Oral Tranexamic Acid with Fluocinolone-Based Triple Combination Cream Versus Fluocinolone-Based Triple Combination Cream Alone in Melasma: An Open Labeled Randomized Comparative Trial.

BACKGROUND: Melasma is a common acquired cause of facial hyperpigmentation with no definitive therapy. Tranexamic acid, a plasmin inhibitor, has demonstrated depigmenting properties and combining this oral drug with other modalities of treatment has shown promising results.
OBJECTIVES: To compare the efficacy of a combination of oral tranexamic acid and fluocinolone-based triple combination cream with that of fluocinolone-based triple combination cream alone in melasma among Indian patients.
MATERIALS AND METHODS: 40 patients of melasma of either sex attending to dermatology OPD were enrolled in this study. Participants were randomly divided into two groups with 20 patients in each group. Group A patients were asked to apply the cream only and Group B patients received oral tranexamic acid 250 mg twice daily and applied a triple combination cream containing fluocinolone acetonide 0.01%, tretinoin 0.05%, and hydroquinone 2% once daily for 8 weeks. Response was evaluated using melasma area severity index (MASI) at baseline, 4 weeks, and 8 weeks.
RESULTS: 40 patients completed the study. The MASI scores at baseline, 4 weeks and 8 weeks in group A were 15.425 + 1.09, 11.075 + 9.167 and 6.995 + 6.056 respectively and in group B 18.243 + 1.05, 6.135 + 4.94 and 2.19 + 3.38. Intergroup comparison showed a faster reduction in pigmentation in Group B as compared to Group A and the results were statistically significant at 4 weeks (P value 0.014) and 8 weeks (P value 0.000). The efficacy was maintained throughout the 6-month follow-up period.
CONCLUSION: Addition of oral tranexamic acid to fluocinolone-based triple combination cream results in a faster and sustained improvement in the treatment of melasma.

RCT Entities:   Population Interventions Outcomes

What was known?

Existing treatment modalities for melasma are not satisfactory.

Tranexamic acid alone or in combination with other modalities like LASER or hydroquinone cream has shown promising result in the treatment in melasma.

Introduction

Melasma is an acquired disorder of hyperpigmentation presenting over the sun-exposed skin. Females in their reproductive age group are commonly affected with cheek, nose, upper lip, and forehead being the predominant areas of involvement. However, it can occur in men and also over areas other than the face.[1] It is classically known to affect females of Asian or Hispanic origin with Fitzpatrick skin type III-V.[2] Clinically, when the area of involvement is taken into consideration, it can be centrofacial, malar or mandibular. Based on histological and Wood's lamp examination, it can be of epidermal, dermal or mixed type. From an etiological point of view, it is related to high intensity ultra violet ray exposure, pregnancy, contraceptives, drugs, hormone therapy, and genetic abnormality.[3]

A predilection for facial skin and relative refractoriness to treatment puts its sufferers into cosmetic disfigurement along with intense psychological distress. It imparts a poor quality of life with adversely affected social interaction, recreation, and emotional well being.[4]

A variety of treatment has been proposed and used in melasma. They include topical medications such as hydroquinone and related drugs, azelaic acid, corticosteroids, procedural treatments like chemical peels, microdermabrasion and LASER, and light-based options like Q-switched Nd: YAG laser, intense pulse light, and so on. All of these target to decrease melanin production over the local area directly or indirectly.

