Original Paper Dermatology 2014;228:145–151 DOI: 10.1159/000356163
Received: August 27, 2013 Accepted after revision: October 1, 2013 Published online: February 8, 2014
Prospective Clinical and Epidemiologic Study of Vulvar Lichen Sclerosus: Analysis of Prevalence and Severity of Clinical Features, together with Historical and Demographic Associations Annarosa Virgili Alessandro Borghi Giulia Toni Sara Minghetti Monica Corazza Department of Medical Sciences, Section of Dermatology, University of Ferrara, Ferrara, Italy
Abstract Background: Few reports have addressed the associations between clinical, demographic and historical variables of vulvar lichen sclerosus (VLS). Objective: To elaborate the prevalence and severity of signs and symptoms and to identify potential factors predicting the severity and course of VLS. Methods: A prospective cohort of 225 patients affected by VLS was included. Data were collected by direct interview and clinical examination. Results: 98% of patients complained of symptoms, principally itching. Pallor and scarringsclerosis-atrophy were the most frequent and severe signs. The severity of VLS signs was not associated with age at onset and duration of the disease. About 70% of the patients had previously undergone treatment. Conclusions: VLS-related symptoms were not associated with the clinical features which resulted less severe. Personal history of autoimmune diseases and familial history of VLS did not influence the age at onset and the severity of VLS. A considerable part of patients had previously received inappropriate treatment. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 1018–8665/14/2282–0145$39.50/0 E-Mail [email protected] www.karger.com/drm
Introduction
Vulvar lichen sclerosus (VLS) is a chronic inflammatory disease of the anogenital area. VLS can be found in patients of any age and race, but is most common in Caucasian females, with two peaks of incidence in the prepubertal and postmenopausal periods [1]. Patients with VLS complain mainly of itching, burning, pain, dyspareunia and sexual dysfunction [2, 3]. Affected women have an increased risk of genital cancers, with a lifetime risk of developing a squamous cell carcinoma estimated to be 2–5% [4, 5]. VLS has a considerable impact on healthrelated quality of life (QoL) and women with VLS have been found to experience a lower health-related QoL than the general population [6]. The number of symptoms seems to be correlated with the health-related QoL of women with VLS. The etiology of VLS is unknown, but there is an association with autoimmune disorders [7, 8] and genetic factors [3, 9]. Among the multiple pathogenetic factors, immunological alterations and chronic inflammatory mechanisms seem to be crucial [2–4]. Currently, a 3-month topical application of potent or ultra-potent corticosteroids is the mainstay of medical treatment for VLS [10–12]; however, the chronic relapsProf. Annarosa Virgili Department of Medical Sciences, Section of Dermatology University of Ferrara, Via Savonarola 9 IT–44100 Ferrara (Italy) E-Mail vri @ unife.it
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Key Words Vulvar lichen sclerosus · Objective signs · Symptoms · Treatment · Autoimmunity · Epidemiology
Materials and Methods Study Setting and Objectives We conducted an observational study in the setting of a prospective cohort of patients affected by VLS attending the Vulva Unit of the Dermatology Section of the University of Ferrara, Italy, between December 2006 and December 2012. Our Vulva Unit is a tertiary referral center for vulvar disorders. The aims of the study were (1) to assess the main demographic and clinical characteristics of patients affected by VLS, including family history of the disease and personal history of other autoimmune disorders, (2) to assess the clinical features of the disease, such as severity of signs and symptoms, (3) to elaborate the prevalence and severity of signs and symptoms and to identify possible associations between demographic and clinical variables, and (4) to assess the treatments usually administered for the disease. Patients and Data Collection Eligible female patients with a clinical and, when available, histological diagnosis of VLS were included in the study. The majority of the study patients received the diagnosis at our Vulva Unit. Demographic, historical and clinical data were collected by direct interview and clinical examination at patient presentation. All data were recorded in a standardized data collection form. In order to avoid misinterpretation of VLS-related clinical features and symptoms, patients were arbitrarily excluded from the study in the presence of: systemic treatment with steroids, retinoids or hormonal replacement therapies and estroprogestinic drugs during the 4 weeks before inclusion; treatment with topical therapy (e.g. corticosteroids, tacrolimus, pimecrolimus, hormonal therapy) at the affected area during the 4 weeks before inclusion; active vulvar infectious diseases or vulvar dermatoses or carcinoma. Refusal or inability to reply to the interview were further exclusion criteria. The following data were recorded by interview: (1) age at inclusion; (2) age at onset of VLS, taken as the age when the women first experienced VLS-related symptoms; (3) age at diagnosis, defined as the age when a clinical or histological diagnosis was established; (4) delay in diagnosis (recorded as the time in months between the patient-reported onset of symptoms and the definite diagnosis);
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Table 1. Demographic, historical and clinical data of the enrolled
patients Patients enrolled Age, years Mean Range SD Age at diagnosis, years Mean Range SD Age at VLS onset, years Mean Range SD Delay in VLS diagnosis, months Mean Range SD Duration of VLS, years Mean Range SD Patients with previous medical therapies Concomitant autoimmune diseases Histology Family history of VLS Asymptomatic patients
225 61.90 31.83 – 84.90 13.04 60.19 32.10 – 84.67 12.32 57.01 24 – 82 13.54 38.04 1 – 252 67.34 5.2 0.1 – 25.25 6.52 155 (68.9%) 46 (20.4%) 137 (60.9%) 12 (5.3%) 4 (1.8%)
SD = Standard deviation.
