British Association of Dermatologists guidelines for the management of lichen sclerosus 2018

Transcription

1 British Association of Dermatologists guidelines for the management of lichen sclerosus 2018 WEB APPENDIX SUPPLEMENTARY INFORMATION Appendix A: Review Protocol Appendix B: Clinical Evidence summary Appendix C: Linking Evidence To Recommendations (LETR) Appendix D: Forest plots Appendix E: GRADE evidence tables Appendix F: Summary of included studies Appendix G: Narrative findings for non-comparative studies Appendix H: Summary of topical steroids case series/reports Appendix I: PRISMA diagram study selection Appendix J: Papers excluded from quantitative analysis Appendix K: Methodology Appendix L: Search strategy References 1

2 Appendix A: Review Protocol Component Review question Objectives Population Strata Subgroups Intervention Comparison (if available) Outcomes Description In people with lichen sclerosus what are the clinical outcomes and cost effectiveness of therapies The aim of this review is to assess the clinical outcomes and cost effectiveness of therapies for the management of patients with lichen sclerosus All people with lichen sclerosus The following groups/interventions will be considered separately if data is available: Females genital disease Males genital disease Children (up to 12 years) & young people (13-17 years) with genital disease Males, females, children and young people with extragenital disease The following factors will be considered for subgroup analysis if heterogeneity is present: Treatment regimen Topical corticosteroids Topical calcineurin inhibitors Testosterone and other hormonal treatments Surgery Cryotherapy Photodynamic therapy (PDT) Phototherapy Laser Systemic therapies Topical corticosteroids Topical calcineurin inhibitors Testosterone and other hormonal treatments Surgery Cryotherapy Photodynamic therapy Phototherapy Laser Systemic therapies Placebo Females Critical 9 Quality of Life (improvement of symptoms) 9 Restoration of sexual function* 9 Abolition of risk of vulval cancer* 8 Serious adverse events Important 6 Physician global assessment Males Critical 9 Quality of Life (improvement of symptoms) 9 Restoration of sexual function* 9 Abolition of risk of penile cancer* 8 Serious adverse events 7 Restoration of urinary function Important 2

3 Study design Population size and directness Setting Search Strategy Review strategy 5 Patient global assessment 4 Minor adverse events *Adults and young people only RCTs or systematic reviews Cohort studies Case series and case reports 6 Physician global assessment 5 Patient global assessment 4 Minor adverse events Sample size no lower limit Studies with indirect populations will not be considered Primary care Secondary care Tertiary care Community settings in which NHS care is received See appendix Appraisal of methodological quality The methodological quality of each study will be assessed using NICE checklists and the quality of the evidence will be assessed by GRADE for each outcome. 3

4 Appendix B: Clinical Evidence Summary B.1 FEMALES (ADULT) Outcomes QoL (improvement of symptoms) CP vs mometasone furoate (12 weeks) QoL (GOS 75) CP vs mometasone furoate (12 weeks) QoL (GSS 75) CP vs mometasone furoate (12 weeks) No of Participants (studies) F/up 54 (Virgili 2014) 54 (Virgili 2014) 54 (Virgili 2014) QoL (improvement of symptoms) - 40 complete response: CP vs testosterone (Bornstein (3 months F/up) 1998) QoL (improvement of symptoms) complete response: CP vs testosterone (Ayhan 2007) (6 months F/up) Quality of the evidence (GRADE) HIGH a LOW b due to imprecision LOW b due to imprecision VERY LOW b,c due to risk of bias, imprecision VERY LOW b,c due to risk of bias, imprecision Relative effect (95% CI) RR 1 (0.83 to 1.21) RR 0.77 (0.41 to 1.44) RR 0.89 (0.59 to 1.34) RR 2.17 (1.03 to 4.55) RR 1.18 (1.03 to 1.36) Anticipated absolute effects Risk with Control Moderate 889 per 1000 Moderate 482 per 1000 Moderate 667 per 1000 Moderate 300 per 1000 Moderate 775 per 1000 QoL (improvement of symptoms) - 40 RR 2.25 Moderate Risk difference with Females (adult) (95% CI) 0 fewer per 1000 (from 151 fewer to 187 more) 111 fewer per 1000 (from 284 fewer to 212 more) 73 fewer per 1000 (from 273 fewer to 227 more) 351 more per 1000 (from 9 more to 1000 more) 139 more per 1000 (from 23 more to 279 more) 4

5 complete & incomplete response: CP vs testosterone (1 year F/up) QoL (improvement of symptoms) responders: mometasone furoate (tapering) vs mometasone furoate (continuous) (3 months) QoL (GOS 75) mometasone furoate (tapering) vs mometasone furoate (continuous) (3 months) QoL (GSS 75) mometasone furoate (tapering) vs mometasone furoate (continuous) (3 months) QoL (improvement of symptoms) itching: UVA-1 vs clobetasol (mean change from baseline at 3 months) QoL (improvement of symptoms) burning/pain: UVA-1 vs clobetasol (mean change from baseline at 3 months) Physician global assessment (total clinicians score): UVA-1 vs clobetasol (Bornstein 1998) 64 (Borghi 2015) 64 (Borghi 2015) 64 (Borghi 2015) 30 (Terras 2014) 30 (Terras 2014) 30 (Terras 2014) VERY LOW c due to risk of bias MODERATE b due to imprecision MODERATE b due to imprecision MODERATE b due to imprecision VERY LOW b,c due to risk of bias, imprecision VERY LOW b,c due to risk of bias, imprecision VERY LOW b,c (1.29 to 3.92) RR 1.08 (0.85 to 1.37) RR 1.67 (0.86 to 3.24) RR 1.1 (0.77 to 1.57) 400 per 1000 Moderate 781 per 1000 Moderate 281 per 1000 Moderate 625 per more per 1000 (from 116 more to 1000 more) 62 more per 1000 (from 117 fewer to 289 more) 188 more per 1000 (from 39 fewer to 629 more) 63 more per 1000 (from 144 fewer to 356 more) The mean QoL (improvement of symptoms) itching: UVA-1 vs clobetasol (mean change from baseline at 3 months) in the intervention groups was 2.5 lower (5.69 lower to 0.69 higher) The mean QoL (improvement of symptoms) burning/pain: UVA-1 vs clobetasol (mean change from baseline at 3 months) in the intervention groups was 1 lower (4.1 lower to 2.1 higher) The mean physician global assessment (total clinicians score): UVA-1 vs clobetasol (mean 5

6 (mean change from baseline at 3 months) Patient global assessment (Skindex-29 score): UVA-1 vs clobetasol (mean change from baseline at 3 months) QoL (improvement of symptoms) complete and partial response: ALA- PDT vs CP (8 weeks) QoL (improvement of symptoms) human fibroblast lysate cream vs placebo (12 weeks) QoL (improvement of symptoms) responders: acitretin vs placebo (16 weeks) Patient global assessment (partially or completely satisfied): acitretin vs placebo (16 weeks) Minor adverse events: acitretin vs placebo (16 weeks) 30 (Terras 2014) 43 (Shi 2016) 30 (Goldstein 2015) 78 (Bousema 1994) 78 (Bousema 1994) 78 (Bousema 1994) due to risk of bias, imprecision VERY LOW b,c due to risk of bias, imprecision LOW b,c due to risk of bias, imprecision VERY LOW b,c due to risk of bias, imprecision MODERATE b due to imprecision MODERATE b due to imprecision HIGH RR 1.45 (0.98 to 2.14) RR 1.8 (0.79 to 4.11) RR 2.33 (1 to 5.44) RR 1.52 (1.15 to 2.02) RR 1.93 (1.42 to 2.61) change from baseline at 3 months) in the intervention groups was 0.5 lower (4.03 lower to 3.03 higher) The mean patient global assessment (skindex- 29 score): UVA-1 vs clobetasol (mean change from baseline at 3 months) in the intervention groups was 24.7 lower (50.17 lower to 0.77 higher) Moderate 591 per 1000 Moderate 333 per 1000 Moderate 154 per 1000 Moderate 590 per 1000 Moderate 513 per more per 1000 (from 12 fewer to 674 more) 266 more per 1000 (from 70 fewer to 1000 more) 205 more per 1000 (from 0 more to 684 more) 307 more per 1000 (from 88 more to 602 more) 477 more per 1000 (from 215 more to 826 more) 6

7 QoL (improvement of symptoms) Dermasilk vs cotton pants (6 months) QoL (improvement of clinical signs) Dermasilk vs cotton pants (6 months) QoL (improvement of symptoms - soreness) Dermasilk vs cotton pants (6 months) QoL (improvement of symptoms - itching) Dermasilk vs cotton pants (6 months) Patients still experiencing dyspareunia: Dermasilk vs cotton pants (6 months) 42 (D Antuono, 2011) 42 (D Antuono, 2011) 42 (D Antuono, 2011) 27 (D Antuono, 2011) 36 (D Antuono, 2011) LOW b,c due to risk of bias, imprecision LOW b,c due to risk of bias, imprecision MODERATE c due to risk of bias LOW b,c due to risk of bias, imprecision MODERATE c due to risk of bias RR 1.23 (0.98 to 1.53) RR 1.72 (1.19 to 2.49) RR 4.78 (2.09 to 10.92) RR 1.38 (0.97 to 1.95) RR 0.47 (0.29 to 0.75) Moderate 810 per 1000 Moderate 571 per 1000 Moderate 191 per 1000 Moderate 714 per 1000 Moderate 1000 per more per 1000 (from 16 fewer to 429 more) 411 more per 1000 (from 108 more to 851 more) 722 more per 1000 (from 208 more to 1000 more) 271 more per 1000 (from 21 fewer to 678 more) 530 fewer per 1000 (from 250 fewer to 710 fewer) a No clinically important difference - between MIDs b Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs c Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias 7

8 B.2 FEMALES (MIXED: ADULTS & CHILDREN) Outcomes QoL (improvement of symptoms): CP vs tacrolimus (3 months) QoL (absence of symptoms): CP vs tacrolimus (2 months) No of Participants (studies) F/up 58 (Funaro, 2014) 58 (Funaro, 2014) Quality of the evidence (GRADE) MODERATE a,b due to risk of bias MODERATE a due to risk of bias Relative effect (95% CI) RR 0.96 (0.85 to 1.09) RR 3.75 (1.41 to 9.95) Anticipated absolute effects Risk with Control Moderate 966 per 1000 Moderate 138 per 1000 Risk difference with Females (mixed: adults and children) (95% CI) 39 fewer per 1000 (from 145 fewer to 87 more) 380 more per 1000 (from 57 more to 1000 more) a Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias b No clinically important difference - between MIDs B.3 MIXED (FEMALES & MALES (ADULT)) Outcomes QoL (improvement of symptoms) paraminobenzote vs placebo (2 months) No of Participants (studies) F/up 25 (Buxton 1990) Quality of the evidence (GRADE) VERY LOW a,b due to risk of bias, imprecision Relative effect (95% CI) RR 0.93 (0.44 to 1.98) Anticipated absolute effects Risk with Control Moderate 539 per 1000 Risk difference with Mixed (females and males) (95% CI) 38 fewer per 1000 (from 302 fewer to 528 more) a Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the 8

9 evidence was at very high risk of bias b Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs B.4 MALES (CHILDREN) Outcomes Physician global assessment: preputioplasty with intralesional triamcinolone vs circumcision (F/up median 14 months vs 6 months) No of Participants (studies) F/up 136 (Wilkinson 2012) Quality of the evidence (GRADE) VERY LOW a,b due to risk of bias, imprecision Relative effect (95% CI) RR 1.12 (0.89 to 1.42) Anticipated absolute effects Risk with Control Moderate 719 per 1000 Risk difference with Males (children) (95% CI) 86 more per 1000 (from 79 fewer to 302 more) a Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias b Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs B.5 MALES (ADULT) Outcomes QoL (improvement of symptoms) DLQI: acitretin vs placebo (mean change from baseline at 20 weeks) No of Participants (studies) F/up 51 (Ionnides, 2010) Quality of the evidence (GRADE) HIGH Relative effect (95% CI) Anticipated absolute effects Risk with Risk difference with Male (adult) (95% CI) Control The mean QoL (improvement of symptoms) DLQI: acitretin vs placebo (mean change from baseline at 20 weeks) in the intervention groups was 4.2 lower (6.68 to 1.72 lower) 9

10 QoL (improvement of symptoms) complete response: acitretin vs placebo (20 weeks) Physician global assessment (total clinical score): acitretin vs placebo (mean change from baseline at 20 weeks) 51 (Ionnides, 2010) 51 (Ionnides, 2010) MODERATE a due to imprecision HIGH RR 6 (0.85 to 42.39) Moderate 59 per more per 1000 (from 9 fewer to 1000 more) The mean physician global assessment (total clinical score): acitretin vs placebo (mean change from baseline at 20 weeks) in the intervention groups was 4.9 lower (7 to 2.8 lower) a Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs 10

11 Appendix C: Linking Evidence To Recommendations (LETR) REVIEW TITLE/QUESTION: In people with lichen sclerosus what are the clinical and cost effectiveness of therapies? Relative values of different outcomes 9-7 Critical for decision making; 6-4 Important but not critical for decision making FEMALES Critical Quality of Life (improvement of symptoms) 9 Restoration of sexual function* 9 Abolition of risk of vulval cancer* 9 Serious adverse events 8 Important Physician global assessment 6 Patient global assessment 5 Minor adverse events 4 *Adults and young people only MALES Critical Quality of Life (improvement of symptoms) 9 Restoration of sexual function* 9 Abolition of risk of penile cancer* 9 Serious adverse events 8 Restoration of urinary function 7 Important Physician global assessment 6 Patient global assessment 5 Minor adverse events 4 Ranked outcomes according to the GRADE methodology as agreed between clinicians and two patient representatives. Balance between desirable and undesirable effects There were very few high-quality studies. In total, fourteen trials with 810 participants and one Cochrane review (7 trials (6 female, 1 male), 249 participants) met our inclusion criteria Eight RCTs, 1-8 one cohort study 9 and one retrospective case analysis 10 looked at adult females, while one RCT also included girls. 11 The remaining three studies (two RCTs and a retrospective case analysis) looked at adults (male & females), 12 adult males 13 and boys, 8 respectively. One of the female studies was a crossover RCT so we were unable to process the data. 15 All the studies were small, underpowered and it was not possible to combine any of them to conduct a meta-analysis or draw firmer conclusions. 11