One of the most popular topical therapy for melasma world wide is the triple combination regimen known as Kligman's formula. Kligman had originally used dexamthasone 0.1% along with tretinoin 0.1% and hydroquinone 5% in a cream base.[5] However, there have been many modifications where dexamethasone has been substituted with other steroids such as hydrocortisone, mometasone, fluocinolone and fluticasone, and the strength of tretinoin and hydroquinone have been altered to suit different skin types. A fluocinolone-based triple combination (fluocinolone acetonide 0.01%, tretinoin 0.05%, and hydroquinone 2%) has been introduced in India since last few years and is considered to be a safer option with studies claiming little or no side effects even when used for a very long time.[6] However, any steroid should ideally not be used on the face for a longer duration as it can promote unpleasant side effects like telangiectasia, hypertrichosis, atrophy, and acneiform eruptions.[7] Similarly, long-term safety profile of topical hydroquinone is also debatable as it often results in paradoxical hyper pigmentation, confetti-like depigmentation, and irritant dermatitis.[8]

Tranexamic acid is known to have skin-lightening effect and has been used topically, intralesionally as microinjections and very recently, orally.[91011] It has shown promising results by enhancing the efficacy of conventional melasma treatment like LASER and hydroquinone.[1213] Considering the atrophogenic and other side effects of individual components of triple combination regimen, concomitant use of oral tranexamic acid would help in decreasing the duration of topical steroid based treatment.

Aims

To compare the efficacy of oral tranexamic acid with fluocinolone-based triple combination cream with fluocinolone-based triple combination cream alone in facial melasma.

Objectives

The primary objective was to assess the degree of improvement in pigmentation objectively using MASI at baseline, 4 weeks and 8 weeks of treatment.

Materials and Methods

The study was approved by Institutional ethics committee. This was a prospective, parallel, randomized, open label, comparative, clinical study, conducted in patients attending the skin OPD of the tertiary care hospital, from January 2013 to June 2013. The study was not registered in clinical trial registry. Written informed consent from patients was obtained for enrolment and photography.

Inclusion criteria

Patients with facial melasma belonging to both sexes, any age group and willing to undergo treatment and to come for follow up were included in the study.

Exclusion criteria

Pregnant and lactating females, those with history of thrombosis or a tendency of blood coagulation approved by laboratory tests, patients having psychological disorders, those on photosensitizing drugs or thyroid hormones and those who were not willing to come for follow up, or had unrealistic expectation from the treatment, those who had taken other melasma therapies within last 6 months and those who refused to allow photographs were excluded from study.

All the patients were explained about the study. Written informed consent was taken from the each patient prior to the treatment.

All patients who fulfilled the selection criteria were allocated in 1:1 ratio with alternate randomization into groups A and B [Figure 1]. Group A patients were asked to apply fluocinolone-based triple combination alone and Group B patients received oral tranexamic acid 250 mg twice daily after food along with application of a topical formulation containing fluocinolone acetonide 0.01%, tretinoin 0.05%, and hydroquinone 2%. Patients were advised to apply triple combination topically once daily at night and wash their face the next morning. All patients were advised to apply broad spectrum sunscreens with an SPF of 15.

Figure 1

Patient flow diagram

Pre- and post-treatment evaluation was done with detailed history, clinical examination, melasma area severity index (MASI) scoring, and colour photographs. MASI scoring and colour photographs were taken at baseline, 4 weeks and 8 weeks after treatment.

General examination (with periodic monitoring of BP) and a detailed ophthalmological examination with special emphasis on colour vision abnormalities and retinal artery occlusion were done at each visit to rule out any side effects of tranexamic acid. Complete blood count, coagulation profile and liver function test were done in all patients before prescribing them tranexamic acid and also at each visit to rule out any coagulation abnormality.

To calculate MASI, we followed the method introduced by Kimbrough-Green CK et al.[14] The face was divided into four regions [forehead (F) 30%; right malar (MR) 30%; left malar (ML) 30%, chin (C) 10%] and each area was given a numerical value (A, 0–6). The sum of severity for darkness (D, 0–4) and homogeneity (H, 0–4) of melasma was multiplied by the numerical value and percentage of each area. These values were then added to obtain MASI by a single-blinded trained dermatologist.