(5) family history of VLS (at least one first-degree relative affected by the disease); (6) personal history of chronic autoimmune disorders (thyroid disease, rheumatoid arthritis, type 1 diabetes mellitus, alopecia areata, autoimmune connective tissue diseases, celiac disease, anemia perniciosa, vitiligo, etc.); (7) previous therapy, defined as every medical or non-pharmacological treatment utilized by the patients for treating VLS prior to being included in the study. Clinical Symptoms and Signs The presence or absence of the following three symptoms, itching, burning and dyspareunia (the latter only when applicable), was investigated by interview using a visual analog scale (VAS); a score of 10 was attributed to the highest intensity of the symptoms, and 0 to their absence. Since VLS is characterized by exacerbations and remissions, patients were asked to specify the number and severity of symptoms they experienced at the moment of the interview. A global subjective score (GSS) was obtained by summing each symptomatological parameter (highest GSS = 30). Patients were arbitrarily subdivided according to the severity of symptoms into three main groups: (1) mild, if the GSS was ≤5, (2) moderate, if the GSS was 6–9, and (3) severe, if the GSS was ≥10. These cutoffs were defined in accordance with our clinical experience on patient discomfort and QoL impairment (unpublished data). The following five objective parameters were considered in order to
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ing nature of VLS is one of its principal troublesome features because it implies long-term therapies and recurrences are common when drugs are discontinued [13, 14]. Although several studies have collected data on the epidemiology of VLS, to date very few reports have specifically addressed the strength of associations between clinical, demographic and historical variables of the diseases. The aim of the present study was to assess the demographic, historical and clinical features of a large population of women affected by VLS and their standard of care. The data collected were elaborated in order to identify possible associations between history, demographic and clinical features and potential factors predicting the severity and course of the disease.
Table 2. Previous topical therapies for VLS
Patients Percent
Number of previous therapies
Kind of previous topical therapiesa
0
1
70 31.1
61 51 27.1 22.7
2
3
4
corticosteroids
antiretimycotics noids
testosterone
antitacrobiotics limus
emol- phytoes- unspeclients trogens ified
17 7.6
5 2.2
79 33.8
24 10.3
14 6.0
12 5.1
68 29.1
22 9.4
4 1.7
9 3.9
21 9.3
a As patients could have been undergone multiple treatments, the total of therapies was greater than the number of patients enrolled in the study.
Table 3. VLS-related symptoms and signs: prevalence and mean
value Symptoms and signs
Patients
Mean ± SD
Itchinga Burninga Dyspareuniab Erythemac Leukoderma (pallor)c Hyperkeratosisc Purpura, itching-related excoriationsc Scarring-sclerosis-atrophyd
203 (90.2%) 174 (77.3%) 75 (33.3%) 21 (9.3%) 120 (53.3%) 50 (22.2%) 38 (16.9%)
6.48 ± 2.99 4.90 ± 3.39 4.47 ± 3.96 0.55 ± 0.70 1.63 ± 0.78 0.80 ± 0.94 0.74 ± 0.79
117 (52.0%)
4.74 ± 0.73
SD = Standard deviation. a Calculated as VAS from 0 to 10. b Dyspareunia VAS was calculated when applicable. c Calculated with a 4-point scale: 0 = absence, 1 = mild, 2 = moderate, 3 = severe. d Calculated with a 4-point scale: 0 = absence, 3 = mild, 6 = moderate, 9 = severe.
Results
Patient Characteristics A total of 225 patients affected by VLS were included in the study. The demographic, historical and clinical data of the 225 women included in the study are reported in table 1. The diagnosis of VLS was based on clinical features and in 137 cases (60.9%) was histopathologically confirmed. 70 patients (31.1%) had not undergone previous treatment. The treatments reported by the other 155 patients (68.9%) are reported in table 2.
Statistical Analyses Correlation between symptom and sign severity in our study patients was assessed by linear regression analysis. The association between severity of VLS signs, evaluated as GOS, and age at onset of the disease, duration of the disease before inclusion, and delay in diagnosis was assessed by Kruskal-Wallis test. χ2 test was used to assess the strength of association between patient history of other autoimmune diseases and both severity of VLS signs and symptoms and age at onset of VLS. Due to the low number of cases, the effect of family history on the severity of VLS signs and symptoms at inclusion was examined using exact Fisher’s test. The association between previous treatment with topical corticosteroids and severity of symptoms (expressed as GSS) and signs (expressed as GOS) at inclusion were assessed by Mann-Whitney U test, since the groups did not have equal variances (not homoscedastic). Statistical significance was defined as p < 0.05.
Clinical Symptoms and Signs Symptoms at inclusion were present in 221 patients (98.2%) while only 4 patients (1.8%) were asymptomatic. In the study patients, the most frequently reported symptom was itching (203 patients, 90.2% of total), while 174
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evaluate the clinical features and severity of the disease at presentation: (1) erythema, (2) leukoderma (pallor), (3) scarring-sclerosisatrophy, (4) hyperkeratosis and (5) purpuric lesions and itchingrelated excoriations. Objective assessment of each sign, with the exception of scarring-sclerosis-atrophy, was performed by the investigators using the following 4-point scale: 0 = absence, 1 = mild, 2 = moderate, 3 = severe. Considering the different role of architectural changes in the global gross appearance and QoL, investigators arbitrarily used the following 4-point scale to judge scarring-sclerosis-atrophy: 0 = absence, 3 = mild, 6 = moderate, 9 = severe. A global objective score (GOS) was obtained by summing each clinical parameter (highest GOS = 21). Patients were also subdivided in accordance with the severity of the objective signs, and independently from the intensity of symptoms, into three main groups: (1) mild clinical signs, if the GOS was ≤5, (2) moderate clinical signs, if the GOS was 6–10, and (3) severe clinical signs, if the GOS was ≥11. Cut-offs for objective disease grading were fixed based on the authors’ experience on VLS clinical severity and reversibility with treatment. Across the entire study duration, objective and subjective patient assessment was performed by the same two investigators (A.V., M.C.). Among the study population, the mean scores of symptoms and signs as well as the prevalence of each clinical parameter were assessed. The percentages of mild, moderate and severe cases according to both signs and symptoms were evaluated and analyses of possible associations between demographic and clinical features were carried out.
