Introduction
Melasma, a common form of acquired non-inflammatory hyper pigmentation is important, because it involves face in cosmetically conscious age group and significantly affects a person’s psychological and social well being, contributing to lower productivity, social functioning and self-esteem.1 It affects individuals of all races and both genders, and is observed in women of childbearing age and with darker skin types (fitzpatrick’s IV-V) who live in areas with high ultraviolet (UV) radiation.2, 3, 4
The precise cause of melasma remains unknown. Multiple etiological factors are implicated, such as exposure to ultraviolet radiation, pregnancy, contraceptive pills, hormone replacement therapy, cosmetics, phototoxic and anti‑seizure medications.3 In addition to the UV light itself, photo‑induced hormones, growth factors, and chemical mediators of inflammation, which influence the function of melanocytes directly or indirectly, might contribute to the UV‑induced pigmentation.5
Depending on the location of melanin, melasma is classified into: 6
Epidermal type
In which the pigment is brown and margins of the lesions are well defined and geographical.
Indeterminate type
In which it is difficult to classify melasma, even with Wood’s light as melasma in dark skinned individuals.7
Based on distribution on face, three patterns of melasma are recognized:
Centrofacial
Most frequent (63%) pattern with pigmentation on cheeks, forehead, upper lip, nose & chin.
Mandibular
Least common (16%) type with pigmentation on ramus of the mandible.
Depending on the natural history of the lesions, melasma may also be classified into:
Persistent type
Which persists for more than a year after withdrawal of hormonal stimulus and is maintained by UVR and other factors.
Due to its high prevalence and psychological impact, many studies have been conducted regarding the therapeutic options for melasma. Different treatment modalities such as topical depigmenting agents, 8, 9 chemical peels, 10 dermabrasion and laser therapies11 have been utilised in different studies with varying outcomes.
The results of recent clinical trials using localized intradermal microinjections of tranexamic acid (TA)12 and transepidermal delivery of TA using microneedling13 in the treatment of melasma are promising.
The aim of this study was to evaluate the efficacy and safety of tranexamic acid and to compare its therapeutic efficacy with that of Modified Kligman formula, which is gold standard for melasma.
Materials and Methods
This is an open labeled, prospective, randomized, comparative study done on 45 clinically diagnosed melasma patients attending outpatient Dermatology, venereology & leprosy (DVL) department from January 2015 to May 2016. Patients between 20-50 years and both sexes were included in the study.
Patients with known hypersensitivity to Modified Kligman’s formula and Tranexamic acid, History of herpes simplex viral infection, Concurrent active disease to facial area (i.e. acne), History of abnormal wound healing, abnormal scarring & bleeding disorders, Pregnant/lactating females were excluded.
Ethical aspects
This study was conducted with prior approval from Research Ethics Committee and was done according to standards of good clinical practice. All patients signed an informed consent.
Methodology
All patients enrolled in this study were instructed to avoid sun exposure, use broad spectrum sunscreen during day time and avoid melasma precipitating drugs like oral contraceptives.
After obtaining detailed personal and medical history, Wood’s lamp examination was performed to classify the type of melasma. MASI scoring system was used to assess the severity of melasma.
All patients were randomly categorized into 3 groups, with 15 patients in each group.
Group A individuals were advised to apply modified kligman formula (2% hydroquinone + 0.025% tretinoin + 0.1% mometasone) at home daily at night for 12 weeks. They were advised to come for review every month.
For Group B individuals, topical anesthesia (EMLA) was applied for 45 min and then using hand held dermaroller with 192 needles of 1.5mm needle length was rolled over the affected area in all directions(vertical, horizontal and diagonal) and then 4mg/ml of Tranexamic acid was applied over rolled areas.
Tranexamic acid (Trapic) 100mg/ml is available as 5ml ampoule. 1ml was taken and diluted with distilled water to get a concentration of 4mg/ml, which was used in this study. The procedure was repeated weekly for 12 weeks.
For Group C individuals, intralesional Tranexamic acid 4mg/ml was given at 1cm intervals upto a maximum of 8mg/ml over the lesional area. The same was repeated weekly upto 12 weeks.
After every 4 weeks, clinical photograph and dermoscopic image was taken and MASI score was calculated for every individual. Patient assessment scoring was also noted.
Results
The Kruskal–Wallis (nonparametric ANOVA) test was used to compare the means of MASI scores before and after treatment in individual groups. The unpaired t‑test with Welch correction was used to compare means of MASI scores between the 1st and 2nd group & 1st and 3rd group.
Out of 45 patients in this study, 2 were males (4.4%) and 43 were females (95.5%), majority were in the age group of 31-40 years (64.44%).(Table 2)
Table 2
Age & sex distribution
|
Age in years |
Males |
Females |
Total |
Percentage |
|
21-30 |
1(2.22%) |
9(20%) |
10 |
22.22% |
|
31-40 |
1(2.22%) |
28(62.22%) |
29 |
64.44% |
|
41-50 |
0 |
6(13.33%) |
6 |
13.33% |
|
Total |
2(4.44%) |
43(95.55%) |
45 |
|
Majority of the patients had centofacial melisma (53.3%), followed by malar type (46.6%) and on woods lamp examination majority had epidermal melisma (48.8%), followed by dermal type (26.6%) and then mixed type (24.4%).(Table 3)
Table 3
Types of melasma
|
Types of melasma |
Epidermal |
Dermal |
Mixed |
|
Centrofacial |
7 |
10 |
7 |
|
Malar |
15 |
2 |
4 |
|
Total |
48.8% |
26.6% |
24.4% |
Various etiological factors involved are sun light (86.7%), familial predisposition (24.4%), OC pills (8.8%), thyroid abnormality (6.6%).Figure 2
The total MASI in group A regressed from 105.9 to 65.5, in group B from 156.3 to 112.1 and in group C from 97.2 to 61.4 by the end of 12 weeks.
