucosa in stress urinary incontinence under conditions of Er:YAG laser treatment.
      LS is characterized histologically by orthohyperkeratosis, epidermal atrophy, basal cell degeneration, a bandlike lymphocytic infiltrate, and a dermal collagen hyalinization zone.
      • Kirtschig G
      • Becker K
      • Günthert A
      • et al.
      Evidence-based (S3) guideline on (anogenital) lichen sclerosus.
      Therefore, patients with LS may benefit from irradiation with a non-ablative laser.
      The aim of this randomized controlled pilot study was to provide the first assessment of the efficacy and safety of non-ablative neodymium: yttrium aluminum garnet (Nd:YAG) laser treatment of LS in comparison with standard treatment with topical corticosteroids. The Nd:YAG 1064-nm laser wavelength has adequate penetration depth to induce a heat response in the affected dermis. Nd:YAG pulse durations, much longer than the thermal relaxation time of the epidermis, do not cause high initial epidermal temperature peaks
      • Lukac M
      • Vizintin Z
      • Pirnat S
      • et al.
      New skin treatment possibilities with PIANO mode on an Nd : YAG Laser.
      and thus avoid causing discomfort or damage to the epidermis of the sensitive vulvar area.

      METHODS

      The study protocol was approved by the National Medical Ethics Committee of the Republic of Slovenia (No. 121/12/15) and registered at ClinicalTrials.gov (Nd: Yttrium Aluminum Garnet Laser Treatment for Lichen Sclerosis; NCT03525522). From January 2016 to January 2017, female patients presenting with LS at two centres in Slovenia (Division of Gynecology and Obstetrics, University Medical Centre Ljubljana, and Juna Gynaecological Clinic, Ljubljana) were screened for inclusion in the study (Figure 1). Patients aged >18 years with a histologically confirmed diagnosis of LS who signed informed consent forms were included in this study. Exclusion criteria were pregnancy, use of photosensitizing medication, presence of pathology (other than lichen) or tissue damage in the treatment area, or other inflammation. Patients were asked to discontinue any hormonal contraception, local hormone therapy, or topical therapy used before the study.
      Figure 1
      Figure 1Consolidated Standards of Reporting Trials (CONSORT) flow diagram of the progress of patients through the phases of this randomized controlled trial.
      Power analysis was based on the primary outcome measure: the sum symptom score at 3-month follow-up. Because no previous study existed to provide effect size data for power analysis, we assumed a large expected effect size of 1 for this pilot study. We calculated that 17 patients per group would be needed to have 80% power to detect such a difference with a test at two-sided α = 0.05. Six additional patients were recruited to account for uncertainties in effect size estimation and loss during follow-up.
      A total of 40 patients were included in the study and were randomized (1:1) into the laser group or control group by random drawing of sealed envelopes. The personnel conducting outcome measurements were blinded to group allocation. The gynaecologist preforming the treatment and the patients could not be blinded.
      The patients in the study (laser) group received 3 Nd:YAG laser (SP Dynamis, Fotona, Slovenia) treatments every 14 days, using the R33 non-contact handpiece with a 9-mm spot size, Piano pulse mode (5 seconds), and 90 J/cm2 fluence. These parameters were previously recommended for wound healing and scar prevention.
      • Lukac M
      • Vizintin Z
      • Pirnat S
      • et al.
      New skin treatment possibilities with PIANO mode on an Nd : YAG Laser.
      Six passes were performed over the affected whitish or reddened areas and borderline granulations. One week before the first laser treatment, the patients in this group started pre-treatment with topical corticosteroid betamethasone (Diprosone) to alleviate symptoms and increase treatment comfort. This therapy lasted 3 weeks with decreasing dosage: twice daily during the first week, once daily during the second week, and every second day during the third week. After laser treatment, the patients were prescribed betamethasone-gentamicin ointment (Diprogenta) to use twice daily over the treated area for 2 days. They were advised to avoid sexual intercourse and swimming pools for at least 3 days, maintain their usual hygiene, keep the area dry, and use cotton underwear. Follow-up was performed 1 month after the start of therapy and at 3 and 6 months after the last treatment.
      The control group received the topical corticosteroid betamethasone for 4 weeks with decreasing dose: twice daily during the first 2 weeks, once daily during the third week, and every second day during the fourth week. Follow-up was performed after the end of therapy and at 3 and 6 months after the end of treatment.
      The effect observed in the laser group is a combination of corticosteroid pre-treatment and laser sessions. Comparison against the control group, in which corticosteroid therapy was used alone, allows the difference in efficacy to be attributed to the effect of laser.

