Q-Switched 1064 nm Fractional Laser with Intradermal Tranexamic Acid for Melasma: A Retrospective Propensity Score–Matched Study

Abstract

Purpose

To evaluate the efficacy and safety of Q-switched 1064 nm fractional laser combined with intradermal tranexamic acid (TXA) injection in the treatment of melasma.

Patients and Methods

This retrospective study initially reviewed 161 female patients with melasma who received laser therapy alone (group A), intradermal TXA injection alone (group B), and combination therapy (group C). After eligibility screening and 1:1:1 propensity score matching, 90 patients were included in the final matched analysis, with 30 patients in each group. Clinical outcomes were assessed using the Melasma Area and Severity Index (MASI), VISIA-derived ultraviolet and brown spot indices, and patient satisfaction. Adverse events and recurrence at 6 months were also evaluated.

Results

All groups demonstrated significant improvements in MASI scores and VISIA parameters (all P < 0.001). The combination group achieved significantly greater reductions in MASI scores and pigmentation indices compared with the other groups (all P < 0.001), along with a higher likelihood of patient satisfaction (OR = 3.82, 95% CI: 1.15–12.69, P = 0.028). Recurrence rates at 6 months were not significantly different among groups (P = 0.31), although numerically lower in the combination group. All treatments were well tolerated, with only mild and transient adverse events.

Conclusion

Q-switched 1064 nm fractional laser combined with intradermal TXA injection was associated with greater clinical improvement and higher patient satisfaction compared with monotherapies.

Plain Language Summary

Melasma is a common skin condition that causes dark patches on the face. It can be difficult to treat, and the condition often returns after therapy. Many patients do not achieve satisfactory results with a single treatment, so better approaches are needed. In this study, we examined whether combining two treatments could improve outcomes. We reviewed the records of 161 women with melasma who received one of three treatments: laser therapy, small injections of tranexamic acid (a medication that reduces pigment formation), or a combination of both. After eligibility screening and statistical matching, 90 women were included in the final analysis. We assessed changes in skin pigmentation using clinical scoring, imaging analysis, and patient-reported satisfaction. All treatments led to visible improvement. However, the combination treatment produced greater reductions in pigmentation and higher patient satisfaction than either treatment alone. The treatments were well tolerated, with only mild and temporary side effects. While melasma can recur, we did not observe a significant difference in recurrence rates between groups over six months, although the combination group showed a trend toward lower recurrence. These results suggest that combining laser therapy with tranexamic acid injections may provide a more effective option for managing melasma, with good safety and improved patient outcomes.

Introduction

Melasma is a common acquired hyperpigmentation disorder characterized by symmetric, irregularly distributed brownish macules, primarily affecting sun-exposed areas of the face.^1,2 It is more prevalent in women and individuals with darker skin types, and is often associated with ultraviolet radiation, hormonal influences, and genetic predisposition.³ Despite its benign nature, melasma can significantly impact patients’ quality of life due to its chronic course and high recurrence rate.⁴

Current treatment strategies for melasma include topical agents, systemic therapies, and various energy-based devices.⁵ Among these, Q-switched 1064 nm Nd:YAG laser has been widely used due to its ability to selectively target melanin and promote pigment clearance. However, monotherapy with laser devices is often associated with suboptimal long-term outcomes and a relatively high rate of recurrence.⁶ TXA, an antifibrinolytic agent, has emerged as an effective treatment option for melasma by inhibiting the plasminogen–plasmin pathway, thereby reducing melanocyte activation and suppressing ultraviolet-induced melanogenesis. TXA can be administered via oral, topical, or intradermal routes, with intradermal injection offering targeted delivery and reduced systemic exposure.⁷ Recent evidence suggests that fractional laser or other energy-based procedures combined with TXA may improve melasma severity in selected patients, possibly by enhancing drug delivery or by addressing epidermal, dermal, and vascular components of the disease.^8,9 In these studies, TXA delivery has varied considerably, including topical application after fractional laser treatment, microneedling-assisted topical delivery, laser-assisted delivery, oral administration, and intradermal microinjection, depending on the study design.^10,11 However, direct evidence specifically evaluating Q-switched 1064 nm Nd:YAG treatment delivered with a fractional handpiece in combination with intradermal TXA injection remains limited. In addition, recurrence continues to be a major challenge in long-term melasma management, underscoring the need for cautious evaluation of both short-term improvement and sustained clinical benefit.¹²