MASI = 0.3(DF + HF) AF + 0.3(DMR + HMR) AMR + 0.3(DML + HML) AML + 0.1(DC + HC) AC

A minimum of 6 months of follow up in each case was done to look for relapse, if any. Data obtained were statistically analyzed using SPSS 16 software. Student t test and ANOVA were used to calculate significant differences between parameters. Variables were considered significant for a confidence interval of 95% (P < 0.05). Effect sizes were also calculated in order to identify the magnitude of effect of the intervention regardless of the sample size; effect sizes exceeding 0.80 were considered large.

Results

There were 40 patients included in the study and with 33 females and only 8 males of age between 24 and 55 years with a mean age 35.85 + 7.614 years [Table 1]. In Group A, 15 patients were female and 5 were male and in Group B 17 patients were female and 3 were male.

Table 1

Age Distribution among melasma patients

The MASI scores at baseline, 4 weeks and 8 weeks in group A were 15.425 + 1.09, 11.075 + 9. 167 and 6.995 + 6.056 respectively and in group B 18.243 + 1.05, 6.135 + 4.94 and 2.19 + 3.38 [Figure 2].

Figure 2

Objective assessment of melasma area severity Index (MASI), MASIb score at baseline, MASI 1 score at 4 weeks, MASI 2 score at 8weeks

Objective response to treatment as studied by fall in MASI scoring after 8 weeks was 54.65% reduction (from 15.425 to 6.995) in group A and 88% reduction (from 18.243 to 2.19) in group B. Of 20 cases of melasma which were treated with oral tranexamic acid and fluocinolone-based triple combination there was greater decrease in MASI scores at 4 weeks and 8 weeks [Figures 3 and 4]. Also the results were statistically significant at both 4 and 8 weeks with P < 0.05 [Table 2].

Figure 3

Pre- and post-treatment photographs in Group A at 0 and 8 weeks

Figure 4

Pre- and post-treatment photographs in Group B at 0 and 8 weeks

Table 2

Melasma area severity index-comparison between Group A and Group B at baseline, 4 weeks and 8 weeks

When the MASI scores were compared within the groups at 0, 4 and 8 weeks, the result was also statistically significant among those taking oral tranexamic acid at the end of 4 and 8 weeks with P < 0.05 [Table 3].

Table 3

Melasma area severity index-comparison within the Group at baseline, 4 weeks and 8 weeks

Effect sizes: The evaluation of the intervention magnitude was considered large with effect size being 1.0 at the end of 8 weeks when MASI scores were compared between group A and B.

When adverse effects were compared between the groups, the results were almost identical. Systemic side effects including ophthalmological adverse effects, a major concern in patients taking tranexamic acid, were not seen in any of the patients receiving the drug [Table 4].

Table 4

Comparison of adverse effects among both groups

The patients were followed up for 6 months and there was no recurrence.

Discussion

Finding a cure for melasma has always been a challenge for the treating dermatologist. Various treatment modalities, all of them aiming at reducing melanin synthesis, exist but come with their own side effect profile. Moreover, none of them are very effective in inducing a long term remission.

Tranexamic acid (trans-4-aminomethyl cyclohexanecarb oxylic acid) is a synthetic derivative of the amino acid lysine.[10] Primarily it is used as an agent to reduce blood loss in menorrhagia or after major surgical procedures by virtue of its plasmin inhibiting action. It exerts its antifibrinolytic action by blocking the lysine binding sites on plasminogen molecule.[10] It is well known that increased level of plasmin in keratinocytes induces synthesis of arachidonic acid and also increases level of α- melanocyte – stimulating hormone (α – MSH) both of which in turn stimulate melanogenesis.[15] UV radiation increases plasmin level and being a plasmin inhibitor, tranexamic acid is believed to block UV-induced melanogenesis.[1617] Moreover, because of structural similarity with tyrosine, tranexamic acid is also believed to be competitively inhibiting tyrosinase action.[17] Use of tranexamic acid in patients of melasma has shown reduction of melanin in the epidermis and decrease in vascularity and mast cell numbers in the dermis.[18] The safety profile of long-term use of oral tranexamic acid has been well established and use up to 4.5 gm/day has not been associated with any serious side effects in menorrhagia and post-surgical blood loss.[19] Whereas the conventional dose of tranexamic acid as a hemostatic is 1500 mg per day, most of the studies evaluating the depigmenting effect of the drug have used either 500 mg or a maximum of 750 mg per day.

