Introduction

Vitiligo is a chronic skin disorder that is characterized by the presence of depigmented patches on the skin [1, 2]. These patches are caused by the loss of melanocytes, which are responsible for producing melanin, in the skin and/or mucous membranes [3,4,5]. The exact mechanisms behind vitiligo are still not fully understood, but several risk factors have been identified, including an autoimmune association, heredity, and trigger events, such as stress, severe sunburn, and exposure to certain chemicals [6,7,8,9,10,11,12,13]. The prevalence of vitiligo varies among different populations, but it is estimated to affect approximately 0.5–1% of the global general population [14,15,16]. In some populations, this number can be as high as 2–3% [17, 18]. Vitiligo often presents in individuals below the age of 20 and typically develops before the age of 40 [3, 17, 18]. It affects both males and females equally and can have a significant negative impact on patients’ self-esteem and confidence, especially for those with facial vitiligo (FV) [1].

In the management of FV, several modalities have been utilized, including the 308 nm excimer laser (308 nm EL) and tacrolimus ointment (TO) [19,20,21,22,23,24,25,26]. The 308 nm EL is a type of phototherapy that delivers a specific wavelength of light, created by the dimerization of xenon and chlorine [27]. Research suggests that 308 nm EL monotherapy can benefit patients with vitiligo [28, 29], but its effects are often unsatisfactory and require a lengthy treatment course. Combining 308 nm EL with other therapies has been shown to produce better outcomes, highlighting the importance of combining modalities in the treatment of FV. TO, on the other hand, is a topical immunomodulatory agent that has shown promise as a treatment for vitiligo [30]. Studies have demonstrated that the combination of 308 nm EL and TO is more effective than either treatment alone [31, 32]. Previous clinical trials have examined the effects and safety of 308 nm EL and TO in individuals with FV [33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51]. However, there is a lack of systematic reviews and meta-analyses that comprehensively assess the efficacy and safety of this combined treatment approach. Therefore, the present study aimed to thoroughly and systematically evaluate the effects and safety of 308 nm EL and TO in the treatment of FV.

Materials and methods

Ethical approval statement

This study sought to gather secondary data from published articles and assessed their relevance to the research question. Therefore, no ethical approval is required in this study.

Eligibility criteria

To ensure the appropriateness of the included studies, certain eligibility criteria were established and applied. Firstly, patients diagnosed with FV, irrespective of their age or gender, were considered eligible for inclusion. In addition, only randomized controlled trials (RCTs) focusing on the treatment of FV using 308 nm EL or TO were included in the study. Furthermore, the treatment group consisted of patients receiving both 308 nm EL and TO, while the control group included patients receiving either 308 nm EL or TO.

On the other hand, certain studies were excluded based on the established exclusion criteria. Studies that did not meet the requirements of being RCTs, such as animal studies, case reports, reviews, conferences, non-clinical studies, and non-RCTs, were excluded. Additionally, studies that did not specifically investigate the use of 308 nm EL or TO for the treatment of FV were also excluded. Finally, studies that provided insufficient information, had inaccurate comparisons, involved combined therapies, or duplication were excluded to maintain the integrity of the data.

Search strategy for eligible records

To identify relevant and eligible studies, a comprehensive search strategy was employed. Electronic databases including Cochrane Library, PUBMED, EMBASE, CNKI, and WANGFANG were searched from their inception to June 1, 2023. Additional literature sources such as dissertations and reference lists of relevant reviews were also identified and assessed. The search strategy involved using specific retrieval terms related to topics such as 308 nm excimer laser, laser therapy, tacrolimus ointment, vitiligo, topical applications, and facial treatments.

Outcome measurement

The outcomes assessed in this study are multiple and comprehensive, including the overall response rate (ORR), the total adverse reaction rate (TARR), the recurrence rate at 3 months (RR-3), and the recurrence rate at 6 months (RR-6). These outcome measures were chosen to provide a comprehensive evaluation of the effects and safety of the intervention being studied.

Study selection, data collection, and risk of bias evaluation

Study selection, data collection, and risk of bias evaluation to ensure the reliability and accuracy of the study findings, a rigorous and systematic approach was employed. Two independent authors conducted the study selection, data collection, and risk of bias evaluation. Any disagreements or discrepancies were resolved through discussions between the two authors, and if necessary, a third author was consulted to reach a consensus. This meticulous process aimed to minimize any potential bias or errors in the study. Data collection was carried out using a pre-designed data collection form, which allowed for consistent and organized data recording. This ensured that all relevant information from the eligible trials was captured accurately and comprehensively. To evaluate the risk of bias in each eligible study, the Cochrane risk-of-bias tool was employed. This tool is a widely recognized and established tool for assessing the methodological quality and risk of bias in RCTs.

