|Year : 2019 | Volume
| Issue : 2 | Page : 84-95
Comparative study of efficacy of intradermal tranexamic acid versus topical tranexamic acid versus triple combination in melasma
Shruti S Patil, Ashish R Deshmukh
Department of Dermatology, MGM Medical College and Hospital, Aurangabad, Maharashtra, India
|Date of Web Publication||19-Dec-2019|
Shruti S Patil
Department of Dermatology, MGM Medical College and Hospital, Aurangabad, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Melasma, a hypermelanotic disorder, is challenging to treat as it needs long-term management. Intradermal tranexamic acid (TA), a plasmin inhibitor, has been tried for melasma in Korean and Iranian patients but not studied in skin type of Indian patients. TA cream topically as well as fluocinolone-based triple combination along with intradermal TA have not been studied in the literature so far in melasma. Objective: This study is designed to study the efficacy of intradermal TA vs topical TA vs triple combination (hydroquinone 2%, tretinoin 0.025%, fluocinolone acetonide 0.01%) for the treatment of melasma. Materials and Methods: A total of205 patients of melasma attending Dermatology OPD were enrolled in the study and randomly assigned into three groups. Groups A, B, and C were given intradermal TA, topical 3% TA, and triple combination, respectively, from November 2016 to May 2018 and asked to follow-up every month for 6 months. Total 180 patients completed the study and clinical evaluation was done using melasma area severity index (MASI) score. The results were analyzed using SPSS-22 and comparison of three groups were assessed by applying analysis of variance. Results: The MASI score at baseline and at 6 months for Groups A, B, and C was 15.4 and 2.2, 15.4 and 6.4, and 15.3 and 5.4, respectively. MASI score decreased in all three groups but it was statistically significant in Group A (TA group) that had the least MASI score followed by triple combination therapy. Conclusion: On the basis of these results, TA can be used as potentially a new, effective, safe, and promising therapeutic agent in melasma.
Keywords: MASI, Melasma, tranexamic acid, triple combination
|How to cite this article:|
Patil SS, Deshmukh AR. Comparative study of efficacy of intradermal tranexamic acid versus topical tranexamic acid versus triple combination in melasma. Pigment Int 2019;6:84-95
| Introduction|| |
Melasma (from the Greek word melas, meaning “black”) is an acquired circumscribed hypermelanosis of the sun-exposed skin., Melasma, which may be symmetric or asymmetric, is an acquired hyperpigmentary disorder characterized by brown–black macules or patches affecting mainly the face.,,,
On the basis of Wood’s lamp examination, melasma can be classified according to the melanin content as follows. Epidermal type in which there is a color accentuation as the light is absorbed by the excess of melanin in the basal or suprabasal regions. In dermal type, such accentuation is not noticeable, and mixed type in which the deposit of melanin occurs in both dermis and epidermis; increased staining is seen only in a few sites. Some even describe a fourth type that would be unnoticed in Wood’s light because it affects individuals of phototypes V and VI. On the face it presents as centrofacial, malar, and mandibular.
Epidemiologically, melasma is found in all geographical and ethnic groups but occurs commonly in Asians and Middle Easterners. Although commonly seen in women, it can also occur in men. With approximately 10% cases occurring in men, it has become universal, across the gender disorder. The disease prevalence among Asians is about 40% in females and about 20% in males. Melasma is the common pigmentary disorder in India, with incidence of approximately 10%. It is also found to occur at a younger age among Indians.
A variety of treatments has been proposed and used in melasma. They include topical medications such as hydroquinone and related drugs, azelaic acid, corticosteroids, and procedural treatment like chemical peels, microdermabrasion, and light-based options like Q-switched Nd:YAG laser, intense pulse light, and so on.,
Fluocinolone-based triple combination (hydroquinone 2%, tretinoin 0.025%, fluocinolone acetonide 0.01%) has been introduced since last few years and is considered to be safer option with studies claiming little or no side effects.