12 FEMALE GENITAL LS Unless there are four clinical signs and symptoms, and the GP is competent in diagnosing and managing LS, all patients should be referred for confirmation of diagnosis. If referring, the patients should not be treated except with emollients and a mild topical steroid such as 1% hydrocortisone. Young women presenting in the reproductive years should have biopsy confirmation of the diagnosis. Topical corticosteroids Six RCTs have compared topical CP 0.05% against other treatments. CP 0.05% was found to be more effective when compared to 0.1% topical tacrolimus, 11 testosterone 2% in petrolatum, 9,10 and UVA-1 homebased phototherapy. 3 A RCT against mometasone furoate 0.1%, 1 showed equal efficacy. One small RCT showed that PDT was more effective (see PDT). 4 A cohort study showed that CP was more effective than subcutaneous triamcinolone and bupivacaine. 16 There were methodological issues with long-term, non-comparative studies of topical steroids in adults 17 and children. 18 However, they show that good control in the long-term reduces scarring and the risk of malignancy. Maintenance treatment needs to be individualised to the patient. All recent studies have used application of treatment once a day (rather than twice a day) and therefore once daily treatment can be recommended. Educating people on the amount used and site of application is vital to achieve optimal outcomes. Most studies had 3 months induction with very little long-term data. Some people with very active LS needed ongoing treatment, while in others the disease had completely resolved after 3 months treatment. After 3 months, 70% of adults will be in remission of disease. 19,20 A RCT comparing different regimens of application of mometasone furoate showed that a tapering regimen was as effective as continuous treatment. 2 An ointment base of mometasone furoate showed increased efficacy when compared to a cream in one study. 21 Combination treatment with a topical retinoid does not improve efficacy. 22 This data is in agreement with the Cochrane review 14 which concluded, CP, 12

13 mometasone furoate and the calcineurin inhibitor pimecrolimus were efficacious in the treatment of genital LS. A potent topical steroid is safe for long-term use when applied appropriately. 23 Emollients used after the application of the topical steroid are helpful. 24 Adjuvant use of Dermasilk underwear may be considered, 7 but are not always generally available on prescription. Topical calcineurin inhibitors There are no comparative studies or RCTs against placebo. A RCT of tacrolimus versus the ultra-potent topical steroid colbetasol propionate 0.05% showed that tacrolimus was less effective than a topical steroid. 11 The use of tacrolimus and pimecrolimus has been studied in women with vulval LS, after initial anecdotal reports and small case series suggested benefit Surgery There are no comparative studies or RCTs. There is no indication for removal of vulval tissue in the management of uncomplicated lichen sclerosus, and surgery should be used exclusively for malignancy and post-inflammatory sequelae. The GDG consensus was that patients with posterior tears and clitoral phimosis need to be referred to a specialised clinic experienced in dealing with these problems. Cryotherapy There are no comparative studies or RCTs. A small case series on cryotherapy shows it might be helpful. 29 Photodynamic therapy An RCT using PDT showed some benefit but follow-up was short and PDT is not widely available. 4 There are small case series showing benefit. Systemics One RCT on the use of acitretin showed some benefit, but all suffered minor side effects. 6 However, it was not clear what background or concomitant treatment was being used in the trials which would lead to the improvements in the placebo arm. Evidence for other systemics (ciclosporin, methotrexate, etc.) is only based on case series and reports. Systemic retinoids have been used to treat LS. 30,31 There is no evidence that these are particularly effective in uncomplicated LS. However, there is some evidence that they may 13

14 have a role in hyperkeratotic and hypertrophic disease that does not respond to an ultra-potent steroid. Others RCTs looking at human fibroblast lysate cream, 5 and oxatomide gel 15 against placebo showed minimal effect. A case series using calcipotriol ointment showed minor benefit. 32 One study of para-aminobenzoate showed no difference against placebo. Children & young people All children with LS should be seen in secondary care dermatology. The treatment of choice is topical CP 0.05% with the same regimen as used in adults. 33 MALE GENITAL LS Topical corticosteroids There are no RCTs, but case series show benefit with CP 0.05% In a retrospective case series 17 patients with preputial disease were treated with CP. 37 Seven of the 17 patients responded to topical treatment alone and did not require circumcision. In this study, the early use of topical steroids in male disease is encouraged to prevent disease progression. A large retrospective series showed that 50% of males with LS responded to CP. 38 CP introduced via catheter, has also been used to treat urethral stricture with one study reporting a success rate of 89%. 36 A suggested regime for use of a topical steroid in urethral stricture disease is the self - introduction of a CP lubricated catheter twice daily for 2 to 3 months and if controlled gradually reduce the frequency of application. There is a lot of variation in regimens used for non-surgical treatments in males. Emollients There is very little data so the GDG agreed to extrapolate from the female studies, where emollients are shown to have benefit. 14

15 Topical calcineurin inhibitors There are no comparative studies or RCTs. The application of tacrolimus twice daily shows benefit in case series. 39,40 Testosterone and other hormonal treatments There are no comparative studies or RCTs. A case series using calcipotriol showed no improvement in males. 32 Surgery Circumcision may represent a cure, 41 although recurrence of LS has been reported post-surgery. 42 Other surgical treatment options showing good outcomes include glans resurfacing with split-skin grafting 43 and division of coronal adhesions. 44 Meatal stricture can be managed by meatotomy or excision and grafting of the distal stricture. 45 Combining meatal surgery with use of topical steroid prevented disease relapse. 37 Early meatal surgery and avoidance of high pressure voiding may prevent progression to urethral disease. 37 Urethral stricture can be managed successfully with urethroplasty, combined with oral mucosa graft, however recurrence of LS within oral grafts has been reported. 49 Good results can also be obtained with perineal urethrostomy, thereby avoiding complex urethral surgery. 50 Obese males should be advised to lose weight; 51 they can also be offered bariatric surgery combined with surgical reconstruction of the buried penis. 52 Outcome for surgical interventions must be viewed with caution where follow-up periods are short, as disease may recur after many years. For procedures beyond circumcision, referral to a specialist centre is recommended. Laser There are no comparative studies or RCTs. CO 2 laser has been used to treat male genital disease successfully Meatal stenosis responded to CO 2 laser in a small case series 53 but urethral lesions did not respond. 55 Systemic therapies There is only one RCT in adult males, which compared the efficacy of acitretin 35 mg with placebo. 13 The acitretin group showed significant improvement at 20 weeks compared to the control group. The acitretin 15

16 group were assessed at 36 weeks and showed significant improvement, but at this point they had deteriorated when compared to the 20-week scores. A small case series using etretinate showed no overall benefit. 56 Stanozolol 2 mg twice daily was given for 3 months in a small case series in which there was no follow up. 57 Clinical assessment showed improvement at 3 months. This treatment cannot be recommended. Penicillin given both orally and intramuscularly and cephalosporin given intramuscularly for between 3 and 8 months have been reported to clear or improve male genital disease in a small case series. 58 The effect of intralesional adalimumab has been shown in two case reports which showed improvement in both cutaneous 59,60 and urethral disease. 60 Adalimumab may be a novel therapeutic option for severe male disease and requires further study. Other treatments Polydeoxyribonucleotide 5-10 mg given intradermally weekly for 20 weeks improved clinical disease and symptoms but did not improve sexual function. 61 This treatment is not readily available and cannot be recommended. Autologous platelet rich plasma injected either subcutaneously or intradermally has been successfully used to treat penile LS, particularly phimosis. 62 There are theoretical concerns about induction of malignancy with platelet rich plasma. This treatment is a complex procedure and its use is not recommended. Children and young people All the studies in boys relate either to phimosis caused by LS or phimosis from all causes with subsets of boys with LS extracted. Steroids In an RCT included in the Cochrane review, topical steroids 14 have been used to treat phimosis caused by LS in boys. 63 Mometasone furoate was compared to placebo applied topically for 5 weeks. There was significant improvement in those boys with early or intermediate LS compared to the control group. Early 16

17 treatment of phimosis caused by LS may prevent further worsening of the disease process. Case series have shown variable responses of LS-induced phimosis. Betamethasone valerate was used in one study for 6 weeks and this was combined with skin stretching; 64 67% of boys with LS developed a retractable foreskin. In a study of phimosis from all causes treated with betamethasone valerate for 4 to 8 weeks, none of the 6 patients with LS responded to this treatment. 65 In a further study, patients with phimosis from all causes were treated with triamcinolone cream for 4 weeks; 66 67% of patients with LSinduced phimosis responded. Treatment of phimosis due to LS with moderately potent topical steroids for 3 months led to improvement or clearance in only 30% of cases. 67 Topical calcineurin inhibitors There are no comparative studies or RCTs. Boys with LS requiring surgical treatment, the majority of which were circumcision, were reviewed at follow-up and tacrolimus 0.1% was applied for 3 weeks. 68 Twenty boys were treated in this way and LS only recurred in 2; both were retreated with a second course of tacrolimus without further relapse. Follow up was for 13 months. In this paper, topical tacrolimus was used as an adjuvant to surgery to prevent future relapse of LS. Following surgery, 9 of the boys were noted to have involvement of the glans by LS. Eight of nine patients cleared following 3 weeks treatment with tacrolimus; one patient cleared after a second course. In these 9 cases treatment was considered both therapeutic and adjuvant. Surgery One RCT treated boys with phimosis due to LS. They were offered preputioplasty combined with intralesional triamcinolone or circumcision. 8 Assessment was of a fully retractable foreskin. Quoted followup showed a median of 14 months for the preputioplasty group and 6 months for the circumcision group. In the preputioplasty group, 81% achieved a fully retractable foreskin whilst 13% has recurrent disease. In the circumcision group 72% were clear of disease. The incidence of subsequent meatal stenosis was lower in the preputioplasty group. The surgical option preputioplasty and intralesional triamcinolone can be considered as an alternative to circumcision. 17

18 EXTRAGENITAL There are no comparative studies or RCTs. There is no proven treatment for extragenital LS, however, options include those listed below. Topical steroids Case series and reports indicate some benefit of topical steroids. Flurandrenolone tape improved 4 of 7 patients. 69 A child treated with LS was treated with CP for 2 weeks followed by retinaldehyde for 4 weeks continued for 3 months and lesions to cleared. 70 Topical calcineurin inhibitors Tacrolimus 0.1% showed no benefit in a case series. 71 A single case report showed no response of extragenital LS to pimecrolimus in an adult 72 but a case report of oral extragenital LS in child treated with pimecrolimus describes complete disease clearance. 73 Surgery Surgical options, pinch grafting 74 and shave (tangential) excision 75 have been used. Photodynamic therapy/phototherapy Various forms of phototherapy have been used including narrow band UVB 76 and PUVA alone, 77,78 or with topical tacrolimus 79 and UVA1. 80,81 The latter appears to be the most successful in reducing clinical disease as well as symptoms. These treatments have only been reported as individual cases or small case series. One study compared the use of methyl-ala pulsed dye laser (PDL) mediated PDT versus pulsed dye laser alone on two areas of extragenital LS in one patient. The site treated with the PDT-PDL showed a slightly better response than the PDL alone. 82 In a case report, long pulsed dye laser( LP PDL) alone was compared to LP PDL combined with topical 5-aminolevulinic acid (ALA-LP PDL). 83 There was significant improvement in the ALA-LP PDL treated lesion compared to treatment with LP PDL alone. Laser CO 2 laser has been reported to induce clearance or improvement in appearance of lesions. 55,84 18

19 Systemic therapies A single case report describes complete clearance of extragenital LS following treatment with methotrexate 10 mg once weekly for 8 months. 85 In a case series, patients are treated with methylprednisolone 1 g for 3 days, then methotrexate 15 mg once weekly for 6 months. 86 All patients showed clinical improvement. Hydroxychloroquine has given rise to improvement in one report 87 and no response in another. 88 Adrenocorticotropic hormone (ACTH) 1 mg on alternate days for 16 days improved extragenital LS. 89 Ciclosporin improved bullous LS but did not clear the lesions. 90 Acitretin has been shown to improve extragenital LS in two case reports. 91,92 Quality of evidence [The overall quality of evidence is based on the lowest quality of all critical outcomes] The quality of the evidence for each outcome was assessed using GRADE criteria (see tables). The following summarises the overall quality of the evidence for various outcomes considered, listed by intervention and its comparator. FEMALES Comparative studies High Moderate Low Very low None Mometasone furoate (tapering) vs. mometasone furoate (continuous) Acitretin vs. placebo CP vs. tacrolimus* ALA-PDT vs. CP Human fibroblast lysate cream vs. placebo CP vs. mometasone CP vs. testosterone furoate Dermasilk vs. cotton pants UVA-1 vs. CP *Mixed adults, children and young people ** Mixed adult males and females Para-aminobenzoate vs. placebo** 19

20 Non-comparative studies (Very low) CO 2 laser Dexamethasone/bupivacaine Ciclosporin Cryotherapy Fat grafting Etretinate Surgical dissection Avocado & soya bean extract cream MALES Comparative studies High Moderate Low Very low None Mometasone furoate vs. placebo* Acitretin vs. placebo *Children and young people ** Mixed adult males and females *** Children Based on important outcomes only Non-comparative studies (Very low) None Para-aminobenzoate vs. placebo** Preputioplasty with intralesional triamcinolone vs. circumcision*** Betamethasone 0.05%* Triamcinolone* Perineal urethrostromy CP 0.05% Glans resurfacing CO 2 laser Tacrolimus 0.1%** Stricture repair Polydeoxyribonucleotide 5-10mg intradermally *Children and young people **Children, young people and adults 20

21 EXTRAGENITAL Non-comparative studies (Very low) CO 2 laser Tacrolimus 0.1% ACTH UVA Flurandrenolone Hydroxychloroquine Methylprednisolone Pinch grafting Ciclosporin ALA-PDT Pimecrolimus 1% Methotrexate Calcipotriol Acitretin PUVA Patient values and preferences Patients should always be seen by a specialist in LS and females should ask their GP for a referral to a specific vulval service There should be a multi-disciplinary or joint-management approach across all relevant specialties (e.g. gynaecology, urology, dermatology, paediatrics and genito-urinary medicine) when managing patients with LS The healthcare professional must give clear instructions about topical treatment. People should be shown how much to use and exactly where to apply it. This can be done with the aid of a mirror or touch and can be backed up with diagrams. This is also important for parents of children with LS. This enables and empowers patients to deal with their disease. All patients with LS should be followed up appropriately according to their individual requirements. Cost There are no studies looking at cost-effectiveness of treatment but topical CP 0.05% ointment and simple emollients are inexpensive with clear efficacy and a good side effect profile. 21

