Acupuncture for vitiligo: An overview of systematic reviews and meta‐analysis

Vitiligo is a kind of refractory, autoimmune locally, or systemically generalized depigmentation spots caused by the disappearance of melanocyte function in the skin. Acupuncture and related therapies are extensively utilized for treating vitiligo in China. The objective of this study is to succinctly encapsulate and meticulously assess the methodological and reporting caliber of systematic reviews (SRs) pertaining to acupuncture and associated therapeutic approaches, while concurrently offering an all‐encompassing body of evidence elucidating their efficacy and safety in the treatment of vitiligo.


| INTRODUC TI ON
4][5] In modern medicine, the primary treatments for vitiligo include immunomodulators, glucocorticoids, calcineurin inhibitors, vitamin D derivatives, phototherapy, and autologous epidermal transplantation. 6,7However, these treatment approaches have a broad impact and lack targeted therapy, while some have severe side effects such as chemotoxicity and varying levels of phototherapy spread.Thus, there is an urgent requirement for novel treatment approaches.
Previous research has indicated that traditional Chinese external treatment methods are frequently utilized in the treatment of vitiligo, showing prominent efficacy.Among these, acupuncture therapy with distinctive Chinese medical characteristics has emerged as a popular modality for vitiligo treatment in recent years. 8In clinical settings, acupuncture is primarily employed either alone or in conjunction with traditional Chinese medicine (TCM) medicine, Western medicine, phototherapy, topical medications, and injectable TCM formulations, among others. 9,10Systematic reviews (SRs) are regarded as the highest level of evidence.However, SRs on acupuncture treatment for vitiligo have been published at different time points, using various intervention approaches and outcome measures, resulting in inconsistent conclusions.Currently, a re-evaluation of SRs is still lacking.This study aims to rigorously assess the quality of SR reports, methodological quality, and evidence quality using stringent methods, thereby offering objective and comprehensive research findings regarding the effectiveness and safety of acupuncture treatment for vitiligo.We believe that this study will provide more reliable references and evidence-based support for clinical practice and related research on acupuncture treatment for vitiligo.
Two reviewers selected studies based on the Cochrane Handbook independently and identified studies that met the following criteria: Assessment of the quality of the included SRs/MAs was conducted by two independent researchers (RR-H and JS-Z), who evaluated the methodological quality, reporting quality, and evidence quality.In case of any discrepancies, a third investigator (D-G) was consulted for resolution.
The methodological quality of these SRs/MAs was independently assessed by two reviewers using the AMSTAR2 tool, designed for evaluating multiple system reviews.As a tool for assessing methodological quality, 11,12 The Assessment of Multiple Systematic Reviews (AMSTAR) demonstrates strong face and content validity in evaluating method quality.In 2017, the AMSTAR expert group published an updated and adapted version of the AMSTAR tool. 13This update aimed to provide a more comprehensive evaluation of SRs, encompassing randomized studies on healthcare interventions, nonhealthcare interventions, or a combination thereof.The AMSTAR2 tool comprises only 16 items, among which 7 key items (items 2, 4, 7, 9, 11, 13, and 15) are used to evaluate the validity of the included SRs.If the item is adequately planned, it is categorized as "Y"; if the correct response is given based on limited information, it is assessed as "Partial Yes"; if the item has not undergone relevant evaluation or the evaluation is incorrect, it is assessed as "No."The overall confidence ratings on the AMSTAR2 scale varied from high to critically low.A rating of critically low was assigned when multiple critical flaws were present, either with or without noncritical flaws.A rating of low quality was given when there was one critical flaw, with or without noncritical weaknesses.A rating of moderate quality was assigned when there were multiple noncritical weaknesses.Finally, a rating of high quality was given when there were no or only one noncritical weakness.
The quality of reporting for the included SRs/MAs was evaluated independently by two reviewers using the PRISMA 2020 checklist. 14,15The PRISMA2020 checklist consists of 27 items that are considered crucial for transparent reporting.An item that is answered accurately is categorized as a "Yes," indicating complete accuracy and proper recording.In cases where the item is answered correctly but based on limited evidence, it is classified as a "Partial Yes."However, if the item has not undergone the appropriate evaluation or if the evaluation itself is incorrect, it is categorized as a "No." The risk of bias for the included SRs/MAs was evaluated using the Risk of Bias in Systematic Reviews tool, independently assessed by two reviewers. 16The risk of bias in systematic reviews (ROBIS) tool comprises two stages, which include four domains: "study eligibility criteria," "identification and selection of studies," "data collection and study appraisal," and "synthesis and findings."Each domain contains signaling questions and assessments for bias risk in that respective domain, with the outcomes classified as "high risk," "low risk," or "unclear risk."

