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107]

Original article 89

Topical tranexamic acid with microneedling versus

microneedling alone in treatment of melasma: clinical,
histopathologic, and immunohistochemical study
Fatma Y. Saleha, Eman S. Abdel-Azima, Maha H. Ragaiea, Mary G. Guendyb

Background
a
Department of Dermatology and Venereology,
Faculty of Medicine, Minia University, Al-Minya, Melasma is an acquired disorder of symmetrical hypermelanosis that involves sun-
Egypt, bDepartment of Dermatology, Samalut
Genera Hospital, Al-Minya, Egypt exposed areas of the skin. Although multiple therapeutic modalities have previously
been tried, successful, truly effective treatment options for this condition have been
Correspondence to Eman Saad Abdel-Azim,
few and quite elusive.
MD, Faculty of Medicine, Minia University,
Al-Minya, 61511, Egypt. Objectives
Tel (office): +20862339894; To compare the therapeutic efficacy of topical tranexamic acid (TXA) with
fax number: +20862342503; microneedling versus microneedling alone in the treatment of melasma and to
e-mail: [email protected] evaluate the changes that occur clinically, histologically, and
Received 24 December 2018 immunohistochemically.
Accepted 16 June 2019 Patients and methods
Journal of the Egyptian Women's This study was conducted on 42 patients with melasma, randomly divided into two
Dermatologic Society 2019, 16:89–96 groups. In group I, each patient was subjected to a series of six sessions of skin
microneedling and TXA application, whereas in group II, six sessions of
microneedling alone were performed, with 2-week interval.
Results
Clinically, the mean melasma area and severity index (MASI) score was
significantly decreased in both groups with statistically significant higher
reduction scores in group I compared with group II. Histopathologically,
epidermal hyperpigmentation and dermal melanophages were significantly
reduced after treatment with more obvious reduction in group I. The number of
melanoma antigen recognized by T cells-1-positive cells showed significant
reduction in both groups; this reduction was statistically higher in group I than
group II.
Conclusions
Although microneedling alone produced significant lightening effect, topical TXA
combined with microneedling achieved more satisfactory results.

Keywords:
immunohistochemical;, melasma, microneedling, tranexamic acid
J Egypt Women’s Dermatol Soc 16:89–96
© 2019 Egyptian Women’s Dermatologic Society | Published by Wolters Kluwer - Medknow
1687-1537

effective treatment options for this condition have

Introduction
been few and difficult to achieve. Such treatment
Melasma is an acquired disorder of symmetrical
approaches include topical medications such as
hyperpigmentation appearing as light brown to dark,
hydroquinone and related drugs, azelaic acid and
muddy brown macules and patches on the face,
corticosteroids; procedural treatments like chemical
especially the forehead, malar areas, and chin [1]. It
peels, microdermabrasion, and LASER; and light-
occurs more commonly in women during their
based devices. All of them target to decrease
reproductive years particularly Fitzpatrick skin
melanin production over the local area either directly
phototypes III and IV [2]. It shows a particular
or indirectly [5].
prominence among Hispanics and Asians [3].
Tranexamic acid (trans-4-aminomethyl
The exact pathogenesis of melasma is not yet clearly
cyclohexanecarboxylic acid) (TXA) is a synthetic
defined; however, some etiological factors have been
lysine derivative that blocks the lysine site on
identified, including genetic background, pregnancy,
plasminogen and inhibits fibrinolysis. Topical TXA
hormonal therapies, and sun exposure. Melasma has a
significant psychological effect on the affected patients
because of its disfiguring nature [4]. This is an open access journal, and articles are distributed under the terms
of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0
License, which allows others to remix, tweak, and build upon the work
Multiple therapeutic modalities have previously been non-commercially, as long as appropriate credit is given and the new
tried and touted as being successful, but the truly creations are licensed under the identical terms.

