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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 6  |  Issue : 1  |  Page : 18-23

A comparative study of topical 5% tranexamic acid and triple combination therapy for the treatment of melasma in Indian population


1 Department of Dermatology, Dr. S.N. Medical College, Jodhpur
2 Assistant prof. University of Rajasthan, Jodhpur
3 Department of Pharmacology, Dr. S.N. Medical College, Jodhpur

Date of Web Publication4-Jul-2019

Correspondence Address:
Dr. Dilip Kachhawa
Department of Dermatology, Venerelogy and Leprosy, Dr. S.N. Medical College, Jodhpur, 342003, Rajasthan

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/Pigmentinternational.Pigmentinternational_

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  Abstract 


Introduction Melasma is an acquired hyperpigmentary disorder and poses great therapeutic challenge and has a high recurrence rate. Topical 5% tranexamic acid (TA) is a novel and safe alternative therapy for melasma. The aim of our study was to evaluate the efficacy of topical solution of 5% TA and compare it with triple combination therapy (hydroquinone, tretinoin, fluocinolone) in Indian population.
Materials and Methods This was a prospective comparative study of 12 weeks. A total number of 25 patients between 18 and 50 years of age were included in the study. Patient’s face was divided into two halves (split face), and on one half of the face (i.e., on left), topical 5% TA and on the other half of the face (i.e., on right), topical triple combination therapy were applied. The melasma area severity index (MASI) and side effects were evaluated at baseline and every 15 days. Photographs were taken at alternate visits (i.e., 30 days) and compared with earlier one by an independent observer.
Results The study was completed on 23 patients. The mean MASI scores decreased significantly in both the groups (P < 0.05), but there was no significant difference between them (P > 0.05). However, the side effects of triple combination therapy were significant compared with TA. At the end of 12 weeks, in group 1, photographic evaluation showed excellent response in 26%, good response in 60.1%, fair response in 8.6%, and poor response in 4.3%. In group 2, there was excellent response in 34.7%, good response in 56.5%, fair response in 4.3%, and poor response in 4.3%.
Conclusion This study revealed that the topical 5% TA is a safe effective, and better alternative with good patient acceptance for the treatment of melasma. The study revealed improved pigmentation in both tested sides, but topical 5% TA has less side effects such as erythema, irritation, and telangiectasia as compared to triple combination.

Keywords: Fluocinolone, hydroquinone, tranexamic acid, tretinoin


How to cite this article:
Khuraiya S, Kachhawa D, Chouhan B, Dua M, Rao P. A comparative study of topical 5% tranexamic acid and triple combination therapy for the treatment of melasma in Indian population. Pigment Int 2019;6:18-23

How to cite this URL:
Khuraiya S, Kachhawa D, Chouhan B, Dua M, Rao P. A comparative study of topical 5% tranexamic acid and triple combination therapy for the treatment of melasma in Indian population. Pigment Int [serial online] 2019 [cited 2019 Aug 21];6:18-23. Available from: http://www.pigmentinternational.com/text.asp?2019/6/1/18/262047




  Introduction Top


Melasma is a commonly acquired pigmentary disorder characterized by dark brown macules and patches involving the sun-exposed areas of the face and occasionally on the neck. The most common sites on face are the cheeks, bridge of the nose, forehead, chin, and above upper lip. It is a common condition affecting individuals of all race and both genders. It is commonly seen in the females of childbearing age and with the Fitzpatrick skin type IV–VI. Although the etiology and pathogenesis of melasma remain unknown, there are several factors such as genetic susceptibility, ultraviolet (UV) light exposure, pregnancy, sex hormones, contraceptive pills, thyroid disease, cosmetics, and phototoxic drugs that have been attributed to melasma.[1],[2],[3]

Different treatment modalities include the elimination of any causative factors, sunscreen triple combination (hydroquinone, tretinoin, fluocinolone), azelaic acid, ascorbic acid, kojic acid, arbutin, chemical peels, and lasers, but none of the above has satisfactory results.

