Journal of Dermatological Treatment

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ijdt20

Melasma treatment: a systematic review

Nicoleta Neagu, Claudio Conforti, Marina Agozzino, Giovanni Francesco

Marangi, Silviu Horia Morariu, Giovanni Pellacani, Paolo Persichetti,
Domenico Piccolo, Francesco Segreto, Iris Zalaudek & Caterina Dianzani

To cite this article: Nicoleta Neagu, Claudio Conforti, Marina Agozzino, Giovanni Francesco
Marangi, Silviu Horia Morariu, Giovanni Pellacani, Paolo Persichetti, Domenico Piccolo, Francesco
Segreto, Iris Zalaudek & Caterina Dianzani (2021): Melasma treatment: a systematic review,
Journal of Dermatological Treatment, DOI: 10.1080/09546634.2021.1914313

To link to this article: https://doi.org/10.1080/09546634.2021.1914313

Accepted author version posted online: 14

Apr 2021.

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Melasma treatment: a systematic review

Nicoleta Neagu1*, Claudio Conforti2*, Marina Agozzino2, Giovanni Francesco Marangi3, Silviu
Horia Morariu1, Giovanni Pellacani4, Paolo Persichetti3, Domenico Piccolo5, Francesco Segreto3,
Iris Zalaudek2, Caterina Dianzani3

1. State Clinic of Dermatology, Mureș County Hospital, Tîrgu Mureș, Romania

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2. Dermatology Clinic, Maggiore Hospital of Trieste, Trieste, Italy

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3. Plastic and Reconstructive Surgery Unit, Campus Bio-Medico University of Rome, Rome,

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Italy

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4. Dermatology Clinic, Department of Clinical Internal, Anesthesiological and Cardiovascular
Sciences, Sapienza University of Rome, Rome, Italy
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5. Skin Center - Dermo Aesthetic Laser Centers, Avezzano, Italy
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* these authors have equally contributed
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Word count: 4287 words

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Tables: 6
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Figures: 1
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Corresponding author: Nicoleta Neagu

Affiliation: State Clinic of Dermatology, Mureș County Hospital, Nr.12, Gh. Doja Street 540015.
Tel, Fax: +40 365 882 534. Tîrgu Mureș, România.

ORCID: 0000-0001-5452-7324

E-mail: [email protected]
The authors received no financial support for the research, authorship, and/or publication of this
article. The authors declare no conflict of interest.

Abstract

Melasma is a common chronic refractory disorder of pigmentation affecting people with darker
skin types. Overall prevalence varies between 8.8% and 40%, depending on the ethnicity of the

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population and the geographical area. Therapeutic management of melasma is challenging, with

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high recurrence rates which significant impacts on the quality of life. No single treatment is

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universally efficacious. Systemic treatments with tranexamic acid and polypodium leucotmatous
had promising results, although the former was related to systemic side effects. Microneedling

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and peeling were also efficacious, although their superiority to topical hydroquinone, the gold
standard in melasma treatment, remains to be established. Similarly, laser and light devices have
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been beneficial. However, recurrence rates remain high in all treatment groups. Combination
therapies, either in double or triple combinations yielded the best results when compared to
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single terapies. Treatment choice should be made after Wood’s lamp examination, as well as
dermatoscopic evaluation, in order to select the best treatment option, targeted at each melasma
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subtype.
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Key words: melasma, tranexamic acid, peeling, microneedling, laser, intense pulsed light
Introduction

Melasma, previously referred to as chloasma, is a common chronic refractory disorder of

pigmentation affecting people with darker skin types, most commonly Fitzpatrick phototypes III-
IV. Based on the ethnic makeup of the population, reported prevalence varies between 8.8% and
40%. (1,2) Clinically, it manifests as symmetric reticulated hypermelanosis and it can appear in
three predominant facial patterns: centrofacial, malar, and mandibular.(3)

Wood’s lamp examination has been used to classify melasma based on the the depth of melanin

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in the skin: epidermal, typified by a light brown coloration, dermal, exhibiting a bluish grey
colour or mixed, seen in a dark brown shade.(4) However, in vivo reflectance confocal

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microscopy showed a heterogenous distribution of melanophages, thus indicating that all

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melasma is “mixed”.(5) It is now thought that melasma is the result of a complex interaction
between epidermal melanocytes, keratinocytes, dermal fibroblasts, mast cells, vascular
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endothelial cells, and hormonal, genetic, as well as UV influence.(6) Histopathologically,
melasma is characterized by solar elastosis, basement membrane disruption, increased
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vascularization and increased mast cell count, which strongly indicate that melasma should also
be regarded as a photoaging skin disorder.(7)
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In a study by Rodríguez-Arámbula et al, conducted on 20 female patients with malar melasma,

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histopathological examination revealed significantly higher inflammatory infiltration of CD4+ T

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cells, CD68+ macrophages and mast cells, as compared to unaffected skin. Additionally, genetic
and immunohistochemical analyses showed significant elevations in the expression of IL-17 and
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COX-2. This indicates that malar melasma contains chronic inflammatory cells and mediators
which can be exacerbated by environmental stimuli, of which cumulative sun exposure is the
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most important. This might explain the recurrence of melasma as well as the favourable
responses to topical anti-inflammatory treatments.(8)

DNA hypermethylation in melasma lesions were described by Campuzano-García et al. They

showed significantly increased levels of DNA methyltransferases (DNMT1 and DNMT3) in
melasma lesions as compared to perilesional skin. Additionally, DNMT levels decreased after
the use of sunscreen in combination with either 0.05% retinoic acid, 4% niacinamide, or placebo,
which correlated with clinical improvement. Therefore, DNA methylation might also be
involved in melasma etiopathogeny, which impacts on the future treatment measures.(9)

Therapeutic management of melasma is challenging, given its chronicity and recurrence rates,
which highly impacts on the patients’ quality of life.(10,11) No single treatment is universally
efficacious. Thus, combination treatment should be applied, along with avoidance of
exacerbating factors such as use of hormonal contraception and UV light exposure.(12)

Novel therapeutic agents act at various levels: the melanogenesis pathway, catalyzed by

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tyrosinase and thyrosinase related proteins (TYRP1 and TYRP2), all of which controlled by
micropthalmia-associated transcription factor (MITF) inflammation; hyperactive melanocytes;

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excess reactive oxygen species (ROS) and inflammation; melanosomal transfer to keratinocytes,

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via the keratinocyte protease-activated receptor 2 (PAR-2); impaired stratum corneum, caused by
a low production of free fatty acids; increased dermal vasculature; increased number of mast
cells; estrogen receptors.(6) (Table 1)
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The aim of this review was to summarise the available treatments for melasma, as well as their
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efficacy, tolerability and recurrence rates. Moreover, we aimed to determine which combination
therapies rendered the most promising results while maintaining an acceptable safety profile.
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Materials and methods

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A systematic review of the literature was conducted following the Preferred Reporting Items for
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Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A search of PubMed and

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Science.gov databases was performed for the period 2015-2021 using the terms: melasma and
chloasma combined with the term treatment. Only articles in English were selected. The last
search was run on 17th january 2021. Studies were limited to prospective, randomized, controlled
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clinical trials evaluating melasma treatments. Only statistically significant results were included
and summarized in categorized tables. Relevant reviews and meta-analyses covering melasma
treatments were selected. Other potentially relevant articles were identified by manually
checking the references of the included literature. Independent extraction of articles was
performed by two investigators using predefined criteria for each category. Disagreement was
resolved by discussion between the two review authors.
Due to treatment and outcome scoring system heterogeneity, we focused on the objective
assessment of the therapies involved, categorized according to the procedure employed: topical
creams and peelings, systemic, as well as physical treatments such as microneedling, lasers,
intense pulsated light, high intensity focused ultrasound. We further analyzed treatments in
categories of single, as well as double and triple combination treatments in search for the best
associations. We summarized the results of the RCTs in Tables 2-6. In the treatment columns (A,
B, C) we did not include any mention of priming before peeling procedures or SPF daily
application considering that all patients used SPF as part of their routine melasma treatment.

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Results

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A total of 492 articles were initially identified in the literature search, of which 162 were

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duplicates and 224 did not meet the inclusion criteria and were therefore removed. We selected
87 randomized controlled trials (RCTs), 9 reviews and 1 meta-analysis (Figure 1). A total of
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4681 patients with melasma were included, for which different treatment measures were
employed: systemic treatments (n=20), microneedling (n=16), peelings (n=10), topical creams
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and solutions (n=56), lasers (n=24), intense pulsated light (n=7), high intensity focused
ultrasound (n=1), dermabrasion (n=1).
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Study heterogenity consisted in the inclusion of patients with: mild, moderate or severe melasma,
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epidermal, dermal or mixed melasma, different photoptypes, the presence or absence of previous
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melasma treatments, short term or long term follow-up, the mention of recurrence rates,
interpretation of therapeutic outcomes according to phototype, melasma subtype or the usage of
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previous melasma treatments. Furthermore, outcome measures included different scoring

systems: Melasma Area and Severity Index (MASI), modified Melasma Area and Severity Index
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(mMASI), Patient Global Assessment (PGA), melanin index (MI) and erythema index (EI). The
lower the score, the higher the improvement rates.

