Comparative Study of Combination of Oral Tranexamic Acid With Modified Kligman’s Formula Versus Oral Tranexamic Acid With Azelaic Acid 15% in the Treatment of Melasma

Background Melasma is a persistent skin condition affecting individuals of Asian, African, and Hispanic backgrounds. It causes dark patches on sun-exposed areas of the face. The exact causes are unclear, but UV light and hormonal factors play a role. Melasma significantly impacts physical appearance and quality of life, causing emotional and social distress. Objective The objective was to compare the efficacy of a combination of oral tranexamic acid and modified Kligman’s formula vs. oral tranexamic acid and 15% azelaic acid. Material and methods This two-year interventional study occurred at the Outpatient Department of Dermatology, Venereology, and Leprosy in Sawangi, Maharashtra. It included male and female patients aged 18-50 with melasma seeking treatment. Ethical approval was obtained, and data collection involved medical histories, skin examinations, and calculating the Melasma Area and Severity Index (MASI). Results The study found no significant association between age groups and subject distribution in Groups A and B. Significant differences were observed in MASI scores within each group over time. There was a significant difference in mean MASI scores between Group A and Group B at the eight-week mark. A burning sensation was significantly associated with the groups, while no significant association was found for erythema. Conclusion This study concludes that combining oral tranexamic acid with a modified Kligman's formula is more effective in treating melasma than combining oral tranexamic acid with azelaic acid 15%.


Introduction
Melasma therapy has relied on topical bleaching chemicals and photoprotection. Chemical peels, dermabrasion, and laser treatments are also ineffective adjuvants [1]. Tranexamic acid (TA) has been studied in melasma recently. Melasma has been treated with topical, intradermal, and oral TA [2]. Antiplasmin fibrinolytic TA may block melanocyte-stimulating paracrine melanogenic substances [1]. TA is safe and effective, although clinical trials are underpowered. Large-scale, randomized, controlled studies are needed to establish a consensus on TA for melasma [3].
There are several treatment methods to treat this condition. The disease's chronicity and recurrence frustrate the patients and the treating physician. Topical agents, lasers, chemical peels, micro-needling, dermabrasion, and oral formulations are now available. They have negative effects and poor outcomes [4]. Lasers, chemical peels, and dermabrasion need skill and expensive equipment [5]. These surgeries are costly and need many clinic visits and follow-ups. This causes patient noncompliance [6]. Thus, a treatment drug that improves outcomes without substantial adverse effects is needed.
Kligman's modified melasma treatment involves triple combination therapy (fluocinolone acetonide 0.01%, 1 1 1 1 1 hydroquinone 2%, tretinoin 0.05%) [7]. It's safe and extensively utilized these days. Steroids may cause telangiectasia and atrophic skin changes over time, making this regimen negative. This research used tranexamic acid as an adjunct to shorten treatment time [8]. Azelaic acid is an effective treatment for melasma because it works by competitively inhibiting tyrosinase and directly killing melanocytes [9].
This study compared the effectiveness of two different treatments for melasma: a combination of oral tranexamic acid with a modified Kligman's formula and a combination of oral tranexamic acid with azelaic acid 15%. It is better than 2% hydroquinone and as effective as 4% hydroquinone but without the adverse effects of hydroquinone. This study aimed to determine which of these two treatments was more effective in treating melasma.

Study design and setting
This comparative interventional study was conducted over two years, from October 2020 to August 2022. This study was conducted at the Outpatient Department of Dermatology, Venereology, and Leprosy at the Acharya Vinobha Bhave Rural Hospital (AVBRH) in Sawangi, Wardha, Maharashtra. The study included all patients, regardless of gender, between the ages of 18-50 diagnosed with melasma and seeking treatment at the Outpatient Department of Dermatology, Venereology, and Leprosy at the AVBRH.

