Comparative efficacy and safety of tranexamic acid for melasma by different administration methods: A systematic review and network meta‐analysis

Tranexamic acid (TA) is a new and promising drug for the treatment of melasma.

prevalence varied between 8.8% and 40%, depending on the ethnic composition of the population. 4,5Although the pathogenesis of this disease is not completely clear, some causes have been identified, including exposure to ultraviolet radiation and visible light, family susceptibility, pregnancy and exogenous hormone use. 6,7though melasma is asymptomatic, it is a disfiguring skin disease, which has a negative impact on the quality of life and self-esteem of patients, and is frustrated by the expensive treatment costs. 8,9aditionally, the first-line treatment for melasma is routine topical agents (RTA), including hydroquinone (HQ) and Kligman formula triple combination cream (TCC). 10They are limited by skin side effects, including irritative dermatitis, hyperpigmentation after inflammation and exogenous melasma. 10Therefore, there is an urgent need for a new drug with good efficacy and less adverse reactions to be applied to patients with melasma.
Tranxemic acid (TA) is a synthetic derivative of lysine.TA was first reported in 1979 for the treatment of melasma. 11Over time, TA has been utilized in various forms, including oral, topical, intradermal injection and microneedle administration, or combined with Q-switched Nd: YAG laser, or in combination with RTA, with encouraging results. 12,13Meta-analyses published in recent years have confirmed that TA is a safe and effective drug for the treatment of melasma. 14,15However, currently there is no definitive consensus regarding the application of TA for melasma treatment.Moreover, the distinction between the effectiveness of local or intradermal adjuvant TA treatment and oral administration remains unclear.In the study conducted by Khurana VK et al., 16 it was found that the oral administration of TA (250 mg twice daily) yielded superior results compared to the intradermal injection (4 mg/mL) of TA.However, Sharma et al. 17 discovered that there was an equivalent whitening effect observed in both the oral TA group with 250 mg twice daily and the intradermal injection group with 4 mg/mL in a period of 4 weeks.The efficacy of TA may be significantly influenced by the drug delivery methods, particularly with intradermal injection and microneedle pathways.Budamakuntlal 18 demonstrated that the microneedle group showed a superior therapeutic response due to the deeper and more uniform drug delivery.Liposome is chosen as the transporter of TA due to its low-loss, high-stability, sustained release and long action time. 19Hence, additional research is imperative to ascertain an optimal method of administering TA for the effective treatment of melasma.
The Melasma Area and Severity Index (MASI), 20 a validated index, may be used to assess the severity of melasma lesions.Based on the degree of homogeneity and pigmentation on the forehead, chin, and right and left malar cheeks, this score is a numerical representation that is weighted by area.The hardest component to accurately analyze in patients, though, was homogeneity.The modified MASI (mMASI) 21,22 was developed when homogeneity as a component was removed because doing so did not affect reliability or validity measurements.So far, the published articles have not studied the difference in efficacy between TA >2 different ways of administration.In this study, 44 selected randomized controlled trials (RCTs) were used for the first time to conduct network meta-analysis (NMA) on the effectiveness of various TA administration methods in the melasma managing.The changes of MASI before and after treatment at a certain time point was taken as the outcome measurement index, and the efficacy of eight TA administration methods were directly and indirectly compared, with a view to providing a reference for clinicians to make more accurate TA treatment plan for melasma.

| ME THODS
Conducting this meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, 23 as well as a prospective protocol was developed and registered with PROSPERO under CRD42023405843.

| Data sources and searches
We conducted a comprehensive search on databases such as the PubMed, Embase, Cochrane Library, and Web of Science databases, to identify relevant studies published between the time of database establishment and April 10, 2023.

| Study selection
We completed the systematic review and meta-analysis following agreement with the 2020 modified 32-item PRISMA extension statement for NMA. 23The screening of studies was performed by two independent assessors (LRZ and PWW), with any disagreements resolved by a third reviewer (LHY).The inclusion criteria were as follows: (1) Original RCTs published in English, focusing on melasma treatment with TA; (2) TA administered alone or combined with extra treatments; (3) Outcomes of this meta-analysis were MASI and adverse events.The measurements of MASI are inclusive of evaluation of MASI, 20 as well as modified MASI (mMASI). 21Studies were excluded if they were: (1) with irrelevant topic, duplicates, reviews, or comment; (2) lacking appropriate or complete data; (3) did not report melasma specific outcome measures.

