Tranexamic acid microinjections versus tranexamic acid mesoneedling in the treatment of facial melasma: A randomized assessor‐blind split‐face controlled trial

Melasma is a hyperpigmentary disorder causing cosmetic disfigurement. We aimed to compare the efficacy and safety of tranexamic acid (TXA) microinjections with TXA mesoneedling for facial melasma.


| INTRODUC TI ON
Melasma is an acquired hyperpigmentary disorder emerging most commonly as symmetric patches and macules on the areas of face and neck exposed to sun. 1 In fact, melasma is considered a cosmetic disfigurement that can adversely influence the quality of life. 2 Melasma can differ in severity as there are differences in the intensity of pigmentation and area of involvement. The patients' appearance can be more affected in severe cases, causing them to seek treatment. 3 Although pregnancy, exposure to ultraviolet, genetic predisposition, inflammatory conditions, phototoxic drugs, contraceptive pills, and sex hormones have been associated with melasma, the exact underlying mechanism is not completely understood. 4 Several treatments exist for melasma, such as depigmenting agents, chemical peeling, and laser ablation; however, none is universally accepted in terms of efficacy and patient satisfaction. 4 Tranexamic acid (TXA) is a plasminogen activation inhibitor and a synthetic lysine analog, primarily used as an antifibrinolytic or antihemorrhagic agent. 5 It has also been used for the treatment of melasma. Evidence shows that TXA contributes to the reduction in epidermal melanin content, mast cell numbers, and dermal vascularity 6 ; nevertheless, its precise mechanism of action remains unknown. TXA has been applied through different modes of administration, including topically, orally, and intradermally, in the treatment of melasma. [7][8][9] Since the uptake of TXA, when used topically, may not be high enough, different strategies have been applied to increase the delivery of TXA to the target tissue. 10 Microneedling uses fine needles to cross the skin barrier and deliver the drug directly to the dermis, resulting in increased penetration of the drug. 11 This method has been effective for the treatment of melasma either alone or in combination with TXA. 12,13 Microinjections of TXA have also been used for melasma, showing promising results. 14 In the current study, we aimed to compare the efficacy and safety of TXA microinjections to topical TXA with microneedling in the treatment of facial melasma.

| Participants and study design
This assessor-blind split-face randomized controlled trial included patients with melasma referred to a dermatology clinic from November 30, 2020, to April 30, 2021. The inclusion criterion was symmetric malar melasma defined as bilateral malar melasma with similar appearance and location. The exclusion criteria were concurrent use of oral contraceptives, use of anticonvulsive, antidepressant, or thyroid medications, coagulopathies or the use of anticoagulants, hypersensitivity to TXA, and pregnancy or lactation. Also, patients who had active herpes, facial wart, or active dermatoses at the time and site of the procedures were excluded from the study. The sample size was calculated as 27 based on the following formula and α = 0.05, The study received ethics approval from the Ethics Committee and complies with the statements of the Declaration of Helsinki. Written informed consent was obtained from the patients. The trial has also been registered while recruiting at the Iranian Registry of Clinical Trials (IRCT).

| Data analysis
We used mean and standard deviation to describe continuous variables and frequency and percentage to describe categorical vari-

| RE SULTS
Initially, 33 patients were evaluated for eligibility, of whom two declined to participate and four did not meet the inclusion criteria ( Figure 1).  Table 3). Photographs of a patient before and after treatment are illustrated in Figure 2.
As for complications, PIH only occurred in 1 patient of the TXA mesoneedling group. All other complications, including erythema, scaling, and edema were significantly more frequent with TXA mesoneedling compared to TXA microinjection (p < 0.001) ( Table 4).

| DISCUSS ION
In the current study, we found comparable improvement in mMASI Of note, there appears to be a potential contradiction; although complications were more frequent with TXA mesoneedling, patients were more satisfied with this treatment method. The patients have seemingly graded their satisfaction based on the improvement of melasma, regardless of the accompanying adverse events.
Intradermal injection of TXA led to better results compared with its topical application in Egyptian melasma patients. 21 However, the superiority of the intradermal over the topical route was not confirmed in the systematic review and meta-analysis by Feng et al. 1 Intradermal TXA injection has also shown promising results in comparison with Erbium-YAG laser. 22 Intralesional TXA has been reported to be superior to cryotherapy regarding both safety and efficacy. 23 On the other hand, microneedling with TXA yielded better but not statistically significant results compared to microneedling with vitamin C. 24 In another study, local infiltration of TXA combined with 4% hydroquinone resulted in significantly better outcomes than hydroquinone alone, 25 showing the efficacy of TXA as an adjunct therapy. 26 Another finding of the current study was the significantly higher Also, randomized trials with a control arm receiving hydroquinone alone can determine the add-on effect of these interventions or their true effect.

AUTH O R CO NTR I B UTI O N S
NP contributed to conceptualization and study validation. MA contributed to implementation and supervision. ZS contributed to data analysis and interpretation. FFN and MA contributed to writing and reviewing. All authors read and approved the final version of the manuscript.

ACK N OWLED G M ENTS
We sincerely appreciate the dedicated efforts of the investigators, the coordinators, the volunteer patients, and the personnel of Isfahan University of Medical Sciences Dermatology Clinic.

FU N D I N G I N FO R M ATI O N
Isfahan University of Medical Sciences funded the current study.

DATA AVA I L A B I L I T Y S TAT E M E N T
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

CO M PE TI N G I NTER E S T
The authors declare that they have no competing interest.

CO N S E NT FO R PU B LI C ATI O N
The patient whose images are presented in the manuscript gave us consent for their publication.

E TH I C A L A PPROVA L A N D CO N S E NT TO PA RTI CI PATE
The study received ethics approval from the Ethics Committee