ADONIS 0007U963910UU0A
Hrilish lourmi of Dermatolofm ( 1 9 9 1 ) 124, 4 6 1 - 4 6 4 .
The treatment of vulval lichen sclerosus with a very potent topical steroid (clobetasol propionate 0-05%) cream K.L.DALZIEL, P.R.MILLARD* AND F.WOJNAROWSKA Department of Dermatology. The Slade Hospital. Oxford. U.K. *t)epartment of Histopathologn, John Radcliffe i-lospitat. Oxford. U.K.
Accepted lor publication 19 November 1990
Summary
The clinical and histological response to 12 weeks of treatment with a very potent topical fluorinated steroid was studied in 15 patients with vulval lichen sclerosus (IiS) who were treated with twice daily applications of clobetasol propionate 0-()5% cream (Dermovate, Glaxo U.K.). Thirteen patients completed the study and all showed a marked clinical improvement. Histological measurements of skin biopsies taken before and after treatment showed a significant reduction in the characteristic features of LS. One patient developed contact sensitivity to clobetasol propionate. There was no evidence of infection or skin atrophy during the study. Patients completing the study have been followed up for up to 22 months and have been maintained in remission with moderately potent topical steroids which had previously been ineffective.
Vulvitl lichen sclerosus (LS) is a distressing condition which often fails to respond adequately to therapy. Although many practitioners use potent topical steroids to treat LS there is often concern about the potential harmful effects of these agents on genital skin. This study was carried out to determine the safety and efficacy of the short term but regular use of a very potent topical steroid to control vulval LS.
Methods Fifteen women with long-standing, biopsy-proven vulval lichen scierosus gave informed consent to the study. The mean age of the patients was 62 years (range 50-78 years) and the mean duration of disease was 9-3 years (range 2-i() years). Several women had been symptomatic for over 20 years. Most had been treated at some time with a variety of mild or moderately potent topical steroids, anti-candidal preparations and topical oestrogens without effect. Two of the patients had received topical testosterone cream more than 5 years previously and in one patient, local intradermai injections of alcohol had been used more than 10 years before this study. None of the patients had ever used a very potent topical steroid and none had used a topical steroid of any Correspondence: [)r K.L.DaUiel. Department of Dermatology, University Hospital. Queen's Medical Centre. Nottingham NG7 2UH. U.K.
kind for at least 1 month preceding the study. No patient was receiving systemic steroids or retinoids. Skin biopsies were obtained from all patients not more than 3 months preceding the study. In most women, a 4mm punch biopsy was taken from clinically involved vulval skin 1 month before starting treatment. In four women referred from the gynaecology department, incisional biopsies had been performed. After 12 weeks of twice daily application of clobetasol propionate ()-05% cream to the affected areas, a second 4-mm punch biopsy was taken from an adjacent or symmetrically involved area of skin. Both the pre- and post-treatment biopsies were taken from the area with the most severe clinical signs of lichen sclerosus. Photographs were taken before and after 12 weeks of treattnent. Six of the patients made a semi-quantitative measure of pruritus and soreness using 100 mm visual analogue scores (VAS) before treatment and after 6 and 12 weeks of therapy. All biopsies were examined by one experienced histopathologist without knowledge of the treatment. 100mm visual analogue scores were used to measure the following features: epidermal atrophy, epidermal basal cell liquefactive degeneration, hyperkeratosis. intensity of inflammatory infiltrate and hyalinization of dermal collagen. The visual analogue scores were analysed using the Wilcoxon matched-pairs signed-rank test. Following the study, the patients have been regularly reviewed for between 2 and 22 months. 461
462
K.L.DALZIEL et al.
Results Thirteen patienls completed the study. In all these patients the clinical appearance ofthe vulval skin was markedly improved and in Hve patients it was no longer possible to make a clinical diagnosis of !,S. In the remaining eight women, there was a considerable reduction in erosions, hyperkeratosis. purpura and thickness of plaques. Established labial fusion was not clinically altered by treatment. Associated with the clinical improvement was a reduction in symptoms of itch and soreness. In the six patients completing visual analogue scores before and after treatment, there was a significant reduction in both symptoms after both 6 and 1 2 weeks of therapy using the Wilcoxon matched-pairs signed-rank test (Table 1). The iOO-mm visual analogue scores ofthe histological parameters assessed by a single histopathologist without knowledge of the treatment showed a signiticant reduction in severity of all the features examined (Table 2). In four ofthe biopsies taken after 12 weeks of treatment no specific features of LS remained. The histological features ofa matched pair of biopsies from one patient taken before (Fig. I) and after (Fig. 2) illustrate the effects of treatment. Table I. Mean 100 mm VAS of pruritus and soreness before and after f> and I 2 weeks of iri-atment with clok-tiisi*! propionate ()()S% cream
Mean IOO-mm VAS
Pruritus Soreness
Pre-Rx
6 wedcs
12 weeks
Si^ificance*
52 3 4Hi
10-7 12 0
2 33 5-83
P = 0014 P=0014
•Wilcoxon matthed-pairs sign-ranked test.