Given the multifactorial pathogenesis of melasma, combination therapies that target different pathogenic pathways have gained increasing attention. The combination of Q-switched 1064 nm laser and TXA may provide complementary effects by integrating direct pigment removal with inhibition of melanogenesis.^13,14 Although previous studies have explored various combinations of fractional laser or other energy-based procedures with TXA, treatment protocols and TXA delivery methods have varied considerably, including topical application, microneedling-assisted delivery, laser-assisted delivery, oral administration, and intradermal injection;¹⁵ direct clinical evidence specifically evaluating Q-switched 1064 nm Nd:YAG laser treatment delivered with a fractional handpiece in combination with intradermal TXA injection remains limited, particularly in studies directly comparing combination therapy with each modality alone. Moreover, recurrence remains a major challenge in the long-term management of melasma, highlighting the need to evaluate both short-term improvement and sustained clinical outcomes. Therefore, the present study aimed to systematically evaluate the efficacy and safety of combining Q-switched 1064 nm fractional laser with intradermal TXA injection in patients with melasma. By incorporating a three-arm comparative design and integrating objective imaging-based assessments with patient-reported outcomes, this study seeks to provide more comprehensive clinical evidence for the role of combination therapy in melasma management.

Materials and Methods

Study Design and Patients

This retrospective study was conducted at the Department of Dermatology, Xijing Hospital, the Fourth Military Medical University. The study was approved by the Institutional Ethics Committee of Xijing Hospital, the Fourth Military Medical University (approval number: KY20192040-F-1) and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients prior to inclusion. Additional written informed consent for the publication of de-identified clinical photographs was obtained from the patients whose images are presented in this article. Medical records of patients diagnosed with melasma and treated between January 2024 and December 2024 were reviewed. Treatment allocation was determined by routine clinical practice rather than by a study protocol, and no prospective intervention was performed for research purposes.

Inclusion criteria were as follows: (1) clinical diagnosis of melasma according to established diagnostic criteria for melasma as described in the Chinese Expert Consensus on the Diagnosis and Treatment of Melasma (2021 Version);¹⁶ and (2) age between 20 and 60 years.

Exclusion criteria included: (1) use of medications affecting pigmentation (eg, retinoids or corticosteroids) within 3 months before treatment; (2) receipt of laser therapy or chemical peeling within 1 month before treatment; (3) presence of significant systemic diseases (eg, hepatic or renal insufficiency, hematologic disorders, or autoimmune diseases); and (4) pregnancy or lactation.

A total of 161 female patients with melasma were initially reviewed, including 48 patients treated with laser therapy alone (Group A), 60 patients treated with intradermal TXA injection alone (Group B), and 53 patients treated with combination therapy (Group C). After applying the predefined inclusion and exclusion criteria, 126 patients remained eligible for propensity score matching, including 39 patients in the laser therapy alone group, 45 patients in the intradermal TXA injection alone group, and 42 patients in the combination therapy group. Following 1:1:1 propensity score matching, 90 patients were included in the final matched analysis, with 30 patients in each treatment group.

Treatment Protocols

Devices and Materials

A Q-switched 1064 nm laser system equipped with an FS20A fractional handpiece (Fotona, Germany) was used. Skin assessment was performed using a VISIA system (Canfield, USA). TXA (5 mL: 0.5 g; Guangdong Starry Pharmaceutical Co., Ltd.) was administered using a hydroinjector (Meimu’en, MES0-01S) with sterile disposable microneedles (Hyuns Medical Co., Ltd., Dermashine PA-NDL9P32G1). Laser parameters included a wavelength of 1064 nm, pulse frequency of 110 Hz, spot size of 10×10 mm, and energy density of 0.2–3.2 J/cm².

Procedure

All patients underwent standardized facial photography and VISIA analysis before treatment. Topical anesthesia with 5% lidocaine cream was applied for 1 hour prior to treatment. After cleansing and disinfection, patients were positioned supine with protective eyewear. Laser parameters were adjusted according to skin type and pigmentation severity. All procedures were performed by experienced dermatologists.