Tranexamic acid (TA) is a plasmin inhibitor, usually used as antifibrinolytic agent and as a new treatment modality for the treatment of melasma. TA has some anti-inflammatory and hypopigmentory effects when administered either topically or systemically. TA inhibits plasminogen activator, which regulates the conversion of plasminogen to plasmin. TA inhibits melanin synthesis in melanocytes by interfering with the interaction of melanocytes and keratinocytes through the inhibition of plasmin system.[4],[5]

Aims and objectives

The aim of our study was to evaluate the efficacy of topical solution of 5% TA and compare it with triple combination cream (hydroquinone, tretinoin, fluocinolone) in the Indian population.


  Materials and methods Top


Study: A prospective comparative study.

Duration of study: 3 months.

Sample size: A total number of 25 patients between 18 and 50 years of age with moderate to severe bilaterally symmetrical or asymmetrical distribution of melasma were included in the study after obtaining written informed consent. Pregnant/lactating females, patients on hormone replacement therapy or oral contraceptive pills, bleeding disorders, concomitant use of anticoagulants, and any known drug allergy especially to TA, associated medical illness, and history of any other depigmenting treatment in the past 1 month were excluded from the study.

It was a self-financing project, and ethical clearance was taken.

After obtaining detailed personal and medical history, Wood’s lamp examination was performed to classify the type of melasma. A modified melasma area and severity index (MASI) scoring system was used to assess the severity of melasma.

Standard photographs and the MASI were recorded at baseline and at 4, 8, and 12 weeks. The MASI is an index devised to more accurately quantify the severity of melasma and changes during therapy. The MASI is calculated based on the area (A) of involvement, the darkness (D) of melasma, and the homogeneity (H) of hyperpigmentation. The right forehead (rf), right malar region (rm), and right chin (rc) correspond to 15, 30, and 5% of the total face, respectively. The same regions are measured on the left side, giving a total facial surface area of 100%.

The area of involvement in each of these six areas is given a numerical value of 0–6, where 0 indicates no involvement, 1 indicates 0–9%, 2 indicates 10–29%, 3 indicates 30–49%, 4 indicates 50–69%, 5 indicates 70–89%, and 6 indicates 90–100%. The severity of melasma can also be determined by measuring two additional variables, that is, darkness (D) and homogeneity (H) rated on a scale from 1 to 4 (0 indicates absent; 1, slight; 2, mild; 3, marked; and 4, maximum). The MASI score is calculated by adding the sum of the severity rating for darkness and homogeneity multiplied by the value of the area of involvement for each side.

To evaluate patient satisfaction, a scoring system was conducted at the end of the study. The patient’s self-assessment of melasma improvement was graded along four scales: 1 = >75% lightening (excellent), 2 = 51–75% (good), 3 = 26–50% (fair), and 4 = 0–25% (poor).

Each melasma patient’s face (split face) was divided into two groups:
  1. Group 1: (the left side of face) each patient in group 1 was given 5% tranexamic acid (TA) twice daily with morning and day time application of sun protection factor −30.
  2. Group 2: (the right side of face) each patient in group 2 is applied with triple combination, that is, tretinoin, hydroquinone, fluocinolone with morning, and day time application of sun protection factor −30.


For each participant, the MASI score was calculated for each half and follow-up of the patient is mandatory after 15 days till 3 months. Patients were kept in follow-up up to 3 months after the completion of the study and they were kept on sunscreens only.

MASI score and clinical photographs were evaluated by an independent person other than the author.

Statistical analysis: P < 0.05 was considered as statistically significant effect.


  Results Top


A total of 25 patients were included in the study and out of that, two participants were dropouts; thus, the study was completed on 23 patients. The average age of the patient was 28.68 years (range 18–47) and all had melasma for more than 6 months. Most of the patients were females and belong to age group between 21 and 30 years [[Table 1]] with high impact on the quality of life in 50% of the patients.
Table 1 Demographical data of patients

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More than half of the patients applied sunscreen on regular basis and had used antimelasma regimen. Baseline data showed that the right side of the face of maximum patient had more pigmentation.