Table 2. Mean VAS of histological features of I^ before and atter 12 weeks of treatment with clobetasol proptonate l)OS%
Mean IOO-mm VAS Hlstologlcal feature
Pre-Rx
Post-Rx
Significance'
Kpidermal atrophy Hypcrkenilosis Epidermal basal cell liquefaction Intensity of intUimmatory infiltrate Hyalinization of dermal colhtgen
42-71 36-36 46-16 41-14 62-14
29-29 20-78 16-71 8-07 14-43
P = 0-064 P=0-018 P=0-024 P=O-OO35 P = O-O22
' Wilcoxon matched-pairs signed-rank test.
Two patients were withdrawn from the study. One experienced burning discomfort on applying the clobetasol propionate U()5% cream. Patch tests were performed but no contact allergic reaction to any of the cream constituents could be determined. Another patient did well Initially but the treatment was temporarily stoppeil so that a non-healing erosion could be biopsied to exclude carcinoma. On restarting treatment with clobetasol dipropionate cream, she gave a clear history of itching and eczematous change after its use, Patch testing revealed contact sensitivity to clobetasoi propionate cream and ointment and to u fourfold dilution ofthe clobetasol propionate in petrolatum. There was no reaction to the other constituents of the cream or ointment. Ijong-term follow up
At the end of 12 weeks of treatment with clobetasol propionate. patients were changed to a moderately pt)tent topical steroid and were told to apply Derniovate on an 'as required' basis. One patient was lost to follow up after 2 months. The remaining 12 patients have been followed for 6-22 months. All use simple emollients for washing the skin. Three patients still use occasional applications of clobetasol propionate 0-0S% (approximately twice a month or less), controlling symptoms at other times with a moderately potent topical steroid cream, clobetasone butyrate 0()S% (Eumovate. (ilaxt>). Seven patients use clobetasone butyrate as their only treatment either regularly or when necessary. In one patient 1% hydrocortisone controls the residual symptoms. Two patients now show no clinical evidence of lichen sclerosus. In ali the others, the lichen sclerosus appears much less active than before treatment. No patient has active erosions and none has needed a further biopsy. Discussion It is not known why lichen sclerosus has such a predilection for genital skin, nor why vulval t,S is often so distressingly symptomatic with severe itch and soreness. Vulval LS may be complicated by tissue destruction leading to labial fusion or vaginal stenosis. Squamous carcinoma may develop in association with genital LS although the exact incidence is not clear.' Mild or moderate topical steroid preparations are commonly used to treat vulval US. but control of symptoms and disease activity is often unsatisfactory. Several studies have reported 2% testosterone propio-
TREATMENT OF VULVAL LICHEN SCLEROSUS
463
V
v*-> Figure 1. Biopsy from clinically worst affected areii of vulval LS before treatment showing hypcrkcrritosis. epidermal thinning and basal fell degeneration, hyalinization of upper dermal collagen and a mid-dermal lymphocytic inflammatory infiltrate.
Figure 2. Resolution of features of I^ in biopsy from ciinicnily worst affected area of vulval LS after 12 weeks of treatment, in same patient as in h'igure I.
nate cream to be an effective treatment for vulval LS with improvement in histological features." However, this is not readily available, can have virilizing side-effects and is not always effective. In normal vulval skin, the enzyme 5a-reduclase metabolizes testosterone to produce amounts of dihydrotestosterone far in excess of that produced in other body sites. Women with vulval LS tend to have lower circulating levels of dihydrotestosterone* but whether this is a primary event or secondary to the disease process is unknown. It has been suggested that topical testosterone supplies an excess of substrate inducing local 5a-reductase activity.'' Systemic therapy
of vulval LS with the synthetic retinoid etretinate has produced clinical and histoiogical improvement during treatment but side-effects are common.'' It is known that potent topical steroids can relieve symptoms in vulval LS but there has heen a reluctance to use them. Concern that they might predispose to local infection was expressed'^ and has often been quoted subsequently. However, there is little evidence to support this, and infection has not been a problem when topical steroids have been used to treat other vulval dermatoses/ There has also been concern that the use of fluorinated topical steroids in I.,S might cause skin
464
K.L.DALZIEL et al.