Query
Search terms #1 "Acupuncture" [mesh] #2 "Acupuncture therapy" OR "needle therapy" OR "needle warming therapy" OR "electroacupuncture" OR "needle" OR "pinprick" OR "acupoint" #5 "leucoderma" OR "leukodermia" #6 #4 OR #5 #7 Meta-analysis as topic [mesh] #8 "Systematic review" OR "meta-analysis" OR "meta analysis" OR "metaanalyses" OR "review, systematic" OR "systematic reviews" The quality of evidence within the included SRs/MAs was assessed utilizing the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach, which is specifically designed for evaluating evidence quality within SRs/ MAs. 17 The pro3.2 software incorporates five downgrading factors (risk of bias, inconsistency, indirectness, imprecision, and publication bias) and three upgrading factors (large effect, residual confounding likely to underestimate the effect, and dose-response gradient).Inconsistency is mainly categorized as no (I 2 < 50%), serious (50% < I 2 < 80%), and very serious (I 2 > 80%).The assessment of imprecision determines whether the total sample size meets the criteria for optimal information, while publication bias is determined using a funnel plot.Two reviewers independently evaluated each outcome from the included studies.Any disagreements were resolved either through consensus among the reviewers or by consulting a third investigator.Since this study exclusively focused on SRs/MAs from RCTs, only five downgrading factors required analysis.
All included SRs/MAs were evaluated independently by two reviewers.Consistency analysis was conducted using SPSS 23.0 statistical software (IBM Corporation), and kappa consistency test was used for evaluation. 18The inconsistent results were reassessed by another reviewer.

| Description of the screening process
We conducted a search and retrieved 317 records based on the search strategy.Screening Process Description: Using both EndNote and manual searches, we identified and excluded 155 duplicate papers.Following the screening of titles and abstracts, an additional 141 articles were excluded.Subsequently, the full texts were evaluated based on predetermined inclusion and exclusion criteria, leading to the exclusion of 11 more articles.Finally, a total of 10 SRs [19][20][21][22][23][24][25][26][27][28] were selected for further analysis.The complete screening and selection process is presented visually in Figure 1.The key items of the AMSTAR 2. H: represents the ranking of quality as high; M: represents the ranking of quality as moderate; L: represents the ranking of quality as low; CL: represents the ranking of quality as critically low.Q1: did the research questions and inclusion criteria for the review include the components of PICO?Q2: did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol?Q3: did the review authors explain their selection of the study designs for inclusion in the review?Q4: did the review authors use a comprehensive literature search strategy?Q5: did the review authors perform study selection in duplicate?Q6: did the review authors perform data extraction in duplicate?Q7: did the review authors provide a list of excluded studies and justify the exclusions?Q8: did the review authors describe the included studies in adequate detail?Q9: did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review?Q10: did the review authors report on the sources of funding for the studies included in the review?Q11: if a meta-analysis was performed, did the review authors use appropriate methods for the statistical combination of results?Q12: if a meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or another evidence synthesis?Q13: did the review authors account for RoB in primary studies when interpreting/ discussing the results of the review?Q14: did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review?Q15:

| Characteristics of SRs
if they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review?Q16: did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?Abbreviations: AMSTAR 2, Assessment of Multiple Systematic Reviews 2; N, no; PY, partial yes; Y, yes.
measures were reported across all included studies.All of the included literature evaluated the clinical efficacy of acupuncture in the treatment of vitiligo and were conducted in China.In the treatment group, acupuncture was employed, while the control group received oral/topical TCM or oral/topical Western medicine treatment, as well as phototherapy.Regarding the quality assessment methods, eight SRs utilized the Cochrane risk of bias tool (20-24, 26-28), while two SRs used both the Jadad scale and the Cochrane risk of bias tool (19, 25).Subgroup analyses were conducted in eight of the studies (19-22, 24-27), and sensitivity analyses were performed in five studies (21, 24, 26-28).Detailed data extraction can be found in Table 2.