Patients Patients
200 180 160 140 120 100 80 60 40 20 0
200 180 160 140 120 100 80 60 40 20 0
Symptoms
9.78% 13.78%
76.44% Mild
Moderate
Severe Mild
Moderate
Severe
Signs 29.33%
20.89%
49.78% Mild
Moderate
Severe Mild
Moderate
Severe
Fig. 1. Severity of signs and symptoms.
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patients, the severity of VLS objective signs, evaluated as GOS, was not significantly associated with either age at onset of the disease (p = 0.12, Kruskal-Wallis test), duration of the disease before inclusion (p = 0.67, KruskalWallis test) or delay in diagnosis (p = 0.39, Kruskal-Wallis test). Neither GSS nor GOS at inclusion were associated with previous treatment with topical corticosteroids (p = 0.19, p = 0.52, respectively, Mann-Whitney U test). Associations Personal history of other autoimmune diseases was found not to correlate with severity of either signs (p = 0.26, χ2 test) or symptoms (p = 0.15, χ2 test) of the disease. Age at onset of VLS was not associated with concomitance of other autoimmune diseases (p = 0.42, t test). Severity of signs and symptoms at inclusion was not associated with family history of VLS (p = 0.49 and p = 0.57, respectively, exact Fisher’s test).
Discussion
The mean age at onset of VLS in our population was 57 years, which is consistent with reports from other series [5, 6, 8, 15]. In spite of the absence of age limits in the Virgili/Borghi/Toni/Minghetti/Corazza
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patients (74.3%) complained of burning. 107 women (47.5%) stated that dyspareunia was not a pertinent symptom in their everyday life; among the remaining 118 patients, 75 (63.6%) reported dyspareunia. The mean severity of itching, burning and dyspareunia is reported in table 3. Based on the protocol-defined overall symptom severity, 22 patients had mild symptoms (9.8%), 31 moderate symptoms (13.8%) and 172 severe symptoms (76.4%) (fig. 1). Leukoderma (pallor) and scarring-sclerosis-atrophy were the most frequent findings in the study population (53.3 and 52.0% of patients, respectively) (table 3). Hyperkeratosis was found in 50 patients (22.2%), purpuric lesions and itching-related excoriations in 38 (16.9%) and erythema in 21 (9.3%). Among the objective signs, pallor and scarring-sclerosis-atrophy had the highest mean values of severity (table 3). With regard to protocol-defined overall sign severity, 47 patients (20.9%) had mild clinical signs, 112 (49.8%) moderate disease and 66 (29.3%) severe signs (fig. 1). In our population, the rate of patients complaining of symptoms judged as severe resulted higher (76.4%) when compared with patients exhibiting clinical pictures judged as severe (29.3%). Consistent with this, analysis using linear regression found no significant correlation between symptom and sign severity (p = 0.42). Among the study
onset of the disease. Concerning a possible association between autoimmunity and clinical features, we found that an autoimmune diathesis did not significantly affect the severity of signs or symptoms. In accordance with these findings, personal history of autoimmune diseases did not seem to predispose patients to either an earlier onset of the disease or a more severe prognosis. A reported familial history of VLS was found not to be associated with severity of symptoms and signs. Even though this is an interesting aspect in a disease with a possible genetic component, a memory bias cannot be excluded, as patients may not remember their family’s past medical history. About 70% of the study patients had undergone medical or non-pharmacological treatments prior to attending our Vulva Unit (table 2). The former had been usually prescribed by physicians, mostly dermatologists. Topical corticosteroids were found to be the most common intervention (33.8% of the previously treated patients), followed by emollients (29.1%). As ultra-potent or potent topical corticosteroids, at different regimens, represent the accepted first-line treatment for both active and maintenance treatment of VLS, the use of topical corticosteroids should be recommended in clinical practice also for improving patients’ QoL [10–12, 22]. In our population, previous treatment with corticosteroids was not found to be associated with a different severity of symptoms and signs at inclusion. This could seem contradictory to the documented effect of corticosteroids in relieving symptoms, reversing signs and preventing the progression of the disease. However, we did not collect information about either the severity of VLS before treatment or the duration and regimen of corticosteroids in treating the disease. Previous inappropriate treatment regimens or corticosteroid strength cannot be excluded. Thus, we cannot draw reliable conclusions on the efficacy of such previous treatments in VLS. Finding that about 10% of patients had been treated with topical antimycotic agents and 5% with topical antibiotics seems to suggest that VLS is a frequently misdiagnosed disorder. This is not a surprise as multiple conditions may mimic VLS. An even higher rate of improper previous prescriptions could be expected. However, previous treatments had been prescribed mainly by dermatologists, who are usually more confident than other physicians in differentiating inflammatory diseases from infectious ones. It is interesting to find that despite the lack of evidence for the efficacy of topical testosterone and progesterone in the treatment of VLS [10, 11], almost 10% of the included patients had been treated with such
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enrolment criteria, it must be stressed that the majority of the patients attending our Vulva Unit are adult females, usually older than 20 years, and this could have conditioned our findings. Other studies have reported an earlier onset of VLS compared with our population. Thomas et al. [16], considering the age at onset in 355 women with anogenital lichen sclerosus, found that 49% of cases occurred in women over 50 years of age and 42% occurred in the reproductive years, while among our patients an onset after 50 years of age was reported by 77.8% of patients and prior to 50 years only by 22.2%. Our findings seem to corroborate that the peak of incidence of VLS in adulthood is characteristically located within the postmenopausal years [17–19]. 