Novel Treatment of Melasma Patients with oral Tranexamic Acid: A case series

Novel Treatment of Melasma Patients with 
Oral Tranexamic Acid: a case series 

I. Jane Hidajat,^1,2 Veronica¹

¹Department of Dermatovenereology, School of Medicine and Health Sciences Atma Jaya Catholic University of Indonesia, 
²Youth & Beauty Clinic Jakarta

ABSTRACT

Introduction: Melasma is a common, relapsing, acquired, symmetrical facial hypermelanosis, and had been recognized for centuries as it was initially reported by Hippocrates. The treatment of melasma is still challenging, various modalities from topical treatment to laser/light therapy have been developed, without satisfactory results, due to side effects and recurrences. Recently, there is a promising novel therapy in treating melasma with tranexamic acid (TA). It can be administered through topical, intradermal, microneedling, and oral routes. The response to oral tranexamic acid was reported to be more efficacious than other administration routes. Here we report the efficacy and safety of oral TA in treating melasma.

Case: A series of melasma cases treated with oral TA 250 mg twice daily combined with laser therapy. The results were observed after 12 weeks by comparing the before-after serial photographs, MASI scores, patients’ satisfaction scores, and adverse effects.

Discussion: TA inhibits ultraviolet-induced activation of plasminogen by blocking the lysine binding sites on plasminogen and in turn downregulates the activators of melanogenesis. From this case series, it can be seen that a combination of laser therapy and oral TA improved the treatment results evaluated from the serial photographs, MASI scores, and patients’ satisfaction scores.  No significant adverse effects were reported from the oral TA.

Conclusion: Oral TA is a safe and effective novel therapy for melasma that can be used as an adjunctive treatment to improve the efficacy with other modalities.

Keywords: melasma, tranexamic acid, laser

INTRODUCTION

Melasma is an acquired disorder of melanogenesis leading to hyperpigmentation and manifested by almost always symmetrical brown to gray-black macules and patches with serrated irregular edges.^1,2 The word melasma comes from the Greek “melas” which means black and refers to its brownish clinical presentation. Disease descriptions are recognized since the reports of Hippocrates (470–360 BC), when its worsening was referred to occur after sun exposure, fire heat, cold, and skin inflammations.¹

Melasma can affects all kind of races, especially people who live in tropical area, commonly in those who have dark skin (Fitzpatrick skin type III through V).^2,3 Melasma occurs in approximately 30% of Southeast Asia population, usually in reproductive-age women with history of chronic sun exposure, although also can occur in men (10%).^2,4 In Indonesia, the ratio of melasma between women and men is 24:1. The most common incidence occurs at age 30-44.² Genetic factors, UV irradiation exposure, pregnancy, oral contraceptives (OCP), thyroid dysfunction, cosmetic products, phototoxic drugs, and antiepileptic drugs have been considered as possible etiologies of melasma.⁵

Melasma occurs especially in sun-exposed areas, most commonly on the face and less commonly, on extra-facial locations such as the neck, arms, and chest.^4,6 Three clinical patterns are usually described: centro-facial, with patches on the frontal region, nasal dorsum, cheek bones, and chin areas (63 % of the cases); malar, which occurs in 21 % of the cases; and mandibular, seen in about 16 % of the patients.^1,2 In spite of being asymptomatic, melasma lesions cause aesthetic impairment and significantly affect the quality of life.^4,6

From a historical perspective, commonly used agents for the treatment of melasma include hydroquinone, kojic acid, retinoids, and corticosteroids. Of these treatments, hydroquinone remains the gold standard.⁷ However, all of these treatments are not without their drawbacks. Hydroquinone may cause erythema, burning, photosensitivity, and in more serious cases, ochronosis. Kojic acid is a known sensitizer and has caused mutagenesis in culture. Retinoids cause irritation, dryness, and scaling, and corticosteroid use on the face can promote unpleasant side effects such as telangiectasia, hypertrichosis, atrophy, and acneiform eruptions.⁸

Many studies have addressed the safety and efficacy of chemical peels and laser/light sources for pigment reduction in melasma. Such procedures are most often considered second- and third-line therapeutic approaches.⁹ Additionally, there is a promising novel therapy in treating melasma with tranexamic acid (TA). It can be administered through topical, intradermal, microneedling, and oral routes. The response to oral tranexamic acid was reported to be more efficacious compared to tranexamic acid soaks and cream.⁷

Given the global negative impact of melasma on quality of life, a quest to find more efficacious treatments that offer sustained long-term remission for patients with this frustrating and therapeutically challenging disorder is ongoing.⁹ Here we report the efficacy and safety of oral TA combined with laser therapy in treating melasma.