| Data extraction and quality assessment
Two investigators utilized a predefined data extraction sheet to collect information from each enrolled research independently.The extracted details encompassed trial information (such as author, the year of publication, sample size, trial duration, and intervention types), population features (age and skin types), efficacy subsequences (change in MASI), and safety data (adverse effects).△MASI represents the posttreatment MASI value minus the baseline MASI value.The ΔMASI at Weeks 4 and 8 were selected as the short-term effect, and ΔMASI at Week 12 and the last visit (≥12 weeks) were selected as the long-term effect.

| Risk of bias of individual studies
To evaluate the risk of bias in each eligible trial, we employed a revised version of the Cochrane risk of bias tool (RoB 2.0) 24 to evaluate the risk of bias in RCTs.Two reviewers independently conducted the RoB assessment, and any disagreements were resolved by a third party, who made the final decision.

| Data synthesis and statistical analysis
We assessed the effect of different administration methods of TA on melasma from △MASI at different time points.The STATA 17.0 MP output network diagram was used to describe direct or indirect comparisons between treatment options.The standard paired meta-analysis utilized the DerSimonian and Laird random-effects model.The efficacy index, represented by the standardized mean difference (SMD) along with its 95% confidence interval (CI), was calculated for each result.To rank the therapies, we summarized and reported the surface under the cumulative ranking curve (SUCRA) as well as mean ranks.SUCRA, presented as a percentage, denotes the probability of the most effective treatment.
The inconsistency test was performed in two steps.First, we compared the degree of fitting between the in-memory consistency model and the inconsistency model.When p > 0.05, the direct and indirect evidence were considered to be completely consistent.Second, we tested the inconsistency of the whole network analysis on each node of a specific comparison by node-splitting analysis or loop inconsistency plot, and a significant inconsistency was indicated when p < 0.05 or the 95% CI interval of each loop not contains 0. All the statistical tests were bilateral tests, with p < 0.05 as the significance level.

| Literature retrieval results
The preliminary search yielded a total of 1651 articles.After excluding repetitive literature (n = 700), reading titles and abstracts, excluding comments, reviews, and animal experiments, we obtained 549 articles.Reading the full text excluded non-RCT and inconformity of outcome indicators.Finally, 44 studies were incorporated into this NMA.See Figure 1 for the specific document screening process.

| Risk of Bias
The ROB graph, assessed using the Cochrane Collaboration's tool, is presented in Figure S1A,B.Among the 44 articles included, 12 were evaluated as low-risk, 31 were evaluated as uncertain, and 1 was high-risk.The reason for uncertainty was that the distribution was hidden or not, and the reason for high risk was that the article did not mention random grouping.In general, ROB is low, the research evidence in the meta-analysis is of ideal quality.

| Publication bias
The funnel plot from this study demonstrated that the majority of scatter points were evenly distributed on both sides of the vertical line, indicating a symmetrical pattern.However, there might be a certain degree of publication bias present.The funnel plot of the ΔMASI scores at Weeks 4, 8, and 12, and the last visit are presented in Figure S2.

| Inconsistency assessment
No significant source of inconsistency was found in the overall in-

