Compound glycyrrhizin tablets combined with the 308 nm excimer laser in the treatment of vitiligo: A systematic review and meta‐analysis

Although the 308 nm excimer laser is commonly used to cure vitiligo, its clinical efficacy is limited. Experts have found that the efficacy of compound glycyrrhizin tablets combined with the 308 nm excimer laser in the treatment of vitiligo is significantly enhanced, but the specific research methods and clinical data must be clarified.


| BACKG ROU N D
A widespread depigmentation-resistant skin condition with a prevalence of 0.2%-2.0%worldwide, vitiligo. 1White patches on skin, mucosa, and hair are the main clinical manifestations, which seriously damage patients' appearances, frequently place a heavy mental and emotional burden on them, and significantly lower their quality of life. 2 Although vitiligo is not fatal, facial skin lesions have a significant negative impact on a person's quality of life and social standing. 3The purpose of treating vitiligo is to restrict the development of skin lesions, promote the repigmentation of white patches, and maintain treatment to avoid further depigmentation.The primary direction of research is combination therapy. 4Phototherapy has demonstrated efficacy as a treatment.Narrowband ultraviolet B (NB-UVB), the 308 nm excimer laser, erbium laser, CO 2 laser, etc., have been utilized extensively in clinical treatments.The 308 nm excimer laser therapy, a high-energy single-light source targeted therapy based on NB-UVB, can reproduce the color more quickly and effectively. 5Compound glycyrrhizin tablets have glucocorticoid-like effects, non-specific anti-inflammatory, and immune regulation effects, etc. 6 Nevertheless, there is no systematic evaluation of compound glycyrrhizin tablets combined with the 308 nm excimer laser for the treatment of vitiligo, preventing us from determining the effectiveness of combination therapy.This study aims to thoroughly analyze the efficacy and safety of compound glycyrrhizin tablets combined with the 308 nm excimer laser in the treatment of vitiligo by analyzing the results of clinical randomized controlled trials (RCT).Finally, providing a reference for clinical practice.

| Search strategy
The following electronic databases were searched: PubMed, the Cochrane Library, the Chinese Biomedical Literature Database (CBM), the China National Knowledge Infrastructure (CNKI), the Chinese Scientific Journal Database, and the Wan Fang Database.
The most recent search of all databases was updated on August 30, 2022, and studies published in Chinese or English publications were included.The search terms "Vitiligo", "the 308nm Excimer Laser", "Compound Glycyrrhizin", "Glycyrrhizin", and "laser" are adjusted according to the characteristics of different databases.

| Inclusion criteria
Types of participants: patients with a clinical diagnosis of vitiligo are not restricted in terms of age, gender, disease duration, etc. Types of studies: only RCTs using compound glycyrrhizin tablets combined with the 308 nm excimer laser for the treatment of vitiligo were included, and other studies such as case reports and animal experiments were excluded.Test group: The intervention for the test group consisted of compound glycyrrhizin tablets combined with the 308 nm excimer laser.The original literature required a clear description of the manufacturer, dosage, and usage of compound glycyrrhizin tablets, as well as the treatment dose and frequency of the 308 nm excimer laser therapy.Control group: the control group consisted of the 308 nm excimer laser alone.

| Exclusion criteria
First, the same study's literature has been repeated.Second, unable to obtain literature for available data or full text through various means.Third, there is no comparison in the literature.Fourth, animal experiments, reviews, cases, experience reports, and other types of literature.Finally, the calculation of the result indicators did not adhere to the same criterion.

| Outcome measures
Primary outcome measures: Clinical effectiveness and adverse events (AEs).The skin recovery area of vitiligo was divided into four grades: (1) Ineffective means that the depigmented spots have not subsided even aggravated or have subsided <10%.(2) Efficiency means that the depigmented spots have a normal skin color and a skin area between 10% and 50%.(3) High efficiency means that the depigmented spots return to normal skin color, with an area of ≥ 50%.
(4) Cure means the essential recovery of the patient's depigmented spots.Secondary outcome measures: Changes in the T helper cell 17 (Th17) and Treg subsets before and after treatment.Efficiency, high efficiency, and cure were defined as effective treatments.

| Study selection and data management
According to the above inclusion and exclusion criteria, two researchers independently extracted all the literature materials.If there were objections, the inclusion was determined by mutual discussion or by a third party.The researchers extracted data from the included studies: publication year, first author, sample size, intervention, and outcome measures.

| Quality evaluation of included literature
The study treatments were evaluated according to the risk of the bias assessment tool in the Cochrane Manual of Systematic Reviews. 7The assessment included seven items of bias risk, including random sequence generation, allocation concealment, blinding of investigators and/or subjects, blinding of study results evaluators, the integrity of results data, selective reporting, and other types of biases.The quality of evidence was categorized as "low risk of bias", "unclear risk of bias", and "high risk of bias".Then the evaluation results were shown by the bias risk assessment chart drawn by Review Manager 5.4.

