Introduction

Vitiligo is a common acquired depigmentary disorder of the skin, affecting 0.5–2% of the general population.1 Individuals with vitiligo experience diminished quality of life (QoL), social isolation, psychological distress, and reduced self-esteem.2 Despite various non-surgical and surgical therapies, phototherapy still remains the first-line and standard therapy for vitiligo. In vitiligo, NB-UVB therapy (311 ± 2 nm) carries a distinct advantage over the psoralen plus ultraviolet A (PUVA) therapy.3 There are various proposed mechanisms by which NB-UVB therapy produces re-pigmentation.4,5

The standard protocol for NB-UVB in vitiligo consists of three sessions per week on alternate days, with the initial treatment time determined by the skin phototype or MED and dose escalation, depending on the patients’ response to treatment and the occurrence of side effects.6 Among an array of phototherapy units, handheld NB-UVB portable home-based devices have been shown to have an important role in the treatment of vitiligo.7 Such devices consist of a plastic case containing TL-9W/01NB-UVB lamps that emit a wavelength of 310–315 nm (peak 311) uniformly over a specific area at uniform distance from the lesion. They are user-friendly and easy to handle at home, thereby reducing frequent hospital visits and improving patient compliance. The ease of use and cost-effectiveness of this target-based therapy with good results in early vitiligo, has led to an increased focus on its utility in vitiligo.8

Although handheld NB-UVB therapy has emerged as a novel and promising treatment modality in vitiligo, the existing studies are limited by their small sample size and heterogeneity in population, disease activity, dosage, and frequency of therapy, resulting in variable outcomes. This systemic review was therefore conducted to precisely evaluate the efficacy and safety of handheld NB-UVB device in the treatment of vitiligo.

Material and methods

Our systemic review followed the Preferred Reporting Items for Systemic Reviews and Meta-analysis (PRISMA) guidelines.9 The study was registered on PROSPERO (CRD42023459348).

Search strategy

Two reviewers (SS and DP) independently conducted systematic searches to identify articles published from 1 January 2002 to 28 November 2023 in the Embase, PubMed and Scopus databases using specific keywords (narrow band ultraviolet B, handheld, targeted, home, vitiligo) and MeSH terms (ultraviolet therapy, phototherapy, vitiligo, home environment) with appropriate Boolean operators [see Appendix S1 for more details]. Additionally, each reviewer performed a manual search, examined references of various articles, and searched for ongoing trials in ClinicalTrials.gov.

Study selection criteria

Inclusion criteria:

1.

Monotherapy with a handheld narrow band UVB device with a lamp system for treatment of vitiligo.

2.

Studies which explicitly reported an absolute number of patients in terms of corresponding percentages of re-pigmentation or the incidence of side effects.

The eligible studies encompassed a range of research designs, including clinical trials, case series, systematic reviews, randomised controlled trials, and meta-analyses. Studies mentioning the specific NB-UVB devices by name were included, after meticulous verification of the technical specifications to confirm their nature as hand-held, portable home-based devices through product documentation; among such studies, those with sample size equal or greater than ten, were included. In situations where multiple studies emanated from a single centre, precedence was given to that which exhibited the largest sample size. No restrictions were imposed on the prior application of alternative therapeutic modalities in the vitiligo patient cohort studied. Geographical and linguistic factors were not deemed as limiting criteria. In the event of any discrepancies or inconsistencies, it was addressed through a process of consensus-building among the investigators or if required, by arbitration by a third reviewer (SK).

Data extraction

A comprehensive dataset encompassing study characteristics was generated, comprising parameters such as the primary author’s nomenclature, year of publication, study typology, detailed demographics of the study cohort (including vitiligo subtype, activity, body surface area [BSA] involvement, total sample size, average or median age of the study population), treatment particulars (initial therapeutic dosage, treatment frequency, dosage escalations and minimal dose erythema calculation), treatment duration and assessment of outcome quality.

The clinical efficacy data included a proportion of patients with re-pigmentation (> 25%, > 50% and > 75%) of skin over discrete time intervals spanning from 3 months to 12 months. Additionally, the percentages of re-pigmentation achieved in distinct anatomical regions, such as the head and neck, extremities, trunk, and acral areas, were meticulously catalogued. The data also included incidence of adverse events following therapy such as erythema, pruritus, burning sensation, dryness, skin atrophy, hyperpigmentation (abnormal skin darkening), herpetic lesions, blistering, the Koebner’s phenomenon and oedema (localised swelling).

