Study reference

Study characteristics

Patient characteristics¹

Intervention (I)

Comparison / control (C) ²

Follow-up

Outcome measures and effect size ³

Comments

Corazza 2016

Type of study:

Open label trial

Setting: extended single-centre, open-label,

comparative trial conducted between June 2012 and July 2014

Country: Italy

Source of funding: unclear.

Inclusion criteria:

judged as responders by the end of the 12-week active treatment

phase (ATP) study (Virgili 2014)

Exclusion criteria:

Non responders from ATP study Virgili 2014

N total at baseline: 48

Clobetasol group: 24

Mometason group: 24

(= ITT population)

Important prognostic factors¹:

All enrolled patients entered this study

directly after the previous trial, with no interruption in their

treatment.

Groups comparable at baseline?

Yes according to the authors. No large differences between groups (table 1).

Describe intervention (treatment/procedure/test):

Clobetasol propionate (CP) 0.05% ointment twice weekly during 52 weeks

Application on previously affected vulvar areas.

No additional treatment nor cosmetics was allowed.

Describe control (treatment/procedure/test):

Mometasone furoate (MMF) 0.1% ointment

Twice weekly during 52 weeks

Length of follow-up:

52 weeks

Loss-to-follow-up:

I: n=2 drop outs

C: n=2 drop outs

Incomplete outcome data:

-

Outcome measures and effect size (include 95%CI and p-value if available):

VAS itching:

Baseline:

I: n=11, mean 1.08 (1.25)
C: n=6, mean 0.87 (2.01)

At 52 weeks (0-10):

I: n=8, mean 1.09 (SD 2.21)

C: n=9, mean 1.18 (SD 2.21)

VAS burning (0-10):

Baseline:

I: n=7, mean 0.06 (1.42)

C: n=4, mean 0.54 (1.41)

At 52 weeks:

I: n=8, mean 1.04 (SD 2.18)

C: n=6, mean 1.09 (SD 2.29) Global subjective score (GSS, 0-20):

Baseline:

I: n=12, mean 1.92 (2.25)

C: n=7, mean 1.41 (2.53)

At 52 weeks:

I: n=10, mean 2.14 (SD 4.24)

C: n=10, mean 2.18 (SD 4.27)

GSS change at 52 weeks:

I: mean 0.22 (2,79)

C: mean 0.77 (2.71)

Global objective score (GOS, 0-12):

Baseline:

I: n=20, mean 1.54 (1.08)

C: n=18, mean 1.54 (1.32)

At 52 weeks:

I: n=13, mean 1.27 (SD 1.74)

C: n=11, mean 1.04 (SD 1.56)

GOS change at 52 weeks:

I: mean -0.27 (1.09)
C: mean -0.50 (0.94)

No sign differences between groups.

Relapse (arbitrarily defined by a score ≥5 for at least one

evaluable symptom and/or a score = 3 for any of the 4 signs

considered reversible):

I: n=2 (8.33%)

C: n=1 (4.17%)

P=1, RR=2 (95% CI 0.1940-20.6149)

The mean time to relapse was 30 weeks (range 20–38, median

32 weeks) (no difference between groups)

Satisfaction:

N=3 (relapsing patients were dissatisfied.)

Safety: no side effects.

Follow up study Virgili 2014

Small sample size

Open label

Not double blind

Per protocol analyses

Virgili 2013 BJD

Type of study:

randomized, parallel-group, open-label, comparative

study

Setting:

conducted between December 2009

and May 2012 at the Vulva Unit of the Dermatology Section

of the University of Ferrara

Country:

Italy

Source of funding: unclear

Inclusion criteria:

clinical and, when available, histological

diagnosis of VLS

At 12 weeks after treatment with mometasone, patients who achieved both a

score < 3 for each evaluable subjective symptom and a global

OS ≤4 were judged as ‘treatment responsive’ and were eligible.