thinning in a condition itself characterized by epidermal atrophy.^ Contact sensitivity induced by clobetasol propionate is well documented** and this must be considered when patients report irritation associated with its use. The long-term follow up of this group of patients demonstrates that once symptoms can be controlled and scratching stops, vulval LS becomes easier to manage and residual symptoms respond to mild or moderate potency steroids. There was no clinical evidence that the use ofa very potent steroid predisposed to infection. No clinical or histoiogical evidence of dermal or epidermal atrophy was seen and there was a significant reduction in epidermal atrophy after treatment. Whether better control ofthe disease will lead to a reduction in the risk of scarring or squamous cell carcinoma remains to be established. In conclusion, the application of a very potent topical steroid for 1 2 weeks appears to be safe and effective treatment for vulval LS. The symptomatic relief obtained by the patient is often dramatic and clinical improve-
ment is accompanied by a normalization of histological features.
References 1 Ridley CM. i Jchen sclerosus et atrophit us. Arch Dermatol 19S7; 12 J: 457-60. 2 Tremaine RDL. Miller RAW. Lichen sclerosus ct atrophicus. Int j Dcrmatol 19S9; 28: lO-lfi. i Friedrich Ed. Kalni PS. Scrum levels of sex hormones in vulvar lichen sclerosus and the effect of topical testosterone. N l-.nfil I Mcil 1984: ilO; 488-91. 4 Tricdrich W.. Vulvar dystrophy. Clin Ohstet Gynaeco! 1985:28:1 7887. 5 Mork N-|. iensen P). Hoel PS. Vulval lichen sclerosus ct atrophicus treated with etretinate (Tegison). Acta Derm Venereol {Stockh) 1986: 66: 36.i-5. 6 Wallace H|. Lichen .sclenwus et atrophicus. Trans St John's Dermatol Soc 1971: 57:9-it). 7 Bergman A. Karram M. Bhatia NN. [xical steroid application for hypcrplastic dystrophy of the vulva: clinical and pathological evaluation. / Kcprorf Med 1988: JJ: 542-4. 8 Tosti A. Guerra L. Manuzv.i P. Lama I,. Contact dermatiiis from clobetasol propionate. CoHlflit Upnnnlitis 1987: 17:25h-7.
Hrilish lourmi of Dermatolofm ( 1 9 9 1 ) 124, 4 6 1 - 4 6 4 .
The treatment of vulval lichen sclerosus with a very potent topical steroid (clobetasol propionate 0-05%) cream K.L.DALZIEL, P.R.MILLARD* AND F.WOJNAROWSKA Department of Dermatology. The Slade Hospital. Oxford. U.K. *t)epartment of Histopathologn, John Radcliffe i-lospitat. Oxford. U.K.
Accepted lor publication 19 November 1990
Summary
The clinical and histological response to 12 weeks of treatment with a very potent topical fluorinated steroid was studied in 15 patients with vulval lichen sclerosus (IiS) who were treated with twice daily applications of clobetasol propionate 0-()5% cream (Dermovate, Glaxo U.K.). Thirteen patients completed the study and all showed a marked clinical improvement. Histological measurements of skin biopsies taken before and after treatment showed a significant reduction in the characteristic features of LS. One patient developed contact sensitivity to clobetasol propionate. There was no evidence of infection or skin atrophy during the study. Patients completing the study have been followed up for up to 22 months and have been maintained in remission with moderately potent topical steroids which had previously been ineffective.
Vulvitl lichen sclerosus (LS) is a distressing condition which often fails to respond adequately to therapy. Although many practitioners use potent topical steroids to treat LS there is often concern about the potential harmful effects of these agents on genital skin. This study was carried out to determine the safety and efficacy of the short term but regular use of a very potent topical steroid to control vulval LS.
Methods Fifteen women with long-standing, biopsy-proven vulval lichen scierosus gave informed consent to the study. The mean age of the patients was 62 years (range 50-78 years) and the mean duration of disease was 9-3 years (range 2-i() years). Several women had been symptomatic for over 20 years. Most had been treated at some time with a variety of mild or moderately potent topical steroids, anti-candidal preparations and topical oestrogens without effect. Two of the patients had received topical testosterone cream more than 5 years previously and in one patient, local intradermai injections of alcohol had been used more than 10 years before this study. None of the patients had ever used a very potent topical steroid and none had used a topical steroid of any Correspondence: [)r K.L.DaUiel. Department of Dermatology, University Hospital. Queen's Medical Centre. Nottingham NG7 2UH. U.K.