The QoL outcomes were derived from studies employing distinct scoring systems, notably VitiQoL, Skindex 29 score, DLQI (Dermatology Life Quality Index) and Tjioe M questionnaire.8.

Statistical analysis

Statistical analyses were performed using MedCalc Statistical Software version 22.005 (MedCalc Software Ltd, Ostend, Belgiumhttp://www.medcalc.org; 2023). We determined the pooled proportions of re-pigmentation exceeding 25%, 50%, and 75%, achieved over a maximum duration of therapy with the device. To evaluate heterogeneity among the studies, we utilised the I2 statistics, where a value greater than 50% indicated significant heterogeneity. Random effect model was used for I2 statistics greater than 50% and the fixed model for I2 statistics less than 50%. Additionally, we conducted a sensitivity analysis to further explore heterogeneity. Subgroup analysis was carried out based on factors such as the number of patients, MED calculation, sessions per week, disease stability/activity, and response adjusted to time. Meta-analysis was used to generate a forest plot summarising the re-pigmentation response rate. Publication bias was evaluated using a Funnel plot and Egger’s regression test, taking into consideration the percentage of re-pigmentation. A p-value less than 0.05 was considered statistically significant in this context.

Results Study characteristics

Through a systematic exploration of databases using predetermined search keywords, 250 articles were obtained. After a screening process, 13 studies were found suitable for inclusion, encompassing a total of 557 patients [Figure 1].8,10–21 Among these 13 studies, eight had a randomised controlled design,3,14,16–21 three were open-label single-arm studies,10–12 and two were open-label non-randomised comparative trials.8,15 The median age of patients was 30.4 years (range: 22.5–48.4 years). In the 13 studies, eight included patients of non-segmental vitiligo,8,10,13,14,16,19–21 two each included all types11,12 and focal/localised vitiligo,17,18 and one study included generalised vitiligo patients.15 Notably, seven studies recruited patients with only stable vitiligo.8,10,15,18–21 The extent of vitiligo involvement varied among the studies, with a reported BSA involvement from less than 2% to 25%,8,10,13,14–16 with other studies not specifying BSA involvement.11,12,17–21 Four studies used a starting dose of therapy based on MED calculation,13,15,17,20 two studies8,10 employed a fixed dose of 500 mJ/cm2, while the remaining studies used energy based on skin type or arbitrary doses that ranged from 50 mJ/cm2 to 400 mJ/cm2 and studies with predominantly patients of skin types IV, V and VI used higher initial energy doses. The increment of energy per sessions was 10–20% in five studies, > 20% in two studies, and < 10% in two studies [Table 1].

Figure 1: Study selection process. The preferred reporting items for systematic reviews and meta-analysis (PRISMA) flow chart.

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Table 1: Characteristics of included studies

Study Year of publication Type of study Duration of vitiligo in years Disease stability BSA involved Age group Type of vitiligo Skin type Total sample size Age (in years) Treatment characteristics Treatment duration Device used Initial dose of treatment Dose increment per session Treatment frequency Minimal erythema dose (calculated/not calculated/not mentioned Singh et al.8 2023 Open-label: Non-randomised Median (range: 14 [0.3–40]) Stable < 2% > 18 years NSV III, IV, V 17 Median age: 28; (range: 18–53) 500 mJ/cm2 Fixed Daily Not mentioned Four months Handheld NB-UVB comb device (V-Care Meditech Pvt. Ltd.) Poolsuwan et al.19 2021 RCT: double-arm

Mean ± SD:

6.08 ± 3.22

Stable NS 18–65 years NSV III, IV, V 36 Mean 48.42 (37–65)

Initial dose: 150 mJ/cm2

Mean cumulative dose: 14, 289.17 mJ/cm2

Increment of 15% for four sessions then by 10%

Decrease by 50% of previous burning dose

Thrice weekly Not mentioned Four months DuaLightTM, TheraLight Inc., Carlsbad, CA, USA) Khandpur et al.10 2020 Open-label: single-arm Mean ± SD: 4.9 ± 4.1 Stable < 2% > 8 years NSV IV, V 10

Mean: 30.4

(range: 21–54)

500 mJ/cm2 Fixed dose Thrice weekly Not calculated Six months NB-UVB comb (V-Care Meditech Pvt. Ltd., Bangalore, India) Thomas et al.13 2020 RCT: three-arm Median (range: 5 [3–11]) Active < 10% > five years NSV I, II, III, IV,V, VI 169 Mean: 36.9

50 mJ/cm2

Maximum time of exposure: 13.42 minutes

Increment by 10% till mild erythema Three to four times weekly Calculated Nine months Zhang et al.15 2019 Open-label