22 Other considerations Relationship between this guideline and other guidance. The following guideline has been referred to, NICE guidelines. Obesity: identification, assessment and management [CG189]. 51 The evidence for recommendations is based on the studies as listed. GDG recommendations relating to referral pathways and follow-up is based on discussion and clinical experience, as evidence based detail is not available at the time of writing. The GDG is aware of the lack of high-quality evidence for these recommendations, therefore strong recommendations with an asterisk (*) are based on available evidence, as well as consensus and specialist experience. RECOMMENDATIONS All people (children, young people & adults: male and female) Recommendation R1 Recommendation R2 Recommendation R3 Recommendation R4 Recommendation R5 Recommendation R6 All people with LS should be managed by a healthcare professional experienced (secondary care specialist or GP with specific training) in treating the condition Commence treatment of LS following a firm clinical diagnosis or with histological confirmation, where necessary Undertake a full history for all people with LS, including dyspareunia and psychosexual issues. Document urinary symptoms. Perform a detailed examination documenting architectural change at baseline (using a diagram or photograph, according to patient preference) Advise all people with LS to avoid all irritant and fragranced products Provide all people with LS up-to-date patient information on the condition All people treated for LS should be followed up (see algorithm) to assess response to treatment and to advise on long-term control 22

23 Adult females Recommendation R7 Recommendation R8 Recommendation R9 Recommendation R10 Recommendation R11 Recommendation R12 Offer* all females with anogenital LS CP 0.05% ointment on a regimen for 3 months (once a day for a month, alternative days for a month, twice weekly for a month), combined with a soap substitute and a barrier preparation Discuss the amount of topical treatment to be used, the site of application and the safe use of an ultrapotent topical steroid with the patient. Offer* continued use of CP 0.05% for ongoing active LS disease (see algorithm) Consider an individualized treatment regimen of topical steroid to maintain disease control and prevent scarring in females with ongoing active LS disease despite good compliance. Treatment should be titrated to maintain symptoms and resolution of skin thickening and ecchymosis although pallor may not completely resolve. Consider referral to a specialist vulval clinic in all females (including children & young people) with LS not responding to a topical steroid, or if any surgical procedure is being considered Consider intralesional triamcinolone (10-20 mg) in females with LS with topical steroid-resistant, hyperkeratotic areas after intra-epithelial neoplasia or malignancy has been excluded by biopsy Adult males Recommendation R13 Recommendation R14 Recommendation R15 Recommendation R16 Offer* all males with genital LS CP 0.05% ointment once daily for 1-3 months with an emollient as a soap substitute and as a barrier preparation Discuss the amount of topical treatment to be used, the site of application and the safe use of an ultrapotent topical steroid with the patient Consider a repeat course of topical treatment for 1-3 months in those who relapse Consider intralesional triamcinolone in males with LS with topical steroid-resistant, hyperkeratotic areas following biopsy to ensure no intra-epithelial neoplasia or malignancy 23

24 Recommendation R17 Offer* all males with phimosis caused by LS who do not respond to an ultra-potent topical steroid after 1-3 months, referral to an experienced urologist for circumcision Recommendation R18 Recommendation R19 Recommendation R20 Recommendation R21 Recommendation R22 Offer males with urinary symptoms due to LS referral for a urology opinion and further investigation and management of lower urinary tract symptoms Offer treatment for meatal involvement by LS with CP 0.05% ointment applied once daily via cotton wool bud or meatal dilator for 1 to 3 months prior to referral to a urologist specialized in the management of LS. Offer all males a urethral stricture due to LS referral to a urologist specialized in the management of LS. A urologist may consider treatment for a urethral stricture with CP introduced into the urethra via a urinary catheter or meatal dilator, depending on stricture length, before proceeding to surgical treatment options. Offer all males with LS who have failed to respond to topical steroids and/or circumcision referral for a specialist urology opinion on other surgical treatment options, for example total or partial glans resurfacing and split-skin grafting Advise obese males with LS and a buried penis to lose weight. Further referral to a specialist urologist and bariatric services may be required. Children/young people - female Recommendation R23 Recommendation R24 Recommendation R25 Recommendation R26 Refer female children and young people with LS to specialized vulval services (vulval clinic, paediatric dermatologist or urologist experienced in managing LS) Consider referral to specialist vulval clinic in females (also adults) with LS not responding to topical steroid, or if surgical management is being considered Offer* all females with anogenital LS CP 0.05% ointment on a regimen for 3 months (once a day for a month, alternative days for a month, twice weekly for a month) with an emollient as a soap substitute and as a barrier preparation Discuss the amount of topical treatment to be used, the site of application and the safe use of an ultrapotent topical steroid with the patient. 24

25 Recommendation R27 Consider an individualized treatment regimen of topical steroid to maintain disease control and prevent scarring in females with ongoing active LS disease despite good compliance Children/young people - male Recommendation R28 Offer* a trial of an ultrapotent topical steroid applied once daily for 1 to 3 months combined with emollients and barrier preparations to all male children & young people with phimosis or severe disease caused by LS. Recommendation R29 Offer all male children with phimosis caused by LS who do not respond to topical steroids after 1 to 3 months, referral to a paediatric urologist for a circumcision. Disease of the glans unmasked by circumcision should be treated with a potent topical steroid once daily for 1 to 3 months. Recommendation R30 Send* all circumcision specimens in males with LS for histological examination Extragenital disease Recommendation R31 Consider potent topical steroids, acitretin, methotrexate and phototherapy for people with extragenital LS. Insufficient evidence (Θ) Currently, there is insufficient evidence to recommend the following interventions for people with LS: Topical calcineurin inhibitors Systemic retinoids Future Research Recommendations Future Research Recommendation FRR1 Future Research Recommendation FRR2 Future Research What is the role of topical calcineurin inhibitors in treating people with LS? What is the role of topical steroids in preventing malignancy in genital LS in females? What is the course of LS after puberty in females? 25

26 Recommendation FRR3 Future Research Recommendation FRR4 Future Research Recommendation FRR5 Future Research Recommendation FRR6 Future Research Recommendation FRR7 Future Research Recommendation FRR8 Future Research Recommendation FRR9 Future Research Recommendation FRR10 What is the optimal surgical management of females with fusion over the clitoris? Would acitretin in combination with a topical steroid as monotherapy be more effective than monotherapy in treating people with resistant LS? What is the safety and efficacy of adalimumab in males with urethral stenosis caused by LS? To set up a national registry for extensive extragenital LS to identify the treatments involved and outcomes achieved. What is the role of urine in the pathogenesis of genital LS and paediatric genital LS? Is there a role for systemic therapy in genital LS? What proportion of patients with LS remit completely? 26

27 Appendix D: Forest plots D.1 FEMALES (ADULT) TOPICAL vs. TOPICIAL Critical outcomes QoL (improvement of symptoms) (CP 0.05% ointment vs. mometasone furoate 0.1% ointment) Decrease in symptoms and signs of LS (12 weeks) Achieving an improvement from baseline of 75% in objective scores (GOS 75) (12 weeks) Achieving an improvement from baseline of 75% in subjective scores (GSS 75) (12 weeks) QoL (improvement of symptoms) (CP 0.05% ointment vs. testosterone 2% in petrolatum) Complete response (3 month follow-up) Symptomatic remission (lesions completely disappeared) (6 month follow-up) 27

28 All responses (Partial/Complete) at 1 year follow-up QoL (improvement of symptoms) (mometasone furoate 0.1% ointment (tapering) vs. mometasone furoate 0.1% ointment (continuous)) Responders (3 months) Achieving an improvement from baseline of 75% in objective scores (GOS 75) (3 months) Achieving an improvement from baseline of 75% in subjective scores (GSS 75) (3 months) PHOTOTHERAPY vs.topical Critical outcomes QoL (improvement of symptoms) (UVA-1 home based phototherapy vs. CP 0.05% ointment) VAS (itching) (mean change from baseline at 3 months) 28

29 VAS (burning and/or pain) (mean change from baseline at 3 months) Important outcomes Physician global assessment Total clinicians score (TCS) (mean change from baseline at 3 months) Patient global assessment Skindex-29 score at end of treatment (mean change from baseline at 3 months) QoL (improvement of symptoms) (ALA-PDT vs. CP 0.05% ointment) Complete and partial response (8 weeks) TOPICAL vs. PLACEBO Critical outcomes QoL (improvement of symptoms) (human fibroblast lysate cream (cutaneous lysate) vs. placebo) Improvement in histological features, symptoms and signs (IGA) (12 weeks) 29

30 SYSTEMIC vs. PLACEBO Critical outcomes QoL (improvement of symptoms) (acitretin vs. placebo) Responders (a patient who showed a decrease of at least two grades in one of the symptoms (pruritus or burning), without any worsening in any other symptom, a decrease of at least one grade in two of the signs (atrophy, hyperkeratosis, and secondary features) without any worsening in the other sign, and no increase in the extent of the lesions) (16 weeks) Important outcomes Patient global assessment (acitretin vs. placebo) Partially or completely satisfied (16 weeks) Minor adverse events (16 weeks) (acitretin vs. placebo) 30

31 DERMASILK vs. COTTON PANTS NB: Both arms also received 0.05% CP and vitamin E emollient once daily Critical outcomes QoL (improvement of symptoms) Overall improvement in symptoms (6 months) Overall improvement of clinical signs (6 months) Improvement in symptoms soreness (6 months) Improvement of symptoms itching (6 months) Restoration of sexual function Patients still experiencing dyspareunia (6 months) 31

32 D.2 FEMALES (CHILDREN, YOUNG PEOPLE & ADULTS, NOT SEPARATED) TOPICAL vs. TOPICIAL Critical outcomes QoL (improvement of symptoms) (CP 0.05% vs. tacrolimus 0.1%) Decrease in symptoms and signs of LS (3 months) No clinical signs or any reported symptoms at end of study (3 months) D.3 MIXED (FEMALES & MALES (ADULTS)) TOPICAL vs. PLACEBO Critical outcomes QoL (improvement of symptoms) (2 months) (paraminobenzoate vs. placebo) Improvement - qualitative only 32

33 D.4 MALES (CHILDREN & YOUNG PEOPLE) TOPICAL CORTICOSTEROIDS vs. PLACEBO Critical outcomes QoL (improvement of symptoms) (mometasone furoate 0.05% vs. placebo) Reduction in phimosis severity according to the Meuli scale (mean change from baseline at 5 weeks) Important outcomes Physician global assessment (preputioplasty plus triamcinolone 10 mg/ml vs. primary circumcision) Fully retractable foreskin with no clinical evidence of LS at Follow-up (median 14 months foreskin preputioplasty; 6 months primary circumcision)- retrospective cases D.5 MALES (ADULT) SYSTEMIC THERAPIES vs. PLACEBO Critical outcomes QoL (improvement of symptoms) (acitretin vs. placebo) Improvement in DLQI (mean change from baseline at 20 weeks) 33

34 Complete response (20 weeks) Important outcomes Physician global assessment (acitretin vs. placebo) Reduction in total clinical score (TCS) mean change from baseline 34

35 Appendix E: GRADE evidence tables E.1 FEMALES (ADULT) Quality assessment No of patients Effect Quality Importance No of studies Design Risk of bias Inconsistency Indirectness Imprecision Other considerations Females (adult) Control Relative (95% CI) Absolute QoL (improvement of symptoms) CP vs mometasone furoate (12 weeks) 1 randomised trials risk of bias inconsistency indirectness imprecision 1 none 24/27 (88.9%) 88.9% RR 1 (0.83 to 1.21) 0 fewer per 1000 (from 151 fewer to 187 more) HIGH CRITICAL QoL (GOS 75) CP vs mometasone furoate (12 weeks) 1 randomised trials risk of bias inconsistency indirectness very serious 2 none 10/27 (37%) 48.2% RR fewer per 1000 (0.41 to 1.44) (from 284 fewer to 212 more) ΟΟ LOW CRITICAL QoL (GSS 75) CP vs mometasone furoate (12 weeks) 1 randomised trials risk of bias inconsistency indirectness very serious 2 none 16/27 (59.3%) 66.7% RR fewer per 1000 (0.59 to 1.34) (from 273 fewer to 227 more) ΟΟ LOW CRITICAL QoL (improvement of symptoms) - complete response: CP vs testosterone (3 months follow-up) 1 observational studies very serious 3 inconsistency indirectness serious 2 none 13/20 (65%) 30% RR 2.17 (1.03 to 4.55) 351 more per 1000 (from 9 more to 1000 more) ΟΟΟ VERY LOW CRITICAL QoL (improvement of symptoms) - complete response: CP vs testosterone (6 months follow-up) 1 observational studies very serious 3 inconsistency indirectness serious 2 none 55/60 (91.7%) 77.5% RR 1.18 (1.03 to 1.36) 139 more per 1000 (from 23 more to 279 ΟΟΟ VERY LOW CRITICAL 35

36 more) QoL (improvement of symptoms) - complete & incomplete response: CP vs testosterone (1 year follow-up) 1 observational studies very serious 3 inconsistency indirectness imprecision none 18/20 (90%) 40% RR 2.25 (1.29 to 3.92) 500 more per 1000 (from 116 more to 1000 more) ΟΟΟ VERY LOW CRITICAL QoL (improvement of symptoms) responders: mometasone furoate (tapering) vs mometasone furoate (continuous) (3 months) 1 randomised trials risk of bias inconsistency indirectness serious 2 none 27/32 (84.4%) 78.1% RR 1.08 (0.85 to 1.37) 62 more per 1000 (from 117 fewer to 289 more) Ο MODERATE CRITICAL QoL (GOS 75) mometasone furoate (tapering) vs mometasone furoate (continuous) (3 months) 1 randomised trials risk of bias inconsistency indirectness serious 2 none 15/32 (46.9%) 28.1% RR 1.67 (0.86 to 3.24) 188 more per 1000 (from 39 fewer to 629 more) Ο MODERATE CRITICAL QoL (GSS 75) mometasone furoate (tapering) vs mometasone furoate (continuous) (3 months) 1 randomised trials risk of bias inconsistency indirectness serious 2 none 22/32 (68.8%) 62.5% RR 1.1 (0.77 to 1.57) 63 more per 1000 Ο (from 144 fewer to 356 MODERATE more) CRITICAL QoL (improvement of symptoms) itching: UVA-1 vs clobetasol (mean change from baseline at 3 months) (Better indicated by lower values) 1 randomised trials serious 3 inconsistency indirectness very serious 2 none MD 2.5 lower (5.69 lower to 0.69 higher) ΟΟΟ VERY LOW CRITICAL QoL (improvement of symptoms) burning/pain: UVA-1 vs clobetasol (mean change from baseline at 3 months) (Better indicated by lower values) 1 randomised trials serious 3 inconsistency indirectness very serious 2 none MD 1 lower (4.1 lower to 2.1 higher) ΟΟΟ VERY LOW CRITICAL Physician global assessment (total clinicians score): UVA-1 vs clobetasol (mean change from baseline at 3 months) (Better indicated by lower values) 1 randomised serious 3 very serious 2 none MD 0.5 lower (4.03 ΟΟΟ IMPORTANT 36