Laser group (group A): Patients received Q-switched 1064 nm fractional laser treatment (fluence: 1.4–1.8 J/cm²) using a non-overlapping stamping technique across the entire face. The endpoint was mild erythema with slight edema and pinpoint bleeding.

Medication group (group B): Patients received intradermal injection of 5 mL TXA using a hydroinjector at a depth of 1–2 mm and negative pressure level of 4–5, with approximately 110–120 evenly distributed microinjections.

Combination group (group C): Patients received laser treatment followed immediately by intradermal TXA injection using the same parameters as above.

Post-treatment care included a 30-minute saline cold compress. Patients were instructed to avoid water exposure for 24 hours and to maintain strict photoprotection and moisturization. All treatments were performed once monthly for five consecutive sessions.

Outcome Measures

Clinical efficacy was evaluated using both objective and subjective measures.

The primary outcome was the change in Melasma Area and Severity Index (MASI) score before and after treatment. The MASI reduction rate was calculated as: (Pre-treatment MASI − Post-treatment MASI)/Pre-treatment MASI × 100%.

Secondary outcomes included VISIA-derived ultraviolet spot index and brown spot index. Patient satisfaction was assessed using a 4-point Likert scale (dissatisfied, neutral, satisfied, and very satisfied).¹⁷ Satisfaction was defined as the proportion of patients reporting “satisfied” or “very satisfied”.

Recurrence was evaluated at 6 months after the final treatment session and was study-defined as a ≥50% loss of the initial treatment-induced improvement in MASI score, calculated as (follow-up MASI − post-treatment MASI)/(baseline MASI − post-treatment MASI). Patients meeting this criterion were classified as having recurrence.¹⁸

Safety outcomes included treatment-related adverse events recorded throughout the study period.

Propensity Score Matching

To minimize baseline confounding, propensity score matching (PSM) was performed.¹⁹ Propensity scores were calculated using a logistic regression model based on age, disease duration, baseline MASI score, ultraviolet spot index, brown spot index, and Fitzpatrick skin type. Patients in the three groups were matched in a 1:1:1 ratio using nearest-neighbor matching without replacement. Covariate balance after matching was assessed using standardized mean differences (SMDs), with values <0.1 indicating adequate balance.

Statistical Analysis

All statistical analyses were performed using SPSS software (version 26.0, IBM Corp., Armonk, NY, USA). Continuous variables were presented as mean ± standard deviation (SD), and categorical variables as number (percentage). Within-group comparisons were performed using paired t-tests. Between-group comparisons of post-treatment MASI scores and VISIA-derived ultraviolet and brown spot indices were performed using analysis of covariance (ANCOVA), with treatment group as a fixed factor and the corresponding baseline value as a covariate. Post hoc pairwise comparisons were adjusted using the Holm method. Categorical variables were analyzed using the χ²-test. Logistic regression analysis was used to evaluate factors associated with patient satisfaction, and results were reported as odds ratios (ORs) with 95% confidence intervals (CIs). A two-sided P value <0.05 was considered statistically significant.

Results

Baseline Characteristics and Covariate Balance After Matching

After propensity score matching, 90 patients were included in the final analysis, with 30 patients in each treatment group. Baseline characteristics were well balanced across all groups (Table 1). No statistically significant differences were observed in age, disease duration, baseline MASI score, ultraviolet spot index, or brown spot index (all P > 0.05). The distribution of Fitzpatrick skin type was identical across the three groups, with 6.7% of patients classified as type II, 53.3% as type III, and 40.0% as type IV. All standardized mean differences were below 0.1, with a maximum pairwise SMD of less than 0.05, confirming excellent covariate balance and successful reduction of baseline bias following matching.

Table 1.