Tranexamic acid (TA), an inhibitor of plasminogen activation, has been recently used in the treatment of melasma in different investigations., Recently, TA has been reported to lighten melasma without serious side effects. The exact mechanism of action of TA is still unknown, but the evidence shows that it can reduce the melanin content of epidermis and decrease the dermal vascularity and mast cell numbers. The aim of our study is to evaluate the efficacy and safety of intradermal TA vs topical TA vs topical triple combination.
| Materials and methods|| |
It was a single-centered, prospective, randomized controlled interventional study aimed at studying the efficacy of intradermal TA vs topical TA vs topical triple combination in melasma. Randomization of patients was done using chit method, in which Group A had 65 patients, Group B had 76, and Group C had 64; ethics committee clearance was obtained prior to the start of the study.
A total of 205 patients with mild-to-severe melasma patients presented to the outpatient clinic of the Dermatology OPD were included in the study. Total of 25 participants were lost in the follow-up period. In Group A, total five participants lost to follow-up. Group B lost 16 participants and Group C lost four; out of total 205 participants, 25 did not complete the study. Hence, a total of 180 participants completed the study.
All melasma patients of any severity, who had completed 18 years of age and given written consent, were included.
Patients who had hypersensitivity to study medication, pregnant/lactating women, patients with clotting disorders or who were on anticoagulant treatment and those who had not given consent were excluded from the study.
Assessment and analysis
History, written consent of the patient, and demographic history such as name, age, sex, address, contact number, marital status, and occupation were noted. Any disease history, duration of illness, onset and progress of illness, and associated symptoms, site, type, and number of lesion were also recorded. Family history, menstrual history, and obstetrics history of the patient were examined.
Drugs and dosage
The patients were randomly divided into three groups. Group A selected 65 patients who were given 0.05 mL (4 mg/mL) intradermal TA in each cm2melasma using an insulin syringe with a 30-gauge needle after application of topical anesthesia with lidocaine and prilocaine every 15 days. Group B selected 76 patients who were given topical application of 3% TA cream once a day. Group C selected 64 patients who were given topical application of triple combination (hydroquinone 2%, tretinoin 0.025%, fluocinolone acetonide 0.01%) once a day with the application of emollient in the morning, out of which only 60 patients from each group completed the study.
Each patient was advised to use sunscreen daily 4 times/day 30 minutes before sun exposure and follow sun protective measures like use of scarfs and umbrellas. Patients of all groups were assessed for safety and efficacy every 4 weeks for 6 months. All the patients were followed up throughout the course of the treatment for any adverse drug reactions.
At each visit, patients were assessed for efficacy by melasma area severity index (MASI) [Table 1].
|Table 1 Melasma area severity index (MASI). Source: http://www.iranjd.ir/download.asp?code=IJD12155911|
Click here to view
Total MASI score was 0 to 48 and there were four regions: forehead (0.3), right malar (0.3), left malar (0.3), and chin (0.1).
Formula to calculate total MASI score is as follows:
Forehead 0.3 (D + H) A + right malar 0.3 (D + H) A + left malar 0.3 (D + H) A + chin 0.1 (D+H) A
Laboratory tests done for the study included complete blood count and coagulation tests (bleeding time and clotting time) for Groups A and B that were checked at first visit and at 6 months, respectively. Patients were asked to follow-up regularly every 1 month for 6 months to assess safety and efficacy.
Posttreatment follow-up was not done since patients had already followed up for 6 months.
The collected data were compiled in MS excel sheet 2007 and for analysis of these data, SPSS version 20.0 was applied. The qualitative data were represented in form of frequency and percentage. These were also represented in the form of usual impression like bar diagram, pie diagram, and others. The quantitative data were represented in the form of mean and standard deviation, etc. For comparison of three groups, analysis of variance was applied. P value was checked at 5% level of significance.
| Observations and results|| |
Total of 25 participants were lost in the follow-up period. In Group A, total five participants lost to follow-up. Group B lost 16 patients and Group C lost four during follow-up; out of total 205 patients, 25 did not complete the study. Hence, total of 180 participants completed the study, 60 in each group.