40% of our patients did not undergo a biopsy due to exceedingly clear clinical features. In our patients there was a considerable mean delay in diagnosis after onset of symptoms (38 months, standard deviation 67.3 months). The reasons for delay were not addressed in this study. However, it may be speculated that the disease location on intimate places, which may cause shame or embarrassment, may lead to a delay in medical consultation. Moreover, a not uncommon misdiagnosis by physicians unfamiliar with the condition could represent a further reason for the delay in diagnosis. Since previous experiences have found that early intervention with topical corticosteroids may revert skin changes and prevent scarring, a prompt diagnosis could have favorable consequences on the prognosis of VLS [5]. Surprisingly, in our series a significant association between age at onset, delay in diagnosis and duration of the disease before inclusion and severity of signs, assessed as GOS, was not found. This finding seems in discordance with the progressive course of the disease and a recognized trend in worsening of clinical appearance. However, we did not consider the intervention of possible previous treatments which could have accounted for a more favorable course of the disease. As a consequence, our data do not allow us to reach definitive conclusions on this issue. In agreement with the supposed autoimmune pathophysiology of the disease, in our population more than 20% of patients had a personal history of other autoimmune diseases, compared with an estimated prevalence of 7.6–9.4% in the general population [20]. This finding is well recognized and in line with the data from the literature [7, 8, 21]. However, a lack of association between VLS and co-existing autoimmune disorders has recently been seen [18]. In our patients, personal history of autoimmune diseases was not found to account for the age at
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tive features. This fact must be taken into account in treating VLS, as the sole assessment of clinical pictures could lead to underestimation and undertreatment of the disease. The main limitation of our study is that personal and familial history bias cannot be excluded when data are collected through interviews. Furthermore, univocal methods for the assessment of VLS severity are not available and severity grades and cut-offs in the present study were arbitrarily defined. In conclusion, our findings show that personal history of autoimmune diseases and familial history of VLS do not seem to influence the age at onset and the overall severity of the disease. The VLS-related symptoms affect almost all patients and are more often moderate to severe, and without an association with the clinical features, which may generally result less severe. Pallor and scarring-sclerosis-atrophy are found in about half of VLS patients and may ease the clinical diagnosis. About one third of our patients had previously been treated with topical corticosteroids, while a not negligible part of our patients had received inappropriate treatments. This may be the consequence of both misdiagnosis and unawareness of the treatment guidelines.
Acknowledgement The authors would like to thank Ms. Silvia Giari for statistical guidance.
Disclosure Statement The authors have no conflicts of interest to declare and no financial disclosures to make.
References
1 Tasker GL, Wojnarowska F: Lichen sclerosus. Clin Exp Dermatol 2003;28:128–133. 2 Meffert JJ, Davis BM, Grimwood RE: Lichen sclerosus. J Am Acad Dermatol 1995;32:393– 412. 3 Powell JJ, Wojnarowska F: Lichen sclerosus. Lancet 1999;353:1777–1783. 4 Pugliese JM, Morey AF, Peterson AC: Lichen sclerosus: review of the literature and current recommendations for management. J Urol 2007;178:2268–2276. 5 Cooper SM, Gao XH, Powell JJ, Wojnarowska F: Does treatment of vulvar lichen sclerosus influence its prognosis? Arch Dermatol 2004; 140:702–706.
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therapies. On the other hand, even if topical calcineurin inhibitors, tacrolimus and pimecrolimus, have been shown to be an effective and well-tolerated therapeutic alternative option in the treatment of VLS, only 4 patients (1.7%) had previously been treated with topical calcineurin inhibitors. It could be supposed that some concerns about the long-term safety profile of these drugs and about an increased risk of neoplasia with their use in a disease with a premalignant potential could discourage their use. Among treated patients, 47.1% reported more than one previous treatment. This could mirror either the need for a combined and/or sequential therapy in managing VLS in the long term or a tendency to change treatment due to a poor response to therapy. Almost all patients in our population complained of symptoms related to the disease. The real rate of asymptomatic VLS cannot be easily estimated, as symptoms are usually the main reason for requesting a medical consultation. A previous cohort study found a similar rate of symptom-free patients [5]. On the other hand, some authors estimated that up to a third of cases are asymptomatic [1, 23]. Itching was the most common symptom reported by our population, in agreement with previous reports [5, 8, 10, 15, 17, 24, 25]. We found that itching was even the most severe symptom, based on VAS mean score. The majority of patients complained of burning as well and 63.3% of the women who answered on dyspareunia reported discomfort on sexual intercourse. These data strongly suggest the dramatic impact on the QoL of patients affected by VLS [6] and further recommend a correct therapeutic intervention in order to ameliorate the physical and mental discomfort. Although the objective features of VLS are well known, only a few previous studies have addressed the prevalence and severity of VLS-related signs in a large population. In our study patients, leukoderma (pallor) and scarringsclerosis-atrophy represented the most common features, which were found in more than half of the patients, in accordance with other reports [5, 24]. Leukoderma (pallor) and scarring-sclerosis-atrophy had also the most severe mean objective scores when compared with the other analyzed features. Hyperkeratosis, purpuric lesions and itching-related excoriations were found in a substantial rate of patients, while less than 10% of patients showed erythema. The identification of the most characteristic clinical features of VLS may be helpful for physicians in correctly diagnosing the disease. It is noteworthy that the severity of objective signs was not significantly associated with the severity of symptoms. In particular, the mean severity of symptoms was found to be greater than objec-
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19 Berger MB, Damico NJ, Menees SB, Fenner DE, Haefner HK: Rates of self-reported urinary, gastrointestinal, and pain comorbidities in women with vulvar lichen sclerosus. J Low Genit Tract Dis 2012;16:285–289. 20 Cooper GS, Bynum ML, Somers EC: Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases. J Autoimmun 2009;33:197–207. 21 Meyrick Thomas RH, Ridley CM, McGibbon DH, Black MM: Lichen sclerosus et atrophicus and autoimmunity. A study of 350 women. Br J Dermatol 1988;118:41–46. 22 Schwegler J, Schwarz J, Eulenburg C, Blome C, Ihnen M, Mahner S, Jaenicke F, Augustin M, Woelber L: 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. 23 Goldstein AT, Marinoff SC, Christopher K, Srodon M: Prevalence of vulvar lichen sclerosus in a general gynecology practice. J Reprod Med 2005;50:477–480. 24 Lorenz B, Kaufman RH, Kutzner SK: Lichen sclerosus. Therapy with clobetasol propionate. J Reprod Med 1998;43:790–794. 25 Sinha P, Sorinola O, Luesley DM: Lichen sclerosus of the vulva. Long-term steroid maintenance therapy. J Reprod Med 1999; 44: 621– 624.