       Outcome Assessment

      Outcome assessment included the following:
      • Patients rated symptoms (burning, itching, and pain) on a 0–10 visual analogue scale (VAS) scale at baseline and every follow-up visit. The improvement in the sum of scores of all three symptoms at 3-month follow-up was the primary outcome measure.
      • Patients reported whether they were sexually active and answered yes or no questions about lack of sensation during intercourse, anorgasmia, and dyspareunia at baseline and during every follow-up visit.
      • Patients rated their satisfaction with the results of treatment (0: very unsatisfied; 1: unsatisfied; 2: satisfied; 3: very satisfied).
      • Histological evaluation was performed by a blinded assessor at baseline and 3 months after the end of treatment. Formalin-fixed and paraffin-embedded punch biopsies of the vulva were cut into 4-μm thick sections and stained with hematoxylin and eosin.
      • Measurement of the thickness of epidermis and sclerosis and assessment of inflammation on a four-point scale (none, mild, moderate, severe) were performed in only one of the two pathology centres used in the study, including seven patients from the laser group and five patients from the control group.
      • Evaluation of clinical photographs of the affected area taken at baseline and 3 months after the end of treatment was performed by three independent blinded evaluators unaware of group assignment and unaware which of the pair of photos was taken before and which was after treatment. The evaluators assigned the order and rated the improvement (0: no improvement; 1: poor improvement; 2: partial improvement; 3: complete improvement). If they incorrectly assigned the order of photographs, their score was given a negative value. The interrater reliability was assessed by using a two-way, consistency, average-measures intraclass correlation as implemented in the R statistical software (R Foundation, Vienna, Austria) package “irr”.
        • Gamer M
        • Lemon J
        • Fellows I
        • et al.
        Various coefficients of interrater reliability and agreement.
        The intraclass correlation coefficient obtained was 0.745 (95% confidence interval [CI] 0.56–0.86; F36,72 = 3.92; P < 0.001) and is considered good to excellent.
        • Hallgren KA
        computing inter-rater reliability for observational data: an overview and tutorial.
      • For the laser group only, patients evaluated the tolerability of every laser treatment on a 0 to 10 VAS scale.

       Statistical Analysis

      Analysis of covariance with baseline value as covariate was used to compare the two groups. The significance of change from baseline was determined by repeated measures t test. The McNemar test was used to compare the proportion of women reporting difficulties in their sex life at baseline and each follow-up. The Fisher exact test was used to compare the frequency distributions between the two groups. Stepwise Bonferroni correction was used to account for multiple comparisons throughout the analysis. Uncorrected P values are reported, with those that are significant after correction is applied printed in bold.

      RESULTS

      The flow of patients through the trial is presented in Figure 1. Demographic characteristics and baseline values of the outcome measures are shown in Table 1. The mean duration of the laser procedure was 15 to 20 minutes. Patients in the laser group reported minimal treatment discomfort, mostly described as a sensation of warmth. Sixteen of 20, 17 of 20, and 20 of 20 patients reported “no discomfort” at first, second, and third laser treatment, respectively. No adverse effects were observed or reported, and there was no new disease on follow-up local gynaecological examination.
      Table 1Characteristics of laser and topical corticosteroid control groups at baseline
      CharacteristicsLaser group