| Methodological quality of included SRs
Table 3 provides an overall confidence rating for each individual quality component based on the AMSTAR2 tool.It is worth noting that all of the included SRs in this analysis received extremely lowquality ratings, with items 7 and 10 specifically identified as having particularly low quality.Among the 10 SRs, they all employed the Patient Intervention Control Outcome (PICO) framework to describe the research question and organized their review accordingly.The authors of all SRs provided information regarding the types of studies included and utilized appropriate statistical methods to combine the results.However, only a small portion (30%) provided detailed descriptions of the included studies 22,27,28 and reported all potential sources of conflicts of interest comprehensively.Unfortunately, none of the SRs provided a list of excluded literature and demonstrated the rationale behind these exclusions.This missing critical item directly impacts the evaluation of the validity of the included SRs.Furthermore, none of the included SRs reported the funding sources of the individual studies included.Overall, the methodological quality of the included SRs is unsatisfactory.Detailed data extraction can be found in Figure 2.

| Reporting quality of included SRs
Table 4 presents the individual quality components of PRISMA.
The overall reporting is relatively comprehensive, with all SRs adequately addressing 10 aspects, including title, theoretical basis, objectives, inclusion criteria, information sources, bias in individual studies, combined effect measures, synthesis of results, summary of evidence, and conclusions.However, there are also some deficiencies.In the "Methods" section, only one out of the 10 SRs (10.00%) reported the protocol and registration status, while three SRs (30.00%) exhibited a risk of bias.In the "Results" section, three SRs (30.00%) did not describe the results of the search and screening processes, and only seven SRs (70%) provided a complete description of the study results for all outcome measures.In the "Discussion" section, three SRs (30.00%) failed to discuss the limitations of the evidence.Figure 3 summarizes the proportions of individual components of PRISMA among the included SRs.Overall, the reporting quality of the included SRs is relatively low.

| Risk of bias of included SRs
Table 5 displays the results of assessing the risk of bias in the included SRs using the ROBIS tool.The tool consists of three stages.
In Stage 1, all SRs/MAs were evaluated as having low risk of bias, F I G U R E 2 Quality evaluation using AMSTAR 2. AMSTAR2 was used to critically appraise the reporting quality of each included SR.The overall confidence of each SR was graded as "high" (no or noncritical weakness in all items), "moderate" (more than one noncritical weakness among all the items), "low" (one critical flaw with or without noncritical weakness), or "critically low" (more than one critical flaw with or without noncritical weakness).AMSTAR 2, Assessment of Multiple Systematic Reviews 2; CL, critically low; L, low; M, moderate; N, no; PT, partial yes; Y, yes.

TA B L E 4
The individual quality components of PRISMA of included SRs. risk.For more detailed information, refer to Table 5.

| Evidence quality of included SRs
This overview includes 10 SRs/MAs, encompassing 13 different outcome measures.The efficacy of treatment is evaluated based on effective rates at different time intervals and different locations.
After conducting subgroup analyses based on intervention intensity, time grouping, or different subgroups, a total of 62 outcomes were examined.Among them, there were 9 outcomes with high-quality evidence, 20 with moderate-quality evidence, 19 with low-quality evidence, and 14 with very low-quality evidence.Evidence was downgraded due to increased risk of bias, imprecision, inconsistency, and indirectness.For more detailed information, please refer to Table 6. reported that there was no significant difference in the recurrence rate between the acupuncture group and the non-acupuncture group.