The most common group among 45% study participants was 31 to 40 age group as shown in [Table 2]. Females formed 144 (80%) of study whereas males formed rest 36 (20%) as shown in [Table 3].
Mixed type of melasma was most common in 79% of this study as shown in [Table 4].
Malar-type pattern of melasma was most commonly seen with 54% of study participants as shown in [Table 5].
Sun exposure was found to be most common (80%) aggravating factors in melasma patients as shown in [Table 6].
MASI score was much improved in Groups A and C compared to Group B as shown in [Table 7].
Group A showed most percentage improvement and Group C was next most improved on MASI score as shown in [Table 8].
Patients with melasma duration less than 5 years showed significant improvement, whereas mixed type of melasma showed significantly better improvement.
[Figure 1],[Figure 2],[Figure 3], [Figure 7],[Figure 8],[Figure 9] and [Figure 13],[Figure 14],[Figure 15] depict before treatment photographs of Groups A, B and C respectively. [Figure 4],[Figure 5],[Figure 6], [Figure 10],[Figure 11],[Figure 12] and [Figure 16],[Figure 17],[Figure 18] depict after treatment photographs of Groups A, B and C accordingly [Table 9]. Occurrence of side effects were more in Group C, depicted in [Figure 19],[Figure 20],[Figure 21].
| Discussion|| |
This study is a randomized controlled clinical trial done during 2016 to 2018. All the patients diagnosed as melasma in Dermatology OPD at tertiary care center during study period were included in the study. Total of 180 patients completed the study. All patients were divided into three groups namely Group A, Group B, and Group C with intradermal TA, topical TA, and triple combination treatment groups, respectively.
This study showed that intradermal TA was more effective than topical triple combination followed by topical TA.
The mechanism of action of TA in treatment of melasma is not completely understood but it seems to suppress ultraviolet-induced plasmin activity in keratinocytes. TA inhibits the binding of plasminogen to keratinocytes, consequently reducing the synthesis of prostaglandins, which are well-known stimulators of tyrosinase activity. Moreover, plasmin increases diffusible forms of vascular endothelial growth factor, resulting in angiogenesis. Thus, inhibition of plasmin by TA leads to reduction of angiogenesis.
Absolute MASI score values at each month did not show any significance between three groups, but there was proportionally greater decrease in MASI score in Group A and Group C than Group B and the P value >0.05 was not significant.
The MASI score at baseline and at 6 months for Groups A, B, and C was 15.4 and 2.2, 15.4 and 6.4, and 15.3 and 5.4, respectively. In our study, Group A showed most percentage improvement in MASI score; Group C was next most improved on MASI score with P value <0.05, which was statistically significant.
There was significant association between occurrences of side effects in all the three study groups, with Groups A and B showing lesser side effects than Group C. Mild discomfort, burning sensation, and erythema were observed when it was used intradermally, which subsided without the need for other interventions.
In this study, age ranged from 18 to 60 years with mean age of 33.7 years. In a study conducted by Achar and Rathi, the ages ranged from 14 to 54 years. In the same study, the mean age of patients was 33.45 years, which was in accordance with our study. Majid also concluded similar findings.
Females formed 144 (80%) of our study whereas males formed the remaining 36 (20%). Similar study was concluded by Katsambas and Stratigos in which men formed 10% of study population. There was female preponderance with a male:female ratio of approximately 1:4 in Achar and Rathi study that was exactly the same as our study.
In our study, 62% study participants were having outdoor occupation whereas remaining 38% were having indoor occupation. This was found to be significant. Khan and Ahamed concluded the same with 60% participants with outdoor occupation.
Majority were from rural areas (62%), and the remaining 38% were from urban areas. On the contrary, Khan and Ahamed had a higher proportion of urban population, that is, 62%, which may be due to different study area and population.