37 trials inconsistency indirectness lower to 3.03 higher) VERY LOW Patient global assessment (Skindex-29 score): UVA-1 vs clobetasol (mean change from baseline at 3 months) (Better indicated by lower values) 1 randomised trials serious 3 inconsistency indirectness very serious 2 none MD 24.7 lower (50.17 lower to 0.77 higher) ΟΟΟ IMPORTANT VERY LOW QoL (improvement of symptoms) complete and partial response: ALA-PDT vs CP (8 weeks) 1 randomised trials serious 3 inconsistency indirectness serious 2 none 18/21 (85.7%) 59.1% RR 1.45 (0.98 to 2.14) 266 more per 1000 (from 12 fewer to 674 more) ΟΟ LOW CRITICAL QoL (improvement of symptoms) human fibroblast lysate cream vs placebo (12 weeks) 1 randomised trials very serious 3 inconsistency indirectness serious 2 none 9/15 (60%) 33.3% RR 1.8 (0.79 to 4.11) 266 more per 1000 (from 70 fewer to 1000 more) ΟΟΟ VERY LOW CRITICAL QoL (improvement of symptoms) responders: acitretin vs placebo (16 weeks) 1 randomised trials risk of bias inconsistency indirectness serious 2 none 14/39 (35.9%) 15.4% RR 2.33 (1 to 5.44) 205 more per 1000 (from 0 more to 684 more) Ο MODERATE CRITICAL Patient global assessment (partially or completely satisfied): acitretin vs placebo (16 weeks) 1 randomised trials risk of bias inconsistency indirectness serious 2 none 35/39 (89.7%) 59% RR 1.52 (1.15 to 2.02) 307 more per 1000 (from 88 more to 602 more) Ο IMPORTANT MODERATE Minor adverse events: acitretin vs placebo (16 weeks) 1 randomised trials risk of bias inconsistency indirectness imprecision none 39/39 (100%) 51.3% RR 1.93 (1.42 to 2.61) 477 more per 1000 (from 215 more to 826 more) HIGH IMPORTANT QoL (improvement of symptoms) Dermasilk vs cotton pants (6 months) 37

38 1 randomised trials serious 3 inconsistency indirectness serious 2 none 21/21 (100%) 81% RR 1.23 (0.98 to 1.53) 186 more per 1000 (from 16 fewer to 429 more) ΟΟ LOW CRITICAL QoL (improvement of clinical signs) Dermasilk vs cotton pants (6 months) 1 randomised trials serious 3 inconsistency indirectness serious 2 none 21/21 (100%) 57.1% RR 1.72 (1.19 to 2.49) 411 more per 1000 (from 108 more to 851 more) ΟΟ LOW CRITICAL QoL (improvement of symptoms - soreness) Dermasilk vs cotton pants (6 months) 1 randomised trials serious 3 inconsistency indirectness imprecision none 21/21 (100%) 19.1% RR 4.78 (2.09 to 10.92) 722 more per 1000 (from 208 more to 1000 more) Ο MODERATE CRITICAL QoL (improvement of symptoms - itching) Dermasilk vs cotton pants (6 months) 1 randomised trials serious 3 inconsistency indirectness serious 2 none 13/13 (100%) 71.4% RR 1.38 (0.97 to 1.95) 271 more per 1000 (from 21 fewer to 678 more) ΟΟ LOW CRITICAL Patients still experiencing dyspareunia: Dermasilk vs cotton pants (6 months) 1 randomised trials serious 3 inconsistency indirectness imprecision none 9/20 (45%) 100% RR 0.47 (0.29 to 0.75) 530 fewer per 1000 (from 250 fewer to 710 fewer) Ο MODERATE CRITICAL 1 No clinical important difference - between MIDs 2 Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs 3 Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias 38

39 E.2 FEMALES (MIXED: ADULTS & CHILDREN) Quality assessment No of patients Effect No of studies Design Risk of bias Inconsistency Indirectness Imprecision Other considerations Females (mixed: adults and children) Control Relative (95% CI) Absolute Quality Importance QoL (improvement of symptoms): CP vs tacrolimus (3 months) 1 randomised trials serious 1 inconsistency indirectness imprecision 2 none 27/29 (93.1%) 96.6% RR 0.96 (0.85 to 1.09) 39 fewer per 1000 (from 145 fewer to 87 more) Ο MODERATE CRITICAL QoL (absence of symptoms): CP vs tacrolimus (2 months) 1 randomised trials serious 1 inconsistency indirectness imprecision none 15/29 (51.7%) 13.8% RR 3.75 (1.41 to 9.95) 380 more per 1000 Ο (from 57 more to 1000 MODERATE more) CRITICAL 1 Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias 2 No clinical important difference - between MIDs 39

40 E.3 MIXED (FEMALES & MALES (ADULT)) Quality assessment No of patients Effect Quality Importance No of studies Design Risk of bias Inconsistency Indirectness Imprecision Other considerations Mixed (females and males) Control Relative (95% CI) Absolute QoL (improvement of symptoms) para-aminobenzoate vs placebo (2 months) 1 randomised trials very serious 1 inconsistency indirectness very serious 2 none 6/12 (50%) 53.9% RR 0.93 (0.44 to 1.98) 38 fewer per 1000 (from 302 fewer to 528 more) ΟΟΟ VERY LOW CRITICAL 1 Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias 2 Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs E.4 MALES (CHILDREN) Quality assessment No of patients Effect Quality Importance No of studies Design Risk of bias Inconsistency Indirectness Imprecision Other considerations Males (children) Control Relative (95% CI) Absolute Physician global assessment: preputioplasty with intralesional triamcinolone vs circumcision (follow-up median 14 months vs 6 months)) 1 observational studies very serious 1 inconsistency indirectness serious 2 none 84/104 (80.8%) 71.9% RR 1.12 (0.89 to 1.42) 86 more per 1000 (from 79 fewer to 302 more) ΟΟΟ VERY LOW IMPORTANT 1 Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias 2 Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs 40

41 E.5 MALES (ADULT) Quality assessment No of patients Effect Quality Importance No of studies Design Risk of bias Inconsistency Indirectness Imprecision Other considerations Male (adult) Control Relative (95% CI) Absolute QoL (improvement of symptoms) DLQI: acitretin vs placebo (mean change from baseline at 20 weeks) (Better indicated by lower values) 1 randomised trials risk of bias inconsistency indirectness imprecision none MD 4.2 lower (6.68 to 1.72 lower) HIGH CRITICAL QoL (improvement of symptoms) complete response: acitretin vs placebo (20 weeks) 1 randomised trials risk of bias inconsistency indirectness serious 1 none 12/34 (35.3%) 5.9% RR 6 (0.85 to 295 more per 1000 (from Ο 42.39) 9 fewer to 1000 more) MODERATE CRITICAL Physician global assessment (total clinical score): acitretin vs placebo (mean change from baseline at 20 weeks) (Better indicated by lower values) 1 randomised trials risk of bias inconsistency indirectness imprecision none MD 4.9 lower (7 to 2.8 lower) HIGH IMPORTANT 1 Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs 41

42 Appendix F: Summary of included studies F.1 SYSTEMATIC REVIEWS (FEMALE & MALE (CHILDREN, YOUNG PEOPLE & ADULTS)) STUDY The review addresses an appropriate and clearly focused question that is relevant to the guideline review question The review collects the type of studies you consider relevant to the guideline review question The literature search is sufficiently rigorous to identify all the relevant studies Study quality is assessed and reported An adequate description of the methodology used is included, and the methods used are appropriate to the question What types of studies are included in the review? Chi, Cochrane Database Syst Rev 2011:CD Yes Yes Yes Yes Yes RCTs COMMENTS: Cochrane review on the topical interventions for genital LS. Outcome measures listed mostly match those set in the guideline protocols. SUMMARY: Seven trials (6 female (adult); male (children, young people), 63 with 249 participants), covering 6 treatments met the inclusion criteria. Six of these RCTs tested the efficacy of one active intervention against placebo or another active intervention, while the final trial tested three active interventions against placebo. When compared to placebo in one trial (female), CP 0.05% was effective in treating genital LS in relation to the following participant-rated improvement or remission of symptoms (risk ratio (RR) 2.85, 95% confidence interval (CI) 1.45 to 5.61) and investigator-rated global degree of improvement (standardised mean difference (SMD) 5.74, 95% CI 4.26 to 7.23). When mometasone furoate 0.05% was compared with placebo in another trial (male), there was a significant improvement in the investigatorrated change in clinical grade of phimosis (SMD -1.04, 95% CI to -0.31) The data from four trials (female) found no significant benefit for topical testosterone, dihydrotestosterone and progesterone. When used as 42

43 maintenance therapy after an initial treatment with topical CP in another trial, topical testosterone worsened the symptoms (P <0.05), but the placebo did not. One trial (female) found no difference between pimecrolimus and CP in relieving symptoms through change in pruritus (itching) (SMD -0.33, 95% CI to 0.33) and burning/pain (SMD 0.03, 95% CI to 0.69). However, pimecrolimus was less effective than CP with regard to the investigator-rated global degree of improvement (SMD -1.64, 95% CI to -0.87). The current limited evidence demonstrates the efficacy of CP, mometasone furoate, and pimecrolimus in treating genital LS. F.2 FEMALES (ADULTS) Study Intervention & Comparator Population Outcomes Comments Ayhan, Int J Gynaecol Obstet 2007; 96: Retrospective case analysis, Turkey, university gynaecology unit, no funding 1. Topical: CP 0.05% ointment twice daily for 6 weeks then once daily 2. Testosterone 2% in petrolatum Same regimen n=140 Mean ages 51.64±12.35 and 49.27±9.53 years respectively Inclusion criteria: Biopsy proven LS as an initial diagnosis Exclusion criteria: SCC/VIN, mixed disease, systemic disease or vulval dermatosis QoL (improvement of symptoms) Attrition: not applicable 43

44 Bornstein, Am J Obstet Gynaecol 1998; 178: Cohort study, Israel, setting and funding not stated 1. Topical: CP 0.05% ointment twice daily for 1 month, once daily for 1 month, then tapering to 2-3 times/week 2. Testosterone 2% in petrolatum twice daily for 3 months, once daily for 3 months then 2-3 times/week n=40 Mean ages 64.4±9.04 and 64.0±7.27 years respectively Inclusion criteria: LS - histologically confirmed Exclusion criteria: not stated QoL (improvement of symptoms) Attrition: None Virgili, Br J Dermatol 2014; 171: Parallel groups RCT, Italy, university dermatology unit, no funding 1. Topical: CP 0.05% ointment once daily for 5 days a week for 4 weeks, alternate days for 4 weeks and twice weekly for 4 weeks 2. Topical: Mometasone furoate 0.1% ointment Same regimen n=54 Mean age 64.2 years (SD 12.7) Inclusion criteria: Clinical features of LS, not all histologically confirmed Exclusion criteria: Systemic treatment or topical therapy in 4 weeks before enrolment, hypersensitivity to study drugs, active infection or dermatosis, pregnancy or breast feeding QoL (improvement of symptoms) Attrition: 5.5% (3/54). Clobetasol, 2 patients lost to F/up; mometasone furoate 1 patient lost to F/up Borghi, Br J Dermatol 2015; 173: Parallel groups RCT, Italy, university dermatology unit, no funding 1. Topical: Mometasone furoate 0.1% (tapering) once daily for 5 days a week for 4 weeks, alternate days for 4 weeks and twice weekly for 4 weeks n=64 Mean ages 59.4±13,6 and 62.5±11.7 years respectively GSS 10.78, GOS 5.53 Inclusion criteria: Clinical features of QoL (improvement of symptoms) Attrition: 3/64. Mometasone furoate 0.1% (tapering), 1 lost to F/up; Mometasone furoate 0.1% (continuous), 3 lost to F/up. 44

45 2. Topical: Mometasone furoate 0.1% (continuous) once daily 5 days/week for 12 weeks LS, not all histologically confirmed Exclusion criteria: histology unclear or overlap with other dermatoses, Systemic treatment or topical therapy in 4 weeks before enrolment, hypersensitivity to study drugs, active infection or dermatosis, pregnancy or breast feeding Terras, JAMA Dermatol 2014; 150: Parallel groups RCT, Germany, university dermatology unit, academic/government funding 1. UVA-1 home based phototherapy 4 times/week % CP ointment once daily for 3 months Both arms also received emollients n=30 Median age 60.3 years (range 20-81) Inclusion criteria: Histologically confirmed LS, over 18 Exclusion criteria: photosensitivity, skin cancer, genodermatoses, phototherapy in last 4 weeks QoL (improvement of symptoms) Physician global assessment Patient global assessment Attrition: 13.3% (4/30). 1 on each arm did not receive intervention and 1 dropped out on each arm Shi, Acta Derm Venereol 2016; 96: Parallel groups RCT, China, university dermatology unit, academic/government funding 1. ALA-PDT 4 cycles every 2 weeks % CP ointment once daily for 8 weeks n=40 Mean age 51.4 ±15.6 years Inclusion criteria: Histologically confirmed LS Exclusion criteria: Wanting to conceive during study QoL (improvement of symptoms) Attrition: 7.5% (3/40). ALA- PDT, 1 dropped out, clobetasol, 2 lost to F/up (relocated) Origoni, Int J Gynaecol Obstet 1. Topical: Oxatamide gel n=22 Mean age 53.2 years (range 23-71) QoL (improvement Attrition: 13.6% (3/22) because of burning side effects 45