Exclusion criteria:

systemic

treatment with steroids, retinoids or hormonal replacement

therapies and oestroprogestinic drugs during the

4 weeks before enrolment; treatment with topical therapy

(e.g. corticosteroids, tacrolimus, pimecrolimus, hormonal

therapy) at the affected area during the 4 weeks before enrolment;

hypersensitivity to any component of the study drugs;

active vulvar infectious diseases or vulvar dermatoses or carcinoma;

pregnancy or breastfeeding.

N total at baseline: 25

Mometasone: 8

Vit E: 9

Cold cream: 8

(=ITT population for efficacy analyses)

Important prognostic factors¹:

age ± SD:

60.53 +/- 11.89

Groups comparable at baseline?

Lower duration of disease in mometasone group.

Describe intervention (treatment/procedure/test):

proactive, twice-weekly application of mometasone

furoate 0.1% ointment

after 12 weeks of treatment with topical corticosteroid (mometason) (open label active phase study)

Describe control (treatment/procedure/test):

Daily pure topical 100% vitamin E oil

(tocopherol acetate, Vea Olio; Hulka, Rovigo, Italy)

or

Cold cream once daily

(a dermatological oil-in-water emulsion containing white petrolatum, cetearyl alcohol, paraffinum

liquidum, water, propylene glycol and ceteareth-20)

Length of follow-up:

52 weeks

Loss-to-follow-up:

Mometasone: n=1

Incomplete outcome data:

Relapsing patients continued with daily application of topical steroid

(total n=10)

VAS displayed for non-relapsing patients only

GSS and GOS not reported.

Outcome measures and effect size (include 95%CI and p-value if available):

VAS burning (0-10, lower is better)

VAS itching

VAS dyspareunia (when applicable)

Global subjective score (GSS, summing each VAS score, max 30): not reported.

Global objective score (GOS: sum clinical parameters erythema, leukoderma, sclerosis scarring, hyperkeratosis, purpuric lesions, score 0-4, lower is better): not reported.

Relapse (defined by a score

≥ 5 for at least one evaluable subjective symptom and/or a

score = 3 for any of the four signs considered reversible. Or any

worsening in sclerosis scarring):

Mometasone: 0

Cold cream: 5

Vit E: 5

>patients withdrew from study and continued with daily application of topical steroid.

The calculation of confidence intervals (CIs) of the odds ratios

(ORs) shows that mometasone furoate 01% twice a week

protects from relapse (OR = 0.0951, 95% CI 0.0177–

0.5106).

Time to relapse:

Relapses were observed during

the first 6 months of maintenance therapy in 80% of cases

(8/10), while only two patients (20%) experienced the relapse in the course of the second semester of the MP. The

median time to relapse was 216 weeks for patients in both

the vitamin E and cold cream groups.

Patient satisfaction (interview, convenient or inconvenient):

patients

in the proactive corticosteroid maintenance group were found

to be more satisfied with treatment (seven out of eight patients)

than those in the vitamin E and cold cream groups (eight of

seventeen patients), even though the difference did not reach

statistical significance (P = 0.0967, Fisher’s test).

Safety:

No side effects

Computer-generated simple randomization schedule

Objective and subjective patient assessment was performed

by the same two investigators (A.V. and M.C.), not blinded to

treatments, at baseline and at all successive 12-week-interval

visits.

Very small number of patients per group.

Incomplete outcome data.

Similar efficacy results were found in the PP population.

Virgili 2013 EJD

Type of study:

Randomized, open-label study

Setting: single centre, 2002-2010

Country:

Italy

Source of funding: not stated. No conflicts of interest.

Inclusion criteria:

VLS

Exclusion criteria:

systemic treatments with steroids, hormones or retinoids

within 4 weeks before enrolment in the study, treatment

with topical therapy (e.g. corticosteroids, tacrolimus, pimecrolimus)

on the affected area within 4 weeks before

enrolment, hypersensivity to any component of the study

drugs, active vulvar herpes, molluscum or condiloma, diagnosis

of other vulvar dermatoses or carcinoma, pregnancy

and breast-feeding.

