INTRODUCTION

Vitiligo is the commonest acquired de-pigmentary disorder of the skin affecting around 1-2% of the world population without particular predilection for any age, race or gender. People affected with vitiligo suffer from low self-esteem, psychological disturbance and diminished quality of life.[1,2]  For the  non-surgical management of vitiligo various treatment modalities are available like corticosteroids, topical calcineurin inhibitors (TCIs) , vitamin D analogues (VDAs), antioxidants or phototherapy including psoralen ultraviolet A (PUVA), narrow band ultraviolet B (NB-UVB) and 308-nm excimer laser[3].

Narrow band UVB therapy (311-312nm) delivered especially via whole body chambers, is standard therapy for vitiligo. It has been shown to produce significant repigmentation with good cosmetic matching with surrounding normal skin and has an excellent safety profile including in children and pregnant women. Devices have also been developed to deliver ultraviolet light to the affected sites without exposing the entire body, which are referred to as targeted phototherapy. The excimer laser/light and hand-held NB UVB equipment are two such devices.The excimer laser is a form of targeted NB-UVB that has been found to be more effective than whole chamber NB-UVB in treatment of both generalized and localized vitiligo. [4-6]. Theexcimer laser contains a mixture of xenon and chloride gas that form unstable “excited dimers”. It releases 308 nm monochromatic UVB light. The mechanism of action of excimer laser in vitiligo is not completely understood, though it seems to stimulate melanocyte migration and proliferation due to increased expression of Endothelin 1(ET1) [7]. The advantage of excimer laser over whole chamber NB-UVB is its targeted nature which reduces damage to the adjoining skin and decreases cumulative UV load, as it has been shownto achieve re-pigmentation faster with easier access to difficult to reach areas.[4] Excimer laser can be combined with  topical agents like tacrolimus 0.1% ointment[8,9], hydrocortisone 17-butyrate cream[10], tetrahydrocurcuminoid cream[11], pimecrolimus 1%[12],khellin 4%[13],calcipotriene[14] and tacalcitol ointment[15] for better results. The main drawbacks of excimer laser are its high cost, its availability only in tertiary care settings and need for expertise in operation, hence the patient has to come to the hospital twice or thrice a week, making it a logistical obstacle and also causes loss of wages both to the patient and his attendant. Excimer light at a wavelength of 308nm is a non-collimated, non monochromatic slightly inexpensive alternative to the excimer laser, but has shown similar efficacy to excimer laser.[35]

Home based phototherapy is an alternative that can solve the aforementioned drawbacks of excimer laser. Currently there are many devices to deliver NB-UVB, at home such as hand and foot units and hand held units.  Hand held NB-UVB units are cheap, portable and suitable for treatment of localized vitiligo. Their benefits include significant reduction in the number of hospital visits, cost benefit, sparing of uninvolved skin (targeted phototherapy) and ability to treat at early stage of vitiligo when intervention might be effective.It is a good option especially for patients residing in inaccessible areas. Besides being handy, patients can take the treatment at their convenient time leading to better compliance and adherence, hence increased response. This treatment can be combined with other medical therapies too. The hand held devices consist of two Philips TL-9W/01 NB-UVB lamps placed in a plastic casing that emit wavelength of 310-315nm (peak 311) over 11x4 cm2 on which parallel arrays of toothed structure of 2 cm length (comb) are attached, which maintains a uniform distance between the device and vitiligo patches. The disadvantage of handheld NB-UVB  device seems to be its output, nearly half of that of the whole-body cabins with a faster rate of decay in irradiance necessitating greater exposure time to the lesion to achieve a therapeutic fluence. So the equipment needs to be periodically calibrated [17].  Another limitation is its inability to be used in generalized vitiligo.

  Many patients are currently buying hand-held NB-UVB units and using them at home and if they prove to be as effective and safe as excimer devices,they will substantially reduce cost, number of hospital visits, long distance travel and also social and economic impact.

Hence the present study is being undertaken to compare the efficacy and side-effects of two targeted phototherapy devices i.e. hand-held NB-UVB comb device with excimer light therapy in localized vitiligo.

AIMS AND OBJECTIVES

To compare two targeted phototherapy devices i.e. home-based hand-held Narrow Band UVB comb device used daily versus biweekly hospital- based excimer light therapy in treatment of localized vitiligo

RESEARCH QUESTION

Is home-based hand-held NB-UVB comb device at least as effective as Excimer light therapy in producing re-pigmentation in localized vitiligo?