46 1996; 55: Crossover RCT, Italy, university gynaecology unit, funding not stated Goldstein, Acta Derm Venereol 2015; 95: Parallel groups RCT, USA, specialised vulval gynaecology unit, principle author funded by industry Bousema, J Am Acad Dermatol 1994; 30: Parallel groups RCT, Europe, 4 hospital gynaecology centres and 1 dermatology centre, study funded by industry D'Antuono, J Low Genit Tract Dis 2011; Twice daily for 14 days sequentially with 7-day wash out 2. Placebo Same regimen 1. Topical: Human fibroblast lysate cream (cutaneous lysate) 1 g twice daily for 12 weeks 2. Placebo Same regimen 1. Systemic: Acitretin 30 mg once daily for 16 weeks, reduced to 20 mg at 4 weeks if adverse reactions 2. Placebo Same regimen Both arms also received emollient ointments and non-alkaline antiseptics Inclusion criteria: Histologically confirmed LS Exclusion criteria: Not stated. n=30 Mean age 57 years Inclusion criteria: Histologically confirmed LS Exclusion criteria: Not stated. n=78 Age range Inclusion criteria: Severe LS for at least 3 months and refractory to previous treatment. (Severe as defined by presence of at least one symptom and one sign of moderate or severe degree) Exclusion criteria: Severe hepatic, renal, cardiovascular, metabolic (hypertriglyceridaemia or hypercholesterolaemia) or neurologic disease of symptoms) QoL (improvement of symptoms) QoL (improvement of symptoms) Patient global assessment Minor adverse events 1. Dermasilk n=42 QoL (improvement 26% of those using oxatomide gel had complete resolution of their symptoms, while only 5.3% on placebo did. Attrition: None Attrition: 44.94% (35/78). 25 patients did not meet efficacy inclusion criteria. 10 patients did not complete study (5 due to adverse reactions (acitretin); 2 withdraw due to lack of response (placebo), 2 withdrew (placebo) and 1 lost to F/up (acitretin). Attrition: None 46

47 15: Cotton briefs Median age 51.5 years (range 22-79) of symptoms) Parallel groups RCT, university dermatology clinic, equipment/drugs provided by industry Both arms also received 0.05% CP once daily and vitamin E emollient once daily Inclusion criteria: Clinical diagnosis, confirmed with histology if not typical Exclusion criteria: Carcinoma, treatment with HRT Restoration of sexual function F.3 FEMALES (CHILDREN, YOUNG PEOPLE & ADULTS, NOT SEPARATED) Study Intervention & Comparator Population Outcomes Comments Funaro, J Am Acad Dermatol 2014; 71: Parallel groups RCT, Canada, hospital dermatology vulval clinic, study funded by industry 1. CP 0.05% ointment Nightly for 3 months until lesions resolved and then twice weekly until end of study 2. Tacrolimus 0.1% ointment Same regimen n=58 Mean age 46.6±2.4 years (range 4-73) (n=5 <18 years) Inclusion criteria; 2 years or older, newly diagnosed LS or untreated for 1 month. Confirmed histologically in adults Exclusion criteria: No LS after biopsy, known hypersensitivity to studied products or vehicle, history of VIN or anogenital carcinoma, condyloma, hyperkeratotic LS, physical limitation preventing application of treatment, children in diapers QoL (improvement of symptoms) Attrition: 5.2% (3/58). Tacrolimus 1 patient did not have LS confirmed on biopsy, CP 2 patients withdrew 47

48 F.4 ADULT MIXED (FEMALES AND MALES NOT SEPARATED) Study Intervention & Comparator Population Outcomes Comments Buxton, J Dermatolog Treat 1990; 1: Parallel groups RCT, UK, university dermatology clinic, funded not stated 1. Para-aminobenzoate 3g four times daily 2. Placebo Citric acid tablets same regimen Both arms also received a 200 g jar of 1% ichthammol paste n=25 22 F: 3 M Mean age 56 ± 3 years Inclusion criteria: LS - genital and extragenital lesions included Exclusion criteria: not stated QoL (improvement of symptoms) Attrition: 16% (4/25). Paraaminobenzoate, 2 did not like taste; placebo, 2 because of vomiting. 48

49 F.5 MALES (CHILDREN & YOUNG PEOPLE) Study Intervention & Comparator Population Outcomes Comments Wilkinson, J Pediatr Surg 2012; 47: Retrospective case analysis, UK, funding not stated 1. Preputioplasty plus 1-3 ml triamcinolone 10 mg/ml intradermally to foreskin 2. Primary circumcision Both arms received topical steroids post-surgery if clinical evidence of LS n=136 Median age 9 years (IQR = 7-11) Inclusion criteria: Boys with phimosis due to biopsy proven LS Physician global assessment Attrition: None F.6 MALES (ADULTS) Study Intervention & Comparator Population Outcomes Comments Ioannides, J Urol 2010; 183: Parallel groups RCT, Greece, funded not stated 1. Systemic therapies Acitretin 35 mg once daily for 20 weeks and emollients 2. Placebo Same regimen with placebo tablet and emollients n=51 Mean age 56 years (range 39-74) With biopsy proven genital LS resistant to potent topical steroids. TCS score >9 Inclusion criteria: Adult males with genital LS Exclusion criteria: Hypersensitivity to retinoids. Systemic diseases on which retinoids may have adverse effect QoL (improvement of symptoms Physician global assessment Attrition: 3.9% (2/51) 1 withdrawn from each arm prior to entry for circumcision 49

50 Appendix G: Narrative findings for non-comparative studies G.1 FEMALES (CHILDREN & YOUNG PEOPLE): CASE SERIES Study reference & design Neuhofer, Acta Derm Venereol 1984; 64: Prospective Anderson, Dermatolog Treat 2016; 27:64-6. Retrospective Boms, BMC Dermatol 2004; 4:14. Böhm, Arch Dermatol 2003; 139: Study population Mixed m/f (n=8)* 3 juvenile females 14 girls Age range 2-10 years 4 girls Age range 4-9 years Mixed m/f adult and female child Relevant population characteristic Intervention Treatment duration/ F/up Outcome Notes Genital LS Etretinate 0.5 mg/kg 3-12 months 2 of 3 cleared PGA *See G.4 for adult female, G.7 for adult male and 1 G.11 for EG Comments that on stopping drug any improvement lost Pre-pubertal population 0.05% CP twice daily bridging to 0.1% tacrolimus with steroid reduced to twice daily at weekends and then replaced with tacrolimus LS Topical 1% pimecrolimus twice daily Genital LS Tacrolimus 0.1% once daily Wide variation in treatment time weeks 3-4 months F/up 3 months 10 months F/up 9 and 11 93% complete clearance (mean 43.1 weeks) Almost complete remission in symptoms. Little effect on signs. 100% Cleared PGA Pruritus improved QOL Regimen not identical for every patient *See G.4 for adult female & G.5 for adult male 50

51 Prospective (n=6)* 3 girls months Improvement maintained at F/up Mean age 7 years (range 5-9) Li, J Pediatr Adolesc Gynecol 2013; 26: girls Age range 4-11 years LS Topical 0.03% tacrolimus twice daily for 16 weeks and then twice weekly for 6 months 6 months F/up 12 months Complete response in 5, 9 and 11 at week 8, week 16 and month 10 respectively. 4 of 5 who stopped treatment at 16 weeks had recurrent symptoms. 2 of 9 who continued twice weekly treatment had recurrent symptoms Serrano, Pediatr Dermatol 1993; 10: girls LS 1% progesterone twice daily for 6 months Assessed at 3 months Clinical improvement in symptoms and signs, not quantified Letter little detail Breech, J Pediatr Adolesc Gynecol 2000; 13: girls Age range years Labial and periclitoral adhesions Sharp surgical dissection then Surgicel applied F/up 12 months No recurrence of adhesions Ostrzenski, Gynecol Surg 2010; 26:41-8. Sequential study 2 girls and 8 women* Age range years LS Hydrodissection and reverse V-plasty for clitoral burial F/up 5 years No recurrence of adhesions at 5 years. Improvement in clitoral pain *See G.3 for adult female 51

52 Kastner, J Dtsch Dermatol Ges 2003; 1: girls and 22 women* LS Cryotherapy 1 treatment Improvement in symptoms. *See G.3 for adult female Mean age 9 years (range 5-15) Davis, Adolescent Pediatr Gynecol 1989; 2: girls Age range 4-14 years Partial response to topical steroids CO 2 laser vaporisation F/up 4-9 months 3 good relief of symptoms, 1 only moderate relief. Labial adhesions occurred requiring surgical treatment G.2 FEMALE (CHILDREN & YOUNG PEOPLE): CASE REPORTS Study reference Landi, Chron Dermatol 1992; 2: Goldstein, J Reprod Med 2004; 49: Matsumoto, J Dermatol 2007; 34: Study population 1 girl 7 years 4 patients* including 1 girl 8 years 1 girl 5 years Intervention Topical ciclosporin twice daily Topical 1% pimecrolimus cream twice daily for 3 months Topical 0.03% tacrolimus once daily Treatment duration/f/up 8 months No F/up 3 months of treatment No F/up 14 weeks treatment F/up 6 months Outcome Pruritus improved after 1 month. Signs resolved after 8 months Complete resolution of symptoms. Complete resolution of signs and pruritus at 14 weeks Notes Concentration not specified *See G.3 for adult female Rabinowitz, L. G. 1 girl 585 nm flash lamp F/up 2 years Bleeding responded to laser but No potent topical 52

53 Arch Dermatol 1993; 129: years pumped pulsed dye laser not symptoms steroids used G.3 FEMALES (ADULT): CASE SERIES Study reference & design Study population Relevant population characteristic Intervention Treatment duration/ F/up Outcome Notes LeFevre, J Low Genit Tract Dis 2011; 15: adult females Biopsy proven LS Topical triamcinolone ointment F/up 3 months Improvement in symptoms. Little information about signs Retrospective Simonart, Menopause 2008; 15:74-7. Prospective 34 adult females Mean age 65.4 years (range 44-87) Postmenopausal with clinical and histological features of LS 0.1% betamethasone cream twice daily for 1 month then cold cream F/up at one month and then twice per year up to 11 years; median 58 months (range ) 24 symptom-free after treatment with topical steroid. 18 remained free of symptoms using emollient alone. 10 required further treatment with a topical steroid Goldstein, J Reprod Med 2004; 49: females (3 >18 years)* Mean age 46 years (range 28-62) Biopsy proven LS Topical 1% pimecrolimus cream twice daily for 3 months 3 months of treatment 2 of 3 reported complete resolution of symptoms. Both had biopsies which showed resolution *See G.2 for female 18 years 53

54 Kauppila, Am J Obstet Gynecol 2010; 202:181 e adult females (25 analysed) LS Topical 1% pimecrolimus cream twice daily for 8 weeks Assessed at 8 weeks 19 of 25 had complete response and 1 a partial response. 5 had no response Histological reduction in number of lymphocytes Mean age 66.5 years (range 41-85) Nissi, Gynecol Obstet Invest 2007; 63: Prospective 29 adult females Mean age 61.2 years (range 42-79) Histologically proven LS, never achieved remission in adult life Topical 1% pimecrolimus cream twice daily for up to 6 months Evaluated at 2 and 6 months of treatment Of 26 who completed study, 42% in complete remission at 6 months. 50% experienced some side effects Oskay, Int J Dermatol 2007; 46: Prospective 16 adult females Mean age 61.2 years (range 48-75) Postmenopausal symptomatic women Topical 1% pimecrolimus cream twice daily for 3 months then as needed F/up every 3 months for 12 months Scoring of severity fell from 130 to 43 at 12 months. 11 had complete remission at 3 months but 4 had relapse Luesley, BJOG 2006; 113: Prospective 16 adult females Mean age 52.7 years (range 26- Symptomatic LS partially responsive to steroids Topical 0.1% tacrolimus twice daily for 3 months F/up 12 months 2 complete response, 8 partial response and 6 no response and changed to other treatments 54

55 79) Sotiriou, Eur J Dermatol 2009; 19: adult females Mean age 53.4 years Recalcitrant LS Topical 0.1% tacrolimus twice daily 8 weeks treatment F/up at 16 weeks Symptoms improved from baseline level of 2.55 to 0.95 at 8 weeks, rose to 1.5 at last F/up visit. DLQI fell by 53%. Little effect on signs. Virgili, Acta Derm Venereol 2007; 87: Prospective 11 adult females Mean age 54 years (range 32-80) Poor or nonresponse to topical steroids Topical 0.1% tacrolimus ointment twice daily for 6 weeks then tapered Assessed every 2 months. F/up maximum 7 months Complete response in 4 patients, good improvement in 4 and slight in 2. One failed to attend for F/up. Gupta, Int J STD AIDS 2005; 16: Prospective Mixed m/f adult (n=23)* 8 females LS Topical 0.005% calcipotriol ointment once daily for 1 week and then twice daily if tolerated 16 weeks No F/up Improvement in symptoms (4.8 to 1.8) and signs (3.4 to 2) at 16 weeks *See G.7 for adult male Mean age 44.8 years Borghi, Eur J Dermatol 2015; 25: Retrospective 17 adult females Mean age 64.3 years LS Topical 0.025% tretinoin cream alternate days 24 weeks 35.3% and 17.6% achieved 75% improvement in subjective and objective scores respectively Virgili, J Reprod Med 1995; 40: Prospective 22 adult females Mean age 59.5 years Histologically confirmed LS Topical 0.025% tretinoin cream twice daily for 12 months 12 months F/up mean 7 months (range 4-13) 75-78% improvement in symptoms. Hyperkeratosis improved 79%. Results maintained during F/up 55

