Clearance in vulvar lichen sclerosus: a realistic treatment endpoint or a chimera?

DOI: 10.1111/jdv.14516 JEADV SHORT REPORT Clearance in vulvar lichen sclerosus: a realistic treatment endpoint or a chimera? A. Borghi,* A. Virgili, S. Minghetti, G. Toni, M. Corazza Dipartimento di Scienze Mediche, Sezione di Dermatologia e Malattie Infettive, Universita degli Studi di Ferrara, Ferrara, Italy *Correspondence: A. Borghi. E-mail: alessandro.borghi@unife.it Abstract Background According to the current guidelines, the aim of vulvar lichen sclerosus (VLS) treatment was to improve symptoms and signs, not to cure. Objective To assess (i) the rate of patients with VLS who achieved complete clearance of symptoms or objective features, or both, with a pharmacological treatment and (ii) the predictive value of therapeutic response to the demographic and clinical features. Methods We retrospectively included patients with VLS who had undergone any topical treatment for 12 weeks; demographics, history, VLS-related symptoms and objective features recorded at baseline and on completion of treatment were collected and elaborated. The primary study endpoint was to assess the rate of patients achieving complete clearance of global subjective score (GSS), or in global objective score (GOS), and in both scores. Results One hundred and ninety-six patients were included; 24 (12.2%) were asymptomatic at baseline, and nine (4.6%) dropped out. After treatment, 78 patients (47.3%) achieved GSS = 0, 40 (21.4%) achieved GOS = 0, and 23 (13.9%) achieved complete clearance of both symptoms and signs. Lower symptom scores at baseline and shorter disease duration were associated with the achievement of symptom clearance at the end of the treatment. Earlier disease onset, diagnosis and beginning of study treatment as well as lower baseline GOS were significantly associated with complete recovery of VLS signs and clearance of both symptoms and signs. Conclusion A relevant part of patients who undergo a topical treatment is not completely cured of VLS. It may be hypothesized that these patients, in spite of a significant improvement, may still have substantial residual disease and, as a result, its effect on their quality of life. Received: 1 February 2017; Accepted: 28 July 2017 Conflicts of interest None declared. Financial disclosure None declared. Introduction In our previous studies on the active treatment of vulvar lichen sclerosus (VLS), complete clearance of symptoms and objective features was not assessed, as it was considered an arduous treatment target in this chronic disease. 1 4 This study purposely investigated the occurrence of complete clearance in a large cohort of patients with VLS treated with different pharmacological therapies. Materials and methods Study design and objectives This study was set up as a single-centre retrospective cohort study. The aim was to assess: (i) the rate of patients with VLS achieving complete clearance of symptoms, objective features or both, with a active treatment phase (ATP); (ii) the predictive demographic and clinical features on achieving VLS clearance. Study patients All adult patients with a clinical and, when available, histological diagnosis of VLS who had undergone any topical pharmacological treatment for a ATP, between January 2012 and June 2016 at our Vulva Unit, were retrospectively evaluated for inclusion. Most of these treatment courses were part of comparative studies, with or without randomization. Patients were excluded from the study in the presence of the following: clinical or histological features showing possible resemblance to other