© 2019 Journal of the Egyptian Women's Dermatologic Society | Published by Wolters Kluwer - Medknow DOI: 10.4103/JEWD.JEWD_25_19
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90 Journal of the Egyptian Women's Dermatologic Society, Vol. 16 No. 2, May-August 2019

inhibits UV-induced plasmin activity in keratinocytes diseases and those using treatment for melasma
by preventing the binding of plasminogen to the (bleaching agents, laser, dermabrasion, chemical
keratinocytes, which ultimately results in decreased peels), anticoagulant therapy, chemotherapy,
free arachidonic acid and a diminished ability to radiotherapy, all types of hormonal contraception or
produce prostaglandins, which in turn decrease systemic steroids within 6 months before starting the
melanocyte tyrosinase activity. TXA is one of the study were also excluded.
treatment strategies for melasma that has been a
focus of attention in recent years [6]. Repetitive UV The selected patients were divided randomly according
irradiation increases the number of mast cells and mast to the random number allocation method into two
cell tryptase which degrades type IV collagen; thus, groups (21 patients each). All patients were subjected
increased numbers of mast cells and tryptase might be to full history taking and dermatological examination.
the cause of weak basement membranes observed in Wood’s light was used to determine the pattern of
melasma lesions. Mast cells also play an important role melasma (epidermal, dermal, or mixed).
in the development of solar elastosis, one of the Photographing of the face was done at baseline,
histological features of melasma [7]. Na et al. [8] in before every session and 2 weeks after the last session.
their study elucidated the effects of oral and topical
TXA on melasma and reported significant reduction of Treatment protocol and postoperative care
epidermal pigmentation, vessel numbers, and mast cell Topical anesthetic cream of 2.5% lidocaine/prilocaine
counts. (Emla cream; AstraZeneca AB, Södertälje, Sweden)
was applied to the treated areas under occlusion 1 h
Transdermal delivery has become a popular route of before microneedling. Six treatment sessions were done
drug delivery in recent years. Microneedle technology in both groups (I and II) with 2-week interval. In each
involves the creation of micron-sized channels in the session, microneedling was performed in both groups,
skin, which can allow the delivery of hydrophilic whereas application of TXA was added to
molecules including large proteins that do not pass microneedling in group I.
the skin barrier passively [9].
Skin microneedling was performed using dermapen
On reviewing the literature, few controlled studies have (electric pen, DPO5; Kimlida Electronic Technology
focused on therapeutic effects of TXA as a topical drug Co., Guangzhou, China) that consists of a hand piece,
in treating melasma. The present study aimed to assess recharging battery and needle tips (12 needles) with
the beneficial therapeutic effects of using topically adjustable needle length of 1.5 mm. The microneedling
applied TXA after microneedling versus was carried out in four different directions
microneedling alone with evaluation of the changes (horizontally, vertically, and diagonally right and
that may occur clinically, histologically, and left) for about four to five times. The end point was
immunohistochemically in patients with melasma. the appearance of erythema with pinpoint bleeding
points.

Patients and methods In group I, TXA solution (Kapron ampoules 100 mg/
Patients 1 ml; Sunny Pharmaceutical, Amoun, Egypt) was
A prospective, randomized study was conducted on 42 repeatedly applied to the treated areas until the
female patients with melasma. They were selected from entire treatment was finished. The amount of TXA
the Dermatology out-patient clinic of Minia University used ranged from 1 to 3 ml according to the surface area
Hospital, Al-Minya, Egypt. An informed written affected of the face, considering 1 ml of TXA for
consent was obtained from each patient to be forehead area, 1 ml for right malar, 1 ml for left
enrolled in the study and to be photographed after malar area, and 1/2 ml for chin area.
full explanation of the procedure. The study was
approved by the Research Ethics Committee of Fusidic acid 2 mg (Fucidin ointment; LEO Mina
Faculty of Medicine, Minia University. Pharm, El-Bardissi St., Heliopolis, Cairo, Egypt)
was applied to guard against secondary bacterial
All types of melasma (epidermal, dermal, and mixed) infection for 24 h. Sunscreen with sun protection
were included. Patients were excluded if they had a factor of 50 or more was used 2 weeks before
history of recurrent herpes infection, dermatitis on the treatment and throughout the study. Other
face or keloidal tendency. Pregnant women or patients concomitant methods of melasma treatment were
with bleeding disorders or immuno-compromising not allowed throughout the treatment period.
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Melasma treatment: Topical tranexamic acid Saleh et al 91