Systemic treatment

For our search period, there were 20 RCTs studying the effects of systemic therapy on different
types of melasma: 1 for polypodium leucomatous (PLE), 1 for dietary carotenoids (DC) and 10
for tranexamic acid (TXA). Since the purpose of this review is to summarize the effects of
melasma treatments in their multitude and variability, in the case of systemic treatments, which
have been used since as early as 2009, we decided to expand our search period and 6 additional
RCTs were included: 2 for TXA, 1 for PLE, 1 for melatonin and 1 for procyanidin + vitamins A,
C, E (13–30).

For PLE studies, in the comparison with placebo by Martin et al, the results were superior in the
PLE group than in the placebo group(24). However, according to Ahmed et al, significant
decrease in MI and MASI scores were noticed in both groups(14). This might be explained by

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the fact that all the patients also applied daily sunscreen. Furthermore, Chuah et al compared the

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effectiveness of PLE in addition to hydroquinone (HQ) 4% cream(15). They showed the

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superiority of PLE + HQ 4% cream, as compared to HQ 4% cream alone at weeks 8 and 12 of
treatment, although at day 84 the difference was no longer statistically significant, even though

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the combination group had a 33% higher improvement of melasma. This might be explained by
the high recurrence rates of melasma, irrespective of the treatment measure applied.
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Nevertheless, no adverse events were reported by the patients who were treated with PLE.

Dietary carotenoids haven’t been extensively studied. Gan et al included them in a case-control
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study, in addition to a topical lightening cream and found no difference in melasma improvement
between the two groups(18). Similarly, the effects of melatonin, either topical or systemic or
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both, as well as procyanidin + vitamins A, C E have been scarcely studied. A significant

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decrease in MASI scores was obtained for the treatment and for the placebo groups, which can
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be explained by the beneficial effect of sunscreen application, as well as the low effectiveness of
the systemic treatment. Mild, reversible adverse events have been reported in the melatonin, as
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well as procyanidin treatment groups.

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TXA was the most studied agent, in different concentrations and dosages, as well as different
delivery methods: oral tablets, topical creams, as well as cocktails for microneedling procedures.
For its systemic effects, 12 RCTs have been conducted: either TXA versus placebo, or in
addition to laser treatment, topical treatment, or part of microneedling sessions. In the placebo
comparison, the TXA group had better results than the placebo group, although not statistically
significant(16,17). Furthermore, recurrence rates were high in both groups. Oral TXA was used
as an adjuvant tool to topical treatments and compared to the effect of topical treatments alone.
In the HQ 4% cream combination(21,23,29), as well as in the TC cream combination(25,26), the
superiority of the combined treatment as compared to the topical treatment alone has been
demonstrated. Similarly, oral TXA in combination with QSNY laser have demonstrated better
results, as compared to oral TXA alone(13,27). However, relapses still occured in either
combination comparisons. TXA delivery systems were also compared: in the microneedling
versus oral delivey method, the latter had significantly superior results in one study(22) and
comparable results in the other(28). With regard to TXA dosage, one study compared the effects
of either 500 mg, 750 mg, 1000 mg or 1500 mg daily(30). There were no significant differences
between the 4 groups in terms of efficacy or safety profile. However, the rates of improvement

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positively correlated with treatment time and dosage. Important adverse events have been
reported, especially after the oral delivery method of TXA: gastrointestinal upset, changes in

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menstrual periods, headache (Table 2).

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Microneedling

16 RCTs evaluating the effects of microneedling on melasma have been included in our
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review(31–43). All studies showed a significant decrease in melasma scores as compared to
baseline. Further comparisons between microneedling cocktails, combinations with topical
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treatment, lasers and peeling have been assessed.
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Cassiano et al conducted an interesting study on a group of 20 females: they performed two 3

mm punch biopsies, one before and one 7 days after the microneedling session. Histologically,
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they discovered significant melanin reduction, while clinically a significant decrease in mMASI
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score was noted(32).

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Regarding the types of needles used, in a study by Hofny et al comparing PRP delivery systems
with either dermapen on mesoneedles, no difference in efficacy was observed. However,
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tolerability was lower in patients treated with dermapen than those treated with mesoneedles(34).

In a comparison between microneedling with TXA, topical silymarin cream and GA peeling, the
best results were obtained with GA peeling, while topical silymarin was the safest(33).
Additionally, microneedling with 0.4% TXA and 1% TXA was inferior to HQ 4% cream(37) in
one RCT and superior to HQ 2% cream at week 4, but not at week 20, in another(38).
Furthermore, microneedling with TXA 10% had comparable results with microneedling with
vitamin C 40%(43). In the comparison between oral TXA and transdermal delivery of TXA, the
former rendered superior results in a population with a majority of mixed type melasma(22) and
the latter showed similar results in a population with a predominant epidermal type of
melasma(28).

Regarding the cocktails used for microneedling sessions, Iraji et al demonstrated the superiority
of a glutathione combination solution with 0.4 % TXA and 3% vitamin C and the absence of
melasma relapse in either group at week 24(35). Additionally, Feng et al compared the efficacy
of microneedling with a combination of TXA and reduced glutathione to topical application of

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HQ cream, with significantly better results in the glutathione-TXA microneedling group(42).

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Microneedling therapy, combined with either topical TXA solution, HQ 4% cream or QSNYL

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demonstrated superiority to the topical and laser therapy alone(39–41). However, it did not
significantly improve the effects of peeling(31).

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Peeling
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Different peeling combination solutions have been tested for the treatment of melasma, including
the following acids: salicylic acid (SA), glycolic acid (GA), azelaic acid (AzA), ascorbic acid
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(AsA), phytic acid (PA), mandelic acid (MA), trichloracetic acid (TCA) and Jessner’s solution.
All studies showed a significant decrease in melasma scores as compared to baseline(44–51).
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GA 20% peel in combination with topical AA 20% cream was superior to the topical treatment
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alone(45). Additionally, the combination of topical ascorbic acid cream 5% and LFQSL with
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peeling agents were superior to the topical and laser treatments alone(50,51).
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In the single versus multiple acid peeling solutions, there was no difference between GA peel
and a combination of AzA, PA and resorcinol peel; neither between GA peel and combination of
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GA and TCA peel(46,47). However, the combination of TCA 20-25% and Jessner’s solution
peeling rendered superior results to TCA alone(44).

Topical treatment

Topical treatments have been extensively studied in the treatment of melasma(52–73). Either as
single active ingredients or in different combinations, they have all been proved efficacious in
decreasing melasma scores and have maintained a relatively high safety profile.
Hydroquinone cream was compared to several other topical treatments: TXA 5%, both
conventional(54,74) and liposomal(55), lignin peroxidase(58), petroselium crispum solution(65),
0.7% and 1.4% silymarin cream(68), 4% diacetyl boldine serum(69) and cosmetic product
combination cream(57), all of which rendered comparable results to HQ cream formulas (2%,
3%, 4%). Conversely, in RCTs comparing HQ topical treatment to 1% flutamide cream(52) and
0.2% thiamidol cream(53), HQ was inferior in efficacy. However, in the HQ versus 5%
methimazol cream comparison, the former maintained superior results. Erythema, dryness,
burning sensation, pruritus were the most frequently reported adverse events in the HQ groups.

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Cysteamine 5%, as well as licorice extract 4% were also efficacious in melasma treatment,

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however their effects were only compared to placebo(60,66,70), thus their superiority to other
topical treatments has not been demonstrated as of yet. Triamcinolone injections, however, seem

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to yield better results than the Kligman formula containing HQ 5%, tretinoin 0.1%,
dexamethasone 0.1%(59).
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TXA combinations appeared to have a significant impact on hypervascular, inflammatory
melasma(61). Azelaic acid 10% combined with d-panthenol 10% was superior to other azelaic
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acid formulas(67).
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Lasers and Light Therapy

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Different light devices have been used in the treatment of melasma(75–80), either fractionated
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intense pulsed light (IPL) or conventional IPL, both with comparable MASI score decrease(80).
Also, different fluences have been utilised, 10 J/ cm2 and 13 J/ cm2, both with significant
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improvement from baseline(75). Combination therapies rendered superior results as compared to

IPL alone: in association with microdermabrasion(76), topical TXA 2%(77) or triple
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combination cream(79).