| Efficacy of acupuncture for vitiligo
Simultaneously, in view of the numerous operation methods of acupuncture treatment, we also conducted a subgroup analysis.When comparing the group receiving a combination of acupuncture therapy and phototherapy (using 308-nm excimer laser or UVB) with the group receiving phototherapy alone, five SRs/ MAs (19, 20, 22, 23, 24) assessed the effectiveness of the treatment, and among them, three SRs/MAs (19, 22, 23, 24) concluded that the combination of acupuncture therapy with phototherapy was significantly more effective in treating vitiligo compared to using phototherapy alone; a study (20) evaluated the comparative efficacy between two scenarios: when the skin damage color was greater than 50% and when it was greater than 10%.The effectiveness was assessed at weeks 4, 6, 8, 12, 15, and 16 of treatment.The results indicated that in the scenario where the skin damage color was greater than 10%, there was no significant statistical difference in efficacy between the combination of fire needle therapy with 308-nm excimer laser and 308-nm excimer laser alone after 15 weeks of treatment (p > 0.05); in the scenario where the skin damage color was greater than 50%, there was no signifi- The analysis provided evidence that the combination of acupuncture therapy with herbal medicine is significantly more effective in terms of efficacy compared to the use of Western medicine alone (p < 0.05); when comparing the efficacy rates between using fire needle therapy alone and using Western medicine alone: MD = -2.93,95% CI: −6.53 to −0.67, p = 0.11, there was no significant difference in efficacy rates between using fire needle therapy alone and using Western medicine alone (p > 0.05).For more detailed information, please refer to Table 6.

| Safety of acupuncture for vitiligo
Among the 10 included SRs/MAs, with the exception of one study (28), the remaining 9 SRs/MAs explicitly reported on the occurrence of adverse events associated with acupuncture treatment for vitiligo, and all included studies failed to identify any significant adverse reactions.Among these, five studies (19, 20, 21, 25, 27)

| DISCUSS ION
This overview aims to identify and evaluate all available evidence regarding the use of acupuncture treatment for vitiligo.Based on the types of results obtained, the research conclusions from this overview were summarized.A total of 10 SRs/MAs published between 2016 and 2023 were identified, which encompassed evidence from 187 primary RCTs and involved a total of 14 287 patients.

| Summary of the main results
In this overview, acupuncture-related treatment approaches appear to hold potential for the treatment of vitiligo.However, it is important to note that all the included SRs/MAs were assessed as

| Implications for future research
In order to mitigate biases pertaining to selectivity, implementation, measurement, and other facets, it is imperative for the original study to undertake a comprehensive expansion in sample size.To ensure methodological rigor and validity, it is crucial to conduct meticulously designed multicenter, long-term clinical RCTs that adhere strictly to the principles of evidence-based medicine.Particular emphasis should be placed on meticulous implementation of the techniques of randomization, hidden allocation plans and blinding, taking care to ensure accuracy and reasonability in their execution. 36During the literature search and screening process, it is essential to list the excluded information from the literature and provide a comprehensive search strategy for all databases, to enable replication by others.In order to ensure the stability of the results, attention should be paid to excluding the results of individual studies one by one when quantitatively calculating the effect quantity.Furthermore, a comprehensive evaluation of publication bias can also improve the accuracy of the meta-analysis results.

| Strengths and limitations
This overview has several strengths.Firstly, this study presents the first-ever summary of SRs/MAs to evaluate the evidence for using acupuncture in the treatment of vitiligo.Secondly, the results of the SRs/MAs are presented in a structured table, which facilitates easy review of the interesting findings for readers.
Thirdly, we initiated this overview with a pre-designed protocol, which helps to minimize the risk of bias.However, this overview also has several limitations.Firstly, it is anticipated that some overlap may exist among the primary articles included in the SRs, but we have not systematically investigated this aspect.This could result in inaccuracies in reporting data such as participant and primary study counts and may lead to "double-counting" of reported data.Secondly, we did not retrieve or analyze data from any primary studies; we relied solely on the information provided by the authors of the SRs.Thirdly, the poor quality of the included SRs/ MAs reduces confidence in the evidence, and the primary studies primarily originate from Chinese research.Lastly, no quantitative analysis was conducted in this overview, which may lead to distorted conclusions.