Clearance in vulvar lichen sclerosus 97 diseases such as lichen planus, vulvar intraepithelial neoplasia or plasma cell vulvitis; lack of agreement between clinical and histological features; treatment with non-pharmacological actives; and active vulvar infectious diseases or carcinoma. One hundred and ninety-six patients were included. Their treatments are reported in Table 1. Study assessment The data were recorded as follows: (i) age at the beginning of treatment; (ii) age at the onset of VLS; (iii) age at diagnosis; (iv) disease duration; (v) previous with topical corticosteroids. Subjective evaluation of the following two symptoms, itching and burning, was obtained for each patient using a visual analogue scale (VAS, which includes a numeric rating scale 0 10). A Table 1 Treatment regimens of the patients included in the study Patients (n.) Treatment regimen ( duration) 79 0.1% of MMF ointment once daily, at tapering regimen, as previously described 1,2 52 0.1% of MMF ointment once daily for five consecutive days per week 27 0.05% of CP ointment once daily, at tapering regimen, as previously described 1,2 21 0.1% of MMF ointment and 0.05% of tretinoin cream, for five consecutive days per week 17 0.025% of tretinoin cream once daily, every other day MMF, mometasone furoate; CP, clobetasol propionate. global subjective score (GSS) was obtained by summing each symptom parameter (highest GSS = 20). As dyspareunia was not evaluated in 99 study patients (50.5%) who avoided sexual activity for reasons other than disease-related pain, this symptom was considered only in the sexually active patients (97, 49.5%). The objective parameters were considered as follows: (i) leukoderma (pallor), (ii) hyperkeratosis and (iii) purpuric lesions and itching-related excoriations; although it is not universally regarded as a specific VLS sign, (iv) erythema was considered as well. Objective assessment of each sign was performed using the following 4-point scale: 0 = absent, 1 = mild, 2 = moderate and 3 = severe. A global objective score (GOS) was obtained by summing each clinical parameter (highest GOS = 12). Objective and subjective patient assessment was performed in consensus by the same investigators at baseline and at the 12- week control visit. The investigators were either blinded or unblinded to treatment depending on the design of the studies from which the patients had been retrospectively recruited (i.e. comparative or non-comparative studies, with or without blinded investigators). Main outcome measures The primary study outcome was to assess the rate of patients achieving complete clearance of symptoms, i.e. GSS = 0, in objective features; GOS = 0; and in both scores, i.e. GSS and GOS = 0. The secondary outcome was to analyse whether demographic or clinical features may condition the achievement of VLS clearance with topical treatments. Statistical analyses Binary data were analysed with chi-squared or Fisher s exact test according to conditions. Quantitative data were analysed by means of t-test, in the case of normality and homoscedasticity, or by means of Mann Whitney U-test. Statistical significance was defined as P < 0.05. Data were analysed using R 3.1.2 statistical program. Results Figure 1 Four cases who achieved a clearance of objective features active treatment phase with (a) 0.1% of mometasone furoate ointment, at tapering regimen; (b) 0.05% of clobetasol propionate ointment, at tapering regimen; (c) 0.1% of mometasone furoate ointment and 0.05% of tretinoin cream, for five consecutive days per week, (d) 0.025% of tretinoin cream once daily, every other day. Baseline (a, b, c, d) and treatment (a 0, b 0,c 0,d 0 ) in the same patients Patient characteristics Demographic and disease features of the study patients, both at baseline and treatment, are reported in Table 2. Twentyfour patients (12.2%) were asymptomatic at baseline; i.e., they had GSS = 0 at treatment initiation. Efficacy evaluations During the treatment courses, nine patients (4.6%) dropped out because they were lost to follow-up; among these patients, two were asymptomatic at baseline.

