Evaluating the effect of tranexamic acid as mesotherapy on persistent post‐acne erythema: A before and after study

Acne vulgaris is a common skin disease that is more common in young population and it can be associated with some sequels after resolving the lesions. Post‐inflammatory erythema is one of these complications that can be disturbing for patients and does not have any definite treatment. This study was aimed to evaluate the efficacy and safety of tranexamic acid (TA) as mesotherapy in treatment of post‐acne erythema (PAE) treatment.

cause complications like different types of scars and pigmentary changes. 7andard treatment for acne is classified according to the severity of the disease and the response to treatment, from topical treatments to systemic treatments.There are also a variety of other modalities for treatment of acne and acne complications, including resurfacing and vascular lasers, micro needling, and fractional radiofrequency; but the efficacy and safety of these treatments are not complete in many cases. 8,9On the other hand, the application of systemic retinoid which is one of the most effective treatments for active acne is limited due to the side effects it causes.Although systemic retinoid has a good response in controlling acne lesions and prevents the appearance of new complications, it cannot resolve previous permanent complications of it.For these reasons, it seems necessary to find a new effective treatment with more safety, especially about the complications. 10gmentary problems that affect many patients after clearing the active acne lesions is one of the complications that suffer patients.
Often, in patients with colored skin, this disorder is known as postinflammatory hyperpigmentation, but in patients with lighter skin color, this pigmentary change is known as erythema after inflammatory acne, which is called acne-related post-inflammatory erythema. 11,12ese acne residues can disappear in some patients spontaneously, but in many of them this problem remains unresolved. 13cepted treatments for post-acne erythema (PAE) vary widely, including radiofrequency, isotretinoin, pulse dye laser, adrenergic receptor agonists, and intense pulsed light device; but the mentioned methods for treatment of erythema do not have a completely acceptable therapeutic effect in all cases and may even cause pigmentation in the skin surface. 6,14anexamic acid (TA) is an anti-fibrinolytic agent that binds reversibly to plasminogen and prevents conversion to plasmin.TA can also reduce the activity of vascular endothelial growth factor and endothelin-1 and thereby decrease angiogenesis, reduce proinflammatory factors and inflammation and also melanogenesis by inhibiting plasminogen activity; hence TA can be useful in the treatment of post-inflammatory erythema and pigmentation. 15It can be used in different doses orally, IV, and topically.Using TA as mesotherapy can be highly cost-effective and safe than systemic usage for therapists and patients. 16erefore, TA has three major effects on dermatological issues, including lightening, anti-inflammatory, and anti-redness, and hence is used widely in dermatology.However, studies carried out to date on the anti-redness property of TA are scarce. 17 the best of our knowledge, no similar study has been examined the usefulness of TA as mesotherapy for post-inflammatory erythema and PAE.The aim of this study was to evaluate the efficacy and safety of TA as mesotherapy in post-acne erythema.

| ME THODS
This before-after split-face clinical trial study was performed at the dermatology clinic from September 2019 to April 2021.The number of patients participating in this study was 17 patients who were treated with TA as mesotherapy for the treatment of persistent post-acne erythema in the split-face target areas.Of these, 15 patients completed the study.One patient did not refer for follow-up photo 1 month after the end of the mesotherapy sessions and one participant did not refer for the second session of treatment due to intolerance.
Inclusion criteria were patients with persistent PAE (no improvement in erythema after 3 months).
Exclusion criteria included history of coagulopathy disorders such as disseminated intravascular coagulation (DIC), pulmonary embolism, stroke, and DVT, as well as cancers and drug allergies in previous use and pregnancy and lactation, or deciding to get pregnant, using medications which have drug interactions with TA and patients who have been treated orally and topically with tretinoid drugs over the past month.Also, patients who suffered from any complications that was related to the treatment process or could not be tolerated by them, and patients who did not want to continue treatment for any reason were excluded from the study.
Patient selection was done by the main researcher of the project and then complete information about the study was explained to them and the patients completed the consent form before entering the study.
All patients were photographed with a Visioface device before starting treatment.Patients were treated for two sessions with 2 weeks interval then 1 month after the end of the treatment sessions, they referred for follow-up and imaging with Visioface device.
In this study, right side of each patient's face is considered for case and the other side is considered as control group and the two sides of patient's faces are compared during the treatment period and 1 month after the completion of treatment.On the right side of the patient's face topical anesthesia Xyla-p cream (lidocaine+pirlocaine) was used 30 min before the start of the treatment.After anesthesia of injection site, the anesthetic cream was removed from the patient's skin and sterilized with an alcohol swab.Then, TA was injected intra-dermally to the right side of each patient's face (5 mg TA ampules with 1 mL gauge30 BD insulin syringes used for injection) at the area with erythema due to post-acne inflammation with intervals of 1 cm in the amount of 0.1 mL.
Depending on the extent of acne erythema, patients were injected with 2-5 mL of TA.After treatment, the site was cleaned with sterile gauze impregnated with normal saline and then 0.25% zinc oxide ointment was applied to the treatment area.Patients were informed not to wash their faces until the end of the treatment day and to apply sunscreen cream to protect themselves from the sun for 3-4 days after treatment.The patient was also explained that the swelling in the area would disappear from the injection until the next day.No drug was injected on the left side of the patient's face and was considered as control group.
The patients' treatment sessions were performed by a physician at 2-week interval and were photographed by the Visioface device in the first visit before the start of the study and 1 month after the last injection.During the evaluation of the treatment, each side of the face were compared before and after treatment by Visioface device at color mode with quantitative scales such as lesions count, area, and area percent.