| CON CLUS IONS
This overview shows that acupuncture therapy was more effective than the control treatment for Vitiligo.However, considering the unsatisfactory methodological quality of the reviews, we strongly advocate for the implementation of studies characterized by heightened rigor in their designs, augmented sample sizes, and elevated methodological and reporting standards.Such endeavors are imperative to foster the generation of robust evidence with substantive strength.
(i) The SRs/meta-analyses (MAs) included randomized controlled trials (RCTs), quasi-RCTs, and controlled clinical trials (CCTs); (ii) acupuncture and related therapies were regarded as a treatment intervention either individually or in combination with other TCM and Western medicine treatments; the control group primarily received diverse treatment interventions, placebos, or conventional care without treatment; (iii) the required outcome measures should include at least the efficacy rate [(%) = number of lesions cured + number of significantly improved lesions + number of lesions with improvement/ total number of lesions × 100%], and the significant improvement rate [(%) = number of lesions cured + number of significantly improved lesions/total number of lesions × 100%] according to the "Clinical Classification and Therapeutic Efficacy Criteria for Vitiligo" (cured: complete disappearance of lesions, restoration of normal skin color; significant improvement: partial regression or reduction of lesions, with the area of restored normal skin color accounting for ≥50% of the lesion area; improvement: partial regression or reduction of lesions; ineffective: no pigment regeneration or reduction of lesions).The secondary outcome measures include complete restoration of (30.65%) presented low-quality evidence, while 14 outcomes (22.58%) indicated very low-quality evidence.Conclusions: This overview shows that Acupuncture therapy was more effective than the control treatment for Vitiligo.Nevertheless, given the subpar methodological quality of the reviews, we recommend conducting studies with stricter designs, larger sample sizes, and improved methodological and reporting quality to yield more robust evidence.K E Y W O R D S Aesthetic Medicine, Pigmentary dermatoses, vitiligo, percutaneous penetration, Phototherapy | 1189 ZHAO et al. facial color, overall increase in pigment dots, changes in cytokine levels, effective treatment duration, treatment efficacy rates in different body areas, recurrence rate [(%) = number of recurrent cases/ total number of cases × 100%], occurrence of adverse events, etc. Skin pigmentation scoring: 0 points (lesional skin color milky white or pure white, no pigment deposition spots observed); 1 point (lesional skin color pale white, few pigment deposition spots observed); 2 points (lesional skin color light brown, more pigment deposition spots observed); 3 points (lesional skin color yellowish-brown, approaching normal or completely normal skin color).(iv) The following criteria were used for exclusion: network MAs, SRs/MAs lacking quantitative synthesis, conference abstracts, comments, editorials, case reports, replication studies, and animal experiments.Any disagreements were resolved through discussion and consensus.Literature screening and data extraction procedures were performed by two independent researchers (XQ-G and RR-H).The retrieved publications were imported into the reference management system (EndNote X9), and initial screening of titles and abstracts was carried out to remove duplicate articles.Subsequently, full-text articles were thoroughly reviewed to make the final selection of literature.In order to maintain data integrity and consistency, two researchers (JS-Z and XQ-G) utilized a pre-designed data extraction form to extract relevant information.The extracted information consisted of the first author's name, publication year, country of origin, number of RCTs (including participant counts), intervention measures, methods used to assess risk of bias, specific interventions employed, and the key findings.