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Received: August 27, 2013 Accepted after revision: October 1, 2013 Published online: February 8, 2014
Prospective Clinical and Epidemiologic Study of Vulvar Lichen Sclerosus: Analysis of Prevalence and Severity of Clinical Features, together with Historical and Demographic Associations Annarosa Virgili Alessandro Borghi Giulia Toni Sara Minghetti Monica Corazza Department of Medical Sciences, Section of Dermatology, University of Ferrara, Ferrara, Italy
Abstract Background: Few reports have addressed the associations between clinical, demographic and historical variables of vulvar lichen sclerosus (VLS). Objective: To elaborate the prevalence and severity of signs and symptoms and to identify potential factors predicting the severity and course of VLS. Methods: A prospective cohort of 225 patients affected by VLS was included. Data were collected by direct interview and clinical examination. Results: 98% of patients complained of symptoms, principally itching. Pallor and scarringsclerosis-atrophy were the most frequent and severe signs. The severity of VLS signs was not associated with age at onset and duration of the disease. About 70% of the patients had previously undergone treatment. Conclusions: VLS-related symptoms were not associated with the clinical features which resulted less severe. Personal history of autoimmune diseases and familial history of VLS did not influence the age at onset and the severity of VLS. A considerable part of patients had previously received inappropriate treatment. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 1018–8665/14/2282–0145$39.50/0 E-Mail [email protected] www.karger.com/drm
Introduction
Vulvar lichen sclerosus (VLS) is a chronic inflammatory disease of the anogenital area. VLS can be found in patients of any age and race, but is most common in Caucasian females, with two peaks of incidence in the prepubertal and postmenopausal periods [1]. Patients with VLS complain mainly of itching, burning, pain, dyspareunia and sexual dysfunction [2, 3]. Affected women have an increased risk of genital cancers, with a lifetime risk of developing a squamous cell carcinoma estimated to be 2–5% [4, 5]. VLS has a considerable impact on healthrelated quality of life (QoL) and women with VLS have been found to experience a lower health-related QoL than the general population [6]. The number of symptoms seems to be correlated with the health-related QoL of women with VLS. The etiology of VLS is unknown, but there is an association with autoimmune disorders [7, 8] and genetic factors [3, 9]. Among the multiple pathogenetic factors, immunological alterations and chronic inflammatory mechanisms seem to be crucial [2–4]. Currently, a 3-month topical application of potent or ultra-potent corticosteroids is the mainstay of medical treatment for VLS [10–12]; however, the chronic relapsProf. Annarosa Virgili Department of Medical Sciences, Section of Dermatology University of Ferrara, Via Savonarola 9 IT–44100 Ferrara (Italy) E-Mail vri @ unife.it
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Key Words Vulvar lichen sclerosus · Objective signs · Symptoms · Treatment · Autoimmunity · Epidemiology
Materials and Methods Study Setting and Objectives We conducted an observational study in the setting of a prospective cohort of patients affected by VLS attending the Vulva Unit of the Dermatology Section of the University of Ferrara, Italy, between December 2006 and December 2012. Our Vulva Unit is a tertiary referral center for vulvar disorders. The aims of the study were (1) to assess the main demographic and clinical characteristics of patients affected by VLS, including family history of the disease and personal history of other autoimmune disorders, (2) to assess the clinical features of the disease, such as severity of signs and symptoms, (3) to elaborate the prevalence and severity of signs and symptoms and to identify possible associations between demographic and clinical variables, and (4) to assess the treatments usually administered for the disease. Patients and Data Collection Eligible female patients with a clinical and, when available, histological diagnosis of VLS were included in the study. The majority of the study patients received the diagnosis at our Vulva Unit. Demographic, historical and clinical data were collected by direct interview and clinical examination at patient presentation. All data were recorded in a standardized data collection form. In order to avoid misinterpretation of VLS-related clinical features and symptoms, patients were arbitrarily excluded from the study in the presence of: systemic treatment with steroids, retinoids or hormonal replacement therapies and estroprogestinic drugs during the 4 weeks before inclusion; treatment with topical therapy (e.g. corticosteroids, tacrolimus, pimecrolimus, hormonal therapy) at the affected area during the 4 weeks before inclusion; active vulvar infectious diseases or vulvar dermatoses or carcinoma. Refusal or inability to reply to the interview were further exclusion criteria. The following data were recorded by interview: (1) age at inclusion; (2) age at onset of VLS, taken as the age when the women first experienced VLS-related symptoms; (3) age at diagnosis, defined as the age when a clinical or histological diagnosis was established; (4) delay in diagnosis (recorded as the time in months between the patient-reported onset of symptoms and the definite diagnosis);
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Table 1. Demographic, historical and clinical data of the enrolled
patients Patients enrolled Age, years Mean Range SD Age at diagnosis, years Mean Range SD Age at VLS onset, years Mean Range SD Delay in VLS diagnosis, months Mean Range SD Duration of VLS, years Mean Range SD Patients with previous medical therapies Concomitant autoimmune diseases Histology Family history of VLS Asymptomatic patients
225 61.90 31.83 – 84.90 13.04 60.19 32.10 – 84.67 12.32 57.01 24 – 82 13.54 38.04 1 – 252 67.34 5.2 0.1 – 25.25 6.52 155 (68.9%) 46 (20.4%) 137 (60.9%) 12 (5.3%) 4 (1.8%)
SD = Standard deviation.