| DISCUSS ION
Melasma is a world difficult disease that is easily diagnosed and intractable, and for many years, no single treatment has guaranteed satisfactory results despite the availability of various treatment options, 66,67 and the search for safe and effective treatments goes on.
Conventional topical treatments for melasma include HQ and TCC.
HQ is still considered the gold standard drug for melasma. 68HQ, a competitive tyrosinase inhibitor, could impede the conversion of tyrosine to melanin and subsequently reducing melanin production 69 and also disrupts melanosomes and melanocytes by obstructing DNA and RNA synthesis. 70Another triple combination cream with HQ 4%, tretinoin 0.05%, fluocinolone acetate 0.1% for routine topical use is gaining popularity due to improved tolerability and efficacy, also approved by FDA (the US) for melasma treatment. 71anexamic acid acts as a plasmin inhibitor which reduces free arachidonic acid by blocking the activation of plasmin, thereby reducing prostaglandins, to a decrease in tyrosinase activity, which leads to a decrease in melanin production. 72As we presently know, the paper is the first NMA to investigate the differences in efficacy of different modes of administration of TA for melasma at different time points.
The present study revealed that the therapeutic effect of oTA combined with routine topical agents is superior to that of oTA alone, topical TA, iTA, MNsTA in the long term.This result is consistent with a previous study in Elkamshoushi's opinion 37 that combining 4%HQ with oTA achieves an earlier and better cosmetic improvement than oTA alone.Natalia et al. 71  combination of oTA with topical therapy utilizing HQ and retinoid products is recommended as a first-line treatment.These studies 42,44,50,52,58,71 suggested that oTA enhanced the efficacy of RTA, and the combination of both resulted in a 1 + 1 ≥ 2 effect due to the effect of both TA and HQ to inhibit melanin formation by melanocytes.It is worth noting that in the ΔMASI results of last follow-up, oTA combined with routine topical agents did not show statistically significant differences from oTA alone.
Elkamshoushi et al. 37 suggested that the reason might be that TA treatment should be long-term and needs long-term maintenance.Once TA is stopped for several months, patients who take TA orally or in combination with conventional external drugs have a certain degree of recurrence and an elevated MASI, which is also consistent with the results reported by Ebrahim et al. 33 In conclusion, we figured that oTA + RTA is the best mode of administration.,51 Therefore, oTA with high-frequency and concentration had a faster effect than iTA and MNsTA.In these studies, oTA or with RTA agents produced an early response and cleared melasma at Week 4, and tTA, iTA and MNsTA responded slowly in the first 4 weeks with only mild improvement or no response, while the improvement continued, with a moderate to good response in most patients at Week 8.
Studies have supported the effectiveness of TA in the melasma treatment by administration of different routes (i.e., oral administration, topical administration, intradermal injection and microneedle).Ebrahim et al. 33 found that both iTA and MNsTA can objectively and effectively treat melasma, and there was no statistical difference between the two cohorts.Although the results had no statistical significance, improvement in the MASI score by microneedle administration was superior to that by intradermal injection in a study by Budamakuntla et al. 18 Similarly, in the Khurana's study, 16 oral doses of TA (500 mg/day) were compared with intradermal injections (4 mg/mL/4 weeks) and showed a more pronounced response in the oral group than in the intradermal injection group.However, Shetty et al. 57 reported that intradermal TA injections achieved significantly higher reductions in mMASI scores compared to oral therapy.These results suggest that the effects of TA may be independent of its route of administration.It is equally questionable in a related meta-analysis 73 and a systematic review 74 whether the effect of oral administration is better than that of intradermal injection, and further studies are needed to determine its effect, especially in the long-term.The results of the present NMA just answered these questions, and in the shortterm, the efficacy of oTA is indeed slightly better than that of iTA, which can be attributed to the lower dose and frequency of the injected drugs compared with oral TA, but there was no statistical difference between them from the long-term results, besides that, our results showed that there was no efficacy difference among oral TA alone, tTA, iTA and MNsTA, and the efficacy of TA treatment alone was independent of the mode of administration.
There are currently limited safety data for TA therapy, and oTA is generally well tolerated, with common side effects including gastrointestinal discomfort and decreased menstruation. 16,17,31,36,42,54,64,75Gastrointestinal symptoms can be reduced when TA is taken after a meal.Low-dose TA for melasma treatment has shown extremely rare occurrences of serious potential side effects, such as deep vein thrombosis, massive pulmonary embolism, and acute myocardial infarction. 75Although the risk of developing serious adverse reactions is low, screening patients for the risk of developing these potential adverse reactions is highly necessary.Oral preparations are contraindicated in patients with a history of active thromboembolic disease or who are at potential risk for thrombotic events.Concomitant use with procoagulant medications, such as oral contraceptives, can increase the risk of thrombosis and must be used with caution.
Intradermal injection and microneedle administration can protect patients from any systemic side effects, with no major adverse effects observed except for injection site pain, mild erythema and edema, which resolve within 48 h. 17,18,36The adverse effects of tTA are skin irritation only and occur at a low-rate. 27,41The major component of RTA is hydroquinone, and adverse effects associated with the use of HQ include mild erythema, burning sensation, dryness, pruritus, and desquamation. 26,28,34,39,41,50,54,55,58,64 patients may exhibit varying tolerances to different modes of administration, it is essential to consider the adverse effects associated with each method when making clinical decisions.This approach enables the formulation of personalized treatment regimens for individuals.
The present meta-analysis has certain limitations.First, subgroup analysis of the administration dose and frequency of TA could not be performed for included studies is still limited.Second, different forms of MASI were used in this meta-analysis.Of all the 44 included studies, 22 used mMASI mediation to calculate the efficacy of TA, and another 22 used MASI, so we used effect size SMD to minimize the effect of "unit", while there is a possibility of exaggerating the effect, and the results need to be treated cautiously.Third, due to the lack of safety data, it cannot be used for statistical analysis, but only for descriptive analysis, lacking comparative evidence.Despite the above shortcomings, the present meta-analysis provides evidence of the efficacy of different modes of TA administration.