9 TA B L E 1
Search strategy for the PubMed database.

3
The individual quality components of AMSTAR 2 of included SRs.
the research topic.Stage 2 consists of four domains.In domain 1, all included SRs/MAs were assessed as low risk.Domain 2 examines study identification and selection, where three SRs/MAs (20, 22, 26) were classified as low risk, while seven SRs/MAs (19, 21, 23-25, 27,28) were rated as high risk due to a lack of searches in clinical trial registries and other databases.In domain 3, only one SRs/MAs (28) was categorized as high risk for lacking descriptions of data extraction procedures.Domain 4 revealed that six SRs/MAs (19,20, 23, 25, 27,28) were classified as high risk for not conducting sensitivity analyses to assess the stability of the results, while the remaining SRs/MAs were considered low risk.In Stage 3, considering overall bias risk, five SRs/MAs (19,20, 23, 25, 28) were evaluated as high risk for not providing explanations or supplements regarding bias risk, while the rest of the SRs/MAs were deemed low phototherapy alone (p < 0.05).When comparing the combination of acupuncture therapy with TCM modalities (such as oral herbal revealed the occurrence of mild adverse reactions following moxibustion treatment, such as tolerable sensations of burning, local redness, and skin itching.Importantly, these adverse reactions often resolved spontaneously or with symptomatic treatment, without affecting the overall progress of the treatment.Four studies (22, 23, 24, 26) reported a comparison of the incidence of adverse reactions between the acupuncture group and the non-acupuncture group (RR = 1.15, 95% CI: 0.89-1.49,p = 0.28; OR = 0.51, 95% CI: 0.17-1.50,p = 0.22; RR = 0.94, 95% CI: 0.44-1.98,p = 0.87; RR = 1.48, 95% CI: 0.93-2.35,p = 0.10).The results consistently demonstrated no statistically significant differences in the incidence of adverse reactions between the two groups (p > 0.05).
having extremely low quality according to AMSTAR-2 criteria.The methodological limitations observed in these studies stem from the lack of providing detailed search strategies, excluded study lists with exclusion reasons, and explicit disclosure of funding sources.Regarding the reporting quality, only one SRs reported all items of PRISMA-A.The remaining SRs/MAs exhibited shortcomings in reporting, mainly focusing on protocol registration, risk of bias assessment, clarity in presenting results, and limitations discussed in the study.According to the ROBIS tool, out of the 10 SRs/MAs examined, it was determined that five of them possessed a significant susceptibility to bias.This can lead to an augmented vulnerability to bias and consequent diminishment of the transparency inherent in the SRs/MAs.The limitations inherent in the methodologies employed by reviewers for the identification, selection, and synthesis of studies have engendered an elevated propensity for bias, thereby exerting a profound influence on the overall robustness of the SRs/MAs.Moreover, with regard to the classification of evidence, no substantiated instances of high-quality evidence were discerned.The predilections toward bias, incongruity, and imprecision constitute the foremost determinants for the downgrading of the encompassed studies.Unaccounted heterogeneity gives rise to incongruity, whereas limited sample sizes or expansive confidence intervals engender imprecision.Given the outcomes obtained, a definitive inference regarding the endorsement of acupuncture as an adjunctive therapeutic approach for vitiligo cannot be presently ascertained.The diminished caliber of evidence derived from the SRs/MAs may be ascribed to non-standardized procedures employed by reviewers or constraints inherent in the methodologies employed within the original RCTs.

4. 2 |
Significance to clinical practiceAcupuncture can be considered a relatively safe treatment method to some extent.Modern research has shown that fire needle therapy can increase the levels of various trace elements, such as zinc and calcium, in chronically injured soft tissues.It can also activate the activity of multiple enzymes, enhance local metabolism, and alter the expression of local tissue inflammatory factors.[29][30][31]Fire needles treatment leads to an increase in skin temperature, which can improve local blood circulation and metabolism, thereby regulating local immunity.32Additionally, fire needles not only promote blood circulation and regulate local immune function but also stimulate local vasodilation and enhance local nutrient supply.Furthermore, it can activate tyrosinase, promoting the production of melanocytes and melanin synthesis.[33][34][35]

Table 2
summarizes the characteristics of the 10 SRs/MAs included in this overview for quantitative analysis.All SRs/MAs were published between 2016 and 2023.Among the 10 SRs, two included English articles and eight included Chinese articles.The number of RCTs included in the SRs/MAs ranged from 7 to 52, with sample sizes ranging from 218 to 3618 participants.A total of eight outcome F I G U R E 1 The flow of studies through the selection.TA B L E 2 Characteristics of included SRs.No TA B L E 2 Continued