      (n = 20)
      Corticosteroid group

      (n = 18)
      Age, mean ± SD59 ± 1057 ± 14
      Parity, mean ± SD1.9 ± 0.91.9 ± 1.1
      Duration of symptoms, no. (%)
       <1 year2 (10)5 (28)
       1–5 years10 (50)6 (33)
       >5 years8 (40)7 (39)
      Symptoms, no. (%)20 (100)18 (100)
       Burning12 (60)17 (94)
       Itching16 (80)17 (94)
       Tingling5 (25)8 (44)
       Pain16 (80)13 (72)
      Sexually active, no. (%)12 (60)10 (56)
      Responded to questions regarding their experience during intercourse, no. (%)16 (80)14 (78)
       Lack of feeling (% of respondents)10 (63)5 (36)
       Anorgasmia (% of respondents)8 (50)7 (50)
       Dyspareunia (% of respondents)11 (69)8 (57)
      Corticosteroid treatment, n (%)16 (80)14 (78)
      Hormone replacement therapy, n (%)10 (50)13 (72)
      Personal history, no. (%)
       Autoimmune disease12 (60)9 (50)
       Malignant disease1 (5)1 (6)
       Neurological disease0 (0)2 (11)
       Diabetes3 (15)3 (17)
       Gynaecological surgery6 (30)4 (22)
       Infections5 (25)6 (33)
      Both laser and corticosteroid treatments reduced the intensity of symptoms (itching, burning, pain) compared with baseline (Figure 2). The reduction was statistically significantly better in the laser group for all symptoms at 1- and 3-month follow-up (Figure 2, Table 2). Too few patients were left in the control group at 6 months (only three) for a valid between-group comparison at this time point. In the laser group, the effect was still significant at 6 months (Figure 2, Table 2). Eight of 20 patients in the laser group were free of symptoms at 3-month follow-up (sum score: 0) compared with none of 16 patients in the control group. Four of 16 patients in the laser group were free of symptoms at 6-month follow-up.
      Figure 2
      Figure 2Symptom assessment (mean visual analogue scale [VAS] ± standard error) before and after treatment in the control (topical corticosteroid) and laser-treated groups. See for the number of patients in each group at each follow-up. Note that only three patients were left in the control group at 6-month follow-up, and results obtained at this time point should be interpreted with caution. (A) Sum score. (B) Itching. (C) Pain. (D) Burning.
      łStatistically significant difference from baseline; *Statistically significant difference between the laser and control groups.
      Table 2Effect size
      Decrease in visual analogue scale (VAS) scores from baseline and 95% confidence interval in laser and control groups at 1 to 6 months follow-up. P value from paired t test. Effect size of laser versus control group (decrease in mean VAS in laser group compared with control and 95% confidence interval) and P value from analysis of covariance with baseline value as covariate. Sum symptom score at 3 months was the main outcome measure. Note that individual symptoms were scored on a 0–10 VAS, and the sum score has a range of 0–30 VAS. P values still significant after stepwise Bonferroni correction are bold.
      SymptomFU (months)Laser vs. baselineControl vs. baselineLaser vs. control
      dfChange (95% CI)P valuedfChange (95% CI)P valuedfEffect size (95% CI)P value
      Burning1194.9 (2.9–6.9)<0.001143.7 (1.8–5.7)0.0011,322.8 (1.1–4.6)0.003
      3195.0 (3.0–6.9)<0.001153.6 (1.5–5.6)0.0021,333.3 (1.5–5.1)0.001
      6154.4 (2.4–6.5)<0.00121.7 (0.2–3.1)0.0381,163.9 (1.2–6.6)0.008
      Itching1196.1 (4.2–8.1)<0.001143.8 (1.7–5.9)0.0021,323.1 (0.8–5.3)0.009
      3196.4 (4.6–8.3)<0.001153.4 (1.7–5.0)0.0011,334.1 (2.5–5.7)<0.001
      6154.9 (2.4–7.4)0.00123.0 (−1.3–7.3)0.0951,163.5 (−0.3–7.3)0.066
      Pain1196.1 (4.3–7.8)<0.001141.8 (−0.1–3.7)0.0561,322.9 (1.1–4.8)0.003
      3196.1 (4.3–7.9)<0.001152.2 (0.1–4.2)0.0371,333.3 (1.4–5.1)0.001
      6155.4 (3.3–7.5)<0.00122.0 (−3.0–7.0)0.2251,160.6 (−4.0–5.1)0.793
      Sum11917.1 (14.3–19.8)<0.001149.3 (4.0–14.7)0.0021,328.4 (3.8–13.1)0.001
      31917.5 (14.4–20.5)<0.001159.1 (5.0–13.2)<0.0011,3310.2 (6.5–14.0)<0.001
      61514.7 (10.5–18.9)<0.00125.7 (0.5–10.8)0.0421,167.6 (−1.0–16.1)0.080
      df: degrees of freedom; FU: follow-up.
