Effectiveness of Narrowband Ultraviolet on Vitiligo: A Systematic Review

Abstract

Background: Narrowband ultraviolet B (nb-UVB) is one of the most popular and effective modalities to treat vitiligo. Given the importance of nb-UBV, as well as its associations, this research searched the literature for answers on how to best treat vitiligo. Objective: To conduct a systematic literature review assessing the efficacy of narrowband ultraviolet B (NB-UVB) therapy for the treatment of vitiligo, in comparison with psoralen plus ultraviolet A (PUVA) therapy and other topical or systemic treatment modalities. Methods: The databases included were PubMed, Embase, Cochrane, Scopus, Web of Science, and LILACS. Gray literature was also used: Google Scholar, Open Grey, and Library of Thesis and Dissertations-CAPES. The search used the keywords: “Vitiligo” AND “Ultraviolet Therapy OR Actinotherapy”. The risk of bias was evaluated using the Cochrane Risk of Bias 2 (RoB 2) tool by two independent, blinded reviewers, with disagreements resolved by a third reviewer. The outcome assessed was repigmentation. Results: Three randomized controlled trials were selected from 2973 records. In three studies, Nb-UVB had superior effects to the comparator. Conclusion: Nb-UVB phototherapy improves repigmentation in patients with vitiligo, with few side effects. However, the variability in the protocols and the risk of bias require caution when interpreting the results.

1. Introduction

Vitiligo is a chronic depigmenting disease that affects the skin, with the appearance of white macules caused by the loss of function and death of melanocytes, also affecting mucosa and hair [1,2,3]. This acquired pigmentary disorder is prevalent across all racial and ethnic groups, affecting about 1% of the total population before the age of 20, but it can affect people of all ages, in different places of the skin and at different times of life [4,5]. The disease has an unpredictable clinical course, generally showing a slow progression, with new lesions appearing or existing lesions expanding, caused by the autoimmune targeting of the skin [6].

The disease exerts significant psychological and social impacts on affected individuals, particularly when lesions occur in visible areas such as the face, neck, or the dorsum of the hands. Clinically, it presents with focal, segmental, generalized (vulgaris), or even universal depigmented patches [7,8]. They are classified as segmental, non-segmental, and unclassified [9]. There are theories on its cause, such as the neural, immune, and self-destructive hypotheses [5,10]. The characterization of vitiligo suggests that predisposing (genetic) and precipitating (environmental) factors make a person more susceptible to the disease. Among the possible mechanisms that lead to vitiligo, resulting from the loss of functional melanocytes, are immune-mediated and toxic ones, as well as the correlation of pathophysiologies for the disease, such as autoimmune, neuronal, cytotoxic, and melanocytorrhagic factors, with substantial evidence suggesting that oxidative stress and immune system dysregulation serve as triggering factors in genetically predisposed individuals [11,12,13,14,15].

Currently, existing treatments for vitiligo include a variety of topical and systemic approaches, immunosuppressants, phototherapy, and surgical techniques. These treatments can be used in combination to prevent further progression of the disease, stabilize depigmented lesions, and encourage repigmentation [4,5,6,15,16]. Various therapeutic options are available, demonstrating differing levels of efficacy. However, the response to these treatments varies, and not all patients achieve favorable outcomes, which leads to the need to combine different therapeutic approaches to treat the disease. These combinations have been shown to be more effective than monotherapy, such as treatments that stimulate melanocytes in the epidermis, both newly arrived cells from the outer root sheath and residual skin cells [17].

Among the treatments available for association, the gold standard is narrowband ultraviolet B (nb-UVB), which stands out as one of the most popular and effective modalities. It has effects on the immune system, such as immune suppression and melanocyte differentiation, as well as promoting melanin production [13,18]. It exerts its effect through a two-step mechanism: it stabilizes the depigmentation process and stimulates the residual follicular melanocytes to initiate repigmentation [19]. It is regarded as an effective and relatively safe therapeutic approach for vitiligo, yielding favorable clinical and histological outcomes with minimal side effects [17,20].

