Efficacy and safety of the combination of oral tranexamic acid and intense pulsed light versus oral tranexamic acid alone in the treatment of refractory Riehl's melanosis: A prospective, comparative study

There is no standardized and effective treatment modality for Riehl's melanosis.


| INTRODUC TI ON
Riehl's melanosis is a persistent hyperpigmentary disorder most commonly affecting the face and neck. 1 Negative impacts on patients' quality of life and emotional well-being are obvious, yet satisfactory and standardized treatment of Riehl's melanosis is still unavailable. 2[5][6] The inhibitory effect of TXA on plasmin activation is thought to further interfere with the release of inflammatory factors (α-arachidonic acid and prostaglandin E2) and angiogenic factors (vascular endothelial growth factor [VEGF] and endothelin-1 [ET-1]), resulting in the reduction of melanogenesis and vascularization in the pathogenesis of hyperpigmentary disorders. 7,8Few case reports and pilot studies demonstrated the efficacy of intense pulsed light (IPL) in the treatment of Riehl's melanosis. 9,10However, expansion of sample size, refinement of study control, and improvement of trial design are needed to draw a more persuasive and solid conclusion.In this research, we conducted a prospective, open-label study of 28 subjects with refractory Riehl's melanosis to compare the efficacy and safety of oral TXA alone versus oral TXA in combination with IPL.Written informed consent was also acquired from patients in this manuscript to public their case details.

| Study design
Twelve subjects were treated with oral TXA 500 mg per day and IPL once a month for 6 months, and 11 (91.7%) of them completed the 6-month follow-up.Sixteen subjects were treated solely with oral TXA 500 mg per day for 6 months, and 14 (87.5%) of them completed the 6-month follow-up (Study Flowchart).Female patients were advised to pause oral TXA treatment during their menstrual period.Laser procedures were performed by an experienced dermatologist (Z.X.) using IPL (Lumenis One, Lumenis Co., Santa Clara, CA).Settings for the IPL were cutoff filters of 560 and 590 with fluences ranging from 10 to 18 J/cm 2 .A triple pulse mode was used with 4 ms pulse width and a delay time of 30-35 ms.The endpoint was observation of mild cutaneous erythema.All patients were instructed to apply SPF 30 + sunscreen every 3 h, no matter indoors or outdoors.

| Clinical assessment
All patients were photographed using unified digital photography and identical lighting conditions before and 1 month after the treatment.SkinColorCatch (Delfin Technologies, Ltd, Finland) was used to examine the mean MI and EI.Two independent blinded investigators completed the DPASI 11 and Physician Global Assessment (PGA), with values ranging from 1-5 (1-least, 2-mild, 3-moderate, 4-severe, and 5 as very severe), to ensure reliability and accuracy.At the end of the study, patients documented their degree of satisfaction using a satisfaction scale (1-poorly satisfied, 2-slightly satisfied, 3-satisfied, and 4-highly satisfied).

| Statistical analysis
Continuous variables were presented as mean ± standard deviation (SD), while constant variables as percentages.Statistical comparisons were conducted using the paired t-test and chi-squared test.

| Demographic characteristics
Of the 28 subjects enrolled in this study, 25 subjects completed all the 6-month follow-up, with 11 subjects in the oral TXA only group and 14 subjects in the group treated with combination therapy.
There was no significant difference in baseline characteristics between the two groups, including age, gender component, Fitzpatrick skin type, and disease duration (Table 1).

| Evaluation of treatment outcomes
Representative clinical photos of the two groups before and after treatment are shown in Figure 1.Overall, no significant difference was observed in the mean MI, EI, and DPASI at the baseline between two groups (Table 2; Figures 2-4).In the group treated with oral TXA and IPL, the mean MI of the subjects declined from 711.80 ± 60.56 to 627.56 ± 63.30 (p = 0.0002), the mean EI decreased from 446.30 ± 26.10 to 418.56 ± 7.50 (p = 0.0014), and the DPASI reduced from 16.64 ± 9.26 to 9.60 ± 7.87 (p = 0.0009) (Table 2; Figures 2-4).
In the oral TXA group, the mean MI of the subjects declined from When compared between the two groups, more significant reduction in the mean MI (p = 0.0009) and DPASI (p = 0.0189) was observed in the oral TXA and IPL group, while no difference in the reduction of EI was found (Table 2; Figures 2-4).In all, 5 (45.5%) and 5 (45.5%) subjects were assessed as least/mild, and moderate, respectively after the final treatment in the combination group, whereas only 1 (7.1%) and 5 (35.7%) subjects showed the same treatment outcomes in the oral TXA only group.Patient satisfaction scale was based on self-reported improvement by the subjects 1 month after the final treatment.Overall, 10 subjects (90.9%) reported "satisfied" to "highly satisfied" in the combination group, while only four subjects (28.6%) reported the corresponding degree of satisfaction in the oral TXA only group.Besides, two subjects, unresponsive to the treatment of oral TXA, also showed significant improvement in facial pigmentation after the combined treatment with IPL.In conclusion, the combination of oral TXA and IPL is a more effective treatment strategy for refractory Riehl's melanosis.
DPASI is a recently proposed scoring system for assessing the severity of acquired dermal macular hyperpigmentation in daily clinical practice.The internal consistency and sensitivity of the DPASI had been tested in a prospective observational study of 55 patients in India. 11However, the reliability of DPASI has not been compared with objective measurements.In this study, we demonstrated that DPASI is significantly correlated with the mean MI (Figure 5), indicating the reliability of DPASI in the clinical evaluation of Riehl's melanosis.