Laser therapy has been extensively studied in melasma treatment(47,51,81–97). Various devices
have been employed: fractional ablative CO2 laser, fractional thulium laser, fractional
picosecond laser, picosecond alexandrite laser, copper bromide laser, ablative pixel Erbium YAG
laser (APEYL), pulsed dye laser (PDL), low-fluence Q-switched Nd: YAG laser (LFQS), long-
pulse Nd: YAG laser (LPNY), Q-switched Nd: YAG laser (QSNY), fractional erbium YAG laser
(FEYL), pixel Q-switched Nd: YAG laser (PQSNY), quick pulse-to-pulse laser (Q-PTP), super
skin rejuvenation device (SSR). These can be included into four main categories: pigment-
specific (Q-switched and long-pulsed lasers, IPL), vascular (pulsed dye and Copper bromide
lasers), fractional and ablative lasers(98). Among these, the non-ablative types are preferred in
melasma treatment for their lower incidence of post-inflammatory hyperpigmentation due to
direct damage to the skin. Q-switched lasers selectively target melanin chromophores, while IPL
is believed to determine the upward shedding of melanosomes destryed by QS laser. Vascular
lasers might prove to be useful in inflammatory, hypervascular melasma(3).

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The majority of the studies compared laser therapy alone to combination therapy, the latter

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rendering significantly better results(81,91,95). Similarly, combination therapy had significantly

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better results than topical therapy alone(83–85) or it rendered similar improvement rates(93,96).
In a RCT by Hammami et al, Kligman formula for triple combination cream (TCC) was superior

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to copper bromide laser(88).

In the laser versus laser comparisons, different technology devices have been evaluated. FEYL
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combined with QSNYL and TCC cream was superior to QSNYL and TCC(82). Dual toning
performed with LFQSNYL and LPNYL 1064 nm had significantly better results than QS toning
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with LFQSNYL(86). In a triple comparison between SSR, PQSNYL and APEYL, the latter had
superior results, although not statistically significant as compared to the other two. Additionally,
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the effects on different types of melasma were studied: SSR and PQSNDY were significantly
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efficacious against all types of melasma, with slightly better results against epidermal measma.
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In contrast, APEYL was significantly efficacious in dermal and mixed melasma, while in
epidermal melasma the results were not statistically significant(99).
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Discussion
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Systemic treatment

Nowadays there are many systemic therapies that can be used as an adjuvant in melasma
treatment. However, their efficacy in melasma has not been clearly demonstrated.

Oral PLE is one of the a valid options and it can be used as an adjuvant to topical treatment of
melasma, especially in association with HQ cream. Further studies are necessary in order to
assess the recurrence rates and the possibility of maintaining the systemic treatment with PLE
after topical treatment cessation, in order to avoid relapses. Dietary carotenoids, melatonin, either
topical or systemic or both, as well as procyanidin + vitamins A, C E seem the least effective of
the systemic treatments(18–20). However, additional studies following patients for longer
periods might be useful. Oral TXA had better results than placebo, although not statistically
significant(16,17). Oral TXA in combination with HQ 4% cream, as well as TC cream, rendered
superior results than the topical treatment alone(23,25,29). In terms of delivery methods, oral
TXA seems to have better results than microneedling(22). Additionally, in terms of TXA dosage,
no significant differences were found between the use of either 500 mg, 750 mg, 1000 mg or

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1500 mg daily(30).

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Microneedling

Microneedling is a minimally invasive, collagen induction therapy that consists in delivery of

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fine needles into the skin, either through needle rollers, stamping or electric-powered pens. It
enhances transdermal drug delivery and has been used in dermatology for scar, striae and
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rhytides therapy(100).
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Microneedling has been repeatedly proven to be an effective measure in melasma treatment,
showing results even after as early as 7 days, from a histological viewpoint(32). Microneedling
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with TXA 0.4% rendered inferior results to GA peeling, silymarin cream(33), HQ 4% cream(37)
and similar results to microneedling with vitamin C 40%(43). In the oral versus intradermal
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delivery of TXA, the former yielded superior results in an Indian cohort with majoritary mixed
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type of melasma(22), while the latter showed similar results between the two treatment groups,
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also in an Indian cohort, but this time with a predominant epidermal type of melasma(28) which
might indicate that oral TXA is more efficacious against dermal and mixed melasma. The
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addition of glutathione to TXA cocktails used for microneedling procedures rendered superior
results and zero recurrence rates.(35) In a study by Feng et al, microneedling with glutathione in
combination with TXA was superior to HQ topical application(42). However, the full article was
not accessible, therefore these results need further confirmation. Microneedling has also been
used as combination therapy with HQ 4% cream, QSNYL and the results were superior to both
topical and laser therapy alone.(39–41)
Tolerability is quite low, especially when dermapen is used, with adverse events varying from
transient erythema, burning sensation, to pain, edema and ecchymosis(34). These local reactions
are however, operator dependent.

Peeling

Chemical peelings have been used for their ability to generate epidermal remodelling and can be
classified as superficial, affecting the epidermis through the papillary dermis, medium, involving
the papillary to the upper reticular dermis and deep, penetrating through the mid-reticular

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dermis.(101) However, in the treatment of melasma, the use of deep or medium-depth peelings is

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not encouraged in dark-skinned patients, because of the risk of hyperpigmentation.

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epidermis-papillary dermis), medium-depth (papillary to upper reticular dermis) and deep

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subtypes based on the depth of their penetration (mid-reticular dermis).

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In a meta-analysis by Dorgham et al, TCA and Jessner's solution were more efficacious than
topical HQ in reducing the severity of melasma, while GA was better than TCA. Additionally,
GA was similar to tretinoin, vitamin C iontophoresis, and amino fruit acid. Also, SA and LA
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were comparable to Jessner's solution in efficacy(102).
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Most frequently used as combination therapy, chemical peelings had superior results in
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association with topical creams(45,50) rather than with microneedling(31) or laser(51).

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Topical treatment
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Topical treatments have been the mainstay of melasma treatment. Photoprotection is the most
important and it has been used as an adjuvant to other melasma treatments, since both UV and
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visible light can cause sustained hyperpigmentation in all skin types. Hydroquinone has been
considered a first-line treatment for melasma and triple combination creams containing
hydroquinone have become increasingly popular, as they yielded superior results. Kligman
formula was the first TCC, containing HQ 5%, tretinoin 0.1% and dexamethasone 0.1%. The
most recent TCC is Tri‐ Luma, which contains HQ 4%, tretinoin 0.05%, 0.1% fluocinolone
acetonide and is FDA‐ approved in USA for the treatment of melasma(103). Mild erythema,
burning sensation, dryness, pruritus and scaling have been most frequently reported after topical
HQ treatment(53,54,62,64,65).
Many other active ingredients have been studied, of which 1% flutamide(52) and thiamidol
0.2%(53) seem to have superior results to HQ, with no adverse events reported. TXA
5%(54,55,74), lignin peroxidase(58), petroselium crispum solution(65), silymarin cream(68), 4%
diacetyl boldine serum(69) and cosmetic product combination cream(57) had comparable results
to HQ cream formulas, which make them a valid alternative to HQ. Furthermore, TXA
combinations seem to be more efficacious against hypervascular, inflammatory melasma(61).

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Also, azelaic acid 10% combined with d-panthenol 10% had better results than other azelaic acid
formulas(67).

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Lasers and Light Therapy

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IPL therapy uses a flash lamp light source with wavelengths between 515 and 1200 nm and it
selectively targets melanosomes, with the added advantage that it can simultaneously treat
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epidermal and dermal melasma(104). However, IPL effectiveness has not been convincingly
demonstrated(77,80).
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Among laser devices, QSNYL is the preferred choice for dermal and mixed types of melasma.
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Its two wavelengths, of 532 and 1064 nm, as well as a spot size of up to 10 mm allows for a
deeper penetration of the laser beam and selective photothermolysis of melanosomes. This
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results in cell death, hyperinflammatory state and damage to the basement membrane, which
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determines exacerbation of melasma and relapse. This is why QSNYL is not recommended as
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first or second line treatment for melasma. It is, however, suggested that it can be used in
recalcitrant cases, as a last resort, after other treatments have failed(105,106). On the other hand,
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LFQSNYL, also known as laser toning, uses a low-fluence, multi-pass technique, by which the
cell membrane and nucleus remain intact, which results in melanocyte downregulation and
hyperactive melanocyte cutoff(106). In a RCT by Kong et al, none of the patients in the
LFQSNYL treatment group relapsed at week 16(89). Conversely, Vachiramon et al had 8
patients who relapsed after LFQSNYL treatment; they only included patients with mixed
melasma(51).
A new class of lasers that generate picosecond- domain pulses, available in different
wavelengths, of 532 nm, 755 nm and 1064 nm, determine melanin fragmentation by
photoacoustic, rather than phototermal effect, thus determining even less inflammation than the
LFQSNYL(104). Lee et al demonstrated picosecond 755 laser superiority to QSNYL(92).