Clinical evaluation independent dermatopathologists through counting

Blinded clinical assessment of the changes in melasma the number of positive (active) melanocytes in the
area and severity index (MASI) score was done and epidermis [11] and dermis (melanophages) [12] in
rated by two blinded independent dermatologists 10 high-power fields with measurement of the mean
(photographic assessment) to grade the severity of value for each biopsy [11,12].
melasma for both groups at baseline and 2 weeks
after last session. Then, the reduction percentage Statistical analysis
[10] was calculated with grading as follows: mild Data were statistically analyzed using SPSS for
(0–25%), moderate (26–50%), good (51–75%), and Windows (version 16.0.1; SPSS Inc., Chicago,
excellent (76–100%). Adverse effects, including Illinois, USA). Descriptive statistics were done for
erythema and pigmentation abnormalities, were parametric quantitative data by mean±SD, whereas
assessed every session and at 2 weeks after treatment. number and percentage were used for qualitative
data. For nonparametric data, Wilcoxon signed-rank
Skin biopsy test was used to compare between before and after data
Two skin biopsies (2 mm in diameter) were obtained within the same group, whereas Mann–Whitney test
from the melasma area in each group. The first one was was used to compare between variables of two different
taken at baseline, whereas the second was taken 2 weeks groups. χ 2 test was used to compare between qualitative
after last session from the nearest point to the first one. data. Significance was expressed in terms of P value,
These sections were stained by hematoxylin and eosin which was considered significant when it was less than
(H&E) and Fontana Masson (MF). The evaluation of or equal to 0.05.
melanin in MF-stained sections was done subjectively.

Immunohistochemical staining was performed using Results

monoclonal mouse anti-melanoma antigen recognized The study included 42 females with melasma; the
by T cells-1 (MART-1) (Melan A, Clone A 103, demographic data of patients in two groups were
monoclonal antibody, diluted 1 : 50; Dako, Santa Clara, comparable with no statistical significant difference
CA, USA). Light microscope [Accu-Scope # 3025 five between two groups regarding age, Fitzpatrick skin
headed (A3025-5); Olympus, Tokyo, Japan] with a built- type, duration of disease, family history, and type and
in camera (digital camera E-330 SLR; Olympus) was used pattern of melasma (Table 1).
to examine and photograph the sections.
Clinical results (photographic assessment)
Interpretation of immunohistochemical marker was Two weeks after the last session, MASI score was
carried out quantitatively by two blinded significantly decreased in both groups when

Table 1 Distribution of demographic data of the studied groups

Demographic data TXA group (N=21) Control group (N=21) P value
Age
Range 25–54 24–56 0.093
Mean±SD 39.28±7.16 40.47±6.14
Skin type [n (%)]
Type III 10 (47.6) 12(57.1) 0.072
Type IV 11(52.4) 9 (42.9)
Disease duration
Range 6 months–7 years 8 months–6 years 0.083
Mean±SD 10.62±24.22 10.22±23.25
Family history [n (%)]
Negative 12 (57.1) 10 (47.6) 0.065
Positive 9 (42.9) 11 (52.4)
Clinical type [n (%)]
Centrofacial 4 (19.1) 5 (23.8) 0.075
Malar 13 (61.8) 14 (66.6)
Mandibular 4 (19.1) 2 (9.5)
Pattern of melisma [n (%)]
Epidermal 13 (61.9) 15 (71.4) 0.094
Mixed 8 (38.1) 6 (28.5)
TXA, tranexamic acid. Mann–Whitney test. χ 2 test.
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92 Journal of the Egyptian Women's Dermatologic Society, Vol. 16 No. 2, May-August 2019

