Study evaluating the efficacy of topical and injected tranexamic acid in treatment of melasma

Abstract

Introduction: Melasma is an acquired hypermelanosis of multifactorial etiology and difficult to treat. Tranexamic acid (TA) has been studied as an alternative therapy. Objective: To evaluate the efficacy and safety of TA in treatment of melasma, comparing the use of localized microinjection versus topical therapy. Material and Method: Eighteen women with melasma were selected and treated for 12 weeks. Group A: at-home topical application of TA 3% twice a day. Group B: intradermal injections of TA (4 mg/ml) weekly. Before and after treatment, the groups were compared according to the following parameters: photographic evolution, MASI evolution, self-assessment and colorimetry. Results: Seventeen patients completed the study. In group A, photographic evaluation showed improvement in 12,5%, worsening in 50%, and 37.5% had no change. In group B, there was improvement in 66.7% and 22.2% had no change. For the MASI, there was significant improvement (p = 0.0026), with no difference between treatments (p = 0.6512). In group A selfassessment, 37.5% of the patients rated as good and 50% as imperceptible. In group B, 66.7% rated as good and 33.3% as imperceptible. Colorimetric evaluation showed significant improvement on both treatments (p = 0.0008). Conclusion: Although the subjective clinical evaluation has demonstrated the superiority of injected treatment, in objective evaluation, both treatments were significantly effective, presenting TA as a promising new therapeutic option for melasma.

Full text

174 Surgical & Cosmetic Dermatology
Authors:
Denise Steiner1
Camila Feola2
Nediana Bialeski3
Fernanda Ayres de Morais e Silva4
André César Pessanha Antiori5
Flavia Alvim Sant’Anna Addor6
Bruno Brandão Folino7
1PhD, Chief of the Medical Residency
Service at UMC
2MD, 3rd year residency
3MD, 3rd year residency
4MD, 2nd year residency
5MD, 2nd year residency
6Master, Associate Professor of the
Department of Dermatology – UNISA
7Pharmacist
Correspondence to:
Denise Steiner
Av. Arnolfo de Azevedo, 84 –
Pacaembu – São Paulo, SP
CEP: 01236-030
Tel/Fax: +55 (11) 3825-9955/3825-
9968
E-mail: steiner@uol.com.br
Submitted on: 10/10/2009
Approved on: 11/11/2009
We declare no con icts of interest.
Original
Article
Tranexamic acid in treatment of melasma
Study evaluating the e cacy of
topical and injected tranexamic acid in
treatment of melasma
ABSTRACT
Introduction: Melasma is an acquired hypermelanosis of multifactorial etiology. It is a
great therapeutic chalenge. Tranexamic acid (TA) has been reported as an alternative therapy.
Objective: To evaluate the effi cacy and safety of TA in treatment of melasma, comparing
the use of localized microinjection versus topical therapy. Method: Eighteen women with
melasma were selected and divided into 2 groups. Group A: At-home topical application of TA
3% twice a day. Group B: 12 applications of intradermal injections of TA (4 mg/ml) weekly.
Before and after treatment, the groups were compared according to the following parameters:
photographic evolution, Melasma Area and Severity Index (MASI) evolution, self-assessment
and colorimetry. Results: Seventeen patients completed the study. In group A, photographic
evaluation showed improvement in 12,5%, worsening in 50%, and 37.5% had no change. In
group B, there was improvement in 66.7% and 22.2% had no change. For the MASI, there was
signifi cant improvement (p = 0.0026), with no difference between treatments (p = 0.6512). In
group A self-assessment, 37.5% of the patients rated as good and 50% as imperceptible. In group
B, 66.7% rated as good and 33.3% as imperceptible. Colorimetric evaluation showed signi cant
improvement on both treatments (p = 0.0008). Conclusion: Although the subjective clinical
evaluation has demonstrated the superiority of injected treatment, in objective evaluation, both
treatments were signifi cantly effective, presenting TA as a promising new therapeutic option for
melasma.
Keywords: tranexamic acid, melasma, therapy.
INTRODUCTION
Melasma is a chronic acquired hypermelanosis affecting sun-exposed skin areas, especially
the frontal and malar regions.1 It is a common condition, affecting individuals of all races
and both genders, and is more observed in women of childbearing age and with higher skin
phototypes (especially IV-V) who live in areas with high ultraviolet (UV) radiation.2,3,4
Although the etiology and pathogenesis of melasma are not completely understood,
there are several factors involved. Familial occurrence in 30% of the cases suggests genetic
predisposition.1 UV radiation is an important factor, but other factors are also related, such as
the use of oral contraceptives, phototoxic drugs, and thyroid dysfunction. Recently, interactions
between cutaneous vasculature and melanogenesis were established.5,6,7 However, most cases in
men and one third of the cases of women present idiopathic feature.8
Given the high prevalence, much has been studied about the therapeutic options for
melasma treatment, especially due to the possible negative psychological impact and treatment
diffi culty, since the condition course is refractory and recurrent. So far there is no therapy with
fully satisfactory results. Steiner et al. observed in a systematic review that the use of a broad
spectrum sunscreen associated with skin lightening creams, such as hydroquinone (with or
without tretinoin), is the cornerstone of treatment, and new therapeutic options have emerged,
requiring more studies designed to assess their effi cacy.1