CASE

Here we report three cases of melasma in female patients, being treated with Q-switched (QS) NdYAG laser Spectra® by Lutronic™ combined with oral tranexamic acid (TA) 2x250 mg daily. The parameter setting for the QS NdYAG laser was 1.1-1.3 J/cm2, with endpoint presented as mild erythema, with treatment interval 3-4 weeks. All patients were female. The treatment results were measured with the patients’ photographs, modified melasma severity index (mMASI) score, and patient’s satisfaction score. The patient’s satisfaction score was evaluated by asking the patient to do self-assessment of melasma improvement which was graded along four scales: 3 = >75% lightening (excellent), 2 = 51-75% (good), 1 = 26-50% (fair), and 0 = 0-25% (poor).We also evaluate if there were any side effects from the treatment.

First patient was a 58-year-old female, came with recalcitrant melasma. Patient had been treated with topical cream from other clinic for around one year, improvement was seen until the 8^th month without further improvement. The mMASI score was 11.9 on the baseline. After 12 weeks of treatment, the mMASI score reduced to 3.6. Patient’s satisfaction score was graded as good (score 2). Patient reported a mild stomach discomfort during the first two weeks taking oral TA, but the complaint was gone after we suggested to take the oral TA immediately right after big meal.

Figure 1. Serial Photos of Case 1

Second patient was a 56-year-old female who refused to take topical treatment due to history of irritation post topical brightening cream, hence we suggested her to be treated with QS NdYAG laser and oral TA. The mMASI score was 5.4 on the baseline and reduced to 1.2. Patient reported that the treatment result was excellent (score 3). 

Figure 2. Serial Photos of Case 2

The third patient was a 46-year-old female with history of recalcitrant melasma to topical treatment. Patient agreed to undergo QS NdYAG treatment and oral TA. The mMASI score was 7.2 initially and reduced to 0.9. The patient was very satisfied with the result and graded the satisfaction score 3 (excellent). There was no side effects from the treatment, both laser and oral TA, in the second and third patients. 

Figure 3. Serial Photos of Case 3 

DISCUSSION

Melasma happens because of the increasing production of melanosome that triggered by hormone or UV exposure.² Keratinocytes produce plasminogen activator (PA). Epidermal basal cells contain plasminogen molecules. Plasmin plays a role in the release of basic fibroblast growth factor, which is a potent growth factor for melanocytes. Ultraviolet light and hormones can induce the synthesis of plasminogen activator and thereby increase plasmin, thus activating melanin synthesis.^3,10,11

The treatment of melasma is still challenging, various modalities have been developed, without satisfactory results, due to side effects and recurrences.¹² Hydroquinone-based therapy is well recognized as the first line of treatment choice. However, irritation, skin dryness, and exfoliation are common side effects associated with these treatments especially in darker skin phototypes. As a result, hydroquinone-free treatments would be an alternative option for melasma.³

Lasers and light devices have a role in the management of melasma. Generally, such devices must be used with caution in skin of color, especially among Asians, as the risk of post-inflammatory hyperpigmentation (PIH) following treatment is high. Melasma may occasionally darken following laser and light treatment.¹³ But as a second- or third-line treatment, lasers and light devices can offer patients with melasma, who are recalcitrant to topical treatment, a respite and improvement in the quality of life. Laser and light treatment can be a therapeutic option that will provide benefits to the patients. One of the most frequently used laser treatments was low fluence QS-NdYAG laser, also known as toning. The mechanism of action is a subcellular photothermolysis that could help eradicate the melanosome without melanocyte destruction. However, the use of this treatment should be in caution for darker skin patients, and a longstanding usage of this modality may cause a confetti-like hypopigmentation.^3,13 In these cases we carefully adjust the fluence to the result, limit the endpoint to mild erythema without causing any discomfort to the patients, and strictly monitor if there was any sign of hypopigmentation. There was no side effect encountered from the laser treatment.