      a Decrease in visual analogue scale (VAS) scores from baseline and 95% confidence interval in laser and control groups at 1 to 6 months follow-up. P value from paired t test. Effect size of laser versus control group (decrease in mean VAS in laser group compared with control and 95% confidence interval) and P value from analysis of covariance with baseline value as covariate. Sum symptom score at 3 months was the main outcome measure. Note that individual symptoms were scored on a 0–10 VAS, and the sum score has a range of 0–30 VAS. P values still significant after stepwise Bonferroni correction are bold.
      The effect of LS on the quality of the patient's sex life was reduced significantly only in the laser group (Figure 3). The problems recurred at 6-month follow-up.
      Figure 3
      Figure 3Proportion of patients reporting a negative effect of lichen sclerosis on their sex life before and after treatment in the control (topical corticosteroid) and laser-treated groups. (A) Proportion reporting any negative effect. (B) Proportion reporting dyspareunia. (C) Proportion reporting decreased sensation. (D) Proportion reporting anorgasmia. Twelve of 20, 11 of 20, 11 of 20, and seven of 16 patients in the laser group were sexually active at baseline and at 1-, 3-, and 6-month follow-up, respectively. Ten of 18, nine of 15, 11 of 16, and one of three patients in the control group were sexually active at baseline and at 1-, 3-, and 6-month follow-up, respectively.
      łStatistically significant difference from baseline; *statistically significant difference between the laser and control groups.
      Patient satisfaction was significantly higher in the laser group than in the control group 3 months after treatment (chi-square = 36.4; P < 0.001). All 20 patients in the laser group were “very satisfied,” whereas only 2 of 16 control patients were “very satisfied,” 5 of 16 were “satisfied,” 5 of 16 were “unsatisfied,” and 4 of 16 were “very unsatisfied.” At 6 months, 11 of 16 patients in the laser group were still “very satisfied” with the effect of treatment, 4 of 16 were “satisfied,” and 1 of 16 was “unsatisfied.”
      At least two of the three blinded evaluators determined the order of photographs correctly in 15 of 20 cases in the laser group and in only four of 11 cases in the control group. The difference was statistically significant (chi-square = 4.47; P = 0.035). The mean improvement score was 0.58 ± 1.25 in the laser group and −0.27 ± 1.27 in the control group. The difference between treatments was not significant (F1,29=3.28; P = 0.80; effect size 0.856 ± 0.472; 95% CI −0.110 to 1.822).
      Biopsy samples taken before and after treatment were analyzed histologically (Figure 4). All patients had LS at baseline. At 3-month follow-up, nine of 17 and six of 16 biopsy samples in the laser and control group, respectively, were negative for lichen. The difference was not significant. The thickness of sclerosis was reduced significantly after laser treatment (−0.67 mm; 95% CI −0.99 to −0.34 mm; P = 0.009) but not after corticosteroid treatment (−0.10 mm; 95% CI −0.48 to 0.20 mm; P = 0.577). The improvement was statistically significantly better in the laser group (by 0.57 mm; 95% CI 0.01–1.13 mm; P = 0.46). No statistically significant differences were observed for the changes of thickness of the epidermis and the degree of inflammation either within or between groups.
      Figure 4
      Figure 4(A) Laser group at baseline; a broad band of dermal sclerosis is apparent, accompanied by moderately intense inflammatory cell infiltrate and acanthosis of the epidermis. (B) Three months after laser treatment; significantly lower degree of dermal sclerosis is seen, associated with mild inflammatory cell infiltrate and normal epidermis. (C) Corticosteroid group at baseline; broad band of dermal sclerosis is accompanied by moderately intense inflammatory cell infiltrate and slight acanthosis of the epidermis. (D) Three months after corticosteroid treatment; although the inflammatory cell infiltrate has diminished significantly after treatment, broad band of dermal sclerosis is still apparent. Epidermis displays mild acanthosis.

