Efficacy and safety of laser‐related therapy for melasma: A systematic review and network meta‐analysis

Melasma is a prevalent, persistent hyperpigmentation disorder that negatively affects the psychological health of patients. However, the treatment outcome remains unsatisfactory due to the complexity of pathogenesis, recurrence characteristics, and relatively high morbidity.


| INTRODUC TI ON
Melasma, also known as chloasma, is a cosmetic condition characterized by uncontrollable pigmentation and increased skin capillaries, a condition that occurs symmetrically on the face. 1 Individuals with dark complexions and Fitzpatrick skin types III-IV are more likely to develop melasma.The prevalence of melasma ranges from 8.8% to 40%, depending on race and geographic location. 2,3Meanwhile, the etiology of melasma is still unclear.Many factors may contribute to the development of the disease, including genetics, sunlight, endocrine stimulation, oxidative conditions, and morphofunctional changes. 4[7][8][9] Treatment options for melasma include systemic treatment, topical treatment, microneedling, peeling, light, and laser therapy. 10vertheless, the treatment effect of melasma currently needs to be more effective due to the complexity of pathogenesis, recurrence characteristics, and relatively high morbidity. 11Laser-related therapy has been widely applied as a third line of treatment for melasma.
A clinical trial by Wang YJ et al. proved that laser treatment effectively reduced pigmentation and improved skin texture. 12Eimpunth S et al. discovered that the CuBr laser did not show effective results in improving melasma. 13ether laser-related treatments have only short-term effects or whether laser-related combinations are preferable to single treatments remains a question to be explored.The number of laser-related treatment modalities and combinations is increasing, but determining which combination will yield the best clinical results remains a problem.Several meta-analyses of different laser treatments have been performed, but no multiple treatment comparison or network meta-analysis has been conducted. 14,15Thus, to confirm the most proper laser-related treatment for melasma, we conducted a systematic review and NMA based on the most recently published studies.

| MATERIAL S AND ME THODS
For conducting the NMA, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) comprehensive statement was followed. 16

| Data sources and searches
Two researchers independently searched the following databases to discover randomized controlled trials that met the inclusion requirements: Cochrane Library, PubMed, and EMBASE from the inception date to November 21, 2022.The electronic database was searched using free words and subject phrases.Details of the search query are summarized in Table S1.We responded to the requests for data from authors when the in-depth information needed for analysis was not available.The study was only canceled if the authors responded within 1 month.

| Selection criteria
The inclusion criteria were as follows: ( 1

| Data extraction and quality assessment
All selected studies were imported into Endnote X9, and duplicates were removed.The papers were then scrutinized by two reviewers (WYM and QG) who reviewed the titles, abstracts, and complete texts.This procedure rigorously adhered to the previously established inclusion and exclusion criteria.The other two authors of this study (TTX and ZLC) used the Cochrane Risk of Bias (ROB) tool to assess the quality and risk of bias of the included studies. 17In case of any disagreement, a third reviewer (JHL) made the final decision.
Patient parameters (age, Fitzpatrick skin type, and length of disease), study details (authors' names, publication date, and sample size), MASI changes, and adverse effects were noted.RevMan V.5.4 software provided visualization of data after the risk of bias evaluation.

| Data synthesis and statistical analyses
The data were analyzed by STATA, version 15.1 (STATA cooperation, USA) based on the frequency method.The mean difference (MD) with 95% CI for each outcome was used as an indicator of efficacy.The larger the absolute value of MD, the stronger the effect of one group over the other.First, evidence network diagrams were mapped to display the close relationships between interventions.
The necessity for consistency testing should be considered for the adverse effects, efficacy, laser treatments, melasma, network meta-analysis presence of a closed loop.Second, each laser-related treatment option will be ranked according to the surface under the cumulative ranking curve (SUCRA) probability.The optimum treatment option is more likely to be selected in each simulation with a greater SUCRA probability.Finally, publication bias for key outcome indicators and adverse reactions will be demonstrated by plotting visual funnel plots using STATA15.1.