Mean ± SD:

5.3 ± 7.4

Stable >2% > 16 years Generalised III, IV 48 Mean age: 33 + 12.2

Initial dose: 400 mJ/cm2

Maximum dose of energy: 3000 mJ/cm2 on body and 1500 mJ/cm2 for face

Final cumulative dose: 84.1 ± 2.5 J/cm2

Increment by 20% till mild erythema Thrice weekly Calculated Six months Philips lamps (Shanghai Sigma High-tech Co. Ltd, Shanghai, China) Liu et al.16 2019 RCT: Double-arm NS Progressive and stable <5% > five years NSV III, IV 52 Mean (SD) age : 25.44 (1.43)

Initial dose: 400 mJ/cm2

Maximum dose: 2500 mJ/cm2

Increment of 100 mj/cm2 (25%) till mild erythema Thrice weekly Not mentioned Five months Sigma SH1b handheld NB-UVB units (Sigma, Shanghai, China) Van et al.17 2019 Observational retrospective NS Active and stable NS 18–58 years Localised NS 16 NS 20% less than MED

Increment of 20% till mild erythema

In cases where erythema was noted, we reduced the dose by 20% in the following treatment

Once weekly Calculated Three months NS Tien Guan et al.18 2015 RCT: Double-arm

Median (range:

2 [1–16])

Stable NS NS Focal II, III, IV, V 22

Median age: 23.5 (range: 15–40)

Mean age: 34.6 years

Power: 5.5 mW/cm2; Thrice weekly

Total cumulative dose: 37.86 J/cm2

NS Thrice weekly Not mentioned Six months

(Daavlin Dermapal system)

Shan X et al.12 2014 Open-label

Mean ± SD:

3.7 ± 4.9

NS NS NS NS NS 93 Mean: 22.5 (range: 2–65)

Initial dose: 300 mJ/cm2

Maximum dose: 900 mj/cm2

Increment by 100 mj/cm2 (33%) till mild erythema Thrice weekly Not calculated Twelve months SS-01 UV phototherapy instrument (Shanghai Sigma High-tech Co. Ltd, Shanghai, China) which bears two Philips TL-9W/01 lamps Eleftheriadou et al.14 2014 RCT: Double-arm

Mean ± SD:

11.36 ± 10.12

Active and stable < 25% > 5 years NSV I, II, III, IV,V, VI 19 Mean age:27.63; (range: 5–71)

Based on Fitzpatrick skin type with initial time of exposure for skin type IV–VI: 30 sec and for skin type I, II, III: 15 sec, 20 sec, 25 sec, respectively

Maximum time of exposure for skin type IV–VI: 6 min and for skin types I–III: 3 min, 4 min, 5 min, respectively

Increment of 20% Three to four times weekly Calculated but not used as basis to start therapy Four months Two different handheld NB-UVB devices were explored: Dermfix 1000™ NB-UVB and Waldmann™ NB-UVB 109 Goel et al.11 2012 Open-label Mean (range: 12 [0.1–18]) NS NS 4–56 years Generalised, segmental IV, V 50 NS Exposure for 2 mins at first sitting 20% increment till mild erythema Twice weekly Not calculated Six months Narrow band UV spot phototherapy unit: 311 nm (PLS 9W/ 01) with mirror reflectors and adjustable spot size. (Dermaindia Spot Phototherapy Unit, Chennai) Klahan and Asawanonda21 2009 RCT: Double-arm

Seven cases: 0–5 years

Three cases: 6–10 years

Five cases: > 10 years

Stable NS NS NSV III, IV, V 15 Mean age: 41.67 (range: 27–65) NS NS Twice weekly Not mentioned Three months DuaLightTM (TheraLight Inc., Carlsbad, CA) Asawanonda et al.20 2008 RCT: Double-arm

Five cases: 0–5 years

Three cases: 6–10 years

One case:

11–15 years

One case:

16–20 years

Stable NS > 16 years NSV III, IV 10 Mean age: 41.8 (range: 22–66) 50% of MED Increment of 10% or 5% Twice weekly Calculated Six months  DuaLight™ (TheraLight. Inc. Carlsbad. CA Q20()8. USA

In the majority of studies, the treatment regimen involved three sessions per week,10,12–16,18,19 whereas three studies employed twice-weekly sessions11,20,21 and one study each employed once-weekly17 and daily sessions.8 The median duration of treatment across the evaluated studies was six months (range: 3–12 months). The studies utilised various tools (VitiQoL, Skindex 29 score, DLQI, Tjioe M questionnaire,8 VIS-22) to assess QoL, which consistently demonstrated improvement compared to baseline.8,10,13–16 The characteristics of each study are mentioned in Table 1.