(5) family history of VLS (at least one first-degree relative affected by the disease); (6) personal history of chronic autoimmune disorders (thyroid disease, rheumatoid arthritis, type 1 diabetes mellitus, alopecia areata, autoimmune connective tissue diseases, celiac disease, anemia perniciosa, vitiligo, etc.); (7) previous therapy, defined as every medical or non-pharmacological treatment utilized by the patients for treating VLS prior to being included in the study. Clinical Symptoms and Signs The presence or absence of the following three symptoms, itching, burning and dyspareunia (the latter only when applicable), was investigated by interview using a visual analog scale (VAS); a score of 10 was attributed to the highest intensity of the symptoms, and 0 to their absence. Since VLS is characterized by exacerbations and remissions, patients were asked to specify the number and severity of symptoms they experienced at the moment of the interview. A global subjective score (GSS) was obtained by summing each symptomatological parameter (highest GSS = 30). Patients were arbitrarily subdivided according to the severity of symptoms into three main groups: (1) mild, if the GSS was ≤5, (2) moderate, if the GSS was 6–9, and (3) severe, if the GSS was ≥10. These cutoffs were defined in accordance with our clinical experience on patient discomfort and QoL impairment (unpublished data). The following five objective parameters were considered in order to
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ing nature of VLS is one of its principal troublesome features because it implies long-term therapies and recurrences are common when drugs are discontinued [13, 14]. Although several studies have collected data on the epidemiology of VLS, to date very few reports have specifically addressed the strength of associations between clinical, demographic and historical variables of the diseases. The aim of the present study was to assess the demographic, historical and clinical features of a large population of women affected by VLS and their standard of care. The data collected were elaborated in order to identify possible associations between history, demographic and clinical features and potential factors predicting the severity and course of the disease.
Table 2. Previous topical therapies for VLS
Patients Percent
Number of previous therapies
Kind of previous topical therapiesa
0
1
70 31.1
61 51 27.1 22.7
2
3
4
corticosteroids
antiretimycotics noids
testosterone
antitacrobiotics limus
emol- phytoes- unspeclients trogens ified
17 7.6
5 2.2
79 33.8
24 10.3
14 6.0
12 5.1
68 29.1
22 9.4
4 1.7
9 3.9
21 9.3
a As patients could have been undergone multiple treatments, the total of therapies was greater than the number of patients enrolled in the study.
Table 3. VLS-related symptoms and signs: prevalence and mean
value Symptoms and signs
Patients
Mean ± SD
Itchinga Burninga Dyspareuniab Erythemac Leukoderma (pallor)c Hyperkeratosisc Purpura, itching-related excoriationsc Scarring-sclerosis-atrophyd
203 (90.2%) 174 (77.3%) 75 (33.3%) 21 (9.3%) 120 (53.3%) 50 (22.2%) 38 (16.9%)
6.48 ± 2.99 4.90 ± 3.39 4.47 ± 3.96 0.55 ± 0.70 1.63 ± 0.78 0.80 ± 0.94 0.74 ± 0.79
117 (52.0%)
4.74 ± 0.73
SD = Standard deviation. a Calculated as VAS from 0 to 10. b Dyspareunia VAS was calculated when applicable. c Calculated with a 4-point scale: 0 = absence, 1 = mild, 2 = moderate, 3 = severe. d Calculated with a 4-point scale: 0 = absence, 3 = mild, 6 = moderate, 9 = severe.
Results
Patient Characteristics A total of 225 patients affected by VLS were included in the study. The demographic, historical and clinical data of the 225 women included in the study are reported in table 1. The diagnosis of VLS was based on clinical features and in 137 cases (60.9%) was histopathologically confirmed. 70 patients (31.1%) had not undergone previous treatment. The treatments reported by the other 155 patients (68.9%) are reported in table 2.
Statistical Analyses Correlation between symptom and sign severity in our study patients was assessed by linear regression analysis. The association between severity of VLS signs, evaluated as GOS, and age at onset of the disease, duration of the disease before inclusion, and delay in diagnosis was assessed by Kruskal-Wallis test. χ2 test was used to assess the strength of association between patient history of other autoimmune diseases and both severity of VLS signs and symptoms and age at onset of VLS. Due to the low number of cases, the effect of family history on the severity of VLS signs and symptoms at inclusion was examined using exact Fisher’s test. The association between previous treatment with topical corticosteroids and severity of symptoms (expressed as GSS) and signs (expressed as GOS) at inclusion were assessed by Mann-Whitney U test, since the groups did not have equal variances (not homoscedastic). Statistical significance was defined as p < 0.05.
Clinical Symptoms and Signs Symptoms at inclusion were present in 221 patients (98.2%) while only 4 patients (1.8%) were asymptomatic. In the study patients, the most frequently reported symptom was itching (203 patients, 90.2% of total), while 174
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evaluate the clinical features and severity of the disease at presentation: (1) erythema, (2) leukoderma (pallor), (3) scarring-sclerosisatrophy, (4) hyperkeratosis and (5) purpuric lesions and itchingrelated excoriations. Objective assessment of each sign, with the exception of scarring-sclerosis-atrophy, was performed by the investigators using the following 4-point scale: 0 = absence, 1 = mild, 2 = moderate, 3 = severe. Considering the different role of architectural changes in the global gross appearance and QoL, investigators arbitrarily used the following 4-point scale to judge scarring-sclerosis-atrophy: 0 = absence, 3 = mild, 6 = moderate, 9 = severe. A global objective score (GOS) was obtained by summing each clinical parameter (highest GOS = 21). Patients were also subdivided in accordance with the severity of the objective signs, and independently from the intensity of symptoms, into three main groups: (1) mild clinical signs, if the GOS was ≤5, (2) moderate clinical signs, if the GOS was 6–10, and (3) severe clinical signs, if the GOS was ≥11. Cut-offs for objective disease grading were fixed based on the authors’ experience on VLS clinical severity and reversibility with treatment. Across the entire study duration, objective and subjective patient assessment was performed by the same two investigators (A.V., M.C.). Among the study population, the mean scores of symptoms and signs as well as the prevalence of each clinical parameter were assessed. The percentages of mild, moderate and severe cases according to both signs and symptoms were evaluated and analyses of possible associations between demographic and clinical features were carried out.