N total at baseline: 80

Vit E: 36

Emollient: 44

Active treatment phase: n=156

At 12 weeks, patients who achieved a

symptomatological VAS global score ≤5/30 and an IGA

score ≤2 (total or almost total healing) were judged as

“treatment responsive” and were eligible for the MP à n=80

Important prognostic factors¹:

Considering the demographics and clinical features

of the dropped-out patients in comparison with those who

had completed the study or experienced a relapse, the two

groups did not differ in age (P = 0.9), severity of symptoms,

such as itching (P = 0.6) and burning (P = 0.06), at the beginning

of the maintenance phase, or place of residence (inside

versus outside the city) (P = 0.18).

Describe intervention (treatment/procedure/test):

12-week active treatment

phase on topical 0.1% mometasone furoate ointment once daily.

Vitamin E

(pure tocopherol acetate, VEA oil® Ulka,

Rovigo, Italy)

Once daily

Describe control (treatment/procedure/test):

Emollient (cold cream) once daily

Length of follow-up:

52 weeks

Efficacy was assessed every 12 weeks.

Loss-to-follow-up:

ATP:

76 subjects did not enter this second phase of the study, in 27 cases (35.5%) due to an unsatisfactory therapeutic

outcome of the topical corticosteroid treatment.

49 patients (64.5%) dropped-out at the first stage

of the study as they did not come to the 12-week control visit at the end of the AP.

MP:

At 26 weeks:

Vit E: n=16 (44.4%)

Emollient: n=18 (40.9%)

At 52 weeks:

Vit E: n=2

Emollient: n=6

Incomplete outcome data:

VAS scores after 52 weeks and global subjective score/IGA were not reported.

Outcome measures and effect size (include 95%CI and p-value if available):

Global subjective score (sum VAS itching, burning, dyspareunia, max 30): not reported

IGA (clinical response vulvar signs; 1) total healing (complete resolution of all

reversible signs), 2) almost total healing, 3) partial healing,

4) no change, or 5) worsening.): not reported.

Relapse rate at 52 weeks (any worsening in clinical features

and/or symptoms requiring a new treatment course with topical corticosteroids were arbitrarily considered relapse):

vit E: n=4/12 (33.3%)

emollient: 3/13 (23%)

(p=0.7)

Cumulative crude relapse rate = ITT:

vit E: n=10/36 (27.8%)

emollient: 10/44 (22.7%)

Time to relapse:

vit E: median 20 weeks

emollient: median 18.7 weeks

Clinical assessments were performed

and recorded by the same investigators (AV and MC) at

baseline and at all successive visits.

computer-generated simple randomization schedule

open label study > high RoB

Large number of patients were lost to follow up

Incomplete outcome data: VAS scores after 52 weeks and global subjective score/IGA not reported.

Lee 2015

Type of study:

Prospective longitudinal cohort study

Setting:

Private practice

Country: Australia

Source of funding: Dermatology Department of Royal

North Shore Hospital

Inclusion criteria:

age older than 18

years, biopsy-proved VLS, and having been followed up for a

minimumof 2 years

Exclusion criteria: not mentioned.

N total at baseline:

507

Important prognostic factors¹:

158 (31.2%)

patients were premenopausal, 307 (60.6%) were postmenopausal

and not using hormone therapy, and 42 (8.3%) were

postmenopausal and using either topical or systemic hormone

therapy

most pt had mild to moderate disease.

Severe disease: n=151 (29.8%)

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

Initial treatment regimens were individualized, with the

target outcome being an objective return of the vulvar skin to normal color and texture. Patients were initially treated with a single TCS agent, applied daily, to achieve symptom

control.