| Statistical analysis
We used one-way Kolmogorov-Smirnov (KS) test to evaluate the normality distribution of the study variables.Since the KS test values showed that the included variables have not follow normal distribution, we used Wilcoxon signed ranks test for the numerical data analysis.A p value of less than 5% was considered statistically significant.We used SPSS (v.22, Chicago, IL) as our analytical software.

| RE SULTS
Out of 17 patients, 15 patients finally completed treatment sessions of study.Eleven patients were female and four of them were male.
Participants were in the age range of 18-33 years old with mean (±SD) of 22.5 (±4) years old.
At Table 1, results of our study including comparison of each sided lesions before and after treatment by quantitative scales such as lesions counts, area, and area percent are presented.
Mean of lesions count before and after treatment at right side of participants faces were 10.9 and 7.1, respectively and at left side were 9.7 and 8.5, respectively.Also mean of lesions area (area percent) of right-sided lesions before and after therapeutic method were 5853Px 2 (1.33%) (Px = pixel) and 3154Px 2 (0.99%), respectively and for the left-sided lesions were 5314 Px 2 (1.11%) and 3925 Px 2 (0.70%), respectively.
According to our results, significant differences at right-sided lesions before and after treatment are noted which p-values of count, area, and area percent are 0.047, 0.002, and 0.035, respectively.Any significant differences at left-sided lesions count, area, and area percent before and after the period of study are detected.
Intradermal injection of TA with local anesthesia had mild to moderate pain for patients and was tolerable for all patients.After the treatment, the patients mentioned that the swelling had disappeared by the end of the treatment day, and the erythema at the injection site had disappeared within 2-3 days, and no side effects such as persistent swelling and inflammation, PIH, and persistent erythema were observed (Figures 1 and 2).The patient was also asked to rate PAE healing on a scale of 1-5 during the last session.This subjective score's mean score was 4.01 (data not shown).