Given the importance of nb-UBV, as well as its associations with other forms of treatment in the management of vitiligo, the aim of this research is to conduct a literature review on the efficacy of this treatment resource in the treatment of the condition when associated with topical and systemic therapies, immunosuppressants, phototherapy, and any other therapeutic techniques.

2. Materials and Methods

2.1. Protocol

This systematic review was conducted and reported in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. It is registered with the Open Science Framework https://doi.org/10.17605/OSF.IO/FTKVD, accessed on 23 September 2024.

2.2. Eligibility Criteria

To formulate the questions to be focused on in this study, the acronym PICOS was used. P (population)—adult individuals diagnosed with vitiligo; I (intervention)—narrowband ultraviolet B (nb-UVB); C (comparison)—psoralen-UVA (PUVA), topical or systemic treatments; O (outcome)—repigmentation; S (study design)—randomized clinical trials.

Inclusion criteria: individuals diagnosed with vitiligo, in any classification, regardless of the affected region of the body and regardless of gender.

Exclusion criteria: clinical trials that did not use nb-UVB as the main treatment, non-randomized studies, not found in full for reading, even after contacting the author.

2.3. Search Strategies

A broad and sensitive search was carried out, with no restrictions on languages or period of publication. The search used the keywords: “Vitiligo” AND “Ultraviolet Therapy OR Actinotherapy”, in the PubMed databases, with the Medical Subject Heading (MeSH) medical metadata system and other keywords. The following databases were searched: PubMed, Embase, Cochrane, Scopus, Lilacs, the Physiotherapy Evidence Database (PEDro) and Web of Science. Grey literature was also consulted via Google Scholar and the CAPES thesis and dissertation catalog.

2.4. Selection of Studies

Two independent reviewers, R1 and R2, selected the included articles in two phases. In Phase 1, the reviewers evaluated the titles and abstracts based on the eligibility criteria. In Phase 2, they reviewed the full texts and selected the articles according to the same criteria as in Phase 1. Subsequently, they verified all the information obtained. In cases of disagreement, a third reviewer, R3, was consulted.

2.5. Data Collected

Data were collected on the characteristics of the studies, including authorship, study design, and year of publication and country, intervention modality, evaluation instruments, outcomes, evaluation time points, results, and conclusion. The primary outcome was the assessment of repigmentation.

2.6. Individual Assessment of the Risk of Bias in Studies

The risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool by two blinded reviewers, R1 and R2. Any disagreements were resolved through consultation with a third reviewer, R3. All included studies were assessed in the following domains: randomization, deviations from planned interventions, loss of outcome data, measurement of outcomes, and selection of reported outcomes. Each domain had an overall score: low risk, some concern, or high risk.

3. Results

3.1. Study Selection

In the search, 2973 records were found, 2872 in the main databases and 101 in the gray literature. The search was carried out in all databases on 9 May 2024 and updated on 11 September 2024 (Appendix A). Of the 2973 records, after excluding duplicates, 1855 studies went to Phase 1—reading titles and abstracts, and 12 studies went to Phase 2—reading the full text. Finally, 3 studies were included (Figure 1).

3.2. Individual Characteristics of the Studies

Table 1. Summary of the most important findings of the included randomized clinical trials (RCT) (n = 3).