56 (range 36-74) Borghi, J Eur Acad Dermatol Venereol 2015; 29: Prospective 23 adult females Mean age 59.8 years (range 19-84) Mild-moderate LS Avocado and soya bean extract cream twice daily and dietary supplement for first 12 weeks 24 weeks 12 and 13 patients achieved 75% improvement in subjective and objective scores respectively Maina, Ital J Gynaecol Obstet 2002; 14:35-7. Prospective 40 adult females Mean age 60.7 years Biopsy proven LS Topical 2.5% progesterone 25 mg twice daily for 2 weeks then once daily for 8 weeks Evaluation at 3 months then F/up mean 19.6 months (range 3-62) At 3 months, 54.5% had complete resolution of symptoms, 33.3% had decrease in baseline scores with no change in 12% Micheletti, Ital J Gynaecol Obstet 2001; 13:42-6. Prospective 20 adult females Mean age 61 years (range 36-78) Biopsy proven LS Topical micronized natural progesterone cream 50mg twice daily for 4 weeks and then once daily for 8 weeks F/up 12- weeks 14 women evaluable at 12 weeks. Resolution of symptoms in 57%. 50% showed an improvement in appearance. No histological change in the 8 patients who had repeat biopsy. Bradford, J Low Genit Tract Dis 2013; 17: adult females 27 with LS Labial adhesions Surgical dissection with application of topical steroid until healing F/up 2 years 31 of 35 had no refusion at 3- month review. 29 had no refusion at 2 years Included 8 patients with LP Mean age 57 years Brauer J Sex Med 2016; 19 adult Histologically Surgery then CP 0.05% 1-4 days per week with Interviewed at 10 68% reported improvement in dyspareunia. 95% reported Post-surgery for scarring 56

57 13: Retrospective females Mean age 56.2 years (range 30-72) confirmed LS emollients. Interviewed to assess effect on sexual functioning months to 5 years after surgery improvement in symptoms in daily life and dyspareunia secondary to LS Rangatchew J Plast, Recon Aes Surg 2017; 70: Retrospective 38 adult females Mean age 52 years (range years) LS verified, 87% had dyspareunia Surgery, local excisions, but including partial and total vulvectomies F/up 10 months and further clinical F/up to 8.4 years 75% reported benefit relating to dyspareunia. Symptoms relapsed with time No mention of topical steroid treatment after surgery Severe scarring secondary to LS Boero, Gynecol Oncol 2015; 139: adult females Mean age 54 years (range 25-80) Failure to respond to first line treatment Fat grafting 1-3 procedures F/up mean 12 months 34 improved appearance and symptoms. 34 able to stop using topical steroids Ostrzenski, J Gynecol Surg 2010; 26: adult females and 2 girls* LS Hydrodissection and reverse V-plasty for clitoral burial F/up 5 years No recurrence of adhesions at 5 years. Improvement in clitoral pain *See G.1 for females 18 years Sequential study Age range Rettenmaier, J Reprod Med 1985; 30:478-4 adult females Failure of medical Skinning vulvectomy and split thickness skin grafting F/up up to 96 months 2 patients developed recurrent disease in skin grafts requiring topical 57

58 80. treatment treatment Mean age 57 years (range 55-60) Rouzier, Am J Obstet Gynecol 2002; 186: Retrospective 64 adult females Median age 49 years Biopsy proven LS with introital stenosis Perineoplasty F/up median 34 months (3-134) 92% relief of dyspareunia 86% improvement in quality of intercourse Kastner, J Dtsch Dermatol Ges 2003; 1: adult females and 9 girls* LS Cryotherapy 1 treatment Improvement in symptoms. 5 required second cycle and two patients a third treatment *See G.1 for females 18 years Mean age 54 years (range 33-74) Biniszkiewicz, Photodiagnosis Photodyn Ther 2005; 2: adult females Mean age 58 years Symptomatic LS PDT with 5-ALA 6 cycles at 14 day intervals 17 patients had complete resolution of itching No information on effect on signs Hillemanns, Obstet Gynecol 1999; 93:71-4. Prospective 12 adult females Mean age 55 years Biopsy proven LS with pronounced pruritus PDT 10 ml of 5-ALA with argon ion-pumped dye laser 4-5 hours later to total of 80J/cm 2 Repeat treatment at 1-3 At 6-8 weeks then every 3 months or when symptoms At 6-8 weeks F/up, mean values for pruritus reduced from 2.6 to 1.0. Duration of symptom reduction was 3-9 months. No biopsies done after treatment 58

59 weeks if needed (2 had 2 cycles and 1 had three) recurred At 6-month F/up 7 of 10 had symptomatic relief. No improvement in clinical appearances Imbernón-Moya, Photodermatol Photoimmunol Photomed 2016; 32: Prospective 8 adult females with clinical features of LS 7 > 60 years & 38 years Refractory to 2 topical treatments with potent steroids and calcineurin inhibitors Methyl aminolevulinate 160 mg/g for 3 hours then red light irradiation 37 J/cm 2. done under sedation and GA in 2 patients 1-3 sessions 6-12 months apart. F/up every 3 months No change in clinical parameters. Improvement in symptoms and DLQI Maździarz, Photodiagnosis Photodynamic therapy 2017; 19: adult females Mean age 55 years (range 19-85) Biopsy proven LS resistant to topical steroids or refused to use them 5% ALA in gel form and halogenic lamp giving dose of 120 J/cm 2 for 10 mins. Repeated weekly for 10 weeks F/up 3 months Complete or partial remission in 87.25% patients. No response in 12.75% Osiecka, Photodiagnosis Photodyn Ther 2017;17: Prospective 11 adult females Mean age 48 years (range 30-66) Histologically confirmed LS, no satisfactory result after many topical treatments 20% ALA in cream base with green light irradiation. 3 sessions at 2 weekly intervals Every 2 months for 6 months Improvement in pruritus in 81% initially but symptoms recurred Skrzypulec, J Sex Med 2009; 6: adult females Histologically confirmed LS PDT with 5-ALA and laser light source 6 cycles at 2 weekly intervals 3 months FSFI reduced from 24.6 to 15.9 and beck depressive index fell from 12 to 9. No detail about clinical improvement 59

60 Mean age 59.6 years (range 50-70) Lubrication disorders increased. No significant difference in depressive symptoms Sotiriou, J Eur Acad Dermatol Venereol 2008; 22: Prospective 5 adult females Mean age 61.4 years (range 55-68) Biopsy proven LS with only temporary response to topical steroids PDT with 5-ALA and red light one treatment F/up 3-6 months Symptom score fell from 2.2 to 1.2 at 8 weeks. Little change in signs Topical steroids required for control after treatment Beattie, Clin Exp Dermatol 2006; 31: adult females Median age 62 years (range 48-68) Severe LS uncontrolled with ultrapotent topical steroid UVA1 3-5x/week treatments given. 2 patients required 2 courses No F/up 5 improved but 1 relapsed Reichrath, Dermatology 2002; 205: Prospective Mixed m/f adult (n=12; including 5 with LS)* 3 adult females Genital (2) and anogenital (1) LS Topical 8-MOP PUVA up to 4x/week, start in 0.5 J/cm 2 increasing by 0.5 J/cm 2 every 3 visits F/up period not stated 2 of 3 markedly improved, 1 of 3 improved. *See G.7 for adult male Baggish, J Gynecol Surg 2016; 32: adult females Mean age 67 Biopsy proven LS with symptoms 3 courses of fractional CO 2 laser at 4-6 week intervals. 20W with 1000 msec pulsing F/up period not stated 24/27 reported resolution of symptoms and 26 demonstrated improvement in clinical signs 60

61 years Prospective Kartamaa, Br J Dermatol 1997; 136: Mixed m/f adult (n=10)* 2 females anogenital LS CO 2 laser 1 treatment F/up 8 months to 5 years Improved significantly not quantified **See G.7 for adult male and G.10 for EG female Mean age 51.5 years (range 47-56)) Only perineal disease treated Lee, Australas J Dermatol 2016; 57: Prospective 5 adult females Mean age 56 years (range 39-65) Severe hyperkeratotic LS CO 2 laser F/up not stated Improvement in symptoms so that disease could be controlled with ultra-potent topical steroids Stuart, Can J Surg 1991; 34: adult females Histologically confirmed LS CO 2 laser ablation to depth of 2 mm F/up months 6 of 7 free of symptoms at F/up Mean age 52.5 years (range 43-62) Bulbul Baskan, J Am Acad Dermatol 2007; 57: adult females Mean age 53 Refractory LS Oral ciclosporin 3-5 mg/kg/day 3 months treatment F/up 12- month Symptom score fell from 8.6 to 0.8. recurrent symptoms managed with topical CP 61

62 Prospective years (range 48-65) Calista, Chron Dermatol 1995; 5: Prospective 20 adult females Median age 64.3 years (range 52-73) Symptomatic LS Oral etretinate 0.3 mg/kg twice daily 3 months treatment, F/up mean 19 months 11 complete responders, 2 non-responders. 2 stopped because of side effects and 1 withdrew Mørk, Acta Derm Venereol 1986; 66: Prospective 8 adult females Mean age 47.4 years (range 21-63) Unresponsive disease Oral etretinate 1 mg/kg/day F/up weeks 6 of 8 improved Dosage reduced according to response and side effects. Niesert, Dermatol Monatsschr 1992; 178: Prospective 5 adult females Mean age 68.2 years (range 62-76) LS Oral etretinate 0.3 mg/kg, increased to 0.8 mg/kg Treated for 6-24 months 4 of 5 improved in symptoms and signs but no change in sclerosis Penneys, J Am Acad Dermatol 1984; 10: adult females Mean age 56.8 years Oral para-aminobenzoate 12 g/day in divided doses 4 months to 2.5 years. No longterm F/up Improvement reported but not quantified Included patients with EG LS 62

63 Open trial (range 35-69) Shelley, Int J Dermatol 2006; 45: Mixed m/f adult (n=15)* 5 females LS Antibiotics penicillin oral or IM Not stated Improvement (2 cleared, 3 result favourable) * See G.7 for adult male and G.10 for EG female Mean age 71.8 years (range 47-89) Baggish, J Gynecol Surg 1995; 11: Case reports 4 adult females Mean age 53.5 (range 31-68) Severe LS, refractory to initial treatment Subdermal injections of dexamethasone/bupivacaine twice weekly until symptoms improved and then reduced to weekly, monthly and continued every 2 months Treatment time varies. No longterm F/up given Improvement in pruritus. Little comment about effect on signs Baggish, J Gynecol Surg 2006; 22: Retrospective 88 adult females Age range (5), (31), (52) Symptomatic LS with poor response to initial treatment Subdermal injections of 2 mg dexamethasone and 0.25% bupivacaine weekly then reduced slowly to every 2 months Up to 54 months 72 symptom-free after 4 injections but topical steroids required between injections for symptoms. 44.3% required monthly injections to prevent relapse Mazdisnian, J Reprod Med 1999; 44: adult females Adverse reaction or refractory to topical steroids or Intralesional triamcinolone 25-30mg injections monthly for 3 months No longterm F/up Severity score fell from 18 to 8. One treatment failure 63

64 Open trial poor patient compliance Casabona, Plast Reconstr Surg 2010; 126:210e- 1e. 15 adult females Age range years Biopsy confirmed LS nonresponsive to topical steroids Injection of adipose derived mesenchymal cells and platelet rich plasma Treatment repeated once or twice after three months if needed. F/up 6-24 months Itch and burning disappeared within 4 weeks. At 4 months, total clearance of symptoms and anatomy reported as normal. Behnia-Willison, Plast Reconstr Surg Glob Open 2016; 4:e adult females Mean age 60 years (range 22-88) 26 confirmed histologically 3 platelet rich plasma treatments 4-6 weeks apart and again at 12 months 2-3 months after final treatment Clearance of lesions in 28.6%, improvement in 60.7% Improvement in symptoms No long-term F/up G.4 FEMALE (ADULT): CASE REPORTS Study reference Neuhofer, Acta Derm Venereol 1984; 64: Prospective Assmann, J Am Acad Dermatol Study population Mixed m/f (n=8)* 1 postmenopausal female Intervention Treatment duration/f/up Outcome Notes Etretinate 0.5 mg/kg 3-12 months No improvement PGA *See G.7 for adult male, G.9 for juveniles and G.11 for EG female 1 female, Topical 0.1% tacrolimus twice daily 6 weeks treatment F/up not stated Resolution of symptoms and signs with histological 64

65 2003; 48: years for 6 weeks confirmation Böhm, M. Arch Dermatol 2003; 139: Mixed m/f adult and female child (n=6)* Topical 0.1% tacrolimus twice daily 6 months Resolution of symptoms at 6 weeks and signs at 16 weeks. Asymptomatic on no treatment at 12 months *See G.1 for females <18 years & G.5 for adult males 1 female, 19 years Filosa, Chron Dermatol 1997; 7: female, 84 years Topical tretinoin 0.01% twice daily for 1 month then 0.025% for 2-month treatment 2 months treatment Pruritus and clinical signs improved after 2 months treatment Anogenital LS and hepatitis C No long-term F/up Han, Acta Derm Venereol 2012; 92: female, 54 years Topical TRPM8 agonist (icilin) twice daily Not stated Itching better after 7 days, recurred 7 days after stopping treatment Length of treatment not stated Kaya, Br J Dermatol 2005; 152: female, 32 years 0.05% retinaldehyde twice daily for 1 month One month Improvement in symptoms and histological features. Restoration of CD44 expression Ercan, East J Med 2013; 18: female, 49 years Surgery with free rotation and advancement V-Y flap 3 weeks post-op Healed after surgery but no further details Patient had not been treated with potent topical steroids Rojavin, J Plast Reconstr Aesthet Surg 2008; 61: female, 64 years Simple vulvectomy and skin grafting F/up at 8 months reported Pain was improved after surgery Figure after surgery shows clinical signs still present. Pain was a significant feature Thibaudeau, J Plast Reconstr Aesthet Surg 1 female, 40 years Blunt surgical technique for clitoroplasty F/up at 3 months Clitoral retraction easily achieved at 3 months. Clobetasone propionate 0.05% used postoperatively 65

66 2013; 66:e Romero, J Am Acad Dermatol 2007; 57:S female, 61 years PDT 20% 5-ALA with 630 nm light 2 treatments 1 month apart F/up at 3 and 6 months Improvement but mild symptoms still present requiring topical clobetasone propionate 0.05% Patient had vaginal lesions suggesting that there may be lichen planus overlap Vano-Galvan, J Eur Acad Dermatol Venereol 2009; 23: female, 68 years PDT with MAL and 585nm laser light source 3 treatments one month apart Relapse after 4 months Improvement in signs after 3 treatments with resolution of pruritus Treatment painful requiring local anaesthesia. Further treatment at relapse refused by patient. Hackenjos, Hautarzt 2000; 51: female, 50 years CO 2 laser in silk touch mode 4 months Improvement in lesions and almost complete remission of symptoms Peterson, Dermatol Surg 2004; 30: females, 62 and 49 years CO 2 laser F/up at 3 and 2 years Good response sustained up to 3 years in one and 2 years in second patient Vulval LS and extragenital disease Response not described in detail Tomson, Br J Dermatol 2007; 157: female, 67 years Hydroxycarbamide 1 g/day F/up at 9 months Symptoms of soreness and pruritus resolved. Minimal scarring remained Hydroxycarbamide given for polycythaemia rubra vera 66