Inclusion and exclusion
Participants eligible for inclusion in this study are male and female patients aged 18-50 years who have been diagnosed with melasma and express their willingness to participate by providing informed consent.
Patients who have previously taken other medications for melasma will be considered for inclusion, provided they undergo a washout period of one month to eliminate the potential effects of those medications.
On the other hand, patients who are currently undergoing treatment for melasma, individuals with severe systemic comorbidities, pregnant and lactating women, and patients with a history of hepatic disease or coagulopathies will be excluded from participation. Additionally, patients who are currently taking anticoagulants will not be eligible for inclusion in this study.

Ethical consideration
All participants gave written informed consent after being thoroughly informed of the study's purpose and concept. Confidentiality and privacy were ensured. The study protocol was reviewed and approved by the

Data collection
The patients who met the inclusion and exclusion criteria and were seeking treatment for melasma at the Outpatient Department of Dermatology, Venereology, and Leprosy at the AVBRH in Sawangi, Wardha, were enrolled in the study after obtaining clearance from the Institutional Ethical Committee (IEC). All participants provided written informed consent in their native language for voluntary study participation. A comprehensive medical history was taken, and the skin was examined, including the Melasma Area and Severity Index (MASI) calculation.

Calculation of MASI score
An assessment was conducted to determine the severity of melasma in four specific areas of the face: the forehead, right cheek, left cheek, and chin. This evaluation was based on three variables: the percentage of the total affected area (A), the darkness of the melasma (D), and the uniformity of the hyperpigmentation (H). Each variable was assigned a numerical value to represent the level of involvement. The values ranged as follows: 0 for no involvement, 1 for less than 10% involvement, 2 for involvement between 10-29%, 3 for involvement between 30-49%, 4 for involvement between 50-69%, 5 for involvement between 70-89%, and 6 for involvement between 90-100%. The darkness of the melasma (D) was compared to the normal skin, while the homogeneity of the hyperpigmentation (H) was graded on a scale of 0 to 4, as indicated in  The MASI score is determined by calculating the combined severity grades for darkness (D) and homogeneity (H) and multiplying them by the numerical value of the affected areas (A) as well as the percentages assigned to the four facial regions (10-30%). The total MASI score is derived by adding the following components: Upon meeting the inclusion criteria, eligible participants were invited to participate in the study and were provided with written informed consent. They were then randomly assigned to either Group A or Group B in equal proportions (using a 1:1 allocation ratio) through the utilization of a computer-generated random number table. Assigning participants to their respective groups was conducted confidentially using the sequentially numbered, opaque, sealed envelope (SNOSE) technique [11].

Group A Participants
This study arm received treatment with a combination of oral tranexamic acid (500mg) once a day and a modified Kligman's formula cream (containing fluocinolone acetonide 0.01%, tretinoin 0.05%, and hydroquinone 2%) applied once a day at night.

Group B Participants
Patients will take oral 500mg tranexamic acid once daily, apply azelaic acid 15% gel daily at night, and use broad-spectrum SPF-30 sunscreen every three hours. Regular follow-up appointments will occur after four and eight weeks, with clinical photos taken and MASI calculated. After two months of treatment, the primary outcome measure will be the reduction of MASI score and a clinical evaluation based on photos.