Clinical efficacy Pooled analysis of efficacy

The response to therapy was graded as a percentage of re-pigmentation in the 13 studies, of which 9, 12, and 13 studies had provided proportions of patients attaining > 25%, > 50%, and > 75% re-pigmentation respectively, compared to baseline [see Appendix S2 for more details]. The pooled proportions of patients achieving > 25%, > 50%, and > 75% re-pigmentation compared to baseline were 63.6% (95% CI: 51.0–75.3%) of 297 patients, 40.8% (95% CI: 30.4–51.6%) of 370 patients and 15.4% (95% CI: 7.6–25.3%) of 506 patients over a median duration of six months of therapy. The pooled proportions of patients achieving > 25%, > 50%, and > 75% re-pigmentation compared to baseline in the non-randomised studies were 73.82% (95% CI: 67.59–79.4%) of 221 patients, 51.1% (95% CI: 44.4–57.8%) of 221 patients and 16.50% (95% CI: 83.2–95.2%) of 221 patients, respectively. The pooled proportions of patients achieving > 25%, > 50%, and > 75% re-pigmentation compared to baseline in the randomised studies were 52.38% (95% CI: 39.2–65.3%) of 59 patients, 27.54% (95% CI: 9.9–49.9%) of 95 patients and 13.03% (95% CI: 5.9–22.5%) of 231 patients, respectively. The details of the response to treatment in terms of the percentage of re-pigmentation in randomised and non-randomised studies are summarised in Table 2.

Table 2: Response to handheld device-based Narrowband ultraviolet B therapy therapy in the included studies

Study Sample size > 25% re-pigmentation n/N > 50% re-pigmentation n/N > 75% re-pigmentation n/N Pooled proportion (95% CI; I2) Non-randomised studies Singh et al.8 17 8/14 (57.1%) 4/14 (28.57%) 3/14 (21.4%) > 25% re-pigmentation > 50% re-pigmentation > 75% re-pigmentation Khandpur et al.10 10 9/10 (90%) 7/10 (70%) 1/10 (10%) 73.82% (95% CI: 67.59–79.4%; 0%) 51.1% (95% CI: 44.4–57.8%; 19.73%) 16.50% (95% CI: 83.2–95.2%; 91.01%) Zhang et al.15 48 30/38 (78.9%) 18/38 (47.36%) 2/38 (5.26%) Van et al.17 16 13/16 (81.25%) 10/16 (62.5%) 6/16 (37.5%) Shan et al.12 93 66/93 (70.9%) 51/93 (54.83%) 35/93 (37.63%) Goel et al.11 50 38/50 (76%) 23/50 (46%) 0/50 Randomised studies Poolsuwan et al.19 36 NS 11/36 (30.5%) 5/36 (13.89%) 52.38% (95% CI: 39.2–65.3%; 42.82%) 27.54% (95% CI: 9.9–49.9%; 77.13%) 13.03% (95% CI: 5.9–22.5%;79.04%) Thomas et al.13 169 NS NS 11/136 (8.1%) Liu B et al.16 52 29/52 (55.76%) 23/52 (44.23%) 12/52 (23.1%) Tien Guan et al.18 22 NS 16/22 (72.7%) 11/22 (50%) Eleftheriadou et al.14 19 3/17 (17.6%) 2/17 (11.7%) 2/17 (11.7%) Klahan and Asawanonda21 15 NS 2/15 (13.33%) 0/15 Asawanonda et al.20 10 2/7 (28.6%) 0/7 0/7 Overall 63.6% (51.0–75.3%; 77.1%) 40.8% (30.4–51.6%; 75.9%) 15.4% (7.6–25.3%; 85.9%) Re-pigmentation based on anatomical sites

Three studies found > 50% re-pigmentation in vitiligo patches over the face and neck in 50% (45/90) of their cases, over the limbs in 50% (53/106) cases, and on the trunk in 39.1% (38/97) cases, but acral regions had only 2.5% (2/80) improvement.12,14,15 In the study by Thomas et al., > 75% re-pigmentation was seen in 32% (20/63) of head and neck lesions, 11% (7/79) of hands and feet macules, and 17% (16/92) of the patches present on the rest of the body.13 In the study by Zhang et al.,15 no significant differences in re-pigmentation based on site were observed, although face, trunk, and extremities showed better response than acral sites.15 In 11 studies, a total of 38 (11.3%) out of 334 patients had no response to therapy.8,10–12,14–18,20,21