In the study conducted by Karn D et al., from Nepal, clinical effect of oral tranexamic acid combined with topical hydroquinone was compared with that of topical hydroquinone alone.[13] Patients were advised to take tranexamic acid orally 500 mg per day for 12 weeks. Statistical analysis was done between within the groups only, i.e. intra-group and not inter-group and the fall in MASI was statistically significant in both the groups at eighth week but not significant in those receiving topical hydroquinone alone at 12th week. In our study MASI was calculated at baseline, 4 and 8 weeks time and fall in MASI was significant at 8 weeks in patients receiving both oral tranexamic acid and topical treatment within the group and also when compared with those receiving topical treatment alone.

The effect of oral tranexamic acid was studied by Wu et al., in which patients received the treatment for 6 months.[11] They did not compare it with any other modality and their criteria of evaluation were reduction in melasma size (expressed as percentage) at the end of 6 months. They graded outcome as follows: excellent: 90% reduction in size, good: 60%, fair: 30%, and poor: <30% reduction in size. After 6 months of treatment, the results were as follows: excellent (10.8%, 8/74), good (54%, 40/74), fair (31.1%, 23/74, and poor (4.1%, 3/74). Thus, the total improvement rate for melasma was 95.9% of the subjects.

Shin et al., in their study tried to evaluate clinical efficacy and safety of oral TA combined with low-fluence 1064-nm quality-switched neodymium-doped yttrium aluminum garnet (QSNY) laser for the treatment of melasma.[12] Patients in the combination group were treated with oral TA at a dose of 750 mg per day for 8 weeks. The resulting data showed that a treatment regimen combining low-fluence QSNY laser with oral TA led to a significantly greater mean reduction in mMASI score than low-fluence QSNY laser treatment alone. The major limitation, however, of this study was the mixed composition of the oral medication used. Patients took a combination oral pill with tranexamic acid, ascorbic acid, L-cysteine, calcium pantothenate, and pyridoxine hydrochloride. Specifically, other ingredients in the formulation – including ascorbic acid and L-cysteine have been reported to influence melanogenesis.

Kato and his colleagues had used oral tranexamic acid at a dose of 750 mg for 4 weeks in patients who underwent treatment with Q-switched Ruby laser for lentigenes and they found no significant change in post inflammatory hyper pigmentation.[20] They concluded that tranexamic acid might be having depigmenting effect but it may not be effective in preventing post inflammatory hyper pigmentation following laser therapy.

Lee and colleagues used microinjections of tranexamic acid where the agent was injected intradermally into the melasma lesion at 1cm interval.[10] The procedure was repeated once a week for 12 weeks and statistically significant reduction in MASI score was seen. They claimed intralesional therapy to be safe as it does not lead to systemic absorption of the drug. However, majority of the trials where oral tranexamic acid has been used, no report of significant systemic side effects has been reported. In our study also, apart from oligomenorrhoea in only one patient, no systemic side effect was found.

In conclusion, addition of oral Tranexamic acid to a conventional fluocinolone based triple regimen may enhance the clinical efficacy of topical treatment. Combining these two treatment modalities in our study resulted in greater and statistically significant improvement in MASI scores. Cases of melasma refractory to topical treatments may benefit from the addition. With a good safety profile, oral tranexamic acid may prove to be an effective agent in reducing the requirement of topical steroid over the face particularly in those who cannot opt for high end LASER-based treatment.

Limitations of our study are that it was not a blinded study so patient bias was present along with observer bias in subjective scoring and the study period was short. Also this was a pseudo-randomized study and no formal sample size determination was done.

What is new

Oral tranexamic acid can be used as an adjunct with fluocinolone based triple combination cream for faster and sustained improvement in melasma treatment.