67 G.5 MALES (CHILDREN & YOUNG PEOPLE): CASE SERIES Study reference & design Study population Intervention Condition Treatment duration/ F/up Outcome Notes Ghysel, Urol Int 2009; 82:81-8. Prospective 462 boys Mean age 4.7 years (range 1 month 13 years) Betamethasone 0.05% cream once daily or twice daily plus skin stretching to achieve retraction of foreskin Phimosis all causes. Subgroup 27 patients with LS 6 weeks F/up meadian 22 months (range 3-55) 383/462 developed retractable foreskin LS cases 18/27 (67%) response PGA Phimosis study with LS subset analysis Wright, Aust N Z J Surg 1994; 64: Prospective 111 boys Age range 3-14 years Betamethasone valerate 0.5% Phimosis all causes Subgroup 6 patients with LS 4-8 weeks 80% response overall No response LS patients - PGA All LS patients had circumcision Ebert, Eur Urol 2008; 54: Prospective Vincent, J Pediatr Surg 2005; 20 boys Mean age 9.7 years (range ) 56 boys Mean age Tacrolimus 0.1% ointment twice daily for 3 weeks repeated if necessary, post circumcision to prevent relapse Moderate potency topical steroids (2.5% hydrocortisone, Tri- Phimosis due to LS, treated with circumcision Phimosis due to LS 21 days F/up mean 17 months (range 8-20) 3 months Decision about 9/20 had active LS post circumcision. (11 had disease only confined to the foreskin). Disease cleared at 3 weeks. One relapsed and cleared with further course of tacrolimus 20 patients clear at F/up PGA and DLQI Clear 18% -PGA Improved 12% PGA Minimal, no improvement or Incidence of LS in circumcision series was 19.4% 67

68 40: years (range 4 15) adcortyl ) circumcision at 3 months worse 70% - PGA Webster, Can J Urol 2002; 9: boys Mean age 7.4 years (range 3-13) Triamcinolone cream BD Phimosis all causes Subgroup 9 patients with LS 4 weeks F/up 6 weeks 92% response other causes 67% LS induced phimosis PGA G.6 MALE (CHILDREN & YOUNG PEOPLE): CASE REPORTS Study reference Study population Intervention Condition Treatment duration/ F/up Outcome Notes Sancaktutar, Scand J Urol Nephrol 2012; 46: boy 13 years Penile LS with phimosis LS complicated by obstructive uropathy Complication G.7 MALES (ADULT): CASE SERIES Study reference & design Study population Intervention Condition Treatment duration/ F/up Outcome Notes Neuhofer, Acta Derm Venereol 1984; 64:171- Mixed m/f (n=8)* 3 adult males Etretinate 0.5 mg/kg Penile LS 3-12 months No improvement PGA *See G.1 for female <18 years, G.4 for adult female and G.11 68

69 4. for EG Prospective Parsad, J Am Acad Dermatol 1998; 38: Prospective 5 adult males Mean age 48 years (ranges 32-65) Stanozolol 2 mg twice daily Penile LS 3 months No F/up Improved PGA Improved sexual function Pruritus improved PGA scored using clinical score. Pretreatment score = 3.6; post-treatment = 1.0 (p=0.05) Shelley, Int J Dermatol 2006; 45: Mixed m/f adult (n=15)* 6 males Penicillin oral or IM (4) Cephalosporin oral or IM (2) Penile LS Up to 3-20 months treatment Clear in 2 patients. Improved in 4 patients PGA *See G.3 for adult females and G.10 for EG Retrospective Mean age 54.8 years (range 44-78) Böhm, Arch Dermatol 2003; 139: Prospective Mixed m/f adult and female child (n=6)* 2 males Aged 30 and 62 years Tacrolimus 0.1% once daily Genital LS 10 months F/up 9 and 11 months 100% Cleared PGA Pruritus improved QOL Improvement maintained at F/up **See G.1 for females <18 years & G.4 for adult female 69

70 Kyriakou, J Dermatolog Treat 2013; 24: Prospective Dahlman- Ghozlan, J Am Acad Dermatol 1999; 40: Retrospective 41 adult males CP 0.05% twice daily for 8 weeks 22 adult males Mean age 37.5 years (range 18-73) Then either tacrolimus 0.1% once daily or methylprednisolone 2 per week 0.1% for 12 weeks CP 0.05% cream once daily/twice daily Genital LS, biopsy proven Pruritus (VAS Score >3 IGA score 0-4, all patients >2 End of CP treatment 2 16 weeks F/up mean 14.6 months (range 2-48) Pruritus VAS mean (SD) Pre-treatment: 4.08 (0.92), median 5; 8 weeks: mean 1.24 (1.33), median 1, (p<0.001) IGA mean (SD) Pre-treatment: 2.29 (0.46), median 2; 8 weeks: mean 0.56 (0.8), median 0, (p=<0.001) DLQI mean (SD) Pre-treatment: (2.95), median 17 8 weeks: 5.29 (4.61), median 4, (p<0.001) 23% clear, 41% improved QOL 43% clear PGA Sexual function: Dyspareunia 2.67 to 1.61, (p<0.001) Erectile pain 2.67 to 1.67, (p<0.001) Data for CP only Complication genital herpes Patient assessment for 7 symptoms or signs Improvement in urinary flow 2.25 to 1.83, (P<0.05) Histology assessed Tausch, J Urol 2012; 43 adult males Mean age 50.2 Initial treatment with CP 0.05% twice Penile genital Not stated F/up mean 7/17 patients with phimosis successfully treated with topical 70

71 187: Retrospective years (range 22-83) daily. Progression to circumcision, meatoplasty and urethroplasty disease, meatal and urethral disease 44 months (range 9-74) steroid (PGA). Rest progressed to circumcision. 12 had meatal disease and had meatal surgery. 14 had urethral stricture and urethroplasty. Edmonds, J Eur Acad Dermatol Venereol 2012; 26: Retrospective 329 Mixed male adults and children Mean age 39 years (range 3-38) CP twice daily for 4 weeks, repeated up to 3 times Penile LS 4 weeks F/up period not stated PGA 50% of patients responded to topical steroids at F/up Potts, J Urol 2016; 195: Retrospective 28 adult males Mean age 52.8 years Intraurethral CP via catheter or meatal dilator twice daily Urethral stricture due to LS (biopsy proven) Treatment 2-3 months frequency reduction after 89% success rate with no further surgical intervention (Restoration urinary function) Majority needed continuous occasional treatment, except 3. Gupta, Int J STD AIDS 2005; 16: Prospective Mixed m/f adult (n=23)* 15 males Mean age 48.6 years Topical calcipotriol 0.005% ointment once daily for 1 week and then twice daily if tolerated Genital LS F/up 25 months 16 weeks No F/up PGA no change in males TSS: pre-treatment 2.6; posttreatment 2.5, (p>0.05) Symptom improvement (QOL) Score pre-treatment 2.8; posttreatment 1.6, (p=0.05) *See G.3 for adult females Total sign score (TSS) 0-9 Total symptom score

72 Zucchi, Urol Int 2016; 97: Prospective 21 adult males Mean age 56 years (range 34-77) Polydeoxyribonucle otide 5-10mg intradermally weekly Penile LS Treatment given for 10 weeks, 4 weeks break then 10 weeks further treatment. F/up mean 16 months (range 12-24) No change in sexual function (IIEF-5 scoring) mean (SD) Pre-treatment (6.99) posttreatment (7.69) (p<0.189). Pt GA 80% improved DLQI (QOL) improved mean (SD); Pre-treatment (8.16); post-treatment 9.57 (9.21), (p=<0.001) DLQI scoring International index of erectile function (IIEF) Casabona, Int Urol Nephrol 2017; 49: Prospective 45 adult males. Mean age 43 years (range 17-66) Autologous protein rich plasma intradermally or subcutaneously Penile LS Treatment was given once and then repeated according to response*. F/up mean 17.6 months (range 12 24) PGA median pre-treatment: 3 (range 2-5); post-treatment 1 (range 0-2), (p=<0.001) Pt GA median pre-treatment 7 (range 5 25); post-treatment 2 (range 0-5), (p<0.001) Effective in treatment of phimosis avoiding circumcision *Review at 1 week, 1 month and 3 months post initial treatment. Median number treatments 4 (range 2 10) Garaffa, J Sex Med 2011; 8: Retrospective 31 adult males Mean age 46 years (range 21 74) Glans resurfacing total or partial SSG from thigh Genital LS of glans penis Surgery F/up median 12.8 months (range 2-48) 84% improvement Pt GA 71% improvement in sexual function Pruritus/pain 90% improvement QOL Peterson, 63 adult males Stricture repair Urethral Surgery 52/63 patients opted for perineal 72

73 Urology 2004; 64: Retrospective Mean age 54 years /Perineal urethrostomy stricture due to LS F/up 38 months (4-117) urethrostomy and were happy with outcome Adverse effect 4/36 Xu, Urology 2014; 83: Retrospective 36 adult males Mean age 52 years (range 32-80) Stricture repair using either BMM or lingual MM Urethral stricture due to LS Surgery F/up mean 39 months (range ) 90% success urinary flow rate. Rourke, J Urol 2012; 187:e36. Retrospective 39 adult males Mean age 52 years Urethral stricture Surgery 1. Staged reconstruction (14) 2. One-stage on-lay reconstruction (13) 3. Urethrostomy (12) Urethral stricture due to LS F/up 40 months 1. 79% success 2. 54% success 3. 92% success (p=0.04 when compared to One-stage on-lay) ii) Persistence of urinary symptoms (6 months) 1. 21%; 2. 62%; 3. 8% Urethral patency on cystoscopy 1. 92%; 2. 83%; % Conference abstract Shows success with urethrostomy Simsek, Arch Ital Urol Androl 2014; 86:23-5. Retrospective Trivedi, Urol Int 2008; 12 adult males Mean age 39.3 years (range 36-49) 153 adult males Mean 35.4 Meatoplasty with buccal MM graft Graft repair of urethral stricture using skin or oral Urethral (distal) stricture due to LS Urethral stricture Surgery F/up mean 21 months (range 4-96) Surgery F/up 12 Consistent improvement in urinary peak flow rate Pre-treatment peak flow rate = 4.18 ml/s mean; post-treatment = 22.4 ml/s mean at 1 month No stricture recurrence at F/up All grafts overall success rate = 57%. Mucosal grafts 92% success 73

74 81: Retrospective years (range 23-65) mucous membrane, ventral onlay due to LS months rate. Measured by uroflowmetry at 3 months and 1 year Acimovic, Int Urol Nephrol 2016; 48: Retrospective 32 adult males Mean age 48.9 years (range 33-64) BMG graft repair of urethral stricture using dorsal urethroplasty (23) or 2-stage repair (9) Urethral stricture due to LS Surgery F/up mean 28.1 (range 10-48) Assessed uroflowmetry mean (range). Pre-treatment 6.2 ml/min ( ); post-treatment (9 months) 18.2 ml/min ( ), (p<0.002) No difference in results between I and 2 stage repair Assessed need for further intervention % had good result Monteiro, Skin Cancer 2002; 17:9-14. Retrospective 10 adult males Mean age 42 years (range 17 74) Patients with LS treated with circumcision LS penis, glans, foreskin Surgery F/up 11 months 3 years Complications 9.4%, haematoma and fistula 9 clear, 1 improved PGA Retrospective review of case notes Reichrath, Dermatology 2002; 205: Prospective Mixed m/f adult (n=12; including 5 with LS)* 2 adult male Topical 8-MOP PUVA up to 4x/week, start in 0.5 J/cm 2 increasing by 0.5 J/cm 2 every 3 visits Genital LS F/up period not stated 1 improved. 1 no change *See G.3 for adult female Mean age 54.5 (range 49-60) 74

75 Hrebinko, J Urol 1996; 156: adult males Mean age 64.5 years (range 51-78) CO 2 laser Genital LS, meatal stenosis Treatment F/up months Improvement in urinary function 100% Kartamaa, Br J Dermatol 1997; 136: Mixed m/f adult (n=10)* 5 males Mean age 32.6 years (range 19-56) CO 2 laser Genital LS, urethral Treatment F/up 3-79 months Clinical clearance of genital disease in all 5 cases (PGA) Urethral lesions did not respond One had urethral lesion which recurred *See G.3 for adult females LS and G.10 for EG Windahl, Scand J Urol Nephrol 2006; 40: Retrospective 62 adult males Mean age 43 years (range 22-78) CO 2 laser Penile LS Treatment F/up median 14 years (range 5-19 years) 80% clear - Pt GA 16% improved, symptoms and appearance Pt GA F/up patient survey: 9 had died and 3 unable to contact 75

76 G.8 MALE (ADULT): CASE REPORTS Study reference Study population Pandher, J Urol 1 adult 2003; 170:923. male 28 years Lowenstein, JAMA Dermatol 2013; 149:23-4. Feig, Br J Dermatol 2016; 174: Abikhair, Australas J Dermatol 2013; 54: adult male 60 years 1 adult male 69 years 1 adult male Intervention Condition Treatment duration/f/up Tacrolimus 0.1% twice Penile LS 3 months daily F/up 9 months Intradermal adalimumab each fortnight for 3 months then 6-weekly for 5 months Adalimumab 40 mg intralesionally each fortnight for 8 weeks then subcutaneous adalimumab each 2 weeks Bariatric surgery for obesity then penile reconstructive surgery Penile LS Treatment for 8 months LS Penile and urethral LS Penile LS and obesity Continuous treatment F/up 15 months Not stated Outcome Improved PGA Nearly clear for 8 months - PGA Clear PGA Urinary function spontaneous voiding of urine but needing occasional catheterisation Significant weight loss that allowed reconstructive plastic surgery to be performed - improvement in appearance, function and QOL Notes After 8 months, the disease relapsed after a 10-week wait for treatment. Resumed fortnightly treatment at 11 months, with similar improvements. Penile and urethral LS with previous urethral surgery and selfcatheterisation. During treatment urethra appeared normal Conference abstract Considered unfit for surgical intervention on presentation due to co-morbidities 76