Eligible Studies/ Country	Sample Description	Intervention Protocol	Body Region	Evaluation Period	Outcomes/ Measuring Instruments	Conclusion
Sapam et al. [20] Nepal	N = 56 EG: 28 CG: 28 Sex: EG: (9) 33.33% (M) (18) 66.67% (F) CG: (10) 37.71% (M) (18) 64.19% (F) Age: EG: 31.25 ± 10.26 CG: 29.17 ± 11.22	EG: nb-UVB CG: UVA + Oral psoralen (PUVA)	EG: Whole body CG: Whole body	T0: Baseline T1: 48 weeks	Percentage of repigmentation on depigmented areas: -(0%) no improvement; -(1–25% mild); -(26–50% moderate); -(51–75% good); -(76–100% excellent).	Nb-UVB is effective and well-tolerated option to treat vitiligo.
Stinco et al. [22] Italy	N = 44 EG: 13 CG1: 15 CG2: 16 Sex: EG: 07 (M) 06 (F) CG1: 05 (M) 10 (F) CG2: 02 (M) 14 (F) Age: EG: 27–72 (median 48.8) CG1: 27–56 (median 42.9) CG2: 30–61 (median 43.2)	EG: nb-UVB CG1: Topical pimecrolimus CG2: Topical tacrolimus	EG: Whole body CG1: Whole body CG2: Whole body	T0: Baseline T1: 24 weeks	Scale from 0 to 4: ’0, absent’ (0), ‘1, bad’ (1–25%), ‘2, moderate’ (26–50%), ‘3, good’ (51–75%), ‘4, excellent’ (>75%).	Nb-UVB may represent the ideal choice in generalized vitiligo with topical immunomodulators in localized vitiligo.
Yones et al. [21]	N = 56 EG: 28 CG: 28 Sex: EG: 68% (M) 32% (F) CG: 48% (M) 52% (F) Age: EG: 18–64 (38 median) CG: 18–70 (36 median)	EG: nb-UVB + Oral placebo of psoralen CG: UVA + Oral psoralen (PUVA)	EG: Whole body CG: Whole body	T0: Baseline T1: Follow up every 3 months for 1 year.	Body surface area (BSA-V) (%)	Nb-UVB therapy is more effective and safer than PUVA.

Legend: nb—narrowband; M: male; F: female; PUVA: Psoraleno + UVA; UVB: ultraviolet B; UVA: ultraviolet A; EG: experimental group; CG: control group; CG1: control group 1; CG2: control group 2.

summarizes the main characteristics of the three randomized clinical trials that were included in this review. The dates of publication were 2007, 2009, and 2012. One of the studies was conducted in England [21], one in Italy [22], and one in Nepal [20]. The time of the disease ranged from 1 to 47 years. The study included 149 individuals with vitiligo of both sexes, 62 men and 87 women.

3.2.1. Types of Vitiligo/Classification of Sun-Reactive Skin

The studies analyzed address different types of vitiligo and the classification of sun-reactive skin in patients. Yones et al. [21] included people with non-segmental vitiligo affecting between 2% and 70% of the body surface area. Stinco et al. [22] focused on patients with chronic vitiligo of at least one year’s duration, affecting more than 5% of the body surface. They also classified the patients according to their sun-reactive skin phototype: 8 patients had phototype II, 26 had phototype III, and 10 had phototype IV. Sapam et al. [20] included patients with focal vitiligo, acrofacial vitiligo, and vitiligo vulgaris, all affecting more than 5% of the body surface.

3.2.2. Evaluation of Repigmentation

Repigmentation was assessed in different ways in the three studies. Yones et al. [21] compared the body surface area (BSA-V) before and after treatment, using photographs for subsequent measurements. In addition, the color quality of the repigmented areas was compared with unaffected skin and as either excellent or not excellent, typically based on the level of repigmentation or treatment outcomes. Sapam et al. [20] evaluated repigmentation by calculating the average percentage of repigmentation in each topographic area. Efficacy was categorized into groups ranging from “no improvement” to “excellent”. Stinco et al. [22] also evaluated repigmentation using similar percentage intervals, categorizing the response to treatment in different anatomical sites on a scale of 0 to 4, where “0” represented no repigmentation and “4” indicated excellent repigmentation (>75%).

3.2.3. Collateral Effects

In the studies on vitiligo treatments, adverse effects, especially related to erythema, have been significantly addressed. In the manuscript by Yones et al. [21], 96% of patients with PUVA developed erythema, compared to 68% in the nb-UVB group. Despite this, only one patient in the PUVA discontinued treatment due to adverse effects, and there was no association between erythema episodes and factors such as gender, age, or skin type. In addition, eight patients changed from 8-MOP (10-mg Puvasoralen tablets) to 5-MOP due to nausea.