98 Borghi et al. Table 2 Demographic and clinical data at baseline and a treatment of the patients included in the study Baseline After treatment Number of patients (%) 196 (100%) 187* (95.4%) Mean age, years Mean value 63.44 (range) (16 89) [SD] [12.67] Mean age at VLS onset, years Mean value 58.49 (range) (12 83) [SD] [13.08] Mean age at diagnosis of VLS, years Mean value 61.02 (range) (16 86) [SD] [12.64] Mean duration of VLS, months Mean value, 4.83 (range) (0 60) [SD] [6.56] Previous treatment with corticosteroids, Patients, n. (%) 87/196 (44.4%) Histology Patients, n. (%) 135/196 (68.9%) Itching Patients, n. (%) 164/196 (83.7%) 68/187 (36.4%) Mean value, 5.82 1.08 (range) (1 10) (1 10) [SD] [3.46] [1.94] Burning Patients, n. (%) 131/196 (66.8%) 68/187 (36.4%) Mean value, 4.30 1.00 (range) (1 10) (1 10) [SD] [3.67] [1.77] Dyspareunia Patients, n. (%) 59/97 (60.8%) 41/94 (43.6%) Mean value, 7.47 2.44 (range) (2 10) (0 10) [SD] [2.44] [2.94] GSS Mean value, 10.13 2.08 (range) (0 20) (0 20) [SD] [6.19] [3.31] Leukoderma (pallor) Patients, n. (%) 186/196 (94.9%) 126/187 (67.4%) Mean value 2.16 0.94 (range) (0 3) (0 3) [SD] [1.03] [0.83] Erythema Patients, n. (%) 83/196 (42.3%) 52/187 (27.8%) Mean value 0.63 0.32 (range) (1 3) (1 2) [SD] [0.86] [0.55] Table 2 Continued Baseline After treatment Hyperkeratosis Patients, n. (%) 146/196 (74.5%) 30/187 (16%) Mean value, 1.13 0.20 (range) (1 3) (1 2) [SD] [1.07] [0.49] Purpuric lesions and itching-related excoriations Patients, n. (%) 170/196 (86.7%) 20/187 (10.7%) Mean value, 1.02 0.13 (range) (1 3) (1 3) [SD] [1.29] [0.43] GOS Mean value, 4.95 1.60 (range) (1 11) (1 8) [SD] [2.64] [1.41] *Nine patients dropped out because they were lost to follow-up. Sexually active patients. Three patients dropped out among those with sexual activity. Calculated as VAS from 0 to 10. Calculated from 0 to 3. GSS, global subjective score (0 20); GOS, global objective score (0 12); VLS, vulvar lichen sclerosus; SD, standard deviation;, not applicable. Regarding the main study efficacy outcome, at the end of the ATP: (i) 78 patients (47.3% of the 165 patients symptomatic at baseline who completed the treatment) achieved GSS = 0; (ii) 40 patients (21.4% of the 187 patients who completed the treatment) achieved GOS = 0 (Fig. 1); and (iii) 23 patients (13.9% of the 165 patients who referred symptoms at baseline and completed the treatment) achieved complete clearance of both symptoms and signs. Among the 59 patients complaining of dyspareunia, 18 (30.5%) reported a resolution of this symptom and 17 (28.8%) full symptom clearance at the end of treatment. Relevance of demographics and clinical features on clearance Demographics and clinical data at baseline of patients who reached, or did not reach, clearance of (i) symptoms, (ii) signs and (iii) both symptoms and signs at the end of the treatment are reported and compared in Table 3. Lower scores of itching, burning and GSS at baseline, shorter mean disease duration and a lower mean score of pallor before treatment were found to be significantly associated with complete clearance of symptoms at the end of treatment (Table 3). Earlier disease onset, diagnosis and initiation of study treatment were significantly associated with complete clearance of VLS signs (Table 3). Lower baseline scores of clinical features were significantly related to the achievement of complete objective healing treatment, too.