Surgical & Cosmetic Dermatology 2009;1(4):174-177
175
Surgical & Cosmetic Dermatology
Tranexamic acid (TA), which is a plasmin-inhibitor
hydrophilic drug, classically used as antifibrinolytic agent,
has been studied as an alternative for treatment of melasma.9
Recent studies have shown that its topical use prevents UV-
induced pigmentation in guinea pigs10 and that its intradermal
intralesional use produces fast bleaching.11
TA blocks plasminogen conversion (present in epidermal
basal cells) into plasmin by inhibiting plasminogen activator.11,12
Plasmin activates the secretion of precursors of phospholipase
A2, which act in the production of arachidonic acid and induce
the release of basic fibroblast growth factor (bFGF). This is a
potent growth factor for melanocytes.12 Arachidonic acid is a
precursor of melanogenic factors, such as prostaglandins and
leukotrienes.
Plasminogen activator is generated by keratinocytes and
increases the activity of melanocytes in vitro. It has increased
serum levels with the use of oral contraceptives and in pregnancy.
This substance blockade may be the paracrine mechanism by
which TA reduces melasma hyperpigmentation.12
The aim of this study was to evaluate the efficacy and
safety of tranexamic acid (TA) in treatment of melasma,
comparing the use of localized microinjection versus topical
therapy.
MATERIAL AND METHOD
This study was conducted at the Outpatient Dermatologic
Clinic at University of Mogi das Cruzes and colorimetric tests
were performed at a private center for clinical research.
This is an open, comparative, and randomized trial in
which 18 patients were studied, aged between 23 and 52 years
(mean 40.58 years, with skin phototypes II-V according to
Fitzpatrick’s classification and clinical diagnosis of melasma.
Exclusion criter ia were clotting disorders and/or use of
anticoagulant; patients with a history of intolerance to the
vehicle or active substance.
All patients enrolled in the study were instructed not
to apply any other product for melasma treatment besides
sunscreen SPF 30 every 4 hours during the day. The patients
were randomly divided into 2 groups: group A, 8 patients, at-
home application of cream with tranexamic acid 3% twice/
day; group B, 10 patients, application of intradermal injections
with tranexamic acid 0.05 ml (4 mg / ml) in each cm² of
melasma, after application of topical anesthesia with lidocaine
hydrochloride 2%, once/week for 12 weeks.
Laboratory tests including complete blood count and
coagulation tests were performed on all participants. Safety
assessments were performed at each follow-up visit.
We evaluated the following parameters before and
after 12 weeks of treatment: photographs examined by an
independent investigator (classified as unchanged, presence
or absence of improvement); MASI SCORE (Melasma
Area and Severity Index); patient satisfaction (rating the
improvement as good, imperceptible, and bad), and through
an equipment colorimetry CR300 with measurements in 3
different areas (right cheek, left cheek and back of right hand
as a control).
The colorimeter provides 3 variables L, a, and b,
coordinate of a three-dimensional axis, where L represents
brightness ranging from 0 (black) to 100 (white), a (degree
of redness), and b (variation in color between blue and
yellow). We also calculated the ITA (arctg [(L-50)/b)] x
180/3.1416), index that measures the skin pigmentation,
where lower values indicate a darker skin and higher values
a lighter skin.
Statistical Analysis
The model used for statistical analysis was linear with
repeated measures, considering the measures before and
after treatment in three different sites of each patient. For
the model in question, we use an autoregressive correla-
tion of 1.
Ethical Aspects
This study was conducted with the prior approval of the
Research Ethics Committee and developed according to the
standards of Good Clinical Practice. All patients signed an
informed consent.
RESULTS
Seventeen patients completed the study, 8 in group A
and 9 in group B. The average duration of melasma was
8.125 years (Graph 1), with high impact on quality of life
in 50% of patients. Factors related to early pregnancy, wor-
sening of sun exposure, and use of oral contraceptives oc-
curred in 31.25%, 87.5%, and 12.5% of cases, respectively,
(Graph 2).
Photographic evaluation showed that in group A there
was improvement in 12,5%, worsening in 50%, and no change
in 37.5%. In group B, 66.7% of patients showed improvement,
11.1% worsening, and 22.2% remained unchanged. Figure 1
shows examples of photographic evaluation.
31,25
87,5
12,5
18,75 onset during
pregnancy
sun
exposure
use of OC
use of other
drugs
Graph 2. Factors associated with
worsening of melasma
Graph 1. Duration of
melasma
Subjects (%)
5 years
5-10 years
>10 years
mean
Interval Mean
duration
(years)