Betamethasone dipropionate: 325 (64.1%)

methylprednisolone aceponate: 156 (30.8%) Clobetasol: 17 (3.4%) hydrocortisone: 9 (1.8%)

Once disease and symptom suppression had been achieved, long-term preventive management was initiated. A

gradual reduction of TCS potency, titrated to the clinical response,

was attempted in all patients. Treatment was outcome based, with the target being as close as possible to normal

skin color and texture. As long as there were no

adverse effects, this treatment was maintained. If atrophy or

corticosteroid dermatitis developed, the potency of the TCS was reduced. If hyperkeratosis returned, the potency of the TCS was increased. Patients used the treatment at least 3 times per

week. For patients with very severe disease, a potent to superpotent

TCS was used daily.

Describe control (treatment/procedure/test):

-

Length of follow-up: at least 2 years;

every 3 to 6 months for the first 2 years and then at least yearly

mean duration of follow-up for all patients

was 4.7 years (range, 2.0-6.8 years)

Loss-to-follow-up:

-

Incomplete outcome data:

-

Outcome measures and effect size (include 95%CI and p-value if available):

Patients were considered

compliant if they self-reported that they followed treatment

instructions “most of the time” or “all of the time” and partially compliant if they self-

reported that they followed treatment

instructions “some of the time,” “little of the time,” or “none of the time,”

Compliant pt: n=357 (70.4%)

Non-compliant pt:

n=150 (29.6%)

Development SCC:

Compliant pt: 0

Non-compliant pt: n=7 (4.7%)

(p<0.001)

Suppression of symptoms (itching, pain):

Compliant pt: n=333 (93.3%)

Non-compliant pt: n=87 (58%)

(p<0.001)

Adhesions and scarring:

Baseline:

Structural changes in the vulvar architecture were

found in approximately half the patients (262 [51.7%]) at presentation

(173 [48.5%] compliant vs 89 [59.3%] partially compliant;

P = .03);

After follow up:

Compliant pt: n=12 (3.4%)

Non-compliant pt:

N=60 (40%)

(p<0.001)

Side effects:

Atrophy:

Compliant pt: n=4 (1.1%)

Non-compliant pt: n=3 (2%)

P=0.43

Corticosteroid dermatitis:

Compliant pt: n=8 (2.2%)

Non-compliant: n=6 (4%).

P=0.37

To detect

a decrease to 1.0% incidence of VSN in the compliant group

compared with the partially compliant group with 80% power at 5% significance, we required a total of 504 patients

Cooper 2004

Type of study:

Descriptive cohort study

Setting: single centre

Country:

England

Source of funding: unclear

Inclusion criteria:

In women, diagnosis was based on

the typical clinical appearances of VLS plus confirmatory histologic

studies; in girls, it was based on typical clinical appearances

alone. Childhood onset of disease was defined as onset

of symptoms prior to menarche and a definite diagnosis at or

before the age of 16 years.

Exclusion criteria:

Unclear

N total at baseline:

327

Important prognostic factors¹:

Women: 253

Girls: 74

None of the

74 girls (23%) had reached menarche, and 55 (17%) of

the women were in their reproductive years and 194 (60%)

were postmenopausal.

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

Women:

Clobetasol: 208 (89%)

Clobetasone butyrate: 10 (4%)

Betamethasone: 7 (3%)

Beclomethasone dipropionate: 7 (3%)

No topical steroid: 1

Most patients were given

topical steroid for intermittent maintenance selftreatment

after the initial treatment period.

Describe control (treatment/procedure/test):

-

Length of follow-up:

Every 3 months

mean follow-up time for women and girls was similar

(65 vs 69 months).

Loss-to-follow-up:

-

Incomplete outcome data:

Reported response of symptoms to topical treatment

was available for 255 patients, 36 girls and 219

women.

Response of the vulvar physical signs to treatment

was determined in 253 patients, 36 girls and 217 women.

Outcome measures and effect size (include 95%CI and p-value if available):

Symptomatic response: good (symptomfree

status reached during the treatment); partial (improvement

and/or partial resolution of individual symptoms); or poor

(no change or worsening):

symptom

free: 142 women (65%)

partial: 67 women (31%)

poor: 10 women (5%).