Fractional resurfacing lasers, either ablative or non-ablative, creates different columns of

microthermal damage in the skin, which determines lower inflammation and risk of
dyspigmentatin(104). Vanaman et al and Wanitphakdee et al demonstrate their efficacy in

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melasma(95,97).

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As an antivascular treatment in melasma, PDL, QSNYL and IPL, either as monotherapy or

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combined with systemic or topical TXA, seems to be efficacious in cases of melasma with
increased vascularity(107).

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Conslusion
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PLE and TXA have been demonstrated to be an efficacious treatment, especially in association
with topical HQ and TCC. Regarding tolerability, PLE is the safer option, while TXA has been
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linked to mild-to-moderate side effects.
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Microneedling with a combination of TXA and glutathione has new and encouraging results that
might prove superior to the gold standard so far, HQ cream and might also lower the recurrence
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rates. Additionally, oral TXA seems to have superior results to intradermal TXA in patients with
pt

dermal and mixed types of melasma. Further studies are needed to determine their effects,
ce

especially on the long term. Adverse events vary from mild to moderate and are operator
dependent.
Ac

Chemical peelings have demonstrated high efficacy when combined with either topical or laser
therapy. Used as monotherapy, TCA 20-25% with Jessner’s solution peeling had promising
results. Transient adverse events are expected during and immediately after the peeling seession.
The use of deep and medium-depth peelings is highly discouraged in dark-skinned patients
because the risk of hyperpigmentation.

Hydroquinone and triple combination creams containing HQ, like Kligman formula and Tri‐
Luma remain one of the best treatment options for melasma. Mild adverse events have been
associated with HQ application. TXA 5%, lignin peroxidase, petroselium crispum solution,
silymarin cream, and 4% diacetyl boldine serum seem to be an efficacious alternative to HQ
products, with comparable results. Newer products, containing 1% flutamide or 0.2% thiamidol
had encouraging results, with no adverse events reported and apparently superior to HQ.

A plethora of laser and light devices have become available in the last few years and many of
them have been used in melasma treatment. Post-treatment hyperpigmentation and high
recurrence rates associated with QSNYL led to the appearance of LFQSNYL and picosecond

t
lasers, which determined less and less inflammation of the skin. Fractional and antivascular

ip
lasers have also proved their efficacy, the latter especially in cases of melasma with increased

cr
vascularity.

There is a lack of studies following melasma patients on the long term. Of course, as presented in

us
the studies we have reviewed, the immediate results are impressive and statistically significant.
However, in a few of the studies following patients for at least 2 months after the cessation of
an
treatments applied, recurrence rates are as high as 100%, which is of great concern and requires
immediate search for alternative therapeutic measures. Combination treatments have been
M
proved time and again to be the best solution, either in double or triple combinations. Treatment
choice should be made after Wood’s lamp examination, as well as dermatoscopic evaluation, in
d

order to determinate the epidermal, dermal or mixed type of melasma, as well as the degree of
e

vascularity.
pt
ce
Ac
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95. Vanaman Wilson MJ, Jones IT, Bolton J, Larsen L, Fabi SG. The Safety and Efficacy of Treatment

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With a 1,927-nm Diode Laser With and Without Topical Hydroquinone for Facial
Hyperpigmentation and Melasma in Darker Skin Types. Dermatol Surg Off Publ Am Soc Dermatol

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Surg Al. 2018 Oct;44(10):1304–10.

96. Wang Y-J, Lin E-T, Chen Y-T, Chiu P-C, Lin B-S, Chiang H-M, et al. Prospective randomized
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controlled trial comparing treatment efficacy and tolerance of picosecond alexandrite laser with
a diffractive lens array and triple combination cream in female asian patients with melasma. J Eur
Acad Dermatol Venereol JEADV. 2020 Mar;34(3):624–32.
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97. Wanitphakdeedecha R, Sy-Alvarado F, Patthamalai P, Techapichetvanich T, Eimpunth S,
Manuskiatti W. The efficacy in treatment of facial melasma with thulium 1927-nm fractional
laser-assisted topical tranexamic acid delivery: a split-face, double-blind, randomized controlled
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pilot study. Lasers Med Sci. 2020 Dec;35(9):2015–21.

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98. Sarma N/ C. Evidence-based Review, Grade of Recommendation, and Suggested Treatment

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Recommendations for Melasma. PubMed Cent. 2017;406–42.

99. Garg S, Vashisht KR, Makadia S. A prospective randomized comparative study on 60 Indian
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patients of melasma, comparing pixel Q-switched NdYAG (1064 nm), super skin rejuvenation (540
nm) and ablative pixel erbium YAG (2940 nm) lasers, with a review of the literature. J Cosmet
Laser Ther Off Publ Eur Soc Laser Dermatol. 2019 Aug;21(5):297–307.
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100. Wu SZ, Muddasani S, Alam M. A Systematic Review of the Efficacy and Safety of Microneedling in
the Treatment of Melasma. Dermatol Surg Off Publ Am Soc Dermatol Surg Al. 2020
Dec;46(12):1636–41.

101. Conforti C, Zalaudek I, Vezzoni R, Retrosi C, Fai A, Fadda S, et al. Chemical peeling for acne and
melasma: current knowledge and innovations. G Ital Dermatol E Venereol Organo Uff Soc Ital
Dermatol E Sifilogr. 2020 Jun;155(3):280–5.

102. Dorgham NA, Hegazy RA, Sharobim AK, Dorgham DA. Efficacy and tolerability of chemical peeling
as a single agent for melasma in dark-skinned patients: A systematic review and meta-analysis of
comparative trials. J Cosmet Dermatol. 2020 Nov;19(11):2812–9.
103. Spierings NMK. Melasma: A critical analysis of clinical trials investigating treatment modalities
published in the past 10 years. J Cosmet Dermatol. 2020 Jun;19(6):1284–9.

104. Trivedi MK, Yang FC, Cho BK. A review of laser and light therapy in melasma. Int J Womens
Dermatol. 2017 Mar;3(1):11–20.

105. Aurangabadkar SJ. Optimizing Q-switched lasers for melasma and acquired dermal melanoses.
Indian J Dermatol Venereol Leprol. 2019 Feb;85(1):10–7.

106. Shah SD/ A. Laser Toning in Melasma. PubMed Cent. 2019;76–84.

107. Masub N, Nguyen JK, Austin E, Jagdeo J. The Vascular Component of Melasma: A Systematic

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Review of Laboratory, Diagnostic, and Therapeutic Evidence. Dermatol Surg Off Publ Am Soc

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Dermatol Surg Al. 2020 Dec;46(12):1642–50.

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Table legends

Table 1. Melasma treatment and mechanism of action.

an
M
Table 2. Systemic treatments.

Table 3. Microneedling.
d

Table 4. Peeling.
e
pt

Table 5. Topical treatments.

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Table 6. Laser and light treatments.

Ac
Table 1. Melasma treatment and mechanism of action.

MELANOGENESIS AND MELANOSOMAL TRANSFER TO EXCESS REACTIVE OXYGEN SPECIES AND

KERATINOCYTES INFLAMMATION
aloesin acidified amino acid peels
alpha lipoic acid alpha tocopherol
antisense oligonucleotides carotenoid
arbutin coffeeberry extract
ascorbic acid curcumin
azelaic acid epigallocatechin-3-gallate
cinnamic acid glutathione

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dimethyl hydroxy furanone hesperidin

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ellagic acid Korean red ginseng powder
epigallocatechin gallate mulberry extract

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flavinoids niacin
gentisic acid N-nicotinoyl dopamine

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ginseng orchid extract
glucosamine petroselinum crispum
glutathione phytic acid
green tea
hydroquinone
an
polyphenol
polypodium leucomatous
hydroxycoumarins proanthocyanidine (oral)
kojic acid pycnogenol
M
licorice silymarin
linoleic acid umbelliferone
liquirtin vitamin A
d

liquorice derivatives vitamin C

e

magnolignan vtamin E
mequinol INCREASED DERMAL VASCULATURE
pt

N-acetyl-4-S-cysteaminylphenol tranexamic acid

niacinamide INCREASED NUMBER OF MAST CELLS AND HISTAMINE
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SYNTHESIS
retinoids tranexamic acid
rucinol zinc
Ac

soymilk ESTROGEN RECEPTORS

flutamide (topical)
EUMELANIN DESTRUCTION
lignin peroxidase
 Table 2. Systemic treatments.