TA use in melasma treatment was described for the first time by Nijor in 1979 in Japan. It is a synthetic derivative of lysine and exerts its effect by reversibly blocking the lysine binding sites on the plasminogen molecule, thereby inhibiting the plasminogen activator (PA) from converting plasminogen to plasmin.^3,14 Generally, studies have shown that TA is the only treatment modality that actually prevents melanocyte activation by sunlight, hormones, and injured keratinocytes via inhibiting the PA activation system. Additionally, TA not only reduces the formation of melasma but also reduces the likelihood of recurrence after the use of other therapeutic agents.¹⁴ TA also has potential for the treatment of PIH after laser treatment.¹⁵

According to systematic review and meta-analysis conducted by Zhang L in 2018, the use of TA was associated with reduced Melasma Area and Severity Index (MASI) and Melanin Index (MI).¹⁶ TA can be administered through various routes (topical, intradermal, microneedling, oral), either alone or with other modalities. When compared to topical hydroquinone (HQ), topical TA has equal efficacy with HQ in reducing MASI score and superior patient satisfaction score due to lesser adverse effects.^17–19 Mesotherapy with TA 4 mg/ml with vitamin C 3% and glutathione 2% had significant efficacy in reduction of mMASI score.⁵ Topical 3% TA  twice daily for 8 weeks combined with 1064-nm Q-switched neodymium-doped yttrium aluminum garnet laser also  reduce mMASI score significantly and  80% of the participants noticed a >50% improvement on the side with combination therapy at every follow-up visit.³ On other side, TA solution combined with fractional ablative CO₂ laser did not give significant result compared to fractional ablative CO₂ laser alone.¹² Compared to TA soaks and cream, oral TA is more efficacious in reducing MASI, Physician Global Assessment (PGA) and Visual Analogue Scale (VAS).⁷

There are several studies that support the significant benefit of oral tranexamic acid for melasma. Studies  used oral formulation of 250 mg bid TA for 3-4 months alone compared against baseline showed significant clinical improvement (49-90% reduction in melasma severity).^8,14,20,21 A retrospective study analyzing TA 250 mg bid in addition to a pre-existing ‘combination’ topical therapy for a mean duration of 3.7 months showed statistically significant reduction in melasma (69% mean improvement in MASI scores) and moderate to marked improvement in PGA scores following a 3-month treatment period.^8,22 When combined with another treatment, such as intense pulsed light (IPL) and low fluence Q-switched Nd:YAG (QSNY) laser, oral TA 250 mg tid or 500 mg daily also reported showed a significantly greater decrease in mean mMASI score and a greater self-assessed improvement in melasma than patients receiving IPL and laser treatment alone, indicating that oral TA may be a useful adjunctive therapy to laser or light treatment for melasma.^8,23,24

The significant adverse effects of oral TA include nausea, diarrhea, orthostatic reactions, anaphylactic shock, skin reactions, acute renal cortical necrosis, disturbances in color vision, abdominal distension, headache, tinnitus, menstrual irregularities, and, rarely, deep vein thrombosis (DVT).¹⁴ Lee et al reported side effects were experienced by 7% of 561 melasma patients treated with oral TA 250 mg BID over a 4-month period at a single center in Singapore; the most common side effects were abdominal bloating and pain (experienced by 2% of patients). One patient developed deep-vein thrombosis and therefore needed to discontinue the oral TA immediately. As a result, oral TA should be prescribed cautiously to those with risk factors of thromboembolism.²⁰ Sharma R reported that the main adverse effects in patients treated with tranexamic acid 250 mg BID for 3-month period were mild epigastric discomfort, hypomenorrhea, and headache, which did not warrant discontinuation of treatment.²⁵ Meanwhile, Rosario ED reported no serious adverse events were noted in melasma patients treated with TA 250 mg BID for 3-month period.²¹ In these three cases, there was no serious side effect noted. In one case a mild side effect was reported, presented as a mild gastric discomfort, which could be improved by taking the oral TA immediately after meal.

CONCLUSION

From these case series, we found that oral TA is a safe and effective novel therapy for melasma that can be used as an adjunctive treatment to improve the efficacy of other modality, such as topical or energy-based devices treatment.

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