Response of vulvar signs: total (complete resolution of all signs and return

to normal color and texture—architectural changes, of

course, remained); partial (complete resolution of purpura, hyperkeratosis,

fissures, and erosions, but persistence of pallor or textural change); minor (partial resolution of some signs);

or poor (no change or worsening).

Total resolution: 50 women (23%)

Partial resolution: 149 women (69%)

Minor resolution: 14 women (6%)

No improvement: 4 women

Thirteen women had undergone surgical treatment

(the Fenton procedure) for introital stenosis.

SCC:

VIN: 4

SCC: 6

SCC on grade 3 VIN: 1

Outcomes were reported for all women in total, not adjusted per type of topical steroid.

Unclear how long patients used which topical steroid. Most patients were given topical steroids for intermittent maintenance selftreatment after initial treatment period.

Renaud-Vilmer 2004

Type of study:

Prospective study

Setting:

1981-2001

Country: France

Source of funding:

Inclusion criteria:

aged 20 years

and older who had VLS and attended the vulvar clinic of the

Hopital Saint-Louis Department of Dermatology, Paris, France,

between January 1981 and June 2001. The lesions had to be

confirmed histologically and were not to have been previously treated.

Exclusion criteria:

N total at baseline:

83

Important prognostic factors¹:

mean age was 59.4 years (range, 30-92

years)

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

0.05% clobetasol propionate

ointment, once daily for 3 months and then 3 times

per week until complete remission. The treatment was ended only when CR was obtained. In the absence of remission after 12 to 18 months,

the frequency of applications was gradually tapered to twice per week.

Describe control (treatment/procedure/test):

-

Length of follow-up:

Median 4.7 years

Loss-to-follow-up:

N=4

Incomplete outcome data:

Outcome measures and effect size (include 95%CI and p-value if available):

Remission

Complete (Complete remission was defined clinically

as an absence of clinical signs of VLS (ie, no pruritus and a regression

of white and sclerotic lesions), and histologically as the disappearance of the infiltrate and hyalinized collagen in the dermis (with the persistence of a slight, mostly subepidermal

fibrosis with some improvement of the elastic network): n=45 54%)

Relapse incidence rate

(clinically as new VLS lesions (areas of

pallor with or without pruritus or pain), and histologically when histologic examination showed the reappearance of hyalinized

foci of collagen with decreased numbers of elastic fibers with or without lymphocyte infiltrate):

50% at 16 months (95% confidence interval, 30%-

64%)

84% at 4 years (95% confidence interval, 57%-94%).

Development SCC:

N=8 (9.6%)

(6 at presentation without treatment until presentation)

Adverse events:

In 2 cases, treatment was interrrupted for 1 month because of local inflammation due to steroid application,

and then resumed

Simonart 2008

Type of study:

Prospective open trial

Setting: 1995-2006

Country: Belgium

Source of funding: unclear

Inclusion criteria:

Vulvar LS with typical appearance plus confirmatory histologic studies. No previous treatment.

Exclusion criteria:

Not reported.

N total at baseline:

34

Important prognostic factors¹:

All patients are postmenopausal

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

1 month of treatment with topical betamethasone valerate once daily

followed by maintenance therapy with moisturizer (cold cream) once daily only

Describe control (treatment/procedure/test):

-

Length of follow-up:

After 1 month end then twice per year

median follow-up time was 58 months (range, 12-139 m)

Loss-to-follow-up:

N=9

Incomplete outcome data:

-

Outcome measures and effect size (include 95%CI and p-value if available):

After 1 month active therapy:

N=24 symptom free

N=10 partial response.

Symptoms:

Pruritus:

Baseline: n=24

End of follow up: n=3

Pain:

Baseline: 9

End of follow up: 2

Response at last follow up visit

(good: symptom-free status reached during treatment; partial: improvement and/or partial resolution of

individual symptoms; poor: no change or worsening)

total n=34

after therapy with a topical steroid

once daily for 1 month. Twenty-four (71%) became

symptom free, and 10 (29%) experienced partial response.