In the study by Sapam et al. [20], therapy was interrupted in cases of moderate or severe adverse events, such as painful erythema and thickening of the skin, and resumed after resolution of the symptoms with a reduced dosage. Adverse effects were more frequent in the PUVA (57.2%) than in the nb-UVB (7.4%), with patients reporting pruritus, hyperpigmentation, dizziness, erythema, thickening, and nausea in the PUVA, while only two patients in the nb-UVB reported pruritus.

In the study by Stinco et al. [22], two patients in the nb-UVB had mild erythema and pruritus, which were controlled by keeping the dose constant. In comparator group B (pimecrolimus), some patients experienced pain, erythema, and other side effects, leading to treatment reduction or discontinuation. In comparator group C (tacrolimus), all patients reported side effects such as a feeling of warmth in the face, itchy eyelids, and facial flushing after drinking alcohol, symptoms which disappeared within 2–3 weeks, sometimes after reducing the frequency of application.

3.2.4. Description of Procedures

In the article by Yones et al. [21], patients in the nb-UVB and PUVA were treated twice a week. The nb-UVB group started with 0.1 J/cm² and increased the dose by 20% per session, until 2 J/cm². The PUVA started with 0.5 J/cm², with increments of 0.25 J/cm² per session, until 5 J/cm². Doses were adjusted based on the occurrence of erythema.

In the manuscript by Stinco et al. [22], there was treatment for 24 weeks. The nb-UVB group received phototherapy three times a week, starting with 280 mJ/cm², with increases of 15% per session. Patients in the pimecrolimus group applied 1% cream twice a day, while those in the tacrolimus group used 0.1% ointment twice a day.

Sapam et al. [20] showed that the PUVA group received 8-methoxypsoralen (0.6 mg/kg) and UVA (initial dose of UVA varied from 0.5 to 2.5 J/cm² depending on the Fitzpatrick skin type) sessions three times a week, with doses adjusted until minimal erythema. The nb-UVB group also had sessions three times a week, starting with 280 mJ/cm², with 15% increments until minimal erythema. Treatment lasted six months or until complete repigmentation.

3.2.5. Individual Study Results

In the research by Yones et al. [21], both PUVA and nb-UVB therapy significantly improved the body surface area affected (BSA-V). At the end of therapy, 64% of patients in the nb-UVB showed over 50% improvement, compared to 36% in the PUVA. The color match of the repigmented skin was classified as excellent in all patients in the NB-UVB group, whereas only 44% of patients in the PUVA group achieved an excellent color match. For patients who completed 48 sessions, the improvement in vitiligo surface area was greater with nb-UVB therapy (p = 0.007).

In the study by Stinco et al. [22] nb-UVB had superior or equal results to pimecrolimus and tacrolimus controls in the neck (2; 1.5; 2), hands/wrists (1; 1; 0.5), upper limbs (1; 1; 1.5), trunk (1; 0.3;1), and lower limbs (1; 0; 1), respectively. In other anatomical regions, the results were lower, such as the face (1.5; 4; 2.5) and feet/ankles (0; 1.5; 0).

And finally, in the study by Sapam et al. [20], the nb-UVB group showed 45% repigmentation at the end of six months, with 85.2% of patients achieving more than 25% repigmentation and fewer side effects (7.4% reported pruritus). In the PUVA group, repigmentation was 40%, with 88.5% of patients achieving more than 25% repigmentation, but with more side effects (57.2%), including itching, thickening of the skin, and dizziness, leading two patients to discontinue treatment. Overall, nb-UVB proved to be more effective and better tolerated than PUVA.