| CON CLUS ION
The results of the present study indicate that among the different modes of TA administration applied to melasma treatment, oTA + RTA has the best efficacy.In the short term, the efficacy of oTA was greater than iTA, and that the onset time of oTA is faster than that of tTA, iTA, MNsTA, in the long term, however, the efficacy of TA treatment alone is independent of the mode of administration and, in addition, the degree of patient tolerance to adverse effects from different modes of administration needs to be considered.Although In the graphical representation, the dot size reflects the sample size of the intervention used, while the line thickness indicated the number of RCTs employing the two-point treatment intervention.The network evidence for the ΔMASI at Weeks 4, 8, and 12, and the last visit are presented in Figure2.
consistency and nodesplit test in the network of ΔMASI at Weeks 4, 8, 12 and the last visit, both of the P values got larger than 0.05, as shown in Figure S5.At the same time, the comparison network of ΔMASI at Weeks 4, 8, 12 and the last visit forms closed loops, and the 95% CI interval of each loop contains 0, which indicates that the direct and indirect comparison is of obvious consistency, as shown in Figure S6.

3. 4 |
Adverse effectAccording to Table1, the adverse reactions of oTA mainly include gastrointestinal discomfort and irregular menstruation.The adverse reactions of RTA include skin irritation, contact dermatitis, pigmentation, etc.The adverse reactions of tTA are only skin irritation.The main adverse reactions of iTA are pain and redness during injection.Although the incidence is high, it can quickly subside.The adverse reactions of MNsTA include skin irritation, erythema, and slight pain.There are few data on adverse reactions of oTA + RTA, mainly including gastrointestinal discomfort, decreased menstrual volume, skin irritation, and discoloration.Because the detailed reports of adverse reactions in the articles included are limited, the results are only for reference.

F I G U R E 1
Flowchart of the study selection.TA B L E 1 Characteristics of included studies.

F I G U R E 3
summarized the clinical trials published in the past decade on the treatment of melasma, critically proposed, such as no contraindications, the F I G U R E 2 Network evidence plot for ΔMASI.OTA, oral tranexamic acid; oTA + laser, oral tranexamic acid+laser; oTA + RTA, oral tranexamic acid+routine topical agents; tTA, topical tranexamic acid; tTA + laser, topical tranexamic acid+laser; iTA, intradermal tranexamic acid; iTA + laser, intradermal tranexamic acid+laser; MNsTA, microneedling tranexamic acid; tVC, topical Vitamin C; MNs, microneedling; RTA, routine topical agents.Forest plot for ΔMASI of the last follow-up.A, oral tranexamic acid; B, oral tranexamic acid+laser; C, oral tranexamic acid+routine topical agents; D, topical tranexamic acid; E, topical tranexamic acid+laser; F, intradermal tranexamic acid; G, intradermal tranexamic acid+laser; H, microneedling tranexamic acid; I, topical Vitamin C; J, microneedling; K, routine topical agents; L, laser; M, placebo.
our present study provides indirect comparisons, direct comparisons between different regimens based on TA are currently lacking, and well-designed, methodologically sound, multicenter, and large sample RCTs are needed to broaden the network in the future.AUTH O R CO NTR I B UTI O N S Rongzhou Liang and Haiyan Luo designed the study and supervised the overall project; Wanwan Pan, Sifen Yang and Xiaoyun Peng participated in Searching literature; Rongzhou Liang, Baizeng Kuang and Hongyin Huang participated in collecting data; Rongzhou Liang, Chengjiang Liu analyzed the data.Rongzhou Liang and Haiyan Luo wrote the paper.All authors have read and approved the final manuscript.