Among the 24 women who became symptom free, 18

remained symptom free while treated with an emollient

cream alone. Among the 10 women who exhibited a partial

response, 6 reported no worsening of their symptoms while

treated with a cold cream alone.

Response of the vulvar signs (total: complete

resolution of all signs and return to normal color and texture; partial: complete resolution of erythema, purpura, hyper-keratosis, and fissures but persistence of pallor and

textural changes; no change; or worsening) after 1 month betamethasone:

total resolution: n=6 (18%)

partial resolution: n=22 (64%)

no change: n=6 (18%)

Compliance (total n=18, self-reporting):

Compliant: n=12

Partial: n=6

Noncompliant: n=0

Safety:

No adverse events

No SCC.

Symptoms and signs reported for all patients with different durations of follow up.

Not only effect from moisturizer, also from previous used betamethasone

Study reference

(first author, publication year)

Describe method of randomisation¹

Random sequence generation (selection bias)²

(high/unclear/low risk)

Allocation concealment (selection bias)³

(high/unclear/low risk)

Blinding of participants and personnel (performance bias)^4,6

All outcomes

(high/unclear/low risk)

Blinding of outcome assessor (detection bias)^5,6

All outcomes

(high/unclear/low risk)

Incomplete outcome data (attrition bias)⁷

All outcomes

(high/unclear/low risk)

Selective reporting (reporting bias)⁸

(high/unclear/low risk)

Other bias⁹

(high/unclear/low risk)

Total RoB

Corazza 2015

In original study computer generated randomization schedule

Low risk

The randomization schedule was prepared prior

to enrolment to ensure allocation concealment.

Low risk

Open label

High risk

Objective and subjective patient assessment was performed

by the same two experienced investigators who were not blinded to treatments at baseline and at the 12-week

control visit.

Unclear if outcome assessors were the same at 52 weeks.

High risk

Low number of dropouts.

Unclear how subjective scores were measured, low number of patients who reported scores?

Unclear risk

Unclear risk

Low risk

High RoB due to opel label design

Virgili 2013 BJD

computer generated randomization schedule

Low risk

Unclear

Open label

High risk

Objective and subjective patient assessment was performed

by the same two investigators who were not blinded to treatments

High risk

VAS displayed for non-relapsing patients only

Relapsing patients continued with daily application of topical steroids

High risk

Unclear risk

Low risk

High RoB due to opel label design

Virgili 2013 EJD

computer generated randomization schedule

Low risk

Unclear

Open label

High risk

Objective and subjective patient assessment was performed

by the same two investigators who were not blinded to treatments

High risk

Large number of patients lost to follow up

High risk

VAS scores after 52 weeks and global subjective score/IGA not reported.

High risk

Low risk

High RoB

Selection

Comparability

Outcomes

Study

Study design

Representativeness of the intervention cohort

Selection of the non intervention cohort

Ascertainment of intervention

Demonstration that outcome of interest was not present at start of study

Comparability of cohorts on the basis of the design or analysis

Assessment of outcome

Was follow up long enough for outcomes to occur

Adequacy of follow up of cohorts

Explanations

Lee 2015

Prospective longitudinal cohort study

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Cooper 2004

Descriptive cohort study

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Incomplete outcome data

Renaud-Vilmer 2004

Prospective study

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6/8 SCC were already present at baseline

Simonart 2008

Prospective open trial

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9/34 patients were lost to follow up

Ventolini 2012

Retrospective clinical medical records review

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No baseline charac-teristics reported.

Artikel

Reden van exclusie

Bradford 2010

Retrospectief, mogelijk zelfde cohort als Lee 2015

Dalziel 1993

N=9

Dalziel 1991

Geen full text

Sinha 1999

Geen full text

Ventolini 2012

Retrospectief, onduidelijk wat voor patiëntenpopulatie (geen karakteristieken beschreven), onduidelijke toewijzing interventies

Virgili 1995

Geen full text