Effectiveness of combination therapy of broadband light and intradermal injection of tranexamic acid in the treatment of chloasma

To investigate the efficacy and safety of broadband light (BBL) combined with intradermal injection of tranexamic acid for treating melasma.


| INTRODUC TI ON
Women in their 30s and 40s are particularly susceptible to melasma, which is characterized by symmetrical yellow or dark brown pigmentation on the face. 1 The treatment for melasma is extremely challenging and is prone to frequent recurrences, affecting patients' appearance and quality of life. 2 Current research suggests that four pathogenesis are involved in the development of melasma, that is, melanogenesis, inflammation, vascularization, and defective skin barrier. 3 At present, there are various treatments for melasma, including photoelectric and drug therapies. 4 Tranexamic acid (TA) has been used in the treatment of melasma and has shown good therapeutic effects; it is given orally or via intradermal injection. [5][6][7] Photoelectric therapy is also one of the main treatment methods for melasma. Broadband light (BBL) is the sixth generation of photon technology, which belongs to nonablative therapy. It targets both melanin and hemoglobin as chromophores, hitting the spots with more precise photon energy and reducing vascularization with mild effects and light side effects.
Although there have been several articles on the use of TA combined with photoelectric therapy in the treatment of melasma, the efficiency of this treatment approach is unclear. Thus, this new combination therapy should be explored. In the present study, we evaluated the effect of BBL combined with the intradermal injection of TA in the treatment of melasma.

| Study design
This single-center, parallel-group, and assessor-and analyst-blinded randomized controlled trial was conducted in the Department of Plastic and Aesthetic Surgery at our hospital between January 2021 and April 2022. The research protocol was examined and approved by the ethics committee of the Chinese Clinical Trial Registry. The benefits, risks, and potential complications were explained to the study participants prior to obtaining written informed consent.

| Study participants
Sample size is calculated by the calculation formula of sample size estimation for superior efficacy clinical trials as follows.
n T = number of group III, n C = number of control group.
Our main evaluation index is the decrease in MASI. πC = result of preliminary experiment in control group≈28% πT = result of preliminary experiment in group III≈62% n T = n C = 7.85 × (0.28 × 0.72 + 0.62 × 0.38)/(0.62-0.28-0) 2 ≈29.7 Altogether, 120 patients with classic clinical features of melasma and skin types III-IV aged between 20-50 years were enrolled in the study and classified into four groups according to treatment received. The inclusion criteria were as follows: (a) met the diagnostic criteria of the 2021 Edition of "Consensus on diagnosis and treatment of melasma in China" 8 (b) normal coagulation function; and (c) willing to sign the informed consent and complete the study. The exclusion criteria included the following: (a) coagulation disorder before treatment; (b) with history of thrombosis and cardiovascular, cerebrovascular, gynecological, and liver diseases; (c) allergic to TA; (d) pregnant and lactating; (e) with immune deficiency diseases; (f) using light-sensitive drugs (such as retinoids and tetracycline); (g) scar history; (h) with mental disorder diagnosed within 2 months; and (i) with high expectations and poor compliance.
114 of 120 patients involved in the study were treatment naïve. 6 patients had been treated with tranexamic acid orally previously and the treatment had been suspended for more than half a year for some reasons. 2, 2, 1, and 1 of the 6 patients were, respectively, involved in the control group, group I, group II and group III.

| Treatment groups
In the control group, TA tablets (Transamin®, 0. combined with intradermal injection of TA was administered once a The BBL treatment and TA intradermal injection were performed same as group I and group II. The BBL treatment went before TA intradermal injection. Given the duration of the anesthetic effect of lidocaine cream, there was no gap between the two procedures to reduce the pain of injection. All participants were instructed to wear sunscreen that was SPF greater than 30 9 and avoid the sun outdoors. Re-examination was done to observe side effects and relapses at one month after the treatment.

| Evaluation method
The MASI score In this study, brown spot (yellow areas in Figure 2), which represents the excess of melanin and lesions deeper within the skin was used to evaluate the pigmentation of melasma. Red area measured with VISIA represents a variety of conditions, such as acne, inflammation, spider veins, or dilated capillaries (blue areas in Figure 2). All measurements were performed in the same room with the same lighting and without daylight. SPSS 22.0 software was used for data analyses. Data were expressed as mean ± standard deviation (X ± S), and statistical significance was assumed for p < 0.05. One-way analysis of variance was used to compare the data among four groups.

| Demographic characteristics of patients
The patients were aged 37.4 ± 4.2 (aged 24-51) years with skin type III or IV (Fitzpatrick skin types). The mean duration of melasma was 8.8 ± 4.2 years. The mean baseline MASI score was 13.6 ± 2.8 ( Table 1).

| MASI score
After the 3-month treatment, all the four groups had decreased MASI scores (p < 0.05 vs. baseline for the four groups), although a significant reduction in MASI scores was observed in group III (p < 0.01 vs. baseline). The reduction in the MASI scores was not significantly different among the control group, group I, and group II. However, the decreased MASI scores were significantly higher in group III than in the other three groups ( Table 2 and Figure 1).