compared with baseline. Although there was no whereas considered as ‘moderate’ in 28.6% and ‘mild’ in
statistical significant difference in MASI score 71.4% in group II (Figs 1, 2). Accordingly, the clinical
between the two groups before treatment (P=0.115), improvement in TXA group was better than in control
the reduction in MASI score was statistically higher in group, and the difference was statistically significant
group I when compared with group II (P=0.001). (P=0.001). No significant adverse effects were reported
Accordingly, the mean reduction percentage of apart from slight transient erythema and burning
MASI score in group I was higher than that in sensation, which were reported by some patients few
group II, which was 62.1 and 22.5%, respectively, hours after the sessions.
with high significant difference between both groups
(P=0.001) (Table 2). The clinical outcome was Histopathological evaluation
considered ‘excellent’ in 23.8%, ‘very good’ in 23.8%, There was no statistically significant difference
‘moderate’ in 42.9% and ‘mild’ in 9.5% in group I, between group I and group II regarding melasma

Table 2 Comparison of MASI score and number of melanoma antigen recognized by T cells-1-positive cells before and after
treatment with their reduction percentage in both groups
TXA group Control group
Before After P Before After P
MASI
Range 6.4–25.2 1–18 0.001* 6.4–22.5 6–21 0.001*
Mean±SD 14.9±4.2 6.1±4.9 15.9±4.3 12.3±4.6
P1 0.115
P2 0.001*
Reduction percentage
Range 20–92 2.6–49.4
Mean±SD 62.1±21.4 22.5±15.8
P3 0.001*
MART-1-positive cell number
Epidermis
Range 9–40 3–24 0.001* 23–35 8–28 0.001*
Mean±SD 22.6±7.2 8.6±5.3 28.5±4.1 18.7±6.8
P1 0.010*
P2 0.001*
Reduction percentage
Range 7.7–88 11.1–69.2
Mean±SD 61.1±19.5 37.8±15.5
P3 0.001*
Dermis
Range 1–13 1–8 0.001* 0–13 0–10 0.007*
Mean±SD 5.5±3.6 2.4±2.3 9.5±2.7 6.9±2.8
P1 0.007*
P2 0.001*
Reduction percentage
Range 0–85.7 16.6–62.5
Mean±SD 54.7±24.1 29.3±14.2
P3 0.001*
Total
Range 10–53 4–32 0.001* 30–47 11–38 0.001*
Mean±SD 28.1±10.3 11.1±7.4 32.1±5.9 20.5±9.5
P1 0.083
P2 0.001*
Reduction percentage
Range 17.6–87.5 15–63.33
Mean±SD 60.8±17.8 37.5±14.8
P3 0.001*
MART-1, melanoma antigen recognized by T cells-1; MASI, melasma area and severity index; TXA, tranexamic acid. P is the P value
between before treatment and after treatment in both groups, P1 is the P value between TXA and control groups before treatment, P2 is
the P value between TXA and control groups after treatment, and P3 is the P value between TXA and control groups of the reduction
percentage. Mann–Whitney test. Wilcoxon signed-rank test. *P value < 0.05 is considered statistically significant.
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Melasma treatment: Topical tranexamic acid Saleh et al 93

histologic pattern (P=0.753). Subjective evaluation of of MART-1-positive cells was significantly higher in
H&E-stained and MF-stained sections obtained 2 group I (60.8%) than that of group II (37.5%)
weeks after treatment from both groups revealed (P=0.001) (Table 2).
that there was evident reduction in the density of
epidermal melanin (in the epidermal type) (Fig. 1f,
h) and dermal melanophages (in mixed type) (Fig. 2f, Discussion
h). The reduction in melanin density was more obvious The treatment of melasma has always been a challenge
in group I than group II sections when compared with for the dermatologists. Various treatment modalities
pretreatment sections. have been tried. All of them aim at reducing melanin
synthesis; however, none of them is very effective in
Immunohistochemical results inducing long-term remission [13]. TXA is one of the
The number of epidermal, dermal and total MART-1- treatment strategies for melasma that has been a focus
positive cells was significantly decreased after treatment of attention in recent years. Oral administration of
in both groups (Fig. 1j, l and Fig. 2j, l). Although there TXA was reported in several studies to be effective for
was no significant difference between the two groups melasma [14,15].
regarding the total number of MART-1-positive cells
before treatment (P=0.083), there was a highly Potential mechanisms for its effectiveness include
significant reduction in the total number in group I inhibition of melanocyte proliferation [16],
compared with group II after treatment (P=0.001). inhibition of melanin synthesis in melanocytes [17],
Consequently, the reduction percentage of the number accelerated recovery of impaired skin barrier function