Reference Year Patients: Comparison Treatment A Treatment B Treat. Melasma Efficacy/ Outcomes Tolerability/ Recurrence
nr, Duration Type Adverse Events rates
ethnicity
Agamia 2020 60, single x oral TXA 250 oral TXA oral TXA 10 epidermal Significant decrease in Gastrointestinal 3 in group
et al(13) Egyptian double mg 250 mg + Qs- 250 mg 4 dermal mMASI score at 6 upset, change in A, 4 in
Nd: YAG daily, 46 mixed months in both groups, menstrual periods group B.
laser (1064 laser with group B showing in both groups.
nm) biweekly, a significantly better Long-standing
for 3 response than A. erythema,
months itching/discomfort
and punctate
leukoderma after
laser treatment.
Ahmed et 2013 33, single x PLE 240 mg Placebo three N/A Significant decrease in No serious N/A

t
al(14) Hispanic single times MI and MASI scores adverse events.

ip
daily, for in both groups.
12 weeks
Chuah et 2018 40, Asian single x 4% 4% daily, for N/A Significant decrease in Mild itching and N/A

cr
al(15) double hydroquinone hydroquinone 12 weeks mMASI scores in both stinging sensation
cream + oral cream groups at weeks 4, 8, in both groups.
PLE 12. mMASI score in
group A at week 8, 12

us
was significantly
lower than in group B,
but at day 84 there
were no significant
an differences between
the two groups.
Colferai 2018 37, single x oral TXA 250 oral placebo oral TXA N/A Significant decrease in Gastrointestinal N/A
et al(16) Brazilian double mg 250 mg MASI, MELASQoL symptoms,
twice and colorimetry scores change in
M
daily, for in group A and in menstrual flow,
12 weeks MELASQoL score in headache in group
group B at week 12. A.
Del 2018 39, single x oral TXA 250 oral placebo oral TXA N/A 49% reduction in Gastrointestinal Increase in
Rosario Americans double mg 250 mg mMASI score in group symptoms, mMASI
d

et al(17) twice A vs. 18% in group B change in scores

daily, for at month 3. menstrual flow, from week
3 months 26% reduction in headache, 12 to 24 in
e

mMASI in group A myalgias in both both

Vs. 19% reduction in groups, groups,
pt

group B at month 6. somnolence, with final

arthralgias, blurry values
vision in group A. lower than
at baseline.
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Gan et 2015 44, Asian single x oral dietary oral placebo once N/A Significant decrease in Stinging, burning, N/A
al(18) double carotenoids + lightening daily, for median mMASI score pruritus in both
800 mg + cream 84 days in both groups, with groups.
lightening no significant
Ac

cream difference between the

groups. Significant
improvement in
erythema scores in
both groups, with
significantly better
scores in group A.
Hamadi 2010 46, single s A: topical C: oral daily, for N/A Significant decrease in Mild, transient N/A
et al(19) Iranians double metalonin; B: melatonin, 3 90 days MASI scores in all drowsiness.
topical mg + topical groups.
metalonin + melatonin D:
sunscreen HQ 4%
cream
Handog 2009 56, single x Oral Placebo twice 56 epidermal Significant decrease in Metallic taste, N/A
et al(20) Filipino single procyanidin daily, for MASI scores in both reversible on
24 mg + 8 weeks groups. discontinuation in
vitamins group A.
 A+C+E:
6 mg
b-carotene, 60
mg ascorbic
acid,15 IU of
D-a-
tocopherol
acetate
Karn et 2012 260, single x TXA 250 mg Placebo + twice 173 Significant decrease of Group A: N/A
al(21) Nepalese double + HQ cream HQ cream daily, for epidermal the MASI scores in oligomenorrhea,
12 weeks 28 dermal group A at weeks 8 belching,
59 mixed and 12 and in group B abdominal
at week 8. cramps,
palpitation,
urticarial rash
with angioedema.
Group B:

t
exogenous

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ochronosis.
Khurana 2019 64, Indian single x microneedling oral TXA A: 17 epidermal Significant decrease in Group A: mild 3 patients
et al(22) single with TXA 250 mg monthly, 3 dermal MASI score in group pain and in group A
0.4% B: twice 44 mixed B as compared to A. erythema. Group and 2 in

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daily, for B: gastritis, group B at
3 months oligomenorrhea. 6 months
Lajevardi 2017 88, Iranian single x oral TXA 250 HQ 4% TXA 250 N/A Significant decrease in Severe abdominal Relapse

us
et al(23) double mg + HQ 4% cream mg three mean MASI score in pain, flank pain, rate of
cream times group A compared to edema of the 30% and
daily, B. Significantly higher hands and feet, 26%, in
cream patient satisfaction in nausea, vomiting, groups A
nighlty,
an group A than B. and headache in and B, at 6
for 3 group A. months.
months
Martin et 2012 21, single x PLE Placebo twice N/A Significant decrease of No serious N/A
al(24) multiracial single daily, for MASI and adverse events.
12 weeks MELASQoL scores
M
in group A as
compared to B.
Minni et 2020 120, single x oral TXA 250 placebo + TC TXA 250 N/A Significant decrease in N/A Recurrence
al(25) Indian double mg + TC cream mg twice mean MASI score in in 18.03%
d

cream daily, TC group A compared to in group A

cream B at week 4, 8. and 64.4%
daily, for in group B
e

8 weeks at week
24.
pt

Padhi et 2015 40, Indian single x oral TXA 250 placebo + TC TXA 250 N/A Significant decrease in Erythema and N/A
al(26) double mg + TC cream mg twice mean MASI score in burning sensation
cream daily, TC group A compared to in both groups,
cream B. hypopigmentation
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daily, for and

12 weeks oligomenorrhoea
in group A.
Sharma et 2017 100, single x microneedling oral TXA A: twice 64 epidermal Both treatment Group A: 2 patients
Ac

al(28) Indian single with TXA 250 mg daily, B: 20 dermal methods were equally injection site pain in group A
0.4% every 4 16 mixed effective. and transient at week
weeks, edema. Group B: 24.
for 12 hypomenorrhea,
weeks epigastric
discomfort
through week 4.
Shihab et 2020 50, single x oral TXA 250 oral placebo oral TXA N/A Significant Erythema and 3 months
al(29) American double mg + HQ 4% + HQ 4% 250 mg improvement in pruritus the first after
cream cream twice mMASI scores in few days after suspending
daily, group A compared to applying the study drug,
cream B, at week 12. hydroquinone 68% of all
nightly, cream in both subjects
for 3 groups. Changes had an
months in the menstrual increased
cycle in group A. mMASI
score,
 although
lower than
baseline.
Shin et 2013 48, single x oral TXA 750 LF-QSNY TXA N/A Significant decrease in No serious N/A
al(27) Korean double mg + LF- laser daily for mMASI scores in both adverse events.
QSNY laser 8 weeks, groups, with
laser at 4 significantly better
weeks results in group A as
interval, compared to B.
2
sessions
Zhu et 2019 72, single x oral TXA 500 - 2 years N/A All four doses of TA Mild stomach N/A
al(30) Japanese single mg, 750 mg, were effective in upset and
1000 mg, treating melasma, and decreased
1500 m the efficacy correlated menstruation.
with treatment time
and dosage.

t
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an
M
e d
pt
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 Table 3. Microneedling.
Referenc Year Patients: Compar Treatment Treatment Treat Treat. Melasm Efficacy/ Outcomes Tolerability/ Recur
e nr, ison A B ment Duration a Type Adverse Events rence
ethnicity C rates
Balevi et 2017 41, single x 30 % SA 30 % SA N/A A,B: every 41 MASI scores significantly Mild to N/A
al(31) Turkish double peel peel + 2 weeks for mixed decreased in both groups, but moderate
microneedli 2 months with no significant difference burning
ng between them. Significant sensation in
(mesoneedl decrease in MelasQoL scores Group B during
es) with in Group A compared to injections.
vitamin C Group B.
Cassiano 2019 20, single x microneedli SPF 50 N/A for 7 days N/A mMASI, colorimetry, and N/A N/A
et al(32) Brazilian double ng sunscreen quality of life parameters
(Dermarolle improved only in group A.
r 1.5 mm) + Histologic assessment:
SPF 50 significant reduction in

t
sunscreen melanin density, pendulous

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melanocytes and basement
membrane damage per
histological field.