77 G.9 MIXED (ADULT MALE & FEMALE and FEMALE CHILDREN & YOUNG PEOPLE): CASE SERIES Study reference & design Study population Intervention Condition Treatment duration/ F/up Outcome Notes Hengge, Br J Dermatol 2006; 155: Prospective Mixed m/f adult and female child (n = 84) 3 females <18 years 49 adult females 32 adult males Mean age 59 years (range 5-82) Tacrolimus 0.1% ointment twice daily EG and anogenital LS, biopsy proven 16 weeks F/up 18 months Results in male/female/eg not distinguished 77% showed partial or complete improvement PGA Complete response 16% at 16 weeks, 43% at 24 weeks Symptoms significant improvement symptom score mean (SD) pretreatment 3.7(2.9); posttreatment at week (2.2); (p=0.05) Attrition (n=14) at 16 weeks, (n=32 at 18 months) Rates of improvement similar in m/f Clinical grading score 0-3; symptom score 0-3 Improved selfesteem - Pt GA 77

78 G.10 EXTRAGENITAL LS: CASE SERIES Study reference & design Shelley, Int J Dermatol 2006; 45: Kartamaa, Br J Dermatol 1997; 136: Kreuter, J Am Acad Dermatol 2002; 46: Prospective Rombold, Photodermatol Photoimmunol Photomed 2008; 24: Study population Mixed m/f adult (n=15)* 4 females 4 cases were extragenital Mean age 53.3 years (range 37-69) Mixed m/f (n=10)* 3 females Mean age 61.3 years (range 54-70) Mixed m/f (n=10) 8 females, 2 males Mixed m/f (n=10) 9 females, 1 male Intervention Condition Treatment duration/ F/up Antibiotics penicillin IM +/- oral or amoxicillin and penicillin Outcome Notes EG LS Not stated Improvement *See G.3 for adult female and G.7 for adult male CO 2 laser EG LS 1 treatment F/up 8 months to 5 years UVA1 4 times/ week - total 40 treatments UVA1 mean no treatment = 20 EG LS 10 weeks F/up 1 year EG LS /-8.7 sessions 1 clear after 2 treatments PGA 1 clear - PGA 1 improved - PGA and QOL PGA CS (mean)pre= 7.6 (0.84), post= 2.3(0.95). Ultrasound, epidermal thickness improved Histopathology - improved 80% improved - PGA (slight 40%, moderate 30%, marked 10%) *See G.3 for adult female and G.7 for adult male Assessed with clinical score (CS) 78

79 Retrospective Kreuter, Arch Dermatol 2009; 145: Retrospective Mixed m/f (n=7) adults 6 females, 1 male Mean age 67 years (range Methylprednislone 1 g once daily for 3/7 each month Methotrexate 15 mg once weekly EG LS 6 months F/up 3 months (no relapse) Symptoms improved in 2 patients Clinical score (mean) pretreatment=8 (5-24); posttreatment = 2(1-4) (p=0.2) Assessed using clinical score 50 80) Kim, J Dermatol 2012; 39: Prospective Mixed m/f (n=6) 4 females, 2 males Mean age 22.5 years (range 9-50) Tacrolimus 0.1% twice daily EG LS Also vulval and male genital 4 12 weeks mean 8/52 No F/up 1/6 improved PGA No response symptoms QOL Graded complete, partial, no response McGilfis, Cutis 1970; 6: adult females Mean age 51.6 years (range 43-70) Flurandrenolone tape 4 mcg/cm 2 EG LS 2 weeks continuous 4/7 improved PGA or Pt GA 2/7 improved symptoms, QOL Malakar, Dermatology 1997; 195:412. Mixed adult m/f (n=2) Male, 24 years, Pinch grafting using technique used in vitiligo EG LS F/up 1 year Clear PGA and histology Case reports female, 32 years 79

80 G.11 EXTRAGENITAL LS: CASE REPORT Study reference Study population Intervention Condition Treatment duration/f/up Outcome Notes Di Silverio, Br J Dermatol 1975; 93: adult male 64 years ACTH 1 mg alternate days for 16 days EG LS 16 days F/up 3 months QOL clear PGA improved García-Doval, Clin Exp Dermatol 1996; 21: adult female 70 years Hydroxychloroquine 200 mg EG LS 4 months No F/up No response PGA Letter Wakelin, Clin Exp Dermatol 1994; 19: adult female 55 years Hydroxychloroquine 200 mg EG LS 3 months No F/up Symptoms clear PGA improvement Lo Scocco, Ital Dermatol Venereol 1994; 129: adult female 19 years Ciclosporin 3 mg/kg/day EG LS LS vulval 4 months No F/up Bullous element cleared but EG lesion remained PGA In Italian. Bullous LS Nayeemuddin, Clin Exp Dermatol 2008; 33: adult female 49 years Methotrexate 10 mg/week EG LS 8 months F/up 6 months Clear - PGA Alexiades- Armenakas, J Drugs Dermatol 2004; 3:S adult female 67 years ALA-LP PDL vs LP PDL. 3 treatments EG LS 3 monthly treatments F/up 1 month Improvement with ALA LP PDL PGA and symptoms None with LP-PDL Used a clinical score (PGA) Pretreatment =8, Post-treatment LP PDL = 6; ALA PDL = 1 Passeron, Dermatol Surg 2009; 35: adult female 60 years PDL PDT vs PDL (control) EG LS 2 treatments 1 month apart F/up 1 month Improvement (+) PDL alone - PGA, PtGA 80

81 Improvement (++) PDL PDT, PGA, PtGA Arican, J Dermatol 2004; 31: adult male 74 years Pimecrolimus 1% twice daily 16 weeks EG LS 16 weeks End of treatment period No response Pt GA Histological assessment no response Kim, Ann Dermatol 2010; 22: female child 7 years Pimecrolimus 1% twice daily Oral LS 2 months F/up 30 months Clear PGA Kreuter, Br J Dermatol 2002; 146: adult female 69 years Calcipotriol twice daily under PO EG LS 3 months F/up 6 months Clear - PGA Letter Basak, J Eur Acad Dermatol Venereol 2002; 16: adult male 57 years Acitretin 30 mg 2 months, 20 mg 3 months EG LS (scalp) 5 months F/up 6 months Improvement - PGA, QOL Letter Formiga Ade, Skinmed 2014; 12: adult female 61 years Acitretin (?dose) EG LS 12 months F/up 2 years Improvement without relapse PGA Neuhofer, Acta Derm Venereol 1984; 64: Mixed m/f (n=8)* 1 female patient EG LS Etretinate 0.5 mg/kg/day EG LS 3 12 months for patient group length of treatment for EGLS not stated Non-responder - PGA *See G.4 for adult female, G.7 for adult male and G.9 for juveniles LS Bookout, J Am Acad Dermatol 2011; 64:AB53. 1 adult female 67 years desoximetasone 0.25% followed by calcitriol 3 mcg/g ointment EG LS 2 months treatment Improvement PGA Conference abstract Brouillard, Photodermatol Photoimmunol 1 adult female 64 years Extracorporeal phototherapy 2 treatments every 2 EG LS 27 months F/up 3 months(relapsed) Improvement PGA and symptoms on treatment 81

82 Photomed 2013; 29: weeks DLQI fell from 15 to 4 QoL Relapsed off treatment at 3 months Colbert, Arch Dermatol 2007; 143: adult female 76 years NB UVB x 3per week EG LS 3 months 3 times/week then 2 times/week F/up 3 months Improvement PGA and symptoms (QOL) Dalmau, J Am Acad Dermatol 2006; 55:S female child 10 years PUVA EG LS 2 times/week for 4 weeks, once/week for 8 week F/up 18 months Clearance - PGA Letter von Kobyletzki, Hautarzt 1997; 48: adult female 66 years Bath PUVA EG LS 24 treatments F/up not stated Improvement - PGA Improvement pruritus QOL In German Improvement histology Valdivielso- Ramos, Am J Clin Dermatol 2008; 9: adult female 62 years PUVA twice weekly Topical tacrolimus 0.1% twice daily reducing to once daily EG LS Tacrolimus given for 18 months PUVA given for 24 weeks F/up 6 months after stopping treatment Improvement PGA Ronger, J Drugs Dermatol 2003; 1 adult male 53 years Calcitriol 0.5 mcg once daily EG LS 12 months F/up 6 months Improvement (PGA) 82

83 2:23-8. Guerriero, Int J Immunopathol Pharmacol 2008; 21: female child 11 years CP 2 weeks, retinaldehyde 4 weeks for 3 months EG LS 3 months no F/up Clear PGA Klein, J Am Acad Dermatol 1984; 10: adult female 68 years Partial thickness tangential excisions EG LS 23 months Disease free for 12 months - PGA Relapsed at 12 months. Retreated 20 months and clear at 3 months Mendieta-Eckert, J Cosmet Laser Ther 2017;19: adult female 63 years Ablative fractional erbium YAG laser, 3 treatments over 6 months EG LS at site of excision 2 years 70% clinical improvement 83

84 Appendix H: Summary of topical steroids case series/reports (female) Study reference No of patients Intervention CP 0.05% Casey, Clin Exp Dermatol 2015; 40: girls (2 studies) CP 0.05% (n=72) compared with a retrospective study of 31 girls treated with moderately potent topical steroids. CP superior (72.6% versus 32.2% clearance of Cooper, Arch Dermatol 2004; 140: Corazza, J Eur Acad Dermatol Venereol 2016; 30: Dalziel, Br J Dermatol 1991; 124: Diakomanolis, Eur J Gynaecol Oncol 2002; 23: Friedman, Cervix Low Female Genital Tract 1994; 12:21-4. Lorenz, J Reprod Med 1998; 43: Murina, J Low Genit Tract Dis 2015; 19: Patrizi, Pediatr Dermatol 2010; 27: Renaud-Vilmer, Arch Dermatol 2004; 140: Schwarz, Geburtshilfe Frauenheilkd; 2008; 68: Schwegler, Dermatology 2011; 223: Smith, Obstet Gynecol 2001; 98: Chari, J Obstet Gynaecol 1994; 14: adult females, 74 girls symptoms) CP 0.05% (208 women and 31 girls), clobetasone butyrate 0.05% (10 women, 20 girls), betamethasone 0.1% (7 women, 4 girls), beclometasone dipropionate 0.025% (7 women, 3 girls) and 1% hydrocortisone in 4 girls 48 adult females CP 0.05% or 0.1% mometasone furoate twice weekly as long-term maintenance treatment 15 adult females CP 0.05% cream twice daily for 12 weeks 54 adult females CP 0.05% for 3 months or 6 months 27 adult females CP 0.05% cream twice daily 81 adult females CP 0.05% 96 adult females CP 0.05% (n=46) or mometasone furoate 0.1% (n=49) for 8 weeks, retrospective comparative case series 15 girls CP 0.05% 83 adult females CP 0.05% once daily for 3 months then 3x/week until remission 96 adult females CP 0.05% for at least 12 weeks 96 adult females CP 0.05% improved quality of life 15 pre-pubertal girls CP 0.05% for 2-4 weeks then reducing to less potent topical steroid 34 adult females CP 0.05% 4 weeks, followed by betamethasone 0.1% 4 weeks, then1% hydrocortisone for 4 weeks 84

85 Cattaneo, J Reprod Med 2003; 48: Corazza, J Eur Acad Dermatol Venereol 2016; 30: Murina, J Low Genit Tract Dis 2015; 19: Virgili, Br J Dermatol 2013; 168: Virgili, J Eur Acad Dermatol Venereol 2014; 28: Cooper, Arch Dermatol 2004; 140: Fischer, Pediatr Dermatol 1997; 14: Cooper, Arch Dermatol 2004; 140: Patsatsi, J Dermatolog Treat 2013; 24: Garzon, Arch Dermatol 1999; 135: Lee, JAMA Dermatol 2015; 151: Clark, J Reprod Med 1999; 44: Sinha, P. J Reprod Med 1999; 44: Mometasone furoate 0.1% 31 adult females Mometasone furoate 0.1% 48 adult females Mometasone furoate 0.1% or CP 0.05% twice weekly of as long-term maintenance treatment 96 adult females Mometasone furoate 0.1% (n=49) or CP 0.05% (n=46) for 8 weeks retrospective comparative case series 27 adult females Mometasone furoate 0.1% for 12 weeks then twice weekly for 52 weeks 137 adult females Mometasone furoate 0.1% for 12 weeks Betamethasone 0.1%/ Betamethasone dipropionate 0.05% 253 adult females, 74 Betamethasone 0.1% (7 women, 4 girls), CP 0.05% (208 women and 31 girls), girls clobetasone butyrate 0.05% (10 women, 20 girls), beclometasone dipropionate 0.025% (7 women, 3 girls) or 1% hydrocortisone (4 girls), 11 girls Betamethasone dipropionate 0.05% three times a day (7 in optimized vehicle) for 3 weeks then twice daily until symptoms and signs cleared Clobetasone butyrate 0.05%, beclometasone dipropionate 0.025% or hydrocortisone 1% 253 adult females, 74 girls Clobetasone butyrate 0.05% (10 women, 20 girls), beclometasone dipropionate 0.025% (7 women, 3 girls), hydrocortisone 1% (4 girls), CP 0.05% (208 women and 31 girls) or betamethasone 0.1% (7 women, 4 girls) Methylprednisolone aceponate 0.1% 46 adult females Methylprednisolone aceponate 0.1% Various topical steroids 10 pre-pubertal girls Various potent topical steroids 507 adult females Various topical steroids individualized to patient requirements 137 adult females 3-month regimen of reducing potency of topical steroids 54 adult females 3-month reducing regime of topical steroids 85

86 Appendix I: PRISMA diagram study selection Records identified through database searching (n=2973) Additional records identified through other sources (n=7) Titles initially screened (n=2980) References excluded by title (n=2086) Abstracts screened for eligibility according to protocol (n=894) References excluded by abstract (n=619) Unable to obtain full text of reference (n=5) Full-text papers assessed for eligibility (n=270) Papers excluded from quantitative review (n=255) Reasons for exclusion: see Appendix J Papers included in quantitative review (n=15) Female (n=11) Male (n=2) Female & Male (n=1) Systematic review (n=1) 86