Figure 1

Female patients with epidermal melasma before treatment (a, c); after treatment with topical tranexamic acid with microneedling, showing
excellent improvement (b); and after treatment with microneedling only, showing moderate improvement (d). Skin biopsies from epidermal
melasma lesions, showing increased density of epidermal melanin (e, g) and MART-1-positive stained cells (i, k) in the epidermis. After both
treatment modalities, biopsies demonstrate decrease in both melanin density (f, h), and number of MART-1-positive stained cells in epidermis (j,
l), which is more evident in cases treated by topical tranexamic acid with microneedling (e–f, MF, ×200; i–l, MART-1, ×200). MART-1, melanoma
antigen recognized by T cells-1; MF, Fontana Masson.
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94 Journal of the Egyptian Women's Dermatologic Society, Vol. 16 No. 2, May-August 2019

Figure 2

Female patients with mixed melasma before treatment (a, c); after treatment with topical tranexamic acid with microneedling showing, excellent
improvement (b); and after treatment with microneedling only showing, mild improvement (d). Skin biopsies from mixed melasma showing,
increased density of melanin (e, g) and MART-1-positive stained cells (i, k) in epidermis and dermis. After treatment, biopsies demonstrate
significant decrease in both melanin (f, h) and MART-1-positive stained cells in epidermis and dermis (j, l) (e–f, MF, ×200; i–l, MART-1, ×400).
MART-1, melanoma antigen recognized by T cells-1; MF, Fontana Masson.

[18], reduced number of blood vessels in the dermis, accompanied by the risk of postinflammatory
and reduced number of mast cells in the dermis [8]. hyperpigmentation [21]. Lima [22] concluded that
The results of topical use of TXA for excessive microneedling alone, without the addition of any
pigmentation have been conflicting. Topical 3% active medication, can cause lightening of skin stains
TXA solution twice per day for 12 weeks was in patients with recalcitrant melasma. The long-term
likewise found to be as effective as a topical solution improvement of recalcitrant melasma after microneedle
of 3% hydroquinone plus 0.01% dexamethasone [19]. treatment has been reported in case series studies;
however, the exact mechanism that promotes skin
Strategies to enhance transdermal delivery of TXA clearance is unknown [22]. In the study of Lima
have been developed. Fractional carbon dioxide laser et al. [23], in histological findings, it was considered
was reported to increase TXA absorption in porcine that microneedle therapy promotes the proliferation of
skin [20], but when applied to humans, the risk of fibroblasts and superior dermal neocollagenesis,
postinflammatory hyperpigmentation caused by the decreases the contact of the melanocytes with
fractional carbon dioxide laser itself should be melanogenic stimuli and improves the protection
considered. Microneedling can provide a minimally against ultraviolet radiation owing to epidermal
invasive means of painless delivery of therapeutic thickening.
molecules through the skin barrier with precision
and convenience. Physically opening microtunnels In this study, we aimed to evaluate and compare the
for drug delivery with microneedling involves a effectiveness of topically applied TXA after
different mechanism of action than lasers and is not microneedling versus microneedling alone in patients
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Melasma treatment: Topical tranexamic acid Saleh et al 95