kind for at least 1 month preceding the study. No patient was receiving systemic steroids or retinoids. Skin biopsies were obtained from all patients not more than 3 months preceding the study. In most women, a 4mm punch biopsy was taken from clinically involved vulval skin 1 month before starting treatment. In four women referred from the gynaecology department, incisional biopsies had been performed. After 12 weeks of twice daily application of clobetasol propionate ()-05% cream to the affected areas, a second 4-mm punch biopsy was taken from an adjacent or symmetrically involved area of skin. Both the pre- and post-treatment biopsies were taken from the area with the most severe clinical signs of lichen sclerosus. Photographs were taken before and after 12 weeks of treattnent. Six of the patients made a semi-quantitative measure of pruritus and soreness using 100 mm visual analogue scores (VAS) before treatment and after 6 and 12 weeks of therapy. All biopsies were examined by one experienced histopathologist without knowledge of the treatment. 100mm visual analogue scores were used to measure the following features: epidermal atrophy, epidermal basal cell liquefactive degeneration, hyperkeratosis. intensity of inflammatory infiltrate and hyalinization of dermal collagen. The visual analogue scores were analysed using the Wilcoxon matched-pairs signed-rank test. Following the study, the patients have been regularly reviewed for between 2 and 22 months. 461
462
K.L.DALZIEL et al.
Results Thirteen patienls completed the study. In all these patients the clinical appearance ofthe vulval skin was markedly improved and in Hve patients it was no longer possible to make a clinical diagnosis of !,S. In the remaining eight women, there was a considerable reduction in erosions, hyperkeratosis. purpura and thickness of plaques. Established labial fusion was not clinically altered by treatment. Associated with the clinical improvement was a reduction in symptoms of itch and soreness. In the six patients completing visual analogue scores before and after treatment, there was a significant reduction in both symptoms after both 6 and 1 2 weeks of therapy using the Wilcoxon matched-pairs signed-rank test (Table 1). The iOO-mm visual analogue scores ofthe histological parameters assessed by a single histopathologist without knowledge of the treatment showed a signiticant reduction in severity of all the features examined (Table 2). In four ofthe biopsies taken after 12 weeks of treatment no specific features of LS remained. The histological features ofa matched pair of biopsies from one patient taken before (Fig. I) and after (Fig. 2) illustrate the effects of treatment. Table I. Mean 100 mm VAS of pruritus and soreness before and after f> and I 2 weeks of iri-atment with clok-tiisi*! propionate ()()S% cream
Mean IOO-mm VAS
Pruritus Soreness
Pre-Rx
6 wedcs
12 weeks
Si^ificance*
52 3 4Hi
10-7 12 0
2 33 5-83
P = 0014 P=0014
•Wilcoxon matthed-pairs sign-ranked test.
Table 2. Mean VAS of histological features of I^ before and atter 12 weeks of treatment with clobetasol proptonate l)OS%
Mean IOO-mm VAS Hlstologlcal feature
Pre-Rx
Post-Rx
Significance'
Kpidermal atrophy Hypcrkenilosis Epidermal basal cell liquefaction Intensity of intUimmatory infiltrate Hyalinization of dermal colhtgen
42-71 36-36 46-16 41-14 62-14
29-29 20-78 16-71 8-07 14-43
P = 0-064 P=0-018 P=0-024 P=O-OO35 P = O-O22
' Wilcoxon matched-pairs signed-rank test.
Two patients were withdrawn from the study. One experienced burning discomfort on applying the clobetasol propionate U()5% cream. Patch tests were performed but no contact allergic reaction to any of the cream constituents could be determined. Another patient did well Initially but the treatment was temporarily stoppeil so that a non-healing erosion could be biopsied to exclude carcinoma. On restarting treatment with clobetasol dipropionate cream, she gave a clear history of itching and eczematous change after its use, Patch testing revealed contact sensitivity to clobetasoi propionate cream and ointment and to u fourfold dilution ofthe clobetasol propionate in petrolatum. There was no reaction to the other constituents of the cream or ointment. Ijong-term follow up
At the end of 12 weeks of treatment with clobetasol propionate. patients were changed to a moderately pt)tent topical steroid and were told to apply Derniovate on an 'as required' basis. One patient was lost to follow up after 2 months. The remaining 12 patients have been followed for 6-22 months. All use simple emollients for washing the skin. Three patients still use occasional applications of clobetasol propionate 0-0S% (approximately twice a month or less), controlling symptoms at other times with a moderately potent topical steroid cream, clobetasone butyrate 0()S% (Eumovate. (ilaxt>). Seven patients use clobetasone butyrate as their only treatment either regularly or when necessary. In one patient 1% hydrocortisone controls the residual symptoms. Two patients now show no clinical evidence of lichen sclerosus. In ali the others, the lichen sclerosus appears much less active than before treatment. No patient has active erosions and none has needed a further biopsy. Discussion It is not known why lichen sclerosus has such a predilection for genital skin, nor why vulval t,S is often so distressingly symptomatic with severe itch and soreness. Vulval LS may be complicated by tissue destruction leading to labial fusion or vaginal stenosis. Squamous carcinoma may develop in association with genital LS although the exact incidence is not clear.' Mild or moderate topical steroid preparations are commonly used to treat vulval US. but control of symptoms and disease activity is often unsatisfactory. Several studies have reported 2% testosterone propio-
TREATMENT OF VULVAL LICHEN SCLEROSUS
463
V
v*-> Figure 1. Biopsy from clinically worst affected areii of vulval LS before treatment showing hypcrkcrritosis. epidermal thinning and basal fell degeneration, hyalinization of upper dermal collagen and a mid-dermal lymphocytic inflammatory infiltrate.
