Topical tacrolimus in the management of lichen sclerosus
Prof DM Luesley, Department of Obstetrics and Gynaecology, City Hospital, Dudley Road, Birmingham B18 7QH, UK. Email email@example.com
The effective management of vulval lichen sclerosus (LS) currently depends upon the use of topical steroids and emollients. There are concerns with regard to the long-term toxicity of potent steroids and therefore is a need to consider effective alternatives. Immunomodulatory macrolactams offer an alternative to steroids in the management of some other inflammatory skin disorders and it would seem reasonable therefore to assess their activity in LS. This pilot study of 16 histologically confirmed cases of LS suggests that macrolactams have a positive pharmacological effect.
Lichen sclerosus (LS) is one of the non-neoplastic epithelial disorders defined by the International Society for the Study of Vulval Disease. It is characterised in most cases by epithelial thinning, inflammation and distinctive histological changes in the dermis. It can affect both sexes and occur at any age, but it is typically found in the anogenital region in postmenopausal women.
The objectives of management are to control symptoms and detect features suggestive of malignant change. Bland emollients are used liberally and can provide significant relief.
Three randomised controlled trials have found that potent topical steroids (e.g. clobetasol propionate) provided significant symptom control, particularly in the short term, and that they are more effective than topical testosterone or petroleum jelly. The use of potent topical steroids, particularly long-term use, is viewed with some disquiet by both patients and their carers. There is concern that protracted use may lead to atrophy and further damage to skin that is already thinned and fragile as a result of the inflammatory process. Our own data suggest that at least 50% of women with confirmed LS will require long-term intermittent use of topical steroids to remain in remission.1
The immunomodulatory macrolactams provide an alternative to glucocorticosteroids for the topical treatment of atopic dermatitis and other inflammatory dermatoses. Tacrolimus has been shown to penetrate the inflamed epidermis and is suitable for topical therapy. Multicentre, randomised, double-blind clinical trials with topical formulations have shown the efficacy and safety of both substances in moderate to severe atopic dermatitis.2 Topical tacrolimus does not produce skin atrophy.3
There have been several case reports of successful treatment of LS with 0.1% topical macrolactams. Furthermore, responses were rapid and apparently maintained following completion of treatment.4–6 This study documents the response to topical tacrolimus in a selected population of women with vulval LS.
Patients and methods
Sixteen symptomatic women were recruited from the hospital vulva clinic. All women selected for inclusion had biopsy-proven LS. Eligible women were those in whom there was no response or an incomplete response to topical fluorinated steroids (n= 10) or where women expressed concern regarding the possible adverse effects of prolonged steroid exposure (n= 6).
All women were clinically assessed prior to commencing therapy and none had evidence suggestive of malignant transformation or evidence of steroid toxicity. Treatment commenced with twice daily applications of 0.1% topical tacrolimus for 3 months at which point all were reassessed. Treatment was continued in responders with twice daily applications of 0.03% topical tacrolimus and 3-monthly assessments were made up to 1 year. Treatment was discontinued if there was no response to the higher dose. Women were offered re-exposure to the higher dose if they relapsed on the lower dose regimen.
Responses were regarded as complete if women became completely asymptomatic and partial if there was an improvement in, but persistence of some symptoms. The overall response rate was estimated 12 months after initiation of treatment.
The results are tabulated in Table 1. The median age was 48 years (range 31–79), eight women were postmenopausal. All women were symptomatic at the time of commencing tacrolimus either because of prior incomplete response to topical steroids or because topical steroids had been discontinued because of concerns regarding toxicity. Twelve subjects were using some form of topical steroid application prior to commencing tacrolimus, the remainder were using emollients only having previously been exposed to topical steroids. The median duration of symptoms and/or treatment prior to commencing tacrolimus was 60 months (range 6–120 months). The indications for commencing tacrolimus were incomplete response to prior medication (n= 10) or patient preference to discontinue topical steroids because of concerns regarding toxicity associated with long-term exposure. The mean duration of previous treatment in those expressing a preference to discontinue topical steroids was 98 months (SD 24.4). The mean duration of previous treatment in those who had an incomplete response to prior treatment was 45 months (SD 30).
Table 1. Women characteristics and response status
Adverse effects of treatment were observed in five women. Four experienced a transient burning shortly following application and one noticed very mild burning lasting 30 minutes only. Overall, the treatment was well tolerated.
Two women (12.5%) achieved a complete response and this was maintained at 12 months. A further eight (50%) women demonstrated a partial improvement in their symptoms and wished to continue on tacrolimus. Six women (37.5%) had not noted any improvement at their first review at 3 months and were changed to other treatments. There was no effect of age, menopausal status or duration of symptoms in predicting responses although this was not the primary intention of the study.
This is the first series of histologically confirmed LS cases that have been systematically exposed to topical tacrolimus. Three isolated case reports had suggested that this approach may be beneficial in this condition.4–6
LS is often symptomatic and the chronicity of this inflammatory skin disorder can often lead to significant anatomic distortion and loss of vulval architecture. There is also the potential for malignant change occurring in a background of LS and the lifetime risk has been estimated as 4%. Good symptomatic responses in excess of 90% have been reported using potent topical fluorinated steroids7 and a proportion of cases can be controlled using emollients alone. It is not known whether symptomatic control translates into reduced damage to the vulval epithelium or reduced risk of malignant transformation. What is of some concern is the potential for steroid-induced atrophy with long-term exposure. In theory, this could exacerbate a condition, which is already associated with atrophic changes in the vulval skin and contour. Because of this, and the fact that not all women with LS will respond to steroid applications, there is a clear need to search for alternative approaches to management.
This small observational study was performed with the sole intention of determining whether or not there were sufficient responses within the vulval LS population to justify a larger phase II study to accurately quantify the response rate. Over 60% of subjects demonstrated some response and two were complete responders. We therefore feel that a larger phase II study is now justified.