Tranexamic acid in treatment of melasma
176 Surgical & Cosmetic Dermatology
Figure 1 – Photos before and after 12 weeks of topical therapy (rst two
photos), and before and after 12 weeks of injection therapy (last two
photos), respectively.
The MASI score had significant improvement, going
on average from 12.45 to 8.84 (p = 0.0026). There was no
difference between both topical and injectable treatments
(p = 0.6512) (Table 1).
About the self-assessment in group A, 37.5% of patients
rated melasma improvement as good, 50% as imperceptible, and
12.5% as bad. In group B, 66.7% rated melasma improvement
as good and 33.3% as imperceptible.
Colorimetric evaluation showed significant improvement
in both treatments, going from -6.44 to -1.56 on average
(p = 0.0008). There was no difference between treatments
(p = 0.8790) (Table 2).
Side effects were minimal, such as erythema, local bruising
and burning, and treatment was well tolerated by patients.
DISCUSSION AND CONCLUSION
Tranexamic acid (TA) is a hydrophilic drug that inhibits
the plasmin classically used as antifibrinolytic agent through
oral or intravenous administration of 0.5 to 2.0 g three or
four times a day. Recently, this drug has been studied as an
alternative for melasma treatment by acting through its
topical use as a prevention of UV-induced pigmentation in
guinea pigs and producing rapid skin lightening through its
intradermal intralesional use.9,10,11
TA blocks the conversion of plasminogen (present in the
epidermal basal cells) into plasmin by inhibiting plasminogen
activator.11,12 Plasmin activates the secretion of phospholipase
A2 precursors, which act in the production of arachidonic acid
(a precursor of melanogenic factors, such as prostaglandins and
leukotrienes) and induce the release of basic fibroblast growth
factor(bFGF) – a powerful melanocyte growth factor.12
The plasminogen activator, which is generated by
keratinocytes and has increased serum levels with oral
contraceptive use and during pregnancy, increases the activity
of melanocytes in vitro, and the blockage of this effect may
be the paracrine mechanism by which TA decreases melasma
hyperpigmentation.12
This study sought to address a new method of treatment
using tranexamic acid in injectable solution or topical
application. The mean dose of TA injected in our patients
was 1.5 mg, which is lower than the usual dose used for
antifibrinolytic effect, and the concentration of topical cream
to 3% has minimal systemic absorption.
Both modalities were compared in several aspects, such
as photographic evolution, MASI score evolution, patient’s
personal impression, colorimetry, tolerance to drug and
vehicles.
Among the subjective assessments in group B there was
a greater improvement in 66.7% of cases by photographic
evaluation, compared with 12.5% of cases in group A.
Difference also seen in self-assessment with 66.7% of group B
patients classied as good response to treatment versus 37.5%
in group A. These results are consistent with MASI results with
evident improvement in the injection group. Mean MASI in
group A was 12.7 to 9.9 after 12 weeks and in group B 12.2
to 7, 8, representing a percentage change of 22.04% in group
A and 36.07% in group B. However, there was a statistically
significant reduction in MASI after 12 weeks in both groups,
with no statistically significant difference between them.
Table I - Statistical measures of MASI score for groups A and B
before and after 12 weeks of treatment
MASI
mean dp median min max
Treatment Application 12.2 5.35 10.5 5.1 19.1
Injection before 12.2 5.35 10.5 5.1 19.1
after 7.8 4.00 6.6 3.4 13.9
Topical before 12.7 7.75 12.2 1.8 26.1
after 9.9 7.07 8.6 2.7 25.1
Table II - Statistical measures of ITA’s* index values of colorimetry
in groups A and B before and after 12 weeks of treatment.
*ITA = (arctg [(L-50)/b)] x 180/3.1416
ITA
mean dp median min max
Treatment local Application
Injection
control before
after
-12.4
-6.6
13.20
12.69
-8.2
-5.2
-34.2
-24.2
8.2
12.1
malar R before
after
-3.3
-0.5
18.45
17.95
-11.5
3.6
-26.4
-24.5
24.3
24.0
malar L before
after
-0.7
1.5
15.50
20.08
-0.9
-1.2
-22.3
-22.9
22.6
38.0
Topical
control before
after
-5.5
-4.5
9.28
12.61
-6.8
-1.6
-15.7
-21.8
8.8
9.1
malar R before
after
-9.3
-2.1
18.55
19.24
-10.3
2.7
-35.1
-37.8
22.5
17.2
malar L before
after
-7.4
2.8
18.87
15.18
-8.2
8.1
-32.2
-20.6
21.8
19.6
*ITA = arctg[(L-50)/b)]x180/3,1416