Statistical analysis

For data analysis, this study utilized RevMan 5.4 software, a commonly used statistical software package for conducting systematic reviews and meta-analyses. All outcome data were calculated as odds ratios (OR) and 95% confidence intervals (CI). The OR provides a measure of the association between the intervention and the outcomes of interest, while the CI indicates the range of values within which the true effect size is likely to fall. To assess heterogeneity across the included RCTs, the I2 index was used. This index quantifies the proportion of total variation across studies that is due to heterogeneity rather than chance. Finally, a fixed-effects model was employed to pool the outcome data, providing a summary measure of the intervention’s effectiveness across the included studies. This statistical approach ensured a robust and reliable analysis of the available evidence.

Results

Study selection

The study initially identified 127 records from electronic databases and other sources. After removing duplicates and irrelevant records, 33 full-text articles were assessed for eligibility. Finally, a total of 19 RCTs involving 2085 patients with FV were included for analysis (Fig. 1) [33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51].

Fig. 1
figure 1

Flowchart of study selection

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Study characteristics

All eligible trials were conducted in China, except for one trial in France (Table 1). The sample sizes of the included RCTs ranged from 20 to 138 in the treatment group and from 20 to 131 in the control group. In all studies, the treatment group utilized 308 nm EL plus TO, while the control group used either 308 nm EL or TO. The follow-up visits for the patients ranged from seven to 24 weeks (Table 1).

Table 1 General characteristics of included studies
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Risk of bias assessment

The risk of bias analysis of the 19 included RCTs revealed that all studies provided sufficient information on random sequence generation, incomplete outcome data, selective reporting, and other forms of bias (Fig. 2) [33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51]. However, all the included studies failed to clearly report information on allocation concealment or blinding of participants, personnel, and outcome assessment (Fig. 2) [33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51].

Fig. 2
figure 2

Risk of bias summary of included studies

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nm EL plus TO vs. 308 nm EL

Meta-analysis of ORR

The meta-analysis included 12 studies with 1246 patients, and the results showed a statistically significant difference in ORR between the two groups (OR = 4.29, 95% CI [2.97, 6.19], I2 = 0%, P < 0.001; Fig. 3) [33,34,35, 38,39,40,41,42,43, 45, 47, 51].

Fig. 3
figure 3

Meta-analysis of ORR comparing 308 nm EL plus TO to 308 nm EL

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Meta-analysis of TARR

Six RCTs involving 672 patients assessed the TARR. The meta-analysis results did not show a statistically significant difference between the two groups (OR = 0.68, 95% CI [0.40, 1.16], I2 = 0%, P = 0.16; Fig. 4A) [33,34,35, 39, 43, 47].

Fig. 4
figure 4

Meta-analysis of TARR (A), RR-3 (B), and RR-6 (C) comparing 308 nm EL plus TO to 308 nm EL

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Meta-analysis of RR-3

Two trials involving 161 patients evaluated RR-3. The meta-analysis results showed a statistically significant difference between the two groups (OR = 0.18, 95% CI [0.05, 0.69], I2 = 0%, P = 0.01; Fig. 4B) [38, 41].

Meta-analysis of RR-6

Two studies involving 131 patients examined the RR-6. The meta-analysis results also showed a statistically significant difference between the two groups (OR = 0.38, 95% CI [0.14, 1.03], I2 = 39%, P = 0.06; Fig. 4C) [38, 41].

nm EL plus TO vs. TO

Meta-analysis of ORR

Nine studies involving 948 patients evaluated ORR. The meta-analysis results showed a statistically significant difference between the two groups (OR = 4.21, 95% CI [2.90, 6.11], I2 = 0%, P < 0.001; Fig. 5A) [36, 37, 42,43,44, 46, 48,49,50].

Fig. 5
figure 5

Meta-analysis of ORR (A), TARR (B), and RR-3 (C) comparing 308 nm EL plus TO to TO

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Meta-analysis of TARR

Four trials involving 465 patients assessed the TARR. The meta-analysis results demonstrated a significant difference between the two groups (OR = 0.42, 95% CI [0.22, 0.81], I2 = 4%, P = 0.009; Fig. 5B) [43, 46, 49, 50].

Meta-analysis of RR-3

One study involving 83 patients investigated RR-3. However, no statistically significant difference was identified between the two groups (OR = 0.32, 95% CI [0.01, 8.03], P = 0.49; Fig. 5C) [43].

Discussion

FV is a common skin disorder characterized by the loss of pigment in certain areas of the skin. It affects approximately 0.5–3% of the population, making it a relatively prevalent condition. If left untreated, FV can have significant socio-psychological consequences, such as low self-esteem, depression, and anxiety, which can greatly impact the quality of life for those affected.

The current treatments for FV mainly include local therapy, phototherapy, and surgical treatment [52, 53]. Local therapy options such as topical medications, corticosteroids, and immunomodulators (e.g., TO) are commonly employed. Phototherapy typically involves ultraviolet B (UVB) phototherapy (e.g., 308 nm EL) and psoralen plus ultraviolet A therapy, which stimulate the activity of skin pigment cells through light exposure, thereby promoting pigment deposition. Surgical options such as skin grafting and pigment cell transplantation may be considered to enhance pigment deposition in affected areas. Among these modalities, 308 nm EL and TO are frequently utilized for FV.