| VISIA skin assessment
After the 3-month treatment, all the four groups had improved brown spot and red zone rankings (p < 0.05 vs. baseline for the four groups).
The improvement rates of brown spot and red zone ranking via VISIA were not significantly different among the control group, group I, and group II; however, the improvement rates were significantly higher in group III than in the other three groups ( Figure 2 and Table 3). The typical VISIA images of the four groups before and after the treatment are shown in Figure 2. The ranking shows the percentile of each patient in comparison with the age-matched controls. For example, a patient with a red zone ranking of 60% means that her red zone situation is better than 60% of the female population of the same age and race. 17%, 23%, 20%, and 60% of the control group and groups I, II, and III, respectively, felt that they got significant improvements (Figure 3).

| Adverse reactions and relapses
Two patients in group I developed transient erythema and pruritus.
One patient in group II had still petechiae left on his skin for 1 week after the injection. No obvious adverse reactions were seen after treatment in the other groups, and no abnormal coagulation function was found during the re-examination at 1 month later. Two patients in control group relapsed at one month after the treatment; there was one relapse in group I and there were no relapses in groups II and III.

| DISCUSS ION
Thus far, the pathogenesis of melasma has not been completely elucidated. Chronic UV exposure, female hormonal stimulation, thyroid dysfunction, cosmetics, drugs, and genetic predisposition all play a role in the development of melasma. 4,12,13 Patients with melasma are prone to frequent recurrences, affecting their appearance and quality of life, and treatment is extremely challenging.
When considering treatment for melasma, the pathogenesis is important. There are various pathophysiological mechanisms that comprise melasma, including (1) biologically active melanocytes; (2) aggregation of melanin and melanosomes in the dermis and epidermis; (3) increased mast cell count, and solar elastosis; (4) altered basement membrane; (5) increased vascularization. 14 Increased vascularity with an increased amount of VEGF and blood vessels within melasma lesion skin was reported to be a major finding in melasma. 15 At present, all kinds of therapy have been used in the treatment of melasma, including administration of oral drugs (such as vitamin C, vitamin E, TA, glutathione, and so on), sunscreens, external use of depigmenting agents, mild topical corticosteroids, tretinoin, and chemical peels, among others. Photoelectric therapy like intense pulsed light and various lasers have also been used. 14, [16][17][18][19] However, the treatment approach of using a single method has certain limitations; thus, combination therapy is more likely to be developed and applied in the clinical treatment of melasma. 5,20 Tranexamic acid (TA) has been used for many years to treat melasma. 21 It is an antifibrinolytic drug, which has been proven to inhibit the synthesis and transport of melanin particles and the formation of neovascularization by blocking plasminogen activator and plasminogen activity. 22 Besides, TA can reduce mast cells count, 23 remodel solar elastosis, 14 and accelerate the recovery of impaired skin barrier function. 24 The significantly reduced  Baseline brown spot ranking (%) 27.6 ± 5.9 26.8 ± 6.9 28.5 ± 5.6 27.8 ± 3.7 Baseline red zone ranking (%) 37.9 ± 8.7 37.1 ± 6.9 36.5 ± 5.3 37.4 ± 5.6 Brown sport ranking after treatment (%) 36.5 ± 7.8 36.5 ± 7.3 37.6 ± 6.1 48.3 ± 6.1 Red zone ranking after treatment (%) 48.9 ± 8.6 46.8 ± 7.5 45.8 ± 5.9 68.2 ± 7.3 Brown spot ranking improvement (%) 9.0 ± 3.0 9.6 ± 3.9 9.1 ± 3.3 20.5 ± 5.7 Red zone ranking improvement (%) 11.0 ± 3.1 9.7 ± 2.6 9.3 ± 2.3 30.8 ± 5.8 Note: Data are presented as mean ± standard deviation.

TA B L E 3
The ranking of brown spots and red zones by VISIA in the four groups before and after treatment F I G U R E 3 Patients' subjective selfassessments of treatments. Gray bar = no change; yellow bar = mild improvement; pink bar = moderate improvement; blue bar = significant improvement.
between blood vessels and melasma. 42 Our results show that BBL not only effectively reduced the pigmentation, but also the vas- The combined application of BBL and TA act on multiple aspects of melasma pathogenesis to achieve synergistic effects, improving melasma more effectively. Besides, topical application of TA has been reported to prevent rebound pigmentation after IPL treatment. 45 Presumably, the same effect may apply to BBL. This combination therapy is simple and effective, avoids the side effects of oral drugs.
One limitation of our study was that we did not test the transepidermal water loss (TEWL) and hydration content. So, the skin barrier integrity or function was not evaluated. The one-month follow-up period was another limitation. Longer follow-up is needed to confirm efficacy and recurrence.

| CON CLUS ION
The effect of BBL combined with the intradermal injection of TA in the treatment of melasma is remarkable. This combination therapy can be an alternative and effective treatment for managing melasma.

CO N FLI C T O F I NTE R E S T
The authors declare no conflicts of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
All of the authors have seen and agreed to the submitted version of the paper and bear responsibility for it. All of the material is original; this has been neither published elsewhere nor submitted for publication simultaneously. The data that support the findings of this study are openly available in Mendeley Data at https://data.mende ley.com.

E TH I C S S TATEM ENT
All procedures were performed in accordance with the Guidelines