| Characteristics of the included studies
A total of 1372 relevant clinical studies were obtained through the initial electronic database search.We removed 364 duplicate studies.Then, by screening the titles and abstracts, we further eliminated 793 studies.Ultimately, 39 randomized clinical trials 12, were included in the network meta-analysis. The fowchart of screening and selection is depicted in Figure 1.
Table 1 summarizes these studies and their characteristics, which were published from the start of the study to 2022.The most common laser therapies, such as the Q-switch Nd: YAG laser (QSND), fractional CO2 laser (FCDL), and picosecond laser, were all concluded.Additional details can be found in the table.

| Adverse events
Common adverse events are erythema, edema, burning sensation, pain, scaling, and itching.This NMA suggests that laser-related treatments usually lead to various adverse outcomes (Table 1).Nevertheless, most of the negative side effects quickly resolved on their own.Notably, postinflammatory hyperpigmentation (PIH) and hypopigmentation are more likely to occur in individuals with darker skin.
Therefore, laser treatments for these groups should be chosen more carefully.

| Publication bias
The In this network meta-analysis, QSND+TM exhibited superior efficacy, as evidenced by SUCRA ranking value and the league table.As one of the most frequently used lasers for melasma therapy, the Q-switched laser was capable of producing laser beams with various wavelengths, including ruby (694 nm), emerald (755 nm), and neodymium yag (532 nm or 1064 nm). 58Compared to microneedling and FCDL, Q-switched Nd:YAG lasers have better performance in reducing MASI. 24,30Agamia N et al. concluded that treatment of melasma with a low-fluence Qs-Nd: Yag laser at 1064 nm is both safe and effective.This is consistent with the results of this meta-analysis.For the Qs-Nd: YAG laser, the basic principle of action is that the laser energy is released in a short time and forms a huge peak pulse.The pigment particles in the skin absorb the huge laser energy instantly, causing expansion and bursting, and then the phagocytes engulf the pigment particles and expel them from the body so that the local pigment of the lesion is reduced. 59,60J. E. Kim et al. demonstrated that after QS-Nd:YAG laser treatment, the number of melanosomes in melasma skin and the expression of melanogenesis-related proteins, such as a-melanocyte-stimulating hormone, tyrosinase, tyrosinase-related protein (TRP)-1, TRP-2, and nerve growth factor, were inhibited. 61is meta-analysis suggests that QSND ameliorates melasma by affecting melanocyte metabolism.
Topical treatments, often combined with laser treatment, include tranexamic acid, retinoic acid, azelaic acid, hydroquinone, and their derivatives. 62The primary topical therapy for melasma is hydroquinone and its variants. 10,58,63The mechanism of action is to In this NMA, oTA (oral tranexamic acid) was ranked in the second position according to the SUCRA ranking value.As a synthetic lysine analog antifibrinolytic agent, tranexamic acid competitively inhibits fibrinogen activation to fibrinolytic enzymes. 11,65TXA also has anti-inflammatory, antifibrotic, and antiangiogenic effects by strongly inhibiting fibrinolytic enzymes, which are important pathogenic mechanisms under the development of melasma. 66Among them, the antiangiogenic effect of TA is associated with its ability to downregulate vascular endothelial growth factor and endothelin-1 expression via fibrin.Endothelin-1, a cutaneous angiogenic factor, is crucial in the etiology of melasma. 67,68Researchers have indicated that oral TA and Qs-Nd:YAG laser are both safe and effective in the treatment of melasma. 32The above indicates that the effectiveness of oral tranexamic acid is very promising and is consistent with the results of our NMA study and previous meta-analysis. 