Figure 2. Resolution of features of I^ in biopsy from ciinicnily worst affected area of vulval LS after 12 weeks of treatment, in same patient as in h'igure I.
nate cream to be an effective treatment for vulval LS with improvement in histological features." However, this is not readily available, can have virilizing side-effects and is not always effective. In normal vulval skin, the enzyme 5a-reduclase metabolizes testosterone to produce amounts of dihydrotestosterone far in excess of that produced in other body sites. Women with vulval LS tend to have lower circulating levels of dihydrotestosterone* but whether this is a primary event or secondary to the disease process is unknown. It has been suggested that topical testosterone supplies an excess of substrate inducing local 5a-reductase activity.'' Systemic therapy
of vulval LS with the synthetic retinoid etretinate has produced clinical and histoiogical improvement during treatment but side-effects are common.'' It is known that potent topical steroids can relieve symptoms in vulval LS but there has heen a reluctance to use them. Concern that they might predispose to local infection was expressed'^ and has often been quoted subsequently. However, there is little evidence to support this, and infection has not been a problem when topical steroids have been used to treat other vulval dermatoses/ There has also been concern that the use of fluorinated topical steroids in I.,S might cause skin
464
K.L.DALZIEL et al.
thinning in a condition itself characterized by epidermal atrophy.^ Contact sensitivity induced by clobetasol propionate is well documented** and this must be considered when patients report irritation associated with its use. The long-term follow up of this group of patients demonstrates that once symptoms can be controlled and scratching stops, vulval LS becomes easier to manage and residual symptoms respond to mild or moderate potency steroids. There was no clinical evidence that the use ofa very potent steroid predisposed to infection. No clinical or histoiogical evidence of dermal or epidermal atrophy was seen and there was a significant reduction in epidermal atrophy after treatment. Whether better control ofthe disease will lead to a reduction in the risk of scarring or squamous cell carcinoma remains to be established. In conclusion, the application of a very potent topical steroid for 1 2 weeks appears to be safe and effective treatment for vulval LS. The symptomatic relief obtained by the patient is often dramatic and clinical improve-
ment is accompanied by a normalization of histological features.
References 1 Ridley CM. i Jchen sclerosus et atrophit us. Arch Dermatol 19S7; 12 J: 457-60. 2 Tremaine RDL. Miller RAW. Lichen sclerosus ct atrophicus. Int j Dcrmatol 19S9; 28: lO-lfi. i Friedrich Ed. Kalni PS. Scrum levels of sex hormones in vulvar lichen sclerosus and the effect of topical testosterone. N l-.nfil I Mcil 1984: ilO; 488-91. 4 Tricdrich W.. Vulvar dystrophy. Clin Ohstet Gynaeco! 1985:28:1 7887. 5 Mork N-|. iensen P). Hoel PS. Vulval lichen sclerosus ct atrophicus treated with etretinate (Tegison). Acta Derm Venereol {Stockh) 1986: 66: 36.i-5. 6 Wallace H|. Lichen .sclenwus et atrophicus. Trans St John's Dermatol Soc 1971: 57:9-it). 7 Bergman A. Karram M. Bhatia NN. [xical steroid application for hypcrplastic dystrophy of the vulva: clinical and pathological evaluation. / Kcprorf Med 1988: JJ: 542-4. 8 Tosti A. Guerra L. Manuzv.i P. Lama I,. Contact dermatiiis from clobetasol propionate. CoHlflit Upnnnlitis 1987: 17:25h-7.