Patients Patients
200 180 160 140 120 100 80 60 40 20 0
200 180 160 140 120 100 80 60 40 20 0
Symptoms
9.78% 13.78%
76.44% Mild
Moderate
Severe Mild
Moderate
Severe
Signs 29.33%
20.89%
49.78% Mild
Moderate
Severe Mild
Moderate
Severe
Fig. 1. Severity of signs and symptoms.
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patients, the severity of VLS objective signs, evaluated as GOS, was not significantly associated with either age at onset of the disease (p = 0.12, Kruskal-Wallis test), duration of the disease before inclusion (p = 0.67, KruskalWallis test) or delay in diagnosis (p = 0.39, Kruskal-Wallis test). Neither GSS nor GOS at inclusion were associated with previous treatment with topical corticosteroids (p = 0.19, p = 0.52, respectively, Mann-Whitney U test). Associations Personal history of other autoimmune diseases was found not to correlate with severity of either signs (p = 0.26, χ2 test) or symptoms (p = 0.15, χ2 test) of the disease. Age at onset of VLS was not associated with concomitance of other autoimmune diseases (p = 0.42, t test). Severity of signs and symptoms at inclusion was not associated with family history of VLS (p = 0.49 and p = 0.57, respectively, exact Fisher’s test).
Discussion
The mean age at onset of VLS in our population was 57 years, which is consistent with reports from other series [5, 6, 8, 15]. In spite of the absence of age limits in the Virgili/Borghi/Toni/Minghetti/Corazza
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patients (74.3%) complained of burning. 107 women (47.5%) stated that dyspareunia was not a pertinent symptom in their everyday life; among the remaining 118 patients, 75 (63.6%) reported dyspareunia. The mean severity of itching, burning and dyspareunia is reported in table 3. Based on the protocol-defined overall symptom severity, 22 patients had mild symptoms (9.8%), 31 moderate symptoms (13.8%) and 172 severe symptoms (76.4%) (fig. 1). Leukoderma (pallor) and scarring-sclerosis-atrophy were the most frequent findings in the study population (53.3 and 52.0% of patients, respectively) (table 3). Hyperkeratosis was found in 50 patients (22.2%), purpuric lesions and itching-related excoriations in 38 (16.9%) and erythema in 21 (9.3%). Among the objective signs, pallor and scarring-sclerosis-atrophy had the highest mean values of severity (table 3). With regard to protocol-defined overall sign severity, 47 patients (20.9%) had mild clinical signs, 112 (49.8%) moderate disease and 66 (29.3%) severe signs (fig. 1). In our population, the rate of patients complaining of symptoms judged as severe resulted higher (76.4%) when compared with patients exhibiting clinical pictures judged as severe (29.3%). Consistent with this, analysis using linear regression found no significant correlation between symptom and sign severity (p = 0.42). Among the study
onset of the disease. Concerning a possible association between autoimmunity and clinical features, we found that an autoimmune diathesis did not significantly affect the severity of signs or symptoms. In accordance with these findings, personal history of autoimmune diseases did not seem to predispose patients to either an earlier onset of the disease or a more severe prognosis. A reported familial history of VLS was found not to be associated with severity of symptoms and signs. Even though this is an interesting aspect in a disease with a possible genetic component, a memory bias cannot be excluded, as patients may not remember their family’s past medical history. About 70% of the study patients had undergone medical or non-pharmacological treatments prior to attending our Vulva Unit (table 2). The former had been usually prescribed by physicians, mostly dermatologists. Topical corticosteroids were found to be the most common intervention (33.8% of the previously treated patients), followed by emollients (29.1%). As ultra-potent or potent topical corticosteroids, at different regimens, represent the accepted first-line treatment for both active and maintenance treatment of VLS, the use of topical corticosteroids should be recommended in clinical practice also for improving patients’ QoL [10–12, 22]. In our population, previous treatment with corticosteroids was not found to be associated with a different severity of symptoms and signs at inclusion. This could seem contradictory to the documented effect of corticosteroids in relieving symptoms, reversing signs and preventing the progression of the disease. However, we did not collect information about either the severity of VLS before treatment or the duration and regimen of corticosteroids in treating the disease. Previous inappropriate treatment regimens or corticosteroid strength cannot be excluded. Thus, we cannot draw reliable conclusions on the efficacy of such previous treatments in VLS. Finding that about 10% of patients had been treated with topical antimycotic agents and 5% with topical antibiotics seems to suggest that VLS is a frequently misdiagnosed disorder. This is not a surprise as multiple conditions may mimic VLS. An even higher rate of improper previous prescriptions could be expected. However, previous treatments had been prescribed mainly by dermatologists, who are usually more confident than other physicians in differentiating inflammatory diseases from infectious ones. It is interesting to find that despite the lack of evidence for the efficacy of topical testosterone and progesterone in the treatment of VLS [10, 11], almost 10% of the included patients had been treated with such
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enrolment criteria, it must be stressed that the majority of the patients attending our Vulva Unit are adult females, usually older than 20 years, and this could have conditioned our findings. Other studies have reported an earlier onset of VLS compared with our population. Thomas et al. [16], considering the age at onset in 355 women with anogenital lichen sclerosus, found that 49% of cases occurred in women over 50 years of age and 42% occurred in the reproductive years, while among our patients an onset after 50 years of age was reported by 77.8% of patients and prior to 50 years only by 22.2%. Our findings seem to corroborate that the peak of incidence of VLS in adulthood is characteristically located within the postmenopausal years [17–19]. 