Efficacy and safety of topical agents in the treatment of melasma: What's evidence? A systematic review and meta‐analysis

Various topical agents have been used to treat melasma; however, a large‐scale evaluation among the currently available treatment is lacking.


| INTRODUC TI ON
Melasma is an acquired chronic pigmentary disorder that commonly affects people with Fitzpatrick skin phototype III-VI. Traditional skin lightening products including hydroquinone (HQ) monotherapy or in combination with retinoic acid and corticosteroids as triple combination therapy (TC) are well established as mainstay treatments of melasma. 1 Although known for their effective results, adverse effects (AEs) such as erythema, allergic or irritant contact dermatitis, skin atrophy, and telangiectasia are commonly reported. 2 Additionally, undesirable exogenous ochronosis can occur after the use of HQ-containing agents for more than 6 months. 3 Moreover, HQ-containing agents are contraindicated in pregnant and breastfeeding women, due to a lack of evidence in the current literature. 4 The concern over AEs or contraindication to HQ led to a search for alternative treatments, and various non-HQ products including tranexamic acid (TXA), azelaic acid (AA), cysteamine, silymarin, kojic acid, methimazole, zinc sulfate, vitamin C, glutathione, carotenoids, and several other additional antioxidants have been proposed. Therefore, a number of clinical trials have compared the efficacy and safety of non-HQ agents to mainstay treatments. 5,6 However, given that these trials have limitations from small sample sizes, we conducted a systematic review and meta-analysis to investigate the efficacy and safety of topical melasma treatment from currently available data at a larger scale.

| MATERIAL S AND ME THODS
Our study followed the Cochrane Collaboration Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. This study protocol was registered on PROSPERO (CRD42022290906). This review was exempt from institutional review board as it involves study data that is publicly available.

| Study selection
All identified studies were assessed independently by two authors (Y.C and T.L), and disagreements were resolved through mutual consensus with a third author (H.C). Studies were included if (1) patients with melasma were treated with topical therapies alone and (2) studies reported the efficacy with outcome measures of mean and standard deviation of pre-and post-treatment Melasma Area Severity Index (MASI) or modified Melasma Area Severity Index (mMASI) and/or AEs. Exclusion criteria consisted of studies that involved non-topical agents, other study types (literature reviews, case reports, case series, and abstracts), non-human studies, other disorders of hyperpigmentation (lentigines, freckles, and postinflammatory hyperpigmentation (PIH)), and topical agents when less than three studies were available.

| Data extraction, analysis, and quality assessment
We extracted the following study characteristics: author, title, publication year, country, study design, population characteristics (number, age, gender, and skin phototypes), drug regimen (frequency of use and treatment duration), mean and standard deviation of pre-and posttreatment MASI or mMASI scores, and AEs. If the above data were unavailable, the corresponding author was contacted with request for raw data. The risk-of-bias assessment was conducted using the Cochrane risk-of-bias (RoB) tool for randomized controlled trials (RCTs), and the Robins-I tool for non-RCTs in the quality of included studies in the quantitative analysis. The risk of study quality assessment was graded as low, moderate, or high risk. Egger's test for publication bias was used to analyze the studies included in the meta-analysis.

| Study outcomes
The primary outcome was the change in MASI or mMASI scores from pre-to post-treatment. The MASI score is a validated measure of melasma severity where darkness and homogeneity are rated, and the sum of their ratings is multiplied by the numerical value of the four areas of involvement on the face, ranging from 0 to 48 points.
The mMASI eliminates homogeneity and scores melasma severity on a scale from 0 to 24 points. To pool these two different scoring systems for efficacy analysis, we used the standardized mean differences (SMD). Standardized mean differences of 0.2-0.5, 0.5-0.8, and >0.8 are considered to effect sizes of small, medium, and large.
The secondary outcome was the incidence of skin irritation, calculated as proportions for safety analysis. We considered erythema, burning, dryness, and pruritus as signs of skin irritation.