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Elfar et 2015 60, single x microneedli Topical 50% A: weekly; 30 Statistically significant Group A: N/A
al(33) Egyptian single ng with Silymarin GA B: twice epiderm difference with the best burning pain
0.4% TXA cream 14 peelin daily; C: al 13 results in mMASI scores in and wheal at the
mg/ ml g every 2 dermal group C>B >A. There was site of injection,

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weeks, for 17 statistically significant erythema.
12 weeks mixed difference between A<B, Group B: no
A<C, group A showing side effects.
weaker response than B and Group C: post
an C. inflammatory
hyperpigmentati
on
Significant
differences
M
between group
A and groups B
and C, groups B
and C being the
safest; also
d

between group
B and C where
e

group B was the

safest.
Feng et 2018 180, single x microneedli topical N/A N/A N/A Significantly higher efficacy N/A N/A
pt

al(42) Chinese double ng with hydroquino in group A than B.

tranexamic ne cream
acid +
ce

reduced
glutathione
Hofny et 2019 23, double x microneedli microneedli N/A monthly, 3 18 MASI and mMASI scores The majority of N/A
al(34) Egyptian double ng 2 mm ng with sessions epiderm decreased significantly. A the patients
with mesoneedle al 5 statistically significant experienced
Ac

dermapen + s + PRP on mixed decrease was noted in the more pain with
PRP on the the left side hemi-MASI score on each mesoneedles
right side of of the face side of the face following than with
the face PRP treatment, but there was dermapen. All
no significant difference on the patients
comparing both sides. observed
less downtime
with
mesoneedles
than with
dermapen.
Iraji et 2019 30, double x microneedli microneedli N/A every 2 6 Significantly more reduction Erythema, no
al(35) Iranian double ng ng weeks, 6 epiderm of mMASI score with edema and relaps
(mesoneedl (mesoneedl sessions al 5 cocktail A than B at week 12. ecchymosis. es at
es) with es) with dermal Patient satisfaction was week
TXA 0.4% TXA 0.4% 19 significantly higher for 24
+ vitamin C + vitamin C mixed cocktail A than B.
 3% + 3% on the
glutathione left half of
2% on the the face
right half of
the face
Kaleem 2020 60, single x microneedli microneedli N/A every 2 20 Mean of H-mMASI score Erythema, N/A
et al(36) Pakistane double ng with ng with weeks for epiderm showed significant reduction swelling, and
se TXA 0.4% saline 0.9% 12 weeks al 33 in group A compared to burning were
on the left on the right dermal group B. documented as
side of the side of the 7 mixed temporary side
face face effects on both
sides.
Pazyar et 2019 41, double x microneedli microneedli N/A microneedli 26 Significant decrease in MASI All patients 6
al(37) Iranian double ng with ng with ng: every 2 epiderm score for group A, group B, experienced patien
TXA 0.4% TXA 1% on weeks, al 1 and HQ cream at week 12 injection site ts in
on the right the right cream: dermal with no significant difference burning pain, group
side of the side of the twice daily, 14 between groups A and B. one patient A and

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face + face; for 12 mixed Significantly better results in reported 2 in

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topical 4% topical 4% weeks the HQ group than 0.4% urticaria. No Grou
HQ cream HQ cream TXA group at weeks 8 and adverse effect p B at
on the left on the left 12. Higher patient satisfaction was seen in the week
side of the side of the rates in group A>B and in HQ group. 24

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face face HQ>A, but not statistically
significant.
Saki et 2018 37, single x hydroquino microneedli N/A cream 13 Colorimetry measurements N/A N/A

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al(38) Iranian single ne 2% ng with nightly for epiderm for melanin value: significant
cream TXA 0.4 % 3 months; al 6 reduction in both groups,
monthly dermal with significantly better
microneedli 12 results in group B than A at
ng sessions,
an mixed week 4, but not at week 20.
3 in total Significantly better patient
satisfaction rates in group B
than A.
Tehranch 2018 55, single x microneedli topical 4% N/A cream 55 Significant decrease in mean Erythema and N/A
inia et Iranian double ng with hydroquino nightly for epiderm MASI scores at week 16 in pruritus in both
M
al(39) TXA 10% ne 12 weeks; al both groups. Significantly groups.
+ topical microneedli better therapeutic outcomes
4% ng sessions and patient satisfaction rates
hydroquino every 4 in group A than B.
ne weeks, 4 in
d

total
Ustuner 2017 16, single x 1,064-nm 1,064-nm N/A every 4 12 Significantly lower mean Transient 5
e

et al(40) Turkish double QS- QS- weeks for 4 mixed MASI scores, significantly erythema, slight patien
Nd:YAG Nd:YAG months 4 better clinical response as hyperpigmentati ts in
pt

laser + laser dermal evaluated by the clinician in on in both group

microneedli group A than B at months 1- groups. A and
ng with 4. Significant decrease in 7 in
vitamin C mean MelasQoL-TR scores group
ce

in group A. B
Xu et 2017 28, single x microneedli topical N/A once N/A Brown spots scores measured No obvious N/A
al(41) Chinese double ng + topical 0.5% TXA weekly for by Visia, MI were adverse
0.5% TXA solution 12 weeks significantly lower in group reactions.
Ac

solution A than B at week 12.

Physician evaluations of
photographs showed better
results in group A. Subjective
satisfaction scores on both
sides increased significantly,
with better results in group A.
Zhao et 2020 17, single x microneedli microneedli N/A weekly, 8 5 Significant decrease in MASI Mild erythema, 1
al(43) Chinese single ng with ng with sessions epiderm scores in both groups. localized patien
TXA 10% vitamin C al, 6 congestion. t at
40% dermal, mont
6 mixed h 2.
 Table 4. Peeling
Reference Year Patients: Comparison Treatment Treatment Treatment Treat. Melasma Efficacy/ Tolerability/ Recurrence
nr, A B C Duration Type Outcomes Adverse Events rates
ethnicity
Abdel- 2017 24, single x TCA 20%– TCA 20%– N/A biweekly, 14 Significant Erythema, burning N/A
Meguid et Egyptian double 25% + 25% 6 epidermal, decrease in sensation,
al(44) Jessner’s sessions 10 mixed MASI score discomfort,
solution in both pruritus,
groups, with hyperpigmentation,
significantly crustation in both
better results groups.
in group A.
Dayal et 2017 60, Indians single x GA peel + 20% AA N/A A: every 60 Significant Erythema, pruritus, N/A
al(45) double 20% AA cream 3 weeks, epidermal decrease in burning sensation,
cream 8 peeling MASI and postinflammatory
sessions; MelasQoL hyperpigmentation

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B: twice scores after and scaling in both

ip
daily, for week 12 in groups.
24 weeks both groups,
but with

cr
significantly
better results
group A.
Faghihi et 2017 41, Iranian single x 20% AA + 50% GA N/A every 2 19 Marked Group A: No N/A

us
al(46) single 10% peel on the weeks, 6 epidermal improvement complications.
resorcinol left side of sessions 22 mixed in MASI Group B: burning
+ 6% the face scores in sensation and
phytic acid both groups. dyspigmentation.
peel on the
right side
of the face
an Significantly
lower patient
discomfort
after
procedure in
M
group A
compared to
B.
Garg et 2019 30, Indians single x 35% GA 35% GA 35% GA every 2 epidermal, Significant Erythema, pruritus, N/A
al(47) double x full-face full-face full-face weeks, 4 mixed reduction of burning sensation,
d

double peel peel peel sessions MASI scores transient

followed by followed in all groups. hyperpigmentation.
e

10% TCA by 20%

spot peel TCA spot
peel
pt

Mahajan et 2015 40, Indian single x TC cream GA peel + N/A for 3 20 Significant Irritation, increased N/A
al(48) single 20% AA months epidermal reduction in dryness,
cream 13 dermal MASI and photosensitivity in
ce

7 mixed VAS scores both groups.

after 6 and
12 weeks of
treatment in
both groups.
Ac

Murtaza et 2016 148, single x 20% TCA 20% TCA N/A A, B: 148 Significant N/A N/A
al(49) Pakistanese double peel + 5% peel weekly, epidermal MASI score
magnesium cream reduction
ascorbyl once both groups.
phosphate daily; for
cream 6 weeks
Sahu P et 2017 60, Indians single x 20% TCA 20% TCA N/A A, B: 60 Statistically N/A
al(50) double peel + 5% peel every epidermal significant
ascorbic two improvement
acid cream weeks, in: MASI, Post peeling
cream MelasQoL, erythema, burning
nightly, percentage and stinging
for 12 decrease in sensation, post-
weeks MASI, in inflammatory
group A hyperpigmentation
compared to in both groups.
group B. Pruritus in group B.
Vachiramon 2015 12, Thai single x LFQS on LFQS + N/A weekly, 5 12 mixed Mean at week 8
et al(51) double one side of 30% GA sessions relative LI and week
the face peel on the index 12
contralateral reduced
side significantly
at week 4 in
both Burning and
treatment stinging sensation
groups, but on both sides of the
increased at face. Superficial
week 8 and skin peeling in
week 12. group B.
Significant Hyperpigmentation,
relative LI, guttate
MASI score hypopigmentation
reduction in on the background
group B of

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compared to hyperpigmentation

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group A. in both groups.