69ong the three treatment modalities of MN + TM, PICO, and TM, MN + TM emerged as our preferred recommendation.Microneedling is a treatment that employs small needles to puncture the skin surface to improve medication delivery and induce collagen renewal. 70Studies have shown that microneedling has demonstrated good clinical success in the clinical treatment of melasma. 24However, there is still uncertainty about the way microneedling treats melasma.One theory contends that microneedling promotes tissue remodeling that may accelerate the eradication of melanin from the skin. 70Although microneedling is not a melasma laser treatment, it is ranked third in the SUCRA rankings.We determined that the limited sample size may be responsible for this.
Q-switched Nd: YAG laser + intense pulse light (QSND+IPL) was ranked in the fourth position according to the SUCRA ranking value.
IPL is not a laser but a noncoherent broad-spectrum light with a wide wavelength range.This mechanism of action produces a therapeutic effect by focusing and filtering a very high-intensity light source to produce light with a broad spectrum.IPL may be more effective than laser because it employs a variety of wavelengths that can target both epidermal and dermal melasma at different depths in the skin.
Thermal spread is greater, and therefore, postinflammatory hyperpigmentation associated with heat is reduced. 71There needs to be more certainty about the dynamic process of pigment elimination by IPL treatment. 72Vachiramon, V et al. hold that melasma clears more quickly when QSND and IPL are used together. 45This NMA endorses this viewpoint.Vascular tissue, which is one of the causes of melasma, may also be effectively treated with IPL.Thus, IPL + QSND can be considered for clinical use.Meanwhile, we should not ignore the adverse effects of guttate hypomelanosis.
Beyond the aforementioned therapeutic modalities, the combination of fractional carbon dioxide laser and topical medications Adverse effects related to melasma laser treatment are erythema, edema, burning sensation, pain, scaling, and itching.These adverse reactions subside quickly after discontinuation of laser treatment.However, the treatment of PIH, a common adverse reaction after laser treatment in dark-skinned patients, remains a considerable challenge.One of the mechanisms of PIH is related to inflammation.A localized inflammatory reaction brought on by laser therapy causes the skin to release cytokines and chemokines, including epidermal growth factor (EGF), interleukin-1 (IL-1), and interleukin-6 (IL-6), which stimulate the growth of melanocytes and the production and movement of melanin granules. 74,75vertheless, this NMA has some limitations.First, the quality of the included literature in this study could have been better, which could influence the reliability of the findings.Second, the sample size of this study was limited, which affected the extrapolation of the conclusions.Third, this NMA study only explored laser and laser-related combination treatment options.Fourth, it remains to be explored which topical agent is the best choice in a Q-modulated Nd:YAG laser.Fifth, In the previous literature, results of long-term follow-ups for efficacy and relapse still need to be included.Different laser machines have different application protocols, and head-to-head comparisons still need to be improved.
The actual clinical choice should take into account the skin type, disease activity, age, and disease duration of the patient, as well as cost, risk-benefit, and patient compliance.Further high-quality controlled studies are needed to improve or confirm our findings.
In the future, a solution with higher safety, better satisfaction, shorter treatment times, better targeting, and fewer recurrence risks will be determined.