3.3. Risk of Study Bias

The three studies present different levels of risk of bias. Sapam et al. [20] showed a high risk of overall bias, mainly due to deviations from the planned interventions and problems in measuring outcomes; however, they demonstrated a good randomization process and adequate treatment of missing data. Stinco et al. [22] and Yones et al. [21] presented a moderate overall risk, with good control in the randomization and treatment of missing data, but with some uncertainties regarding the measurement of outcomes and the selection of reported results. These uncertainties can influence the reliability of the results in these studies (Figure 2).

Figure 3 presents an analysis of the risk of bias, showing the distribution of risks in different domains. The randomization process and the measurement of outcomes were well conducted in most of the studies, with a low risk of bias. However, there were some concerns about deviations from the planned interventions and the selection of reported outcomes. Missing data presented a high risk in some cases, impacting the overall bias, which was considered high in a significant proportion of the studies evaluated.

4. Discussion

This study is a systematic review that sought to analyze randomized experimental protocols on the efficacy of narrowband ultraviolet B (nb-UVB) phototherapy as a therapy for vitiligo compared to PUVA, topical, or systemic treatments, with optimistic results regarding the technique despite the small number of studies included and possible biases.

According to the World Health Organization, the concept of health is defined as a state of complete physical, mental, and social well-being, and does not consist solely of the absence of disease or infirmity [23]. The importance of addressing the impact of vitiligo is due to its visible nature, especially when it affects exposed areas, such as the face and hands, which can significantly influence self-esteem and body image and lead to social isolation and reduced quality of life [24,25].

In skin repigmentation, the aim of vitiligo treatment, it is necessary to stimulate melanocytes, which must be present in adequate numbers in the area to be stimulated. However, a diffuse pattern of repigmentation is often observed [26,27]. The most common forms of treatment are PUVA, monochromatic excimer light, and nb-UVB [28]. Therapy with nb-UVB is considered the first choice of treatment, especially when large areas of the body need to be exposed. It has been shown to be effective in patients with vitiligo, helping to repigment affected areas, improving the appearance of the skin and, consequently, patients’ self-esteem and body image [29,30].

In the studies included in this research, the study by Sapam et al. [20] compared nb-UVB with PUVA; for the application, they calculated the minimum dose that produced erythema 24 h after exposure, using 70% of this dose, or 280 mJ/cm², with subsequent increases of 15% each session, obtaining an adequate repigmentation response. Yones et al. [21] performed a similar comparison, starting with a dose of nb-UVB at 0.1 J/cm², with 20% increases in subsequent sessions, observing superior results for nb-UVB. Finally, Stinco et al. [22] compared nb-UVB with a pimecrolimus group and another with tacrolimus; the minimum dose for erythema was 280 mJ/cm², and they used this as the initial dose, with increases of 15% per session (if there were no side effects); they also obtained good repigmentation.

Irradiation with nb-UVB accelerates the differentiation and migration of stem cells that generate melanocytes, inducing stability in these cells and thus producing repigmentation. It also acts to reduce the concentrations of various cytokines (INF-gamma, IL-12, IL-17A, CXCL9, and CXCL10), prevents the destruction of melanocytes, and promotes melanin synthesis [28]. Other approaches aimed at modulating the immune response, such as the use of immunosuppressants or immunomodulators, can help stop the vitiligo progression, such as the use of calcineurin inhibitors (tacrolimus and pimecrolimus), and have shown efficacy in modulating the immune response in skin affected by vitiligo [31].

In PUVA therapy, the patient is first exposed to psoralen, and then the skin is irradiated with UV-A. This can help restore skin pigmentation in areas affected by vitiligo, promoting repigmentation. However, as presented in several reports, PUVA treatment can cause adverse effects, such as erythema, nausea, and other symptoms due to itching, thickening of the skin, and dizziness, being much more common than nb-UVB side effects, thus obtaining greater relevance [16,20,21,30].

Anbar et al. [12] explored the continuous versus interrupted form of nb-UVB treatment, concluding that both protocols are effective, but the interrupted courses showed greater patient compliance and fewer side effects. Another interesting comparison was between the home and hospital form, addressed by Liu et al. [18], in which the authors showed that home nb-UVB phototherapy was as effective compared to hospital treatment, with lower costs and better patient compliance, despite a higher incidence of mild side effects in the home group.