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an
M
e d
pt
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Ac
 Table 5. Topical treatments.
Reference Year Patients: Comparis Treatment A Treatmen Treat Treat. Melasm Efficacy/ Outcomes Tolerability/ Recurr
nr, on tB ment Duration a Type Adverse Events ence
ethnicity C rates
Adalatkhah 2015 74, single x 1% flutamide 4% N/A nightly, for N/A Significant decrease in N/A N/A
et al(52) Swedish single cream hydroqui 4 months MASI scores in both
none groups, with better results
cream in group A. Significantly
higher patient satisfaction
in group A as compared to
B.
Arrowitz et 2019 59, single x thiamidol 4% place twice daily, N/A Significant improvement Erythema in N/A
al(53) multiraci single 0.2% hydroqui bo for 12 of mMASI scores in both groups.
al none weeks groups A and B, with
cream sigificantly better results
in group A than B and C.

t
Significantly better L*-

ip
value in group A
compared to C.
Atefi et 2017 60, single x TXA 5% 2 % N/A twice daily, N/A Significant decrease in Erythema, skin N/A

cr
al(54) Iranian single hydroqui for 12 MASI scores in both irritation in
none weeks groups. Significantly group B.
higher satisfaction rates in
group A than B.

us
Banihashe 2015 23, single x 5% liposomal 4% N/A twice daily, N/A Significant decrease in Skin irritation in N/A
mi et al(55) Iranian single TA hydroqui for 12 MASI scores in both group B.
none weeks groups.
cream
Boukari et
al(56)
2015 N/A single
single
x sunscreen
formula A
sunscree
n formula
B
N/A an
daily, for 6
months
N/A Significant increase of
MASI scores in group B,
as compared to A.
N/A N/A

Bronzina et 2020 43, single x cosmetic 4% N/A A: daily, B: N/A Statistically significant Mild burning N/A
al(57) multiraci single product hydroqui nightly, for decrease in the mMASI sensation in
M
al combination none 12 weeks scores in both groups. group A. Mild
Significant increase of acneiform
ITA° parameter calculated lesions in group
by spectrophotometer in B.
both groups.
d

Draelos et 2015 59, single x lignin lignin N/A twice daily N/A Significantly improved N/A N/A
al(58) multiraci double peroxidase vs peroxidas for 12 skin texture, roughness,
e

al placebo e vs weeks overall appearance, spot

hydroqui size and MASI scores in
none 4 % comparison A. Significant
pt

cream improvement on both

sides of the face in
comparison B.
ce

Eshghi et 2016 42, single x Triamcinolon Kligman' N/A for 8 weeks N/A A decrease in MASI was N/A N/A
al(59) Iranians single e injections s formula observed in both groups,
(hydroqu with group A having
inone significantly better results
5%, than group B.
Ac

tretinoin
0.1%,
and
dexameth
asone
0.1%)
Farshi et 2018 40, single x cysteamine placebo N/A nightly, for 40 Significantly lower MASI, Erythema, N/A
al(60) Swiss single 5% cream 4 months epiderm IGA scores and patient dryness,
al viewpoints in group A as pruritus, burning
compared to B. sensation,
hyperpigmentati
on in group A.
Fioranelli et 2020 60, single x cream A cream B place twice daily, 60 Significant decrease in Slight pruritus N/A
al(61) multiraci double x + TXA bo 10 weeks epiderm MASI scores in groups A and erythema in
al single al and B compared to group groups A and B.
C. Hypervascular,
inflammatory melasma
 had significantly better
results with cream B
compared to A.
Gheisari et 2020 40, single x 4% 5% N/A nightly for 8 40 Significant decrease in Erythema, N/A
al(62) Iranian single hydroquinone methima weeks epiderm MASI scores in both burning
cream zole al groups, with better results sensation,
cream in group A. Physicians and dryness in both
patients were significantly groups.
more satisfied in group A.
Gong et 2015 226, single x FAHT cream placebo N/A nightly for 8 N/A Signficantly higher Erythema, N/A
al(63) Chinese single (4 % weeks efficacy in group A stabbing pain,
hydroquinone compared to B. peeling,
, 0.05 % telangiectasia,
tretinoin, and burning, red
0.01 % swelling, dry
fluocinolone skin, itching,
acetonide) and darker

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pigmentation in

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group A.
Burning,
tautening, and
pruritus in group

cr
B.
Ibrahim et 2015 100, single x G1: 4% G2: 4% G4: nightly for N/A Significant decrease in Mild pruritus, 6 in
al(64) Egyptian double x hydroquinone hydroqui 4% 12 weeks mMASI in groups I- IV, erythema, and group

us
double x cream none + hydro with the best results in scaling in all I, 4 in
triple x 10% quino descending order: groups. Peeling group
single glycolic ne + IV>III>I>II. effect in groups III.
acid 10% II, IV.
cream/ glyco an
G3: 4% lic
hydroqui acid
none + +
0.01% 0.01
hyaluroni %
M
c acid hyalu
ronic
acid/
G5:
place
d

bo
Janney et 2019 100, single x topical 5% 3% HQ N/A daily, for 12 22 Significant improvement N/A N/A
e

al(74) Indian single TXA solution cream weeks epiderm in MASI scores in both
al 15 groups. Patient satisfaction
pt

dermal score was significantly

63 better in group A.
mixed significantly higher
incidence of adverse
ce

effects in group B.
Khosravan 2017 54, single x petroselium 4% N/A solution for 54 Significant reduction in Erythema and N/A
et al(65) Iranian single crispum hydroqui 6 days a epiderm MASI scores in both pruritus.
solution none week, cream al groups.
cream nightly, for
Ac

8 weeks
Mansouri et 2015 53, single x cysteamine placebo N/A nightly, for 50 Significant decrease in Erythema, N/A
al(66) Iranian single cream 4 months epiderm MASI and Investigator hyperpigmentati
al Global Assessment scores on in group A.
in group A as compared to
B.
Mazurek et 2016 60, double x azelaic acid: azelaic azelai twice daily N/A Significant reduction in N/A N/A
al(67) Polish double x 10% + d- acid: 5% c for 24 pigment level in all
quintuple panthenol: + pyruvic acid: weeks groups, with significantly
10% acid: 5% 20% better results in group A
+ compared to B and C.
mand
elic
acid:
10%
+
 phyti
c
acid:
5% +
4N-
butyl
resorc
inol:
5% +
feruli
c
acid:
2%
Nofal et 2019 42, single x silymarin silymarin hydro nightly for 3 34 Significantly reduced Erythema, N/A
al(68) Egyptian single x 0.7% cream 1.4% quino months epiderm MASI scores in all groups. burning
single cream ne al 3 sensation,
4% dermal scaling in group

t
cream 5 mixed C. None in

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groups A or B.
Pratchyapur 2016 38, Thai single x DAB 4% HQ 4% HQ for 12 15 Significant improvement Erythema, N/A
it et al(69) single x serum cream 2% weeks epiderm in MASI and MI scores in pruritus, skin
single cream al 25 all groups. exfoliation,

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mixed dryness and
hyperpigmentati
on in all groups.

us
Shamsi et 2016 44, single x 4% licorice placebo N/A for 12 N/A Significant reduction in N/A N/A
al(70) Iranian single extract cream weeks mMASI scores in both
groups.
Taghavi et 2019 20, single x topical conventi N/A daily, for 3 N/A Significant reduction in N/A N/A
al(71) Iranian single liposomal onal months
an MASI scores in both
hydroquinone hydroqui groups.
4% none 4%
Vachiramo 2020 21, Thai single x HIFU 2% N/A HIFU 21 Significant reduction of Burning no
n et al(72) single hydroqui monthly, 3 mixed relative lightness index sensation, recurre
none sessions in and MASI in both groups, scaling, nces
M
cream total, cream but with no significant erythema in both after 3
nightly, for differences between the groups. month
20 weeks groups. s
Zhang et 2019 90, single x herbal cream arbutin place twice daily N/A Significant decrease in Mild erythema N/A
d

al(73) Chinese single x cream bo for 12 MASI scores in groups A and pruritus in
single weeks and B, with better results group B.
in group A. Significantly
e

reduced EI and density of

inflammatory cells in
pt

group A.
ce
Ac
 Table 6. Laser and light treatments.
Referenc Year Patients: Comparis Treatment Treatment Treatment Treat. Melasm Efficacy/ Outcomes Tolerability/ Recurrence
e nr, on A B C Duration a Type Adverse rates
ethnicity Events
Abdel- 2019 22, single x FEYL on FEYL + N/A laser 22 Significant decrease in: N/A N/A
Raouf Egyptian double the right topical biweekly, epider MASI scores, basal
Mohame side of the mometason 6 sessions, mal hyperpigmentation on HE
d et face e on the left cream staining, MPSA/ESA
al(81) side of the nightly percentage on MF
face staining, MART‐ 1‐
positive‐ stained cells in
both groups. MASI scores
were significantly lower
in group B than A.
Alavi et 2017 41, double x QSNYL- QSNYL + N/A laser N/A Significantly lighter skin None reported. N/A
al(82) Iranian triple FEYL + topical biweekly, colour and decrease in

t
topical Klingam 4 sessions, melanin content in both

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Klingam formula cream groups with significantly
formula cream nightly better results in group A
cream than B.

cr
Badawi 2018 30, single x FEYL + 4% HQ N/A laser 15 Significantly higher Transient and 2 patients in
et al(83) French double 4% HQ cream biweekly, epider decrease in the degree of mild erythema, both groups.
cream 6 sessions, mal 6 pigmentation on the 4- burning
cream dermal point scale and MASI sensation, and

us
twice 9 scores in group A than B. itching were
daily mixed reported in
both groups.
Superficial