| CON CLUS ION
Of all the laser-related treatments, our highest recommendation is QSND+TM.Meanwhile, combined therapy provides better clinical outcomes than a single treatment alone.Among the ) Population: all types of melasma; (2) Intervention: laser-related treatment, single therapy, or combination therapy; (3) Comparator: laser therapy alone; (4) Outcomes: MASI score and adverse effects.MASI measures include assessment of MASI, modified MASI (MSI), and hemi-MASI; (5) Study design: randomized controlled trials (RCTs).The exclusion criteria were as follows: (1) Review articles, case reports, thesis, patient series, and nonhuman subjects (animal, cell lines, and in vitro); (2) Observational studies and retrospective studies; (3) No relevant and complete data; (4) Full text is not available.
Twenty-four randomized clinical studies utilized an adequate sequence generation method.Twenty-four trials demonstrated a low risk of bias for allocation concealment.Twenty-five studies used blinding strategies for allocation concealment.Twenty-eight clinical F I G U R E 1 Process for identifying studies eligible for the network meta-analysis.TA B L E 1 Characteristics of included studies.

57 F I G U R E 2
funnel plots for the above outcome indicators are shown in Figure S2.The different colored dots in the graphs indicate direct comparisons between two different interventions.In general, the funnel diagram could be more symmetrical, and potential publication bias should be considered.4 | DISCUSS ION In this research, 39 randomized controlled trials compared 25 laserrelated treatments, changes in MASI scores, and adverse outcomes for patients before and after treatment.The study indicates that QSND+TM results in a more significant reduction in MASI scores compared to ERYL+TM, QSND, PICO+TM, SSR, PICO, and TM.Meanwhile, MN + TM, QSND+IPL, FCDL, and FCDL+TM perform better than TM in reducing MASI scores.MN + TM outperforms PICO in decreasing the MASI score.Nevertheless, the NMA comparisons of QSND+TM, TM, and MN + TM with other treatment measures were not statistically significant.Therefore, this result must be interpreted with caution.The SUCRA rankings summarize the efficacy of 25 treatment modalities and may provide some reference for clinical selection.However, the SUCRA rankings themselves have some flaws and may risk low quality and inaccurateevidence, which should be taken into account by clinicians.56The top five SUCRA ranking treatments for melasma are as follows: QSND+TM, oTA, MN + TM, QSND+IPL, and FCDL+TM, three of which include laser treatment.The general theory of operation of laser treatment can be described as follows: when a laser beam is released, water and melanin in the skin absorb the light energy and transform it into heat energy, which is then used to destroy surrounding tissue to achieve the desired therapeutic effect.Risk of bias graph: Review authors' judgments about each risk of bias item presented as percentages across all included studies.

E 3
Risk of bias summary: Review authors' judgments about each risk of bias item for each included study.F I G U R E 4 Network evidence graph.The network graph shows the evidence network for all the selected interventions.The dots in the diagram represent the different interventions, and the size of the dots represents the sample size included.The line between two dots indicates a direct comparison between interventions, and the thickness of the line indicates the number of included studies.
produce reversible skin discoloration by blocking the enzymatic oxidation of tyrosine to 3,4-dihydroxy alanine and by blocking other metabolic functions of melanocytes.64Namazi, N et al. suggest that melasma therapy with HQ 4% alone is inferior to the use of HQ 4% plus the Er:YAG laser, which may indicate a novel trend of laser combined with topical medication for melasma treatment.33Considering the sample size and SUCRA ranking score of this NMA, QSND+TM is the primary recommended treatment for melasma.TM in isolation demonstrated lower effectiveness compared to MN + TM, QSND+IPL, FCDL, and FCDL+TM.Consequently, in accordance with the findings of this NMA study, the standalone application of TM is not recommended.We propose that the incorporation of topical medications with complementary external therapies should be considered to enhance treatment efficacy.

(
FCDL+TM) has also demonstrated enhanced efficacy in diminishing melasma MASI scores.Its placement in the rankings, as determined by SUCRA values, positioned FCDL+TM in the fifth position.The F I G U R E 5 Ranking of treatment strategies based on treatment effects for melasma according to the cumulative ranking area (SUCRA).Larger probability, stronger treatment effects.CO 2 laser produces a wavelength of 10.6 μm, which is significantly absorbed by water in skin cells.The amount of water in the skin cells determines how deeply the wavelength penetrates.71Depending on the purpose of the treatment, numerous tiny wounds are irradiated on the superficial skin tissues by controlling parameters such as scan shape and scan coverage with reasonable accuracy to remove epidermal aging tissues through extrusion and regeneration while stimulating collagen remodeling for skin regeneration.73Combining low-power CO 2 laser therapy with other therapies is a reasonably efficient and secure way to treat melasma.26,35Zamanian, A et al.proposed that the ND:YAG+CO 2 fraction and hydroquinone cream were a good combination for skin toning and had low morbidity and high efficiency compared to the ND:YAG+CO 2 fraction alone.44As a common clinical laser, FCDL also tends to cause postinflammatory hyperpigmentation (PIH).Whether the combination with topical medication reduces the probability of PIH remains to be further investigated.
three treatment modalities, namely MN + TM, PICO, and TM, we endorse the utilization of MN + TM as the preferred option for enhancing the curative efficacy of melasma.As more high-quality clinical studies become available, better reviews will be available in the future, providing better clinical options for laser combination therapy options.AUTH O R CO NTR I B UTI O N SWYM contributed to the concept and design, systematic review process, and writing of the manuscript.QG, JHL, XJZ, TTX, QYW, ZLC, and NNL contributed to the systematic review process.