| DISCUSS ION
Acne vulgaris is a common skin problem among adults and young people. 18The side effects of this problem are so great that it can even cause suicidal thoughts in a person.Consequences of this problem can be hyperpigmentation after acne, scars, and one of the important issues that it can have a wide range of psychological effects is PAE. 6,19,20This problem in patients with lighter skin color is more common and prominent and presented as a separate erythematous macule. 21lated changes in the micro-papillary unit of the skin occur during wound healing process of post-acne stage that are not seen as telangiectasia but are seen as erythema instead.Also in this stage, the epidermis has not yet reached full maturity, as we know that the dermis is also thin and inflammatory mediators are active.These changes can cause post-acne erythema.When visiting patients in this stage, a combination of hyperpigmentation, subsequent erythema, and scarring is usually seen.It is important to determine the patient's priority in treating because there are different treatments method for each of these cases. 11,22 this study, for the first time, the effects of TA as mesotherapy on erythematous lesions after acne have been studied because of TA B L E 1 Comparison of each sided lesions before and after treatment, and comparison of them together after procedure by quantitative scales such as lesions counts, area, and area percent.anti-inflammatory, anti-redness, and anti-angiogenesis of it.In this study, patients were examined as split-face to prevent all factors that could interfere with the patient's clinical outcomes.
The results showed that according to the documentation and video evaluations of patients before and after the intervention, a significant improvement of acne erythema can be seen in this method.
Patients were treated in two sessions 2 weeks apart and then followed up for 1 month that showed very good results.Patients improved significantly 4 weeks after starting treatment.All patients were satisfied with the healing of the treated side and the results showed that the rate of healing of lesions in number, area, and surface had no significant relationship with the duration of erythema after acne.
TA is a substance that widely used in bleeding control.There are also important contraindications to TA, for example, DVT, pulmonary embolism, cerebrovascular thrombosis, and certain contraindications to TA. 19 It is an anti-fibrinolytic and plasminogen activator inhibitor with hemostatic function and anti-inflammatory, anti-angiogenesis, and anti-allergic effects.Many studies have shown its positive effect on wound healing and in addition it inhibits pigmentation caused by ultraviolet rays.The exact mechanism of action of TA is still unknown, but experimental observations show that it can reduce melanin in the epidermis and reduce the vascularity and the number of mast cells.Also, TA is the only drug that can prevent melanocytes from being activated by ultraviolet light in the hormonal field. 23For these reasons, it has shown positive outcomes in melasma and erythema produced by rosacea, as well as pigmentation induced by UV radiation, as compared to alternative therapies. 24gh levels of serine protease such as kallikrein, urokinase, and plasmin have been observed in the skin of patients with rosacea.
TA is a serine protease inhibitor and also exhibits anti-inflammatory TA suppresses the neovascularization caused by the growth of basal fibroblasts. 25,26[29] In a 2020 study by Batory et al. on the effect of topical TA 5% with and without microderm abrasion on skin pigmentation and lipids showed significant reduction of melanogenesis and increase hydration of the epidermis. 302021 study by Behrangi et al., on patients with melasma identified the benefits of this substance.In this study, patients with melasma were studied by two methods, Nd-Yag Fraction 1064 + microinjection of TA and Nd-Yag Fraction 1064+ oral TA.The result of this study showed that there is no significant relationship between micro injection and oral methods but the oral use of TA is much more tolerable for patients. 31 mentioned, TA can affect vascular component of skin and its effects on skin manifestations of rosacea was shown in a study conducted in 2019.It was found that application of TA can have significant effects on the erythema of rosacea and the severity score of rosacea significantly improved. 32 a study by Daadaa et al., patients with rosacea were examined for the effect of microinjection of TA on these manifestations.
In this study, patients were studied from January 2019 to February 2020.The average number of TA injections was 5.1 ± 1.3 per month, which resulted in a decrease of 2.15 ± 0.5 in IGA-RSS on average.
No specific side effects were mentioned and the set of use TA was considered useful. 33 our knowledge, no study has been performed to date to investigate the effects of TA as mesotherapy in PAE.
In the field of post-inflammatory hyperpigmentation, TA is also used as an injection.Although some cases of oral use of TA have been reported in this field, the acceptable effectiveness of the method has not been proven.The erythema, telangiectasia and burning sensation reduces significantly within 4-6 weeks of application. 35 another study, Agamia et al. used a combination of the tranexamic contents, oxymetazoline and brimonidine tartrate, an alpha-2 receptor agonist in patients with persistent post-acne erythema.These compounds have been used topically on 40 patients for at least 3 months.This study was in the form of split face and after analysis, it was found that the side treated with the above compounds was much better than the side treated with placebo. 36 a study in 2019, Jakhar et al. used topical 5% TA in the treatment of post-acne erythema.In their study, the formula of topical 5% TA solution was the injectable TA (500 mg/5 mL) with 0.9% sodium chloride solution.The formulation was stored in an ethylene/ propylene copolymer plastic container.They found that daily application of this solution was reduced erythema after 6-8 weeks with no side effect. 23

| CON CLUS ION
According to the results of this study, because of anti-inflammatory and anti-redness effects of TA, utilization of it as mesotherapy for PAE can be useful and promising.TA is also a safe, cost-effective, and affordable treatment with low side effects that can be considered alone or in combination with microneedling, as a suitable treatment option for PAE and final residue of acne lesions with earlier reduction of inflammation in the involved skin.However, due to lack of sufficient evidences further studies are needed.Topical TA formulations may also be used in combination with microneedling in future studies to reduce pain and further tolerability.

| LI M ITATI O N
Since the present pilot study was a before-and-after study with a small sample size, the present findings should be approved in the form of a larger case-control study.
properties in rosacea patients by suppressing proinflammatory cytokines such as interleukin-6 and TNF alpha.It is also involved in the suppression of chemokine TH-17 and TLR 2. On the other hand, F I G U R E 1 (A) Right side of face before tranexamic acid (TA) mesotherapy, (B) right side of face after treatment, (C) left side of face before TA mesotherapy, (D) left side of face after treatment.
The latest study in this field was conducted in 2021 by Shereen Osama Tawfic et al.Twenty-five patients with post-acne hyperpigmentation participated in the study, who did not respond to routine F I G U R E 2 (A) Right side of face before tranexamic acid (TA) mesotherapy, (B) right side of face after mesotherapy of TA, (C) right side of face before TA mesotherapy, (D) right side of face after mesotherapy of TA.treatment for 6 months.The researchers enrolled the patients in a split-face study, using a carbon dioxide laser on one side and TA on the other.The sequence of injections was every 2 weeks and the duration of the study was 3 months; The results of this study show that both methods used have responded well and patients' recovery has been quite significant, although this study preferred carbon dioxide laser.34In a study was conducted in 2022, Jakhar et al., were used topical 10% TA for treatment of erythematotelangiectatic steriod-induced rosacea.The formula for topical 10% TA is formulated directly from injectable TA (500 mg/5 mL) and the solution can be provided to the patient in an ethylene/propylene copolymer plastic containers.The Patients used TA solution twice daily on the affected area of face.