Baseline Characteristics of the Study Population After Propensity Score Matching

Variable	Group A (n=30)	Group B (n=30)	Group C (n=30)	P value	Max Pairwise SMD
Age (years)	38.50 ± 5.20	38.53 ± 5.85	38.60 ± 5.44	0.997	0.019
Disease duration (years)	6.23 ± 3.02	6.13 ± 3.26	6.17 ± 3.05	0.992	0.032
Baseline MASI score	15.40 ± 2.60	15.50 ± 3.10	15.39 ± 3.66	0.989	0.034
Ultraviolet spot index	24.76 ± 4.47	24.80 ± 4.67	24.64 ± 5.32	0.991	0.033
Brown spot index	58.20 ± 6.03	58.29 ± 6.94	58.22 ± 5.79	0.998	0.014
Fitzpatrick skin type				1.000	0.000
Type II	2 (6.7%)	2 (6.7%)	2 (6.7%)
Type III	16 (53.3%)	16 (53.3%)	16 (53.3%)
Type IV	12 (40.0%)	12 (40.0%)	12 (40.0%)

Notes: Data are presented as mean ± standard deviation (SD) for continuous variables and number (percentage) for categorical variables. Continuous variables were compared using one-way analysis of variance (ANOVA), and categorical variables were compared using the χ²-test. Covariate balance after propensity score matching was assessed using standardized mean differences (SMDs), with values <0.1 indicating negligible imbalance.

MASI Score Outcomes

All three groups demonstrated significant reductions in MASI scores after treatment compared with baseline (all P < 0.001) (Table 2 and Figure 1). In group A, MASI decreased from 15.40 ± 2.60 to 8.04 ± 2.08 (Δ = 7.36 ± 2.51; reduction rate: 47.40% ± 12.27%). In group B, MASI decreased from 15.50 ± 3.10 to 8.44 ± 1.71 (Δ = 7.06 ± 2.43; reduction rate: 44.80% ± 9.23%). In group C, MASI decreased from 15.39 ± 3.66 to 3.97 ± 1.58 (Δ = 11.42 ± 3.33; reduction rate: 73.78% ± 8.84%). Intergroup comparisons revealed significant differences among the three groups (P < 0.001). Pairwise analyses showed no significant difference between groups A and B (P = 0.358), whereas group C demonstrated significantly greater improvement than both groups A and B (both P < 0.001), as shown in Figure 1.

Table 2.

Comparison of Treatment Effects Based on MASI Scores Among the Three Groups

Group	Pre-Treatment MASI	Post-Treatment MASI	MASI Reduction (Δ)	Reduction Rate (%)	Within-Group P
A	15.40 ± 2.60	8.04 ± 2.08	7.36 ± 2.51	47.40 ± 12.27	<0.001
B	15.50 ± 3.10	8.44 ± 1.71	7.06 ± 2.43	44.80 ± 9.23	<0.001
C	15.39 ± 3.66	3.97 ± 1.58	11.42 ± 3.33	73.78 ± 8.84	<0.001
Overall (ANCOVA)					<0.001
A vs B					0.358
A vs C					<0.001
B vs C					<0.001

Notes: Data are presented as mean ± standard deviation. Δ indicates the change in MASI score from pre-treatment to post-treatment values. The reduction rate was calculated as (pre-treatment MASI − post-treatment MASI)/pre-treatment MASI × 100%.

Figure 1.

Comparison of MASI reduction rates among the three treatment groups. Data are presented as mean ± standard deviation. All groups showed significant improvement after treatment. ***P < 0.001; ns = not significant.

Changes in VISIA Ultraviolet and Brown Spot Indices

For both the ultraviolet and brown spot indices, all three groups demonstrated significant reductions after treatment compared with baseline (all P < 0.001) (Table 3). For the ultraviolet spot index, the mean decrease was 1.64 ± 2.44 in group A, 1.75 ± 1.54 in group B, and 6.13 ± 2.46 in group C. For the brown spot index, the corresponding reductions were 3.35 ± 2.75, 3.37 ± 2.96, and 10.45 ± 5.78, respectively. Intergroup comparisons revealed significant differences among the three groups for both indices (all P < 0.001). Pairwise analyses showed no significant differences between groups A and B (ultraviolet: P = 0.833; brown: P = 0.983), whereas group C demonstrated significantly greater improvements than both groups A and B for both ultraviolet and brown spot indices (all P < 0.001).

Table 3.