      DISCUSSION

      At 1- and 3-month follow-up, patients in the laser group had significantly greater improvement of LS symptoms (burning, itching, pain, and dyspareunia) than patients in the topical corticosteroid group. At 6-month follow-up, the effect was only significant for burning, which was more greatly reduced in the laser group. Although other scores were also better in the laser group, the difference was not significant because there was high loss to follow-up in the control group.
      We found it very difficult to motivate patients in the control group to adhere to the study protocol. This was in part because of the recurrence of symptoms and in part because of the negative attitude of the patients to the control treatment. Most of the recruited patients had used topical corticosteroids before and came to us looking for a better or more permanent solution. With the chosen study design, it was impossible to blind the patients. In the future, designs in which blinding is possible would be recommended (e.g., including sham laser treatment in the control group). In this way the placebo effect, which can be significant for patient-reported subjective symptoms,
      • Hróbjartsson A
      • Gøtzsche PC
      Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment.
      would be better controlled, and loss to follow-up resulting from problems with motivation could possibly be reduced.
      Objective outcome measures (blinded histological evaluation and photograph assessment), which are less influenced by the placebo effect,
      • Hróbjartsson A
      • Gøtzsche PC
      Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment.
      were also included in this study. During blinded assessment of photographs, evaluators take into account such vulvar clinical signs as erythema, pallor, atrophy (revealed by wrinkled skin and textural change), purpura, erosions, hyperkeratosis, and fissuring.
      • Cooper SM
      • Powell JJ
      • Wojnarowska F
      Does treatment of vulvar lichen sclerosus influence its prognosis?.
      In our case, assessment was complicated by the quality of the available photographs. Improvement in signs was nevertheless more obvious in the laser-treated group. Clinical signs improved less readily than symptoms. For example, in a case series of over 200 women with LS treated mostly with topical corticosteroids, complete resolution of symptoms was observed in 65% of patients, whereas complete resolution of clinical signs, including return to normal colour and texture, occurred in only 23% of patients.
      • Cooper SM
      • Powell JJ
      • Wojnarowska F
      Does treatment of vulvar lichen sclerosus influence its prognosis?.
      In this study, sclerosis was more greatly reduced with laser than with corticosteroid treatment, whereas other histological variables did not differ between the two treatments. A negative finding for LS on post-treatment biopsy did not correlate with a lack of patient-reported symptoms. In a recent attempt to develop a consensus standard severity scale for adult vulvar LS,
      • Sheinis M
      • Selk A
      Development of the adult vulvar lichen sclerosus severity scale - a Delphi consensus exercise for item generation.
      66 members of the International Society for Study of Vulvovaginal Disease voted for symptoms and signs to be included in the scale. Histological and immunohistochemical markers were not proposed for inclusion by any of the experts throughout the consensus exercise. The authors concluded that it may be objective to look at biopsy changes in response to treatment, but it is unclear whether this outcome is important to patients and it likely should be used as an adjunct to other measures.
      • Sheinis M
      • Selk A
      Development of the adult vulvar lichen sclerosus severity scale - a Delphi consensus exercise for item generation.
      The control corticosteroid in this study was less effective in reducing symptoms compared with results reported in the literature.
      • Cooper SM
      • Powell JJ
      • Wojnarowska F
      Does treatment of vulvar lichen sclerosus influence its prognosis?.
      A shorter course of topical corticosteroid therapy than is common practice was used in this study. This was done out of concern that prolonging the trial duration in the control arm would increase loss to follow-up. Consequently, the treatment period was shortened to match that in the laser arm (1 month). Furthermore, a high proportion of patients (78%) had already received topical corticosteroid treatment before this study, and the fact that they sought further treatment would indicate that they were among poor responders, a factor that could also account for our results.
      A 3-month application of topical corticosteroid reportedly induces remission of symptoms in 80% to 90% of patients.
      • Cooper SM
      • Powell JJ
      • Wojnarowska F
      Does treatment of vulvar lichen sclerosus influence its prognosis?.
      In a large retrospective case series, response of symptoms to topical treatment at the end of treatment period was available for 219 women; response was graded as symptom-free in 142 women (65%), partial (improvement and/or partial resolution of individual symptoms) in 67 women (31%), and poor (no change or worsening) in 10 women (5%).
      • Cooper SM
      • Powell JJ
      • Wojnarowska F
      Does treatment of vulvar lichen sclerosus influence its prognosis?.
      In comparison, 50% of laser-treated patients in this study were symptom-free after two treatment sessions, and the remaining patients had at least a 67% reduction in the total symptom score. No woman had a poor response to laser treatment. Non-ablative laser treatment can thus be an important additional treatment option for patients with poor response to topical treatment. Furthermore, significant relief from symptoms was still observed 3 and 6 months after laser treatment. Incorporating laser treatment could thus reduce the need for long-term maintenance corticosteroid therapy, thereby lowering the possibility of side effects of long-term use.
      Ablative lasers (carbon dioxide laser) have previously been used for recalcitrant vulvar LS,
      • Lee A
      • Lim A
      • Fischer G
      Fractional carbon dioxide laser in recalcitrant vulval lichen sclerosus.
      • Origoni M
      Fractional carbon dioxide laser in recalcitrant vulvar lichen sclerosus [letter].
      • Stuart GC
      • Nation JG
      • Malliah VS
      • et al.
      Laser therapy of vulvar lichen sclerosus et atrophicus.
      but as far as we know, this is the first study examining the use of non-ablative lasers. Because of the minimally invasive non-ablative approach, Nd:YAG laser therapy for vulvar LS demonstrated minimal treatment discomfort with no serious adverse effects. The laser-treated group showed significantly better results than the control group 3 months after treatment. Improvement of symptoms in the laser group was still significant at 6 months. Parameters previously recommended for wound healing and scar prevention
      • Lukac M
      • Vizintin Z
      • Pirnat S
      • et al.
      New skin treatment possibilities with PIANO mode on an Nd : YAG Laser.
      were used in the study, with protocol details (number of treatments, time interval) based on our previous clinical experience. Clinical studies comparing different protocols would help establish clear optimal treatment guidelines.

      CONCLUSION

      If further studies with longer follow-up and patient blinding confirm the promising results of this pilot study, non-ablative laser treatment may become a valuable alternative for patients not responding to topical corticosteroid therapy or patients wishing to avoid long-term corticosteroid maintenance use.

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