The 308 nm EL enables precise targeting of vitiligo-affected areas on the face, delivering controlled doses of UVB radiation specifically to the depigmented patches [54]. A typical 308 nm EL treatment protocol often involves applying the laser with a dosage of 50 mJ/cm2 on affected areas twice weekly for at least 12 weeks. This focused UVB light stimulates melanocyte activity, promoting repigmentation in characteristic vitiligo depigmented patches [54].

In the case of TO, it offers a localized treatment approach for FV. Direct application to the depigmented patches allows for targeted therapy, minimizing exposure to unaffected areas of the skin [55]. A typical TO treatment protocol involves applying topical 0.1% TO twice daily on the target lesion for a total of at least 12 weeks. Tacrolimus functions by inhibiting the activity of specific immune cells, namely T lymphocytes, which contribute to the inflammatory response associated with vitiligo [55].

Previous studies have explored the use of 308 nm EL and TO therapy for the treatment of FV. These treatment modalities have shown some promising results in repigmenting the affected areas. However, there is limited evidence available to support the effectiveness and safety of combining 308 nm EL with TO therapy compared to using either therapy alone. To address this gap in knowledge, this study conducted a systematic investigation to evaluate the effects and safety of combining 308 nm EL with TO therapy in the treatment of FV. The researchers aimed to assess the repigmentation outcomes, evaluate the side effects and adverse events associated with the combined therapy, and provide evidence-based recommendations for clinicians and patients considering this treatment approach. By thoroughly examining the effects and safety of combining 308 nm EL with TO therapy, this study aimed to contribute to the existing body of knowledge on FV treatment options and potentially provide a more effective and safe treatment approach for individuals with this skin disorder.

The analysis included 19 RCTs with a total of 2085 patients diagnosed with FV. The meta-analysis results showed that when comparing the combination therapy of 308 nm EL with TO to using only 308 nm EL, there were significant differences in the ORR. The combination therapy demonstrated a higher ORR than using 308 nm EL alone. Additionally, there were significant differences observed in the RR-3 and RR-6. However, there was no significant difference in the TARR between the two treatment modalities. These findings suggest that combining 308 nm EL with TO is more effective in treating FV compared to using 308 nm EL alone, while maintaining a similar safety profile for the patients. Similarly, when comparing the combination therapy of 308 nm EL with TO to using only TO, significant differences were observed in the ORR, TARR, and RR-3. This indicates that the combination therapy yields better treatment outcomes for FV patients compared to using TO alone. However, it is important to note that the safety profile of TO monotherapy was found to be better than that of combining TO with 308 nm EL. Therefore, while the combination therapy shows superior treatment effects, clinicians should consider the potential risks associated with this combination therapy and carefully assess the individual patient’s condition before proceeding with the treatment.

The results of this study highlight the potential of this combined approach in achieving better repigmentation outcomes for patients with FV. By combining the precise and targeted action of the 308 nm EL with the occlusion provided by topical application, a synergistic effect is observed. The EL delivers focused ultraviolet light to the depigmented areas of the skin, stimulating melanocyte proliferation and repigmentation. Concurrently, topical occlusion helps enhance the penetration of medications and increases the absorption of ultraviolet radiation, further promoting the therapeutic effects of the laser. However, it is important to note that while the results are promising, further research needs to be conducted to validate these findings. Future systematic reviews should involve RCTs with larger sample sizes to provide a more robust analysis of the combined therapy’s effectiveness. Additionally, a more standardized approach across different research studies would help ensure consistency and comparability of the results. Overall, this study provides valuable insights into the potential benefits of combining 308 nm EL therapy with topical occlusion for the treatment of FV. Further research and validation are necessary to solidify these findings and establish the combined therapy as a preferred and widely adopted treatment option for FV.

It is crucial to recognize and highlight the limitations of this retrospective study. Firstly, the small number of eligible RCTs available for analysis can significantly impact the overall validity and generalizability of the study findings. A limited sample size may compromise the statistical power and reliability of the results, making it challenging to draw definitive conclusions. Furthermore, the variations in the implementation of the included studies can introduce potential biases into the analysis. Each study might have adopted different methodologies, inclusion criteria, and interventions, leading to heterogeneity in the data. This heterogeneity can potentially obscure the true effect of the treatments being evaluated. In addition, differences in the treatments and controls used across the included studies can contribute to the complexity of interpreting the results. These variations might involve variations in dosages, administration protocols, or even the choice of comparators. Such differences can introduce confounding factors, making it difficult to isolate the effects of the specific interventions being investigated. Moreover, the variance in follow-up duration among the included studies may have limited the ability to establish concrete and robust conclusions. Different studies might have utilized varying follow-up durations, which can impact the assessment of long-term outcomes and the reliability of the observed effects. The lack of consistency in follow-up duration increases the potential for uncertainty and may hinder the comprehensive understanding of the intervention’s efficacy or safety. In conclusion, while this retrospective study provides valuable insights, it is important to be cautious in interpreting the results due to the limitations inherent in the study design.

Conclusion

In conclusion, this study demonstrates that combining 308 nm EL with TO is a superior treatment option for FV compared to using either therapy alone.