The mean MASI score of baseline was 3.3 in group 1 and after 12 weeks, it reached to 1.02 (P = 0.000) and in group 2, it was 3.7 at baseline, and after 12 weeks, it reached to 1.2 (P = 0.000) [[Table 2] and [Table 3]]. The mean MASI score was decreased in both groups, indicating that both the groups showed significant improvement during the study period (P < 0.005) [[Figure 1]] . However, there was no statistical significant difference between treatment with TA and triple combination therapy at baseline and all reassessment visits (P > 0.05). Group 1 shows similar decrease in pigmentation compared to triple combination group 2 but response was delayed in the initial weeks of treatment.
Table 2 Mean MASI score at baseline and all reassessment visits after treatment with TA (group 1) and triple combination therapy (group 2)

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Table 3 Statistical assessment of Mean MASI score for groups 1 and 2 before and after 12 weeks of treatment

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Figure 1 Improvement seen in clinical melasma area and severity index (MASI) scores during the study in both groups (P = 0.000)

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The patients’ self-assessment of melasma improvement was evaluated at 4 weeks interval. At the end of 12th week, in group 1, excellent response was seen by 26% of the patients, 60.1% showed good response, 8.6% showed fair response, 4.3% showed poor response, and in group 2, excellent responses were seen by 34.7%, 56.5% showed good response, 4.3% showed fair response, and 4.3% showed poor response [[Table 4]]. In this case, the chi-square test showed no significant difference between these two types of treatments: chi-square value of 0.656 and P-value = 0.883.
Table 4 Comparison of results in both groups

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Side effects were more clinically evident in group 2, such as erythema, irritation, and telangiectasia compared to group 1. In group 1, side effects are much less, only 13% showed erythema, 8.6% showed irritation, and none of the patient showed telangiectasia. In group 2, 52.1% showed side effects, 43.1% showed irritation, and 16% showed telangiectasia [[Figure 2]].
Figure 2 Side effect profile in both the groups

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  Discussion Top


In present study, the efficacy and safety of topical 5% TA were compared with triple combination therapy in the treatment of melasma. It had shown that the TA is as effective as triple combination in the treatment of melasma in terms of efficiency with fewer side effects. So, it is a better alternative to triple combination in the treatment of melasma [[Figure 3] and [Figure 4]].
Figure 3 (a) The left side which was treated with TA at baseline. (b) The left side which was treated with TA at 12 weeks

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Figure 4 (a) The right side which was treated with triple combination at baseline. (b) The right side which was treated with triple combination at 12 weeks

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Recently, topical TA (trans-4-aminomethylcyclohexanecarboxylic acid) is a new drug entity for the treatment of melasma. TA is a white, crystalline odorless powder. It is freely soluble in water and in glacial acetic acid, practically insoluble in methanol, ethanol, acetone, diethyl ether, and benzene. The pKa is 4.3.

It is prescribed as an antifibrinolytic agent. Nowadays, oral as well as topical TA is used in the treatment of melasma. TA was effective in UV-induced hyperpigmentation. Topical TA inhibits UV-induced plasmin activity in the keratinocyte by preventing the binding of plasminogen to the keratinocyte, thus suppressing the production of prostaglandins,[4],[5] thereby suppressing melanogenesis pathway.

UV rays → plasminogen activator → plasmin synthesis → phospolipase A2 arachidonic acid → PGE2 → melanogenesis.

This study showed statistically significant decrease in melanin pigmentation on both the TA-tested side (group 1) and triple combination tested side (group 2) when compared to baseline (P = 0.000). Although decrease in pigmentation was noted in the MASI score, readings were considerable at 12 weeks compared to baseline (P < 0.05), independent observer as well as the participants, and were unable to detect any significant differences between both sides of the face (P > 0.05). Our results were similar to the study conducted on Thai women by Kanechorn-Na-Ayuthaya et al.[6]

A prior study by Ebrahimi and Naeini[7] demonstrated that 27.3% of the patients rated melasma improvement as excellent, 42.4% as good, and 30.3% as fair. It was a double-blind split phase trial of 12 weeks on 50 Iranian patients with melasma with the topical solution of 3% TA.

In another study, Steiner et al.[8] with 3% TA demonstrated that 37.5% of the patients rated melasma improvement as good, 50% as imperceptible, and 12.5% as bad in 18 patients.Wu et al.[9] also demonstrated total improvement rate of 80.9% in 256 patients with the long-term oral administration of TA.

In a study by Kim et al.,[10] the mean score of MASI considerably reduced following the use of topical TXA with a total response rate of 95.6%.