Negative history of melasma in the family was seen in 78% participants. Achar and Rathi in their study observed a positive family history of melasma in 104 (33.33%) patients, which was in accordance with our study. Resnik and Vazquez et al. reported positive family history varying form 20% to 70%, which correlates in this study.
Mixed type of melasma was most common in 79%; next was dermal type with 12% in this study. The study by Nicolaidou et al. also suggested that the mixed variety was the most common, as in our study. Achar and Rathi on Wood’s lamp examination showed the dermal type being the most common in 54.48% and epidermal and mixed were seen in 21.47% and 24.03% of the cases, respectively. This variation of results might be due to environmental or regional differences.
The malar pattern of melasma was most commonly seen with 54% of study participants. In contrast to our findings, Achar and Rathi reported centrofacial as the most common pattern (55.44%) in their study. This variation may be due to different sample and environmental conditions.
Thappa and Goh and Dlova in their studies from Singapore and South India, respectively, observed that malar distribution was the most common, which was in accordance with our study.
Sun exposure was found to be the most common (80%) aggravating factor in melasma patients; next common was pregnancy with 50%. Guinot et al. concluded the same. In the study by Achar and Rathi, about 55.12% of patients reported that their disease exacerbated during sun exposure. It is in great contrast to the report by Pathak et al., which suggests that sunlight exacerbates melasma in all patients. Few other studies have also reported a minimum relation with either pregnancy or oral contraceptives like the ones by Sanchez et al. and Pathak et al, whereas in our study, we found pregnancy and oral contraceptive pills to be an aggravating factor in 50% and 38% participants, respectively.
Absolute MASI score values at each month did not show any significance between three groups, but there was proportionally greater decrease in MASI score in Group A and Group C than Group B and the P value >0.05 was not significant. In split-face trial, Ebrahimi and Naeini used topical 3% TA suspension for one side of the face and a 3% hydroquinone, 2% vitamin C, and 0.01% dexamethasone suspension for the other side of the face. A significant decrease in MASI score was observed in both the groups, but with no significant difference between them. This was in accordance with our study. Lee et al. conducted a prospective open-label study to evaluate the effectiveness of weekly microinjection of TA in the treatment of melasma. They observed statistically significant decline in MASI score from baseline to 8 and 12 weeks. Kaushik et al. also reported statistically significance in the different treatment groups.In our study, Group A showed most percentage improvement in MASI score. Group C was next most improved on MASI score with P value <0.05, which was statistically significant. Ayuthaya et al. reported that therapeutic effect of 5% TA gel on melasma was neither superior nor different from its vehicle.
There was significant association between occurrences of side effects in all the three study groups, with Group A and B that showed much less side effects than Group C. Mild discomfort, burning sensation, and erythema were observed when it was used intradermally, which subsided without the need for other interventions as with Budanmakuntla et al.
Patients with melasma duration less than 5 years showed significant improvement, with mean age of melasma of 3.2 ± 4.2 years. Similar duration was seen in the studies by Kothari et al. (3.1 ± 3.39 years), Pawar et al., and Achar and Rathi (3.59 years) whereas mixed type of melasma showed significantly better improvement. TA microinjection was said to cause mild discomfort, burning sensation, and erythema for 1 to 2 days in one study by Budanmakuntla et al.; these findings are in consistence with our study.
| Conclusion|| |
Triple combination is the mainstay treatment of melasma since decades but because of its side effects, new emerging and promising treatment options are available and TA is one of them. On the basis of these results, TA can be used as potentially a new, effective, safe, and promising therapeutic agent in melasma. The medication is easily available and affordable. Better therapeutic response to treatment in the intralesional group could be attributed to the deeper and uniform delivery of the medication through intradermal route.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, patients have given their consent for their images and other clinical information to be reported for publication.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16], [Figure 17], [Figure 18], [Figure 19], [Figure 20], [Figure 21]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]
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