| Data synthesis and analysis
EndNote X7 was utilized for the literature search, and Review Manager 5.4 was utilized for data statistics and analysis.Count data were expressed as odds ratio (OR), measurement data were defined as weighted mean difference (WMD) or standardized mean difference (SMD), and each effect size was expressed as a 95% confidence interval (CI).The random effect model was employed for analysis if the heterogeneity test revealed significant heterogeneity among the study results (p ≤ 0.05, I 2 ≥ 50%).On the contrary, the fixed effect model was utilized to analyze the data.When the results showed extensive or considerable heterogeneity, subgroup and sensitivity analyses were performed to identify potential explanations.Finally, the bias test of the effective rate is carried out, and the results are displayed using a funnel plot.

| Search Result
A total of 65 articles were included in this study.47 duplicate articles, 8 incompatible articles, and 1 article that could not be obtained were excluded.][10][11][12][13][14][15][16] The trials were designed as two eligible arms and used the parallel-group design.
The screening process is shown in Figure 1.

| Methodological quality of literature research
The risk of bias in the included studies was assessed according to the Cochrane risk of bias assessment tool.All nine studies were RCTs, four studies were grouped by "random number table method", two studies were grouped by "simple random sampling method", one study was grouped according to the order of visit, and two studies did not report the detailed randomization genera-

| The clinical efficacy rates
1502 patients were evaluated in nine studies [8][9][10][11][12][13][14][15][16] for clinical effectiveness.Compound glycyrrhizin tablets combined with the 308 nm excimer laser were used as the test group, while the 308 nm excimer laser alone was used as the control group.The results were tested for heterogeneity (p < 0.00001, I 2 = 0%).The results showed that the heterogeneity was minimal, hence the fixed effect model was utilized for the meta-analysis.OR = 3.33, 95% CI = 2.25-4.92,which was statistically significant at the α = 0.05 test level, and the clinical efficacy of the test group was better than the control group, as shown in Figure 3.

F I G U R E 3
The meta-analysis for compound glycyrrhizin tablets combined with the 308 nm excimer laser versus the 308 nm excimer laser for the outcome of the clinical efficacy rates.
).The results showed that the heterogeneity was minimal, hence the fixed effect model was utilized for the meta-analysis.OR = 0.73, 95% CI = 0.50-1.08,with the little square crossing the invalid line, as shown in Figure 4. Therefore, the study was not considered statistically significant.Comparable safety existed between the test group and the control group.We also collated the AEs mentioned in the 8 studies into Table 3, through which we can visualize that the highest incidence of painful erythema, pruritus, eyelid edema, and individual patients experienced side effects such as dizziness and bloating, which also reaffirms the comparable safety of the experimental and control groups.At the same time, it has been suggested in the literature that long-term use of compound glycyrrhizin tablets does not cause osteoporosis or peptic ulcers, and it has also been outlined that no other AEs have been observed, so it is reasonable to conclude that compound glycyrrhizin tablets are safe.However, because the study did not examine the 308 nm excimer laser and compound glycyrrhizin tablets separately in the test group, we cannot know the specific adverse effects of each treatment.

| The level of Th17 and Treg subsets in peripheral blood
1][12] Before treatment, the level of Th17 and Treg subsets in peripheral blood did not statistical difference between the experimental and control groups (p > 0.05).
After treatment, the level of Th17 subsets in peripheral blood decreased, with the test group seeing a greater decline than the control group, this difference was statistically significant (p < 0.05).After treatment, the level of Treg subsets in peripheral blood increased, with the test group showing more improvement than the control group, this difference was statistically significant (p < 0.05).

F I G U R E 4
The test group and the control group the meta-analysis for the AEs.
TA B L E 3 Incidence of adverse events (AEs).

| The level of MIF and ICAM-1 in peripheral blood
In two studies involving 626 patients, 10,11 the level of monocytemacrophage migration inhibitory factor (MIF) and intercellular cell adhesion molecule-1 (ICAM-1) in peripheral blood was assessed.Before treatment, the level of MIF and ICAM-1 in peripheral blood did not statistical difference between the experimental and the control groups (p > 0.05).After treatment, the level of MIF and ICAM-1 in peripheral blood decreased, with the test group seeing a greater decline than the control group, this difference was statistically significant (p < 0.05).