| DISCUSS ION
In the present study, treatment efficacy and safety were evaluated and compared between oral TXA 500 mg per day in combination with IPL at monthly intervals and oral TXA 500 mg per day alone for 6 months.
One of the key findings of this study is that both oral TXA and IPL combination therapy and oral TXA only are safe and effective in the treatment of recalcitrant Riehl's melanosis.Overall, 5 (45.5%) and 1 (7.1%) subjects were assessed as least/mild after the final treatment in the oral TXA and IPL combination group, and the oral TXA only group, respectively, exhibiting significant improvement on a professional assessment.The underlying mechanism remains unclear and needs further investigation.TXA is a synthetic derivative of the amino acid lysine that inhibits the conversion of plasminogen to plasmin. 12Generally, it was reported that TXA could reduce VEGF and ET-1-induced angiogenesis, therefore decreasing the appearance of pigmentation.Moreover, it inhibits melanin synthesis by disrupting UV-induced interaction of melanocytes and keratinocytes through the plasminogen/plasmin system. 13Treatment with TXA could directly downregulate the production of melanogenesis-associated proteins, including tyrosinase (TYR), tyrosinase-related protein 1 and 2 (TRP1/2) and microphthalmia-associated transcription factor (MITF), as well as suppress the expression of α-melanocytestimulating hormone (α-MSH) after UVB irradiation. 14,15TXA is now extensively used off-labeled in several pigmented diseases, including

2. 1 |
Patients This prospective, single-center, open-label, comparative study included 28 subjects with Riehl's melanosis aged between 28 and 69 with Fitzpatrick skin type III-IV who visited our clinic between January 2017 and October 2023.Riehl's melanosis was diagnosed according to clinical examination, medical history, and exclusion of other skin conditions with similar presentations.Refractory Riehl's melanosis was defined as minimal or no response after traditional topical skin-lightening therapies.Exclusion criteria included pregnancy and breastfeeding, a history of thromboembolism or associated risks, other systemic or skin diseases, or receiving any treatment for Riehl's melanosis within the previous 3 months.Patients were guided to use sunscreen during the course of treatment.This study complied to the ethical guidelines of the Declaration of Helsinki and was approved by the Medical Ethics and Human Research Committee of our clinic (No.2024-597).All patients provided appropriate written and verbal informed consent.

F I G U R E 1
Clinical photos of a female Riehl's melanosis patient (skin type IV) taken at baseline pretreatment (left) and 6 months followup (right) postfinal treatment with the combination of oral tranexamic acid and intense pulsed light therapy (A) or with oral tranexamic acid only (B).
Figures2-4).These results indicated that both treatment modalities are effective in the treatment of Riehl's melanosis.
observed in one subject in the combination group and two subjects in the oral TXA only group.Mild headaches were observed in one F I G U R E 3 Mean erythema index (EI) of patients with Riehl's melanosis at baseline (A) and 6 months follow-up (B).The change of mean erythema index after treatment (C).Mean erythema index of patients in the oral TXA + IPL group (D) and in the oral TXA group (E).subject in the oral TXA only group.However, no subject discontinued treatment due to the above side effects.During the IPL treatment, all of the subjects reported tolerable pain of mild to moderate degree.Transient erythema and slight edema were noticed but resolved within a few hours.No blistering, scarring, post-inflammatory hyperpigmentation (PIH), or hypopigmentation was observed.All subjects resumed regular daily activity immediately after the treatment with no downtime.

F I G U R E 4
The acquired dermal macular hyperpigmentation area and severity index (DPASI) score of patients with Riehl's melanosis at baseline (A) and 6 months follow-up (B).The change of DPASI score after treatment (C).The DPASI score of patients with Riehl's melanosis in the oral TXA + IPL group (D) and in the oral TXA group (E).XU et al.Riehl's melanosis.Kwon et al. delivered triad treatment of daily 250 mg TXA, 4% hydroquinone cream per night and Q-Switched Nd: YAG (QSNY) laser treatment every 3 weeks for eight patients with recalcitrant Riehl's melanosis.Significant improvement was observed in all of the enrolled patients after the course of treatment. 16The efficacy of oral TXA in conjunction with oral glycyrrhizin compound was demonstrated by Xu et al. 5 In this prospective pilot study, 10 patients suffering from Riehl's melanosis got a combination of 500 mg F I G U R E 5 Normality test (D'Agostino & Pearson test) of the mean melanin index (MI) and acquired dermal macular hyperpigmentation area and severity index (DPASI) score (A).Simple linear regression analysis between the mean melanin index and DPASI score (B).