Clearance in vulvar lichen sclerosus 99 Table 3 Comparison of demographic and clinical data between patients who achieved or did not achieve (a) symptom clearance (i.e. GSS = 0 vs. GSS 1); (b) sign clearance (i.e. GOS = 0 vs. GSS 1); (c) symptom and sign clearance (i.e. GSS and GOS = 0 vs. GSS and GOS 1) 12 weeks of treatment Number of patients* GSS = 0 GSS 1 P GOS = 0 GOS 1 P Overall clearance GOS = 0) Not clearance GOS 1) 78/165 (47.3%) 87/165 (52.7%) 40/187 (21.4%) 147/187 (78.6%) 23/165 (13.9) 142/165 (86.1%) Mean age, years Mean value 62.52 64.86 0.41 59.42 64.51 0.01 58.30 64.64 0.03 (range) (16 86) (17 89) (40 80) (16 89) (40 80) (16 89) [SD] [14.07] [11.76] [12.39] [12.63] [13.37] [12.67] Mean age at VLS onset, years Mean value 58.39 59.20 0.94 54.69 59.38 0.02 53.60 59.70 0.03 (range) (12 83) (17 83) (37 75) (12 83) (37 73) (12 83) [SD] [14.36] [12.57] [12.47] [13.01] [13.18] [13.27] Mean age at diagnosis of VLS, years Mean value 60.74 62.33 0.70 56.85 64.51 0.02 55.69 62.53 0.02 (range) (16 86) (17 84) (37 78) (16 89) (37 73) (16 86) [SD] [14.13] [11.91] [11.99] [12.39] [12.38] [12.88] Mean duration of VLS, months Mean value 3.63 5.65 0.05 4.89 4.93 0.84 4.69 4.73 0.76 (range) (0 23) (0 60) (0 23) (0 60) (0 23) (0 60) [SD] [4.70] [7.99] [5.73] [6.90] [6.30] [6.83] Previous treatment with corticosteroids Patients, n. (%) 22/78 (28.21%) 48/87 (55.17%) <0.01 20/40 (50%) 63/147 (42.86%) 0.42 9/23 (39.13%) 61/142 (42.96%) 0.73 Itching Patients, n. (%) 73/78 (93.58%) 83/87 (95.40%) 34/40 (85%) 123/147 (83.67%) 21/23 (91.30%) 135/142 (95.07%) Mean value 6.10 7.11 0.02 6.02 5.80 0.77 6.82 6.60 0.55 (range) (0 10) (0 10) (0 10) (0 10) (0 10) (0 10) [SD] [2.97] [2.75] [3.47] [3.47] [3.21] [2.85] Burning Patients, n. (%) 28/78 (35.89%) 72/87 (82.75%) 21/40 (52.5%) 101/147 (68.70%) 12/23 (52.17%) 110/142 (77.46%) Mean value 4.07 5.51 <0.01 3.30 4.53 0.06 3.78 5.00 0.16 (range) (0 10) (0 10) (0 10) (0 10) (0 10) (0 10) [SD] [3.53] [3.45] [3.71] [3.64] [4.04] [3.45] GSS Patients, n. (%) 78/78 (100%) 87/87 (100%) 35/40 (87.5%) 130/147 (88.43%) 23/23 (100%) 142/142 (100%) Mean value, 10.17 12.63 <0.01 9.32 10.34 0.32 10.60 11.61 0.33 (range) (1 20) (2 20) (0 20) (0 20) (2 20) (1 20) [SD] [5.17] [5.08] [5.76] [6.27] [5.44] [5.22] Leukoderma (pallor) Patients, n. (%) 75/78 (96.15%) 83/87 (95.40%) 38/40 (95%) 139/147 (94.55%) 23/23 (100%) 135/142 (95.07%) Mean value 2 2.34 0.03 1.62 2.29 <0.01 1.82 2.23 0.03 (range) (0 3) (0 3) (0 3) (0 3) (1 3) (0 3) [SD] [0.68] [1.26] [0.74] [1.07] [0.57] [1.09] Erythema Patients, n. (%) 44/78 (56.41%) 37/87 (42.52%) 12/40 (30%) 67/147 (45.57%) 7/23 (30.43%) 62/142 (43.66%) Mean value 0.62 0.62 0.95 0.32 0.72 0.04 0.30 0.67 0.13 (range) (0 3) (0 3) (0 2) (0 3) (0 1) (0 3) [SD] [0.86] [0.83] [0.52] [0.91] [0.47] [0.88] P

100 Borghi et al. Table 3 Continued Hyperkeratosis GSS = 0 GSS 1 P GOS = 0 GOS 1 P Overall clearance GOS = 0) Not clearance GOS 1) Patients, n. (%) 53/78 (67.94%) 46/87 (52.87%) 20/40 (50%) 94/147 (63.94%) 17/23 (73.91%) 82/142 (57.74%) 0.83 Mean value, 1.23 0.97 0.13 0.77 1.20 0.03 1.08 1.09 (range) (0 3) (0 3) (0 2) (0 3) (0 2) (0 3) [SD] [1.05] [1.04] [0.86] [1.08] [0.79] [1.09] Purpuric lesions and itching-related excoriations Patients, n. (%) 52/78 (66.66%) 39/87 (44.82%) 17/40 (42.5%) 80/147 (54.42%) 12/23 (52.17%) 79/142 (55.63%) Mean value, 1.12 0.18 0.05 0.62 1.10 0.07 0.69 1.11 0.28 (range) (0 3) (0 3) (0 3) (0 3) (0 2) (0 3) [SD] [0.98] [0.56] [0.83] [1.38] [0.76] [1.37] GOS Patients, n. (%) 78/78 (100%) 87/87 (100%) 40/40 (100%) 