HYPOTHESIS

Null hypothesis: Hand held NB-UVB therapy is inferior to excimer light therapy in treatment of localized vitiligo.

Alternate hypothesis: Hand held NB-UVB therapy is not inferior to excimer light therapy in treatment of localized vitiligo.

AIMS AND OBJECTIVES

To compare two targeted phototherapy devices i.e. daily use of home-based hand-held Narrow Band UVB comb device versus biweekly hospital-based excimer light therapy in treatment of localized vitiligo

1. Primary objective:

Comparison of percentage of re-pigmentation of the representative vitiligo patch* at the end of 4 months of treatment between the two study groups.

2. Secondary objective:

• Comparison of percentage re-pigmentation in vitiligo between the two groups based on global assessment using Lund & Browder (L & B) score

• Assessment of re-pigmentation using photographic assessment (investigator global assessment)- assessment done by two independent dermatologists who are not part of the study.

·         Comparison of degree of re-pigmentation at the end of four months in acral versus non acral sites

• Comparison of patients’ perspective of re-pigmentation in vitiligo by Patient global assessment (PGA) score using visual analogue scale (VAS) from 0-10

• Change in dermatology life quality index, using Tjioe M et al questionnaire (annexure 3).

• Comparison of Quality of life (QOL) score between the 2 groups using VIS-22(a vitiligo-specific QoL instrument) (annexure 4).

*Representative vitiligo patch will be the largest patch on the body excluding that on bony prominences, hands and feet or mucosae, and without predominant leukotrichia.

MATERIALS AND METHODS

• Study design: Prospective, open, non-randomized study. The therapy to be administered will be based on patients’preference.

·         Number of patients:At least 20 patients will be included in each group

·         SAMPLE SIZE CALCULATION:Sample size for the study has been computed to compare percentage of re-pigmentation at 4 months of follow up in both the groups by parallel non- inferior trial based on following assumption: -

1. Non – inferiority margin 5%

2. Observed or expected difference in re-pigmentation is zero

3. Pull standard deviation 0.05 i.e. effect size is 0.1

4. Power of the study 90%

5. Confidence level 95%

Based on above assumption the required number of patients in each group will be 18. Taking in consideration for the loss to follow-up, we will take at least 20 patients in each group.

• Dosage of therapy:

GROUP A:-(hand-held NB-UVB comb device)-dosage of 500mJ/cm² once daily will be administered to all vitiligo patches.

The exposure time for each patch will be calculated by recording the irradiance of the lamps (in mW/cm²) using a UV tester (Waldmann UV tester, Germany) and keeping the fluence to be delivered as 500 mJ/cm² using the formula-

Time of exposure (seconds) = Dose in mJ/cm² /Irradiance in mW/cm²

The irradiance of each device will be measured at 45sec, 1min, 2min, 3min, 4min, and 5min.

The patients will be explained in detail regarding the use of hand held NB-UVB comb device and will be provided with written details regarding the time of exposure on each patch. The patients will take this therapy every day at home. After switching the lamp on for 45 seconds, they will start exposing the patches to NB-UVB light. The first patch to be exposed would be the representative patch, followed by sequential exposure of next 2 patches. The handheld comb device will be switched off for 5 minutes and subsequently next 3 patches will be exposed and then device will be switched off for 5 minutes. This procedure will be repeated for rest of the patches in similar manner once daily.

If the vitiligo patch is on face or in an area that is inaccessible, participants will be advised to seek help from someone else to administer the treatment. All devices will be supplied with UV protective goggles (for both the participants and their helper as required), which will be worn at all times during use. In addition, participants will receive training on management of side effects and adherence to treatment schedule. The patient would be advised for adequate photoprotection on the exposed site i.e. both physical and chemical.

GROUP B: - (excimer light therapy) –dosage will be based on minimal erythema dose (MED)for each site. MED will be based on those calculated for each site based on previous literature. MED for each site will be taken as--:

1. Perioral, peri ocular area: 100 mJ/cm²
2. Rest of the face and neck: 150 mJ/cm²
3. Upper limb: 200 mJ/cm²
4. Trunk: 200mJ/cm²
5. Lower limb: 300mJ/cm²
6. Elbow: 300mJ/cm²
7. Knee: 350mJ/cm²
8. Hand: 250mJ/cm²
9. Foot: 400mJ/cm²

Each vitiligo patch will be exposed to starting dose of 50 mJ/cm2 lower than the MED, which will be increased by 10% every session to reach patient’s MED i.e the minimal dose sufficient to produce barely perceptible well-defined erythema in the vitiliginous area after 24 hours of application.If erythema remains for ≤48 hours, the dose willbe kept the same. If erythema persists for more than 48 hours, the dose will be reduced to the last well tolerated one. This therapy will be hospital based, twice a week on non-consecutive days.