| Statistical analysis
Analyses were conducted using R Studio (version 4.1.2), using the "metafor" package (version 3.0.2). SMD was analyzed with the Hedges' g methods and proportions of AEs were calculated with the Clopper-Pearson interval method. A meta-analysis was performed to obtain pooled effect estimates for both primary and secondary outcomes. Overall efficacy and AEs were evaluated with randomeffects model. Given the anticipated differences between trials with respect to patient populations and interventions, statistical heterogeneity was assessed with I 2 statistics. All statistical tests and confidence intervals (CI) were two-sided, with a significance level of p < 0.05.

| Study selection
The initial literature search revealed 3580 unique records. After  Table S2. Among the included studies from 13 different countries, most studies were from Iran, India, and Egypt.

| Efficacy of topical therapies
The total melasma participants involving 2359 patients, age ranged from 18 to 60 years (mean age 38.2), with 93.2% female participants. The mean treatment course was 12 weeks. The 67 treatment arms and three placebo arms were plotted ( Figure 2). We  Figure S1). There was high heterogeneity among the studies (I 2 = 84% and 81%, respectively).
Among the non-HQ agents, cysteamine showed a significantly higher risk of irritation compared with AA, kojic acid, and TXA. Other reported AEs than skin irritation included hypertrichosis from HQ monotherapy and HQ-containing combination therapy, 6-8 hypopigmentation, telangiectasia, and photosensitivity from HQ-containing combination therapy, 6,9-11 strong odor from cysteamine, 12-15 acne or rosacea from kojic acid, cysteamine, HQ monotherapy, and HQcontaining combination therapy, 6,15-19 edema from TXA, 20 and PIH from cysteamine, TXA, and HQ monotherapy. 12,21,22 Of note, zinc sulfate did not meet our inclusion criteria for safety analysis, as only one study reported the total number of patients experiencing AEs. 23 Egger's test (p = 0.0512) revealed no significant publication bias among these studies ( Figure 3B).

| Risk-of-bias assessment
The RCT studies included in this meta-analysis mostly ranged from 7 low-risk studies, 24 studies with moderate risk, and 11 studies with high risk of concerns ( Figure S2A). Non-RCT studies had more risk of bias with 11 high risk and 5 moderate risk of concerns ( Figure S2B).
The high risk of concerns was mainly due to the randomization process as the study did not report concealment allocation or randomization. In addition, some studies have concerns in measurement of outcome when evaluating treatment efficacy through unblinded evaluations.

| DISCUSS ION
Increasing topical therapeutic options is available for the treatment of melasma, making it challenging for clinicians to compare across the available treatments. There are three important findings from our systematic review and meta-analysis, providing a large-scale F I G U R E 2 Forest plot of random-effects meta-analysis demonstrating the efficacy of topical agents for melasma. AA, azelaic acid; Beta, betamethasone; BID, twice daily; BIW, biweekly; CI, confidence interval; Cys, cysteamine; Dexa, dexamethasone; FA, fluocinolone acetonide; GA, glycolic acid; HA, hyaluronic acid; HC, hydrocortisone; HQ, hydroquinone; IV, inverse variance-weighted average method; KA, kojic acid; QD, once daily; QN, once nightly; RA, retinoic acid; SA, salicylic acid; SMD, standard mean difference; TIW, thrice weekly; TXA, tranexamic acid; ZS, zinc sulfate.