Surgical & Cosmetic Dermatology 2009;1(4):174-177
177
Surgical & Cosmetic Dermatology
A study by Lee et al. in 2006, using only subjective
measures to evaluate the efcacy of tranexamic acid injection
in melasma treatment, showed a decrease of 42.74% in MASI
score after 12 weeks of treatment, and the patients’ evaluation,
86% of them considered the results as good, and these results
are similar to those found in the present study.11
One of the disadvantages of subjective methods of
evaluation is a possible bias in clinical trials. Thus, this study
has also used objective evaluation by colorimetric measure
that allows quantitative analysis of pigmentation during
treatment. The colorimetric evaluation showed significant
improvement in both groups, ranging from -6.44 to -1.56, on
average, where lower values indicate darker skin and higher
values lighter skin. There was no difference between groups.
Laboratory tests of patients enrolled in the study – complete
blood count and international normalized ratio (INR) –
showed no changes before and after treatment. Side effects
were minimal, such as erythema, bruising and local burning.
Patients’ tolerance to treatment showed that the treatment is
safe and feasible. Although the subjective clinical evaluation
has demonstrated the superiority of injection treatment, in
objective evaluation both treatments were effective, with no
statistical difference between groups.
In conclusion, this treatment was effective, without
significant side effects. For this reason, TA is presented as a
promising new therapeutic option for melasma, and can be
used either as cream or injection. Further studies with a larger
number of participants are needed to determine the optimal
dosage, application frequency, benefits and sustained results.
In addition, trials to evaluate the use of TA combined with
standard treatments such as topical bleaching (hydroquinone,
Kligman’s formula) and chemical peelings are needed to
identify any additive effects in the search for better melasma
treatments.
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