Bae et 2015 20, single x 10 J/cm2 13 J/cm2 N/A

an
weekly, 6 N/A Significant decrease in
crusting
group A.
Transient and
in

N/A
al(75) Korean single fluence IPL fluence IPL sessions MASI scores and melanin mild erythema,
index in both groups, burning
M
with no significant sensation in
differences between the both groups.
groups.
Barolet et 2018 7, single x microderm microderm N/A weekly, 7 Statistically significant N/A N/A
al(76) Canadian double abrasion + abrasion for 8 dermal pigment reduction in
d

photobiom weeks group A than B.

odulation Significant reduction in
e

LED MASI score in group A at

device week 12.
Chalermc 2018 30, Thai single x fractional 4% HQ N/A laser N/A Significantly decreased Transient mild N/A
pt

hai et double picosecond cream monthly, mMASI scores at the 12- erythema, mild
al(84) 1,064 nm cream week visit in group A skin
laser + 4% daily than B. desquamation,
ce

HQ cream mild burning

sensation in
group A.
Choi et 2015 360, single x dual QS toning= N/A weekly, N/A Significant median Mottled N/A
al(86) Korean double toning: LFQSNYL 10 decrease of mMASI in hypopigmentat
Ac

LFQSNYL sessions group A as compared to ion and

+ LPNYL B. Significantly lower rebound
1064 nm adverse events in group A hyperpigmenta
than B. tion in both
groups.
Choi et 2017 74, single x picosecond 2% HQ N/A laser N/A Significant improvement Mild dermatitis 30/39 in
al.(85) Korean double laser with cream weekly, 5 in RL*I, significant in both groups. group A and
dual- sessions, decrease of mMASI Mild pain 27/39
wavelength cream scores, better subjective during laser (69.23%) in
s (1 064 daily for 7 satisfaction rates in group treatment and group B at
and 595 weeks A than B. mild erythema week 18.
nm) + 2 % in group A.
HQ cream
Chung et 2016 13, single x IPL + IPL N/A monthly, 4 N/A Significant decrease in None reported. N/A
al(77) Korean double topical sessions MI and mMASI in group
TXA 2% A.
Garg et 2019 60, single x SSR 540 PQSNYL APEYL at 3 weeks 22 Significantly decreased group A: N/A
al(99) Indian single x nm 1064 nm 2940 nm interval, 5 epider mMASI scores in all 3 transient
single sessions mal 12 groups, with better results dryness. Group
dermal in group C. B, C: post-
26 inflammatory
mixed hyperpigmenta
tion, acne
brakouts.
Group C:
herpes labialis.
Guo et 2019 12, single x QSNYL QSNYL N/A at 4 weeks N/A Significant decrease in Significantly 3 patients at
al(87) Chinese single 1064-nm 1064-nm interval, 5 mean mMASI scores at lower pain and week 12.
Q-PTP single- sessions week 4 and 12 in both erythema in
mode on pulse mode groups. group A
the right on the left compared to B.
side side Urticaria and
petechiae in

t
group B.

ip
Hammam 2015 16, single x copper Kligman N/A laser at 2- N/A Significantly better N/A 100%
i et al(88) French double bromide formula 3 weeks decrease in MASI scores recurrence
laser + triple interval, 4 in group B than A at the rates at 6
Kligman combinatio sessions, end of the treatment. months

cr
formula n cream cream follow-up.
triple daily for 4
combinatio months

us
n cream
Hassan et 2018 28, single x PDL on the IPL on the N/A at 3-5 20 Significant reduction in Mild erythema, N/A
al(78) Egyptian single right left weeks epider hemifacial mMASI scores edema and
hemiface hemiface interval mal 8 in both groups with no pain during
an mixed significant difference and after
between them. Better treatment,
patient tolerance and microcrust
satisfaction in group B formation,
than A. post-
inflammatory
M
hyperpigmenta
tion in both
groups.
Kong et 2017 17, single x PDL + LFQSNYL N/A QSNY N/A Significant decrease in Mild burning 1 patient at
al(89) Korean double LFQSNYL weekly, 9 MASI scores in both sensation and week 16 in
d

sessions, groups. erythema in group A.

PDL at 4 both groups.
e

weeks Focal purpura,

interval, 3 postinflammat
pt

sessions ory
hyperpigmenta
tion in group
A.
ce

Laothaw 2018 25, Thai single x 1064-nm 1064-nm N/A laser at 4 14 Significant decrease in Mild erythema Rebound at
orn et double QSNYL + QSNYL weeks mixed MASI scores in group A. and burning week 8
al(90) 3% TXA interval, 2 11 Significant decrease in sensations in shown by
cream sessions, epider mean MI in group A at both groups. increased
cream mal week 4. MI starting
Ac

twice after week 4

daily for 8 in both
weeks groups.
Lee et 2015 8, single x QSNYL QSNYL N/A monthly, 4 N/A Significant improvement None reported. No rebound
al(91) Taiwanes double 1,064 nm 1,064 nm + sessions in group B compared to A at 3 month
e ultrasonic in both patient and follow-up.
application physician assessment.
of topical
vitamin C
Lee et 2018 12, single x picosecond QSNYL N/A monthly, 4 dermal, Significant improvement Temporary None
al(92) Taiwanes single 755 nm 1064 nm sessions mixed in group A compared to erythema. reported.
e alexandrite B, according to both
laser physician and patient
assessment.
Nourmoh 2019 37, single x HQ 4% HQ 4% N/A laser at 3 N/A Significant reduction in Erythema and N/A
ammadi Iranian double cream + cream week darkness at week 3 in burning
et al(93) fractional interval, 3 group A and at week 6 in sensation.
CO2 laser sessions, group B. Reduction in
cream homogeneity became
significant at week 6 in
both groups.
Shakeeb 2018 96, single x triple IPL IPL + cream 96 Significantly better MASI N/A N/A
et al(79) Pakistane single x combinatio triple nightly, epider score reduction in group
se double n cream combinati IPL mal C than A or B.
on cream biweekly,
for 2
months
Tawfic S 2019 28, single x fractional fractional N/A every 4-6 N/A Significant reduction in Mild burning N/A
et al(94) Egyptian double ablative ablative weeks, 5 mean MASI, MI and EI sensation in
CO2 laser CO2 laser sessions scores in group A. both groups.
+ Significant reduction in Post-
microneedl mean MASI score in inflammatory
ing with group B. hyperpigmenta

t
TXA 10% tion in group

ip
B.
Vachiram 2015 18, Thai single x LFQSNYL LFQSNYL N/A LFQS 18 Significant improvement Slight 6 in group A
on et double + IPL weekly, 5 mixed of mean relative lightness erythema, mild and 2 in
al(51) sessions, index and mMASI in both stinging in group B at

cr
IPL groups. both groups. In week 16.
biweekly, group A:
3 sessions microcrust,

us
guttate
hypomelanosis.
Vanaman 2018 40, single x nonablative nonablative N/A biweekly, N/A Significant improvement Mild-to- N/A
et al(95) American double , fractional, , fractional, 4 sessions in MoPASI, blinded moderate
1,927-nm 1927nm an investigator–assessed erythema, mild
diode laser diode laser hyperpigmentation and peeling.
+ topical photodamage in both
2% HQ groups. Investigator-rated
cream Global Aesthetic
Improvement Scale
M
scores were significantly
better in group B.
Satisfaction was higher in
group A.
d

Wang et 2020 26, single x Picosecond Picosecond triple laser at 4 N/A Significant decrease in transient N/A
al(96) Taiwanes single x alexandrite alexandrite combinati weeks MASI scores, VISIA
e single laser laser on cream interval, 3 analysis in all three
e

treatment treatment sessions groups.

using a using a (A), 5
pt

diffractive diffractive sessions

lens array lens array (B), cream
daily for 8
weeks
ce

Wanitpha 2020 46, Thai single x fractional fractional N/A weekly, 4 10 Significant improvement Mild N/A
kdeedech double 1927-nm 1927-nm sessions epider in MI, mMASI and hyperpigmenta
a et thulium thulium mal 3 patient satisfaction scores tion, slight
al(97) laser laser + dermal in both groups. pain.
Ac

TXA 1.2% 33
mixed
Yun et 2015 26, Asian single x fractionate convention N/A fractionate N/A In group A, the modified Marked Rebound in
al(80) single d IPL al IPL d IPL MASI score decreased darkening of week 4 in
weekly, 6 continuously, while in melasma in group B.
sessions, group B the MASI score one patient in
conventio rebounded during the group B after
nal IPL treatment course. the third
biweekly, treatment.
3 sessions
Figure legends

Figure 1. Literature search and article selection.

t
ip
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an
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e d
pt
ce
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