F I G U R E 3 (A) Funnel plot for the efficacy analysis. (B) Funnel plot for the safety analysis.
evaluation for the efficacy and safety of topical treatment for melasma. First, the result from our study suggested that all topical agents resulted in a significant reduction in melasma severity from baseline except zinc sulfate. Second, this study showed similar efficacy among HQ-containing agents (HQ monotherapy and HQcontaining combination therapy) and non-HQ topical agents (TXA, AA, cysteamine, and kojic acid). Finally, we identified that HQcontaining combination therapy and cysteamine demonstrated the highest incidence of skin irritation. Overall, non-HQ agents other than cysteamine showed a favorable safety profile compared to all HQ-containing agents.
Among non-HQ topical agents, TXA is a plasmin inhibitor that achieves skin-whitening effects by preventing UV-induced melanogenesis and mast cell activity. 24 Our findings suggested that topical TXA cream ranging from 2% to 5% has similar efficacy to HQ-containing agents, with fewer AEs as previously suggested. 25,26 Additionally, antioxidants including AA and cysteamine have been nominated as alternative treatments based on the well-defined role of oxidative stress in melasma pathogenesis. Azelaic acid inhibits tyrosinase and other complex molecules regulating follicular keratinization and epidermal melanogenesis by reducing free radical production. 27 Based on our study results, 20% AA has shown to be an effective and well-tolerated treatment for melasma. Another old drug with high potential, cysteamine (a form of aminothiol in mammalian cells with recognized antioxidant characteristics), inhibits tyrosinase and peroxidase, removes dopaquinone, chelates iron and copper ions, increases intracellular levels of glutathione, and reduces melanin in the stratum corneum into a lighter form. 28 Even though cysteamine cream was notorious for its offensive odor, new formulas have overcome this adversity. 15 The results from our study demonstrated that cysteamine showed comparable results to other treatment regimens, but a significantly higher incidence of skin irritation was noted.
Botanical and organic acid products are recently being studied to improve the safety caused by classic treatments. Kojic acid, derived from a certain species of a hydrophilic fungal metabolite, is known to inhibit the production of free tyrosinase. 29 Kojic acid has gained popularity as a skincare ingredient to treat melasma and hyperpigmentation with mild AEs reported. 17,[30][31][32] A previous study has suggested HQ was found to better penetrate the skin, 33 which may explain reported kojic acid with HQ further improves melasma. 17 Lastly, zinc sulfate is a physical blocker and an antioxidant that could protect the skin from a wide spectrum of UV lights and are essential to skin health. 23 However, its application in melasma is controversial.
Two studies reported that topical 10% zinc sulfate was not as effective as 4% HQ. 5,23,34 Sharquie et al. 34 reported topical zinc sulfate 10% solution to be a beneficial and safe formulation in the treatment of melasma. As our results indicated that zinc sulfate failed to show a significant reduction in melasma severity, we agreed that the minimal effect may be due to sunblock effects.
The main limitation of this meta-analysis is due to moderate-tohigh heterogeneity arising from different treatment protocols, study designs, and participants' baseline characteristics across the studies.
Therefore, the estimates generated should be interpreted with caution. Few studies have small patient sample sizes and high dropout rates, which led to wide CIs and high rankings. Lastly, several large RCTs were excluded from our study due to using different melasma severity scores from the MASI and mMASI scores, which could have affected our results. Considering the scarcity of well-designed clinical trials on both efficacy and safety studies in the treatment of melasma, future studies comparing different topical agents with a large sample size are desired. In addition, further standardization of severity scales in melasma across the discipline should be considered.

| CON CLUS IONS
In summary, due to the absence of large-scale evaluation of topical treatments for melasma, this finding provides a comprehensive assessment of efficacy and safety among novel treatments. Overall, HQ-containing agents (HQ monotherapy and HQ-containing combination therapy) and non-HQ topical agents (TXA, cysteamine, kojic acid, and azelaic acid) showed comparable efficacy for the treatment of melasma. HQ-containing combination therapy and cysteamine demonstrated the highest incidence of skin irritation, whereas non-HQ agents including tranexamic acid and kojic acid demonstrated a lower risk of irritation. Clinicians may consider non-HQ agents with photoprotection as an alternative or long-term maintenance treatment, especially for patients with contraindications to HQ or on HQ drug holidays. However, decisions on treatment should be guided by safety profile, patient preference, cost, and physician's familiarity.

AUTH O R CO NTR I B UTI O N S
Yu-Feng Chang conceived and designed the analysis, collected the data, performed the analysis, and wrote the paper. Tai-Lin Lee contributed data/analysis tools, performed the analysis, and edited the manuscript. Oyetewa Oyerinde and Seemal Desai contributed to reviewing and editing the manuscript. Ali Aljabban, Camden Bay, and Paul Bain contributed to the methodology and review of the manuscript. Hye Jin Chung collected the data, edited and reviewed the manuscript, and supervised the study. All authors read and approved the final version.

DATA AVA I L A B I L I T Y S TAT E M E N T
All data generated or analyzed during this study are included in this published article [and its supplementary information files].

E TH I C A L A PPROVA L
Not applicable.