40% of our patients did not undergo a biopsy due to exceedingly clear clinical features. In our patients there was a considerable mean delay in diagnosis after onset of symptoms (38 months, standard deviation 67.3 months). The reasons for delay were not addressed in this study. However, it may be speculated that the disease location on intimate places, which may cause shame or embarrassment, may lead to a delay in medical consultation. Moreover, a not uncommon misdiagnosis by physicians unfamiliar with the condition could represent a further reason for the delay in diagnosis. Since previous experiences have found that early intervention with topical corticosteroids may revert skin changes and prevent scarring, a prompt diagnosis could have favorable consequences on the prognosis of VLS [5]. Surprisingly, in our series a significant association between age at onset, delay in diagnosis and duration of the disease before inclusion and severity of signs, assessed as GOS, was not found. This finding seems in discordance with the progressive course of the disease and a recognized trend in worsening of clinical appearance. However, we did not consider the intervention of possible previous treatments which could have accounted for a more favorable course of the disease. As a consequence, our data do not allow us to reach definitive conclusions on this issue. In agreement with the supposed autoimmune pathophysiology of the disease, in our population more than 20% of patients had a personal history of other autoimmune diseases, compared with an estimated prevalence of 7.6–9.4% in the general population [20]. This finding is well recognized and in line with the data from the literature [7, 8, 21]. However, a lack of association between VLS and co-existing autoimmune disorders has recently been seen [18]. In our patients, personal history of autoimmune diseases was not found to account for the age at
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tive features. This fact must be taken into account in treating VLS, as the sole assessment of clinical pictures could lead to underestimation and undertreatment of the disease. The main limitation of our study is that personal and familial history bias cannot be excluded when data are collected through interviews. Furthermore, univocal methods for the assessment of VLS severity are not available and severity grades and cut-offs in the present study were arbitrarily defined. In conclusion, our findings show that personal history of autoimmune diseases and familial history of VLS do not seem to influence the age at onset and the overall severity of the disease. The VLS-related symptoms affect almost all patients and are more often moderate to severe, and without an association with the clinical features, which may generally result less severe. Pallor and scarring-sclerosis-atrophy are found in about half of VLS patients and may ease the clinical diagnosis. About one third of our patients had previously been treated with topical corticosteroids, while a not negligible part of our patients had received inappropriate treatments. This may be the consequence of both misdiagnosis and unawareness of the treatment guidelines.
Acknowledgement The authors would like to thank Ms. Silvia Giari for statistical guidance.
Disclosure Statement The authors have no conflicts of interest to declare and no financial disclosures to make.
References
1 Tasker GL, Wojnarowska F: Lichen sclerosus. Clin Exp Dermatol 2003;28:128–133. 2 Meffert JJ, Davis BM, Grimwood RE: Lichen sclerosus. J Am Acad Dermatol 1995;32:393– 412. 3 Powell JJ, Wojnarowska F: Lichen sclerosus. Lancet 1999;353:1777–1783. 4 Pugliese JM, Morey AF, Peterson AC: Lichen sclerosus: review of the literature and current recommendations for management. J Urol 2007;178:2268–2276. 5 Cooper SM, Gao XH, Powell JJ, Wojnarowska F: Does treatment of vulvar lichen sclerosus influence its prognosis? Arch Dermatol 2004; 140:702–706.
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therapies. On the other hand, even if topical calcineurin inhibitors, tacrolimus and pimecrolimus, have been shown to be an effective and well-tolerated therapeutic alternative option in the treatment of VLS, only 4 patients (1.7%) had previously been treated with topical calcineurin inhibitors. It could be supposed that some concerns about the long-term safety profile of these drugs and about an increased risk of neoplasia with their use in a disease with a premalignant potential could discourage their use. Among treated patients, 47.1% reported more than one previous treatment. This could mirror either the need for a combined and/or sequential therapy in managing VLS in the long term or a tendency to change treatment due to a poor response to therapy. Almost all patients in our population complained of symptoms related to the disease. The real rate of asymptomatic VLS cannot be easily estimated, as symptoms are usually the main reason for requesting a medical consultation. A previous cohort study found a similar rate of symptom-free patients [5]. On the other hand, some authors estimated that up to a third of cases are asymptomatic [1, 23]. Itching was the most common symptom reported by our population, in agreement with previous reports [5, 8, 10, 15, 17, 24, 25]. We found that itching was even the most severe symptom, based on VAS mean score. The majority of patients complained of burning as well and 63.3% of the women who answered on dyspareunia reported discomfort on sexual intercourse. These data strongly suggest the dramatic impact on the QoL of patients affected by VLS [6] and further recommend a correct therapeutic intervention in order to ameliorate the physical and mental discomfort. Although the objective features of VLS are well known, only a few previous studies have addressed the prevalence and severity of VLS-related signs in a large population. In our study patients, leukoderma (pallor) and scarringsclerosis-atrophy represented the most common features, which were found in more than half of the patients, in accordance with other reports [5, 24]. Leukoderma (pallor) and scarring-sclerosis-atrophy had also the most severe mean objective scores when compared with the other analyzed features. Hyperkeratosis, purpuric lesions and itching-related excoriations were found in a substantial rate of patients, while less than 10% of patients showed erythema. The identification of the most characteristic clinical features of VLS may be helpful for physicians in correctly diagnosing the disease. It is noteworthy that the severity of objective signs was not significantly associated with the severity of symptoms. In particular, the mean severity of symptoms was found to be greater than objec-
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