As vitiligo presents major challenges in its treatment, this issue has encouraged authors to investigate the combination of nb-UVB with complementary therapies to achieve better repigmentation results and overall efficacy. By analyzing the efficacy of different therapeutic combinations with nb-UVB, studies show that combining nb-UVB with other therapies can improve the treatment. Vachiramon et al. [17] showed that the addition of fractional CO₂ laser to the NB-UVB regimen, and clobetasol propionate cream, increases the rate of repigmentation in vitiligo lesions on the hands by up to 23.1% in the combined group, compared to 3.9% in the group treated with nb-UVB and clobetasol alone. Similarly, Ghasemloo et al. [4] indicated that the use of fractionated CO₂ laser with nb-UVB resulted in more significant repigmentation compared to the use of nb-UVB alone.

IFN-gamma plays a key role in vitiligo, as it stimulates keratinocytes to produce chemokines that attract and further activate CD8+ T cells. Innate immune cells play a critical role in the onset of vitiligo. CXCL10 is responsible for the initial apoptosis of certain melanocytes, leading to the release of autoantigens. This, in turn, triggers an autoimmune response, resulting in the destruction of melanocytes by T cells. These data highlight the potential benefit of targeting the immune system to halt the progression of vitiligo and facilitate repigmentation, particularly when combined with ultraviolet (UV) exposure [13].

Topical immunomodulators, such as pimecrolimus and tacrolimus, in combination with nb-UVB, were evaluated in the study by Stinco et al. [22]. Repigmentation varied according to the location of the lesions, with better results for facial and neck lesions. These treatments proved to be good therapeutic options, especially in cases of localized vitiligo, however, not without side effects, such as a feeling of warmth in the face, itchy eyelids, and facial flushing after drinking alcohol. Khemis et al. [13] investigated the combination of nb-UVB with apremilast, an oral immunomodulator. Although both groups (apremilast + nb-UVB and placebo + nb-UVB) showed improvement, the difference between them was not statistically different, indicating that more research is wanted to determine the additional efficacy of apremilast to nb-UVB.

Zhang et al. [19] analyzed combined nb-UVB therapy with autologous melanocyte transplantation. They observed repigmentation of over 90% in 81.3% of patients. Furthermore, the addition of topical tacrolimus to nb-UVB showed slightly greater repigmentation in lesions treated with the combination; however, the difference was not significant. These findings suggest that the combination may be beneficial, but the magnitude of the additional benefit may vary [31].

The addition of topical and systemic approaches, thermal immunosuppressants, phototherapy and surgical techniques, and optimized nb-UVB protocols can improve the rate of repigmentation and patient satisfaction. However, the variability in response to treatment and the presence of side effects underline the need for individualized approaches and further research to validate these findings on a large scale, which is why, despite understanding the logic of combined therapies, this study looked at nb-UVB in isolation, even when used as a comparison group for associated therapies.

Although the three studies included in this systematic review used nb-UVB, there are differences in the protocols and evaluation methodologies of the individual studies, such as the criteria for measuring repigmentation and the impact on quality of life, which can introduce bias and make direct comparisons between the studies difficult. Therefore, the standardization of evaluation methods is essential to improve comparability between different studies and protocols, thus enabling future meta-analyses. It should be borne in mind that there is a lot of research into new drugs, such as topical ruxolitinib and the oral JAK inhibitors baracitinib (a JAK1/2 inhibitor), upadacitinib, and povorcitinib, and ritlecitinib (a JAK3/TEC inhibitor) [32], but considering that physical resources are also important.

5. Conclusions

Nb-UVB phototherapy shows a significant improvement in repigmentation in patients with vitiligo, with relatively few side effects compared to other forms of therapy. However, the variability of protocols and forms of evaluation, as well as the risks of bias in the studies included, indicate caution in these results.