In another study, Atefi et al.[11] demonstrated that patients who were treated with 5% TA had a significantly higher level of the satisfaction level of 33.3% compared with 6.7% in patients who were treated with hydroquinone (P = 0.015).

Melasma is a common cosmetic problem especially in women and causes tremendous psychological impact. The exact mechanisms remain unknown. Histologically, in melasma, there is an increased proliferation of melanocyte, which exhibits enlarged perikaryon with increased branching of their dendrites.[12] There is also increased transfer of melanosomes to basal and suprabasal layers. The treatment of melasma is based on (1) sun protection, (2) inhibition of melanocyte hyperactivity, and (3) removal of melanin. Currently, there are many treatments that are available but none of the treatment is satisfactory or up to the mark till date.


  Conclusion Top


Topical 5% TA as a monotherapy was as effective as triple combination treatment to decrease pigmentation significantly in middle-aged Indian population. Moreover, 5% TA had lesser side effects such as erythema, irritation, and telangiectasia as compared to triple combination therapy. Therefore, topical TA is a promising new therapeutic option for melasma. Further studies with large study group will be required to determine long-term benefits, optimal dosage, and combination therapy with other medications in the treatment of melasma.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Lee JH, Park JG, Lim SH, Kim JY, Ahn KY, Kim MY et al. Localized intradermal microinjection of tranexamic acid for treatment of melasma in Asian patients: A preliminary clinical trial. Dermatol Surg 2006;32:626-31.  Back to cited text no. 1
    
2.
Hassun KM, Bagatin E, Ventura KF. Melasma. Rev Bras Med 2008;65:11-6.  Back to cited text no. 2
    
3.
Morelli JG, Norris DA. Influence of inflammatory mediators and cytokines on human melanocyte function. J Invest Dermatol 1993;100:191-5S.  Back to cited text no. 3
    
4.
Maeda K, Tomita Y. Mechanism of the inhibitory effect of tranexamic acid on melanogenesis in cultured human melanocytes in the presence of keratinocyte-conditioned medium. J Health Sci 2007;53:389-96.  Back to cited text no. 4
    
5.
Wang N, Zhang L, Miles L, Hoover-Plow J. Plasminogen regulates pro-opiomelanocortin processing. J Thromb Haemost 2004;2:785-96.  Back to cited text no. 5
    
6.
Kanechorn-Na-Ayuthaya P, Niumphradit N, Manosroi A, Nakakes A. Topical 5% tranexamic acid for the treatment of melasma in Asians: A double-blind randomized controlled clinical trial. J Cosmet Laser Ther 2012;14:150-4. doi: 10.3109/14764172.2012.685478.  Back to cited text no. 6
    
7.
Ebrahimi B, Naeini FF. Topical tranexamic acid as a promising treatment for melasma. J Res Med Sci 2014;19:753-7.  Back to cited text no. 7
    
8.
Steiner D, Feola C, Bialeski N, Ayresde F, Silva M, Antiori AC et al. Evaluation study of the effectiveness of topical and injectable tranexamic acid in the treatment of melasma. J Surg Cosmet Dermatol 2009;1:174-177.  Back to cited text no. 8
    
9.
Wu S, Shi H, Chen Y, Yan Sh, Chen D, Guo J et al. Treatment of melasma with oral administration of tranexamic acid. Chin J Aesthetic Plast Surg 2008;19:106-10.  Back to cited text no. 9
    
10.
Kim SJ, Park JY, Shibata T, Fujiwara R, Kang HY. Efficacy and possible mechanisms of topical tranexamic acid in melasma. Clin Exp Dermatol 2016;41:480-5.  Back to cited text no. 10
    
11.
Atefi N, Dalyand B, Ghassemi M, Mehran G, Heydarian A. Therapeutic effects of topical tranexamic acid in comparison with hydroquinone in treatment of women with melasma. Dermatol Ther 2017;7:417-24.  Back to cited text no. 11
    
12.
Sanchez NP, Pathak MA, Sato S, Fitzpatrick TB, Sanchez JL, Mihm MC Jr. Melasma: A clinical, light microscopic, ultrastructural and immunofluorescence study. J Am Acad Dermatol 1981;4:698-710.  Back to cited text no. 12
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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