| Assessment of publication bias
Based on the clinical effectiveness rate, Review Manager 5.4 assessed publication bias.Funnel plots are primarily used to see if there is bias (e.g., publication bias or other bias) in the results of a systematic evaluation or meta-analysis.If there is bias in the study, an asymmetric funnel plot will appear, and the more pronounced the asymmetry, the greater the degree of bias. Figure 5 shows that all research projects were roughly concentrated and symmetric, indicating that the publication bias of this study is slight.

| DISCUSS ION
Vitiligo is a common acquired autoimmune skin hypopigmentation disorder with an increasing prevalence rate among genetic relatives.Depigmentation plaques, caused by melanocyte loss, are the primary clinical symptom.Vitiligo has a protracted start and recovery period, and its progression is unpredictable.It has a complex pathophysiology and is a multifactorial disease.The immune system plays an essential role in vitiligo's etiology.Th17 cells are one of the recently discovered CD4 + T cell effectors.Due to their high expression of the specific proinflammatory factor IL-17, which can mediate the inflammatory reaction that destroys melanocytes and lead to vitiligo.The CD4 + CD25 + Foxp3 + regulatory T (Treg) cell family is a subset of immunosuppressive helper T cells that maintain T cell homeostasis by inhibiting effector T cell proliferation. 17The purpose of vitiligo treatment is to reduce skin lesions and repigmentation.Systemic therapy, local therapy, photoelectric therapy, etc., are common treatment methods.Laser therapy is the primary treatment, while UV laser with a wavelength of 308 nm has a higher irradiance and can induce melanocyte proliferation more effectively.
Compound glycyrrhizin tablets derived from the traditional Chinese medicine licorice can inhibit the metabolic enzymes of steroid hormones and slow down the metabolic speed of glucocorticoids, which has a steroid-like synergistic effect and can improve the abnormal immune function of the body with high safety. 18The metaanalysis showed that compound glycyrrhizin tablets combined with the 308 nm excimer laser were more effective than the 308 nm excimer laser alone in curing vitiligo.The reasons include the following: ( F I G U R E 5 Funnel plot of the clinical efficacy rates: compound glycyrrhizin tablets combined with the 308 nm excimer laser versus the 308 nm excimer laser.
There was a total of nine RCTs involving 1502 participants, including 753 participants in the test group and 749 participants in the control group.All trials were conducted in China and published in Chinese.After collecting and organizing all the experimental data, compound glycyrrhizin tablets combined with the 308 nm excimer laser were compared to the 308 nm excimer laser alone.Eight trials reported a treatment duration of 12 weeks, and one study reported a treatment duration of 10 weeks.Participants ranged in age from 3 months to 72 years.The disease's duration ranged from 1 month to 25 years.In each group, the dosage of compound glycyrrhizin tablets was 50-75 mg per time and 3 times daily, and the frequency of the 308 nm excimer laser treatment was 1-2 times per week.Nine RCTs reported clinical effects, seven RCTs reported AEs, and three RCTs reported the Th17 and Treg subsets level.
tion plan.None of the nine studies involved allocation concealment and blinding.The number of participants and outcome indicators were identical across all nine studies, and the data integrity was sound.Selective reporting and other biases were not mentioned in any of the studies.Figure 2 illustrates the methodological quality of the included literature.F I G U R E 1 Flow diagram of study selection and identification.TA B L E 1 Characteristics of the included trials.

1 )
The 308 nm excimer laser acts on local T lymphocytes, regulates cellular immunity, inhibits IL-17 secretion, regulates Thl7/Treg balance, regulates T-cell subset function, promotes cellular immune balance, and corrects the immune status of the body.It can stimulate the production of a variety of cytokines, including interleukin 21 (IL 21), tumor necrosis factor (TNF), leukotriene, etc.It also can promote the proliferation and differentiation of melanocytes outside the root sheath of hair follicles, produce melanin, migrate to the decolorization site in the epidermis, and promote pigment recovery.(2)Compound glycyrrhizin tablets have immunoregulatory and anti-inflammatory, anti-allergic, and glucocorticoid-like functions.It can reduce the inhibitory Thl7 cells, promote the regulating T cell activation, induce interferon generation, adjust the natural killer (NK) cells, enhance the capacity of T cell differentiation, reduce melanin cell damage, and restore melanin cell function.Both compound glycyrrhizin tablets and the 308 nm excimer laser have synergy and contribute to the ideal effect.[19][20][21] Table 1 displays the fundamental information of the included literature.Table 2 displays the quality control of compound glycyr-

Study ID Country Sample size (M/F) Age (Mean ± SD), years Course of disease Course of treatment Intervention vs. Control Drug dosage Outcomes
C: 308 nm excimer laser Abbreviations: C, control; F, female; M, male; m, month; NR, not reported; T, Test; w, week; Y, year.TA B L E 2 Quality control of compound glycyrrhizin tablets.