Pooled analysis of adverse events

Handheld NB-UVB therapya-ssociated adverse events were reported in 12 studies with a total 542 patients (see Appendix S3 for more details). The most common side effect was erythema, with the pooled proportion of patients having erythema being 33.4% (95% CI: 19.3–49.2%) of 411 patients. Grades 3 and 4 erythema were reported in 27 and 15 patients, respectively. Pruritus was reported in five studies, with a pooled proportion of 22.1% (95% CI: 8.6–39.8%) among 227 patients.8,11,12,14,15 Four studies mentioned burning sensation, with a pooled proportion of 16.4% (95% CI: 6.4–29.9%) among 210 patients.8,12,15,16 Two studies reported dryness, with a pooled proportion of 9.8% (95% CI: 2.8–20.4%) among 112 patients.12,14 Hyperpigmentation around the vitiligo patch was reported in two studies, with a pooled proportion of 19.1% (95% CI: 11–28.9%) out of 71 patients.14,16 Blister formation was reported in two studies, with a pooled proportion of 9.7% (95% CI: 0.8–27.1%) out of 69 patients.8,16 One study each had mentioned skin thinning (two patients),13 cold sore (one patient),14 Koebner’s phenomenon (one patient),16 and oedema (three patients)8 as side effects of handheld NB-UVB therapy.

Heterogeneity

There was clinical heterogeneity noted in the included studies in terms of the study design, disease activity, BSA involvement, MED calculation, frequency of administration, and energy dosing. There was no significant heterogeneity noted among the non-randomised studies for pooled estimates of re-pigmentation of > 25% (I2 = 0%; 95% CI 0–%, 71.9, p = 0.49) and > 50% (I2 = 19.73%; 95% CI 0–64.4%, p = 0.28), but for > 75% repigmentation, they showed significant heterogeneity (I2 = 91.01%; 95% CI 83.2–95.2%, p < 0.01). There was significant heterogeneity noted among the randomised studies for pooled estimates of re-pigmentation of > 50% (I2 = 77.13%; 95% CI 25.54–92.9%, p = 0.01) and > 75% (I2 = 79.04%; 95% CI 59.01–89.28%, p < 0.01, but no such heterogeneity was noted for estimates of repigmentation of > 25% (I2 = 42.82%, p < 0.18), expect for). Based on sensitivity analysis, no articles were found to be a specific source of heterogeneity. There was significant heterogeneity for pooled estimates of erythema (I2 = 89.3%; 95% CI 81.9–93.7%, p < 0.001), burning sensation (I2 = 80.60%; 95% CI 49–92.6%, p < 0.01) and pruritus (I2 = 87.4%; 95% CI 72.9–94.1%, p < 0.01). There was insignificant statistical heterogeneity noted for dryness (I2 = 44.2%%, p = 0.18), hyperpigmentation (I2 = 0%, p = 0.82) and blistering (I2 = 67.1%, p = 0.08).

Subgroup analysis

Subgroup analyses of the percentage of re-pigmentation achieved based on the number of patients, MED calculation, vitiligo activity, the number of sessions per week and response adjusted to time were conducted. In studies with > 20 patients, there were significantly higher rates of > 25% re-pigmentation response (70.1% [95% CI: 60.7–78.7%] vs 55.5% [95% CI: 27.7–81.5%]; p = 0.02) and > 50% re-pigmentation response (48.6% [95% CI: 20.5–64.3%] vs 29.6% [95% CI: 11.1–52.5]; p = 0.002) compared to studies with < 20 patients. However, the pooled proportions of > 75% re-pigmentation showed no difference (16.6% [95% CI: 6.01–31.1%] vs 13.9% [95% CI: 4.6–27.1%]; p = 0.54] between studies including less than 20 patients and those including more patients. The number 20 was chosen to reflect the minimum sample size needed for a phase 1 clinical trial.

The patients who had used handheld NB-UVB therapy based on MED calculation showed no significantly better response for > 25% (67.5% [95% CI: 42.3–88.2%] vs 61.5% [95% CI: 45.8–76.1%]; p = 0.39), > 50% (36.0% [95% CI: 9.3–68.8%] vs 41.5% [95% CI: 29.9–53.5%]; p = 0.43) or > 75% (11.5% [95% CI: 3.4–23.7%) vs 17.1% [95% CI: 6.6–31.1%]; p = 0.08) re-pigmentation compared to patients who were treated without MED calculation.

The pooled > 25% re-pigmentation response was observed to be better in the four studies,8,10,15,20 which included only stable vitiligo than in the three studies