Within-Group and Between-Group Comparisons of VISIA Ultraviolet and Brown Spot Indices

Group	Ultraviolet Spot Index Pre	Ultraviolet Spot Index Post	Ultraviolet Spot Index Δ	Ultraviolet Spot Index Within P	Brown Spot Index Pre	Brown Spot Index Post	Brown Spot Index Δ	Brown Spot Index Within P
A	24.76 ± 4.47	23.12 ± 4.03	1.64 ± 2.44	<0.001	58.20 ± 6.03	54.85 ± 6.54	3.35 ± 2.75	<0.001
B	24.80 ± 4.67	23.05 ± 4.22	1.75 ± 1.54	<0.001	58.29 ± 6.94	54.92 ± 7.50	3.37 ± 2.96	<0.001
C	24.64 ± 5.32	18.51 ± 4.63	6.13 ± 2.46	<0.001	58.22 ± 5.79	47.77 ± 8.91	10.45 ± 5.78	<0.001
Overall (ANCOVA)				<0.001				<0.001
A vs B				0.833				0.983
A vs C				<0.001				<0.001
B vs C				<0.001				<0.001

Notes: Data are presented as mean ± standard deviation. Δ indicates the change in VISIA-derived ultraviolet or brown spot index from pre-treatment to post-treatment values.

Representative Clinical and VISIA Images

Representative clinical photographs and VISIA images of one patient from each treatment group at baseline and after treatment are presented in Figure 2. Visible reductions in facial pigmentation were observed in the representative patients from all three groups. Corresponding changes were also observed in the VISIA ultraviolet and brown spot images, illustrating improvements in pigment-related imaging features after treatment. These images are provided as representative examples of the clinical and imaging changes observed during the study, whereas between-group treatment effects were evaluated based on the quantitative MASI and VISIA outcomes described above.

Figure 2.

Representative clinical photographs and VISIA images before and after treatment in the three treatment groups. From left to right, the columns show baseline and post-treatment images for laser therapy alone (Group A), TXA injection alone (Group B), and combination therapy (Group C). From top to bottom, the rows show standard clinical photographs, VISIA ultraviolet spot images, and VISIA brown spot images. Written informed consent for publication of the clinical images was obtained from all patients shown.

Patient Satisfaction Outcomes

The distribution of patient satisfaction differed significantly among the three groups (χ²-test, P < 0.05) (Table 4 and Figure 3). Group C exhibited a higher proportion of “very satisfied” responses and a lower proportion of dissatisfied responses compared with groups A and B, which showed similar distribution patterns. When satisfaction was defined as the proportion of patients reporting “satisfied” or “very satisfied”, group C achieved a higher satisfaction rate (83.3%) than both group A (56.7%) and group B (56.7%). Logistic regression analysis further demonstrated that patients in group C were more likely to achieve satisfaction compared with those in group A (odds ratio [OR] = 3.82, 95% confidence interval [CI]: 1.15–12.69, P = 0.028), while no significant difference was observed between groups A and B.

Table 4.

Comparison of Patient Satisfaction Outcomes Among the Three Treatment Groups

Group	Satisfied or Very Satisfied, n (%)	Odds Ratio (95% CI)	P value
A (reference)	17 (56.7%)	1.00 (reference)	—
B	17 (56.7%)	1.00 (0.36–2.78)	1.000
C	25 (83.3%)	3.82 (1.15–12.69)	0.028

Figure 3.

Distribution of patient satisfaction across the three treatment groups. Patient satisfaction was assessed using a 4-point Likert scale (dissatisfied, neutral, satisfied, and very satisfied). Data are presented as percentages.

Treatment-Related Adverse Events and Recurrence

All adverse events were mild and self-limiting. Transient dryness and pruritus were observed in five patients in group A, while periorbital bruising occurred in five patients in group B and three patients in group C. All adverse events resolved spontaneously within one week. Common immediate post-treatment reactions, such as pinpoint bleeding and petechiae, subsided within 2–5 days. No cases of scarring, hypopigmentation, or hyperpigmentation were reported during the study period.

At 6 months after the final treatment session, recurrence occurred in 6 patients (20.0%) in group A, 5 patients (16.7%) in group B, and 2 patients (6.7%) in group C. No significant difference in recurrence rate was observed among the three groups (χ²-test, P = 0.31), although the recurrence rate was numerically lower in group C, suggesting a potential trend toward improved durability.