When mean MASI (± sd) was compared, in group A it regressed from 7.06±6.5 to 4.3±4 with 42% improvement, in group B it regressed from 10.42±8.3 to 7.47±6 with 30% improvement and in group C it regressed from 6.48±4.47 to 4.09±2.76 with 37% improvement with p value <0.001 in all the groups.(Table 4)
Table 4
Mean MASI scores, percentage improvement, and P value of all the groups
The p value (t test) between 1st and 2nd group is 0.125 (p>0.05), and between 1st and 3rd group is 0.084 (p>0.05), indicating that there is no statistical significant difference between any two groups.
When compared in various types of melasma, Tranexamic acid showed marginally superior results in mixed and dermal melasma when compared to modified kligman formula.(Table 5)
Table 5
Results in various types of melasma
|
Type of melasma |
Improvement of MASI in terms of percentage |
||
|
|
Modified kligman |
Microneedling + TXA |
Intralesional TXA |
|
Epidermal |
43.22% |
29% |
37% |
|
Dermal |
32.99% |
30.28% |
35.58% |
|
Mixed |
35.48% |
29.17% |
37.43% |
Clinical and dermoscopic photographs before and after treatment:
Group 1 : Modified kligman formula group
Figure 4
Dissolution of pigmentation with perilesional hypopigmentation, telangiectasias are also seen over the treated lesional skin
Group 2: Microneedling with Tranexamic acid
Group 3: Intralesional Tranexamic acid
Discussion
Tranexamic acid is a hydrophilic drug that inhibits plasmin, clinically used as antifibrinolytic agent. The skin whitening effects of tranexamic acid was incidentally found when it was used in the treatment of aneurysmal subarachnoid hemorrhage. It is a synthetic derivative of lysine and its therapeutic role in melasma was first studied by Nijor as early as in 1979, but only limited data exist in the literature regarding its use in melasma. Recent studies have revealed that topical trans‑4‑(aminomethyl) cyclohexanecarboxylic acid (trans‑AMCHA, TA), a plasmin inhibitor, prevents UV‑induced pigmentation in guinea pigs and producing rapid skin lightening through its intradermal intralesional use. 14, 12, 13
TA blocks the conversion of plasminogen (present in the epidermal basal cells) into plasmin by inhibiting plasminogen activator. 13, 15 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.15 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. 15
This study sought to address a new method of treatment using tranexamic acid in injectable solution.
A therapeutic trial was conducted to assess and compare the efficacies of topical Modified kligman’s formula (2%hydroquinone+0.025% tretinoin+0.1% mometasone), Microneedling with Tranexamic acid and Intralesional Tranexamic acid for a period of 3 months.
Modified kligman formula
In the modified kligman’s formula treated group, the response was excellent in 40%, good in 40%, fair in 20% with 42% reduction in MASI by the end of 12 weeks. The therapeutic benefits began to appear after 4 weeks of starting the therapy. Clinically, the areas of melasma were noted to become lighter with gradual decrease in size. Our results were in concordance with a study by Sarkar R et al 16 (2002), who had 33% and 63% reduction in MASI score at 12 and 21 weeks respectively. Two studies conducted by Torok HM et al 17 (2005), and Taylor SC et al 18 (2005), for a period of 12 months, showed 94% reduction in MASI score, which was higher than the present study(58%), as their study was conducted for a period of 12 months.
Microneedling +TXA
In the second group where microneedling was done followed by application of Tranexamic acid the response was excellent in 7%, good in 7%, fair in 60% and poor in 26%, with 30% reduction in MASI by the end of 12 weeks. Clinically, homogenous patches of melasma reduced to specks of pigmentation. A study by Budamakuntla et al19 (2013) showed 44.41% improvement which was higher than our study. When compared in various patterns of melasma, mixed and dermal melasma responded better with this method when compared to modified kligman formula.
When first and second groups were compared, P value is 0.125 (t test), which is not significant.
Intralesional TXA
In the Intralesional Tranexamic acid treated group, the response was excellent in 20%, good in 40%, fair in 26.6%, poor in 13.3% with 36% reduction in MASI by the end of 12 weeks. In an open study by Lee et al on 100 Korean women with melasma, tranexamic acid given intradermally (4 mg/ml) every week for 12 weeks caused significant decrease in MASI score (P value < 0.05), and 76.5% subjects reported lightening of melasma with minimal side effects., 20 which was in favour to our study.
Overall, in the present study there was no significant difference statistically between the three modalities (p>0.05) with ANOVA t test.
Tranexamic acid showed marginally superior results in mixed and dermal melasma when compared to modified kligman formula. Which is explained by its mechanism of action, that it decreases number of blood vessels in lesional skin which is dermal related change in melasma.21 It also inhibits α-MSH which is increased in lesional skin.
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