·         Duration of treatment: 4 months

·         Study Setting: The study will be conducted in the outpatient department and Phototherapy clinic of the Department of Dermatology and Venereology at All India Institute of Medical Sciences, New Delhi

• Ethical considerations: Approval will be taken from the Institutional Ethics Committee for Post Graduate Research of the All India Institute of Medical Sciences, New Delhi before starting this study.

·         Approval of CTRI will also be taken before starting the study

• Investigation specifically related to projects: None

• Inclusion criteria:

✓ Consecutive patients of localized vitiligo i.e. ≤2% BSA or ≤10 patches.

✓ Patients ≥18 years of age.

✓ Patients who have not taken any topical therapy in last 2 weeks or systemic therapy in last 4 weeks

✓ Patients giving consent for using hand held NB-UVB/excimer light

• Exclusion criteria:

✓ Patients with rapidly spreading vitiligo i.e.development of ≥ 5 new lesions in the past 1 month or ≥ 15 lesions in the past 3 months.

✓ Patients with recalcitrant forms of vitiligo i.e., lip-tip vitiligo, segmental vitiligo, genital vitiligo and with predominant leukotrichia on patches.

✓ Patients with concomitant photo-aggravated dermatoses.

✓ Patients who are unable to adhere to instructions on use of the hand-held NB-UVB comb device or maintain it or patients unable to visit the hospital for excimer light therapy

·        Efficacy Parameters for assessment

1.      Primary efficacy parameter:-

Comparison of percentage re-pigmentation of the representative vitiligo patch at the end of 4 months of treatment between the two study groups.

2.      Secondary parameters: -

• Percentage re-pigmentation in vitiligo based on global assessment using Lund & Browder score

• Assessment of re-pigmentation using photographic assessment (Investigator Global Assessment -IGA)-

• Patient global assessment (PGA) score using visual analogue scale (VAS) from 0-10

• Change in dermatology life quality index, using Tjioe M et al questionnaire

• Quality of life (QOL) score using VIS-22 (a vitiligo-specific QoL instrument)

• Comparison of side-effects such as erythema, edema, pruritus, pain, vesiculation

Patients fulfilling inclusion criteria will be enrolled in either of the two groups in a non-randomized manner, based on patients’ convenience. A detailed history followed by a thorough general physical, dermatological and systemic examination will be undertaken as per proforma attached. The representative vitiligo patch will be selected and graphical assessment will be done to measure the area of involvement. A transparency sheet will be used to delineate the area involved, which will be subsequently used to calculate the exact area involved using a standard graph paper. The representative patch will be marked as 1(one) and rest of the patches will be numbered in a sequence. These will be depicted and numbered on a body chart made in the proforma and one proforma will be given to patient. Baseline disease severity will be assessed using following parameters:

1. Area of involvement by vitiligo will be calculated using Lund and Browder (L & B) chart (Annexure 2)

2. Patient global assessment (PGA) on a scale of 0–10 (to assess degree of improvement on a VAS scale from 0-10, 0 being the baseline disease and 10 indicating complete re-pigmentation)

3. Investigator global assessment (IGA; done by two independent dermatologists, on a scale of −1 to 5, where:−1 = worsening, 0 = no change, 1 = <25% re-pigmentation, 2 = 26–50%, 3 = 51–75%, 4 = 76–90% and 5 = 91–100% re-pigmentation) comparing pre- and post-treatment photographs.

4. Quality of life (QOL) score (using Tjioe M et al. questionnaire which compares QOL before and after phototherapy and rates it on a scale of −28 to 28) (Annexure 3)

5. Quality of life (QOL) score using VIS-22(vitiligo- specific QoL instrument). (Annexure 4)

6. Recording of adverse events- Participants will be instructed to record adverse events in their treatment diaries and to contact us if they experience side effects of concern. For treatment-related side effects, or drug-induced photosensitivity, we will provide telephonic advice

Follow up period: 0, 2, 4, 8, 12, 16 weeks

• Graphical assessment, L & B scoring, IGA, PGA (at each visit)

• Quality of life assessment using score by Tjioe M et al and using VIS-22(a vitiligo- specific QoL instrument) (baseline and end of treatment)

·         Assessment of side-effects in the 2 groups (at each visit)