with melasma clinically, histopathologically and MART-1 is considered the most important
immunohistochemically. In the present study, all melanocytic marker [29]. Moreover, MART-1
patients in two groups were age matched females. stains macrophages in the dermis [30] as they may
The age range was quiet similar to that in studies of have the ability to engulf melanosomes. Kang et al.
Xu et al. [21], Kim et al. [24] and Budamakuntla et al. [28] observed increased intensity for NKI-beteb and
[25]. In the current study, a positive family history was Mel-5 stains with increased number of positive
observed in a percentage that was in agreement with epidermal melanocytes in melasma lesions
that found by Achar and Rathi [2]. Our patients were compared with control skin. In our study, the
of Fitzpatrick skin types similar to studies of Xu et al. pretreated biopsy specimens, stained by MF and
[21] and Kim et al. [24]. The most common MART-1 stains, showed the previous findings of
distribution of lesions was the malar pattern, and increased melanin and staining reaction of MART-
this was in agreement with the study of 1-positive cells in epidermis (melanocytes) and
Yalamanchili et al. [26]. dermis (melanophages) in both treatment groups.
Although, we observed significant decrease in the
Subjective evaluation of the patients showed a number of MART-1-positive cells after treatment in
significant decrease in MASI score 2 weeks after both groups, this reduction was higher in TXA
the end of treatment in both groups when compared +microneedling group than microneedling alone
with baseline. The scores showed better group, and the difference was statistically
improvement in patients treated with TXA significant (P<0.001). On reviewing the literature,
+microneedling than with microneedling alone, there were no studies that had evaluated melanocytes
and the difference was statistically significant and melanophages objectively using MART-1 stain
(P<0.001). This can be attributed to the before and after treatment with microneedling alone
synergistic effects of both topically applied TXA, and/or TXA+microneedling.
with its effectiveness being confirmed in many
clinical trials [21,27], together with the There were no significant adverse effects reported in
enhancement of its delivery into the skin by the current study. Slight transient erythema and
microneedling, which was proved by the study of burning sensation, which were well tolerated, were
Lima [22], to cause lightening of skin stains without reported by some patients few hours after sessions,
the addition of any active medication in patients suggesting a very good safety profile of the procedure.
with recalcitrant melasma. Our higher improvement Our finding was in agreement with the study of Perper
scores in patients treated with TXA+microneedling et al. [31].
were in agreement with that obtained by Xu et al.
[21] and Budamakuntla et al. [25] On the contrary, One limitation of our study was the subjective
our scores obtained in patients treated by evaluation of H&E and MF sections and
microneedling alone were not consistent with that consequently, we could not compare the changes in
of Lima, 2015, who observed scores from good to melanin density in epidermis and dermis in both
very good on a scale of very good, good, reasonable groups statistically. Other limitations of this study
and poor. were the lack of correlation of results with the type
of melisma and the inadequate follow-up period after
In melasma, increased melanin is found in the last session, which is too short to confirm the efficacy of
epidermis, dermis or, most commonly, both treatment and to evaluate recurrence rates.
locations. Dermal melanin is found in the superficial
and mid-dermis either free or within melanophages In conclusion, although microneedling alone produced
[28]. In the present study, subjective evaluation of significant lightening effect, topical TXA combined
melanin pigment in the epidermis, dermis, and both with microneedling achieved more satisfactory results
showed significant decrease in the epidermal suggesting the effectiveness of topical TXA which was
hyperpigmentation and dermal melanophages. This significantly enhanced by microneedling. Perhaps a
reduction in pigment density was more impressive in long-term follow-up is required to confirm the
sections of TXA+microneedling-treated patients. This efficacy results of combined therapy in treating
was similar to the observations of Kim et al. [24]. melasma as it is cheap, easily affordable and safe,
However, their evaluation was objective with no significant adverse effects.
measurement for pigment reduction which was not
the case in our study which lack this objective analysis Financial support and sponsorship
for pigment reduction. Nil.
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96 Journal of the Egyptian Women's Dermatologic Society, Vol. 16 No. 2, May-August 2019

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keratinocyte-conditioned medium. J Health Sci 2007; 53:389–396.
17 Kim MS, Bang SH, Kim JH, Shin HJ, Choi JH, Chang SE. Tranexamic acid
diminishes laser-induced melanogenesis. Ann Dermatol 2015;
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