Discussion

This study demonstrated that the combination of Q-switched 1064 nm fractional laser and intradermal TXA was associated with greater clinical improvements compared with either modality alone in the treatment of melasma. Significant improvements were observed across multiple objective and subjective endpoints, including MASI scores, VISIA-derived ultraviolet and brown spot indices, and patient-reported satisfaction, with consistent findings indicating greater improvements in the combination group.

The greater improvements observed in the combination group are likely attributable to the complementary mechanisms of laser therapy and TXA. Q-switched 1064 nm laser primarily targets melanin and disrupts pigment-containing cells, facilitating pigment clearance and epidermal turnover. In contrast, TXA exerts its effects by inhibiting the plasminogen–plasmin system, thereby reducing the release of arachidonic acid and prostaglandins, which are known to stimulate melanocyte activity.⁵ In addition, TXA has been reported to suppress vascular endothelial growth factor (VEGF) expression, potentially mitigating the vascular component increasingly recognized in melasma pathogenesis.²⁰ The combination of these approaches may therefore provide both immediate pigment reduction and sustained inhibition of melanin production, resulting in greater overall improvement.

In the present study, the combination therapy resulted in a markedly greater reduction in MASI scores and higher improvement rates compared with monotherapy groups. These findings are consistent with previous studies reporting enhanced efficacy of combination approaches in melasma management, where multimodal treatment strategies have been shown to produce greater improvements than single-modality interventions.^20–22 In addition, VISIA-based assessments further supported these results, demonstrating significantly greater reductions in both ultraviolet and brown spot indices in the combination group, suggesting a more comprehensive improvement in pigment-related skin parameters.

Patient-reported outcomes further reinforced the clinical benefits of combination therapy. The proportion of patients reporting satisfaction was significantly higher in the combination group, and logistic regression analysis confirmed a significantly increased likelihood of achieving satisfaction compared with laser monotherapy. These findings highlight the importance of integrating subjective outcomes alongside objective measures when evaluating treatment efficacy in melasma.

Although the recurrence rate was numerically lower in the combination group, no statistically significant difference was observed among the groups. This may be attributable to the relatively small sample size and limited number of recurrence events, which may have reduced the statistical power to detect differences. Nevertheless, the observed trend toward lower recurrence suggests that combination therapy may have the potential to provide more durable improvement, potentially due to the sustained inhibitory effect of TXA on melanogenesis.²³

Importantly, all treatments were well tolerated, with only mild and transient adverse events observed. No serious adverse events, including scarring or pigmentary complications, were reported, indicating a favorable safety profile for both monotherapy and combination therapy. These findings support the clinical feasibility of combining Q-switched laser and TXA in routine practice.²⁴

Several limitations should be acknowledged. First, this was a retrospective study, which may introduce inherent selection bias despite the use of propensity score matching to balance baseline characteristics. Treatment allocation was not randomized, and although propensity score matching reduced measured baseline imbalance, residual confounding from unmeasured variables cannot be excluded. Second, the sample size was relatively small, which may limit the generalizability of the findings and reduce statistical power, particularly for recurrence analysis. Third, because this was a single-center study including only female patients, the external generalizability of the findings may be limited. Finally, the follow-up duration was limited to 6 months, and longer-term studies are needed to better evaluate sustained efficacy and recurrence patterns.

Conclusion

The combination of Q-switched 1064 nm fractional laser and intradermal TXA injection may represent a promising multimodal therapeutic strategy. By integrating complementary mechanisms of pigment clearance and melanogenesis inhibition, this approach was associated with greater clinical improvements and higher patient satisfaction without compromising safety. Although recurrence rates did not differ significantly, the observed trend toward improved durability suggests a possible benefit of combination therapy. These findings highlight the potential value of multimodal treatment strategies in melasma and warrant further validation in larger, long-term prospective studies.

Funding Statement

This work was supported by grants from the National Natural Science Foundation of China (No. 82373480).

Ethics Statement

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of Xijing Hospital, the Fourth Military Medical University (Approval No. KY20192040-F-1). Written informed consent was obtained from all participants prior to inclusion in the study. All patient data were anonymized to ensure confidentiality.

Disclosure

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.