147/147 (100%) 23/23 (100%) 142/142 (100%) Mean value, 4.98 4.94 0.70 3.35 5.33 <0.01 3.91 5.13 0.04 (range) (1 11) (1 18) (1 6) (1 11) (1 6) (1 11) [SD] [2.42] [2.83] [1.67] [2.70] [1.50] [2.74] *24 patients were asymptomatic at baseline; i.e., they had GSS = 0 at treatment initiation, and nine patients dropped out because they were lost to follow-up. Two patients among those who dropped out were asymptomatic at baseline. Calculated as VAS from 0 to 10; calculated from 0 to 3; GSS, global subjective score (0 20); GOS, global objective score (0 12). Mann Whitney test; P value was calculated for differences in mean values or rates of patients. VLS, vulvar lichen sclerosus; SD, standard deviation. P Complete clearance of both symptoms and signs was associated with earlier VLS onset, diagnosis and treatment, as well as with lower GOS at baseline. Discussion The ultimate goal for patients with VLS undergoing specific treatments is to be free from the distressing symptoms and sexual dysfunction caused by the disease. 5 Achieving objective normality of skin colour and texture is another key endpoint of treatment. 6 However, according to the current guidelines, the aim of VLS treatment is not to cure, but simply to improve symptoms and objective features. 7,8 It may be hypothesized that patients who respond to treatment, even with significant improvement, but without complete clearance, may still have substantial residual disease and its resultant effect on their quality of life. This study specifically addressed the issue of the occurrence of VLS clearance with a topical treatment. The results of our study indicate that less than half of the patients reached complete resolution of VLS-related symptoms, namely itching and burning, on completion of a treatment. The rate of patients who reached complete resolution of objective features was even lower than this, i.e. 21%. Only about 14% of the study patients achieved complete resolution of both symptoms and signs. These findings strongly support the view that clearance of VLS is a hard treatment outcome, despite the significant improvement of symptoms and signs on completion of the treatment (Table 2). In accordance with previous experiences, 6 it may be hypothesized that treatment courses that are longer than the conventional duration of the active phase may be necessary to increase the likelihood of complete clearance. Prospective comparative studies are needed to assess the treatment duration aimed to achieve a complete VLS resolution. Our results also showed that with treatments of duration, as previously reported, 8 10 complete clearance of symptoms is a more realistic outcome than the clearance of objective features. Among the sexually active patients, the rate of those who reported resolution of dyspareunia was lower in comparison with the patients who achieved resolution of itching (OR = 0.3110, 95% CI 0.1647 0.5870, P < 0.001) and burning (OR = 0.4739, 95% CI 0.2470 0.9092, P = 0.02) on completion of treatment. It is worthy of note that the patients who achieved complete resolution of VLS-related symptoms had had a less severe overall symptom profile than those who did not. Clearance of symptoms was associated with both shorter duration of disease and lower scores of pallor. Younger age, both at diagnosis and at treatment administration, was found to be associated with clearance of objective features. Moreover, higher objective scores prior to beginning treatment were found to inversely affect the complete reversal of cutaneous changes.