Statistical analysis
The statistical analysis was conducted utilizing IBM's SPSS version 20, released in 2011 and commonly referred to as the Statistical Package for Social Sciences (IBM Corp., Armonk, NY, USA). The data was inputted into an Excel spreadsheet (Microsoft, Redmond, WA, USA), and descriptive statistics were computed for quantitative variables (mean and standard deviation) and qualitative variables (frequency and proportion). The Chi-square test was employed to assess qualitative variables, while the independent sample t-test was used to compare quantitative variables between different groups over time. Repeated measures ANOVA was employed to examine the within-group comparisons of quantitative variables, followed by posthoc Bonferroni correction. The significance level was predetermined at 5%. Table 2 and Table 3 revealed no statistically significant association between the age groups and the distribution of subjects in Groups A and B. The chi-square value of 3.82 suggests some degree of association, but the associated p-value of 0.147 indicates that this association is insignificant at a significance level of 0.05.       Table 6 shows the results of an independent sample t-test comparing the mean MASI between Group A and Group B at different time intervals. The t-tests reveal a statistically significant difference in mean MASI scores between Group A and Group B at the eight-week time interval, with a mean difference of 3.84 and a pvalue of 0.001. However, no significant differences are observed at baseline or four weeks. These findings suggest that the two groups may respond differently to the treatment or intervention being assessed, as indicated by the significant difference in MASI scores at eight weeks.   Table 7 presents the distribution of subjects based on the occurrence of side effects in Group A and Group B. There was a statistically significant association between the occurrence of a burning sensation and the groups, with a chi-square value of 6.4 and a p-value of 0.011. However, no significant association is observed for erythema. These findings suggest that the two groups may differ regarding experiencing a burning sensation as a side effect but not in terms of erythema.

Discussion
Melasma is a frequent hyperpigmentation disease in India. Clinicians diagnose melasma. This research identified melasma similarly and categorized lesions by MASI score. Seventy patients were recruited and randomized into two groups of two. Group A took oral 500mg tranexamic acid OD + modified Kligman's formula (fluocinolone acetonide 0.01%, tretinoin 0.05%, and hydroquinone 2%), and Group B received azelaic acid 15% gel once a day at night alone.
In this research, Group A had a mean age of 36.43 ± 6.90 and Group B 33.50 ± 7.31. The groups had no significant association in mean age (p=0.115). Nineteen patients (31.7%) were aged 21-30, with six (20%) in Group A and 13 (43.3%) in Group B. Twenty-five patients (41.7%) were aged 31-40, with 15 (50%) in Group A and 10 (33.3%) in Group B. Nine Group A patients (30%) and seven Group B patients (23.3%) were 41-50 years old. Age and melasma therapy did not correlate significantly (p=0.147). However, Goh et al. [12] in Singapore patient research found an average age of 42.3 years. Our findings matched the Achar et al. [13] 33.45-year average.
Centro facial, malar, or mandibular involvement is clinically considered. Histological and Wood's lamp investigation indicate the epidermal, dermal, or mixed type. High-intensity UV ray exposure, pregnancy, contraception, medications, hormone treatment, and genetic abnormalities cause it [14]. Patients are aesthetically damaged and psychologically distressed due to a face skin preference and therapy refractoriness. It impairs social interaction, leisure, and emotional well-being [15]. Contrary to Quillen et al. [16], the centro facial pattern predominates. This reveals ethnicity affects clinical presentation. It often affects Fitzpatrick skin Type III-V Asian or Hispanic women [16]. Melasma treatments vary. Modified Kligman's formula, hydroquinone, azelaic acid, kojic acid, and glycolic acid are topicals. Tranexamic acid can be used orally. Chemical peels, microdermabrasion, and lasers are procedure-based [17].

Limitations of the study
The limitation of the study was no long-term follow-up to assess relapse after the study duration.

Conclusions
This research suggests that oral tranexamic acid and modified Kligmans formula can effectively treat melasma. Patients improved quicker than our other group with azelaic acid and maintained results for longer, minimizing treatment time. A combination of oral tranexamic acid and modified Kligman's formula was shown to provide significantly better and faster improvements in resolving hyperpigmentation. Thus, there was a higher number of excellent responders in our first group at the end of eight weeks. The adverse effects noted were mostly minimal and self-resolving in our study. Oral tranexamic acid and modified Kligmans regimen decreased melasma recurrences; however, longer-term research is required to validate this.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Datta Meghe Institute of Medical Sciences, Sawangi (M) Wardha, Maharashtra, India issued approval DMIMS(DU)/IEC/Dec-2020-21/9316. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.