Clearance in vulvar lichen sclerosus 101 Earlier diagnosis and initiation of treatment, as well as the younger age of patients and a lower global objective score at baseline, were the main predictive factors for complete clearance of both symptoms and signs. All these findings highlight the favourable effect of adequate and early treatment of VLS on its response to treatment and the course of the disease, as previously found. 6 A worst clinical picture, intense symptom presentation, advanced patient age and long-lasting disease seem to conspire against the possibility of a complete cure. The main limitation of this study is its retrospective design. All of the patients included were identified from a tertiary referral clinic; as such, the results of this study may not be representative of all the patient population. Sclerosis scarring and tissue atrophy were not included in the assessment of VLS response as they are not reversible to medical, or are only scarcely so. In this retrospective analysis, different pharmacological treatments and regimens have been grouped together. A comparison of VLS response to among the different treatment groups was not performed due to their numerical inhomogeneity. In conclusion, a topical treatment, although highly effective in ameliorating both symptoms and objective changes, is unlikely to induce a complete cure of VLS. As a result, a relevant part of the patients labelled as responders are not actually clear of the disease, and this may account for a divergence between physicians and patients perspectives regarding treatment outcome and satisfaction. 11 Acknowledgement The Authors would like to thank Ms. Silvia Giari for statistical guidance. References 1 Virgili A, Borghi A, Toni G, Minghetti S, Corazza M. First randomized trial on clobetasol propionate and mometasone furoate in the treatment of vulvar lichen sclerosus: results of efficacy and tolerability. Br J Dermatol 2014; 171: 388 396. 2 Borghi A, Corazza M, Minghetti S, Toni G, Virgili A. Continuous vs. tapering application of the potent topical corticosteroid mometasone furoate in the treatment of vulvar lichen sclerosus: results of a randomized trial. Br J Dermatol 2015; 173: 1381 1386. 3 Borghi A, Corazza M, Minghetti S, Virgili A. Topical tretinoin in the treatment of vulvar lichen sclerosus: an advisable option? Eur J Dermatol 2015; 25: 404 409. 4 Borghi A, Corazza M, Minghetti S, Toni G, Virgili A. Avocado and soybean extracts as active principles in the treatment of mild-to-moderate vulvar lichen sclerosus: results of efficacy and tolerability. J Eur Acad Dermatol Venereol 2015; 29: 1225 1230. 5 Schwegler J, Schwarz J, Eulenburg C et al. Health-related quality of life and patient-defined benefit of clobetasol 0.05% in women with chronic lichen sclerosus of the vulva. Dermatology 2011; 223: 152 160. 6 Lee A, Bradford J, Fischer G. Long-term management of adult vulvar lichen sclerosus: a prospective cohort study of 507 women. JAMA Dermatol 2015; 151: 1061 1067. 7 Kirtschig G, Becker K, G unthert A et al. Evidence-based (S3) Guideline on (anogenital) Lichen sclerosus. J Eur Acad Dermatol Venereol 2015; 29: e1 e43. 8 van der Meijden WI, Boffa MJ, Ter Harmsel WA et al. 2016 European guideline for the management of vulval conditions. J Eur Acad Dermatol Venereol 2017; 31: 925 941. 9 Neill SM, Lewis FM, Tatnall FM, Cox NH. British Association of Dermatologists guidelines for the management of lichen sclerosus 2010. Br J Dermatol 2010; 163: 672 682. 10 Virgili A, Borghi A, Minghetti S, Corazza M. Mometasone fuoroate 0.1% ointment in the treatment of vulvar lichen sclerosus: a study of efficacy and safety on a large cohort of patients. J Eur Acad Dermatol Venereol 2014; 28: 943 8. 11 van Cranenburgh OD, Nijland SB, Lindeboom R et al. Patients with lichen sclerosus experience moderate satisfaction with treatment and impairment of quality of life: results of a cross-sectional study. Br J Dermatol 2017; 176: 1508 1515.